Payers’ Guide to New FDA Approvals

JUNE 2012

VOLUME 5 I NUMBER 3 I SPECIAL FEATURE

THE PEER-REVIEWED FORUM FOR EVIDENCE IN BENEFIT DESIGN ™

FOR PAYERS, PURCHASERS, POLICYMAKERS, AND OTHER HEALTHCARE STAKEHOLDERS

PAYERS’ GUIDE TO NEW FDA APPROVALS ™

INTRODUCTION: New Drug Approvals in 2011 FDA Approvals of Brand-Name Prescription Drugs in 2011 Ruxolitinib a New Oral Option for Patients with Intermediate- or High-Risk Myelofibrosis Disorders An Overview of Metastatic Castration-Resistant Prostate Cancer and Treatment Tradjenta® (linagliptin) Tablets The 2012 Drug Pipeline

Special Feature

©2012 Engage Healthcare Communications, LLC www.AHDBonline.com

JUNE 2012

VOLUME 5, NUMBER 3, SPECIAL FEATURE THE PEER-REVIEWED FORUM FOR EVIDENCE IN BENEFIT DESIGN ™

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FOR PAYERS, PURCHASERS, POLICYMAKERS, AND OTHER HEALTHCARE STAKEHOLDERS

TABLE OF CONTENTS 6

INTRODUCTION New Drug Approvals in 2011: Novel Therapies Mark a Year of Increased FDA Approvals Gary M. Owens, MD

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FDA Approvals of Brand-Name Prescription Drugs in 2011

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Ruxolitinib a New Oral Option for the Treatment of Patients with Intermediate- or High-Risk Myelofibrosis Disorders

By Rhonda Williams

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An Overview of Metastatic Castration-Resistant Prostate Cancer and Treatment PERSPECTIVE Patients’ Impact on Quality Ratings: Are the Stars Aligned in Your Favor?

Schumarry Chao, MD, MBA

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Tradjenta® (linagliptin) Tablets: A Single-Dose Treatment Option for Adults with Type 2 Diabetes

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The 2012 Pharmaceutical Pipeline

By Karen Cooksey and Dalia Buffery

Publisher Nicholas Englezos nick@engagehc.com 732-992-1884 Associate Publisher Maurice Nogueira maurice@engagehc.com 732-992-1895 Editorial Director Dalia Buffery dalia@engagehc.com 732-992-1889 Associate Editor Lara J. Lorton 732-992-1892 Editorial Assistant Jennifer Brandt jennifer@generaladminllc.com 732-992-1536 Sales Assistant Zach Ceretelle Senior Production Manager Lynn Hamilton Quality Control Director Barbara Marino Business Manager Blanche Marchitto Founding Editor-in-Chief Robert E. Henry

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INTRODUCTION

New Drug Approvals in 2011: Novel Therapies Mark a Year of Increased FDA Approvals Gary M. Owens, MD President, Gary Owens Associates

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he year 2011 was one of change and optimism for the pharmaceutical industry as a result of the 30 new drugs that were approved by the US Food and Drug Administration (FDA). The 30 approvals, which included 24 new molecular entities and 6 biologics, is the highest number of drugs approved in 1 year since 2004, when 36 agents were approved by the FDA (Figure).1 This group includes many novel agents that will help fill substantial unmet needs for patients. Topping the list of 2011 FDA approvals were 8 new drugs for cancer, many with novel mechanisms of action. In addition, 2 new oral agents for the treatment of hepatitis C were introduced in 2011, as well as the first new drug in 50 years for the treatment of lupus. In 2011, we also saw approval of traditional, small-molecule products in categories such as anticoagulants, seizure disorders, and chronic obstructive pulmonary disease (COPD).

Overall, 2011 could be considered a year of significant progress for drug approvals. But, does this represent a trend in the FDA process, coupled with increasing output of industry research and development (R&D) processes? Will this be a one-time event in a general downward trend in new FDA approvals?

Notable Changes in 2011 There were a number of significant milestones in 2011 in addition to the increased number of drugs approved, including: 1. The majority of drugs approved by the FDA in 2011 received priority review. The priority review process gives the FDA a 6-month goal to complete its evaluation for safety and effectiveness. This process can substantially shorten the time to approval. According to the FDA, priority review requires that additional attention and resources be directed to drugs that have the potential to provide significant advances in treatment. Such advances can be demonstrated by2: • Evidence of increased effectiveness in treatment, prevention, or diagnosis of disease • Elimination or substantial reduction of a treatmentlimiting drug reaction

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• Documented enhancement of a patient’s willingness or ability to take the drug according to the required schedule and dose • Evidence of safety and effectiveness in a new subpopulation, such as children 2. Of the new approvals, 19 (~66%) drugs did not require their manufacturers to provide additional information to the FDA, so their reviews were completed in a single cycle3 3. Approximately 70% of the new drugs were approved in the United States before any other country, including the European Union3 4. Almost every new drug approval was on or before the Prescription Drug User Fee Act date.3 In general, the FDA met its goals of improving the timeliness of drug reviews, and there were relatively few surprise delays in approval.

A Decade of Change The past decade has seen major changes in the pharmaceutical industry. Mergers and acquisitions in the pharmaceutical industry over the past 10 years have been the norm and a way to bolster underperforming R&D efforts. Of the 42 members of the Pharmaceutical Research and Manufacturers of America in 1988, only 11 remained in 2011.4 Although there has been a reranking of the top 10 pharmaceutical manufacturers based on market capitalization, 8 companies from 2001 remained on the list by 2011.5 The total market capitalization of the leading 10 pharmaceutical companies was lower in 2011 than in 2001, despite the total inflation rate of >25% over the same period.5 Of note, the cumulative dollars attributed to the top 10 drugs by sales amount rose during that period from $41 billion in 2001 to $76 billion in 2011.5 What has changed dramatically in the past decade is the composition of the top 10 drug list by sales. In 2001, that list was dominated by small-molecule blockbuster drugs, such as simvastatin (Zocor), atorvastatin (Lipitor), omeprazole (Prilosec), and amlodipine (Norvasc). By contrast, in 2011, 3 of the leading 10 drugs by sales were specialty products, namely, etaner-

INTRODUCTION

cept (Enbrel), adalimumab (Humira), and infliximab (Remicade). This change is a reflection of the shift of developmental emphasis by the industry to complex molecules and specialty pharmaceuticals.

Finally, there has been a shift in focus of drug development targets over the past decade. Cancer is now the largest therapeutic area of drug development, replacing traditional categories such as hypertension, hyperlipidemia, and dyspepsia. This shift may be largely a result of the availability of relatively inexpensive generics that are safe, effective, and broadly used in these categories.

Cancer Therapies Dominate As already noted, 8 new drugs for cancer were approved in 2011, targeting prostate cancer, lymphoma, leukemia, myelofibrosis, thyroid cancer, and melanoma, with many being first-in-class agents.

For example, abiraterone (Zytiga) is the first oral drug approved for use in patients with castration-resistant prostate cancer. A phase 3 clinical trial demonstrated that for patients receiving abiraterone with prednisone after previous treatment with docetaxel, the overall survival (OS) rate improved from 10.9 months to 14.8 months.

Ipilimumab (Yervoy) is the first drug in a class of immune-boosting agents for the treatment of malignant melanoma. Ipilimumab is a monoclonal antibody that blocks a molecule that downregulates the body’s immune system and limits its ability to fight tumor cells.

Ruxolitinib (Jakafi) is the first of the Janus kinase inhibitors and is the first drug specifically approved for the treatment of myelofibrosis, a myeloproliferative disorder.

Adcetris (brentuximab vedotin) is an antibody conjugate targeted to CD30, making the drug effective in patients with Hodgkin lymphoma and anaplastic largecell lymphoma.

Vandetanib (Caprelsa), a tyrosine kinase inhibitor, is the first drug to be specifically approved for the treatment of medullary carcinoma of the thyroid. Additional cancer drugs approved in 2011 include asparaginase Erwinia chrysanthemi (Erwinaze), which is used to treat acute lymphoblastic leukemia; crizotinib (Xalkori); and vemurafenib (Zelboraf).

Personalized Medicine Emerging The sequencing of the human genome ushered in the era of genomics in medicine. For the most part, the use of genetic testing to guide cancer therapy has been more promise than reality. But 2011 was a year of change in that respect as well. Two drugs were approved for use specifically with companion diagnostics. The first agent, crizotinib treats select patients with non–small-cell lung cancer (NSCLC) who express the abnormal anaplastic

lymphoma kinase (ALK) gene, which promotes cancer growth. Crizotinib was approved with a companion diagnostic test, the ALK Break-Apart FISH Probe Kit, to determine if the patient has the l ALK gene mutation, which occurs in approximately 1 of 20 patients with NSCLC. The diagnostic kit was approved simultaneously with crizotinib.

The oral drug vemurafenib was the second FDAapproved agent for malignant melanoma in 2011. Like ipilimumab, vemurafenib demonstrated an improvement in OS in the phase 3 clinical trials. Vemurafenib is only effective in treating patients with advanced melanoma who have the BRAF V600E mutation. The genetic test, the cobas 4800 BRAF V600 mutation test, is a companion diagnostic for vemurafenib.

For the drug industry, 2011 certainly was an exciting year. Approvals of new drugs increased significantly, with the majority of approvals being for novel agents that offer first-in-class treatments for patients with life-threatening diseases.

Crizotinib and vemurafenib—which are also designated as orphan drugs—may represent the beginning of a trend toward more targeted therapies that will be approved with accompanying diagnostic tests, allowing physicians to more effectively target the right patient for the right therapy.

Significant Therapeutic Advances in Other Categories Although cancer dominated drug approvals in 2011, other significant advances were apparent. For example, belimumab (Benlysta) is the first new treatment approved for systemic lupus erythematosus in more than 50 years. It is designed to target the B-lymphocyte stimulator (BLyS) protein. By decreasing the proliferation of BLyS, belimumab ultimately decreases the production of cells that can attack a patient’s vascularity and major organ systems.

The 2 oral protease inhibitors telaprevir (Incivek) and boceprevir (Victrelis) represent a new class of agents for the treatment of hepatitis C virus infection. Hepatitis C is a silent, but often deadly, virus that can cause cirrhosis and liver failure and can increase a patient’s risk for liver cancer.

These 2 drugs, used in combination with ribavirin and an interferon, offer the potential for improved treatment outcomes in patients with hepatitis C and the abil-

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INTRODUCTION

ity to re-treat selected patients who have previously not achieved virologic cure from standard therapies.

Among the small-molecule agents, ticagrelor (Brilinta) is an oral antiplatelet drug approved for reducing the risk for cardiovascular mortality for patients with acute coronary syndrome.

Rivaroxaban (Xarelto) is the first available oral direct factor Xa inhibitor. It can be taken once daily to reduce the risk for stroke in nonvalvular atrial fibrillation.

Finally, roflumilast (Daliresp) is a new oral treatment for COPD. Roflumilast is the first phosphodiesterase type 4 inhibitor, and it targets patients with severe COPD.

Looking Forward For the drug industry, 2011 certainly was an exciting year. Approvals of new drugs increased significantly, with the majority of approvals being for novel agents that offer first-in-class treatments for patients with lifethreatening diseases. Although 1 year of increased FDA approvals does not make a trend, the fact that the majority of the agents were approved on first review suggests

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improved communications between the FDA and the industry about the trial and data thresholds needed for approval. For example, 2012 has already seen the approval of 6 new specialty agents in the first quarter alone, including 3 cancer or cancer-related drugs. Did 2011 usher in a new era of novel drug approvals and industry growth? Only time will tell. â&#x2013; Author Disclosure Dr Owens is a consultant to Boston Scientific, CardioDX, Genentech, Genzyme, Johnson and Johnson, OncoMed Pharmaceuticals, and Towers Watson.

References

1. Mullard A. 2011 FDA Drug Approvals. Nat Rev Drug Discov. 2012;11:91-94.

2. US Food and Drug Administration, Department of Health and Human Services.

Fast track, accelerated approval and priority review. May 28, 2010. www.fda.gov/ forconsumers/byaudience/forpatientadvocates/speedingaccesstoimportantnewther apies/ucm128291.htm. Accessed April 2, 2012.

3. Edlin M. Almost half of new molecular entities approved in 2011 considered significant therapeutic advances. Formulary. 2012;47:26-38.

4. LaMattina J. The impact of mergers on pharmaceutical R&D. Nat Rev Drug Discov. 2011;10:559-560.

5. Arrowsmith J. A decade of change. Nat Rev Drug Discov. 2012;11:17-18.

FDA Approvals of Brand-Name Prescription Drugs in 2011 I. New Pharmaceuticals, NMEs, Biologics Adcetris (BLA) (Brentuximab vedotin; Seattle Genetics) Class: CD30-directed antibody-drug conjugate Indications: Treatment of Hodgkin lymphoma after failure of autologous stem-cell transplant (ASCT) or of previous chemotherapy regimens in patients who are not ASCT candidates, and treatment of systemic anaplastic large-cell lymphoma after failure of previous multiagent chemotherapy Approval considerations: Priority review, orphan drug Arcapta Neohaler (NME) (Indacaterol maleate inhalation powder; Novartis) Class: Long-acting beta2-adrenergic agonist Indication: Long-term, once-daily maintenance bronchodilator treatment of airflow obstruction in patients with chronic obstructive pulmonary disease Approval consideration: REMS Benlysta (BLA) (Belimumab; Human Genome Sciences/ GlaxoSmithKline) Class: B-lymphocyte stimulator-specific inhibitor Indication: Treatment of adult patients with active, autoantibody-positive systemic lupus erythematosus Approval consideration: Priority review Brilinta (NME) (Ticagrelor; AstraZeneca) Class: P2Y12 platelet inhibitor Indication: Reduces the rate of thrombotic cardiovascular events in patients with acute coronary syndrome Approval consideration: REMS Caprelsa (NME) (Vandetanib; AstraZeneca) Class: Tyrosine kinase inhibitor Indication: Treatment of medullary thyroid cancer that cannot be removed by surgery or that has spread Approval considerations: Orphan drug; priority review, REMS Corifact (BLA) (Factor XIII concentrate, human; CSL Behring) Class: Fibrin-stabilizing factor concentrate

Indication: Routine prophylactic treatment of congenital factor XIII deficiency Daliresp Tablets (NME) (Roflumilast; Forest Research Institute) Class: Selective phosphodiesterase-4 inhibitor Indication: To reduce the risk of chronic obstructive pulmonary disease (COPD) exacerbations in patients with severe COPD and a history of exacerbations DaTscan (NME) (Ioflupane I-123 injection; GE Healthcare) Class: Radiopharmaceutical Indication: To assist in the evaluation of adult patients with suspected parkinsonian syndromes Approval consideration: Priority review Dificid (NME) (Fidaxomicin; Optimer Pharmaceuticals) Class: Macrolide antibacterial Indication: Treatment of Clostridium difficile–associated diarrhea Approval consideration: Priority review Edarbi (NME) (Azilsartan medoxomil; Takeda) Class: Angiotensin 2 receptor blocker Indication: Treatment of hypertension Edurant (NME) (Rilpivirine; Tibotec) Class: Human immunodeficiency virus type 1 (HIV-1)specific, nonnucleoside reverse transcriptase inhibitor Indication: Treatment of HIV-1 infection in treatmentnaïve patients Erwinaze (BLA) (Asparaginase Erwinia chrysanthemi; EUSA Pharma) Class: Asparagine-specific enzyme Indication: Treatment of acute lymphoblastic leukemia in patients who have developed hypersensitivity to Escherichia coli–derived asparaginase Approval consideration: Orphan drug

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2011 FDA APPROVALS

Eylea (BLA) (Aflibercept; Regeneron Pharmaceuticals) Class: Vascular endothelial growth factor trap Indication: Treatment of neovascular age-related macular degeneration Approval consideration: Priority review

Nulojix (BLA) (Belatacept; Bristol-Myers Squibb) Class: Selective T-cell lymphocyte costimulation blocker Indication: Prophylaxis of organ rejection in adult patients receiving a kidney transplant Approval considerations: Orphan drug, REMS

Ferriprox (NME) (Deferiprone; ApoPharma) Class: Iron chelator Indication: Treatment of transfusional iron overload caused by thalassemia syndromes when current chelation therapy is inadequate Approval consideration: Orphan drug

Onfi (NME) (Clobazam; Lundbeck) Class: Benzodiazepine Indication: Adjunctive treatment of seizures associated with Lennox-Gastaut syndrome Approval consideration: Orphan drug

Firazyr (NME) (Icatibant acetate; Shire Orphan Therapies) Class: Bradykinin B2â&#x20AC;&#x201C;receptor antagonist Indication: Treatment of acute attacks of hereditary angioedema in adults Approval considerations: Priority review, orphan drug

Potiga (NME) (Ezogabine; GlaxoSmithKline) Class: Potassium channel opener Indication: Adjunctive treatment for adult patients with partial-onset seizures with or without secondary generalization Approval consideration: REMS

Gadovist (NME) (Gadobutrol; Bayer HealthCare) Class: Macrocyclic gadolinium-based contrast agent Indication: For intravenous use in diagnostic magnetic resonance imaging to visualize areas with disrupted bloodâ&#x20AC;&#x201C;brain barrier and/or abnormal central nervous system vascularity

Sylatron (NME) (Peginterferon alfa-2b; Merck) Class: Alpha interferon Indication: Adjuvant treatment of melanoma with microscopic or gross nodal involvement within 84 days of surgical resection

Horizant (NME) (Gabapentin enacarbil; GlaxoSmithKline) Class: Gamma-aminobutyric acid analog Indication: Treatment of moderate-to-severe primary restless legs syndrome

Tradjenta (NME) (Linagliptin; Boehringer Ingelheim) Class: Dipeptidyl peptidase-4 inhibitor Indication: To improve glycemic control in adults with type 2 diabetes mellitus

Incivek (NME) (Telaprevir; Vertex Pharmaceuticals) Class: Hepatitis C virus NS3/4A protease inhibitor Indication: Treatment of genotype 1 chronic hepatitis C in adult patients with compensated liver disease Approval consideration: Priority review

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Victrelis (NME) (Boceprevir; Schering) Class: Hepatitis C virus NS3/4A protease inhibitor Indication: Treatment of chronic hepatitis C genotype 1 infection Approval consideration: Priority review

Jakafi (NME) (Ruxolitinib phosphate; Incyte) Class: Janus-associated kinase inhibitor Indication: Treatment of intermediate- or high-risk myelofibrosis Approval considerations: Priority review, orphan drug

Viibryd (NME) (Vilazodone hydrochloride; Forest Laboratories) Class: Selective serotonin reuptake inhibitor and 5HT1A-receptor partial agonist Indication: Treatment of major depressive disorder

Natroba (NME) (Spinosad; ParaPRO) Class: Pediculicide Indication: Topical treatment of head lice infestations

Xalkori (NME) (Crizotinib; Pfizer) Class: Tyrosine kinase inhibitor Indication: Treatment of locally advanced or metastatic,

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anaplastic lymphoma kinase–positive non–small-cell lung cancer Approval considerations: Priority review, orphan drug Xarelto (NME) (Rivaroxaban; Johnson & Johnson) Class: Factor Xa inhibitor Indications: Prophylaxis of deep-vein thrombosis and pulmonary embolism in patients undergoing hip replacement surgery or knee replacement surgery Yervoy (BLA) (Ipilimumab; Bristol-Myers Squibb) Class: Human cytotoxic T-lymphocyte antigen 4– blocking antibody Indication: For unresectable or metastatic melanoma Approval considerations: Orphan drug, REMS

Zelboraf (NME) (Vemurafenib; Hoffmann-La Roche) Class: Kinase inhibitor Indication: Treatment of unresectable or metastatic melanoma with the BRAF V600E mutation Approval considerations: Priority review, orphan drug Zytiga (NME) (Abiraterone acetate; Centocor Ortho Biotech) Class: CYP17 (cytochrome P450 17 alpha-hydroxylase/ C17, 20 lyase) inhibitor Indication: Treatment of patients with metastatic castration-resistant prostate cancer who have received prior chemotherapy containing docetaxel Approval consideration: Priority review

II. New Combinations, Formulations, Indications Abstral (new formulation) (Fentanyl citrate; ProStrakan) Class: Opioid analgesic Indication: Management of breakthrough pain in cancer patients aged ≥18 years who are already receiving and are tolerant to opioid therapy for their underlying persistent cancer pain Approval consideration: REMS Afinitor (new indication) (Everolimus; Novartis) Class: Serine/threonine kinase inhibitor Indications: Treatment of progressive neuroendocrine tumors of pancreatic origin in patients with unresectable, locally advanced or metastatic disease; previously approved for advanced renal-cell carcinoma and subependymal giant-cell astrocytoma Approval consideration: Priority review

Combivent Respimat (new formulation) (Ipratropium bromide, albuterol sulfate; Boehringer Ingelheim) Class: Anticholinergic agent and beta-adrenergic agonist Indication: Treatment of chronic obstructive pulmonary disease in patients who do not respond to previous treatment with a regular aerosol bronchodilator Complera (new combination) (Emtricitabine + rilpivirine hydrochloride + tenofovir disoproxil fumarate; Gilead Sciences) Class: Two nucleoside analog HIV-1 reverse transcriptase inhibitors + 1 nonnucleoside reverse transcriptase inhibitor Indication: Treatment of HIV-1 infection in treatmentnaïve adults Approval consideration: Priority review

Androgel (new formulation) (Testosterone; Abbott) Class: Androgen Indication: Testosterone replacement therapy in males for conditions associated with a deficiency or absence of endogenous testosterone

Duexis (new combination) (Famotidine + ibuprofen; Horizon Pharma) Class: Nonsteroidal anti-inflammatory drug + histamine H2-receptor antagonist Indications: Relief of signs and symptoms of rheumatoid arthritis and osteoarthritis and to decrease the risk of developing upper gastrointestinal ulcers

Banzel (new formulation) (Rufinamide; Eisai) Class: Antiepileptic Indication: Adjunctive treatment of seizures associated with Lennox-Gastaut syndrome Approval consideration: Orphan drug

Edarbyclor (new combination) (Azilsartan medoxomil + chlorthalidone; Takeda Pharmaceuticals) Class: Angiotensin 2 receptor blocker + thiazide-like diuretic Indication: Treatment of hypertension

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2011 FDA APPROVALS

Erbitux (new indication) (Cetuximab; Bristol-Myers Squibb/Lilly) Class: Epidermal growth factor receptor antagonist Indications: Combined with platinum-based therapy plus 5-fluorouracil for the first-line treatment of recurrent locoregional disease and/or metastatic squamouscell carcinoma of the head and neck; previously approved in combination with radiation therapy for locally or regionally advanced squamous-cell carcinoma of the head and neck, after platinum-based therapy in the treatment of recurrent or metastatic squamous-cell carcinoma of the head and neck, and in the treatment of colorectal cancer

Forfivo XL (new formulation) (Bupropion hydrochloride; IntelGenx) Class: Aminoketone antidepressant Indication: Treatment of major depressive disorder Gralise (new formulation) (Gabapentin; Depomed) Class: Gamma-aminobutyric acid analog Indication: Treatment of postherpetic neuralgia Intermezzo (new formulation) (Zolpidem tartrate; Transcept Pharmaceuticals) Class: Gamma-aminobutyric acid Aâ&#x20AC;&#x201C;receptor agonist Indication: Treatment of middle-of-the-night insomnia Isentress (new formulation) (Raltegravir; Merck Sharp & Dohme) Class: HIV-1 integrase strand transfer inhibitor Indication: Treatment of HIV-1 infection Approval consideration: Priority review Juvisync (new combination) (Simvastatin + sitagliptin; Merck Sharp & Dohme) Class: Dipeptidyl peptidase-4 inhibitor + an HMGCoA reductase inhibitor Indications: Treatment of patients with type 2 diabetes mellitus and hypercholesterolemia Lazanda (new formulation) (Fentanyl citrate; Archimedes Pharma) Class: Opioid agonist Indication: Treatment of breakthrough pain in adult

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Nucynta ER (new formulation) (Tapentadol hydrochloride; Janssen) Class: Mu-opioid receptor agonist Indication: Treatment of moderate-to-severe chronic pain in adults Approval consideration: REMS Phoslyra (new formulation) (Calcium acetate; Fresenius Medical Care) Class: Phosphate binder Indication: Reduction of serum phosphorus in patients with end-stage renal disease Approval consideration: Orphan drug

Exparel (new formulation) (Bupivacaine; Pacira Pharmaceuticals) Class: Amide local anesthetic Indication: Postsurgical analgesia

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patients with cancer who are already receiving and who are tolerant to opioid therapy for their underlying persistent cancer pain Approval consideration: REMS

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Prezista (new formulation) (Darunavir; Tibotec) Class: HIV-1 protease inhibitor Indication: Treatment of HIV-1 infection in adult patients and pediatric patients aged â&#x2030;Ľ3 years Approval consideration: Priority review Prolia (new indication) (Denosumab; Amgen) Class: Receptor activator of nuclear factor kappa-B ligand inhibitor Indications: For increasing bone mass in patients at high risk for fracture during androgen deprivation therapy for nonmetastatic prostate cancer or adjuvant aromatase inhibitor therapy for breast cancer; previously approved for the treatment of osteoporosis in postmenopausal women at high risk for fracture Approval consideration: REMS Rectiv (new formulation) (Nitroglycerin; ProStrakan) Class: Nitrate vasodilator Indication: Treatment of moderate-to-severe pain associated with chronic anal fissure Rezira (new combination) (Hydrocodone bitartrate + pseudoephedrine hydrochloride; Hawthorn Pharmaceuticals) Class: Semisynthetic centrally acting opioid antitussive + sympathomimetic amine nasal decongestant Indication: Relief of cough and nasal congestion associated with the common cold

2011 FDA APPROVALS

Rituxan (new indication) (Rituximab; Genentech) Class: CD20-directed cytolytic antibody Indications: Maintenance therapy in patients with previously untreated follicular, CD20-positive, B-cell nonHodgkin lymphoma and for the treatment of Wegener’s granulomatosis and of microscopic polyangiitis; previously approved for chronic lymphocytic leukemia and rheumatoid arthritis Soliris (new indication) (Eculizumab; Alexion Pharmaceuticals) Class: Recombinant humanized monoclonal antibody Indications: Treatment of atypical hemolytic uremic syndrome; previously approved for treatment of paroxysmal nocturnal hemoglobinuria Approval consideration: REMS Suprenza (new formulation) (Phentermine hydrochloride; Akrimax Pharmaceuticals) Class: Sympathomimetic amine anorectic Indication: Treatment of exogenous obesity in patients with an initial body mass index ≥30 kg/m2 or ≥27 kg/m2 in the presence of other risk factors (eg, controlled hypertension, diabetes, hyperlipidemia)

Sutent (new indication) (Sunitinib malate; Pfizer) Class: Tyrosine kinase inhibitor Indication: Treatment of progressive, well-differentiated pancreatic neuroendocrine tumors in patients with unresectable, locally advanced, or metastatic disease Viramune XR (new formulation) (Nevirapine; Boehringer Ingelheim) Class: HIV-1–specific, nonnucleoside reverse transcriptase inhibitor Indication: Treatment of HIV-1 infection in adults Zutripro (new combination) (Hydrocodone bitartrate + chlorpheniramine maleate + pseudoephedrine hydrochloride; Hawthorn Pharmaceuticals) Class: Semisynthetic centrally acting opioid antitussive + antihistamine + sympathomimetic amine nasal decongestant Indications: Relief of cough and nasal congestion associated with the common cold and of symptoms associated with upper respiratory allergies

BLA indicates biologic license application; NME, new molecular entity; REMS, Risk Evaluation and Mitigation Strategy.

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ZYTIGA® (abiraterone acetate) in combination with prednisone is indicated for the treatment of patients with metastatic castration-resistant prostate cancer (mCRPC) who have received prior chemotherapy containing docetaxel.

ADRENALS

PROSTATE TUMOR TISSUE

TESTES

Mechanism of action

Important Safety Information Contraindications—ZYTIGA® may cause fetal harm (Pregnancy Category X) and is contraindicated in women who are or may become pregnant.

Hypertension, Hypokalemia, and Fluid Retention Due to Mineralocorticoid Excess—Use with caution in patients with a history of cardiovascular disease or with medical conditions that might be compromised by increases in hypertension, hypokalemia, and fluid retention. ZYTIGA® may cause hypertension, hypokalemia, and fluid retention as a consequence of increased mineralocorticoid levels resulting from CYP17 inhibition. Safety has not been established in patients with LVEF < 50% or New York Heart Association (NYHA) Class III or IV heart failure because these patients were excluded from the randomized clinical trial. Control hypertension and correct hypokalemia before and during treatment. Monitor blood pressure, serum potassium, and symptoms of fluid retention at least monthly.

Adrenocortical Insufficiency (AI)—AI has been reported in clinical trials in patients receiving ZYTIGA® in combination with prednisone, after an interruption of daily steroids, and/or with concurrent infection or stress. Use caution and monitor for symptoms and signs of AI if prednisone is stopped or withdrawn, if prednisone dose is reduced, or if the patient experiences unusual stress. Symptoms and signs of AI may be masked by adverse reactions associated with mineralocorticoid excess seen in patients treated with ZYTIGA®. Perform appropriate tests, if indicated, to confirm AI.

Increased dosages of corticosteroids may be used before, during, and after stressful situations.

Hepatotoxicity—Increases in liver enzymes have led to drug interruption, dose modification, and/or discontinuation. Monitor liver function and modify, withhold, or discontinue ZYTIGA® dosing as recommended (see Prescribing Information for more information).

Measure serum transaminases [alanine aminotransferase (ALT) and aspartate aminotransferase (AST)] and bilirubin levels prior to starting treatment with ZYTIGA®, every two weeks for the first three months of treatment, and monthly thereafter. Promptly measure serum total bilirubin, AST, and ALT if clinical symptoms or signs suggestive of hepatotoxicity develop. Elevations of AST, ALT, or bilirubin from the patient’s baseline should prompt more frequent monitoring.

If at any time AST or ALT rise above five times the upper limit of normal (ULN) or the bilirubin rises above three times the ULN, interrupt ZYTIGA® treatment and closely monitor liver function.

Food Effect—ZYTIGA® must be taken on an empty stomach.

Exposure of abiraterone increases up to 10-fold when abiraterone acetate is taken with meals. No food should be eaten for at least two hours before the dose of ZYTIGA® is taken and for at least one hour after the dose of ZYTIGA® is taken. Abiraterone C max and AUC 0-∞ (exposure) were increased up to 17- and 10-fold higher, respectively, when a single dose of abiraterone acetate was administered with a meal compared to a fasted state.

KAPLAN-MEIER SURVIVAL CURVES OF PATIENTS TREATED WITH EITHER ZYTIGA® + PREDNISONE OR PLACEBO + PREDNISONE (INTERIM ANALYSIS) 100

P < 0.0001; HR = 0.646; 95% CI: 0.543, 0.768

% Survival

80 ZYTIGA®: 14.8 months (median) (95% CI: 14.1, 15.4)

60 Placebo: 10.9 months (median) (95% CI: 10.2, 12.0)

40 20 0 0

3

6

9

12

15

18

21

68 30

2 3

0 0

Time to Death (Months) ZYTIGA® 797 Placebo 398

736 355

657 306

520 210

282 105

The median duration of treatment with ZYTIGA® was 8 months.

Proven survival benefit At the interim analysis of the phase 3 study,*† ZYTIGA® in combination with prednisone showed a statistically significant improvement in overall survival compared with placebo plus prednisone and resulted in a 35% reduction in the risk of death (hazard ratio [HR] = 0.646; P < 0.0001; 95% confidence interval [CI]: 0.543, 0.768; median survival: 14.8 months vs 10.9 months, respectively) In an updated survival analysis,‡ results were consistent with those from the interim analysis (HR = 0.74; 95% CI: 0.638, 0.859; median survival: 15.8 months vs 11.2 months)

*Study Design: ZYTIGA®, in combination with prednisone, was evaluated in a phase 3, randomized, double-blind, placebo-controlled, multicenter

Janssen Biotech, Inc. © Janssen Biotech, Inc. 2012 3/12 08Z12066

study in patients with metastatic castration-resistant prostate cancer (mCRPC) who had received prior chemotherapy containing docetaxel (N = 1,195). Patients were randomized 2:1 to receive ZYTIGA® 1,000 mg orally once daily + prednisone 5 mg orally twice daily (n = 797) or placebo orally once daily + prednisone 5 mg orally twice daily (n = 398).

Patients were using a gonadotropin-releasing hormone (GnRH) agonist or were previously treated with orchiectomy and were at castration levels of testosterone (serum testosterone ≤ 50 ng/dL).1 The primary efficacy endpoint was overall survival. †552 events. ‡775 events.

08Z11121R3

Adverse Reactions—The most common adverse reactions (≥ 5%) are joint swelling or discomfort, hypokalemia, edema, muscle discomfort, hot flush, diarrhea, urinary tract infection, cough, hypertension, arrhythmia, urinary frequency, nocturia, dyspepsia, fractures and upper respiratory tract infection.

Drug Interactions—ZYTIGA® is an inhibitor of the hepatic drug-metabolizing enzyme CYP2D6. Avoid coadministration with CYP2D6 substrates that have a narrow therapeutic index. If an alternative cannot be used, exercise caution and consider a dose reduction of the CYP2D6 substrate. Additionally, abiraterone is a substrate of CYP3A4 in vitro. Strong inhibitors and inducers of CYP3A4 should be avoided or used with caution.

Use in Specific Populations—The safety of ZYTIGA® in patients with baseline severe hepatic impairment has not been studied.

These patients should not receive ZYTIGA®.

Reference: 1. de Bono JS, Logothetis CJ, Molina A, et al. Abiraterone and increased survival in metastatic prostate cancer. N Engl J Med. 2011;364(21):1995-2005.

Please see adjacent pages for brief summary of full Prescribing Information.

www.zytiga.com

ZYTIGA® (abiraterone acetate) Tablets Brief Summary of Prescribing Information.

INDICATIONS AND USAGE ZYTIGA in combination with prednisone is indicated for the treatment of patients with metastatic castration-resistant prostate cancer (CRPC) who have received prior chemotherapy containing docetaxel.

CONTRAINDICATIONS Pregnancy: ZYTIGA may cause fetal harm when administered to a pregnant woman. ZYTIGA is contraindicated in women who are or may become pregnant. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus.

WARNINGS AND PRECAUTIONS Hypertension, Hypokalemia and Fluid Retention Due to Mineralocorticoid Excess: Use ZYTIGA with caution in patients with a history of cardiovascular disease. ZYTIGA may cause hypertension, hypokalemia, and fluid retention as a consequence of increased mineralocorticoid levels resulting from CYP17 inhibition [see Adverse Reactions and Clinical Pharmacology (12.1) in full Prescribing Information]. Co-administration of a corticosteroid suppresses adrenocorticotropic hormone (ACTH) drive, resulting in a reduction in the incidence and severity of these adverse reactions. Use caution when treating patients whose underlying medical conditions might be compromised by increases in blood pressure, hypokalemia or fluid retention, e.g., those with heart failure, recent myocardial infarction or ventricular arrhythmia. The safety of ZYTIGA in patients with left ventricular ejection fraction <50% or NYHA Class III or IV heart failure has not been established because these patients were excluded from the randomized clinical trial. Monitor patients for hypertension, hypokalemia, and fluid retention at least once a month.

Control hypertension and correct hypokalemia before and during treatment with ZYTIGA. Adrenocortical Insufficiency: Adrenocortical insufficiency has been reported in clinical trials in patients receiving ZYTIGA in combination with prednisone, following interruption of daily steroids and/or with concurrent infection or stress. Use caution and monitor for symptoms and signs of adrenocortical insufficiency, particularly if patients are withdrawn from prednisone, have prednisone dose reductions, or experience unusual stress.

Symptoms and signs of adrenocortical insufficiency may be masked by adverse reactions associated with mineralocorticoid excess seen in patients treated with ZYTIGA. If clinically indicated, perform appropriate tests to confirm the diagnosis of adrenocortical insufficiency. Increased dosage of corticosteroids may be indicated before, during and after stressful situations [see Warnings and Precautions].

Hepatotoxicity: Marked increases in liver enzymes leading to drug discontinuation or dosage modification have occurred [see Adverse Reactions]. Measure serum transaminases (ALT and AST) and bilirubin levels prior to starting treatment with ZYTIGA, every two weeks for the first three months of treatment and monthly thereafter. In patients with baseline moderate hepatic impairment receiving a reduced ZYTIGA dose of 250 mg, measure ALT, AST, and bilirubin prior to the start of treatment, every week for the first month, every two weeks for the following two months of treatment and monthly thereafter. Promptly measure serum total bilirubin, AST, and ALT if clinical symptoms or signs suggestive of hepatotoxicity develop.

Elevations of AST, ALT, or bilirubin from the patient’s baseline should prompt more frequent monitoring. If at any time AST or ALT rise above five times the ULN, or the bilirubin rises above three times the ULN, interrupt ZYTIGA treatment and closely monitor liver function. Re-treatment with ZYTIGA at a reduced dose level may take place only after return of liver function tests to the patient’s baseline or to AST and ALT less than or equal to 2.5X ULN and total bilirubin less than or equal to 1.5X ULN [see Dosage and Administration (2.2) in full Prescribing Information].

The safety of ZYTIGA re-treatment of patients who develop AST or ALT greater than or equal to 20X ULN and/or bilirubin greater than or equal to 10X ULN is unknown.

Food Effect: ZYTIGA must be taken on an empty stomach. No food should be consumed for at least two hours before the dose of ZYTIGA is taken and for at least one hour after the dose of ZYTIGA is taken. Abiraterone Cmax and AUC0-∞ (exposure) were increased up to 17- and 10-fold higher, respectively, when a single dose of abiraterone acetate was administered with a meal compared to a fasted state. The safety of these increased exposures when multiple doses of abiraterone acetate are taken with food has not been assessed [see Dosage and Administration (2.1) and Clinical Pharmacology (12.3) in full Prescribing Information].

ADVERSE REACTIONS The following are discussed in more detail in other sections of the labeling: Hypertension, hypokalemia, and fluid retention due to mineralocorticoid excess [see Warnings and Precautions].

Adrenocortical insufficiency [see Warnings and Precautions].

Hepatotoxicity [see Warnings and Precautions].

Food effect [see Warnings and Precautions].

ZYTIGA® (abiraterone acetate) Tablets Clinical Trial Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

In a placebo-controlled, multicenter phase 3 clinical trial of patients with metastatic castration-resistant prostate cancer who were using a gonadotropin-releasing hormone (GnRH) agonist or were previously treated with orchiectomy, ZYTIGA was administered at a dose of 1,000 mg daily in combination with prednisone 5 mg twice daily in the active treatment arm (N = 791). Placebo plus prednisone 5 mg twice daily was given to control patients (N = 394). The median duration of treatment with ZYTIGA was 8 months.

The most common adverse drug reactions (≥5%) reported in clinical studies were joint swelling or discomfort, hypokalemia, edema, muscle discomfort, hot flush, diarrhea, urinary tract infection, cough, hypertension, arrhythmia, urinary frequency, nocturia, dyspepsia, fractures and upper respiratory tract infection.

The most common adverse drug reactions that resulted in drug discontinuation were aspartate aminotransferase increased, alanine aminotransferase increased, urosepsis and cardiac failure (each in <1% of patients taking ZYTIGA).

Adverse reactions and laboratory abnormalities related to mineralocorticoid effects were reported more commonly in patients treated with ZYTIGA than in patients treated with placebo: hypokalemia 28% versus 20%, hypertension 9% versus 7% and fluid retention (edema) 27% versus 18%, respectively (see Table 1). In patients treated with ZYTIGA, grades 3 to 4 hypokalemia occurred in 5% of patients and grades 3 to 4 hypertension was reported in 1% of patients [see Warnings and Precautions].

Table 1 shows adverse reactions due to ZYTIGA that occurred with either a ≥ 2% absolute increase in frequency compared to placebo, or were events of special interest (mineralocorticoid excess, cardiac adverse reactions, and liver toxicities).

Table 1: Adverse Reactions due to ZYTIGA in a Placebo-Controlled Phase 3 Trial ZYTIGA with Placebo with Prednisone Prednisone (N=791) (N=394) System/Organ Class All Grades1 Grade 3-4 All Grades Grade 3-4 Adverse reaction % % % % Musculoskeletal and connective tissue disorders Joint swelling/discomfort2 29.5 4.2 23.4 4.1 Muscle discomfort3 26.2 3.0 23.1 2.3 General disorders 4 Edema 26.7 1.9 18.3 0.8 Vascular disorders Hot flush 19.0 0.3 16.8 0.3 Hypertension 8.5 1.3 6.9 0.3 Gastrointestinal disorders Diarrhea 17.6 0.6 13.5 1.3 Dyspepsia 6.1 0 3.3 0 Infections and infestations Urinary tract infection 11.5 2.1 7.1 0.5 Upper respiratory tract infection 5.4 0 2.5 0 Respiratory, thoracic and mediastinal disorders Cough 10.6 0 7.6 0 Renal and urinary disorders Urinary frequency 7.2 0.3 5.1 0.3 Nocturia 6.2 0 4.1 0 Injury, poisoning and procedural complications Fractures5 5.9 1.4 2.3 0 Cardiac disorders Arrhythmia6 7.2 1.1 4.6 1.0 Chest pain or chest discomfort 7 3.8 0.5 2.8 0 Cardiac failure8 2.3 1.9 1.0 0.3 1 2 3 4

Adverse events graded according to CTCAE version 3.0 Includes terms Arthritis, Arthralgia, Joint swelling, and Joint stiffness Includes terms Muscle spasms, Musculoskeletal pain, Myalgia, Musculoskeletal discomfort, and Musculoskeletal stiffness Includes terms Edema, Edema peripheral, Pitting edema, and Generalized edema

ZYTIGA® (abiraterone acetate) Tablets

ZYTIGA® (abiraterone acetate) Tablets

5

Drugs that Inhibit or Induce CYP3A4 Enzymes: Based on in vitro data, ZYTIGA is a substrate of CYP3A4. The effects of strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, nefazodone, saquinavir, telithromycin, ritonavir, indinavir, nelfinavir, voriconazole) or inducers (e.g., phenytoin, carbamazepine, rifampin, rifabutin, rifapentine, phenobarbital) on the pharmacokinetics of abiraterone have not been evaluated, in vivo. Avoid or use with caution, strong inhibitors and inducers of CYP3A4 during ZYTIGA treatment [see Clinical Pharmacology (12.3) in full Prescribing Information].

Includes all fractures with the exception of pathological fracture Includes terms Arrhythmia, Tachycardia, Atrial fibrillation, Supraventricular tachycardia, Atrial tachycardia, Ventricular tachycardia, Atrial flutter, Bradycardia, Atrioventricular block complete, Conduction disorder, and Bradyarrhythmia 7 Includes terms Angina pectoris, Chest pain, and Angina unstable.

Myocardial infarction or ischemia occurred more commonly in the placebo arm than in the ZYTIGA arm (1.3% vs. 1.1% respectively).

8 Includes terms Cardiac failure, Cardiac failure congestive, Left ventricular dysfunction, Cardiogenic shock, Cardiomegaly, Cardiomyopathy, and Ejection fraction decreased Cardiovascular Adverse Reactions: Cardiovascular adverse reactions in the phase 3 trial are shown in Table 1. The majority of arrhythmias were grade 1 or 2. Grade 3-4 arrhythmias occurred at similar rates in the two arms. There was one death associated with arrhythmia and one patient with sudden death in the ZYTIGA arm. No patients had sudden death or arrhythmia associated with death in the placebo arm. Cardiac ischemia or myocardial infarction led to death in 2 patients in the placebo arm and 1 death in the ZYTIGA arm.

Cardiac failure resulting in death occurred in 1 patient on both arms.

Hepatotoxicity: Drug-associated hepatotoxicity with elevated ALT, AST, and total bilirubin has been reported in patients treated with ZYTIGA. Across all clinical trials, liver function test elevations (ALT or AST increases of > 5X ULN) were reported in 2.3% of patients who received ZYTIGA, typically during the first 3 months after starting treatment. In the phase 3 trial, patients whose baseline ALT or AST were elevated were more likely to experience liver function test elevations than those beginning with normal values.

When elevations of either ALT or AST > 5X ULN, or elevations in bilirubin > 3X ULN were observed, ZYTIGA was withheld or discontinued. In two instances marked increases in liver function tests occurred [see Warnings and Precautions]. These two patients with normal baseline hepatic function, experienced ALT or AST elevations 15 to 40X ULN and bilirubin elevations 2 to 6 X ULN. Upon discontinuation of ZYTIGA, both patients had normalization of their liver function tests and one patient was re-treated with ZYTIGA without recurrence of the elevations.

In clinical trials, the following patients were excluded: patients with active hepatitis, patients with baseline ALT and/or AST ≥ 2.5X ULN in the absence of liver metastases, and patients with ALT and/or AST > 5X ULN in the presence of liver metastases. Abnormal liver function tests developing in patients participating in clinical trials were managed by treatment interruption, dose modification and/or discontinuation [see Dosage and Administration (2.2) in full Prescribing Information and Warnings and Precautions]. Patients with elevations of ALT or AST > 20X ULN were not re-treated.

Other Adverse Reactions: Adrenal insufficiency occurred in two patients on the abiraterone arm of the phase 3 clinical trial (< 1%).

Laboratory Abnormalities of Interest: Table 2 shows laboratory values of interest from the phase 3 placebo-controlled clinical trial. Grade 3-4 low serum phosphate (7.2%) and potassium (5.3%) occurred more frequently in the ZYTIGA arm.

6

Table 2: Laboratory Abnormalities of Interest in a Phase 3 Placebo-Controlled Clinical Trial Abiraterone (N=791) Placebo (N=394) All Grades Grade 3-4 All Grades Grade 3-4 Laboratory Abnormality (%) (%) (%) (%) High Triglyceride High AST Low Potassium Low Phosphorus High ALT High Total Bilirubin

62.5 30.6 28.3 23.8 11.1 6.6

0.4 2.1 5.3 7.2 1.4 0.1

53.0 36.3 19.8 15.7 10.4 4.6

0 1.5 1.0 5.8 0.8 0

DRUG INTERACTIONS Effects of Abiraterone on Drug Metabolizing Enzymes: ZYTIGA is an inhibitor of the hepatic drug-metabolizing enzyme CYP2D6. In a CYP2D6 drug-drug interaction trial, the Cmax and AUC of dextromethorphan (CYP2D6 substrate) were increased 2.8- and 2.9-fold, respectively, when dextromethorphan was given with abiraterone acetate 1,000 mg daily and prednisone 5 mg twice daily. Avoid co-administration of abiraterone acetate with substrates of CYP2D6 with a narrow therapeutic index (e.g., thioridazine). If alternative treatments cannot be used, exercise caution and consider a dose reduction of the concomitant CYP2D6 substrate drug [see Clinical Pharmacology (12.3) in full Prescribing Information].

In vitro, ZYTIGA was shown to inhibit the hepatic drug-metabolizing enzyme CYP2C8. There are no clinical data on the use of ZYTIGA with drugs that are substrates of CYP2C8.

USE IN SPECIFIC POPULATIONS Pregnancy: Pregnancy Category X [see Contraindications]. ZYTIGA is contraindicated in women who are or may become pregnant while receiving the drug. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus and the potential risk for pregnancy loss. Women of childbearing potential should be advised to avoid becoming pregnant during treatment with ZYTIGA. Nursing Mothers: ZYTIGA is not indicated for use in women. It is not known if abiraterone acetate is excreted in human milk. Because many drugs are excreted in human milk, and because of the potential for serious adverse reactions in nursing infants from ZYTIGA, a decision should be made to either discontinue nursing, or discontinue the drug taking into account the importance of the drug to the mother.

Pediatric Use: ZYTIGA is not indicated in children.

Geriatric Use: Of the total number of patients in a phase 3 trial of ZYTIGA, 71% of patients were 65 years and over and 28% were 75 years and over. No overall differences in safety or effectiveness were observed between these elderly patients and younger patients.

Patients with Hepatic Impairment: The pharmacokinetics of abiraterone were examined in subjects with baseline mild (n = 8) or moderate (n = 8) hepatic impairment (Child-Pugh Class A and B, respectively) and in 8 healthy control subjects with normal hepatic function. The systemic exposure (AUC) of abiraterone after a single oral 1,000 mg dose of ZYTIGA increased by approximately 1.1-fold and 3.6-fold in subjects with mild and moderate baseline hepatic impairment, respectively compared to subjects with normal hepatic function.

No dosage adjustment is necessary for patients with baseline mild hepatic impairment. In patients with baseline moderate hepatic impairment (ChildPugh Class B), reduce the recommended dose of ZYTIGA to 250 mg once daily. If elevations in ALT or AST >5X ULN or total bilirubin >3X ULN occur in patients with baseline moderate hepatic impairment, discontinue ZYTIGA treatment [see Dosage and Administration (2.1) and Clinical Pharmacology (12.3) in full Prescribing Information].

The safety of ZYTIGA in patients with baseline severe hepatic impairment has not been studied. These patients should not receive ZYTIGA. For patients who develop hepatotoxicity during treatment, interruption of treatment and dosage adjustment may be required [see Dosage and Administration (2.2) in full Prescribing Information, Warnings and Precautions, and Clinical Pharmacology (12.3) in full Prescribing Information].

Patients with Renal Impairment: In a dedicated renal impairment trial, the mean PK parameters were comparable between healthy subjects with normal renal function (N=8) and those with end stage renal disease (ESRD) on hemodialysis (N=8) after a single oral 1,000 mg dose of ZYTIGA. No dosage adjustment is necessary for patients with renal impairment [see Dosage and Administration (2.1) and Clinical Pharmacology (12.3) in full Prescribing Information].

OVERDOSAGE: There have been no reports of overdose of ZYTIGA during clinical studies. There is no specific antidote. In the event of an overdose, stop ZYTIGA, undertake general supportive measures, including monitoring for arrhythmias and cardiac failure and assess liver function.

Storage and Handling: Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [see USP controlled room temperature]. Based on its mechanism of action, ZYTIGA may harm a developing fetus. Therefore, women who are pregnant or women who may be pregnant should not handle ZYTIGA without protection, e.g., gloves [see Use in Specific Populations].

Manufactured by: Patheon Inc. Mississauga, Canada Manufactured for: Janssen Biotech, Inc. Horsham, PA 19044 Issued: May 2012

08Z12155B

Ruxolitinib a New Oral Option for the Treatment of Patients with Intermediateor High-Risk Myelofibrosis Disorders

By Rhonda Williams

M

yeloproliferative neoplasms (MPNs) are a group of closely related hematologic malignancies that arise from abnormal development and function of the body’s bone marrow cells. Primary myelofibrosis (PMF), polycythemia vera (PV), and essential thrombocythemia (ET) comprise the Philadelphia chromosome (Ph)-negative MPNs.1 Myelofibrosis (MF) can arise on its own, which is called PMF, or it can result from the progression of other MPNs, such as postpolycythemia vera MF (PPV-MF) and postessential thrombocythemia MF (PET-MF).1

The Burden of Disease and Its Impact MF is characterized by cytopenias, splenomegaly, poor quality of life, and shortened survival.1 Because chronic MPNs previously were not classified as hematologic malignancies, limited epidemiologic studies are available to estimate the incidence of MF. Multiple regional studies suggest that an estimated 6328 new cases of chronic myeloproliferative disorders (CMPDs as they were previously known) occurred in the US population in 2004.2 Of these patients, 45% had PV, 24% had ET, and 10% had PMF.2 The average annual age-adjusted incidence in the United States between 2001 and 2003 was 2.1 per 100,000 persons, with rates ranging among states from a low of 0.8 per 100,000 persons in Delaware to as high as 4.1 per 100,000 persons in Idaho.2 The incidence was significantly higher in males (2.6 per 100,000) than in females (1.8 per 100,000; P <.05).2 In addition, the incidence increased significantly with age, reaching 13.3 per 100,000 persons among individuals aged ≥80 years.2 Although appropriate treatment of patients with ET and PV is associated with prolonged survival, patients with symptomatic forms of PMF have a median survival of <5 years.1 The prognosis of MF is quite variable; however, those who develop anemia generally have a poorer prognosis. Patients with a good prognosis can live for many years without experiencing major symptoms, whereas those with a poor prognosis may have a significantly shorter survival. A small percentage of patients with MF can transform to acute myeloid leukemia, which is often difficult to treat and can be fatal.

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Few treatment options exist for patients with MF. Until recently, the choice of treatment was often dictated by a patient’s symptoms and specific circumstances.

Some patients with MF may remain symptom-free for many years, without undergoing treatment; however, monitoring for any signs or symptoms that may suggest worsening of the disease is required. For patients who require symptomatic treatment, chemotherapeutic agents, immunomodulatory drugs, and biological response modifiers (eg, hydroxyurea, androgen therapies, corticosteroids, thalidomide, lenalidomide, and interferon) are often used.

It is important to note that these therapies are not always directed to the biological processes that underlie the origin of disease or lead to progression of PMF. Therefore, these strategies are often primarily palliative in nature, and their effect on survival is uncertain.

Finally, surgery or radiation therapy may also be used in those who fail to respond to other treatments. For many patients with MF, however, available treatments may be ineffective and allogeneic stem-cell transplantation may be the only potential known cure.

A decisive advance in our understanding of the underlying molecular mechanisms of MPNs has been the discovery of a somatic gain-of-function point mutation in the Janus kinase (JAK) 2 gene, which is a common clinical feature in patients with ET, PV, and PMF.3,4 We now know that approximately 50% of patients with MF have a gain-of-function mutation in the JAK2 gene.5,6 Discoveries in the molecular pathogenesis of PV, ET, and PMF enabled the genetic classification and molecular diagnosis of these neoplasms. The World Health Organization diagnostic criteria, which were based largely on clinical and pathologic descriptions, were subsequently revised for PV, ET, and PMF to include the incorporation of testing for JAK2 and other genetic mutations.7 In addition to modifying the criteria for diagnosing, monitoring, and assessing patients with ET, PV, and PMF, the discovery of JAK2 involvement in patients with MF also led to the development of small-molecule inhibitors that specifically target JAK2. Although JAK2 mutations are responsible for the majority of dysregulat-

Ruxolitinib a New Oral Option

ed signaling in Ph-negative MPNs, JAK1 and JAK2 may interact, resulting in their transactivation.8,9 Armed with this information and a greater understanding of the cellular and molecular events that lead to the development of PMF, the possibility of more targeted and effective therapies for this disorder has become a reality.

In November 2011, the US Food and Drug Administration (FDA) granted marketing approval of oral Jakafi (ruxolitinib) tablets for the treatment of patients with intermediate- or high-risk MF, including PMF, PPV-MF, and PET-MF.10

Clinical Pharmacology Mechanism of Action Jakafi, a kinase inhibitor, inhibits the Janus-associated kinases JAK1 and JAK2, which mediate the signaling of a number of cytokines and growth factors that are important for hematopoiesis and immune function. JAK signaling involves recruitment of signal transducers and activators of transcription (STATs) to cytokine receptors, activation, and subsequent localization of STATs to the nucleus, leading to modulation of gene expression.10 MF is known to be associated with dysregulated JAK1 and JAK2 signaling. In a mouse model of JAK2V617Fpositive MPN, oral administration of ruxolitinib prevented splenomegaly, preferentially decreased JAK2V617F mutated cells in the spleen, and decreased circulating inflammatory cytokines (eg, tumor necrosis factor–alpha and interleukin-6).10 Pharmacodynamics. In healthy persons and in patients with MF, ruxolitinib inhibited cytokine-induced STAT3 phosphorylation in whole blood. The maximal inhibition of STAT3 phosphorylation occurred 2 hours after dosing, returning to near-baseline levels by 10 hours in both groups of people.

Pharmacokinetics. Maximal plasma concentration (Cmax) of ruxolitinib occurred 1 to 2 hours after oral administration. Pharmacokinetic studies demonstrated no evident food effect on the absorption of ruxolitinib; when administered with a high-fat meal, the mean Cmax decreased moderately (24%) and the area under the curve remained nearly unchanged (ie, 4% increase). In early clinical trials, the volume of distribution at steady state was between 53 L and 65 L in patients with MF.10 Phase 3 Clinical Trials Jakafi was approved by the FDA based on the results of 2 randomized, phase 3 trials (Study 1 and Study 2) conducted in patients with MF.10 These trials are described in detail in the product prescribing information, with key data highlighted in this article.

Trial Designs Study 1 was a randomized, double-blind trial that compared ruxolitinib with placebo in patients with MF who were refractory to or were not candidates for available therapy. The primary end point was the proportion of patients achieving a reduction in spleen volume of >35% from baseline at week 24, as measured by magnetic resonance imaging (MRI) or computed tomography (CT). Secondary end points included the duration of >35% reduction in spleen volume from baseline and the proportion of patients with a >50% reduction in Total Symptom Score from baseline to week 24. The latter was measured using the modified Myelofibrosis Symptom Assessment Form (MFSAF) v2.0 diary.10

In November 2011, the FDA approved ruxolitinib for the treatment of patients with intermediate- or high-risk MF, including PMF, PPV-MF, and PET-MF. Study 2 was a randomized, open-label trial that compared ruxolitinib with the best available therapy in patients with MF. The study investigators selected the best available therapy on a patient-by-patient basis, with the most frequently used agents, including hydroxyurea (N = 47%) and glucocorticoids (N = 16%). The primary end point of this trial was similar to that in Study 1—the proportion of patients achieving a reduction in spleen volume of >35% from baseline, but at week 48 (as measured by MRI or CT). The secondary end point of Study 2 was the proportion of patients achieving a >35% reduction in spleen volume from baseline to week 24.10 In both trials, patients were required to have palpable splenomegaly >5 cm below the costal margin, as well as an MF risk category of intermediate-2-risk (2 prognostic factors) or high-risk (>3 prognostic factors).10 Dosing in these trials was based on platelet counts.

The starting dose of ruxolitinib was 15 mg administered orally twice daily in patients with baseline platelet counts of 100 to 200 ⳯ 109/L and 20 mg administered orally twice daily in patients with baseline platelet counts >200 ⳯ 109/L. The doses of ruxolitinib were then adjusted during the course of therapy based on efficacy and tolerability. Maximum doses based on platelet counts were as follows10: • Platelet count 100 to ≤125 ⳯ 109/L: 20 mg twice daily • Platelet count 75 to ≤100 ⳯ 109/L: 10 mg twice daily • Platelet count 50 to ≤75 ⳯ 109/L: 5 mg twice daily.

Patient Populations Baseline characteristics of patients enrolled in Study

June 2012

www.AHDBonline.com

19

Baseline Characteristics of Patients in Study 1 Table 1 and Study 2 Baseline characteristic

Study 1 (N = 309)

Study 2 (N = 219)

Median age, yrs (range)

68 (40-91)

66 (35-85)

Patients aged >65 yrs, %

61

52

Male patients, %

54

57

Primary myelofibrosis, %

50

53

Postpolycythemia vera myelofibrosis, %

31

31

Postessential thrombocythemia myelofibrosis, %

18

16

10.5

10.4

Median platelet count, × 10 /L

251

236

Median palpable spleen length below the costal margin, cm

16

15

2595 (478-8881)

2381 (451-7765)

Disease state

Hematologic value Median hemoglobin, g/dL 9

Median spleen volume, cm3 (range) Source: Reference 10.

Table 2 Percentage of Patients with ≥35% Reduction in Baseline Spleen Volume Study 1 (24 wks)

Study 2 (48 wks)

Best available Ruxolitinib Placebo Ruxolitinib treatment (N = 155) (N = 154) P value (N = 146) (N = 73) P value 41.9%

0.7%

<.001

28.5%

0%

<.001

Source: Reference 10.

1 and Study 2 are shown in Table 1. The 2 patient populations were very similar in terms of demographics and the extent of disease before study treatment.10

Efficacy The primary end point in both phase 3 trials was the proportion of patients achieving a reduction in spleen volume of ≥35% from baseline at week 24 in Study 1 and at week 48 in Study 2 (Table 2). A significantly greater percentage of ruxolitinib-treated patients achieved this magnitude of reduction in baseline spleen volume com-

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pared with either placebo (41.9% vs 0.7%, respectively; P <.001) or best available therapy (28.5% vs 0%, respectively; P <.001).10 In Study 1, a secondary end point was improvement in symptoms, as measured by the MFSAF v2.0. This scale captures MF-related symptoms, including abdominal discomfort, pain under the left ribs, night sweats, itching, bone or muscle pain, and early satiety. A higher proportion of ruxolitinib-treated patients experienced a ≥50% reduction in Total Symptom Score compared with placebo (45.9% vs 5.3%, respectively; P <.001). The median time to symptom response was <4 weeks.10

Safety Profile Because clinical trials are conducted under widely varying conditions, rates of adverse reactions observed in the clinical trials of a particular drug cannot be compared directly with rates observed in the clinical trials of another drug and may not reflect the rates observed in clinical practice. The safety of ruxolitinib was assessed in 617 patients in 6 clinical studies with a median duration of follow-up of 10.9 months, including 301 patients with MF in 2 phase 3 studies. In these 2 studies, patients had a median duration of exposure to ruxolitinib of 9.5 months (range, 0.5-17 months), with 88.7% of patients treated for >6 months and 24.6% treated for >12 months. A total of 111 patients started treatment at 15 mg orally twice daily and 190 patients started at 20 mg orally twice daily.10 The most often reported adverse events were thrombocytopenia and anemia; the most frequent nonhematologic adverse events were bruising, dizziness, and headache.9 A total of 11.0% of patients receiving ruxolitinib and 10.6% of patients receiving placebo discontinued therapy because of adverse events.9 The rates of adverse reactions and laboratory abnormalities reported in Study 1 are summarized in Table 3.

The median time to onset of grade 2 or higher anemia was approximately 6 weeks. Mean decreases in hemoglobin of 1.5 to 2 g/dL below baseline after 8 to 12 weeks of therapy were reported in ruxolitinib-treated patients, recovering gradually to reach a new steady state of approximately 1.0 g/dL below baseline.10 The median time to onset of grade 3 or 4 thrombocytopenia was approximately 8 weeks. Patients with baseline platelet counts of 100 to 200 ⳯ 109/L experienced a higher incidence of grade 3 or 4 thrombocytopenia than did those with baseline platelet counts >200 ⳯ 109/L.10 Dosing Ruxolitinib is dosed orally and can be administered with or without food. If a dose is missed, the patient should not take an additional dose, but should take the

Ruxolitinib a New Oral Option

next usual prescribed dose. When discontinuing ruxolitinib therapy for reasons other than thrombocytopenia, gradual tapering of the dose may be considered—for example, by 5 mg twice daily each week.10 In patients who are unable to ingest tablets, ruxolitinib can be administered through a nasogastric tube (8 French or greater) by suspending 1 tablet in approximately 40 mL of water and stirring for approximately 10 minutes. Within 6 hours after the tablet has dispersed, the suspension can be administered via a nasogastric tube using an appropriate syringe. After use, the tube should be rinsed with approximately 75 mL of water.

The effect of tube-feeding preparations on ruxolitinib exposure during administration through a nasogastric tube has not been evaluated.10 The recommended starting dose of ruxolitinib is based on platelet count (Table 4). A complete blood count (CBC) and platelet count must be performed prior to initiating therapy, every 2 to 4 weeks until doses are stabilized, and then as clinically indicated.

Doses may be titrated based on safety and efficacy.10 Treatment with ruxolitinib should be interrupted in patients with platelet counts <50 ⳯ 109/L. Once the platelet count recovers to >50 ⳯ 109/L, dosing may be restarted or increased following recovery of platelet counts to acceptable levels. Table 5 shows the maximum allowable dose that may be used when restarting ruxolitinib therapy following a previous interruption.10 Patients who develop anemia may require blood transfusions. Dose modifications of ruxolitinib in patients who develop anemia may also be considered.10 Neutropenia (absolute neutrophil count [ANC] <0.5 ⳯ 109/L) was generally reversible and was managed by temporarily withholding ruxolitinib. CBCs should be monitored as clinically indicated, with dosing adjusted as required.10

Dose Modification Based on Response If efficacy is considered insufficient and platelet and neutrophil counts are adequate, doses may be increased in 5-mg twice-daily increments to a maximum of 25 mg twice daily. Doses should not be increased during the first 4 weeks of therapy and not more often than every 2 weeks. Discontinue treatment after 6 months if no reduction in spleen size or symptom improvement is observed since initiation of ruxolitinib therapy.10 Based on limited clinical data, long-term maintenance with a 5-mg twice-daily dose has not demonstrated responses, and continued use of this dose should be limited to patients in whom the benefits outweigh the potential risks.10 Dose increases may be considered in patients who meet all of the following criteria10:

Adverse Reactions and Laboratory Abnormalities Table 3 Reported in Study 1: Ruxolitinib versus Placebo Ruxolitinib (N = 155) Reported outcomes

Placebo (N = 151)

All All grades, Grade 3, Grade 4, grades, Grade 3, Grade 4, % % % % % %

Adverse reaction Bruisinga

23.2

0.6

0

14.6

0

0

Dizzinessb

18.1

0.6

0

7.3

0

0

Headache

14.8

0

0

5.3

0

0

Urinary tract infectionc

9.0

0

0

5.3

0.7

0.7

Weight gaind

7.1

0.6

0

1.3

0.7

0

Flatulence

5.2

0

0

0.7

0

0

Herpes zostere

1.9

0

0

0.7

0

0

Laboratory abnormalityf Thrombocytopenia

69.7

9.0

3.9

30.5

1.3

0

Anemia

96.1

34.2

11.0

86.8

15.9

3.3

Neutropenia

18.7

5.2

1.9

4.0

0.7

1.3

Elevated ALT

25.2

1.3

0

7.3

0

0

Elevated AST

17.4

0

0

6.0

0

0

a

Includes contusion, ecchymosis, hematoma, injection-site hematoma, periorbital hematoma, vessel puncture-site hematoma, increased tendency to bruise, petechiae, and purpura. b Includes dizziness, postural dizziness, vertigo, balance disorder, Ménière disease, and labyrinthitis. c Includes urinary tract infection, cystitis, urosepsis, urinary tract infection bacterial, kidney infection, pyuria, bacteria urine, bacteria urine identified, and nitrite urine present. d Includes weight increased and abnormal weight gain. e Includes herpes zoster and postherpetic neuralgia. f Worst grade values are presented, regardless of baseline.

ALT indicates alanine aminotransferase; AST, aspartate aminotransferase.

Source: Reference 10.

Table 4 Proposed Ruxolitinib Starting Doses Platelet count, × 109/L

Starting oral dose

>200

20 mg twice daily

100 to 200

15 mg twice daily

Source: Reference 10.

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zole), the recommended starting dose is 10 mg twice daily for patients with platelet counts ≥100 ⳯ 109/L. Additional dose modifications should be made with careful monitoring of safety and efficacy. Concurrent administration of ruxolitinib with strong CYP3A4 inhibitors should be avoided in patients with platelet counts <100 ⳯ 109/L.10

Maximum Restarting Doses for Ruxolitinib after Table 5 Safety Interruption Current platelet count, × 109/L

Maximum restarting dosea

≥125

20 mg twice daily

100 to <125

15 mg twice daily

75 to <100

10 mg twice daily for at least 2 wks; if patient is stable, may increase to 15 mg twice daily

50 to <75

5 mg twice daily for at least 2 wks; if patient is stable, may increase to 10 mg twice daily

<50

Continue hold

a

When restarting therapy, begin with a dose at least 5 mg twice daily below the dose at interruption.

Source: Reference 10.

Table 6 Dosing Recommendations for Thrombocytopenia Dose at time of platelet decline 25 mg 20 mg 15 mg 10 mg 5 mg Platelet twice daily twice daily twice daily twice daily twice daily count, New dose × 109/L 100 to <125

20 mg 15 mg twice daily twice daily

75 to <100

10 mg 10 mg 10 mg twice daily twice daily twice daily

50 to <75

5 mg 5 mg 5 mg 5 mg twice daily twice daily twice daily twice daily

<50

Hold

Hold

No change

Hold

No change

No change

No change

No change

Hold

No change Hold

Source: Reference 10.

• Failure to achieve a reduction from pretreatment baseline in either palpable spleen length of 50% or a 35% reduction in spleen volume, as measured by CT or MRI • Platelet count >125 ⳯ 109/L at 4 weeks and platelet count never <100 ⳯ 109/L • ANC >0.75 ⳯ 109/L.

Dose Adjustment, Concomitant Strong CYP3A4 Inhibitors On the basis of pharmacokinetic studies in healthy volunteers, when administering ruxolitinib along with strong cytochrome (CY)P3A4 inhibitors (eg, boceprevir, clarithromycin, conivaptan, grapefruit juice, indinavir, itraconazole, ketoconazole, lopinavir/ritonavir, mibefradil, nefazodone, nelfinavir, posaconazole, ritonavir, saquinavir, telaprevir, telithromycin, voricona-

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Contraindications, General Warnings, and Precautions There are no black box warnings or contraindications associated with the use of ruxolitinib. Warnings and precautions associated with use of the agent include such hematologic adverse reactions as thrombocytopenia, anemia, and neutropenia. As indicated earlier, a CBC and platelet count must be performed prior to initiating therapy with ruxolitinib.

In clinical trials, patients with platelet counts <200 ⳯ 109/L at the start of therapy were more likely to develop thrombocytopenia during treatment. Thrombocytopenia was generally reversible, however, and was usually managed by modifying or interrupting the dose of ruxolitinib in clinical trials. Patients may also require a platelet transfusion, if clinically indicated. Dose reductions should be considered if platelet counts decrease, with the goal being to avoid dose interruptions for thrombocytopenia (Table 6).10 Patients should be assessed for the risk of developing serious bacterial, mycobacterial, fungal, and viral infections. Active serious infections should have resolved prior to initiating ruxolitinib therapy. Physicians should carefully observe patients receiving ruxolitinib for signs and symptoms of infection, and should initiate appropriate treatment promptly. Physicians should inform patients about early signs and symptoms of herpes zoster, and should advise patients to seek treatment as early as possible. ■ References

1. Verstovsek S, Kantarjian H, Mesa R, et al. Safety and efficacy of INCB018424, a JAK1 and JAK2 inhibitor, in myelofibrosis. N Engl J Med. 2010;363:1117-1127.

2. Rollison DE, Howlader N, Smith MT, et al. Epidemiology of myelodysplastic syndromes and chronic myeloproliferative disorders in the United States, 2001-2004, using data from the NAACCR and SEER programs. Blood. 2008;112:45-52.

3. Levine RL, Wadleigh M, Cools J, et al. Activating mutation in the tyrosine kinase JAK2 in polycythemia vera, essential thrombocythemia, and myeloid metaplasia with myelofibrosis. Cancer Cell. 2005;7:387-397.

4. Kralovics R, Passamonti F, Buser AS, et al. A gain-of-function mutation of JAK2 in myeloproliferative disorders. N Engl J Med. 2005;352:1779-1790.

5. Santos FPS, Kantarjian HM, Jain N, et al. Phase 2 study of CEP-701, an orally available JAK2 inhibitor, in patients with primary or post-polycythemia vera/essential thrombocythemia myelofibrosis. Blood. 2010;115:1131-1136.

6. Baxter EJ, Scott LM, Campbell PJ, et al. Acquired mutation of the tyrosine kinase JAK2 in human myeloproliferative disorders. Lancet. 2005;365:1054-1061.

7. Cervantes F, Dupriez B, Pereira A, et al. New prognostic scoring system for primary myelofibrosis based on a study of the International Working Group for Myelofibrosis Research and Treatment. Blood. 2009;113:2895-2901.

8. Mertens C, Darnell JE Jr. SnapShot: JAK-STAT signaling. Cell. 2007;131:612.e1.

9. Jatiani SS, Baker SJ, Silverman LR, Reddy EP. JAK/STAT pathways in cytokine signaling and myeloproliferative disorders: approaches for targeted therapies. Genes Cancer. 2010;1:979-993.

10. Jakafi [prescribing information]. Wilmington, DE: Incyte Corporation; 2011.

An Overview of Metastatic CastrationResistant Prostate Cancer and Treatment Prostate cancer is the most commonly diagnosed cancer in men, aside from skin cancer The American Cancer Society estimates that more than 241,000 new cases of prostate cancer will be diagnosed in 2012, representing approximately 1 in 4 new cases of cancer in US men.2 National prevalence of metastatic CRPC (mCRPC) has been estimated to be approximately 35,000. Prostate cancer was the second most common cause of cancer death among US men in 2009 and will be associated with approximately 28,000 deaths this year.2,3

Treatment options for mCRPC For more than half a century, suppressing androgens—in particular, testosterone—has remained the focus of treatment for metastatic prostate cancer.7 Various androgen deprivation approaches have been developed, including orchiectomy and treatment with gonadotropin-releasing hormone (GnRH) analogs, with or without antiandrogens. Both types of ADT target the testes as the primary site of androgen synthesis, but do not affect androgen production by the adrenals or in prostatic tumor tissue.1

Estimated Annual Cases of Prostate Cancer

*

2012 incidence estimate.

2009 prevalence estimate. ‡ 2012 estimated deaths based on US Mortality Data, 1994 to 2008. †

Castration-resistant prostate cancer, defined The term castration-resistant describes disease that is progressing despite castrate levels of testosterone.4,5 Clinically, metastatic CRPC may present as an increase in prostate-specific antigen (PSA) or the appearance of new metastases and/or clinical symptoms after treatment with androgen deprivation therapy (ADT); one or both of these clinical features may be present.5 When CRPC presents with metastases, it is known as metastatic castration-resistant prostate cancer, or mCRPC. Patients with mCRPC may be symptomatic or asymptomatic.4,6

The adrenal glands are better known for their ability to produce hormones for regulation of metabolism, such as adrenaline.8 However, they also produce androgens, including androstenedione, dehydroepiandrosterone (DHEA), and dehydroepiandrosterone-sulphate (DHEA-S).

These androgens are the precursors to testosterone, which is further converted to dihydrotestosterone (DHT).9,10

In mCRPC, the tumor may remain androgen sensitive Recent clinical evidence suggests that prostate cancer tumor cells may use multiple mechanisms to adapt to a low-androgen environment. Two such mechanisms are

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cellular hypersensitivity and intratumoral androgen production.11-13 Cellular hypersensitivity can be achieved through a mutation in which tumor cells become hypersensitive to androgen by increasing the supply of androgen receptors (ARs), thereby improving the cells’ androgen capture rate. Adaptive mechanisms (such as AR mutation and AR overexpression) contribute to tumor sensitivity to androgen. Such cellular hypersensitivity increases the stimulatory effects of even low levels of testosterone and DHT.14,15

androgen within the tumor microenvironment. De novo synthesis allows androgen concentrations in tumor tissue to sufficiently activate the AR.13,16-19 Intratumoral Production of Androgen

Testosterone Passes Through the Tumor Cell Membrane

The second of these mechanisms, and perhaps the more astonishing, is the tumor’s ability to produce its own supply of androgen.1 Cellular mutations enable the tumor to recruit locally available androgen and androgen precursors and convert them, enzymatically, into testosterone and DHT; this cultivates a supply of

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Additions to the treatment options after diagnosis of symptomatic mCRPC Standard treatment for patients with symptomatic mCRPC is chemotherapy with docetaxel in combination with prednisone.4 Over the past few years, 2 additional treatments that may improve the overall survival of patients with mCRPC have been approved in the United States—the taxane cabazitaxel (Jevtana®; sanofi-aventis) and abiraterone acetate (Zytiga®; Janssen Biotech, Inc.).

Cabazitaxel, in combination with prednisone, is indicated for patients with mCRPC who have received treatment with docetaxel.20 Abiraterone acetate with prednisone is also indicated for men with mCRPC who have received treatment with docetaxel; however, unlike cabazitaxel (and docetaxel, for that matter), abiraterone acetate is not a chemotherapy, but rather an oral oncolytic 17αhydroxylase/C17,20-lyase (CYP17) inhibitor.1,21 We will talk more about a treatment option for patients with mCRPC, post-docetaxel.

ZYTIGA速 (abiraterone acetate) in combination with prednisone is indicated for the treatment of metastatic castration-resistant prostate cancer (CRPC) post-docetaxel.

Abiraterone acetate, converted in vivo to abiraterone, inhibits CYP17, which directly affects the androgen biosynthesis pathway. This enzyme, which is expressed in testicular, adrenal, and prostatic tumor tissues, is required to produce androgen. With treatment, androgen biosynthesis may be inhibited at 3 sources.1

Mechanism of action Abiraterone acetate, converted to abiraterone in vivo, is an androgen biosynthesis inhibitor that directly affects the androgen biosynthesis pathway by inhibiting CYP17.

The CYP17 enzyme, which is expressed in testicular, adrenal, and prostatic tumor tissues, is required to produce androgen.1 Consequently, androgen biosynthesis is inhibited at 3 sources of testosterone production: the testes, adrenal glands, and prostate tumor tissue.1 Hypertension, hypokalemia, and fluid retention due to mineralocorticoid excess Abiraterone acetate should be used with caution in patients with a history of cardiovascular disease.

Abiraterone acetate may cause hypertension, hypokalemia, and fluid retention as a consequence of increased mineralocorticoid levels resulting from CYP17 inhibition. Coadministration of a corticosteroid suppresses adrenocorticotropic hormone drive, resulting in a reduction in the incidence and severity of these adverse reactions. Use caution when treating patients whose underlying medical conditions may be compromised by increases in blood pressure, hypokalemia, or fluid retention (eg, those with heart failure, recent myocardial infarction, or ventricular arrhythmia). The safety of abiraterone acetate in patients with left ventricular ejection fraction less than

ZYTIGA速 Inhibits 3 Sources of Androgen* Production

DHEA=dehydroepiandrosterone.

DHT=dihydrotestosterone. * Androgens include DHEA, androstenedione, DHT, and testosterone. Testosterone is the primary androgen.

50% or New York Heart Association (NYHA) Class III or IV heart failure has not been established because these patients were excluded from the randomized clinical trial. Monitor patients for hypertension, hypokalemia, and fluid retention at least once a month.

Control hypertension and correct hypokalemia before and during treatment with abiraterone acetate.1

Clinical trials The efficacy and safety of abiraterone acetate plus prednisone were studied in a phase 3, randomized, placebo-controlled, multicenter clinical trial involving 1195 patients with mCRPC who had received prior chemotherapy containing docetaxel. Patients were

Study Design1,22

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Kaplan-Meier Overall Survival Curves of Patients Treated With Either ZYTIGA® Plus Prednisone or Placebo Plus Prednisone (Interim Analysis)

randomized 2:1 to receive abiraterone acetate 1,000 mg daily in combination with prednisone 5 mg twice daily or placebo once daily in combination with prednisone 5 mg twice daily (control arm). Per study protocol, patients were using a GnRH agonist or were previously treated with orchiectomy and had confirmed castration levels of testosterone (serum testosterone ≤50 ng/dL).1,22 The study population had a median age of 69 years; 89% had an Eastern Cooperative Oncology Group (ECOG) performance score of 0 to 1; bone metastases were present in 90% of participants, with visceral involvement in 30%; 70% had radiographic evidence of disease progression, whereas 30% had PSA-only progression; and 70% had received 1 regimen of cytotoxic chemotherapy, whereas 30% had received 2 rounds of cytotoxic chemotherapy.1

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AMERICAN HEALTH & DRUG BENEFITS

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Median overall survival (OS) difference At the prespecified interim survival analysis, treatment with abiraterone acetate plus prednisone resulted in a 3.9-month difference in median OS compared with placebo plus prednisone (median OS: 14.8 months vs 10.9 months [hazard ratio (HR)=0.646; 95% confidence interval (CI): 0.543, 0.768; P<0.0001]).1 In an updated analysis, results were consistent with those from the interim analysis, with a 4.6-month difference in median OS between the 2 arms (15.8 months vs 11.2 months [HR=0.74; 95% CI: 0.638, 0.859]).1 The most common adverse reactions (≥5%) were joint swelling or discomfort, hypokalemia, edema, muscle discomfort, hot flush, diarrhea, urinary tract infection, cough, hypertension, arrhythmia, urinary frequency, nocturia, dyspepsia, fractures, and upper respiratory tract infection.

Overall Survival of Patients Treated With Either ZYTIGA® Plus Prednisone or Placebo Plus Prednisone (Intent-to-Treat Analysis) ZYTIGA® (n=797)

Placebo (n=398)

Deaths

333 (42%)

219 (55%)

Median survival (months) (95% CI)

14.8 (14.1, 15.4)

10.9 (10.2, 12.0) <0.0001

P value* Hazard ratio

†

0.646 (0.543, 0.768)

P value is derived from a log-rank test stratified by ECOG performance status score (0-1 vs 2), pain score (absent vs present), number of prior chemotherapy regimens (1 vs 2), and type of disease progression (PSA only vs radiographic). † Hazard ratio is derived from a stratified proportional hazards model. Hazard ratio <1 favors ZYTIGA®.

*

Important Safety Information Contraindications - ZYTIGA® (abiraterone acetate) may cause fetal harm (Pregnancy Category X) and is contraindicated in women who are or may become pregnant.

Hypertension, Hypokalemia and Fluid Retention Due to Mineralocorticoid Excess - Use with caution in patients with a history of cardiovascular disease or with medical conditions that might be compromised by increases in hypertension, hypokalemia, and fluid retention. ZYTIGA® may cause hypertension, hypokalemia, and fluid retention as a consequence of increased mineralocorticoid levels resulting from CYP17 inhibition.

Safety has not been established in patients with LVEF <50% or New York Heart Association (NYHA) Class III or IV heart failure because these patients were excluded from the randomized clinical trial. Control hypertension and correct hypokalemia before and during treatment. Monitor blood pressure, serum potassium, and symptoms of fluid retention at least monthly.

Adrenocortical Insufficiency (AI) - AI has been reported in clinical trials in patients receiving ZYTIGA® in combination with prednisone, after an interruption of daily steroids and/or with concurrent infection or stress.

Use caution and monitor for symptoms and signs of AI if prednisone is stopped or withdrawn, if prednisone dose is reduced, or if the patient experiences unusual stress.

Symptoms and signs of AI may be masked by adverse reactions associated with mineralocorticoid excess seen in patients treated with ZYTIGA®. Perform appropriate tests, if indicated, to confirm AI. Increased dosages of corticosteroids may be used before, during, and after stressful situations.

Hepatotoxicity - Increases in liver enzymes have led to drug interruption, dose modification, and/or discon-

tinuation. Monitor liver function and modify, withhold, or discontinue ZYTIGA® dosing as recommended (see Prescribing Information for more information). Measure serum transaminases (alanine aminotransferase [ALT] and aspartate aminotransferase [AST]) and bilirubin levels prior to starting treatment with ZYTIGA®, every two weeks for the first three months of treatment, and monthly thereafter. Promptly measure serum total bilirubin, AST, and ALT if clinical symptoms or signs suggestive of hepatotoxicity develop. Elevations of AST, ALT, or bilirubin from the patient’s baseline should prompt more frequent monitoring. If at any time AST or ALT rise above five times the upper limit of normal (ULN) or the bilirubin rises above three times the ULN, interrupt ZYTIGA® treatment and closely monitor liver function.

Food Effect - ZYTIGA® must be taken on an empty stomach. Exposure of abiraterone increases up to 10-fold when abiraterone acetate is taken with meals. No food should be eaten for at least two hours before the dose of ZYTIGA® is taken and for at least one hour after the dose of ZYTIGA® is taken. Abiraterone Cmax and AUC0-∞ (exposure) were increased up to 17- and 10-fold higher, respectively, when a single dose of abiraterone acetate was administered with a meal compared to a fasted state.

Adverse Reactions - The most common adverse reactions (≥5%) are joint swelling or discomfort, hypokalemia, edema, muscle discomfort, hot flush, diarrhea, urinary tract infection, cough, hypertension, arrhythmia, urinary frequency, nocturia, dyspepsia, fractures, and upper respiratory tract infection.

Drug Interactions - ZYTIGA® is an inhibitor of the hepatic drug-metabolizing enzyme CYP2D6. Avoid

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coadministration with CYP2D6 substrates that have a narrow therapeutic index. If an alternative cannot be used, exercise caution and consider a dose reduction of the CYP2D6 substrate. Additionally, abiraterone is a substrate of CYP3A4 in vitro. Strong inhibitors and inducers of CYP3A4 should be avoided or used with caution.

Use in Specific Populations - The safety of ZYTIGA® in patients with baseline severe hepatic impairment has not been studied. These patients should not receive ZYTIGA®.

08Z11121R3

Conclusion The prevalence of mCRPC was estimated to be approximately 35,000 in 2009.3 As prostate cancer disease becomes more advanced, fewer treatment options are available. Until recently, therapeutic options for mCRPC were limited to treatment with the chemotherapy docetaxel as the standard treatment.

However, despite castrate levels of androgens, some tumors remain androgen sensitive.11-13,15 Abiraterone acetate inhibits the CYP17 enzyme, which directly affects the androgen biosynthesis pathway.

This enzyme, which is expressed in testicular, adrenal, and prostatic tumor tissues, is required to produce androgen.1 Results of the pivotal study for this agent demonstrate that patients receiving abiraterone acetate plus prednisone achieved a statistically significant difference in median OS compared with those receiving placebo with prednisone.1 Androgen biosynthesis inhibition, along with other classes of therapy already commercialized and under investigation, holds promise for the future of men with mCRPC who have received treatment with docetaxel. ■ References

1. ZYTIGA® Prescribing Information. Horsham, PA: Janssen Biotech, Inc. 2. American Cancer Society. Cancer facts & figures 2012. http://www.cancer.org/

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Research/CancerFactsFigures/index. Accessed January 31, 2012.

3. Solo K, Mehra M, Dhawan R, Valant J, Scher HI. Prevalence of prostate cancer (PC) clinical states (CS) in the United States: estimates using a dynamic progression model. J Clin Oncol. 2011;29(suppl):4637.

4. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology™: Prostate Cancer. v.2.2012. Fort Washington, PA: National Comprehensive Cancer Network; 2011.

5. Hotte SJ, Saad F. Current management of castrate-resistant prostate cancer. Curr Oncol. 2010;17(suppl 2):S72-S79.

6. MacVicar GR. Metastatic castration-resistant prostate cancer 2011: exciting advances, new challenges. Presented at: 2011 Annual Meeting of the American Society of Clinical Oncology; June 1-5; Chicago, IL. http://www.asco.org/ASCOv2/ Home/Education%20&%20Training/Educational%20Book/PDF%20Files/2011/zds0 0111000177.PDF. Accessed March 15, 2012.

7. Sowery RD, So AI, Gleave ME. Therapeutic options in advanced prostate cancer: present and future. Curr Urol Rep. 2007;8(1):53-59.

8. University of Maryland Medical Center Web site. Encyclopedia. Adrenal gland hormone secretion. http://www.umm.edu/imagepages/8719.htm. Accessed March 15, 2012.

9. Heffner LJ, Schust DJ. Steroid hormone mechanism of action and metabolism. In: The Reproductive System at a Glance. 3rd ed. Oxford, England: Wiley-Blackwell; 2010.

10. Balk SP. Increased expression of genes converting adrenal androgens to testosterone in castration-recurrent prostate cancer. In: Tindall D, Mohler J, eds. Androgen Action in Prostate Cancer. New York, NY: Springer; 2009.

11. Chen Y, Clegg NJ, Scher HI. Anti-androgens and androgen-depleting therapies in prostate cancer: new agents for an established target. Lancet Oncol.

2009;10(10):981-991.

12. Scher HI, Steineck G, Kelly WK. Hormone-refractory (D3) prostate cancer: refining the concept. Urology. 1995;46(2):142-148.

13. Titus MA, Schell MJ, Lih FB, Tomer KB, Mohler JL. Testosterone and dihydrotestosterone tissue levels in recurrent prostate cancer. Clin Cancer Res. 2005;11(13):4653-4657.

14. Gregory CW, Johnson RT Jr, Mohler JL, French FS, Wilson EM. Androgen receptor stabilization in recurrent prostate cancer is associated with hypersensitivity to low androgen. Cancer Res. 2001;61(7):2892-2898.

15. Chen CD, Welsbie DS, Tran C, et al. Molecular determinants of resistance to antiandrogen therapy. Nat Med. 2004;10(1):33-39.

16. Stanbrough M, Bubley GJ, Ross K, et al. Increased expression of genes converting adrenal androgens to testosterone in androgen-independent prostate cancer.

Cancer Res. 2006;66(5):2815-2825.

17. Locke JA, Guns ES, Lubik AA, et al. Androgen levels increase by intratumoral de novo steroidogenesis during progression of castration-resistant prostate cancer.

Cancer Res. 2008;68(15):6407-6415.

18. Montgomery RB, Mostaghel EA, Vessella R, et al. Maintenance of intratumoral androgens in metastatic prostate cancer: a mechanism for castration-resistant tumor growth. Cancer Res. 2008;68(11):4447-4454.

19. Holzbeierlein J, Lal P, LaTulippe E, et al. Gene expression analysis of human prostate carcinoma during hormonal therapy identifies androgen-responsive genes and mechanisms of therapy resistance. Am J Pathol. 2004;164(1):217-227.

20. Jevtana® Prescribing Information. Bridgewater, NJ: Sanofi-Aventis US LLC; 2010.

21. Logothetis CJ, Efstathiou E, Manuguid F, Kirkpatrick P. Fresh from the pipeline: abiraterone acetate. Nature Rev Drug Discov. 2011;10:573-574.

22. de Bono JS, Logothetis CJ, Molina A, et al. Abiraterone and increased survival in metastatic prostate cancer. N Engl J Med. 2011;364(21):1995-2005.

PERSPECTIVE

Patients’ Impact on Quality Ratings: Are the Stars Aligned in Your Favor?

Schumarry Chao, MD, MBA

O

ver the past few years, the treatment options for metastatic castration-resistant prostate cancer (mCRPC) have grown from 1 (docetaxel) to 4.

In addition, a number of investigational drugs with new mechanisms of action have the potential for making additional inroads on this advanced stage of the disease.

With the advent of these new—and expensive—treatments, P&T committee members have had to become experts on mCRPC quickly. In the absence of head-tohead trials, committees have become well versed on the clinical profiles of the various new agents: their mechanisms of action, survival benefits, tolerability profiles, delivery, dosing convenience, and the likelihood for compliance/persistence. As committees strive to find the right balance of access and cost, they need to also stay abreast of new information, such as rapidly evolving evidence-based guidelines.

In addition to the boilerplate issues described above, there is another consideration that managed care organizations will need to factor into the mix: patient satisfaction. Per the Patient Protection and Affordable Care Act, how patients feel about their plan—as scored by the Medicare Health Outcomes Survey and the Consumer Assessment of Healthcare Providers and Systems (CAHPS) survey—is a critical component of plan performance. Results of these surveys, along with other tools that capture consumer sentiment and overall performance, determine the number of stars awarded to a plan by the Medicare Star Quality Rating System (MSQRS). To the payer, the importance of the MSQRS is already being felt, as consumers are increasingly using the stars system to help them select the plan they will sign with and stay with. Starting in 2012, however, the impact of the MSQRS on our industry will be felt financially, as stars ratings will determine which plans can offer year-round enrollment and whether a plan qualifies for a cut of an estimated $3 billion in incentive payments from the Centers for Medicare & Medicaid Services in 2012.1 Ultimately, the success or failure of a plan could be determined by MSQRS.

Consider Question 21 of the overall ratings for the CAHPS health plan survey: “In the last 12 months, how often was it easy to get the care, tests, or treatment you thought you needed through your health plan?”2 The mCRPC patient who is educated and given access to treatment recommended by his trusted physician––treatment effective enough to extend his life––will rate his plan higher than the patient whose choices are restricted. Tolerability profiles and mode of administration (eg, oral or IV) are other examples of highly valued choices. In effect, with all this newfound influence on the quality of care, the patient has become a de facto decision-making member of the P&T committee.

Proactive payers will prepare for this brave new world by recognizing the need for an mCRPC therapy that offers a survival benefit, is well tolerated, and affords members a mode of administration that is compatible with their lifestyle. Looking ahead to the increased role patient satisfaction will play in the delivery of healthcare, the best approach is to allow physicians to prescribe FDA-approved treatments that offer their patients what the physicians feel is the best care. Access to the best care will result in the healthiest outcome for the plan as well as the patient. ■ Disclosure Statement: Dr. Chao is a consultant to Janssen Biotech, Inc. Board certified in emergency medicine, her academic appointments include clinical professor of emergency medicine and family medicine, as well as adjunct professor of pharmacoeconomics at the University of Southern California. She also serves on the Board of Trustees, University of the Sciences, Philadelphia.

References

1. CMS unveils 5-star Medicare advantage plans. Margaret Dick Tocknell, for HealthLeaders Media. http://www.healthleadersmedia.com/content/HEP-272053/ CMS-Unveils-5Star-Medicare-Advantage-Plans.html. Published October 13, 2011.

Accessed January 26, 2012.

2. CAHPS® Health Plan Survey 4.0 Version: Adult Commercial Questionnaire Language: English. https://www.cahps.ahrq.gov/Surveys-Guidance/HP/Get-Surveysand-Instructions/Survey-Summary.aspx?scn=HP. Updated December 1, 2008.

Accessed January 26, 2012.

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ZYTIGA® (abiraterone acetate) Tablets Brief Summary of Prescribing Information.

INDICATIONS AND USAGE ZYTIGA in combination with prednisone is indicated for the treatment of patients with metastatic castration-resistant prostate cancer (CRPC) who have received prior chemotherapy containing docetaxel.

CONTRAINDICATIONS Pregnancy: ZYTIGA may cause fetal harm when administered to a pregnant woman. ZYTIGA is contraindicated in women who are or may become pregnant. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus.

WARNINGS AND PRECAUTIONS Hypertension, Hypokalemia and Fluid Retention Due to Mineralocorticoid Excess: Use ZYTIGA with caution in patients with a history of cardiovascular disease. ZYTIGA may cause hypertension, hypokalemia, and fluid retention as a consequence of increased mineralocorticoid levels resulting from CYP17 inhibition [see Adverse Reactions and Clinical Pharmacology (12.1) in full Prescribing Information]. Co-administration of a corticosteroid suppresses adrenocorticotropic hormone (ACTH) drive, resulting in a reduction in the incidence and severity of these adverse reactions. Use caution when treating patients whose underlying medical conditions might be compromised by increases in blood pressure, hypokalemia or fluid retention, e.g., those with heart failure, recent myocardial infarction or ventricular arrhythmia. The safety of ZYTIGA in patients with left ventricular ejection fraction <50% or NYHA Class III or IV heart failure has not been established because these patients were excluded from the randomized clinical trial. Monitor patients for hypertension, hypokalemia, and fluid retention at least once a month.

Control hypertension and correct hypokalemia before and during treatment with ZYTIGA. Adrenocortical Insufficiency: Adrenocortical insufficiency has been reported in clinical trials in patients receiving ZYTIGA in combination with prednisone, following interruption of daily steroids and/or with concurrent infection or stress. Use caution and monitor for symptoms and signs of adrenocortical insufficiency, particularly if patients are withdrawn from prednisone, have prednisone dose reductions, or experience unusual stress.

Symptoms and signs of adrenocortical insufficiency may be masked by adverse reactions associated with mineralocorticoid excess seen in patients treated with ZYTIGA. If clinically indicated, perform appropriate tests to confirm the diagnosis of adrenocortical insufficiency. Increased dosage of corticosteroids may be indicated before, during and after stressful situations [see Warnings and Precautions].

Hepatotoxicity: Marked increases in liver enzymes leading to drug discontinuation or dosage modification have occurred [see Adverse Reactions]. Measure serum transaminases (ALT and AST) and bilirubin levels prior to starting treatment with ZYTIGA, every two weeks for the first three months of treatment and monthly thereafter. In patients with baseline moderate hepatic impairment receiving a reduced ZYTIGA dose of 250 mg, measure ALT, AST, and bilirubin prior to the start of treatment, every week for the first month, every two weeks for the following two months of treatment and monthly thereafter. Promptly measure serum total bilirubin, AST, and ALT if clinical symptoms or signs suggestive of hepatotoxicity develop.

Elevations of AST, ALT, or bilirubin from the patient’s baseline should prompt more frequent monitoring. If at any time AST or ALT rise above five times the ULN, or the bilirubin rises above three times the ULN, interrupt ZYTIGA treatment and closely monitor liver function. Re-treatment with ZYTIGA at a reduced dose level may take place only after return of liver function tests to the patient’s baseline or to AST and ALT less than or equal to 2.5X ULN and total bilirubin less than or equal to 1.5X ULN [see Dosage and Administration (2.2) in full Prescribing Information].

The safety of ZYTIGA re-treatment of patients who develop AST or ALT greater than or equal to 20X ULN and/or bilirubin greater than or equal to 10X ULN is unknown.

Food Effect: ZYTIGA must be taken on an empty stomach. No food should be consumed for at least two hours before the dose of ZYTIGA is taken and for at least one hour after the dose of ZYTIGA is taken. Abiraterone Cmax and AUC0-∞ (exposure) were increased up to 17- and 10-fold higher, respectively, when a single dose of abiraterone acetate was administered with a meal compared to a fasted state. The safety of these increased exposures when multiple doses of abiraterone acetate are taken with food has not been assessed [see Dosage and Administration (2.1) and Clinical Pharmacology (12.3) in full Prescribing Information].

ADVERSE REACTIONS The following are discussed in more detail in other sections of the labeling: Hypertension, hypokalemia, and fluid retention due to mineralocorticoid excess [see Warnings and Precautions].

Adrenocortical insufficiency [see Warnings and Precautions].

Hepatotoxicity [see Warnings and Precautions].

Food effect [see Warnings and Precautions].

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ZYTIGA® (abiraterone acetate) Tablets Clinical Trial Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

In a placebo-controlled, multicenter phase 3 clinical trial of patients with metastatic castration-resistant prostate cancer who were using a gonadotropin-releasing hormone (GnRH) agonist or were previously treated with orchiectomy, ZYTIGA was administered at a dose of 1,000 mg daily in combination with prednisone 5 mg twice daily in the active treatment arm (N = 791). Placebo plus prednisone 5 mg twice daily was given to control patients (N = 394). The median duration of treatment with ZYTIGA was 8 months.

The most common adverse drug reactions (≥5%) reported in clinical studies were joint swelling or discomfort, hypokalemia, edema, muscle discomfort, hot flush, diarrhea, urinary tract infection, cough, hypertension, arrhythmia, urinary frequency, nocturia, dyspepsia, fractures and upper respiratory tract infection.

The most common adverse drug reactions that resulted in drug discontinuation were aspartate aminotransferase increased, alanine aminotransferase increased, urosepsis and cardiac failure (each in <1% of patients taking ZYTIGA).

Adverse reactions and laboratory abnormalities related to mineralocorticoid effects were reported more commonly in patients treated with ZYTIGA than in patients treated with placebo: hypokalemia 28% versus 20%, hypertension 9% versus 7% and fluid retention (edema) 27% versus 18%, respectively (see Table 1). In patients treated with ZYTIGA, grades 3 to 4 hypokalemia occurred in 5% of patients and grades 3 to 4 hypertension was reported in 1% of patients [see Warnings and Precautions].

Table 1 shows adverse reactions due to ZYTIGA that occurred with either a ≥ 2% absolute increase in frequency compared to placebo, or were events of special interest (mineralocorticoid excess, cardiac adverse reactions, and liver toxicities).

Table 1: Adverse Reactions due to ZYTIGA in a Placebo-Controlled Phase 3 Trial ZYTIGA with Placebo with Prednisone Prednisone (N=791) (N=394) System/Organ Class All Grades1 Grade 3-4 All Grades Grade 3-4 Adverse reaction % % % % Musculoskeletal and connective tissue disorders Joint swelling/discomfort2 29.5 4.2 23.4 4.1 Muscle discomfort3 26.2 3.0 23.1 2.3 General disorders 4 Edema 26.7 1.9 18.3 0.8 Vascular disorders Hot flush 19.0 0.3 16.8 0.3 Hypertension 8.5 1.3 6.9 0.3 Gastrointestinal disorders Diarrhea 17.6 0.6 13.5 1.3 Dyspepsia 6.1 0 3.3 0 Infections and infestations Urinary tract infection 11.5 2.1 7.1 0.5 Upper respiratory tract infection 5.4 0 2.5 0 Respiratory, thoracic and mediastinal disorders Cough 10.6 0 7.6 0 Renal and urinary disorders Urinary frequency 7.2 0.3 5.1 0.3 Nocturia 6.2 0 4.1 0 Injury, poisoning and procedural complications Fractures5 5.9 1.4 2.3 0 Cardiac disorders Arrhythmia6 7.2 1.1 4.6 1.0 Chest pain or chest discomfort 7 3.8 0.5 2.8 0 Cardiac failure8 2.3 1.9 1.0 0.3 1 2 3 4

Adverse events graded according to CTCAE version 3.0 Includes terms Arthritis, Arthralgia, Joint swelling, and Joint stiffness Includes terms Muscle spasms, Musculoskeletal pain, Myalgia, Musculoskeletal discomfort, and Musculoskeletal stiffness Includes terms Edema, Edema peripheral, Pitting edema, and Generalized edema

ZYTIGA® (abiraterone acetate) Tablets

ZYTIGA® (abiraterone acetate) Tablets

5

Drugs that Inhibit or Induce CYP3A4 Enzymes: Based on in vitro data, ZYTIGA is a substrate of CYP3A4. The effects of strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, nefazodone, saquinavir, telithromycin, ritonavir, indinavir, nelfinavir, voriconazole) or inducers (e.g., phenytoin, carbamazepine, rifampin, rifabutin, rifapentine, phenobarbital) on the pharmacokinetics of abiraterone have not been evaluated, in vivo. Avoid or use with caution, strong inhibitors and inducers of CYP3A4 during ZYTIGA treatment [see Clinical Pharmacology (12.3) in full Prescribing Information].

Includes all fractures with the exception of pathological fracture Includes terms Arrhythmia, Tachycardia, Atrial fibrillation, Supraventricular tachycardia, Atrial tachycardia, Ventricular tachycardia, Atrial flutter, Bradycardia, Atrioventricular block complete, Conduction disorder, and Bradyarrhythmia 7 Includes terms Angina pectoris, Chest pain, and Angina unstable.

Myocardial infarction or ischemia occurred more commonly in the placebo arm than in the ZYTIGA arm (1.3% vs. 1.1% respectively).

8 Includes terms Cardiac failure, Cardiac failure congestive, Left ventricular dysfunction, Cardiogenic shock, Cardiomegaly, Cardiomyopathy, and Ejection fraction decreased Cardiovascular Adverse Reactions: Cardiovascular adverse reactions in the phase 3 trial are shown in Table 1. The majority of arrhythmias were grade 1 or 2. Grade 3-4 arrhythmias occurred at similar rates in the two arms. There was one death associated with arrhythmia and one patient with sudden death in the ZYTIGA arm. No patients had sudden death or arrhythmia associated with death in the placebo arm. Cardiac ischemia or myocardial infarction led to death in 2 patients in the placebo arm and 1 death in the ZYTIGA arm.

Cardiac failure resulting in death occurred in 1 patient on both arms.

Hepatotoxicity: Drug-associated hepatotoxicity with elevated ALT, AST, and total bilirubin has been reported in patients treated with ZYTIGA. Across all clinical trials, liver function test elevations (ALT or AST increases of > 5X ULN) were reported in 2.3% of patients who received ZYTIGA, typically during the first 3 months after starting treatment. In the phase 3 trial, patients whose baseline ALT or AST were elevated were more likely to experience liver function test elevations than those beginning with normal values.

When elevations of either ALT or AST > 5X ULN, or elevations in bilirubin > 3X ULN were observed, ZYTIGA was withheld or discontinued. In two instances marked increases in liver function tests occurred [see Warnings and Precautions]. These two patients with normal baseline hepatic function, experienced ALT or AST elevations 15 to 40X ULN and bilirubin elevations 2 to 6 X ULN. Upon discontinuation of ZYTIGA, both patients had normalization of their liver function tests and one patient was re-treated with ZYTIGA without recurrence of the elevations.

In clinical trials, the following patients were excluded: patients with active hepatitis, patients with baseline ALT and/or AST ≥ 2.5X ULN in the absence of liver metastases, and patients with ALT and/or AST > 5X ULN in the presence of liver metastases. Abnormal liver function tests developing in patients participating in clinical trials were managed by treatment interruption, dose modification and/or discontinuation [see Dosage and Administration (2.2) in full Prescribing Information and Warnings and Precautions]. Patients with elevations of ALT or AST > 20X ULN were not re-treated.

Other Adverse Reactions: Adrenal insufficiency occurred in two patients on the abiraterone arm of the phase 3 clinical trial (< 1%).

Laboratory Abnormalities of Interest: Table 2 shows laboratory values of interest from the phase 3 placebo-controlled clinical trial. Grade 3-4 low serum phosphate (7.2%) and potassium (5.3%) occurred more frequently in the ZYTIGA arm.

6

Table 2: Laboratory Abnormalities of Interest in a Phase 3 Placebo-Controlled Clinical Trial Abiraterone (N=791) Placebo (N=394) All Grades Grade 3-4 All Grades Grade 3-4 Laboratory Abnormality (%) (%) (%) (%) High Triglyceride High AST Low Potassium Low Phosphorus High ALT High Total Bilirubin

62.5 30.6 28.3 23.8 11.1 6.6

0.4 2.1 5.3 7.2 1.4 0.1

53.0 36.3 19.8 15.7 10.4 4.6

0 1.5 1.0 5.8 0.8 0

DRUG INTERACTIONS Effects of Abiraterone on Drug Metabolizing Enzymes: ZYTIGA is an inhibitor of the hepatic drug-metabolizing enzyme CYP2D6. In a CYP2D6 drug-drug interaction trial, the Cmax and AUC of dextromethorphan (CYP2D6 substrate) were increased 2.8- and 2.9-fold, respectively, when dextromethorphan was given with abiraterone acetate 1,000 mg daily and prednisone 5 mg twice daily. Avoid co-administration of abiraterone acetate with substrates of CYP2D6 with a narrow therapeutic index (e.g., thioridazine). If alternative treatments cannot be used, exercise caution and consider a dose reduction of the concomitant CYP2D6 substrate drug [see Clinical Pharmacology (12.3) in full Prescribing Information].

In vitro, ZYTIGA was shown to inhibit the hepatic drug-metabolizing enzyme CYP2C8. There are no clinical data on the use of ZYTIGA with drugs that are substrates of CYP2C8.

USE IN SPECIFIC POPULATIONS Pregnancy: Pregnancy Category X [see Contraindications]. ZYTIGA is contraindicated in women who are or may become pregnant while receiving the drug. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus and the potential risk for pregnancy loss. Women of childbearing potential should be advised to avoid becoming pregnant during treatment with ZYTIGA. Nursing Mothers: ZYTIGA is not indicated for use in women. It is not known if abiraterone acetate is excreted in human milk. Because many drugs are excreted in human milk, and because of the potential for serious adverse reactions in nursing infants from ZYTIGA, a decision should be made to either discontinue nursing, or discontinue the drug taking into account the importance of the drug to the mother.

Pediatric Use: ZYTIGA is not indicated in children.

Geriatric Use: Of the total number of patients in a phase 3 trial of ZYTIGA, 71% of patients were 65 years and over and 28% were 75 years and over. No overall differences in safety or effectiveness were observed between these elderly patients and younger patients.

Patients with Hepatic Impairment: The pharmacokinetics of abiraterone were examined in subjects with baseline mild (n = 8) or moderate (n = 8) hepatic impairment (Child-Pugh Class A and B, respectively) and in 8 healthy control subjects with normal hepatic function. The systemic exposure (AUC) of abiraterone after a single oral 1,000 mg dose of ZYTIGA increased by approximately 1.1-fold and 3.6-fold in subjects with mild and moderate baseline hepatic impairment, respectively compared to subjects with normal hepatic function.

No dosage adjustment is necessary for patients with baseline mild hepatic impairment. In patients with baseline moderate hepatic impairment (ChildPugh Class B), reduce the recommended dose of ZYTIGA to 250 mg once daily. If elevations in ALT or AST >5X ULN or total bilirubin >3X ULN occur in patients with baseline moderate hepatic impairment, discontinue ZYTIGA treatment [see Dosage and Administration (2.1) and Clinical Pharmacology (12.3) in full Prescribing Information].

The safety of ZYTIGA in patients with baseline severe hepatic impairment has not been studied. These patients should not receive ZYTIGA. For patients who develop hepatotoxicity during treatment, interruption of treatment and dosage adjustment may be required [see Dosage and Administration (2.2) in full Prescribing Information, Warnings and Precautions, and Clinical Pharmacology (12.3) in full Prescribing Information].

Patients with Renal Impairment: In a dedicated renal impairment trial, the mean PK parameters were comparable between healthy subjects with normal renal function (N=8) and those with end stage renal disease (ESRD) on hemodialysis (N=8) after a single oral 1,000 mg dose of ZYTIGA. No dosage adjustment is necessary for patients with renal impairment [see Dosage and Administration (2.1) and Clinical Pharmacology (12.3) in full Prescribing Information].

OVERDOSAGE: There have been no reports of overdose of ZYTIGA during clinical studies. There is no specific antidote. In the event of an overdose, stop ZYTIGA, undertake general supportive measures, including monitoring for arrhythmias and cardiac failure and assess liver function.

Storage and Handling: Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [see USP controlled room temperature]. Based on its mechanism of action, ZYTIGA may harm a developing fetus. Therefore, women who are pregnant or women who may be pregnant should not handle ZYTIGA without protection, e.g., gloves [see Use in Specific Populations].

Manufactured by: Patheon Inc. Mississauga, Canada Manufactured for: Janssen Biotech, Inc. Horsham, PA 19044 Issued: May 2012

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Making

PRO gress with patient-reported outcomes How PROs were successfully integrated into the Jakafi® (ruxolitinib) drug development program1 A novel approach to engage clinicians and FDA

TAILORING a PRO tool for myelofibrosis

PROs are an important means to demonstrate treatment

Myelofibrosis (MF) is a life-threatening, progressive disease

2,3

Use of a PRO instrument can

characterized by splenomegaly, debilitating symptoms and

evaluate symptoms best judged by the patient, whether

cytopenias.5-7 Measures to assess both the splenomegaly

caused by the disease or treatment toxicity. Assessment

and core symptoms of MF were incorporated into the phase III,

of symptom burden is important because it can be a major

double-blind placebo-controlled study, COMFORT-I, for Jakafi.

indicator of disease severity, progression or improvement.

Spleen reduction, as measured by imaging (MRI or CT), was the

Incorporating PROs into a clinical trial program provides a

primary and biologic endpoint, and a reduction in total symptom

means for evaluating the impact of therapy from the patient’s

score (TSS), the PRO measure, was a key secondary endpoint.8,9

perspective and helps patients and clinicians make better-

The TSS encompassed the following symptoms: abdominal

benefits in clinical trials.

4

informed decisions.

discomfort, pain under left ribs, early satiety, pruritus, night sweats and bone/muscle pain.9 To include PROs in the trial, a novel instrument had to be specifically developed. After patient interviews, advice from clinical experts and extensive input from the FDA, the modified Myelofibrosis Symptom Assessment Form, version 2.0 (modified MFSAF v2.0) was finalized as part of the Special Protocol Assessment prior to the initiation of COMFORT-I. Ultimately, Jakafi was approved by the FDA for the treatment of intermediate or high-risk MF.1,8 This became Incyte’s first approved drug and also the first oncology medicine approved with symptom data in its label since the FDA’s draft guidance on PROs was finalized in 2009.2,4

Indications and Usage Jakafi is indicated for treatment of patients with intermediate or high-risk myelofibrosis, including primary myelofibrosis, post–polycythemia vera myelofibrosis and post–essential thrombocythemia myelofibrosis.

Important Safety Information • Treatment with Jakafi can cause hematologic adverse reactions, including thrombocytopenia, anemia and neutropenia, which are each dose-related effects, with the most frequent being thrombocytopenia and anemia.

A complete blood count must be performed before initiating therapy with Jakafi. Complete blood counts should be monitored as clinically indicated and dosing adjusted as required • The three most frequent non-hematologic adverse reactions were bruising, dizziness and headache • Patients with platelet counts <200 × 109/L at the start of therapy are more likely to develop thrombocytopenia

during treatment. Thrombocytopenia was generally reversible and was usually managed by reducing the dose or temporarily withholding Jakafi. If clinically indicated, platelet transfusions may be administered • Patients developing anemia may require blood transfusions.

Dose modifications of Jakafi for patients developing anemia may also be considered • Neutropenia (ANC <0.5 × 109/L) was generally reversible and was managed by temporarily withholding Jakafi • Patients should be assessed for the risk of developing serious bacterial, mycobacterial, fungal and viral infections.

Active serious infections should have resolved before starting Jakafi. Physicians should carefully observe patients receiving Jakafi for signs and symptoms of infection (including herpes zoster) and initiate appropriate treatment promptly • A dose modification is recommended when administering Jakafi with strong CYP3A4 inhibitors or in patients with

JAKAFI endpoints included both biologic and patient-reported outcomes8,9 COMFORT-I: Percent Change in Spleen Volume in Individual Patients From Baseline to Week 24 or Last Observation9,a

COMFORT-I: Percent Change in TSS in Individual Patients From Baseline to Week 24 or Last Observation9,a,b 150

-20 -40

35% Reduction

-60 -80

Upper 50th Percentile

Jakafi (n = 155)

Upper 50th Percentile

Placebo (n = 153)

Each bar represents an individual patient’s response.

50 0 -50

-100

WORSENING

0

100

IMPROVEMENT

20

Change From Baseline (%)

40

WORSENING

60

IMPROVEMENT

Change From Baseline (%)

80

50% Improvement

Upper 50th Percentile

Jakafi (n = 145)

Upper 50th Percentile

Placebo (n = 145)

Each bar represents an individual patient’s response. Worsening of TSS is truncated at 150%.

PROVIDING proof of patient benefit MF is progressive, and spleen size and symptoms can become increasingly burdensome to patients over time.5-7 Jakafi is proven to decrease total symptom score in patients with intermediate or high-risk MF—this is an important consideration when evaluating and treating patients.9 The FDA approval included patients with intermediate-2 risk and high risk, as well as patients with intermediate-1 risk, since intermediate-1 patients may also have symptoms that require treatment. Clinical experience with Jakafi has shown that with the right process, manufacturers can successfully collaborate with regulatory agencies and academic experts to develop relevant and validated PRO instruments that can be incorporated into clinical trials.1,8 The approval of Jakafi marks a significant milestone in which validated PRO instruments can provide symptom data and demonstrate clinical benefit.

The experience with Jakafi may provide a model for the future use of PROs in marketing applications.8

renal or hepatic impairment [see Dosage and Administration].

Patients should be closely monitored and the dose titrated based on safety and efficacy • There are no adequate and well-controlled studies of Jakafi in pregnant women. Use of Jakafi during pregnancy is not recommended and should only be used if the potential benefit justifies the potential risk to the fetus • Women taking Jakafi should not breast-feed. Discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother References: 1. McCallister E, et al. BioCentury. Reprint from December 5, 2011. 2. Haley S. The Pink Sheet. November 21, 2011;73:47. Symptom Measurement in Clinical Trials.

3. US Department of Health and Human Services Guidance for Industry: Patientreported outcome measures: Use in medical product development to support labeling claims. December 2009. 4. Basch E, et al. Issue brief from Conference on Clinical Cancer Research, November 2011. 5. Cervantes F, et al. Blood. 2009;113:2895-2901.

6. Mesa RA, et al. Leuk Res. 2009;33:1199-1203. 7. Verstovsek S, et al. N Engl J Med. 2012;366:799-807. 8. Deisseroth AB, et al. Clin Cancer Res. 2012 Apr 27. (Epub ahead of print). 9. Jakafi Prescribing Information. Incyte Corporation. November 2011.

10. Data on File, Incyte Corporation.

a As studied in COMFORT-I, a randomized, double-blind, placebo-controlled phase III

study with 309 total patients (United States, Canada, Australia). The primary endpoint was the proportion of subjects achieving a ≥35% reduction in spleen volume from baseline to Week 24 as measured by MRI or computed tomography (CT). A secondary endpoint was the proportion of subjects with a ≥50% reduction in TSS from baseline to Week 24 as measured by the daily patient diary, the modified MFSAF v2.0.9,10 b Symptom scores were captured by a daily patient diary recorded for 25 weeks. TSS encompasses debilitating symptoms of MF: abdominal discomfort, pain under left ribs, early satiety, pruritus, night sweats and bone/muscle pain. Symptom scores ranged from 0 to 10 with 0 representing symptoms “absent” and 10 representing “worst imaginable” symptoms. These scores were added to create the daily total score, which has a maximum of 60. At baseline, mean TSS was 18.0 in the Jakafi group and 16.5 in the placebo group.9,10

Please see Brief Summary of Full Prescribing Information on the following page.

Jakafi is a registered trademark of Incyte Corporation. © 2012, Incyte Corporation. All rights reserved.

RUX-1130 05/12

Table 2: Worst Hematology Laboratory Abnormalities in the Placebo-controlled Studya Jakafi Placebo (N=155) (N=151) Laboratory All All b Parameter Grades Grade 3 Grade 4 Grades Grade 3 Grade 4 BRIEF SUMMARY: For Full Prescribing Information, see package insert. (%) (%) (%) (%) (%) (%) INDICATIONS AND USAGE Jakafi is indicated for treatment of patients with intermediate or high-risk Thrombocytopenia 69.7 9.0 3.9 30.5 1.3 0 myelofibrosis, including primary myelofibrosis, post-polycythemia vera myelofibrosis and post-essential Anemia 96.1 34.2 11.0 86.8 15.9 3.3 thrombocythemia myelofibrosis.

Neutropenia 18.7 5.2 1.9 4.0 0.7 1.3 CONTRAINDICATIONS None.

WARNINGS AND PRECAUTIONS Thrombocytopenia, Anemia and Neutropenia Treatment a Presented values are worst Grade values regardless of baseline b National Cancer Institute Common Terminology Criteria for Adverse Events, version 3.0 with Jakafi can cause hematologic adverse reactions, including thrombocytopenia, anemia and neutropenia.

A complete blood count must be performed before initiating therapy with Jakafi [see Dosage and Additional Data from the Placebo-controlled Study 25.2% of patients treated with Jakafi and 7.3% of Administration (2.1) in Full Prescribing Information]. Patients with platelet counts of less than 200 X 109/L patients treated with placebo developed newly occurring or worsening Grade 1 abnormalities in alanine transat the start of therapy are more likely to develop thrombocytopenia during treatment. Thrombocytopenia was aminase (ALT). The incidence of greater than or equal to Grade 2 elevations was 1.9% for Jakafi with 1.3% Grade 3 and no Grade 4 ALT elevations. 17.4% of patients treated with Jakafi and 6.0% of patients treated generally reversible and was usually managed by reducing the dose or temporarily withholding Jakafi. If with placebo developed newly occurring or worsening Grade 1 abnormalities in aspartate transaminase clinically indicated, platelet transfusions may be administered [see Dosage and Administration (2.2) in Full (AST). The incidence of Grade 2 AST elevations was 0.6% for Jakafi with no Grade 3 or 4 AST elevations.

Prescribing Information, and Adverse Reactions]. Patients developing anemia may require blood trans- 16.8% of patients treated with Jakafi and 0.7% of patients treated with placebo developed newly occurring or fusions. Dose modifications of Jakafi for patients developing anemia may also be considered. Neutropenia worsening Grade 1 elevations in cholesterol. The incidence of Grade 2 cholesterol elevations was 0.6% for (ANC less than 0.5 X 109/L) was generally reversible and was managed by temporarily withholding Jakafi Jakafi with no Grade 3 or 4 cholesterol elevations. [see Adverse Reactions]. Complete blood counts should be monitored as clinically indicated and dosing DRUG INTERACTIONS Drugs That Inhibit or Induce Cytochrome P450 Enzymes Ruxolitinib adjusted as required [see Dosage and Administration (2.2) in Full Prescribing Information, and Adverse is predominantly metabolized by CYP3A4. Strong CYP3A4 inhibitors: The C max and AUC of ruxolitinib Reactions]. Infections Patients should be assessed for the risk of developing serious bacterial, mycobac- increased 33% and 91%, respectively, with Jakafi administration (10 mg single dose) following ketoconazole terial, fungal and viral infections. Active serious infections should have resolved before starting therapy with 200 mg twice daily for four days, compared to receiving Jakafi alone in healthy subjects. The half-life was also Jakafi. Physicians should carefully observe patients receiving Jakafi for signs and symptoms of infection and prolonged from 3.7 to 6.0 hours with concurrent use of ketoconazole. The change in the pharmacodynamic initiate appropriate treatment promptly. Herpes Zoster Physicians should inform patients about early signs marker, pSTAT3 inhibition, was consistent with the corresponding ruxolitinib AUC following concurrent adminand symptoms of herpes zoster and advise patients to seek treatment as early as possible [see Adverse istration with ketoconazole. When administering Jakafi with strong CYP3A4 inhibitors a dose reduction is Reactions]. recommended [see Dosage and Administration (2.4) in Full Prescribing Information]. Patients should be ADVERSE REACTIONS Clinical Trials Experience Because clinical trials are conducted under closely monitored and the dose titrated based on safety and efficacy. Mild or moderate CYP3A4 inhibitors: widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly There was an 8% and 27% increase in the Cmax and AUC of ruxolitinib, respectively, with Jakafi administration compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The (10 mg single dose) following erythromycin, a moderate CYP3A4 inhibitor, at 500 mg twice daily for 4 days, safety of Jakafi was assessed in 617 patients in six clinical studies with a median duration of follow-up of 10.9 compared to receiving Jakafi alone in healthy subjects. The change in the pharmacodynamic marker, pSTAT3 months, including 301 patients with myelofibrosis in two Phase 3 studies. In these two Phase 3 studies, inhibition was consistent with the corresponding exposure information. No dose adjustment is recommended patients had a median duration of exposure to Jakafi of 9.5 months (range 0.5 to 17 months), with 88.7% of when Jakafi is coadministered with mild or moderate CYP3A4 inhibitors (eg, erythromycin). CYP3A4 patients treated for more than 6 months and 24.6% treated for more than 12 months. One hundred and inducers: The Cmax and AUC of ruxolitinib decreased 32% and 61%, respectively, with Jakafi administration eleven (111) patients started treatment at 15 mg twice daily and 190 patients started at 20 mg twice daily. In (50 mg single dose) following rifampin 600 mg once daily for 10 days, compared to receiving Jakafi alone in a double-blind, randomized, placebo-controlled study of Jakafi, 155 patients were treated with Jakafi. The healthy subjects. In addition, the relative exposure to ruxolitinib’s active metabolites increased approximately most frequent adverse drug reactions were thrombocytopenia and anemia [see Table 2]. Thrombocytopenia, 100%. This increase may partially explain the reported disproportionate 10% reduction in the pharmacoanemia and neutropenia are dose related effects. The three most frequent non-hematologic adverse reactions dynamic marker pSTAT3 inhibition. No dose adjustment is recommended when Jakafi is coadministered with were bruising, dizziness and headache [see Table 1]. Discontinuation for adverse events, regardless of a CYP3A4 inducer. Patients should be closely monitored and the dose titrated based on safety and efficacy. causality, was observed in 11.0% of patients treated with Jakafi and 10.6% of patients treated with placebo. USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Category C: There are no adequate Following interruption or discontinuation of Jakafi, symptoms of myelofibrosis generally return to and well-controlled studies of Jakafi in pregnant women. In embryofetal toxicity studies, treatment with pretreatment levels over a period of approximately 1 week. There have been isolated cases of patients discon- ruxolitinib resulted in an increase in late resorptions and reduced fetal weights at maternally toxic doses. tinuing Jakafi during acute intercurrent illnesses after which the patient’s clinical course continued to worsen; Jakafi should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. however, it has not been established whether discontinuation of therapy contributed to the clinical course in Ruxolitinib was administered orally to pregnant rats or rabbits during the period of organogenesis, at doses these patients. When discontinuing therapy for reasons other than thrombocytopenia, gradual tapering of the of 15, 30 or 60 mg/kg/day in rats and 10, 30 or 60 mg/kg/day in rabbits. There was no evidence of teratodose of Jakafi may be considered [see Dosage and Administration (2.6) in Full Prescribing Information]. genicity. However, decreases of approximately 9% in fetal weights were noted in rats at the highest and maternally toxic dose of 60 mg/kg/day. This dose results in an exposure (AUC) that is approximately 2 times Table 1 presents the most common adverse reactions occurring in patients who received Jakafi in the doublethe clinical exposure at the maximum recommended dose of 25 mg twice daily. In rabbits, lower fetal weights blind, placebo-controlled study during randomized treatment. of approximately 8% and increased late resorptions were noted at the highest and maternally toxic dose of Table 1: Adverse Reactions Occurring in Patients on Jakafi in the Double-blind, Placebo-controlled 60 mg/kg/day. This dose is approximately 7% the clinical exposure at the maximum recommended dose. In Study During Randomized Treatment a pre- and post-natal development study in rats, pregnant animals were dosed with ruxolitinib from implanJakafi Placebo tation through lactation at doses up to 30 mg/kg/day. There were no drug-related adverse findings in pups for (N=155) (N=151) fertility indices or for maternal or embryofetal survival, growth and development parameters at the highest Adverse All All dose evaluated (34% the clinical exposure at the maximum recommended dose of 25 mg twice daily).

Reactions Gradesa Grade 3 Grade 4 Grades Grade 3 Grade 4 Nursing Mothers It is not known whether ruxolitinib is excreted in human milk. Ruxolitinib and/or its metabolites were excreted in the milk of lactating rats with a concentration that was 13-fold the maternal (%) (%) (%) (%) (%) (%) plasma. Because many drugs are excreted in human milk and because of the potential for serious adverse Bruisingb 23.2 0.6 0 14.6 0 0 reactions in nursing infants from Jakafi, a decision should be made to discontinue nursing or to discontinue Dizzinessc 18.1 0.6 0 7.3 0 0 the drug, taking into account the importance of the drug to the mother. Pediatric Use The safety and effecHeadache 14.8 0 0 5.3 0 0 tiveness of Jakafi in pediatric patients have not been established. Geriatric Use Of the total number of Urinary Tract Infectionsd 9.0 0 0 5.3 0.7 0.7 myelofibrosis patients in clinical studies with Jakafi, 51.9% were 65 years of age and older. No overall differWeight Gaine 7.1 0.6 0 1.3 0.7 0 ences in safety or effectiveness of Jakafi were observed between these patients and younger patients. Renal Impairment The safety and pharmacokinetics of single dose Jakafi (25 mg) were evaluated in a study in Flatulence 5.2 0 0 0.7 0 0 healthy subjects [CrCl 72-164 mL/min (N=8)] and in subjects with mild [CrCl 53-83 mL/min (N=8)], Herpes Zosterf 1.9 0 0 0.7 0 0 moderate [CrCl 38-57 mL/min (N=8)], or severe renal impairment [CrCl 15-51 mL/min (N=8)]. Eight (8) a National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE), version 3.0 b includes contusion, ecchymosis, hematoma, injection site hematoma, periorbital hematoma, vessel puncture site additional subjects with end stage renal disease requiring hemodialysis were also enrolled. The pharmacokinetics of ruxolitinib was similar in subjects with various degrees of renal impairment and in those with hematoma, increased tendency to bruise, petechiae, purpura c includes dizziness, postural dizziness, vertigo, balance disorder, Meniere’s Disease, labyrinthitis normal renal function. However, plasma AUC values of ruxolitinib metabolites increased with increasing d includes urinary tract infection, cystitis, urosepsis, urinary tract infection bacterial, kidney infection, pyuria, bacteria severity of renal impairment. This was most marked in the subjects with end stage renal disease requiring urine, bacteria urine identified, nitrite urine present hemodialysis. The change in the pharmacodynamic marker, pSTAT3 inhibition, was consistent with the e includes weight increased, abnormal weight gain corresponding increase in metabolite exposure. Ruxolitinib is not removed by dialysis; however, the removal f includes herpes zoster and post-herpetic neuralgia of some active metabolites by dialysis cannot be ruled out. When administering Jakafi to patients with Description of Selected Adverse Drug Reactions Anemia In the two Phase 3 clinical studies, median moderate (CrCl 30-59 mL/min) or severe renal impairment (CrCl 15-29 mL/min) with a platelet count time to onset of first CTCAE Grade 2 or higher anemia was approximately 6 weeks. One patient (0.3%) between 100 X 109/L and 150 X 109/L and patients with end stage renal disease on dialysis a dose reduction discontinued treatment because of anemia. In patients receiving Jakafi, mean decreases in hemoglobin is recommended [see Dosage and Administration (2.5) in Full Prescribing Information]. Hepatic reached a nadir of approximately 1.5 to 2.0 g/dL below baseline after 8 to 12 weeks of therapy and then Impairment The safety and pharmacokinetics of single dose Jakafi (25 mg) were evaluated in a study in gradually recovered to reach a new steady state that was approximately 1.0 g/dL below baseline. This pattern healthy subjects (N=8) and in subjects with mild [Child-Pugh A (N=8)], moderate [Child-Pugh B (N=8)], or was observed in patients regardless of whether they had received transfusions during therapy. In the severe hepatic impairment [Child-Pugh C (N=8)]. The mean AUC for ruxolitinib was increased by 87%, 28% randomized, placebo-controlled study, 60% of patients treated with Jakafi and 38% of patients receiving and 65%, respectively, in patients with mild, moderate and severe hepatic impairment compared to patients placebo received red blood cell transfusions during randomized treatment. Among transfused patients, the with normal hepatic function. The terminal elimination half-life was prolonged in patients with hepatic median number of units transfused per month was 1.2 in patients treated with Jakafi and 1.7 in placebo impairment compared to healthy controls (4.1-5.0 hours versus 2.8 hours). The change in the pharmacotreated patients. Thrombocytopenia In the two Phase 3 clinical studies, in patients who developed Grade 3 dynamic marker, pSTAT3 inhibition, was consistent with the corresponding increase in ruxolitinib exposure or 4 thrombocytopenia, the median time to onset was approximately 8 weeks. Thrombocytopenia was except in the severe (Child-Pugh C) hepatic impairment cohort where the pharmacodynamic activity was generally reversible with dose reduction or dose interruption. The median time to recovery of platelet counts more prolonged in some subjects than expected based on plasma concentrations of ruxolitinib. When above 50 X 109/L was 14 days. Platelet transfusions were administered to 4.7% of patients receiving Jakafi administering Jakafi to patients with any degree of hepatic impairment and with a platelet count between and to 4.0% of patients receiving control regimens. Discontinuation of treatment because of thrombo- 100 X 109/L and 150 X 109/L, a dose reduction is recommended [see Dosage and Administration (2.5) in cytopenia occurred in 0.7% of patients receiving Jakafi and 0.9% of patients receiving control regimens. Full Prescribing Information].

Patients with a platelet count of 100 X 109/L to 200 X 109/L before starting Jakafi had a higher frequency of Grade 3 or 4 thrombocytopenia compared to patients with a platelet count greater than 200 X 109/L (16.5% Jakafi is a trademark of Incyte Corporation. All rights reserved. versus 7.2%). Neutropenia In the two Phase 3 clinical studies, 1.0% of patients reduced or stopped Jakafi U.S. Patent No. 7,598,257 because of neutropenia. Table 2 provides the frequency and severity of clinical hematology abnormalities © 2011 Incyte Corporation. All rights reserved. reported for patients receiving treatment with Jakafi or placebo in the placebo-controlled study.

Issued: November 2011 RUX-1040

Tradjenta (linagliptin) Tablets: A 速

Single-Dose Treatment Option for Adults with Type 2 Diabetes

T

he various classes of oral antihyperglycemic agents differ in terms of their mechanisms of action. Among the traditional agents, metformin and the thiazolidinediones enhance insulin sensitivity, the sulfonylureas and glinides enhance insulin secretion, and the alpha-glucosidase inhibitors inhibit intestinal carbohydrate absorption.1 Dipeptidyl peptidase (DPP)-4 inhibitors, a relatively recent addition to the armamentarium of oral antihyperglycemic drugs, act by potentiating the activity of the incretins glucagon-like peptide (GLP)-1 and glucose-dependent insulinotropic polypeptide (GIP) and enhancing glucose-dependent insulin secretion.1 Tradjenta速 (linagliptin) tablets, a DPP-4 inhibitor indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes, was approved by the US Food and Drug Administration in May 2011.2,3 TRADJENTA has not been studied in combination with insulin and should not be used in patients with type 1 diabetes or for the treatment of diabetic ketoacidosis.3 TRADJENTA is available in a single 5-mg dose.3 Because linagliptin is primarily excreted via the bile and gut, no dose adjustment is recommended in patients with renal insufficiency.3 Likewise, the administration of linagliptin in patients with hepatic impairment did not result in reductions in DPP-4 inhibition; therefore, dose adjustment is not necessary in this patient population.3 Linagliptin is not a clinically relevant substrate or inhibitor of cytochrome P450 or P-glycoprotein. As a result, TRADJENTA can be coadministered with other drugs frequently prescribed to patients with type 2 diabetes, such as metformin, glyburide, simvastatin, warfarin, and digoxin.3,4 When TRADJENTA is used in combination with an insulin secretagogue such as a sulfonylurea, a lower dose of the insulin secretagogue may be required to reduce the risk of hypoglycemia.3

Clinical Pharmacology Linagliptin binds selectively to DPP-4, thereby increasing the concentrations of the active incretin hor-

mones GLP-1 and glucose-dependent insulinotropic peptide (GIP).5,6 These hormones are secreted at low basal levels in the fasting state, with circulating levels increasing rapidly after food ingestion.5 In the postprandial state, GLP-1 and GIP act on pancreatic beta-cells to stimulate glucose-dependent insulin secretion. GLP-1, but not GIP, inhibits gastric emptying, glucagon secretion, and food intake.3,7 Through these physiologic mechanisms, linagliptin increases insulin secretion and lowers glucagon secretion in a glucosedependent manner, resulting in improved regulation of glucose homeostasis in patients with type 2 diabetes.3 The pharmacokinetics of linagliptin is similar in healthy persons and in patients with type 2 diabetes.3 After oral administration of a single 5-mg dose to healthy persons, peak plasma concentrations of linagliptin are reached at approximately 1.5 hours postdose.3 Plasma concentrations of linagliptin decline in at least a biphasic manner with a terminal half-life of more than 100 hours; however, the prolonged elimination phase does not contribute to the accumulation of the drug.3 The effective half-life for accumulation of linagliptin is approximately 12 hours. After once-daily dosing, steady-state plasma concentrations of linagliptin 5 mg are reached by the third dose.3 The mean apparent volume of distribution at steady state (1110 L) indicates that linagliptin extensively distributes to the tissues.3 Plasma protein binding of linagliptin is concentration-dependent, reflecting saturation of binding to DPP-4 with increasing concentration of linagliptin. When DPP-4 is fully saturated, 70% to 80% of linagliptin remains bound to plasma proteins and 20% to 30% is unbound in plasma. Plasma binding is not altered in patients with renal or hepatic impairment.3 The absolute bioavailability of linagliptin is approximately 30%, and TRADJENTA may be administered with or without food.3

Clinical Studies TRADJENTA has been studied as monotherapy, as add-on combination with metformin, as add-on combination with metformin and sulfonylureas, and in initial

Please see Indication, Limitations of Use, and Important Safety Information on page 42, and see full Prescribing Information, including Patient Information, begining on page 43.

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Figure Prespecified Subgroup Analysis: A1C Percent Reductions with Tradjenta® (linagliptin) tablets at Week 24a 0.8 Comparator: Results for patients receiving placebo alone or in combination with other antihyperglycemic agents as applicable per respective study designs

0.6

TRADJENTA: Results for patients receiving TRADJENTA as monotherapy or in combination with other antihyperglycemic agents as applicable per respective study designs

A1C reduction at 24 weeks, %

0.4

0.2 8.2b

+0.02

8.2b

8.2b

8.2b

–0.02

8.1b

8.1b

–0.1

–0.2

–0.4 –0.5

–0.6

–0.7 –0.8

P <0.0001 (N = 194) (N = 442) Age ≤50 yrs

P <0.0001 (N = 363) (N = 970) Age 51 to 64 yrs

–0.7

(N = 171) (N = 464) Age 65 to ≥75 yrsc

a Model includes baseline A1C, washout, treatment, study, body mass index, subgroup, and treatment-by-subgroup interaction; full analysis set (intention-to-treat), last observation carried forward. b Mean baseline A1C. c Data for patients aged ≥65 years were calculated as weighted means based on data for patients aged 65 to 74 years and patients aged ≥75 years. TRADJENTA demonstrated a statistically significant difference in reduction from baseline A1C in patients aged 65 to 74 years (adjusted mean change, –0.6%; P <0.0001 [placebo: –0.1% from mean baseline of 8.1%, N = 152; TRADJENTA: –0.7% from mean baseline of 8.1%, N = 398]) and in patients aged ≥75 years (adjusted mean change, –0.8%; P = 0.0002 [placebo: +0.0% from mean baseline of 8.1%, N = 19; TRADJENTA: –0.8% from mean baseline of 8.0%, N = 66]).

Source: Reference 11.

therapy with pioglitazone. Approximately 3800 patients with type 2 diabetes were enrolled in 8 randomized, placebo-controlled, safety and efficacy studies that evaluated the effects of linagliptin on glycemic control.3 In clinical studies, patients receiving Tradjenta® (linagliptin) tablets achieved clinically meaningful A1C reductions with oral monotherapy, dual therapy, and triple therapy at 24 weeks.4,8-10 With TRADJENTA, patients across a broad range of ages achieved statistically significant A1C reductions.11 In a prespecified subgroup analysis using pooled data from 4 pivotal phase 3 studies, A1C reduction for adult patients with type 2 diabetes was evaluated in 4 different age groups. Results showed significant A1C reductions

in each age group at 24 weeks. The placebo-adjusted mean change in A1C from baseline was –0.6% for patients aged ≤50 years (P <0.0001), –0.6% for patients aged 51 to 64 years (P <0.0001), –0.6% for patients aged 65 to 74 years (P <0.0001), and –0.8% for patients aged ≥75 years (P = 0.0002).11 The 2 older age groups were combined in the Figure for ease of readability. Clinical experience with TRADJENTA has not identified differences in response between the elderly and younger patients; however, greater sensitivity of some older individuals cannot be ruled out.

Monotherapy with TRADJENTA In a randomized, multicenter, double-blind, placebo-

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controlled study, treatment-naïve and treatment-experienced adult patients with type 2 diabetes were randomized to Tradjenta® (linagliptin) tablets 5 mg daily or to placebo for 24 weeks.3,8 The primary endpoint was the change in A1C levels at 24 weeks, and the secondary endpoints included the changes in fasting plasma glucose (FPG) and 2-hour postprandial glucose (PPG) levels.8 Treatment with TRADJENTA provided statistically significant improvements in A1C levels, FPG, and 2-hour PPG compared with placebo. At study week 24, the adjusted mean change in A1C from baseline was –0.4% among patients given TRADJENTA and 0.3% among those receiving placebo, representing a placebo-adjusted improvement in mean A1C of –0.7% (P <0.0001) (Table 1).3,8 Patients also achieved significant reductions in PPG and FPG. After 24 weeks, treatment with TRADJENTA resulted in a placebo-adjusted mean change in 2-hour PPG of –58.4 mg/dL (P <0.0001) and a placebo-adjusted mean change in FPG of –23.3 mg/dL (P <0.0001).3,8 In this study, 20.9% of patients in the placebo group required use of rescue therapy versus 10.2% of patients in the TRADJENTA group.3

Combination Therapy with TRADJENTA TRADJENTA has demonstrated clinically meaningful A1C reductions as an add-on therapy to metformin and as an add-on therapy to metformin and a sulfonylurea, and in initial combination therapy with pioglitazone, respectively.4,9,10 Add-on Combination Therapy with Metformin In a randomized, double-blind, placebo-controlled, parallel-group study of TRADJENTA in adult patients with type 2 diabetes and insufficient glycemic control despite metformin therapy, patients were randomized to TRADJENTA 5 mg daily or to placebo in combination with metformin ≥1500 mg daily for 24 weeks.3,9 The primary endpoint was the change from baseline in A1C at 24 weeks, and the secondary endpoints included changes from baseline in FPG and 2-hour PPG.9 In this study, treatment with TRADJENTA provided a significant placebo-adjusted improvement in mean A1C of –0.6% after 24 weeks (P <0.0001).3,9 With regard to secondary endpoints, after 24 weeks of treatment, patients receiving TRADJENTA showed a placebo-adjusted mean change in 2-hour PPG of –67.1 mg/dL from baseline (P <0.0001) and a placebo-adjusted mean change in FPG of –21.1 mg/dL from baseline (P <0.0001).3,9 In the study, 18.9% of patients in the placebo group required use of rescue therapy versus 7.8% of patients in the TRADJENTA group.3

Add-on Combination Therapy with Metformin and a Sulfonylurea In a randomized, double-blind, placebo-controlled, parallel-group study, triple therapy with TRADJENTA was compared with triple therapy with placebo in adult patients with type 2 diabetes and insufficient glycemic control despite treatment with metformin in combination with a sulfonylurea.3,10 Patients were randomized to TRADJENTA 5 mg daily or placebo as an add-on to existing metformin plus sulfonylurea therapy.3,10 The primary endpoint was change from baseline A1C at 24 weeks.10 When added to metformin and a sulfonylurea, treatment with TRADJENTA provided a significant, placebo-adjusted mean A1C improvement of –0.6% at 24 weeks (P <0.0001).3,10 A total of 13% of patients in the placebo group required use of rescue therapy versus 5.4% of patients in the TRADJENTA group.3 Add-on Combination Therapy with Pioglitazone In a third study evaluating the safety and efficacy of TRADJENTA as initial combination therapy in type 2 diabetes, patients were randomized to receive either TRADJENTA 5 mg or placebo, both in addition to pioglitazone 30 mg once daily for 24 weeks.3,4 The primary endpoint was the change from baseline in A1C at 24 weeks, and secondary endpoints included the change in baseline FPG.4 At study week 24, treatment with TRADJENTA plus pioglitazone showed a statistically significant placebo-adjusted improvement (P <0.0001) in mean A1C of –0.5% compared with placebo plus pioglitazone.3,4 TRADJENTA also provided a statistically significant improvement in FPG levels, providing a statistically significant placebo-adjusted improvement (P <0.0001) in mean FPG of –14.2 mg/dL at week 24 following treatment with TRADJENTA plus pioglitazone.3,4 Rescue therapy was used in 7.9% of patients who received TRADJENTA 5 mg/pioglitazone 30 mg and 14.1% of patients who received placebo/pioglitazone 30 mg.3 Active-Control Study versus Glimepiride in Combination with Metformin The goal of a 104-week, double-blind, glimepiridecontrolled noninferiority study was to evaluate the comparative efficacy and safety of TRADJENTA versus glimepiride.3 Adult patients with type 2 diabetes and insufficient glycemic control despite metformin therapy were randomized to add-on therapy with TRADJENTA 5 mg daily or to glimepiride. Patients receiving glimepiride were given an initial dose of 1 mg daily that was titrated to a maximum dose of 4 mg daily, as needed.3 The

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Summary of Selected Phase 3 Clinical Trials Evaluating Tradjenta® (linagliptin) tablets for the Treatment Table 1 of Type 2 Diabetes in Adult Patientsa TRADJENTA Monotherapy3,8 Study design

Study population

Full analysis set

Phase 3, randomized, multicenter, double-blind, placebo-controlled, parallel group

Adults aged 18-80 yrs with type 2 diabetes and insufficient glycemic control

Placebo (N = 163) TRADJENTA (N = 333)

Key endpoints Primary: Change in A1C at 24 weeks Secondary: Change in FPG Change in 2-hr PPG

Analysis

Key efficacy results

Prespecified primary analysis • Significant improveof study endpoints ment in A1C levels (P <0.0001)b Primary endpoint: Full analysis • Significant improveset (ITT), last observation ment in FPG carried forward (P <0.0001) Secondary endpoints: Full analysis • Significant improveset (ITT), last observation ment in 2-hr PPG carried forward (P <0.0001)

TRADJENTA Combination Therapy Add-on to metformin3,9 Study design

Study population

Full analysis set

Phase 3, randomized, multicenter, double-blind, placebo-controlled, parallel group

Adults aged 18-80 yrs with type 2 diabetes with insufficient glycemic control despite metformin therapy

Placebo (N = 175) TRADJENTA (N = 513)

Key endpoints Primary: Change in A1C at 24 weeks Secondary: Change in FPG Change in 2-hr PPG

Analysis

Key efficacy results

Prespecified primary analysis • Significant improveof study endpoints ment in A1C levels (P <0.0001)b Primary endpoint: Full analysis • Significant improveset (ITT), last observation ment in FPG carried forward (P <0.0001) Secondary endpoint: Full analysis • Significant improveset (ITT), last observation ment in 2-hr PPG carried forward (P <0.0001)

Add-on to metformin and sulfonylureaa,3,10 Study design

Study population

Full analysis set

Phase 3, randomized, multicenter, double-blind, placebo-controlled, parallel group

Adults aged 18-80 yrs with type 2 diabetes and insufficient glycemic control despite metformin therapy in combination with a sulfonylurea

Placebo (N = 262) TRADJENTA (N = 778)

Key endpoints Primary: Change in A1C at 24 weeks

Analysis

Key efficacy results

Prespecified primary analysis • Significant improveof study endpoints ment in A1C levels (P <0.0001)b Primary endpoint: Full analysis • Significant improveset (ITT), last observation ment in FPG carried forward (P <0.0001) Secondary endpoint: Full analysis set (ITT), last observation carried forward

Initial combination with pioglitazone3,4 Study design

Study population

Full analysis set

Phase 3, randomized, multicenter, double-blind, placebo-controlled, parallel group

Adults aged 18-80 yrs with type 2 diabetes with insufficient glycemic control

Placebo (N = 128) TRADJENTA (N = 252)

Key endpoints Primary: Change in A1C at 24 weeks Secondary: Change in FPG

Analysis

Key efficacy results

Prespecified primary analysis of study endpoints Primary endpoint: Full analysis set (ITT), last observation carried forward Secondary endpoint: Full analysis set (ITT), last observation carried forward

• Significant improvement in A1C levels (P <0.0001)b • Significant improvement in FPG (P <0.0001)

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Table 1 (Continued ) Tradjenta® (linagliptin) tablets Combination Therapy Active-control study vs glimepiride in combination with metformin (52-week interim analysis)3,11 Study design

Study population

Full analysis set

Key endpoints

Analysis

Key efficacy results

Phase 3, randomized, double-blind, active-control, parallel group

Adults aged 18-80 yrs with type 2 diabetes and insufficient glycemic control, despite metformin therapy

Glimepiride (N = 761) TRADJENTA (N = 766)

Primary: Change in A1C at 52 weeks Secondary: Change in body weight from baseline to week 52 Occurrence of hypoglycemic events up to 52 weeks

Primary endpoint: Analysis of covariance (ANCOVA) with baseline A1C as covariate Secondary endpoints: Confirmatory testing of treatment superiority with linagliptin vs glimepiride

• Noninferiority of TRADJENTA to glimepiride in A1C levels (P = 0.0007, 1-sided for noninferiority) • Significant lower incidence of hypoglycemia with TRADJENTA vs glimepiride (P < 0.0001) • Significant mean decrease in baseline body weight with TRADJENTA vs glimepiride (P < 0.0001)

a

Model includes continuous baseline A1C and treatment.

Defined as all randomized patients treated with at least 1 dose of study drug who had a baseline A1C value and at least 1 on-treatment A1C value. The full analysis set is the basis for the ITT analysis.

FPG indicates fasting plasma glucose; ITT, intention to treat; PPG, postprandial glucose.

b

average daily dose of glimepiride was 3 mg.

The primary endpoint in this interim analysis was the change from baseline in A1C after 52 weeks of treatment.11 Patients in the intent-to-treat population (last observation carried forward) who received Tradjenta® (linagliptin) tablets achieved an adjusted mean A1C reduction of 0.4% (N = 766) from baseline at 52 weeks versus a 0.6% reduction with glimepiride (N = 761), showing noninferiority of TRADJENTA to glimepiride (P = 0.0007, 1-sided for noninferiority).3,11 Furthermore, statistically similar proportions of patients receiving TRADJENTA (39.6%) or glimepiride (44.7%) achieved the A1C goal of <7.0%.11 Although the 2 drugs demonstrated similar efficacy, the incidence of hypoglycemia was nearly 6 times greater for patients treated with glimepiride (31.8%) versus TRADJENTA (5.4%).3 Patients treated with TRADJENTA showed a significant mean decrease from baseline body weight compared with a significant weight gain in patients receiving glimepiride (–1.1 kg vs +1.4 kg, respectively; P <0.0001).3

Safety The safety of linagliptin has been evaluated in more than 4000 patients with type 2 diabetes in clinical trials.3 In placebo-controlled clinical studies, adverse reactions reported in ≥5% of patients treated with TRADJENTA and more frequently than in patients treated with placebo included nasopharyngitis.3 In placebo‐controlled studies, 195 (7.6%) of the 2566 patients who received TRADJENTA 5 mg reported hypoglycemia compared with 49 (4.1%) of the 1183 patients who received placebo. The incidence of hypoglycemia was similar to that with placebo when TRADJENTA was administered as monotherapy or in combination with metformin or pioglitazone.3 Hypoglycemia was more frequently reported in patients who received the combination of TRADJENTA and sulfonylurea compared with those who received the combination of placebo and sulfonylurea.3 When TRADJENTA was administered in combination with metformin and a sulfonylurea, 181 of 791 (22.9%) patients reported hypoglycemia compared with 39 of 263 (14.8%) patients receiving placebo in

Please see Indication, Limitations of Use, and Important Safety Information on page 42, and see full Prescribing Information, including Patient Information, begining on page 43.

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Treated with Tradjenta® (linagliptin) tablets and ≥2-Fold More Table 2 Adverse Reactions Reported in ≥2% of Patients than with Placebo in Placebo-Controlleda Clinical Studies of TRADJENTA Monotherapy or Combination Therapy Combination with metforminc N (%)

Monotherapyb N (%) Adverse reaction

Combination with metformin and SU N (%)

Combination with pioglitazone N (%)

TRADJENTA (N = 765)

Placebo (N = 458)

TRADJENTA (N = 590)

Placebo (N = 248)

TRADJENTA (N = 791)

Placebo (N = 263)

TRADJENTA (N = 259)

Placebo (N = 130)

Nasopharyngitis

–

–

–

–

–

–

–

–

Hyperlipidemia

–

–

–

–

–

–

7 (2.7)

1 (0.8)

Cough

–

–

–

–

19 (2.4)

3 (1.1)

–

–

Hypertriglyceridemiad

–

–

–

–

–

–

–

–

Weight increased

–

–

–

–

–

–

6 (2.3)

1 (0.8)

a In the active-control, noninfertioty, 104-week study of TRADJENTA versus glimepiride, the most frequently reported adverse events in both groups were infections and infestations (39.1% vs 41.1%, respectively); musculoskeletal and connective tissue disorders (25.2% vs 22.3%, respectively); and gastrointestinal disorders (21.6% vs 22.7%, respectively).11 a Pooled data from 7 studies. b Pooled data from 2 studies. c Includes reports of hypertriglyceridemia (N = 2; 1.2%) and blood triglycerides increased (N = 2; 1.2%).

SU indicates sulfonylurea.

Source: Reference 3.

combination with metformin and a sulfonylurea.3 In the clinical trial program, the incidence of pancreatitis was 1 case per 538 person-years with TRADJENTA versus 0 in 433 person-years with a comparator. Three additional cases of pancreatitis were reported after the last administered dose of TRADJENTA.3 Adverse reactions reported in ≥2% of patients who received Tradjenta® (linagliptin) tablets and at least 2 times greater than with placebo are shown in Table 2.

The safety and effectiveness of TRADJENTA in patients aged <18 years have not been established.3

Conclusion TRADJENTA 5 mg is the only single-dosage DPP-4 inhibitor available for adult patients with type 2 diabetes.3,12,13 When administered as monotherapy, dual therapy, or triple therapy in adults with inadequate glycemic control, TRADJENTA produced statistically significant A1C percent reductions at 24 weeks.4,8-10 Furthermore, a prespecified subgroup analysis demonstrated significant A1C percent reductions across a broad range of age groups.11 TRADJENTA also showed significant reduc-

tions in FPG and 2-hour PPG when administered as monotherapy or as add-on combination therapy with metformin.3,8,9 Compared with glimepiride in combination with metformin, TRADJENTA and glimepiride demonstrated similar A1C reductions from baseline after 52 weeks; however, patients experienced a lower incidence of hypoglycemia and significant mean decrease from baseline body weight with TRADJENTA compared with glimepiride.3 TRADJENTA has a demonstrated safety and tolerability profile based on safety data from more than 4000 patients.3 It is primarily excreted via the bile and gut.3,12,13 No dose adjustment is recommended for patients with renal impairment or with hepatic impairment.3,12,13 ■

References

1. Levetan C. Oral antidiabetic agents in type 2 diabetes. Curr Med Res Opin. 2007; 23:945-952.

2. US Food and Drug Administration. FDA approves new treatment for type 2 diabetes. FDA news release. May 2, 2011. www.fda.gov/NewsEvents/Newsroom/Press Announcements/ucm253501.htm. Accessed May 9, 2011.

3. Tradjenta® (linagliptin) tablets prescribing information. Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals; 2011.

4. Gomis R, Espadero R-M, Jones R, et al. Efficacy and safety of initial combination therapy with linagliptin and pioglitazone in patients with inadequately controlled

Please see Indication, Limitations of Use, and Important Safety Information on page 42, and see full Prescribing Information, including Patient Information, begining on page 43.

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AMERICAN HEALTH & DRUG BENEFITS

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TradjentaÂŽ (linagliptin) Tablets

type 2 diabetes: a randomized, double-blind, placebo controlled study. Diabetes Obes Metab. 2011;13:653-661.

5. Drucker DJ, Sherman SI, Gorelick FS, et al. Incretin-based therapies for the treatment of type 2 diabetes mellitus: evaluation of the risks and benefits. Diabetes Care.

2010;33:428-433.

6. Nauck MA, Vilsbøll T, Gallwitz B, et al. Incretin-based therapies: viewpoints on the way to consensus. Diabetes Care. 2009;32(suppl 2):S223-S231.

7. Drucker DJ. Enhancing incretin action for the treatment of type 2 diabetes.

Diabetes Care. 2003;26:2929-2940.

8. Del Prato S, Barnett HA, Huisman H, et al. Effect of linagliptin monotherapy on glycaemic control and markers of beta-cell function in patients with inadequately controlled type 2 diabetes: a randomised controlled trial. Diabetes Obes Metab. 2011;

13:258-267.

9. Taskinen M-R, Rosenstock J, Tamminen I, et al. Safety and efficacy of linagliptin as add-on therapy to metformin in patients with type 2 diabetes: a randomized, double-blind, placebo-controlled study. Diabetes Obes Metab. 2011;13:65-74.

10. Owens DR, Swallow R, Dugi KA, Woerle HJ. Efficacy and safety of linagliptin in persons with type 2 diabetes inadequately controlled by a combination of metformin and sulphonylurea: a 24-week randomised study. Diabet Med. 2011;28:1352-1361.

11. Data on file. Boehringer Ingelheim International GmbH; 2011.

12. Januvia (sitagliptin) prescribing information. Whitehouse Station, NJ: Merck & Co.; 2011.

13. Onglyza (saxagliptin) prescribing information. Princeton, NJ: Bristol-Myers Squibb Company; 2011.

Please see Indication, Limitations of Use, and Important Safety Information on page 42, and see full Prescribing Information, including Patient Information, begining on page 43.

June 2012

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41

Indication and Important Limitations of Use TRADJENTA is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.

TRADJENTA should not be used in patients with type 1 diabetes or for the treatment of diabetic ketoacidosis.

TRADJENTA has not been studied in combination with insulin.

Important Safety Information CONTRAINDICATIONS TRADJENTA is contraindicated in patients with a history of hypersensitivity reaction to linagliptin, such as urticaria, angioedema or bronchial hyperreactivity.

WARNINGS AND PRECAUTIONS Use with Medications Known to Cause Hypoglycemia Insulin secretagogues are known to cause hypoglycemia. The use of TRADJENTA in combination with an insulin secretagogue (e.g., sulfonylurea) was associated with a higher rate of hypoglycemia compared with placebo in a clinical trial. Therefore, a lower dose of the insulin secretagogue may be required to reduce the risk of hypoglycemia when used in combination with TRADJENTA. Macrovascular Outcomes There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with TRADJENTA or any other antidiabetic drug.

ADVERSE REACTIONS Adverse reactions reported in â&#x2030;Ľ5% of patients treated with TRADJENTA and more commonly than in patients treated with placebo included nasopharyngitis.

Hypoglycemia was more commonly reported in patients treated with the combination of TRADJENTA and sulfonylurea compared with those treated with the combination of placebo and sulfonylurea. When linagliptin was administered in combination with metformin and a sulfonylurea, 181 of 791 (22.9%) patients reported hypoglycemia compared with 39 of 263 (14.8%) patients administered placebo in combination with metformin and a sulfonylurea.

In the clinical trial program, pancreatitis was reported in 8 of 4687 patients (4311 patient-years of exposure [1 per 538 personyears]) while being treated with TRADJENTA compared with 0 of 1183 patients (433 patient-years of exposure) treated with placebo. Three additional cases of pancreatitis were reported following the last administered dose of linagliptin.

DRUG INTERACTIONS The efficacy of TRADJENTA may be reduced when administered in combination with a strong P-glycoprotein or CYP3A4 inducer (e.g., rifampin). Therefore, use of alternative treatments to TRADJENTA is strongly recommended.

USE IN SPECIFIC POPULATIONS There are no adequate and well-controlled studies in pregnant women. Therefore, TRADJENTA should be used during pregnancy only if clearly needed.

It is not known whether linagliptin is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when TRADJENTA is administered to a nursing woman.

The safety and effectiveness of TRADJENTA in patients below the age of 18 have not been established.

TJ PROF ISI FEB162012

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ADVERSE REACTIONS s !DVERSE REACTIONS REPORTED IN Â&#x2022; OF PATIENTS TREATED WITH 42!$*%.4! AND MORE COMMONLY THAN IN PATIENTS TREATED WITH PLACEBO INCLUDED NASOPHARYNGITIS s (YPOGLYCEMIA WAS MORE COMMONLY REPORTED IN PATIENTS TREATED WITH THE COMBINATION OF 42!$*%.4! (linagliptin) tablets AND SULFONYLUREA COMPARED WITH THOSE TREATED WITH THE COMBINATION OF PLACEBO AND SULFONYLUREA s 0ANCREATITIS WAS REPORTED MORE OFTEN IN PATIENTS RANDOMIZED TO LINAGLIPTIN PER PERSON YEARS Initial U.S. Approval: 2011 VERSUS ZERO IN PERSON YEARS FOR COMPARATOR INDICATIONS AND USAGE To report SUSPECTED ADVERSE REACTIONS, contact Boehringer Ingelheim Pharmaceuticals, Inc. 42!$*%.4! IS A DIPEPTIDYL PEPTIDASE $00 INHIBITOR INDICATED AS AN ADJUNCT TO DIET AND EXERCISE TO at 1-800-542-6257 or 1-800-459-9906 TTY, or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

IMPROVE GLYCEMIC CONTROL IN ADULTS WITH TYPE DIABETES MELLITUS DRUG INTERACTIONS )MPORTANT LIMITATIONS OF USE s 3HOULD NOT BE USED IN PATIENTS WITH TYPE DIABETES OR FOR THE TREATMENT OF DIABETIC KETOACIDOSIS 0 GLYCOPROTEIN #90 ! INDUCER 4HE EFlCACY OF 42!$*%.4! MAY BE REDUCED WHEN ADMINISTERED IN COMBINATION E G WITH RIFAMPIN 5SE OF ALTERNATIVE TREATMENTS IS STRONGLY RECOMMENDED s (AS NOT BEEN STUDIED IN COMBINATION WITH INSULIN USE IN SPECIFIC POPULATIONS DOSAGE AND ADMINISTRATION s 0REGNANCY 4HERE ARE NO ADEQUATE AND WELL CONTROLLED STUDIES IN PREGNANT WOMEN 42!$*%.4! s 4HE RECOMMENDED DOSE OF 42!$*%.4! IS MG ONCE DAILY TABLETS SHOULD BE USED DURING PREGNANCY ONLY IF CLEARLY NEEDED 42!$*%.4! CAN BE TAKEN WITH OR WITHOUT FOOD s .URSING MOTHERS #AUTION SHOULD BE EXERCISED WHEN 42!$*%.4! IS ADMINISTERED TO A NURSING DOSAGE FORMS AND STRENGTHS WOMAN 4ABLETS MG s 0EDIATRIC PATIENTS 3AFETY AND EFFECTIVENESS OF 42!$*%.4! IN PATIENTS BELOW THE AGE OF HAVE NOT BEEN ESTABLISHED CONTRAINDICATIONS s 2ENAL OR HEPATIC IMPAIRMENT .O DOSE ADJUSTMENT RECOMMENDED

(ISTORY OF HYPERSENSITIVITY REACTION TO LINAGLIPTIN SUCH AS URTICARIA ANGIOEDEMA OR BRONCHIAL HYPERREACTIVITY See 17 for PATIENT COUNSELING INFORMATION and FDA-approved patient labeling.

HIGHLIGHTS OF PRESCRIBING INFORMATION

These highlights do not include all the information needed to use TRADJENTA safely and effectively. See full prescribing information for TRADJENTA.

Tradjentaâ&#x201E;¢

WARNINGS AND PRECAUTIONS s 7HEN USED WITH AN INSULIN SECRETAGOGUE E G SULFONYLUREA CONSIDER LOWERING THE DOSE OF THE INSULIN SECRETAGOGUE TO REDUCE THE RISK OF HYPOGLYCEMIA s 4HERE HAVE BEEN NO CLINICAL STUDIES ESTABLISHING CONCLUSIVE EVIDENCE OF MACROVASCULAR RISK REDUCTION WITH 42!$*%.4! OR ANY OTHER ANTIDIABETIC DRUG

Revised: 7/2011

10

'ERIATRIC 5SE 2ENAL )MPAIRMENT (EPATIC )MPAIRMENT OVERDOSAGE

11

DESCRIPTION

12

CLINICAL PHARMACOLOGY -ECHANISM OF !CTION 0HARMACODYNAMICS 0HARMACOKINETICS NONCLINICAL TOXICOLOGY #ARCINOGENESIS -UTAGENESIS )MPAIRMENT OF &ERTILITY CLINICAL STUDIES -ONOTHERAPY #OMBINATION 4HERAPY HOW SUPPLIED/STORAGE AND HANDLING

FULL PRESCRIBING INFORMATION: CONTENTS* 1

2

3

INDICATIONS AND USAGE -ONOTHERAPY AND #OMBINATION 4HERAPY )MPORTANT ,IMITATIONS OF 5SE DOSAGE AND ADMINISTRATION 2ECOMMENDED $OSING #ONCOMITANT 5SE WITH AN )NSULIN 3ECRETAGOGUE E G 3ULFONYLUREA DOSAGE FORMS AND STRENGTHS

4

CONTRAINDICATIONS

5

WARNINGS AND PRECAUTIONS 5SE WITH -EDICATIONS +NOWN TO #AUSE (YPOGLYCEMIA -ACROVASCULAR /UTCOMES ADVERSE REACTIONS #LINICAL 4RIALS %XPERIENCE DRUG INTERACTIONS )NDUCERS OF 0 GLYCOPROTEIN AND #90 ! %NZYMES USE IN SPECIFIC POPULATIONS 0REGNANCY .URSING -OTHERS 0EDIATRIC 5SE

6 7 8

FULL PRESCRIBING INFORMATION 1 INDICATIONS AND USAGE 1.1 Monotherapy and Combination Therapy 42!$*%.4! TABLETS ARE INDICATED AS AN ADJUNCT TO DIET AND EXERCISE TO IMPROVE GLYCEMIC CONTROL IN ADULTS WITH TYPE DIABETES MELLITUS [see Clinical Studies (14.1)] 1.2 Important Limitations of Use 42!$*%.4! SHOULD NOT BE USED IN PATIENTS WITH TYPE DIABETES OR FOR THE TREATMENT OF DIABETIC KETOACIDOSIS AS IT WOULD NOT BE EFFECTIVE IN THESE SETTINGS 42!$*%.4! HAS NOT BEEN STUDIED IN COMBINATION WITH INSULIN

2

DOSAGE AND ADMINISTRATION

2.1 Recommended Dosing 4HE RECOMMENDED DOSE OF 42!$*%.4! IS MG ONCE DAILY 42!$*%.4! TABLETS CAN BE TAKEN WITH OR WITHOUT FOOD 2.2 Concomitant Use with an Insulin Secretagogue (e.g., Sulfonylurea) 7HEN 42!$*%.4! IS USED IN COMBINATION WITH AN INSULIN SECRETAGOGUE E G SULFONYLUREA A LOWER DOSE OF THE INSULIN SECRETAGOGUE MAY BE REQUIRED TO REDUCE THE RISK OF HYPOGLYCEMIA [see Warnings and Precautions (5.1)].

3

DOSAGE FORMS AND STRENGTHS

42!$*%.4! LINAGLIPTIN MG TABLETS ARE LIGHT RED ROUND BICONVEX BEVEL EDGED lLM COATED TABLETS WITH h$ v DEBOSSED ON ONE SIDE AND THE "OEHRINGER )NGELHEIM LOGO DEBOSSED ON THE OTHER SIDE

4

CONTRAINDICATIONS

42!$*%.4! IS CONTRAINDICATED IN PATIENTS WITH A HISTORY OF A HYPERSENSITIVITY REACTION TO LINAGLIPTIN SUCH AS URTICARIA ANGIOEDEMA OR BRONCHIAL HYPERREACTIVITY [see Adverse Reactions (6.1)]

5

WARNINGS AND PRECAUTIONS

13 14

16 17

PATIENT COUNSELING INFORMATION )NSTRUCTIONS ,ABORATORY 4ESTS

3ECTIONS OR SUBSECTIONS OMITTED FROM THE FULL PRESCRIBING INFORMATION ARE NOT LISTED

PARED WITH PLACEBO IN A CLINICAL TRIAL [see Adverse Reactions (6.1)]. 4HEREFORE A LOWER DOSE OF THE INSULIN SECRETAGOGUE MAY BE REQUIRED TO REDUCE THE RISK OF HYPOGLYCEMIA WHEN USED IN COMBINATION WITH 42!$*%.4!

5.2 Macrovascular Outcomes 4HERE HAVE BEEN NO CLINICAL STUDIES ESTABLISHING CONCLUSIVE EVIDENCE OF MACROVASCULAR RISK REDUCTION WITH 42!$*%.4! TABLETS OR ANY OTHER ANTIDIABETIC DRUG

6

ADVERSE REACTIONS

6.1 Clinical Trials Experience "ECAUSE CLINICAL TRIALS ARE CONDUCTED UNDER WIDELY VARYING CONDITIONS ADVERSE REACTION RATES OBSERVED IN THE CLINICAL TRIALS OF A DRUG CANNOT BE DIRECTLY COMPARED TO RATES IN THE CLINICAL TRIALS OF ANOTHER DRUG AND MAY NOT REmECT THE RATES OBSERVED IN PRACTICE 4HE SAFETY OF LINAGLIPTIN HAS BEEN EVALUATED IN OVER PATIENTS WITH TYPE DIABETES IN CLINICAL TRIALS

INCLUDING PLACEBO CONTROLLED STUDIES AND ACTIVE CONTROLLED STUDY WITH GLIMEPIRIDE 42!$*%.4! MG ONCE DAILY WAS STUDIED AS MONOTHERAPY IN TWO PLACEBO CONTROLLED TRIALS OF AND WEEKS DURATION &IVE PLACEBO CONTROLLED TRIALS INVESTIGATED LINAGLIPTIN IN COMBINATION WITH OTHER ORAL ANTIHYPERGLYCEMIC AGENTS TWO WITH METFORMIN AND WEEKS TREATMENT DURATION ONE WITH A SULFONYLUREA WEEKS TREATMENT DURATION ONE WITH METFORMIN AND SULFONYLUREA WEEKS TREATMENT DURATION AND ONE WITH PIOGLITAZONE WEEKS TREATMENT DURATION )N PLACEBO CONTROLLED CLINICAL TRIALS ADVERSE REACTIONS THAT OCCURRED IN Â&#x2022; OF PATIENTS RECEIVING 42!$*%.4! N AND MORE COMMONLY THAN IN PATIENTS GIVEN PLACEBO N INCLUDED NASOPHARYNGITIS VS !DVERSE REACTIONS REPORTED IN Â&#x2022; OF PATIENTS TREATED WITH 42!$*%.4! MG DAILY AS MONOTHERAPY OR IN COMBINATION WITH PIOGLITAZONE SULFONYLUREA OR METFORMIN AND AT LEAST FOLD MORE COMMONLY THAN IN PATIENTS TREATED WITH PLACEBO ARE SHOWN IN 4ABLE NEXT PAGE &OLLOWING WEEKS TREATMENT IN A CONTROLLED STUDY COMPARING LINAGLIPTIN WITH GLIMEPIRIDE IN WHICH ALL PATIENTS WERE ALSO RECEIVING METFORMIN ADVERSE REACTIONS REPORTED IN Â&#x2022; PATIENTS TREATED WITH LINAGLIPTIN N AND MORE FREQUENTLY THAN IN PATIENTS TREATED WITH A SULFONYLUREA N WERE ARTHRALGIA VS BACK PAIN VS AND HEADACHE VS

5.1 Use with Medications Known to Cause Hypoglycemia )NSULIN SECRETAGOGUES ARE KNOWN TO CAUSE HYPOGLYCEMIA 4HE USE OF 42!$*%.4! IN COMBINATION WITH AN INSULIN SECRETAGOGUE E G SULFONYLUREA WAS ASSOCIATED WITH A HIGHER RATE OF HYPOGLYCEMIA COM-

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43

Adverse Reactions Reported in Â&#x2022;2% of Patients Treated with TRADJENTA and at Least 2-Fold Greater than with Placebo in Placebo-Controlled Clinical Studies of TRADJENTA Monotherapy or Combination Therapy

Table 1

.ASOPHARYNGITIS (YPERLIPIDEMIA #OUGH (YPERTRIGLYCERIDEMIAâ&#x20AC; 7EIGHT INCREASED

Monotherapy* n (%)

Combination with Metformin# n (%)

Combination with SU n (%)

Combination with Metformin + SU n (%)

Combination with Pioglitazone n (%)

TRADJENTA n = 765 â&#x20AC;&#x201C; â&#x20AC;&#x201C; â&#x20AC;&#x201C; â&#x20AC;&#x201C; â&#x20AC;&#x201C;

TRADJENTA n = 590 â&#x20AC;&#x201C; â&#x20AC;&#x201C; â&#x20AC;&#x201C; â&#x20AC;&#x201C; â&#x20AC;&#x201C;

TRADJENTA n = 161

â&#x20AC;&#x201C; â&#x20AC;&#x201C;

â&#x20AC;&#x201C;

TRADJENTA n = 791 â&#x20AC;&#x201C; â&#x20AC;&#x201C;

â&#x20AC;&#x201C; â&#x20AC;&#x201C;

TRADJENTA n = 259 â&#x20AC;&#x201C;

â&#x20AC;&#x201C; â&#x20AC;&#x201C;

Placebo n = 458 â&#x20AC;&#x201C; â&#x20AC;&#x201C; â&#x20AC;&#x201C; â&#x20AC;&#x201C; â&#x20AC;&#x201C;

Placebo n = 248 â&#x20AC;&#x201C; â&#x20AC;&#x201C; â&#x20AC;&#x201C; â&#x20AC;&#x201C; â&#x20AC;&#x201C;

Placebo n = 84

â&#x20AC;&#x201C; â&#x20AC;&#x201C;

â&#x20AC;&#x201C;

Placebo n = 263 â&#x20AC;&#x201C; â&#x20AC;&#x201C;

â&#x20AC;&#x201C; â&#x20AC;&#x201C;

Placebo n = 130 â&#x20AC;&#x201C;

â&#x20AC;&#x201C; â&#x20AC;&#x201C;

35 SULFONYLUREA

0OOLED DATA FROM STUDIES # 0OOLED DATA FROM STUDIES â&#x20AC; )NCLUDES REPORTS OF HYPERTRIGLYCERIDEMIA N AND BLOOD TRIGLYCERIDES INCREASED N

/THER ADVERSE REACTIONS REPORTED IN CLINICAL STUDIES WITH TREATMENT OF 4RADJENTA© LINAGLIPTIN WERE HYPERSENSITIVITY E G URTICARIA ANGIOEDEMA LOCALIZED SKIN EXFOLIATION OR BRONCHIAL HYPERREACTIVITY

AND MYALGIA )N THE CLINICAL TRIAL PROGRAM PANCREATITIS WAS REPORTED IN OF PATIENTS PATIENT YEARS OF EXPOSURE WHILE BEING TREATED WITH 42!$*%.4! COMPARED WITH OF PATIENTS PATIENT YEARS OF EXPOSURE TREATED WITH PLACEBO 4HREE ADDITIONAL CASES OF PANCREATITIS WERE REPORTED FOLLOWING THE LAST ADMINISTERED DOSE OF LINAGLIPTIN Hypoglycemia )N THE PLACEBO CONTROLLED STUDIES OF THE TOTAL PATIENTS TREATED WITH 42!$*%.4! MG REPORTED HYPOGLYCEMIA COMPARED TO PATIENTS OF PLACEBO TREATED PATIENTS 4HE INCIDENCE OF HYPOGLYCEMIA WAS SIMILAR TO PLACEBO WHEN LINAGLIPTIN WAS ADMINISTERED AS MONOTHERAPY OR IN COMBINATION WITH METFORMIN OR WITH PIOGLITAZONE 7HEN LINAGLIPTIN WAS ADMINISTERED IN COMBINATION WITH METFORMIN AND A SULFONYLUREA OF PATIENTS REPORTED HYPOGLYCEMIA COMPARED WITH OF PATIENTS ADMINISTERED PLACEBO IN COMBINATION WITH METFORMIN AND A SULFONYLUREA Laboratory Tests #HANGES IN LABORATORY lNDINGS WERE SIMILAR IN PATIENTS TREATED WITH 42!$*%.4! MG COMPARED TO PATIENTS TREATED WITH PLACEBO #HANGES IN LABORATORY VALUES THAT OCCURRED MORE FREQUENTLY IN THE 42!$*%.4! GROUP AND Â&#x2022; MORE THAN IN THE PLACEBO GROUP WERE INCREASES IN URIC ACID IN THE PLACEBO GROUP IN THE 42!$*%.4! GROUP .O CLINICALLY MEANINGFUL CHANGES IN VITAL SIGNS WERE OBSERVED IN PATIENTS TREATED WITH 42!$*%.4!

7

DRUG INTERACTIONS

7.1 Inducers of P-glycoprotein and CYP3A4 Enzymes 2IFAMPIN DECREASED LINAGLIPTIN EXPOSURE SUGGESTING THAT THE EFlCACY OF 42!$*%.4! MAY BE REDUCED WHEN ADMINISTERED IN COMBINATION WITH A STRONG 0 GP OR #90 ! INDUCER 4HEREFORE USE OF ALTERNATIVE TREATMENTS IS STRONGLY RECOMMENDED WHEN LINAGLIPTIN IS TO BE ADMINISTERED WITH A 0 GP OR #90 !

INDUCER [see Clinical Pharmacology (12.3)]

8

USE IN SPECIFIC POPULATIONS

8.1 Pregnancy Pregnancy Category B 2EPRODUCTION STUDIES HAVE BEEN PERFORMED IN RATS AND RABBITS 4HERE ARE HOWEVER NO ADEQUATE AND WELL CONTROLLED STUDIES IN PREGNANT WOMEN "ECAUSE ANIMAL REPRODUCTION STUDIES ARE NOT ALWAYS PREDICTIVE OF HUMAN RESPONSE THIS DRUG SHOULD BE USED DURING PREGNANCY ONLY IF CLEARLY NEEDED ,INAGLIPTIN ADMINISTERED DURING THE PERIOD OF ORGANOGENESIS WAS NOT TERATOGENIC AT DOSES UP TO MG KG IN THE RAT AND MG KG IN THE RABBIT OR APPROXIMATELY AND TIMES THE CLINICAL DOSE BASED ON !5# EXPOSURE $OSES OF LINAGLIPTIN CAUSING MATERNAL TOXICITY IN THE RAT AND THE RABBIT ALSO CAUSED DEVELOPMENTAL DELAYS IN SKELETAL OSSIlCATION AND SLIGHTLY INCREASED EMBRYOFETAL LOSS IN RAT TIMES THE CLINICAL DOSE AND INCREASED FETAL RESORPTIONS AND VISCERAL AND SKELETAL VARIATIONS IN THE RABBIT TIMES THE CLINICAL DOSE ,INAGLIPTIN ADMINISTERED TO FEMALE RATS FROM GESTATION DAY TO LACTATION DAY RESULTED IN DECREASED BODY WEIGHT AND DELAYS IN PHYSICAL AND BEHAVIORAL DEVELOPMENT IN MALE AND FEMALE OFFSPRING AT MATERNALLY TOXIC DOSES EXPOSURES TIMES THE CLINICAL DOSE .O FUNCTIONAL BEHAVIORAL OR REPRODUCTIVE TOXICITY WAS OBSERVED IN OFFSPRING OF RATS EXPOSED TO TIMES THE CLINICAL DOSE ,INAGLIPTIN CROSSED THE PLACENTA INTO THE FETUS FOLLOWING ORAL DOSING IN PREGNANT RATS AND RABBITS 8.3 Nursing Mothers !VAILABLE ANIMAL DATA HAVE SHOWN EXCRETION OF LINAGLIPTIN IN MILK AT A MILK TO PLASMA RATIO OF )T IS NOT KNOWN WHETHER THIS DRUG IS EXCRETED IN HUMAN MILK "ECAUSE MANY DRUGS ARE EXCRETED IN HUMAN MILK CAUTION SHOULD BE EXERCISED WHEN 42!$*%.4! IS ADMINISTERED TO A NURSING WOMAN 8.4 Pediatric Use 3AFETY AND EFFECTIVENESS OF 42!$*%.4! IN PEDIATRIC PATIENTS HAVE NOT BEEN ESTABLISHED 8.5 Geriatric Use /F THE TOTAL NUMBER OF PATIENTS N IN CLINICAL STUDIES OF 42!$*%.4!

PATIENTS WERE YEARS AND OVER WHILE PATIENTS WERE YEARS AND OVER .O OVERALL DIFFERENCES IN SAFETY OR EFFECTIVENESS WERE OBSERVED BETWEEN PATIENTS YEARS AND OVER AND YOUNGER PATIENTS 7HILE THIS AND OTHER REPORTED CLINICAL EXPERIENCE HAVE NOT IDENTIlED DIFFERENCES IN RESPONSE BETWEEN THE ELDERLY AND YOUNGER PATIENTS GREATER SENSITIVITY OF SOME OLDER INDIVIDUALS CANNOT BE RULED OUT .O DOSE ADJUSTMENT IS RECOMMENDED IN THIS POPULATION 8.6 Renal Impairment .O DOSE ADJUSTMENT IS RECOMMENDED FOR PATIENTS WITH RENAL IMPAIRMENT [see Clinical Pharmacology (12.3)] 8.7 Hepatic Impairment .O DOSE ADJUSTMENT IS RECOMMENDED FOR PATIENTS WITH HEPATIC IMPAIRMENT [see Clinical Pharmacology (12.3)]

10

OVERDOSAGE

$URING CONTROLLED CLINICAL TRIALS IN HEALTHY SUBJECTS WITH SINGLE DOSES OF UP TO MG OF 42!$*%.4!

EQUIVALENT TO TIMES THE RECOMMENDED DAILY DOSE THERE WERE NO DOSE RELATED CLINICAL ADVERSE DRUG REACTIONS 4HERE IS NO EXPERIENCE WITH DOSES ABOVE MG IN HUMANS )N THE EVENT OF AN OVERDOSE CONTACT THE 0OISON #ONTROL #ENTER )T IS ALSO REASONABLE TO EMPLOY THE USUAL SUPPORTIVE MEASURES E G REMOVE UNABSORBED MATERIAL FROM THE GASTROINTESTINAL TRACT EMPLOY CLINICAL

44

AMERICAN HEALTH & DRUG BENEFITS

June 2012

MONITORING AND INSTITUTE SUPPORTIVE TREATMENT AS DICTATED BY THE PATIENT S CLINICAL STATUS ,INAGLIPTIN IS NOT EXPECTED TO BE ELIMINATED TO A THERAPEUTICALLY SIGNIlCANT DEGREE BY HEMODIALYSIS OR PERITONEAL DIALYSIS

11

DESCRIPTION

42!$*%.4! LINAGLIPTIN TABLETS CONTAIN AS THE ACTIVE INGREDIENT AN ORALLY ACTIVE INHIBITOR OF THE DIPEPTIDYL PEPTIDASE $00 ENZYME ,INAGLIPTIN IS DESCRIBED CHEMICALLY AS ( 0URINE DIONE ; 2 AMINO PIPERIDINYL= BUTYN YL DIHYDRO METHYL ; METHYL QUINAZOLINYL METHYL= 4HE EMPIRICAL FORMULA IS # H . / AND THE MOLECULAR WEIGHT IS G MOL 4HE STRUCTURAL FORMULA IS o N

N

N N

o

N N

N NH2

,INAGLIPTIN IS A WHITE TO YELLOWISH NOT OR ONLY SLIGHTLY HYGROSCOPIC SOLID SUBSTANCE )T IS VERY SLIGHTLY SOLUBLE IN WATER MG M, ,INAGLIPTIN IS SOLUBLE IN METHANOL CA MG M, SPARINGLY SOLUBLE IN ETHANOL CA MG M, VERY SLIGHTLY SOLUBLE IN ISOPROPANOL MG M, AND VERY SLIGHTLY SOLUBLE IN ACETONE CA MG M, %ACH lLM COATED TABLET OF 42!$*%.4! CONTAINS MG OF LINAGLIPTIN FREE BASE AND THE FOLLOWING INACTIVE INGREDIENTS MANNITOL PREGELATINIZED STARCH CORN STARCH COPOVIDONE AND MAGNESIUM STEARATE )N ADDITION THE lLM COATING CONTAINS THE FOLLOWING INACTIVE INGREDIENTS HYPROMELLOSE TITANIUM DIOXIDE TALC

POLYETHYLENE GLYCOL AND RED FERRIC OXIDE

12

CLINICAL PHARMACOLOGY

12.1 Mechanism of Action ,INAGLIPTIN IS AN INHIBITOR OF $00 AN ENZYME THAT DEGRADES THE INCRETIN HORMONES GLUCAGON LIKE PEPTIDE ',0 AND GLUCOSE DEPENDENT INSULINOTROPIC POLYPEPTIDE ')0 4HUS LINAGLIPTIN INCREASES THE CONCENTRATIONS OF ACTIVE INCRETIN HORMONES STIMULATING THE RELEASE OF INSULIN IN A GLUCOSE DEPENDENT MANNER AND DECREASING THE LEVELS OF GLUCAGON IN THE CIRCULATION "OTH INCRETIN HORMONES ARE INVOLVED IN THE PHYSIOLOGICAL REGULATION OF GLUCOSE HOMEOSTASIS )NCRETIN HORMONES ARE SECRETED AT A LOW BASAL LEVEL THROUGHOUT THE DAY AND LEVELS RISE IMMEDIATELY AFTER MEAL INTAKE ',0 AND ')0 INCREASE INSULIN BIOSYNTHESIS AND SECRETION FROM PANCREATIC BETA CELLS IN THE PRESENCE OF NORMAL AND ELEVATED BLOOD GLUCOSE LEVELS &URTHERMORE ',0 ALSO REDUCES GLUCAGON SECRETION FROM PANCREATIC ALPHA CELLS RESULTING IN A REDUCTION IN HEPATIC GLUCOSE OUTPUT 12.2 Pharmacodynamics ,INAGLIPTIN BINDS TO $00 IN A REVERSIBLE MANNER AND THUS INCREASES THE CONCENTRATIONS OF INCRETIN HORMONES ,INAGLIPTIN GLUCOSE DEPENDENTLY INCREASES INSULIN SECRETION AND LOWERS GLUCAGON SECRETION

THUS RESULTING IN BETTER REGULATION OF GLUCOSE HOMEOSTASIS ,INAGLIPTIN BINDS SELECTIVELY TO $00 AND SELECTIVELY INHIBITS $00 BUT NOT $00 OR $00 ACTIVITY IN VITRO AT CONCENTRATIONS APPROXIMATING THERAPEUTIC EXPOSURES Cardiac Electrophysiology )N A RANDOMIZED PLACEBO CONTROLLED ACTIVE COMPARATOR WAY CROSSOVER STUDY HEALTHY SUBJECTS WERE ADMINISTERED A SINGLE ORAL DOSE OF LINAGLIPTIN MG LINAGLIPTIN MG TIMES THE RECOMMENDED DOSE MOXImOXACIN AND PLACEBO .O INCREASE IN 14C WAS OBSERVED WITH EITHER THE RECOMMENDED DOSE OF MG OR THE MG DOSE !T THE MG DOSE PEAK LINAGLIPTIN PLASMA CONCENTRATIONS WERE APPROXIMATELY FOLD HIGHER THAN THE PEAK CONCENTRATIONS FOLLOWING A MG DOSE 12.3 Pharmacokinetics 4HE PHARMACOKINETICS OF LINAGLIPTIN HAS BEEN CHARACTERIZED IN HEALTHY SUBJECTS AND PATIENTS WITH TYPE DIABETES !FTER ORAL ADMINISTRATION OF A SINGLE MG DOSE TO HEALTHY SUBJECTS PEAK PLASMA CONCENTRATIONS OF LINAGLIPTIN OCCURRED AT APPROXIMATELY HOURS POST DOSE 4MAX THE MEAN PLASMA AREA UNDER THE CURVE !5# WAS NMOL H , AND MAXIMUM CONCENTRATION #MAX WAS NMOL , 0LASMA CONCENTRATIONS OF LINAGLIPTIN DECLINE IN AT LEAST A BIPHASIC MANNER WITH A LONG TERMINAL HALF LIFE HOURS RELATED TO THE SATURABLE BINDING OF LINAGLIPTIN TO $00 4HE PROLONGED ELIMINATION PHASE DOES NOT CONTRIBUTE TO THE ACCUMULATION OF THE DRUG 4HE EFFECTIVE HALF LIFE FOR ACCUMULATION OF LINAGLIPTIN AS DETERMINED FROM ORAL ADMINISTRATION OF MULTIPLE DOSES OF LINAGLIPTIN MG IS APPROXIMATELY HOURS !FTER ONCE DAILY DOSING STEADY STATE PLASMA CONCENTRATIONS OF LINAGLIPTIN MG ARE REACHED

BY THE THIRD DOSE AND #MAX AND !5# INCREASED BY A FACTOR OF AT STEADY STATE COMPARED WITH THE lRST DOSE 4HE INTRA SUBJECT AND INTER SUBJECT COEFlCIENTS OF VARIATION FOR LINAGLIPTIN !5# WERE SMALL AND RESPECTIVELY 0LASMA !5# OF LINAGLIPTIN INCREASED IN A LESS THAN DOSE PROPORTIONAL MANNER IN THE DOSE RANGE OF TO MG 4HE PHARMACOKINETICS OF LINAGLIPTIN IS SIMILAR IN HEALTHY SUBJECTS AND IN PATIENTS WITH TYPE DIABETES Absorption 4HE ABSOLUTE BIOAVAILABILITY OF LINAGLIPTIN IS APPROXIMATELY (IGH FAT MEAL REDUCED #MAX BY AND INCREASED !5# BY THIS EFFECT IS NOT CLINICALLY RELEVANT 42!$*%.4! MAY BE ADMINISTERED WITH OR WITHOUT FOOD Distribution 4HE MEAN APPARENT VOLUME OF DISTRIBUTION AT STEADY STATE FOLLOWING A SINGLE INTRAVENOUS DOSE OF

LINAGLIPTIN MG TO HEALTHY SUBJECTS IS APPROXIMATELY , INDICATING THAT LINAGLIPTIN EXTENSIVELY DISTRIBUTES TO THE TISSUES 0LASMA PROTEIN BINDING OF LINAGLIPTIN IS CONCENTRATION DEPENDENT DECREASING FROM ABOUT AT NMOL , TO AT Â&#x2022; NMOL , REmECTING SATURATION OF BINDING TO $00 WITH INCREASING CONCENTRATION OF LINAGLIPTIN !T HIGH CONCENTRATIONS WHERE $00 IS FULLY SATURATED TO OF LINAGLIPTIN REMAINS BOUND TO PLASMA PROTEINS AND TO IS UNBOUND IN PLASMA 0LASMA BINDING IS NOT ALTERED IN PATIENTS WITH RENAL OR HEPATIC IMPAIRMENT Metabolism &OLLOWING ORAL ADMINISTRATION THE MAJORITY ABOUT OF LINAGLIPTIN IS EXCRETED UNCHANGED INDICATING THAT METABOLISM REPRESENTS A MINOR ELIMINATION PATHWAY ! SMALL FRACTION OF ABSORBED LINAGLIPTIN IS METABOLIZED TO A PHARMACOLOGICALLY INACTIVE METABOLITE WHICH SHOWS A STEADY STATE EXPOSURE OF RELATIVE TO LINAGLIPTIN

Table 2

Effect of Coadministered Drugs on Systemic Exposure of Linagliptin

Coadministered Drug

Dosing of Coadministered Drug*

-ETFORMIN 'LYBURIDE 0IOGLITAZONE 2ITONAVIR 2IFAMPIN

MG 4)$ MG# MG 1$ MG ")$ MG 1$

Geometric Mean Ratio (ratio with/ without coadministered drug) Dosing of Linagliptin* No effect = 1.0 #MAX !5#â&#x20AC; MG 1$

MG 1$

MG 1$

MG#

MG 1$

-ULTIPLE DOSE STEADY STATE UNLESS OTHERWISE NOTED Excretion # &OLLOWING ADMINISTRATION OF AN ORAL ; #= LINAGLIPTIN DOSE TO HEALTHY SUBJECTS APPROXIMATELY OF THE â&#x20AC; 3INGLE DOSE !5# !5# TO HOURS FOR SINGLE DOSE TREATMENTS AND !5# !5# 4!5 FOR MULTIPLE DOSE TREATMENTS ADMINISTERED RADIOACTIVITY WAS ELIMINATED VIA THE ENTEROHEPATIC SYSTEM OR URINE WITHIN 1$ ONCE DAILY ")$ TWICE DAILY DAYS OF DOSING 2ENAL CLEARANCE AT STEADY STATE WAS APPROXIMATELY M, MIN

Specific Populations 2ENAL )MPAIRMENT !N OPEN LABEL PHARMACOKINETIC STUDY EVALUATED THE PHARMACOKINETICS OF LINAGLIPTIN MG IN MALE AND FEMALE PATIENTS WITH VARYING DEGREES OF CHRONIC RENAL IMPAIRMENT 4HE STUDY INCLUDED HEALTHY SUBJECTS WITH NORMAL RENAL FUNCTION CREATININE CLEARANCE ;#R#L= Â&#x2022; M, MIN PATIENTS WITH MILD RENAL IMPAIRMENT #R#L TO M, MIN PATIENTS WITH MODERATE RENAL IMPAIRMENT #R#L TO M, MIN

PATIENTS WITH TYPE DIABETES MELLITUS AND SEVERE RENAL IMPAIRMENT #R#L M, MIN AND PATIENTS WITH TYPE DIABETES MELLITUS AND NORMAL RENAL FUNCTION #REATININE CLEARANCE WAS MEASURED

BY HOUR URINARY CREATININE CLEARANCE MEASUREMENTS OR ESTIMATED FROM SERUM CREATININE BASED ON THE #OCKCROFT 'AULT FORMULA 5NDER STEADY STATE CONDITIONS LINAGLIPTIN EXPOSURE IN PATIENTS WITH MILD RENAL IMPAIRMENT WAS COMPARABLE TO HEALTHY SUBJECTS )N PATIENTS WITH MODERATE RENAL IMPAIRMENT UNDER STEADY STATE CONDITIONS MEAN EXPOSURE OF LINAGLIPTIN INCREASED !5#o ss BY AND #MAX BY COMPARED WITH HEALTHY SUBJECTS 4HIS INCREASE WAS NOT ASSOCIATED WITH A PROLONGED ACCUMULATION HALF LIFE TERMINAL HALF LIFE OR AN INCREASED ACCUMULATION FACTOR 2ENAL EXCRETION OF LINAGLIPTIN WAS BELOW OF THE ADMINISTERED DOSE AND WAS NOT AFFECTED BY DECREASED RENAL FUNCTION 0ATIENTS WITH TYPE DIABETES MELLITUS AND SEVERE RENAL IMPAIRMENT SHOWED STEADY STATE EXPOSURE APPROXIMATELY HIGHER THAN THAT OF PATIENTS WITH TYPE DIABETES MELLITUS AND NORMAL RENAL FUNCTION INCREASE IN !5#o ss BY AND #MAX BY &OR BOTH TYPE DIABETES MELLITUS GROUPS RENAL EXCRETION WAS BELOW OF THE ADMINISTERED DOSE 2ESULTS OF THIS STUDY SUPPORTED BY RESULTS OF POPULATION PHARMACOKINETIC ANALYSES INDICATE THAT NO DOSE ADJUSTMENT IS RECOMMENDED IN PATIENTS WITH RENAL IMPAIRMENT (EPATIC )MPAIRMENT )N PATIENTS WITH MILD HEPATIC IMPAIRMENT #HILD 0UGH CLASS ! STEADY STATE EXPOSURE !5#o ss OF LINAGLIPTIN WAS APPROXIMATELY LOWER AND #MAX SS WAS APPROXIMATELY LOWER THAN IN HEALTHY SUBJECTS )N PATIENTS WITH MODERATE HEPATIC IMPAIRMENT #HILD 0UGH CLASS " !5#ss OF LINAGLIPTIN WAS ABOUT LOWER AND #MAX SS WAS APPROXIMATELY LOWER THAN IN HEALTHY SUBJECTS 0ATIENTS WITH SEVERE HEPATIC IMPAIRMENT #HILD 0UGH CLASS # HAD COMPARABLE EXPOSURE OF LINAGLIPTIN IN TERMS OF !5# AND APPROXIMATELY LOWER #MAX COMPARED WITH HEALTHY SUBJECTS 2EDUCTIONS IN THE PHARMACOKINETIC PARAMETERS SEEN IN PATIENTS WITH HEPATIC IMPAIRMENT DID NOT RESULT IN REDUCTIONS IN $00 INHIBITION .O DOSE ADJUSTMENT OF LINAGLIPTIN IS NECESSARY IN PATIENTS WITH HEPATIC IMPAIRMENT "ODY -ASS )NDEX "-) 7EIGHT .O DOSE ADJUSTMENT IS NECESSARY BASED ON "-) WEIGHT "-) WEIGHT HAD NO CLINICALLY MEANINGFUL EFFECT ON THE PHARMACOKINETICS OF LINAGLIPTIN BASED ON A POPULATION PHARMACOKINETIC ANALYSIS 'ENDER .O DOSE ADJUSTMENT IS NECESSARY BASED ON GENDER 'ENDER HAD NO CLINICALLY MEANINGFUL EFFECT ON THE PHARMACOKINETICS OF LINAGLIPTIN BASED ON A POPULATION PHARMACOKINETIC ANALYSIS 'ERIATRIC .O DOSE ADJUSTMENT IS RECOMMENDED BASED ON AGE AS AGE DID NOT HAVE A CLINICALLY MEANINGFUL IMPACT ON THE PHARMACOKINETICS OF LINAGLIPTIN BASED ON A POPULATION PHARMACOKINETIC ANALYSIS 0EDIATRIC 3TUDIES CHARACTERIZING THE PHARMACOKINETICS OF LINAGLIPTIN IN PEDIATRIC PATIENTS HAVE NOT YET BEEN PERFORMED 2ACE .O DOSE ADJUSTMENT IS NECESSARY BASED ON RACE 2ACE HAD NO CLINICALLY MEANINGFUL EFFECT ON THE PHARMACOKINETICS OF LINAGLIPTIN BASED ON AVAILABLE PHARMACOKINETIC DATA INCLUDING SUBJECTS OF 7HITE

(ISPANIC "LACK !SIAN AND OTHER RACIAL GROUPS Drug Interactions In vitro !SSESSMENT OF $RUG )NTERACTIONS ,INAGLIPTIN IS A WEAK TO MODERATE INHIBITOR OF #90 ISOZYME #90 !

BUT DOES NOT INHIBIT OTHER #90 ISOZYMES AND IS NOT AN INDUCER OF #90 ISOZYMES INCLUDING #90 ! ! " # # # $

% AND ! ,INAGLIPTIN IS A 0 GLYCOPROTEIN 0 GP SUBSTRATE AND INHIBITS 0 GP MEDIATED TRANSPORT OF DIGOXIN AT HIGH CONCENTRATIONS "ASED ON THESE RESULTS AND in vivo DRUG INTERACTION STUDIES LINAGLIPTIN IS CONSIDERED UNLIKELY TO CAUSE INTERACTIONS WITH OTHER 0 GP SUBSTRATES AT THERAPEUTIC CONCENTRATIONS In vivo !SSESSMENT OF $RUG )NTERACTIONS )NDUCERS OF #90 ! OR 0 GP E G RIFAMPIN DECREASE EXPOSURE TO LINAGLIPTIN TO SUBTHERAPEUTIC AND LIKELY INEFFECTIVE CONCENTRATIONS &OR PATIENTS REQUIRING USE OF SUCH DRUGS AN ALTERNATIVE TO LINAGLIPTIN IS STRONGLY RECOMMENDED In vivo STUDIES INDICATED EVIDENCE OF A LOW PROPENSITY FOR CAUSING DRUG INTERACTIONS WITH SUBSTRATES OF #90 ! #90 # #90 # 0 GP AND ORGANIC CATIONIC TRANSPORTER /#4 .O DOSE ADJUSTMENT OF 4RADJENTA© LINAGLIPTIN IS RECOMMENDED BASED ON RESULTS OF THE DESCRIBED PHARMACOKINETIC STUDIES

4)$ THREE TIMES DAILY

Table 3

Effect of Linagliptin on Systemic Exposure of Coadministered Drugs

Coadministered Drug

Dosing of Coadministered Drug*

Dosing of Linagliptin*

-ETFORMIN 'LYBURIDE 0IOGLITAZONE

MG 4)$ MG# MG 1$

MG 1$ MG 1$ MG 1$

$IGOXIN 3IMVASTATIN

MG 1$ MG 1$

MG 1$ MG 1$

7ARFARIN

MG#

MG 1$

%THINYLESTRADIOL AND LEVONORGESTREL

ETHINYLESTRADIOL MG AND LEVONORGESTREL MG 1$

MG 1$

Geometric Mean Ratio (ratio with/ without coadministered drug) No effect = 1.0 #MAX !5#â&#x20AC; METFORMIN

GLYBURIDE

PIOGLITAZONE

METABOLITE - )))

METABOLITE - )6 DIGOXIN SIMVASTATIN SIMVASTATIN ACID 2 WARFARIN 3 WARFARIN ).2 04 ETHINYLESTRADIOL LEVONORGESTREL

-ULTIPLE DOSE STEADY STATE UNLESS OTHERWISE NOTED # 3INGLE DOSE â&#x20AC; !5# !5# ).& FOR SINGLE DOSE TREATMENTS AND !5# !5# 4!5 FOR MULTIPLE DOSE TREATMENTS

!5# !5# AND #MAX %MAX FOR PHARMACODYNAMIC ENDPOINTS ).2 )NTERNATIONAL .ORMALIZED 2ATIO 04 0ROTHROMBIN 4IME 1$ ONCE DAILY ")$ TWICE DAILY 4)$ THREE TIMES DAILY

13

NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility ,INAGLIPTIN DID NOT INCREASE THE INCIDENCE OF TUMORS IN MALE AND FEMALE RATS IN A YEAR STUDY AT DOSES OF

AND MG KG 4HE HIGHEST DOSE OF MG KG IS APPROXIMATELY TIMES THE CLINICAL DOSE OF MG DAY BASED ON !5# EXPOSURE ,INAGLIPTIN DID NOT INCREASE THE INCIDENCE OF TUMORS IN MICE IN A YEAR STUDY AT DOSES UP TO MG KG MALES AND MG KG FEMALES OR APPROXIMATELY AND TIMES THE CLINICAL DOSE BASED ON !5# EXPOSURE (IGHER DOSES OF LINAGLIPTIN IN FEMALE MICE MG KG INCREASED THE INCIDENCE OF LYMPHOMA AT APPROXIMATELY TIMES THE CLINICAL DOSE BASED ON !5# EXPOSURE ,INAGLIPTIN WAS NOT MUTAGENIC OR CLASTOGENIC WITH OR WITHOUT METABOLIC ACTIVATION IN THE !MES BACTERIAL MUTAGENICITY ASSAY A CHROMOSOMAL ABERRATION TEST IN HUMAN LYMPHOCYTES AND AN in vivo MICRONUCLEUS ASSAY )N FERTILITY STUDIES IN RATS LINAGLIPTIN HAD NO ADVERSE EFFECTS ON EARLY EMBRYONIC DEVELOPMENT MATING

FERTILITY OR BEARING LIVE YOUNG UP TO THE HIGHEST DOSE OF MG KG APPROXIMATELY TIMES THE CLINICAL DOSE BASED ON !5# EXPOSURE

14

CLINICAL STUDIES

42!$*%.4! HAS BEEN STUDIED AS MONOTHERAPY AND IN COMBINATION WITH METFORMIN GLIMEPIRIDE AND PIOGLITAZONE THERAPY 42!$*%.4! HAS NOT BEEN STUDIED IN COMBINATION WITH INSULIN 4HERE WERE APPROXIMATELY PATIENTS WITH TYPE DIABETES RANDOMIZED IN DOUBLE BLIND PLACEBO CONTROLLED CLINICAL SAFETY AND EFlCACY STUDIES CONDUCTED TO EVALUATE THE EFFECTS OF LINAGLIPTIN ON GLYCEMIC CONTROL 4HE OVERALL ETHNIC RACIAL DISTRIBUTION IN THESE STUDIES WAS APPROXIMATELY 7HITE !SIAN

AND "LACK AND INCLUDED (ISPANIC ,ATINO PATIENTS &IFTY TWO PERCENT OF PATIENTS WERE MALE 0ATIENTS HAD AN OVERALL MEAN AGE OF YEARS RANGE TO YEARS )N ADDITION AN ACTIVE GLIMEPIRIDE CONTROLLED STUDY OF WEEKS DURATION WAS CONDUCTED IN OVER PATIENTS WITH TYPE DIABETES WHO HAD INADEQUATE GLYCEMIC CONTROL ON METFORMIN )N PATIENTS WITH TYPE DIABETES TREATMENT WITH 42!$*%.4! PRODUCED CLINICALLY SIGNIlCANT IMPROVEMENTS IN HEMOGLOBIN ! C ! # FASTING PLASMA GLUCOSE &0' AND HOUR POST PRANDIAL GLUCOSE 00' COMPARED WITH PLACEBO 14.1 Monotherapy ! TOTAL OF PATIENTS WITH TYPE DIABETES PARTICIPATED IN DOUBLE BLIND PLACEBO CONTROLLED STUDIES ONE OF WEEKS AND ANOTHER OF WEEKS DURATION TO EVALUATE THE EFlCACY AND SAFETY OF 42!$*%.4! MONOTHERAPY )N BOTH MONOTHERAPY STUDIES PATIENTS CURRENTLY ON AN ANTIHYPERGLYCEMIC AGENT DISCONTINUED THE AGENT AND UNDERWENT A DIET EXERCISE AND DRUG WASHOUT PERIOD OF ABOUT WEEKS THAT INCLUDED AN OPEN LABEL PLACEBO RUN IN DURING THE LAST WEEKS 0ATIENTS WITH INADEQUATE GLYCEMIC CONTROL ! # TO AFTER THE WASHOUT PERIOD WERE RANDOMIZED PATIENTS NOT CURRENTLY ON ANTIHYPERGLYCEMIC AGENTS OFF THERAPY FOR AT LEAST WEEKS WITH INADEQUATE GLYCEMIC CONTROL ! # TO WERE RANDOMIZED AFTER COMPLETING THE WEEK OPEN LABEL PLACEBO RUN IN PERIOD )N THE WEEK STUDY ONLY PATIENTS INELIGIBLE FOR METFORMIN WERE RECRUITED )N THE WEEK STUDY PATIENTS WERE RANDOMIZED TO PLACEBO AND TO LINAGLIPTIN MG IN THE WEEK STUDY PATIENTS WERE RANDOMIZED TO PLACEBO AND TO LINAGLIPTIN MG 0ATIENTS WHO FAILED TO MEET SPECIlC GLYCEMIC GOALS

June 2012

www.AHDBonline.com

45

DURING THE WEEK STUDY RECEIVED RESCUE THERAPY WITH PIOGLITAZONE AND OR INSULIN METFORMIN RESCUE THERAPY WAS USED IN THE WEEK TRIAL 4REATMENT WITH 4RADJENTA© LINAGLIPTIN MG DAILY PROVIDED STATISTICALLY SIGNIlCANT IMPROVEMENTS IN ! #

&0' AND HOUR 00' COMPARED WITH PLACEBO 4ABLE )N THE WEEK STUDY OF PATIENTS RECEIVING 42!$*%.4! MG AND WHO RECEIVED PLACEBO REQUIRED RESCUE THERAPY )N THE WEEK STUDY

OF PATIENTS RECEIVING 42!$*%.4! MG AND OF PATIENTS RECEIVING PLACEBO REQUIRED RESCUE THERAPY 4HE IMPROVEMENT IN ! # COMPARED WITH PLACEBO WAS NOT AFFECTED BY GENDER AGE RACE PRIOR ANTIHYPERGLYCEMIC THERAPY BASELINE "-) OR A STANDARD INDEX OF INSULIN RESISTANCE (/-! )2 !S IS TYPICAL FOR TRIALS OF AGENTS TO TREAT TYPE DIABETES THE MEAN REDUCTION IN ! # WITH 42!$*%.4! APPEARS TO BE RELATED TO THE DEGREE OF ! # ELEVATION AT BASELINE )N THESE AND WEEK STUDIES THE CHANGES FROM BASELINE IN ! # WERE AND RESPECTIVELY FOR THOSE GIVEN 42!$*%.4!

AND AND

RESPECTIVELY FOR THOSE GIVEN PLACEBO #HANGE FROM BASELINE IN BODY WEIGHT DID NOT DIFFER SIGNIlCANTLY BETWEEN THE GROUPS Table 4

Glycemic Parameters in Placebo-Controlled Monotherapy Studies of TRADJENTA* 18-Week Study 24-Week Study TRADJENTA Placebo TRADJENTA Placebo 5 mg 5 mg

A1C (%) .UMBER OF PATIENTS "ASELINE MEAN #HANGE FROM BASELINE ADJUSTED MEAN $IFFERENCE FROM PLACEBO ADJUSTED MEAN #) 0ATIENTS ;N = ACHIEVING ! # FPG (mg/dL) .UMBER OF PATIENTS "ASELINE MEAN #HANGE FROM BASELINE ADJUSTED MEAN $IFFERENCE FROM PLACEBO ADJUSTED MEAN #)

N

N

â&#x20AC;&#x201C;

N

N

â&#x20AC;&#x201C;

2-hour PPG (mg/dL) .UMBER OF PATIENTS

$ATA NOT AVAILABLE "ASELINE MEAN â&#x20AC;&#x201C; #HANGE FROM BASELINE ADJUSTED MEAN â&#x20AC;&#x201C; $IFFERENCE FROM PLACEBO ADJUSTED MEAN #) â&#x20AC;&#x201C;

$ATA NOT AVAILABLE â&#x20AC;&#x201C; â&#x20AC;&#x201C; â&#x20AC;&#x201C;

N

N

â&#x20AC;&#x201C;

Table 6

N

N

â&#x20AC;&#x201C;

N

N

A1C (%) .UMBER OF PATIENTS "ASELINE MEAN #HANGE FROM BASELINE ADJUSTED MEAN $IFFERENCE FROM GLIMEPIRIDE ADJUSTED MEAN #) FPG (mg/dL) .UMBER OF PATIENTS "ASELINE MEAN #HANGE FROM BASELINE ADJUSTED MEAN Hypoglycemia incidence (%) .UMBER OF PATIENTS )NCIDENCE

â&#x20AC;&#x201C;

&ULL ANALYSIS POPULATION USING LAST OBSERVATION ON STUDY

14.2 Combination Therapy Add-on Combination Therapy with Metformin ! TOTAL OF PATIENTS WITH TYPE DIABETES PARTICIPATED IN A WEEK RANDOMIZED DOUBLE BLIND

PLACEBO CONTROLLED STUDY DESIGNED TO ASSESS THE EFlCACY OF LINAGLIPTIN IN COMBINATION WITH METFORMIN 0ATIENTS ALREADY ON METFORMIN N AT A DOSE OF AT LEAST MG PER DAY WERE RANDOMIZED AFTER COMPLETING A WEEK OPEN LABEL PLACEBO RUN IN PERIOD 0ATIENTS ON METFORMIN AND ANOTHER ANTIHYPERGLYCEMIC AGENT N WERE RANDOMIZED AFTER A RUN IN PERIOD OF APPROXIMATELY WEEKS ON METFORMIN AT A DOSE OF AT LEAST MG PER DAY IN MONOTHERAPY 0ATIENTS WERE RANDOMIZED TO THE ADDITION OF EITHER LINAGLIPTIN MG OR PLACEBO ADMINISTERED ONCE DAILY 0ATIENTS WHO FAILED TO MEET SPECIlC GLYCEMIC GOALS DURING THE STUDIES WERE TREATED WITH GLIMEPIRIDE RESCUE )N COMBINATION WITH METFORMIN LINAGLIPTIN PROVIDED STATISTICALLY SIGNIlCANT IMPROVEMENTS IN ! # &0'

AND HOUR 00' COMPARED WITH PLACEBO 4ABLE 2ESCUE GLYCEMIC THERAPY WAS USED IN OF PATIENTS TREATED WITH LINAGLIPTIN MG AND IN OF PATIENTS TREATED WITH PLACEBO ! SIMILAR DECREASE IN BODY WEIGHT WAS OBSERVED FOR BOTH TREATMENT GROUPS Table 5

Glycemic Parameters in Placebo-Controlled Study for TRADJENTA in Combination with Metformin* TRADJENTA 5 mg + Metformin

Placebo + Metformin

.UMBER OF PATIENTS

N

N

"ASELINE MEAN

#HANGE FROM BASELINE ADJUSTED MEAN

A1C (%)

$IFFERENCE FROM PLACEBO METFORMIN ADJUSTED MEAN #)

â&#x20AC;&#x201C;

0ATIENTS ;N = ACHIEVING ! #

.UMBER OF PATIENTS

N

N

"ASELINE MEAN

#HANGE FROM BASELINE ADJUSTED MEAN

$IFFERENCE FROM PLACEBO METFORMIN ADJUSTED MEAN #)

â&#x20AC;&#x201C;

.UMBER OF PATIENTS

N

N

"ASELINE MEAN

#HANGE FROM BASELINE ADJUSTED MEAN

$IFFERENCE FROM PLACEBO METFORMIN ADJUSTED MEAN #)

â&#x20AC;&#x201C;

FPG (mg/dL)

2-hour PPG (mg/dL)

&ULL ANALYSIS POPULATION USING LAST OBSERVATION ON STUDY

46

Active-Controlled Study vs Glimepiride in Combination with Metformin 4HE EFlCACY OF LINAGLIPTIN IS BEING EVALUATED IN A WEEK DOUBLE BLIND GLIMEPIRIDE CONTROLLED NON INFERIORITY STUDY IN PATIENTS WITH TYPE DIABETES WITH INSUFlCIENT GLYCEMIC CONTROL DESPITE METFORMIN THERAPY 0ATIENTS BEING TREATED WITH METFORMIN ONLY ENTERED A RUN IN PERIOD OF WEEKS DURATION

WHEREAS PATIENTS PRETREATED WITH METFORMIN AND ONE ADDITIONAL ANTIHYPERGLYCEMIC AGENT ENTERED A RUN IN TREATMENT PERIOD OF WEEKS DURATION WITH METFORMIN MONOTHERAPY DOSE OF * MG DAY AND WASHOUT OF THE OTHER AGENT !FTER AN ADDITIONAL WEEK PLACEBO RUN IN PERIOD THOSE WITH INADEQUATE GLYCEMIC CONTROL ! # TO WERE RANDOMIZED TO THE ADDITION OF LINAGLIPTIN MG ONCE DAILY OR GLIMEPIRIDE 0ATIENTS RECEIVING GLIMEPIRIDE WERE GIVEN AN INITIAL DOSE OF MG DAY AND THEN ELECTIVELY TITRATED OVER THE NEXT WEEKS TO A MAXIMUM DOSE OF MG DAY AS NEEDED TO OPTIMIZE GLYCEMIC CONTROL 4HEREAFTER THE GLIMEPIRIDE DOSE WAS TO BE KEPT CONSTANT EXCEPT FOR DOWN TITRATION TO PREVENT HYPOGLYCEMIA !FTER WEEKS LINAGLIPTIN AND GLIMEPIRIDE BOTH HAD REDUCTIONS FROM BASELINE IN ! # FOR LINAGLIPTIN FOR GLIMEPIRIDE FROM A BASELINE MEAN OF 4ABLE 4HE MEAN DIFFERENCE BETWEEN GROUPS IN ! # CHANGE FROM BASELINE WAS WITH SIDED CONlDENCE INTERVAL

FOR THE INTENT TO TREAT POPULATION USING LAST OBSERVATION CARRIED FORWARD 4HESE RESULTS WERE CONSISTENT WITH THE COMPLETERS ANALYSIS 0ATIENTS TREATED WITH LINAGLIPTIN EXHIBITED A SIGNIlCANT MEAN DECREASE FROM BASELINE BODY WEIGHT COMPARED TO A SIGNIlCANT WEIGHT GAIN IN PATIENTS ADMINISTERED GLIMEPIRIDE KG VS KG P

AMERICAN HEALTH & DRUG BENEFITS

June 2012

Glycemic Parameters at 52 Weeks in Study Comparing TRADJENTA to Glimepiride as Add-On Therapy in Patients Inadequately Controlled on Metformin** TRADJENTA 5 mg Glimepiride + Metformin + Metformin (mean Glimepiride dose 3 mg) N

â&#x20AC;&#x201C;

N

N

N

N

N

P VS GLIMEPIRIDE

&ULL ANALYSIS POPULATION USING LAST OBSERVATION ON STUDY

Add-On Combination Therapy with Pioglitazone ! TOTAL OF PATIENTS WITH TYPE DIABETES PARTICIPATED IN A WEEK RANDOMIZED DOUBLE BLIND

PLACEBO CONTROLLED STUDY DESIGNED TO ASSESS THE EFlCACY OF LINAGLIPTIN IN COMBINATION WITH PIOGLITAZONE 4HERAPY WAS STOPPED IN PATIENTS ON ORAL ANTIHYPERGLYCEMIC THERAPY FOR A PERIOD OF WEEKS WEEKS FOLLOWED BY A WEEK OPEN LABEL PLACEBO RUN IN PERIOD $RUG NAÃ&#x2022;VE PATIENTS ENTERED DIRECTLY INTO THE WEEK PLACEBO RUN IN PERIOD !FTER THE RUN IN PERIOD PATIENTS WERE RANDOMIZED TO RECEIVE EITHER LINAGLIPTIN MG OR PLACEBO BOTH IN ADDITION TO PIOGLITAZONE MG DAILY 0ATIENTS WHO FAILED TO MEET SPECIlC GLYCEMIC GOALS DURING THE STUDIES WERE TREATED WITH METFORMIN RESCUE 'LYCEMIC ENDPOINTS MEASURED WERE ! # AND &0' )N INITIAL COMBINATION WITH PIOGLITAZONE MG LINAGLIPTIN MG PROVIDED STATISTICALLY SIGNIlCANT IMPROVEMENTS IN ! # AND &0' COMPARED TO PLACEBO WITH PIOGLITAZONE 4ABLE 2ESCUE THERAPY WAS USED IN OF PATIENTS TREATED WITH LINAGLIPTIN MG PIOGLITAZONE MG AND OF PATIENTS TREATED WITH PLACEBO PIOGLITAZONE MG 0ATIENT WEIGHT INCREASED IN BOTH GROUPS DURING THE STUDY WITH AN ADJUSTED MEAN CHANGE FROM BASELINE OF KG AND KG IN THE LINAGLIPTIN MG PIOGLITAZONE MG AND PLACEBO PIOGLITAZONE MG GROUPS RESPECTIVELY P Table 7

Glycemic Parameters in Placebo-Controlled Study for TRADJENTA in Combination Therapy with Pioglitazone* TRADJENTA 5 mg + Pioglitazone Placebo + Pioglitazone

A1C (%) .UMBER OF PATIENTS "ASELINE MEAN #HANGE FROM BASELINE ADJUSTED MEAN $IFFERENCE FROM PLACEBO PIOGLITAZONE ADJUSTED MEAN #) 0ATIENTS ;N = ACHIEVING ! # FPG (mg/dL) .UMBER OF PATIENTS "ASELINE MEAN #HANGE FROM BASELINE ADJUSTED MEAN $IFFERENCE FROM PLACEBO PIOGLITAZONE ADJUSTED MEAN #)

N

N

â&#x20AC;&#x201C;

N

N

â&#x20AC;&#x201C;

&ULL ANALYSIS POPULATION USING LAST OBSERVATION ON STUDY

Add-On Combination with Sulfonylureas ! TOTAL OF PATIENTS WITH TYPE DIABETES PARTICIPATED IN AN WEEK RANDOMIZED DOUBLE BLIND

PLACEBO CONTROLLED STUDY DESIGNED TO ASSESS THE EFlCACY OF LINAGLIPTIN IN COMBINATION WITH SULFONYLUREA 35 0ATIENTS ON SULFONYLUREA MONOTHERAPY N WERE RANDOMIZED AFTER COMPLETING A WEEK

SINGLE BLIND PLACEBO RUN IN PERIOD 0ATIENTS ON A SULFONYLUREA PLUS ONE ADDITIONAL ORAL ANTIHYPERGLYCEMIC AGENT N WERE RANDOMIZED AFTER A WASH OUT PERIOD OF WEEKS AND A WEEK SINGLE BLIND

PLACEBO RUN IN PERIOD 0ATIENTS WERE RANDOMIZED TO THE ADDITION OF LINAGLIPTIN MG OR TO PLACEBO EACH ADMINISTERED ONCE DAILY 0ATIENTS WHO FAILED TO MEET SPECIlC GLYCEMIC GOALS DURING THE STUDIES WERE TREATED WITH METFORMIN RESCUE 'LYCEMIC ENDPOINTS MEASURED INCLUDED ! # AND &0'

)N COMBINATION WITH A SULFONYLUREA LINAGLIPTIN PROVIDED STATISTICALLY SIGNIlCANT IMPROVEMENTS IN ! # COMPARED WITH PLACEBO FOLLOWING WEEKS TREATMENT THE IMPROVEMENTS IN &0' OBSERVED WITH LINAGLIPTIN WERE NOT STATISTICALLY SIGNIlCANT COMPARED WITH PLACEBO 4ABLE 2ESCUE THERAPY WAS USED IN OF PATIENTS TREATED WITH LINAGLIPTIN MG AND OF PATIENTS TREATED WITH PLACEBO 4HERE WAS NO SIGNIlCANT DIFFERENCE BETWEEN LINAGLIPTIN AND PLACEBO IN BODY WEIGHT Table 8

Glycemic Parameters in Placebo-Controlled Study for TRADJENTA in Combination with Sulfonylurea*

A1C (%) .UMBER OF PATIENTS "ASELINE MEAN #HANGE FROM BASELINE ADJUSTED MEAN $IFFERENCE FROM PLACEBO 35 ADJUSTED MEAN #) 0ATIENTS ;N = ACHIEVING ! # FPG (mg/dL) .UMBER OF PATIENTS "ASELINE MEAN #HANGE FROM BASELINE ADJUSTED MEAN $IFFERENCE FROM PLACEBO 35 ADJUSTED MEAN #)

TRADJENTA 5 mg + SU

Placebo + SU

N

N

â&#x20AC;&#x201C;

N

N

â&#x20AC;&#x201C;

35 SULFONYLUREA

&ULL ANALYSIS POPULATION USING LAST OBSERVATION ON STUDY

)NSTRUCT PATIENTS TO READ THE 0ATIENT )NFORMATION BEFORE STARTING 42!$*%.4! THERAPY AND TO REREAD IT EACH TIME THE PRESCRIPTION IS RENEWED )NSTRUCT PATIENTS TO INFORM THEIR DOCTOR OR PHARMACIST IF THEY DEVELOP ANY UNUSUAL SYMPTOM OR IF ANY KNOWN SYMPTOM PERSISTS OR WORSENS 17.2 Laboratory Tests )NFORM PATIENTS THAT RESPONSE TO ALL DIABETIC THERAPIES SHOULD BE MONITORED BY PERIODIC MEASUREMENTS OF BLOOD GLUCOSE AND ! # LEVELS WITH A GOAL OF DECREASING THESE LEVELS TOWARD THE NORMAL RANGE ! # MONITORING IS ESPECIALLY USEFUL FOR EVALUATING LONG TERM GLYCEMIC CONTROL $ISTRIBUTED BY "OEHRINGER )NGELHEIM 0HARMACEUTICALS )NC 2IDGElELD #4 53!

-ARKETED BY "OEHRINGER )NGELHEIM 0HARMACEUTICALS )NC 2IDGElELD #4 53!

AND %LI ,ILLY AND #OMPANY )NDIANAPOLIS ). 53! ,ICENSED FROM "OEHRINGER )NGELHEIM )NTERNATIONAL 'MB( )NGELHEIM 'ERMANY #OPYRIGHT "OEHRINGER )NGELHEIM )NTERNATIONAL 'MB( !,, 2)'(43 2%3%26%$

)4 $' Add-On Combination Therapy with Metformin and a Sulfonylurea ! TOTAL OF PATIENTS WITH TYPE DIABETES PARTICIPATED IN A WEEK RANDOMIZED DOUBLE BLIND

PLACEBO CONTROLLED STUDY DESIGNED TO ASSESS THE EFlCACY OF LINAGLIPTIN IN COMBINATION WITH A SULFONYLUREA AND METFORMIN 4HE MOST COMMON SULFONYLUREAS USED BY PATIENTS IN THE STUDY WERE GLIMEPIRIDE

GLIBENCLAMIDE AND GLICLAZIDE NOT AVAILABLE IN THE 5NITED 3TATES 0ATIENTS ON A SULFONYLUREA AND METFORMIN WERE RANDOMIZED TO RECEIVE LINAGLIPTIN MG OR PLACEBO EACH ADMINISTERED ONCE DAILY 0ATIENTS WHO FAILED TO MEET SPECIlC GLYCEMIC GOALS DURING THE STUDY WERE TREATED WITH PIOGLITAZONE RESCUE 'LYCEMIC ENDPOINTS MEASURED INCLUDED ! # AND &0' )N COMBINATION WITH A SULFONYLUREA AND METFORMIN 42!$*%.4! PROVIDED STATISTICALLY SIGNIlCANT IMPROVEMENTS IN ! # AND &0' COMPARED WITH PLACEBO 4ABLE )N THE ENTIRE STUDY POPULATION PATIENTS ON 42!$*%.4! IN COMBINATION WITH SULFONYLUREA AND METFORMIN A MEAN REDUCTION FROM BASELINE RELATIVE TO PLACEBO IN ! # OF AND IN &0' OF MG D, WAS SEEN 2ESCUE THERAPY WAS USED IN OF PATIENTS TREATED WITH 42!$*%.4! MG AND IN OF PATIENTS TREATED WITH PLACEBO #HANGE FROM BASELINE IN BODY WEIGHT DID NOT DIFFER SIGNIlCANTLY BETWEEN THE GROUPS Table 9

Glycemic Parameters in Placebo-Controlled Study for TRADJENTA in Combination with Metformin and Sulfonylurea*

)4 $

PATIENT INFORMATION

TRADJENTAâ&#x201E;¢ (TRAD gen ta) (linagliptin) Tablets

TRADJENTA 5 mg + Placebo + Metformin + SU Metformin + SU A1C (%) .UMBER OF PATIENTS "ASELINE MEAN #HANGE FROM BASELINE ADJUSTED MEAN $IFFERENCE FROM PLACEBO ADJUSTED MEAN #) 0ATIENTS ;N = ACHIEVING ! # FPG (mg/dL) .UMBER OF PATIENTS "ASELINE MEAN #HANGE FROM BASELINE ADJUSTED MEAN $IFFERENCE FROM PLACEBO ADJUSTED MEAN #)

N

N

â&#x20AC;&#x201C;

N

N

â&#x20AC;&#x201C;

35 SULFONYLUREA

&ULL ANALYSIS POPULATION USING LAST OBSERVATION ON STUDY

16

HOW SUPPLIED/STORAGE AND HANDLING

42!$*%.4! TABLETS ARE AVAILABLE AS LIGHT RED ROUND BICONVEX BEVEL EDGED lLM COATED TABLETS CONTAINING MG OF LINAGLIPTIN 42!$*%.4! TABLETS ARE DEBOSSED WITH h$ v ON ONE SIDE AND THE "OEHRINGER )NGELHEIM LOGO ON THE OTHER SIDE 4HEY ARE SUPPLIED AS FOLLOWS "OTTLES OF .$# "OTTLES OF .$# "OTTLES OF .$# #ARTONS CONTAINING BLISTER CARDS OF TABLETS EACH X .$# )F REPACKAGING IS REQUIRED DISPENSE IN A TIGHT CONTAINER AS DElNED IN 530 Storage Store at 25°C (77°F); excursions permitted to 15°-30°C (59°-86°F) ;SEE 530 #ONTROLLED 2OOM 4EMPERATURE= 3TORE IN A SAFE PLACE OUT OF REACH OF CHILDREN

17

PATIENT COUNSELING INFORMATION

See FDA-Approved Patient Labeling.

17.1 Instructions )NFORM PATIENTS OF THE POTENTIAL RISKS AND BENElTS OF 42!$*%.4! AND OF ALTERNATIVE MODES OF THERAPY !LSO INFORM PATIENTS ABOUT THE IMPORTANCE OF ADHERENCE TO DIETARY INSTRUCTIONS REGULAR PHYSICAL ACTIVITY

PERIODIC BLOOD GLUCOSE MONITORING AND ! # TESTING RECOGNITION AND MANAGEMENT OF HYPOGLYCEMIA AND HYPERGLYCEMIA AND ASSESSMENT FOR DIABETES COMPLICATIONS !DVISE PATIENTS TO SEEK MEDICAL ADVICE PROMPTLY DURING PERIODS OF STRESS SUCH AS FEVER TRAUMA INFECTION OR SURGERY AS MEDICATION REQUIREMENTS MAY CHANGE )NSTRUCT PATIENTS TO TAKE 42!$*%.4! ONLY AS PRESCRIBED )F A DOSE IS MISSED ADVISE PATIENTS NOT TO DOUBLE THEIR NEXT DOSE

)4 !

2EAD THIS 0ATIENT )NFORMATION BEFORE YOU START TAKING 42!$*%.4! TABLETS AND EACH TIME YOU GET A RElLL 4HERE MAY BE NEW INFORMATION 4HIS INFORMATION DOES NOT TAKE THE PLACE OF TALKING TO YOUR DOCTOR ABOUT YOUR MEDICAL CONDITION OR YOUR TREATMENT

What is TRADJENTA? s 42!$*%.4! IS A PRESCRIPTION MEDICINE USED ALONG WITH DIET AND EXERCISE TO LOWER BLOOD SUGAR IN ADULTS WITH TYPE DIABETES s 42!$*%.4! IS NOT FOR PEOPLE WITH TYPE DIABETES s 42!$*%.4! IS NOT FOR PEOPLE WITH DIABETIC KETOACIDOSIS INCREASED KETONES IN THE BLOOD OR URINE s )T IS NOT KNOWN IF 42!$*%.4! IS SAFE AND EFFECTIVE WHEN USED WITH INSULIN s )T IS NOT KNOWN IF 42!$*%.4! IS SAFE AND EFFECTIVE IN CHILDREN

Who should not take TRADJENTA? Do not take TRADJENTA if you: s ARE ALLERGIC TO LINAGLIPTIN OR ANY OF THE INGREDIENTS IN 42!$*%.4! 3EE THE END OF THIS LEAmET FOR A COMPLETE LIST OF INGREDIENTS IN 42!$*%.4!

Symptoms of a serious allergic reaction to TRADJENTA are: s RASH s RAISED RED PATCHES ON YOUR SKIN HIVES s SWELLING OF YOUR FACE LIPS AND THROAT THAT MAY CAUSE DIFlCULTY BREATHING OR SWALLOWING

What should I tell my doctor before using TRADJENTA? Before you take TRADJENTA, tell your doctor if you: s HAVE ANY OTHER MEDICAL CONDITIONS s ARE PREGNANT OR PLANNING TO BECOME PREGNANT )T IS NOT KNOWN IF 42!$*%.4!

WILL HARM YOUR UNBORN BABY )F YOU ARE PREGNANT TALK WITH YOUR DOCTOR ABOUT THE BEST WAY TO CONTROL YOUR BLOOD SUGAR WHILE YOU ARE PREGNANT s ARE BREASTFEEDING OR PLAN TO BREASTFEED )T IS NOT KNOWN IF 42!$*%.4! PASSES INTO YOUR BREAST MILK 4ALK WITH YOUR DOCTOR ABOUT THE BEST WAY TO FEED YOUR BABY IF YOU TAKE 42!$*%.4!

Tell your doctor about all the medicines you take, INCLUDING PRESCRIPTION AND NON PRESCRIPTION MEDICINES VITAMINS AND HERBAL SUPPLEMENTS June 2012

www.AHDBonline.com

47

4RADJENTA© LINAGLIPTIN MAY AFFECT THE WAY OTHER MEDICINES WORK AND OTHER MEDICINES MAY AFFECT HOW 42!$*%.4! WORKS Especially tell your doctor if you take s OTHER MEDICINES THAT CAN LOWER YOUR BLOOD SUGAR s RIFAMPIN 2IFADIN® 2IMACTANE® 2IFATER® 2IFAMATE®

AN ANTIBIOTIC THAT IS USED TO TREAT TUBERCULOSIS

How should I store TRADJENTA? s 3TORE 42!$*%.4! AT ª& TO ª& ª# TO ª# Keep TRADJENTA and all medicines out of the reach of children.

General information about the safe and effective use of TRADJENTA.

-EDICINES ARE SOMETIMES PRESCRIBED FOR PURPOSES OTHER THAN THOSE LISTED IN 0ATIENT )NFORMATION LEAmETS $O NOT USE 42!$*%.4! FOR A CONDITION FOR WHICH IT WAS NOT PRESCRIBED $O NOT GIVE 42!$*%.4! TO OTHER PEOPLE EVEN IF THEY HAVE THE SAME SYMPTOMS YOU HAVE )T MAY HARM THEM 4HIS 0ATIENT )NFORMATION SUMMARIZES THE MOST IMPORTANT INFORMATION ABOUT 42!$*%.4! )F YOU WOULD LIKE MORE INFORMATION TALK WITH YOUR DOCTOR 9OU CAN ASK How should I take TRADJENTA? s 4AKE 42!$*%.4! TIME EACH DAY EXACTLY AS YOUR DOCTOR TELLS YOU TO TAKE IT YOUR PHARMACIST OR DOCTOR FOR INFORMATION ABOUT 42!$*%.4! THAT IS WRITTEN FOR HEALTH PROFESSIONALS s 4ALK WITH YOUR DOCTOR IF YOU DO NOT UNDERSTAND HOW TO TAKE 42!$*%.4! s 9OUR DOCTOR WILL TELL YOU WHEN TO TAKE 42!$*%.4! &OR MORE INFORMATION GO TO WWW 42!$*%.4! COM OR CALL "OEHRINGER )NGELHEIM s 4AKE 42!$*%.4! WITH OR WITHOUT FOOD 0HARMACEUTICALS )NC AT OR 449 s )F YOU MISS A DOSE TAKE IT AS SOON AS YOU REMEMBER )F YOU DO NOT REMEMBER UNTIL IT IS TIME FOR YOUR NEXT DOSE SKIP THE MISSED DOSE AND GO BACK TO YOUR What are the ingredients in TRADJENTA? REGULAR SCHEDULE $O NOT TAKE TWO DOSES OF 42!$*%.4! AT THE SAME TIME !CTIVE )NGREDIENT LINAGLIPTIN s 9OUR DOCTOR MAY TELL YOU TO TAKE 42!$*%.4! ALONG WITH OTHER DIABETES MEDI)NACTIVE )NGREDIENTS MANNITOL PREGELATINIZED STARCH CORN STARCH COPOVIDONE AND CINES ,OW BLOOD SUGAR CAN HAPPEN MORE OFTEN WHEN 42!$*%.4! IS TAKEN MAGNESIUM STEARATE 4HE lLM COATING CONTAINS THE FOLLOWING INACTIVE INGREDIENTS WITH CERTAIN OTHER DIABETES MEDICINES 3EE h7HAT ARE THE POSSIBLE SIDE HYPROMELLOSE TITANIUM DIOXIDE TALC POLYETHYLENE GLYCOL AND RED FERRIC OXIDE EFFECTS OF 42!$*%.4! v s )F YOU TAKE TOO MUCH 42!$*%.4!

CALL YOUR DOCTOR OR 0OISON #ONTROL #ENTER AT What is type 2 diabetes?

OR GO TO THE NEAREST HOSPITAL EMERGENCY ROOM RIGHT AWAY 4YPE DIABETES IS A CONDITION IN WHICH YOUR BODY DOES NOT MAKE ENOUGH INSULIN

s 7HEN YOUR BODY IS UNDER SOME TYPES OF STRESS SUCH AS FEVER TRAUMA SUCH AND OR THE INSULIN THAT YOUR BODY PRODUCES DOES NOT WORK AS WELL AS IT SHOULD 9OUR AS A CAR ACCIDENT INFECTION OR SURGERY THE AMOUNT OF DIABETES MEDICINE BODY CAN ALSO MAKE TOO MUCH SUGAR 7HEN THIS HAPPENS SUGAR GLUCOSE BUILDS THAT YOU NEED MAY CHANGE 4ELL YOUR DOCTOR RIGHT AWAY IF YOU HAVE ANY OF UP IN THE BLOOD 4HIS CAN LEAD TO SERIOUS MEDICAL PROBLEMS THESE CONDITIONS AND FOLLOW YOUR DOCTOR S INSTRUCTIONS 4HE MAIN GOAL OF TREATING DIABETES IS TO LOWER YOUR BLOOD SUGAR TO A NORMAL LEVEL s #HECK YOUR BLOOD SUGAR AS YOUR DOCTOR TELLS YOU TO s 3TAY ON YOUR PRESCRIBED DIET AND EXERCISE PROGRAM WHILE TAKING 42!$*%.4! (IGH BLOOD SUGAR CAN BE LOWERED BY DIET AND EXERCISE AND BY CERTAIN MEDICINES s 4ALK TO YOUR DOCTOR ABOUT HOW TO PREVENT RECOGNIZE AND MANAGE LOW BLOOD WHEN NECESSARY SUGAR HYPOGLYCEMIA HIGH BLOOD SUGAR HYPERGLYCEMIA AND COMPLICATIONS 4HIS 0ATIENT )NFORMATION HAS BEEN APPROVED BY THE 5 3 &OOD AND $RUG !DMINISTRATION OF DIABETES s 9OUR DOCTOR WILL CHECK YOUR DIABETES WITH REGULAR BLOOD TESTS INCLUDING YOUR $ISTRIBUTED BY BLOOD SUGAR LEVELS AND YOUR HEMOGLOBIN ! # "OEHRINGER )NGELHEIM 0HARMACEUTICALS )NC !SK YOUR DOCTOR OR PHARMACIST FOR A LIST OF THESE MEDICINES IF YOU ARE NOT SURE IF YOUR MEDICINE IS ONE THAT IS LISTED ABOVE +NOW THE MEDICINES YOU TAKE +EEP A LIST OF THEM AND SHOW IT TO YOUR DOCTOR AND PHARMACIST WHEN YOU GET A NEW MEDICINE

What are the possible side effects of TRADJENTA? TRADJENTA may cause side effects, including: s low blood sugar (hypoglycemia). )F YOU TAKE 42!$*%.4! WITH ANOTHER MEDICINE THAT CAN CAUSE LOW BLOOD SUGAR SUCH AS A SULFONYLUREA OR INSULIN

YOUR RISK OF GETTING LOW BLOOD SUGAR IS HIGHER 4HE DOSE OF YOUR SULFONYLUREA MEDICINE OR INSULIN MAY NEED TO BE LOWERED WHILE YOU TAKE 42!$*%.4! 3IGNS AND SYMPTOMS OF LOW BLOOD SUGAR MAY INCLUDE s HEADACHE s DROWSINESS s WEAKNESS s DIZZINESS s CONFUSION

s IRRITABILITY s HUNGER s FAST HEART BEAT s SWEATING s FEELING JITTERY

4HE BRANDS LISTED ARE TRADEMARKS OF THEIR RESPECTIVE OWNERS AND ARE NOT TRADEMARKS OF "OEHRINGER )NGELHEIM 0HARMACEUTICALS )NC 4HE MAKERS OF THESE BRANDS ARE NOT AFlLIATED WITH AND DO NOT ENDORSE "OEHRINGER )NGELHEIM 0HARMACEUTICALS )NC OR ITS PRODUCTS #OPYRIGHT "OEHRINGER )NGELHEIM )NTERNATIONAL 'MB( !,, 2)'(43 2%3%26%$

4HE MOST COMMON SIDE EFFECTS OF 42!$*%.4! INCLUDE s STUFFY OR RUNNY NOSE AND SORE THROAT 4ELL YOUR DOCTOR IF YOU HAVE ANY SIDE EFFECT THAT BOTHERS YOU OR THAT DOES NOT GO AWAY 4HESE ARE NOT ALL THE POSSIBLE SIDE EFFECTS OF 42!$*%.4! &OR MORE INFORMATION

ASK YOUR DOCTOR OR PHARMACIST #ALL YOUR DOCTOR FOR MEDICAL ADVICE ABOUT SIDE EFFECTS 9OU MAY REPORT SIDE EFFECTS TO &$! AT &$!

48

AMERICAN HEALTH & DRUG BENEFITS

2IDGElELD #4 53!

-ARKETED BY "OEHRINGER )NGELHEIM 0HARMACEUTICALS )NC 2IDGElELD #4 53!

AND %LI ,ILLY AND #OMPANY )NDIANAPOLIS ). 53! ,ICENSED FROM "OEHRINGER )NGELHEIM )NTERNATIONAL 'MB( )NGELHEIM 'ERMANY

June 2012

)4 $'

)4 $

)4 !

2EVISED *ULY

4* 02/&

CALL FOR PAPERS Value-Based Care in Cardiometabolic Health American Health & Drug Benefits offers an open forum for all healthcare participants to exchange ideas and present their data, innovations, and initiatives to facilitate patient-centered healthcare and benefit design models that meet the needs of all stakeholders—Distributors, Employers, Manufacturers, Patients, Payers, Providers, Purchasers, Regulators, and Researchers.

American Health & Drug Benefits is publishing a theme issue on cardiometabolic health this year.

Readers are invited to submit articles on topics relevant to the clinical, business, and policy aspects of cardiometabolic health. Original research studies, white papers, evidence-based comprehensive reviews, case studies, and commentaries are of particular interest.

Articles must be original and should aim at improving the quality of patient care and patient wellbeing while controlling costs.

Areas of High Interest: • Benefit design and cardiometabolic outcomes

• Initiatives in cardiometabolic health and wellness

• Best practices in insulin control, lipid management, obesity, or blood pressure control

• Lifestyle strategies and cardiometabolic health • Lipid management

• Comparative effectiveness analyses of best therapies for cardiovascular health

• Medication adherence and diabetes progression

• Cost-effectiveness comparisons

• New biomarkers for assessing cardiometabolic risk

• Glycemic control in the outpatient/ inpatient setting

• New and emerging therapies • Obesity management

• Employer strategies to improve employees’ CVD health • Hot topics in diabetes, obesity, or CVD

• Prevention strategies for cardiometabolic risk reduction

Extended deadline for article submission: August 6, 2012.

All articles will undergo the Journal’s standard peer-review process.

Articles should follow the Manuscript Instructions for Authors (www.AHDBonline.com) Submit articles to editorial@engagehc.com, or call 732-992-1889

50

AMERICAN HEALTH & DRUG BENEFITS

June 2012

The 2012 Pharmaceutical Pipeline (As of June 8, 2012)

By Karen Cooksey and Dalia Buffery

L

ast year, the US Food and Drug Administration (FDA) approved approximately 32 new drugs (35 in fiscal year 2011), depending on which drugs are counted; this included 10 orphan drugs, a trend that is expected to continue, as well as many drugs with new mechanisms of action or first-ever medications for certain conditions.1 Although the total number of FDA approvals for new drugs will likely be smaller in 2012 than in 2011, other recent trends in the pharmaceutical pipeline will continue and perhaps intensify in 2012, such as a growing surge in cancer drugs and orphan drugs in the pipeline, the steady focus by pharmaceutical companies on specialty drugs, the increasing number of companion testing with targeted therapies, and the transition from injections to oral administration of biologic agents for a variety of disease states, including cancer.

The focus on specialty drugs has gradually been transforming drug development, as can be seen in the number of traditional versus specialty drugs approved by the FDA. In 2008, the FDA approved 16 small-molecule traditional drugs and 8 specialty drugs; in 2011, that ratio was reversed, with a total of 12 traditional and 18 specialty drugs approved.2 So far in 2012, the FDA has signaled it would continue to expedite its review process by applying the priority review process when the evidence is deemed appropriate.

By mid-June, 14 new brand-name drugs were approved by the FDA (Table 1), and many important drugs are expected to be approved throughout the year, although it is generally accepted that the era of the “blockbuster drug” is over.

Cancer drugs continue to lead the way in 2012 in the pharmaceutical pipeline. Early in June, the FDA indicated it expected another 20 cancer drug applications to be submitted this year for approval.3 Since then, 1 new cancer drug has been approved (Table 1), and several New Drug Applications (NDAs) have been accepted.

One trend that may be reversed in 2012 is the number of new drugs that are approved with the Risk Evaluation and Mitigation Strategy (REMS) program.

Compared with 2011, the number of new drugs, including biologics, approved with the REMS requirement has so far decreased considerably in 2012.

Among the significant drugs that are likely to come up for FDA approval this year are 4 new drugs for the treatment of multiple sclerosis, including new oral disease-modifying drugs; as well as the 2 obesity drugs,

lorcaserin hydrochloride and phentermine/topiramate.

Currently, the disease states with the highest number of drugs in the pipeline are: • Cancer, >320 drugs • Central nervous system (CNS) disorders, >150 drugs • Diabetes, >80 drugs • Cardiovascular disease (CVD) and infectious diseases, >70 drugs each • Respiratory diseases, >60 drugs • Rheumatic diseases, >50 drugs.

Promising Drugs in Late-Stage Development Table 2 lists some of the major drugs expected to come up for approval in 2012 or in early 2013.

Cancer

By June 8, 2012, 5 new cancer drugs have been approved by the FDA. The approval of the most recent cancer drug, Perjeta (pertuzumab), which is indicated for HER2-positive metastatic breast cancer, was expedited by the FDA under the priority review process.

Among the 20 or so cancer drugs expected to be considered by the FDA in 2012,1 perhaps the 3 to watch for include carfilzomib, a proteasome inhibitor for the treatment of refractory or relapsed multiple myeloma, with a PDUFA (Prescription Drug User Fee Act) date of July 27, 2012; pomalidomide, a new immunomodulating drug, to be combined with low-dose dexamethasone, also for the treatment of patients with relapsed or refractory multiple myeloma; and enzalutamide (MDV3100), an androgen receptor antagonist for chemotherapyrefractory prostate cancer, with an NDA submitted this year; if approved, it would be competing with Zytiga (abiraterone acetate) for the treatment of metastatic castration-resistant prostate cancer in patients who have received previous docetaxel chemotherapy. (Enzalutamide is also being studied in patients who have not received chemotherapy.)

CNS Disorders The CNS drug closest to approval is most likely Levadex (dihydroergotamine [DHE]), an orally inhaled agent for the acute treatment of migraine. Levadex is a novel formulation of DHE, which is currently available in other formulations for the treatment of migraine. The FDA issued a complete response letter on March 26, 2012, identifying nonclinical issues that will need to be

June 2012

www.AHDBonline.com

51

THE 2012 PHARMACEUTICAL PIPELINE

Table 1 Significant Drugs Approved by the FDA through June 8, 2012 Approval date

Drug

Indication/route

Voraxaze (glucarpidase)

Methotrexate toxicity, IV

1/17/2012

Picato (ingenol mebutate)

Actinic keratosis, gel

1/23/2012

Inlyta (axitinib)

Advanced renal-cell carcinoma, oral

1/27/2012

Erivedge (vismodegib)

Basal-cell carcinoma, oral

1/30/2012

Kalydeco (ivacaftor)

Cystic fibrosis, oral

1/31/2012

Zioptan (tafluprost ophthalmic solution)

Glaucoma, eye drop

2/10/2012

Korlym (mifepristone)

Cushingâ&#x20AC;&#x2122;s syndrome, oral

2/17/2012

Surfaxin (lucinactant)

Respiratory distress syndrome in infants, intratracheal

3/6/2012

Omontys (peginesatide)

Anemia in dialysis patients with chronic kidney disease, oral

3/27/2012

Amyvid (florbetapir F-18)

4/6/2012 Estimation of brain amyloid plaque content in patients with cognitive decline, IV

Votrient (pazopanib)

Soft-tissue sarcoma, oral

4/26/2012

Stendra (avanafil)

Erectile dysfunction, oral

4/27/2012

Elelyso (taliglucerase alfa)

Gaucher disease, IV

5/1/2012

Perjeta (pertuzumab)

HER2-positive metastatic breast cancer, IV

6/8/2012

Note: Pertzye (pancrelipase) was approved for the treatment of pancreatic exocrine dysfunction on May 17, 2012. It had previously been marketed but without an approved New Drug Application.

resolved, but this will not necessarily prevent an FDA approval later this year.

Diabetes In 2012, only 2 new drugs were expected to be approved

52

AMERICAN HEALTH & DRUG BENEFITS

June 2012

for diabetes. The first is alogliptin, an orally administered dipeptidyl peptidase (DPP)-4 inhibitor, that is being investigated for use as an adjunct to diet and exercise for the treatment of type 2 diabetes. The FDA issued a complete response letter on April 25, 2012, but the company intends to continue working with the FDA on this approval. The second antidiabetes drug is degludec, an ultralong-acting basal insulin, with a July 29, 2012, PDUFA date; if approved, it would be competing with Lantus (insulin glargine) and Levemir (insulin detemir) in this growing marketplace of patients with diabetes.

Cardiovascular Diseases Of the many drugs in the pipeline being developed for CVD conditions, only a few are scheduled for FDA review in 2012. Several new NDAs have been filed or will be filed later in the year, with 1 or 2 drugs expected to be approved in 2012. A July PDUFA date is set for AMR101, an oral agent for patients with very high triglyceride levels (>500 mg/dL).

Infectious Diseases In 2012, the main activity in drug development will involve HIV drugs, with 2 drugs expected to be approved including QUAD (elvitegravir, cobicistat, emtricitabine, tenofovir), a once-daily, 4-drug oral combination that could simplify the antiretroviral treatment in this patient population, and dolutegravir, a new-generation integrase inhibitor that is the first competitor to the sole-approved drug in its class, Isentress (raltegravir).

The anticipated once-daily dosing of dolutegravir will greatly help the marketing of the drug. NDA filing is expected by end of the year.

Respiratory Diseases The front-runner among drugs in the pipeline for respiratory diseases is Eklira (aclidinium), a twice-daily, long-acting muscarinic antagonist oral inhaler for maintenance treatment of bronchospasm associated with chronic obstructive pulmonary disease. Two inhalers containing this agent are in development, one with aclidinium monotherapy and the other with a combination of aclidinium with formoterol.

Rheumatic Diseases Several exciting developments are taking place in the various rheumatic diseases, with an increasing number of biologics entering the pipeline for these conditions. The majority of these agents are expected to reach FDA approval in 2013 or 2014.

Arcalyst (rilonacept), the much anticipated subcutaneous (SC) biologic agent investigated for an expanded indication for the treatment of gout, is scheduled for

THE 2012 PHARMACEUTICAL PIPELINE

Table 2 Key Drugs in the 2012 Pipeline, by Clinical Category, through June 8, 2012 Drug

Drug type, potential indication, route

Expected timeline/comment

Pomalidomide

Next-generation IMiD for relapsed/refractory multiple myeloma, oral

NDA: 6/8/2012 PDUFA: 2/10/2013

Marqibo

Philadelphia negative ALL, IV

Updated PDUFA: 8/12/2012

CANCER

Taltorvic (ridaforolimus) Sarcomas, IV

CRL: 6/5/2012

Carfilzomib

Proteasome inhibitor for refractory multiple myeloma, IV

PDUFA: 7/27/2012

Zaltrap (aflibercept)

Colorectal cancer, IV

PDUFA: 8/4/2012

Ponatinib

First-in-class BCR-ABL inhibitor for CML and ALL, oral

NDA: 3Q 2012

Bosutinib

Leukemia, oral

NDA: 1/27/2012

Enzalutamide (MDV3100)

Androgen receptor antagonist for chemotherapyrefractory prostate cancer, oral

NDA: 5/21/2012; fast track and approval by end of year

CARDIOVASCULAR DISEASES

Eliquis (apixaban)

Factor Xa inhibitor for prevention of VTE and stroke in patients with AF, oral

CRL: 6/25/2012

AMR101

Therapy for very high (>500 mg/dL) triglycerides, oral

PDUFA: 7/26/2012

Lomitapide

Inhibitor of MTP-I for homozygous familial hypercholesterolemia, oral

NDA: 4/30/2012 PDUFA: 12/29/2012

Kynamro (mipomersen)

Apo-B synthesis inhibitor for homozygous familial hypercholesterolemia, SC

NDA: 3/29/2012 PDUFA: 1/29/2013

Edoxaban

Factor Xa inhibitor for AF and VTE, oral

US filing strategy unknown

SAR236553

PCSK9 inhibitor for hypercholesterolemia, SC

Phase 3 trial starting 2Q 2012

CENTRAL NERVOUS SYSTEM DISORDERS

Levadex (dihydroergotamine)

Dihydroergotamine via oral inhaler for migraine

CRL: 3/26/2012

Adasuve (loxapine)

Loxapine in a single-dose inhaler for agitation in patients with schizophrenia or bipolar mania

CRL: 5/3/2012

Suvorexant

Orexin receptor antagonist for primary insomnia, oral

NDA in 2012

Cariprazine

Atypical antipsychotic for schizophrenia and bipolar mania, oral

NDA in 2012

Levomilnacipran

SNRI for depression, oral

NDA: 3Q 2012 Continued

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THE 2012 PHARMACEUTICAL PIPELINE

Table 2 Key Drugs in the 2012 Pipeline, by Clinical Category, through June 8, 2012 (continued) Drug

Drug type, potential indication, route

Expected timeline/comment

Alogliptin

DPP-4 inhibitor for type 2 diabetes, oral

CRL: 4/25/2012

Degludec

Ultralong-acting basal insulin, SC

PDUFA: 7/29/2012

Dapagliflozin

SGLT-2 inhibitor, oral

CRL: 1/19/2012 requesting additional data

Canagliflozin

SGLT-2 inhibitor, oral

NDA: 6/1/2012

Lyxumia (lixisenatide)

GLP-1 analogue (daily dosing), SC

NDA: 4Q 2012

DIABETES

INFECTIOUS DISEASES

QUAD (elvitegravir, Two new drugs combined with 2 existing drugs cobicistat, emtricitabine, for HIV, oral tenofovir)

PDUFA: 8/27/2012

Dolutegravir

NDA: by the end of 2012

Integrase inhibitor for HIV, oral

RESPIRATORY DISEASES

Eklira (aclidinium)

Twice-daily muscarinic antagonist (LAMA), oral inhaler for bronchospasm associated with COPD

FDA advisory committee voted for approval PDUFA: 7/30/2012

Inhaled, fixed-dose LABA/LAMA combination Zephyr (vilanterol/GSK573719) for COPD

Phase 3 data by end of 2012

Olodaterol/tiotropium

Phase 3 data in 1-2Q 2013

Inhaled, fixed-dose LABA/LAMA combination for COPD

RHEUMATIC DISEASES

Arcalyst (rilonacept)

Gout, SC

PDUFA: 7/30/2012

Tofacitinib

JAK1 and JAK3 inhibitor for RA, oral

PDUFA: 8/2012

Apremilast

Psoriatic arthritis, oral

2013 approval

AF indicates atrial fibrillation; ALL, acute lymphoblastic leukemia; apo-B, apolipoprotein B; CETP, cholesteryl ester transfer protein; CML, chronic myelogenous leukemia; CNS, central nervous system; COPD, chronic obstructive pulmonary disease; CRL, complete response letter; DPP, dipeptidyl peptidase; FDA, US Food and Drug Administration; GLP, glucagon-like peptide; IMiD, immunomodulatory drug; IV, intravenous; JAK, Janus kinase; LABA, long-acting beta-2 agonist; LAMA, long-acting muscarinic antagonist; MTP-I, microsomal triglyceride transfer protein inhibitor; NDA, New Drug Application; NHL, non-Hodgkin lymphoma; NSCLC, nonâ&#x20AC;&#x201C;small-cell lung cancer; PCSK9, proprotein convertase subtilisin/kexin type 9; PDUFA, Prescription Drug User Fee Act; Q, quarter; RA, rheumatoid arthritis; SC, subcutaneous; SGLT, sodium glucose cotransporter; SNRI, serotonin norepinephrine reuptake inhibitor; VTE, venous thromboembolism.

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THE 2012 PHARMACEUTICAL PIPELINE

FDA review in July (PDUFA date, July 30, 2012); however, an FDA advisory panel voted 11 to 0 against this gout indication on May 4, 2012.4 The manufacturer intends to pursue this expanded indication nevertheless.

The second SC biologic drug for gout in the pipeline is Ilaris, which is in an earlier stage of development, with FDA approval expected in 2014.

Tofacitinib, a novel oral Janus kinase (JAK) inhibitor, is being investigated as a targeted immunomodulator and disease-modifying antirheumatic drug (DMARD) for rheumatoid arthritis (RA, as well as for psoriasis).

Unlike more recent FDA-approved therapies for RA, which are directed at extracellular targets such as proinflammatory cytokines, tofacitinib targets multiple intracellular immune response pathways. The safety profile is problematic. If approved, tofacitinib would be the first new oral DMARD approved by the FDA for RA in more than 10 years, and the first in the new class of antirheumatic JAK inhibitors approved for RA. In addition, 2 biologics being developed for the treatment of lupus are Lupuzor and LymphoCide, but these too are expected to come up for approval in 2014. Similarly, the biologic drug for psoriatic arthritis to watch, Apremilast, is expected to come up for approval in 2013.

Substantial Activity in 2012 So far, 2012 continues the trends of new-generation

drug therapies for a variety of disease categories, increasing oral formulations of biologics, growing competition in the cancer arena, and the FDA’s intent on using priority review when warranted. However, the agency has also delivered some surprises for drugs that were widely expected to be approved but instead were issued a complete response letter requesting additional data or new information that had not been anticipated by the manufacturers and the entire pharmaceutical industry. Still, 2012 has all the signs of prolific activity in the drug pipeline, despite the apparent end of the blockbuster era. And with these trends, new issues to be confronted by providers and payers will likely include the problem of medication adherence and potentially increasing adverse events, as more drugs are being taken orally by the patient instead of being administered by the clinic or the provider. ■

References

1. US Food and Drug Administration. FDA: 35 innovative new drugs approved in fiscal year 2011. November 3, 2011. www.fda.gov/NewsEvents/Newsroom/Press Announcements/ucm278383.htm. Accessed June 4, 2012.

2. Tharaldson A. Specialty pharmaceutical pipeline update. Presented at the Academy of Managed Care Pharmacy, April 19, 2012, San Francisco, CA. 3. Reuters. US on track to approve more cancer drugs in 2012. June 4, 2012. www.reuters.com/article/2012/06/04/us-cancer-fda-idUSBRE8530KE20120604.

Accessed June 5, 2012.

4. Edney A. Regeneron’s Arcalyst fails to win panel backing for gout. Bloomberg News. www.bloomberg.com/news/2012-05-08/regeneron-s-arcalyst-fails-to-winpanel-backing-for-gout.html. Accessed June 14, 2012.

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Š2012 Engage Healthcare Communications, LLC www.AHDBonline.com Supplement to American Health & Drug Benefits