49 minute read
Hitchhikers' Guide to the Galaxy?
BY IDSE NEWS STAFF
An organism travels on a returning space craft and spreads around the world causing a widespread and deadly pandemic. Sound like something from a sci-fi movie? It might not be, if good biosecurity measures are not taken— especially now that private companies are in the space program.
Scientiss are calling for greater recognition of the biosecurity risks ahead of the private space industry (BioScience 2021 Nov 17. doi:10.1093/biosci/biab115 https:// bit.ly/31TgweG-idse).
“In addition to government-led space missions, the arrival of private companies such as SpaceX has meant there are now more players in space exploration than ever before,” said Phill Cassey, an associate professor and the head of the Department of Ecology and Evolutionary Biology at the University of Adelaide, in Australia.
“We need to take action now to mitigate those risks.” Space biosecurity concerns itself with both the transfer of organisms from Earth to space (forward contamination) and vice versa (backward contamination). While the research points out that the risk for alien organisms surviving the journey is low, it’s not impossible. (See the Infectious Disease Special Edition article “The Final ID Frontier” about NASA’s infectious disease concerns and studies in space. https://bit.ly/30g31Fw-IDSE).
“Risks that have low probability of occurrence, but have the potential for extreme consequences, are at the heart of biosecurity management, because when things go wrong, they go really wrong,” Dr. Cassey said.
The research provides clear evidence of how humans have spread organisms to the most remote regions of the Earth and sea, and even into space.
To address the risks for invasive species from space travel, the scientists suggest the emerging field of “invasion science,” which deals with the causes and consequences of introducing organisms into new environments, could offer valuable knowledge. This includes the fact that insular systems, such as islands, lakes and remote habitats, are most vulnerable to invasion threats.
Further insights that could be applied include protocols for early detection, hazard assessment, rapid response and containment procedures currently used in response to threats of invasive species.
“It is far cheaper to prevent biological contamination by implementing protocols on Earth than it is on Mars, for example.” Despite the value to space biosecurity, the authors stated that invasion biologists have yet to be involved in Committee on Space Research Planetary Protection planning. In the research they argue this should change because “greater collaboration between invasion biologists and astrobiologists would enhance existing international protocols for planetary biosecurity—both for Earth and for extraterrestrial bodies that could contain life.” ■
The sources reported no relevant financial disclosures.
ACIP Zoster Shot
continued from page 37
than 50 (Clin Infect Dis 2020;71[7]:e125-e134). “The risk of herpes zoster and … complications is generally higher in immunocompromised populations, although there is variability across and within these groups,” she said. The workgroup found the desired anticipated effects of RZV in immunocompromised adults were substantial and unfavorable anticipated effects were small.
“Given the burden of [herpes zoster] and its complications in these patients, it is anticipated that more immunocompromised patients would pursue vaccination with RZV if recommended by ACIP and their provider,” Dr. Anderson said. “Despite lack of a recommendation from ACIP, many physicians are already recommending RZV to patients with these conditions. Physicians need more direction on which patients are eligible for RZV.”
ACIP Committee member Katherine Poehling, MD, a professor of pediatrics and epidemiology and prevention and the director of pediatric population health in the Department of Pediatrics at Wake Forest School of Medicine, in Winston-Salem, N.C., noted the importance of pharmacy communication as this recommendation is rolled out. “The data presented today show that 60% to 65% of recombinant zoster vaccine is distributed through pharmacies,” she said. “This highlights the importance of making sure that information flows between pharmacies and providers so that all are clearly aware of what the patient’s vaccination status is, and highlights the importance of having a universal adult immunization registry that all can see.” ■
The sources reported no relevant financial disclosures.
40 Years
continued from page 14
establishment to ignore. And gay people were getting fed up: They wanted answers faster than their friends and lovers were dying, and they weren’t getting them.
“It was hard to work. It was hard to get money. It was hard to generate any empathy from the public, and the Reagan administration chose to leave these people behind,” Dr. Gottlieb said.
Groups such as ACT UP (AIDS Coalition to Unleash Power) and The Gay Men’s Health Crisis were crucial in getting those research grants, as well as being integral partners in HIV research, they said.
In addition to demonstrations in cities around the world, activists also were a vocal presence at the AIDS medical conferences. Several people interviewed for this story told about presentations being disrupted by activists, of speakers at the podium when demonstrators entered and threw symbolic blood—red paint—on them, and researchers who had guards outside their hotel room doors during the conference because they were afraid. Dr. Mildvan thought some of that anger, disruption and theater was misdirected at the physicians and researchers who were just trying to help.
But there was also unity.
During the Sixth International Conference on AIDS in San Francisco, protesters drowned out then Health and Human Services Secretary Louis W. Sullivan, MD, while he was delivering the closing address. Dr. Mildvan remembers all of the physicians also turned their back on him, and everyone was shouting.
“Everybody, to a person, all the delegates were on our feet with our backs turned to the stage where he was trying to speak,” Dr. Mildvan said. “It was just so loud and so overpowering, and everybody was unified in our dismay at what the government had been doing—or not doing—with Sullivan as the representative.
“So, we were grateful to the activists because as delegates, we would not have protested without them,” she said.
“Their [AIDS activists’] role was huge in moving the ball forward,” Dr. Gottlieb said. “Larry Kramer and his associates were prophets in their day, said things that other people
COVID-19 Versus HIV BY MARIE ROSENTHAL, MS
Because they are both viral pandemics, COVID-19 was compared quite a bit with HIV, especially in the beginning of the pandemic. Both are seeing a high morbidity, but is that where the similarities end? The answer is yes and no.
“Well, they’re both viruses, but apart from that, they are very different,” said Paul Volberding, MD, of San Francisco. “The epidemiology is completely different. What we learned is that COVID-19 can, but rarely, kills people, and HIV always kills people. HIV is very difficult to transmit; COVID is very easy to transmit. Everyone is susceptible to COVID, and most people have no great risk for HIV, even before treatments were developed just by nature of how the virus is commonly transmitted.”
Michael S. Gottlieb, MD, agreed: “The modes of transmission are so different. HIV resembles type B hepatitis
in its transmission, whereas COVID-19 represents common respiratory viruses. COVID-19 affects everyone. Theoretically speaking, everyone is at risk for HIV, but only through certain routes of transmission. COVID-19 is out there for everyone to contract,” said Dr. Gottlieb, of Los Angeles. The high mortality rates are certainly similar, but the time and line is very different, with HIV killing millions over 40 years, and COVID-19 killing millions in just two, said Jonathan Z. Li, MD, of Boston, but there is more stigma attached to HIV—even today—because it is a sexually transmitted how infection. However, the groundwork set for a drug approval during the early days of HIV was certainly used during COVID-19, “allowing the FDA to be more flexible
line k i infe HIV, hHIV in a time of emergency. Without those early HIV activists pushing against the initial, ossified way that the FDA used to do things, I’m not sure that to d they would be able to be as t nimble as the FDA and the U.S. government have been for the current pandemic.” The treatments have a commonality, too, he said. “ “Some of the vaccines and treatments for COVID-19 were built treat on a foundation of HIV research,” Dr. Li said. “If you look at the J & J vaccine, that was an adenoviral-based vaccine that was developed in Dan Barouch’s lab and built off of a platform that he’s been studying for 20 years for HIV vaccine. There’s no way that that vaccine could have been created in such a short time frame without the two decades of research that had gone into it as part of HIV research.”
In addition, the research in neutralizing antibodies that has been done for
An ACT-UP organized protest outside of the FDA's headquarters in Rockville, Md., in 1988. Source: FDA
didn’t want to hear about safe sex, and ACT UP was incredibly important in getting to where we are now—in pushing the federal government, the NIH to study treatments for people with HIV and liberalizing access to experimental therapies.”
Dr. Fauci was one person who was instrumental in bringing the communities together, several people said, and brought the gay community, pharmaceutical companies and the government together as partners in research. He worked with activists and changed the way clinical trials were done to include patient input. He also helped them get access to experimental drugs and helped speed up the approval process within the FDA.
In 1984, he became the director of the National Institute of Allergy and Infectious Diseases, where he made sure HIV was a major research concern. He was also instrumental in developing the plan, “Ending the HIV Epidemic in the U.S.,” in 2019 (bit.ly/3pLfn1n-IDSE).
“At first he was criticized by activists, but then he worked together with activists in a very meaningful way,” Dr. Gandhi said.
“I have to hand it to Tony Fauci, because he partnered with them rather than excluded them,” Dr. Sax added.
“The signal-to-noise finally got through as a signal, and they made all the difference once they arrived. They made an enormous amount of contributions,” Dr. Mildvan explained.
Breakthroughs and Challenges
Azidothymidine (AZT), also known as zidovudine, developed for HIV by Burroughs Wellcome, was approved in 1987—25 months after demonstrating activity against HIV in the lab—one of the shortest periods of drug development until COVID-19. It did not prevent viral replication, but slowed the progression to AIDS.
“It was a groundbreaker because it was the first effective
HIV treatment led to monoclonal antibodies, and Pfizer is working on a protease inhibitor, another HIV technology, for COVID-19.
The biggest difference is the time line, according to Julia B. Garcia-Diaz, MD, of New Olreans. “HIV lasted for years and years, and COVID was rapid, and so the time line was very different,” she said.
“These are different times with different technology. I think that we did things for HIV as quickly as we could have done it, but that is a span of 15-plus years; research did not start until the mid-, late 80s. We did not have HAART [highly active antiretroviral therapy] until about the mid-90s, and here we have remdesivir within six months. [In contrast,] COVID just spread like a wildfire throughout the world,” Dr. Garcia-Diaz said.
So many infectious diseases are diseases of poverty and vulnerable populations, such as HIV and tuberculosis, observed Dr. Rajesh T. Gandhi, MD, of Boston, and COVID-19 highlighted that by disproportionately affecting vulnerable populations. “I don’t think we learned the lesson, though.”
Both are global infections. “I think it’s highlighted to the extreme with COVID, but this idea that we can attempt to treat HIV here and not be concerned about it globally. … In the late 1990s, it became clear that it just was totally unethical to have treatments that were available to Americans, but not to people in resource-limited settings,” he said.
COVID-19 has had a direct effect on the HIV pandemic, however, in that many resources were diverted from HIV research and care to the COVID-19 response, they said.
This is especially true for the federal plan for ending HIV in America, Anthony Fauci, MD, admitted. “Well, I think COVID has upended everything everyone does on the planet,” he said. “So, you can’t say it hasn’t interfered with the plans to end HIV because it interfered with access to health care on the part of some people who otherwise would get tested and put on therapy early, [and] it interferes with people getting the counseling that gets them into PrEP or preexposure prophylaxis.
“It interferes in the developing world who has supply chain issues of getting drugs to people. So, I think anyone who has anything that requires a stability in society has actually been upended,” he said.
“The impact of COVID on HIV, TB, malaria and probably every aspect of medical care has been substantial,” Dr. Volberding said. People have decreased their uptake of PrEP; there is less testing; and it probably has affected adherence because patients were not seeing their physicians regularly.
“I think that COVID has delayed research in all areas,” Dr. Garcia-Diaz added. “HIV research has slowed down because the big companies have diverted their focus to COVID-19 [therapeutics and vaccines].”
And money for research is finite, she reminded, “very finite.”
drug,” Dr. Fauci said. “We had nothing before AZT. It saved a lot of lives. It wasn’t a durable effect in most people, but it saved a lot of lives.”
Dr. Volberding agreed. “The fact that it wasn’t very potent is almost not as important as that it opened the door. It did not reverse the disease, but it slowed it down.”
Dr. Gandhi added that one of most important contributions of AZT was that it gave patients hope.
Treatment took a huge leap forward again in 1996, with research presented at the Vancouver International AIDS Conference on combination antiretroviral therapy.
It was not only groundbreaking, it was thrilling, according to Dr. Sax, who quickly saw the benefits of treatment in his patients. “The treatment group made remarkable recoveries. Patients who had lost 30, 40 pounds and looked as if they were at death’s door, within six to eight to 12 weeks they gained weight, put color in their cheeks and went back to work. Wow.”
Today HIV is a very different disease from what it was 40 years ago because it is considered a chronic condition, not a death sentence. There have been so many breakthroughs in treatment—preexposure prophylaxis, one-pill-daily treatments and injectables that last weeks between doses—and all with fewer adverse events. Many of these treatments make viral loads so low they are undetectable, and undetectable means untransmissible, Dr. Fauci reminded.
“The pills are much smaller, the regimens are more tolerable, and the side effects are better,” Dr. Garcia-Diaz said.
But there is still much work to be done, and many challenges lie ahead, they said.
“We want the cure,” said Dr. Garcia-Diaz, who is a member of the Infectious Disease Special Edition editorial advisory board. “I don’t know if it is going to be in my lifetime, but I am hoping that I could have that conversation with my patients, ‘Hey, this is the pill that is going to cure you,’” she said.
“I’m an optimistic person,” said Jonathan Z. Li, MD, an associate professor of medicine at Harvard Medical School and the Brigham and Women's Hospital, in Boston. “First of all, there have already been a couple of instances of HIV cures, but of course, both of those instances required a bone marrow transplantation, which has a high up-front mortality, so it’s not broadly applicable. But it is a proof of principle that HIV cure is possible.”
Dr. Li, who also is a member of the Infectious Disease Special Edition editorial advisory board, studies elite controllers— those HIV patients who control viral replication without antiretroviral therapy—and hopes they will help promote cure research. The Esperanza patient, an elite controller who appeared to have cleared HIV without antiretroviral therapy, is a very exciting development, he said (Ann Intern Med 2021 Nov 16. https://doi.org/10.7326/L21-0297). Researchers are taking a close look at her cells to see if that information could translate to treatment and the eventual cure of HIV infection.
Dr. Li began his medical career in the 2000s—later than the other physicians interviewed for this story—but he said his early work spent in Mexico and China gives him a better understanding of what patients and physicians were going through in the early 1980s. “Those were regions of the world you still saw stigma and lack of access to care and end-stage HIV, and the kind of desperation of the patients [that was seen in the United States in the 1980s],” he said.
It also helped him to understand the importance of making sure that breakthroughs in the West make it to developing countries.
Dr. Gandhi agreed. “We need to give equal attention to making sure there is equitable distribution of life-saving technologies,” he said.
Vaccination is another challenge, they said, but one that still has a lot of interest, despite disappointing results in the past. As Infectious Disease Special Edition was going to press, there was a report that the messenger RNA technology used for the COVID-19 vaccines was successful in preventing simian immunodeficiency in primates (Nature Med 2021 Dec 9. doi:10.1038/s41591-021-01574-5). So, there is some hope in that area, too.
Despite all the education and knowledge, there is still stigma attached to being gay and having HIV, Dr. Sax said. “It is maddening,” he said, that some patients still won’t take their medications because of that stigma. “I think if the stigma was removed completely, they would be able to do it because they take their medicines for other conditions, but they just don’t take their HIV medications.”
Despite all the challenges, not one physician interviewed for this article said they were sorry they went into the field of HIV. They all agreed that caring for this special group of patients is its own reward.
Yet, all of the early pioneers in HIV, who have treated thousands of patients, remember those early young men who started them on their career paths, and those first patients are particularly special, the early HIV doctors told Infectious Disease Special Edition.
“The patients trusted us,” Dr. Gottlieb said. “We had a bond with them. Those first patients I remember better than the patients I saw last week. I remember them by name, and I remember their faces.
“And people still tell me they remember where they were when they read that first report,” he said. ■
with CABENUVA, the first and only, once-monthly, long-acting, complete injectable treatment regimen for virologically suppressed adults living with HIV-1.1*
Michael, living with HIV.
CABENUVA is a DHHS
STRONGLY
RECOMMENDED (AI)† REGIMEN
for appropriate patients with HIV-12‡
CABENUVA is administered monthly as 2 intramuscular injections by a healthcare professional. Adherence to the dosing schedule is strongly recommended.1
‡Patients must have sustained viral suppression for 3 to 6 months (optimal duration is not defined), have good adherence and engagement in care, have no baseline resistance to cabotegravir or rilpivirine, have no prior virologic failures, have no active or occult HBV infection (unless receiving an oral HBV regimen), not be pregnant or plan on becoming pregnant, and not be receiving medications with significant drug interactions with oral or injectable cabotegravir or rilpivirine.2
INDICATION
CABENUVA is indicated as a complete regimen for the treatment of human immunodeficiency virus type 1 (HIV-1) infection in adults to replace the current antiretroviral regimen in those who are virologically suppressed (HIV-1 RNA less than 50 copies per mL) on a stable antiretroviral regimen with no history of treatment failure and with no known or suspected resistance to either cabotegravir or rilpivirine.
IMPORTANT SAFETY INFORMATION
CONTRAINDICATIONS
• Do not use CABENUVA in patients with previous hypersensitivity reaction to cabotegravir or rilpivirine • Do not use CABENUVA in patients receiving carbamazepine, oxcarbazepine, phenobarbital, phenytoin, rifabutin, rifampin, rifapentine, systemic dexamethasone (>1 dose), and
St John’s wort
Please see additional Important Safety Information for CABENUVA throughout. Please see following pages for Brief Summary of full Prescribing Information for CABENUVA.
ONCE-MONTHLY TREATMENT IS POSSIBLE WITH CABENUVA
Proven as effective as continuing a daily oral regimen1,3†
Preferred by 9 out of 10 patients in clinical trials3-5
In an exploratory endpoint in ATLAS and FLAIR Phase 3 clinical trials, patients completed a single-item question assessing their preference for CABENUVA vs their previous oral regimen.† At Week 48, 88% (523/591) of ITT-E population preferred CABENUVA vs 2% (9/591) who preferred their previous oral regimen†;59 patients did not respond to the question. These results are descriptive in nature and should not be used to infer clinical significance.
* HIV-1 RNA <50 copies/mL.1 † Based on a pooled analysis from two Phase 3, international, randomized, non-inferiority trials (ATLAS and FLAIR) in virologically suppressed (HIV-1 RNA <50 copies/mL) adults ≥18 years with HIV-1.1,3-5 In ATLAS, 616 treatment-experienced, virologically suppressed (for ≥6 months) patients on 2 NRTIs + an INSTI, NNRTI, or PI were randomized 1:1 to receive either CABENUVA (after a 4-week oral lead-in of daily cabotegravir 30 mg and rilpivirine 25 mg) or to remain on their current therapy.1,4 In FLAIR, patients without previous ARV exposure were given ABC/DTG/3TC (or DTG + 2 NRTIs if HLA-B*5701-positive) for 20 weeks to achieve suppression and then randomized 1:1 (N=566) to receive either CABENUVA (after a 4-week oral lead-in of daily cabotegravir 30 mg and rilpivirine 25 mg) or to remain on their current regimen.1,5 At baseline, in FLAIR and ATLAS, the median age was 34 and 40 years, respectively.1 In both studies, 7% had CD4+ cell count <350 cells/mm3 . 1 In ATLAS, baseline third-agents were 50% NNRTIs, 33% INSTIs, or 17% PIs.1 Patients were excluded if they were pregnant or breastfeeding, had moderate to severe hepatic impairment, or evidence of HBV infection at screening.4,5 Non-inferiority of CABENUVA would be shown if the upper bound of the 95% CI for the treatment difference was <6% for the individual studies or <4% for the pooled analysis.3-5 Primary endpoint was proportion of patients with HIV-1 RNA ≥50 copies/mL at Week 48 via FDA Snapshot Algorithm.3 Proportion of patients with HIV-1 RNA ≥50 copies/mL at Week 48 in pooled analysis was 2% for CABENUVA vs 2% for daily oral comparator (non-inferior treatment difference: 0.2% [95% CI: -1.4, 1.7]).1,3 3TC=lamivudine; ABC=abacavir; ARV=antiretroviral; CI=confidence interval; DTG=dolutegravir; FDA=Food and Drug Administration; HLA-B=human leukocyte antigen complex B; INSTI=integrase strand transfer inhibitor; ITT-E=intent-to-treat efficacy; NNRTI=non-nucleoside reverse transcriptase inhibitor; NRTI=nucleoside reverse transcriptase inhibitor; PI=protease inhibitor.
References: 1. CABENUVA [package insert]. Research Triangle Park, NC: ViiV Healthcare; 2021. 2. Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents with HIV. Department of Health and Human Services. https://clinicalinfo.hiv.gov/sites/default/files/guidelines/documents/AdultandAdolescentGL.pdf. Accessed June 30, 2021. 3. Rizzardini G, Overton ET, Orkin C, et al. Long-acting injectable cabotegravir + rilpivirine for HIV maintenance therapy: Week 48 pooled analysis of phase 3 ATLAS and FLAIR trials. J Acquir Immune Defic Syndr. 2020;85(4):498-506. 4. Swindells S, Andrade-Villanueva JF, Richmond GJ, et al. Long-acting cabotegravir and rilpivirine for maintenance of HIV-1 suppression. N Engl J Med. 2020;382(12):1112-1123. 5. Orkin C, Arasteh K, Górgolas Hernández-Mora M, et al. Long-acting cabotegravir and rilpivirine after oral induction for HIV-1 infection. N Engl J Med. 2020;382(12):1124-1135.
WARNINGS AND PRECAUTIONS
Hypersensitivity Reactions:
• Hypersensitivity reactions, including cases of Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), have been reported during postmarketing experience with rilpivirine-containing regimens. While some skin reactions were accompanied by constitutional symptoms such as fever, other skin reactions were associated with organ dysfunctions, including elevations in hepatic serum biochemistries • Serious or severe hypersensitivity reactions have been reported in association with other integrase inhibitors and could occur with CABENUVA • Discontinue CABENUVA immediately if signs or symptoms of hypersensitivity reactions develop. Clinical status, including liver transaminases, should be monitored and appropriate therapy initiated. Prescribe the oral lead-in prior to administration of CABENUVA to help identify patients who may be at risk of a hypersensitivity reaction
Post-Injection Reactions:
• Serious post-injection reactions (reported in less than 1% of subjects) were reported within minutes after the injection of rilpivirine, including dyspnea, agitation, abdominal cramping, flushing, sweating, oral numbness, and changes in blood pressure. These events may have been associated with inadvertent (partial) intravenous administration and began to resolve within a few minutes after the injection • Carefully follow the Instructions for Use when preparing and administering CABENUVA to avoid accidental intravenous administration. Observe patients briefly (approximately 10 minutes) after the injection. If a post-injection reaction occurs, monitor and treat as clinically indicated
Hepatotoxicity:
• Hepatotoxicity has been reported in patients receiving cabotegravir or rilpivirine with or without known pre-existing hepatic disease or identifiable risk factors • Patients with underlying liver disease or marked elevations in transaminases prior to treatment may be at increased risk for worsening or development of transaminase elevations • Monitoring of liver chemistries is recommended and treatment with CABENUVA should be discontinued if hepatotoxicity is suspected
Depressive Disorders:
• The concomitant use of CABENUVA and other drugs may result in known or potentially significant drug interactions (see Contraindications and Drug Interactions) • Rilpivirine doses 3 and 12 times higher than the recommended oral dosage can prolong the QTc interval. CABENUVA should be used with caution in combination with drugs with a known risk of Torsade de Pointes
• Residual concentrations of cabotegravir and rilpivirine may remain in the systemic circulation of patients for prolonged periods (up to 12 months or longer). Select appropriate patients who agree to the required monthly injection dosing schedule because non-adherence to monthly injections or missed doses could lead to loss of virologic response and development of resistance • To minimize the potential risk of developing viral resistance, it is essential to initiate an alternative, fully suppressive antiretroviral regimen no later than 1 month after the final injection doses of CABENUVA. If virologic failure is suspected, switch the patient to an alternative regimen as soon as possible
ADVERSE REACTIONS
The most common adverse reactions (incidence ≥2%, all grades) with CABENUVA were injection site reactions, pyrexia, fatigue, headache, musculoskeletal pain, nausea, sleep disorders, dizziness, and rash.
DRUG INTERACTIONS
• Refer to the applicable full Prescribing Information for important drug interactions with CABENUVA, VOCABRIA, or EDURANT • Because CABENUVA is a complete regimen, coadministration with other antiretroviral medications for the treatment of HIV-1 infection is not recommended • Drugs that are strong inducers of UGT1A1 or 1A9 are expected to decrease the plasma concentrations of cabotegravir. Drugs that induce or inhibit CYP3A may affect the plasma concentrations of rilpivirine • CABENUVA should be used with caution in combination with drugs with a known risk of Torsade de Pointes
USE IN SPECIFIC POPULATIONS
•Pregnancy: There are insufficient human data on the use of CABENUVA during pregnancy to adequately assess a drug-associated risk for birth defects and miscarriage. Discuss the benefit-risk of using CABENUVA during pregnancy and conception and consider that cabotegravir and rilpivirine are detected in systemic circulation for up to 12 months or longer after discontinuing injections of CABENUVA. An Antiretroviral Pregnancy Registry has been established •Lactation: The CDC recommends that HIV-1−infected mothers in the United States not breastfeed their infants to avoid risking postnatal transmission of HIV-1 infection. Breastfeeding is also not recommended due to the potential for developing viral resistance in HIV-positive infants, adverse reactions in a breastfed infant, and detectable cabotegravir and rilpivirine concentrations in systemic circulation for up to 12 months or longer after discontinuing injections of CABENUVA
Visit CABENUVAhcp.com
CABENUVA (cabotegravir extended-release injectable suspension; rilpivirine extended-release injectable suspension), co-packaged for intramuscular use
The following is a brief summary only; see full prescribing information for complete product information.
CONTRAINDICATIONS
CABENUVA is contraindicated in patients: ∞ with previous hypersensitivity reaction to cabotegravir or rilpivirine. ∞ receiving the following coadministered drugs for which significant decreases in cabotegravir and/or rilpivirine plasma concentrations may occur due to uridine diphosphate (UDP)-glucuronosyl transferase (UGT)1A1 and/or cytochrome P450 (CYP)3A enzyme induction, which may result in loss of virologic response: • Anticonvulsants: Carbamazepine, oxcarbazepine, phenobarbital, phenytoin • Antimycobacterials: Rifabutin, rifampin, rifapentine • Glucocorticoid (systemic): Dexamethasone (more than a single-dose treatment) • Herbal product: St John’s wort (Hypericum perforatum)
WARNINGS AND PRECAUTIONS
Hypersensitivity Reactions: Hypersensitivity reactions have been reported during postmarketing experience with rilpivirine-containing regimens. Reactions include cases of Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS). While some skin reactions were accompanied by constitutional symptoms such as fever, other skin reactions were associated with organ dysfunctions, including elevations in hepatic serum biochemistries. Serious or severe hypersensitivity reactions have been reported in association with other integrase inhibitors and could occur with CABENUVA. Remain vigilant and discontinue CABENUVA if a hypersensitivity reaction is suspected. Discontinue CABENUVA immediately if signs or symptoms of hypersensitivity reactions develop (including, but not limited to, severe rash, or rash accompanied by fever, general malaise, fatigue, muscle or joint aches, blisters, mucosal involvement [oral blisters or lesions], conjunctivitis, facial edema, hepatitis, eosinophilia, angioedema, difficulty breathing). Clinical status, including liver transaminases, should be monitored and appropriate therapy initiated. For information regarding the long-acting properties of CABENUVA, see section below. Administer oral lead-in dosing prior to administration of CABENUVA to help identify patients who may be at risk of a hypersensitivity reaction. Post-Injection Reactions: In clinical trials, serious post-injection reactions were reported within minutes after the injection of rilpivirine, including dyspnea, agitation, abdominal cramping, flushing, sweating, oral numbness, and changes in blood pressure. These events were reported in less than 1% of subjects and began to resolve within a few minutes after the injection. These events may have been associated with inadvertent (partial) intravenous administration. Carefully follow the Instructions for Use when preparing and administering CABENUVA to avoid accidental intravenous administration. Observe patients briefly (approximately 10 minutes) after the injection. If a patient experiences a post-injection reaction, monitor and treat as clinically indicated. Hepatotoxicity: Hepatotoxicity has been reported in patients receiving cabotegravir or rilpivirine with or without known pre-existing hepatic disease or identifiable risk factors. Patients with underlying liver disease or marked elevations in transaminases prior to treatment may be at increased risk for worsening or development of transaminase elevations. Monitoring of liver chemistries is recommended and treatment with CABENUVA should be discontinued if hepatotoxicity is suspected. For information regarding long-acting properties of CABENUVA, see section below. Depressive Disorders: Depressive disorders (including depressed mood, depression, major depression, mood altered, mood swings, dysphoria, negative thoughts, suicidal ideation or attempt) have been reported with CABENUVA or the individual drug products. Promptly evaluate patients with depressive symptoms to assess whether the symptoms are related to CABENUVA and to determine whether the risks of continued therapy outweigh the benefits.
Risk of Adverse Reactions or Loss of Virologic Response Due to Drug
Interactions: The concomitant use of CABENUVA and other drugs may result in known or potentially significant drug interactions, some of which may lead to adverse events, loss of virologic response of CABENUVA, and possible development of viral resistance. Rilpivirine 75-mg and 300-mg once-daily oral doses (3 and 12 times the recommended oral dosage) in healthy adults resulted in mean steady-state Cmax values 4.4-fold and 11.6fold higher than Cmax values associated with the recommended 600-mg dose of rilpivirine extended-release injectable suspension and prolonged the QTc interval. CABENUVA should be used with caution in combination with drugs with a known risk of Torsade de Pointes. See the Drug Interactions section for steps to prevent or manage these possible and known significant drug interactions, including dosing recommendations. Consider the potential for drug interactions prior to and during therapy with, and after discontinuation of CABENUVA; review concomitant medications during therapy with CABENUVA. Long-Acting Properties and Potential Associated Risks with CABENUVA: Residual concentrations of both cabotegravir and rilpivirine may remain in the systemic circulation of patients for prolonged periods (up to 12 months or longer). It is important to carefully select patients who agree to the required monthly injection dosing schedule because non-adherence to monthly injections or missed doses could lead to loss of virologic response and development of resistance. To minimize the potential risk of developing viral resistance, it is essential to initiate an alternative, fully suppressive antiretroviral regimen no later than 1 month after the final injection doses of CABENUVA. If virologic failure is suspected, switch the patient to an alternative regimen as soon as possible.
ADVERSE REACTIONS
Clinical Trials 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 with rates in the clinical trials of another drug and may not reflect rates observed in practice. The safety assessment of CABENUVA is based on the analysis of pooled 48-week data from 1,182 virologically suppressed subjects with HIV-1 infection in 2 international, multicenter, open-label pivotal trials, FLAIR and ATLAS. Additional safety information from other ongoing or earlier clinical trials in the cabotegravir and rilpivirine program have been considered in assessing the overall safety profile of CABENUVA. Adverse reactions were reported following exposure to CABENUVA extended-release injectable suspensions (median time exposure: 54 weeks) and data from VOCABRIA (cabotegravir) tablets and EDURANT (rilpivirine) tablets administered in combination as oral lead-in therapy (median time exposure: 5.3 weeks). Adverse reactions included those attributable to both the oral and injectable formulations of cabotegravir and rilpivirine administered as a combination regimen. Refer to the prescribing information for EDURANT for other adverse reactions associated with oral rilpivirine. The most common adverse reactions regardless of severity reported in greater than or equal to 2% of adult subjects in the pooled analyses from FLAIR and ATLAS are presented in Table 3. Selected laboratory abnormalities are included in Table 4. Overall, 4% of subjects in the group receiving CABENUVA and 2% of subjects in the control group discontinued due to adverse events. Non-injectionsite-related adverse events leading to discontinuation and occurring in more than 1 subject were headache, diarrhea, hepatitis A, and acute hepatitis B (all with an incidence less than 1%).
Injection-Associated Adverse Reactions: Local Injection Site Reactions (ISRs): The most frequent adverse reactions associated with the intramuscular administration of CABENUVA were ISRs. After 14,682 injections, 3,663 ISRs were reported. One percent (1%) of subjects discontinued treatment with CABENUVA because of ISRs. Most ISRs were mild (Grade 1, 75%) or moderate (Grade 2, 36%). Four percent (4%) of subjects experienced severe (Grade 3) ISRs, and no subjects experienced Grade 4 ISRs. The most commonly reported ISR was localized pain/discomfort (79%) regardless of severity or relatedness. Other manifestations of ISRs reported in more than 1% of subjects over the duration of the analysis period included nodules (14%), induration (12%), swelling (8%), erythema (4%), pruritus (4%), bruising (3%), warmth (2%), and hematoma (2%). Abscess and cellulitis at the injection site were each reported in less than 1% of subjects. The median duration of ISR events was 3 days. Other Injection-Associated Adverse Reactions: In the ATLAS and FLAIR clinical trials, an increased incidence of pyrexia (8%) was reported by subjects receiving cabotegravir plus rilpivirine injections compared with no events among subjects receiving current antiretroviral regimen. No cases were serious or led to withdrawal and the occurrences of pyrexia may represent a response to administration of CABENUVA via intramuscular
Table 3. Adverse Reactionsa (Grades 1 to 4) Reported in at Least 2% of Subjects with HIV-1 Infection in FLAIR and ATLAS Trials (Week 48 Pooled Analyses)
Adverse Reactions
Injection site reactionsb
Pyrexiac
Fatigued
Headache
Cabotegravir plus Rilpivirine (n=591) Current Antiretroviral Regimen (n=591)
All Grades At Least Grade 2 All Grades At Least Grade 2
83% 37% 0 0
8%
5%
4% 2%
1%
<1% 0
<1%
<1% 0
<1%
<1%
Musculoskeletal paine
Nausea
Sleep disordersf
Dizziness
Rashg 3%
3%
2%
2%
2% 1%
<1%
<1%
<1%
<1% <1%
1%
<1%
<1%
0 0
<1%
0
0
0
a Adverse reactions defined as “treatment-related” as assessed by the investigator. b See Injection-Associated Adverse Reactions for additional information. c Pyrexia: includes pyrexia, feeling hot, chills, influenza-like illness, body temperature increased. d Fatigue: includes fatigue, malaise, asthenia. e Musculoskeletal pain: includes musculoskeletal pain, musculoskeletal discomfort, back pain, myalgia, pain in extremity. f Sleep disorders: includes insomnia, poor quality sleep, somnolence. g Rash: includes erythema, pruritus, pruritus generalized, purpura, rash, rash- erythematous, generalized, macular.
BRIEF SUMMARY for CABENUVA (cabotegravir extended-release injectable suspension; rilpivirine extended-release injectable suspension), co-packaged for intramuscular use (cont'd)
injection. Reports of musculoskeletal pain (3%) and less frequently, sciatica, were also more common in subjects receiving cabotegravir plus rilpivirine compared with the current antiretroviral regimen and some events had a temporal association with injection. Vasovagal or pre-syncopal reactions were reported in less than 1% of subjects after injection with rilpivirine or cabotegravir. Less Common Adverse Reactions: The following select adverse reactions (regardless of severity) occurred in less than 2% of subjects receiving cabotegravir plus rilpivirine. Gastrointestinal Disorders: Abdominal pain (including upper abdominal pain), gastritis, dyspepsia, vomiting, diarrhea, and flatulence. Hepatobiliary Disorders: Hepatotoxicity. Investigations: Weight increase (see below). Psychiatric Disorders: Anxiety (including anxiety and irritability), depression, abnormal dreams. Skin and Hypersensitivity Reactions: Hypersensitivity reactions. Weight Increase: At Week 48, subjects in FLAIR and ATLAS who received cabotegravir plus rilpivirine had a median weight gain of 1.5 kg; those in the current antiretroviral regimen group had a median weight gain of 1.0 kg (pooled analysis). In the FLAIR trial, the median weight gain in subjects receiving cabotegravir plus rilpivirine or a dolutegravir-containing regimen was 1.3 kg and 1.5 kg, respectively, compared with 1.8 kg and 0.3 kg in the ATLAS trial in subjects receiving either cabotegravir plus rilpivirine or a protease inhibitor-, non-nucleoside reverse transcriptase inhibitor (NNRTI)-, or integrase strand transfer inhibitor (INSTI)-containing regimen, respectively. Laboratory Abnormalities: Selected laboratory abnormalities with a worsening grade from baseline and representing the worst-grade toxicity are presented in Table 4.
Table 4. Selected Laboratory Abnormalities (Grades 3 to 4; Week 48 Pooled Analyses) in FLAIR and ATLAS Trials
Laboratory Parameter Cabotegravir plus Rilpivirine (n=591) Current Antiretroviral Regimen (n=591)
ALT (≥5.0 x ULN) 2% <1%
AST (≥5.0 x ULN) 2% <1%
Total bilirubin (≥2.6 x ULN) <1% <1%
Creatine phosphokinase (≥10.0 x ULN)
Lipase (≥3.0 x ULN) 8%
5% 4%
3%
ULN = Upper limit of normal. Changes in Total Bilirubin: Small, non-progressive increases in total bilirubin (without clinical jaundice) were observed with cabotegravir plus rilpivirine. These changes are not considered clinically relevant as they likely reflect competition between cabotegravir and unconjugated bilirubin for a common clearance pathway (UGT1A1). Serum Cortisol: In pooled Phase 3 trials of EDURANT (rilpivirine), the overall mean change from baseline in basal cortisol was -0.69 (-1.12, 0.27) micrograms/ dL in the group receiving EDURANT compared with -0.02 (-0.48, 0.44) micrograms/ dL in the control group. Abnormal responses to ACTH stimulation tests were also higher in the group receiving EDURANT. The clinical significance of the higher abnormal rate of ACTH stimulation tests in the group receiving EDURANT is not known. Refer to the prescribing information for EDURANT for additional information. Postmarketing Experience: The following adverse reactions have been identified during postmarketing experience in patients receiving an oral rilpivirine-containing regimen. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Renal and Genitourinary Disorders: Nephrotic syndrome. Skin and Subcutaneous Tissue Disorders: Severe skin and hypersensitivity reactions, including DRESS.
DRUG INTERACTIONS
Concomitant Use with Other Antiretroviral Medicines: Because CABENUVA is a complete regimen, coadministration with other antiretroviral medications for the treatment of HIV-1 infection is not recommended. Use of Other Antiretroviral Drugs after Discontinuation of CABENUVA: Residual concentrations of cabotegravir and rilpivirine may remain in the systemic circulation of patients for prolonged periods (up to 12 months or longer). These residual concentrations are not expected to affect the exposures of antiretroviral drugs that are initiated after discontinuation of CABENUVA. Potential for Other Drugs to Affect CABENUVA: Refer to the prescribing information for VOCABRIA and EDURANT for additional drug interaction information related to oral cabotegravir and oral rilpivirine, respectively. Cabotegravir: Cabotegravir is primarily metabolized by UGT1A1 with some contribution from UGT1A9. Drugs that are strong inducers of UGT1A1 or 1A9 are expected to decrease cabotegravir plasma concentrations and may result in loss of virologic response; therefore, coadministration of CABENUVA with these drugs is contraindicated. Rilpivirine: Rilpivirine is primarily metabolized by CYP3A. Coadministration of CABENUVA and drugs that induce CYP3A may result in decreased plasma concentrations of rilpivirine and loss of virologic response and possible resistance to rilpivirine or to the class of NNRTIs. Coadministration of CABENUVA and drugs that inhibit CYP3A may result in increased plasma concentrations of rilpivirine. QT-Prolonging Drugs: At mean steady-state Cmax values 4.4-fold and 11.6-fold higher than those with the recommended 600-mg dose of rilpivirine extended-release injectable suspension, rilpivirine may prolong the QTc interval. CABENUVA should be used with caution in combination with drugs with a known risk of Torsade de Pointes. Established and Other Potentially Significant Drug Interactions: Refer to the prescribing information for VOCABRIA and EDURANT for additional drug interaction information related to oral cabotegravir and oral rilpivirine, respectively. Information regarding potential drug interactions with cabotegravir and rilpivirine is provided below. These recommendations are based on either drug interaction trials following oral administration of cabotegravir or rilpivirine or predicted interactions due to the expected magnitude of the interaction and potential for loss of virologic response. The following includes potentially significant interactions but is not all inclusive. ∞ Anticonvulsants: carbamazepine, oxcarbazepine, phenobarbital, phenytoin— coadministration is contraindicated with CABENUVA due to potential for loss of virologic response and development of resistance. ∞ Antimycobacterials: rifampin, rifapentine—coadministration is contraindicated with CABENUVA due to potential for loss of virologic response and development of resistance. ∞ Antimycobacterial: rifabutin—coadministration is contraindicated with CABENUVA due to potential for loss of virologic response and development of resistance. ∞ Glucocorticoid (systemic): dexamethasone (more than a single-dose treatment)—coadministration is contraindicated with CABENUVA due to potential for loss of virologic response and development of resistance. ∞ Herbal product: St. John’s wort (Hypericum perforatum)—coadministration is contraindicated with CABENUVA due to potential for loss of virologic response and development of resistance. ∞ Macrolide or ketolide antibiotics: azithromycin, clarithromycin, erythromycin— macrolides are expected to increase concentrations of rilpivirine and are associated with a risk of Torsade de Pointes. Where possible, consider alternatives, such as azithromycin, which increases rilpivirine concentrations less than other macrolides. ∞ Narcotic analgesic: methadone—no dose adjustment of methadone is required when starting coadministration of methadone with CABENUVA. However, clinical monitoring is recommended as methadone maintenance therapy may need to be adjusted in some patients.
Drugs without Clinically Significant Interactions: Cabotegravir: Based on drug interaction study results, the following drugs can be coadministered with cabotegravir (non-antiretrovirals and rilpivirine) or given after discontinuation of cabotegravir (antiretrovirals and non-antiretrovirals) without a dose adjustment: etravirine, midazolam, oral contraceptives containing levonorgestrel and ethinyl estradiol, and rilpivirine. Rilpivirine: Based on drug interaction study results, the following drugs can be coadministered with rilpivirine (non-antiretrovirals and cabotegravir) or given after discontinuation of rilpivirine (antiretrovirals and non-antiretrovirals): acetaminophen, atorvastatin, cabotegravir, chlorzoxazone, dolutegravir, ethinyl estradiol, norethindrone, raltegravir, ritonavir-boosted atazanavir, ritonavir-boosted darunavir, sildenafil, tenofovir alafenamide, and tenofovir disoproxil fumarate. Rilpivirine did not have a clinically significant effect on the pharmacokinetics of digoxin or metformin.
USE IN SPECIFIC POPULATIONS
Pregnancy: Pregnancy Exposure Registry: There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to CABENUVA during pregnancy. Healthcare providers are encouraged to register patients by calling the Antiretroviral Pregnancy Registry (APR) at 1-800-258-4263. Risk Summary: There are insufficient human data on the use of CABENUVA during pregnancy to adequately assess a drugassociated risk of birth defects and miscarriage. While there are insufficient human data to assess the risk of neural tube defects (NTDs) with exposure to CABENUVA during pregnancy, NTDs were associated with dolutegravir, another integrase inhibitor. Discuss the benefit-risk of using CABENUVA with individuals of childbearing potential or during pregnancy. Cabotegravir and rilpivirine are detected in systemic circulation for up to 12 months or longer after discontinuing injections of CABENUVA; therefore, consideration should be given to the potential for fetal exposure during pregnancy. Cabotegravir use in pregnant women has not been evaluated. Available data from the APR show no difference in the overall risk of birth defects for rilpivirine compared with the background rate for major birth defects of 2.7% in a U.S. reference population of the Metropolitan Atlanta Congenital Defects Program (MACDP) (see Data). The rate of miscarriage is not reported in the APR. The background risk for major birth defects and miscarriage for the indicated population is unknown. The background rate for major birth defects in a U.S. reference population of the Metropolitan Atlanta Congenital Defects Program (MACDP) is 2.7%. The estimated background rate of miscarriage in clinically recognized pregnancies in the U.S. general population is 15% to 20%. The APR uses the MACDP as the U.S. reference population for birth defects in the general population. The MACDP evaluates women and infants from a limited geographic area and does not include outcomes for births that occurred at less than 20 weeks’
BRIEF SUMMARY for CABENUVA (cabotegravir extended-release injectable suspension; rilpivirine extended-release injectable suspension), co-packaged for intramuscular use (cont'd)
gestation. In animal reproduction studies with oral cabotegravir, a delay in the onset of parturition and increased stillbirths and neonatal deaths were observed in a rat pre- and postnatal development study at greater than 28 times the exposure at the recommended human dose (RHD). No evidence of adverse developmental outcomes was observed with oral cabotegravir in rats or rabbits (greater than 28 times or similar to the exposure at the RHD, respectively) given during organogenesis (see Data). No adverse developmental outcomes were observed when rilpivirine was administered orally at exposures 15 (rats) and 70 (rabbits) times the exposure in humans at the RHD (see Data). Clinical Considerations: Lower exposures with oral rilpivirine were observed during pregnancy. Viral load should be monitored closely if the patient remains on CABENUVA during pregnancy. Cabotegravir and rilpivirine are detected in systemic circulation for up to 12 months or longer after discontinuing injections of CABENUVA; therefore, consideration should be given to the potential for fetal exposure during pregnancy. Data: Human Data: Cabotegravir: Data from an observational study in Botswana showed that dolutegravir, another integrase inhibitor, was associated with increased risk of NTDs when administered at the time of conception and in early pregnancy. Data from clinical trials are insufficient to address this risk with cabotegravir. Rilpivirine: Based on prospective reports to the APR of over 390 exposures to oral rilpivirine-containing regimens during the first trimester of pregnancy and over 170 during second/third trimester of pregnancy, the prevalence of birth defects in live births was 1.3% (95% CI: 0.4% to 3.0%) and 1.1% (95% CI: 0.1% to 4.0%) following first and second/third trimester exposures, respectively compared with the background birth defect rate of 2.7% in the U.S. reference population of the MACDP. In a clinical trial, total oral rilpivirine exposures were generally lower during pregnancy compared with the postpartum period. Refer to the prescribing information for EDURANT for additional information on rilpivirine. Animal Data: Cabotegravir: Cabotegravir was administered orally to pregnant rats at 0, 0.5, 5, or 1,000 mg/ kg/day from 15 days before cohabitation, during cohabitation, and from Gestation Days 0 to 17. There were no effects on fetal viability when fetuses were delivered by caesarean, although a minor decrease in fetal body weight was observed at 1,000 mg/ kg/day (greater than 28 times the exposure in humans at the RHD). No drug-related fetal toxicities were observed at 5 mg/kg/day (approximately 13 times the exposure in humans at the RHD) and no drug-related fetal malformations were observed at any dose. Cabotegravir was administered orally to pregnant rabbits at 0, 30, 500, or 2,000 mg/kg/day from Gestation Days 7 to 19. No drug-related fetal toxicities were observed at 2,000 mg/kg/day (approximately 0.7 times the exposure in humans at the RHD). In a rat pre- and postnatal development study, cabotegravir was administered orally to pregnant rats at 0, 0.5, 5, or 1,000 mg/kg/day from Gestation Day 6 to Lactation Day 21. A delay in the onset of parturition and increases in the number of stillbirths and neonatal deaths by Lactation Day 4 were observed at 1,000 mg/kg/day (greater than 28 times the exposure in humans at the RHD); there were no alterations to growth and development of surviving offspring. In a cross-fostering study, similar incidences of stillbirths and early postnatal deaths were observed when rat pups born to cabotegravir-treated mothers were nursed from birth by control mothers. There was no effect on neonatal survival of control pups nursed from birth by cabotegravir-treated mothers. A lower dose of 5 mg/kg/day (13 times the exposure at the RHD) was not associated with delayed parturition or neonatal mortality in rats. Studies in pregnant rats showed that cabotegravir crosses the placenta and can be detected in fetal tissue. Rilpivirine: Rilpivirine was administered orally to pregnant rats (40, 120, or 400 mg/kg/day) and rabbits (5, 10, or 20 mg/kg/day) through organogenesis (on Gestation Days 6 through 17, and 6 through 19, respectively). No significant toxicological effects were observed in embryo-fetal toxicity studies performed with rilpivirine in rats and rabbits at exposures 15 (rats) and 70 (rabbits) times the exposure in humans at the RHD. In a pre- and postnatal development study, rilpivirine was administered orally up to 400 mg/kg/day through lactation. No adverse effects were noted in the offspring at maternal exposures up to 63 times the exposure in humans at the RHD. Lactation: Risk Summary: The Centers for Disease Control and Prevention recommends that HIV-1−infected mothers in the United States not breastfeed their infants to avoid risking postnatal transmission of HIV-1 infection. It is not known if the components of CABENUVA are present in human breast milk, affect human milk production, or have effects on the breastfed infant. When administered to lactating rats, cabotegravir and rilpivirine were present in milk (see Data). If cabotegravir and/or rilpivirine are present in human milk, residual exposures may remain for 12 months or longer after the last injections have been administered. Because of the potential for (1) HIV-1 transmission (in HIV-negative infants), (2) developing viral resistance (in HIV-positive infants), (3) adverse reactions in a breastfed infant similar to those seen in adults, and (4) detectable cabotegravir and rilpivirine concentrations in systemic circulation for up to 12 months or longer after discontinuing injections of CABENUVA, instruct mothers not to breastfeed if they are receiving CABENUVA. Data: Animal Data: Cabotegravir: Animal lactation studies with cabotegravir have not been conducted. However, cabotegravir was detected in the plasma of nursing pups on Lactation Day 10 in the rat pre- and postnatal development study. Rilpivirine: Animal lactation studies with rilpivirine have not been conducted. However, rilpivirine was detected in the plasma of nursing pups on Lactation Day 7 in the rat pre- and postnatal development study. Pediatric Use: The safety and efficacy of CABENUVA have not been evaluated in pediatric patients. Geriatric Use: Clinical trials of CABENUVA did not include sufficient numbers of subjects aged 65 and older to determine whether they respond differently from younger subjects. In general, caution should be exercised in administration of CABENUVA in elderly patients reflecting greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. Renal Impairment: Based on studies with oral cabotegravir and population pharmacokinetic analyses of oral rilpivirine, no dosage adjustment of CABENUVA is necessary for patients with mild (creatinine clearance greater than or equal to 60 to less than 90 mL/min) or moderate renal impairment (creatinine clearance greater than or equal to 30 to less than 60 mL/min). In patients with severe renal impairment (creatinine clearance 15 to less than 30 mL/min) or end-stage renal disease (creatinine clearance less than 15 mL/min), increased monitoring for adverse effects is recommended. In patients with end-stage renal disease not on dialysis, effects on the pharmacokinetics of cabotegravir or rilpivirine are unknown. As cabotegravir and rilpivirine are greater than 99% protein bound, dialysis is not expected to alter exposures of cabotegravir or rilpivirine. Hepatic Impairment: Based on separate studies with oral cabotegravir and oral rilpivirine, no dosage adjustment of CABENUVA is necessary for patients with mild or moderate hepatic impairment (Child-Pugh A or B). The effect of severe hepatic impairment (Child-Pugh C) on the pharmacokinetics of cabotegravir or rilpivirine is unknown.
OVERDOSAGE
There is no known specific treatment for overdose with cabotegravir or rilpivirine. If overdose occurs, monitor the patient and apply standard supportive treatment as required, including monitoring of vital signs and ECG (QT interval) as well as observation of the clinical status of the patient. As both cabotegravir and rilpivirine are highly bound to plasma proteins, it is unlikely that either would be significantly removed by dialysis. Consider the prolonged exposure to cabotegravir and rilpivirine (components of CABENUVA) following an injection when assessing treatment needs and recovery.
Manufactured for:
ViiV Healthcare Research Triangle Park, NC 27709
by: GlaxoSmithKline Research Triangle Park, NC 27709 ©2021 ViiV Healthcare group of companies or its licensor. CBN:1PI CABENUVA and VOCABRIA are trademarks owned by or licensed to the ViiV Healthcare group of companies. The other brand listed is a trademark owned by or licensed to its respective owner and is not a trademark owned by or licensed to the ViiV Healthcare group of companies. The maker of this brand is not affiliated with and does not endorse the ViiV Healthcare group of companies or its products.
©2021 ViiV Healthcare or licensor. CBRJRNA210004 July 2021 Produced in USA.
