Adverse reactions

RPV-based regimens* and FTC/TAF backbone regimens have a demonstrated safety and tolerability profile in treatment-naive and virologically suppressed adults1-6

Study 109: Safety outcomes in virologically suppressed adults through Week 48

Discontinuations due to AEs

of adults who switched to an FTC/TAF backbone + EVG/COBI discontinued treatment5
of adults who remained on their baseline FTC/TDF backbone + 3rd agent§ discontinued treatment5
Most common treatment-emergent AEs5 Switched
to FTC/TAF +
EVG/COBI
(n=959)
Remained on
FTC/TDF +
3rd agent§
(n=477)
Upper respiratory tract infection (%) 16 11
Diarrhea (%) 10 9
Nasopharyngitis (%) 9 8
Headache (%) 7 4
Cough (%) 7 5
Syphilis (%) 5 6
Insomnia (%) 5 6
Arthralgia (%) 6 5
Bronchitis (%) 6 5
Depression (%) 4 6
Osteopenia (%) 6 5
Back pain (%) 5 5
Nausea (%) 5 3
Sinusitis (%) 5 5
  • Overall, the safety profile of an FTC/TAF backbone regimen in virologically suppressed adults was similar to that of treatment-naive adults3
  • Common AEs (incidence ≥5%; all grades) in clinical studies of treatment-naive adults who received an FTC/TAF backbone regimen were nausea (10%), diarrhea (7%), headache (6%), and fatigue (5%)3

See the Study 109 Study Design

Study 112: Safety outcomes in virologically suppressed adults with renal impairment through Week 48

Discontinuations due to AEs

of virologically suppressed adults with renal impairment who switched to an FTC/TAF backbone + EVG/COBI discontinued treatment6
Most common treatment-emergent AEs (incidence ≥5%)6 Switched to
FTC/TAF +
EVG/COBI
(n=242)
Diarrhea (%) 11
Arthralgia (%) 9
Upper respiratory tract infection (%) 9
Bronchitis (%) 8
Osteopenia|| (%) 8
Nausea (%) 8
Headache (%) 7
Pain in extremity (%) 7
Back pain (%) 7
Dizziness (%) 6
Fatigue (%) 6
Renal cyst (%) 6
Cough (%) 6
  • Patients with impaired renal function are at increased risk of renal-related AEs; otherwise, the safety profile of an FTC/TAF backbone regimen in patients in Study 112 was similar to that of patients with normal renal function3
  • Common AEs (incidence ≥5%; all grades) in clinical studies of treatment-naive adults through Week 48 were nausea (10%), diarrhea (7%), headache (6%), and fatigue (5%)3

See the Study 112 Study Design

Important Safety Information

BOXED WARNING: LACTIC ACIDOSIS/SEVERE HEPATOMEGALY WITH STEATOSIS and POST TREATMENT ACUTE EXACERBATION OF HEPATITIS B

  • Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogs in combination with other antiretrovirals.
  • ODEFSEY is not approved for the treatment of chronic hepatitis B virus (HBV) infection, and the safety and efficacy of ODEFSEY have not been established in patients coinfected with HIV-1 and HBV. Severe acute exacerbations of hepatitis B have been reported in patients who are coinfected with HIV-1 and HBV and have discontinued products containing emtricitabine and/or tenofovir disoproxil fumarate (TDF), and may occur with discontinuation of ODEFSEY. Hepatic function should be monitored closely with both clinical and laboratory follow-up for at least several months in patients who are coinfected with HIV-1 and HBV and discontinue ODEFSEY. If appropriate, initiation of anti-hepatitis B therapy may be warranted.

Contraindications

  • Coadministration: Do not use with drugs that induce CYP3A or increase gastric pH as this may lead to loss of efficacy and possible resistance to ODEFSEY or the NNRTI class. Do not use with carbamazepine, oxcarbazepine, phenobarbital, phenytoin, rifampin, rifapentine, proton pump inhibitors (e.g., dexlansoprazole, esomeprazole, lansoprazole, omeprazole, pantoprazole, rabeprazole), systemic dexamethasone (>1 dose) and St. John's wort.

Warnings and precautions

  • Skin and hypersensitivity reactions: Severe skin and hypersensitivity reactions have been reported with the use of rilpivirine-containing regimens, including cases of Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS). In rilpivirine clinical trials, most rashes were Grades 1-2 and occurred in the first 4-6 weeks of treatment; Grades 2-4 rash occurred in 1% of subjects. Discontinue ODEFSEY immediately if severe skin or hypersensitivity reactions occur, including severe rash or rash accompanied by fever, blisters, mucosal involvement, conjunctivitis, facial edema, angioedema, hepatitis or eosinophilia. Monitor clinical status including laboratory parameters and initiate appropriate therapy.
  • Loss of virologic response due to drug interactions: See Contraindications and Drug Interactions sections. Consider the potential for drug interactions prior to and during ODEFSEY therapy and monitor for adverse reactions.
  • Prolongation of QTc interval: Rilpivirine doses 3 and 12 times higher than the recommended dose can prolong the QTc interval. Consider alternatives to ODEFSEY in patients at higher risk for Torsade de Pointes or when coadministered with a drug with known risk of Torsade de Pointes.
  • Depressive disorders: Evaluate patients with severe depressive symptoms to assess if symptoms are due to ODEFSEY and if the risks of continued treatment outweigh the benefits. In rilpivirine adult clinical trials (N=686), the incidence of depressive disorders was 9%, Grades 3-4 depressive disorders was 1%, discontinuation due to depressive disorders was 1%, and suicidal ideation and suicide attempt was reported in 4 and 2 subjects, respectively. In a rilpivirine adolescent clinical trial (N=36), the incidence of depressive disorders was 19%, Grades 3-4 depressive disorders was 6%, and suicidal ideation and suicide attempt were reported in 1 subject.
  • Hepatotoxicity: Hepatic adverse events have been reported, including cases of hepatic toxicity, in patients without pre-existing hepatic disease or other identifiable risk factors. In patients with hepatic abnormalities (e.g., hepatitis, elevated liver-associated tests), order laboratory tests before starting treatment and monitor for hepatotoxicity during treatment; consider testing and monitoring in all patients.
  • Fat redistribution or accumulation has been observed in patients receiving antiretroviral therapy.
  • Immune reconstitution syndrome, including the occurrence of autoimmune disorders with variable time to onset, has been reported.
  • New onset or worsening renal impairment: Cases of acute renal failure and Fanconi syndrome have been reported with the use of tenofovir prodrugs. In clinical trials of emtricitabine and tenofovir alafenamide with elvitegravir and cobicistat, there have been no cases of Fanconi syndrome or proximal renal tubulopathy (PRT). Do not initiate ODEFSEY in patients with estimated creatinine clearance (CrCl) <30 mL/min. Patients with impaired renal function and/or taking nephrotoxic agents (including NSAIDs) are at increased risk of renal-related adverse reactions. Discontinue ODEFSEY in patients who develop clinically significant decreases in renal function or evidence of Fanconi syndrome.
    Renal monitoring: In all patients, monitor CrCl, urine glucose, and urine protein prior to initiating and during therapy. In patients with chronic kidney disease, additionally monitor serum phosphorus.
  • Bone loss and mineralization defects: Decreases in bone mineral density (BMD) have been reported with the use of tenofovir prodrugs. Consider monitoring BMD in patients with a history of pathologic fracture or risk factors for bone loss. Mineralization defects, including osteomalacia associated with PRT, have been reported with the use of TDF-containing products.

Adverse reactions

  • Most common adverse reactions with rilpivirine (incidence ≥2%, Grades 2-4) are depressive disorders (2%), insomnia (2%) and headache (2%); and with emtricitabine and tenofovir alafenamide (incidence ≥10%, all grades) is nausea (10%).

Drug interactions

  • Prescribing information: Consult the full prescribing information for ODEFSEY for more information on Contraindications, Warnings, and potentially significant drug interactions, including clinical comments.
  • Metabolism: Drugs that induce CYP3A or P-gp and drugs that increase gastric pH can decrease the concentrations of components of ODEFSEY. Drugs that inhibit CYP3A or P-gp can increase the concentrations of components of ODEFSEY.
  • QT prolonging drugs: Consider alternatives to ODEFSEY in patients taking a drug with known risk of Torsade de Pointes.
  • Drugs affecting renal function: Coadministration of ODEFSEY with drugs that reduce renal function or compete for active tubular secretion may increase concentrations of emtricitabine and tenofovir and the risk of adverse reactions.

Dosage and administration

  • Dosage: Patients 12 years and older (≥35 kg): 1 tablet taken orally once daily with a meal.
  • Renal impairment: Not recommended in patients with CrCl <30 mL/min.
  • Testing prior to initiation: Test patients for HBV infection and assess CrCl, urine glucose and urine protein.
  • Testing after initiation: In virologically-suppressed patients, additional monitoring of HIV-1 RNA and regimen tolerability is recommended.

Pregnancy and lactation

  • Pregnancy: There are insufficient data on the use of ODEFSEY during pregnancy. In animal studies, no adverse developmental effects were observed with the components of ODEFSEY. An Antiretroviral Pregnancy Registry has been established.
  • Lactation: Women infected with HIV-1 should be instructed not to breastfeed, due to the potential for HIV-1 transmission.

Indication

ODEFSEY is indicated as a complete regimen for the treatment of HIV-1 infection in patients 12 years and older who have no antiretroviral (ARV) treatment history with HIV-1 RNA ≤100,000 copies/mL; or to replace a stable ARV regimen in patients who are virologically-suppressed (HIV-1 RNA <50 copies/mL) for ≥6 months with no history of treatment failure and no known resistance to any component of ODEFSEY.

*Administered in combination with FTC/TDF.
Administered in combination with EVG and COBI as an STR.
Administered as an STR.
§Third agents included EVG + COBI (as an STR), EFV (as an STR), ATV + COBI, or ATV + RTV.3,5
||Of 19 patients, 16 had osteopenia at baseline; the other 3 had an AE of osteopenia reported within 12 days after switching to an FTC/TAF backbone regimen, indicating identification with baseline dual-energy X-ray absorptiometry (DXA) scan.7

References:

  1. ODEFSEY [package insert]. Foster City, CA: Gilead Sciences, Inc.; 2016.
  2. COMPLERA [package insert]. Foster City, CA: Gilead Sciences, Inc.; 2016.
  3. GENVOYA [package insert]. Foster City, CA: Gilead Sciences, Inc.; 2016.
  4. Data on file. Gilead Sciences, Inc. 2015.
  5. Mills A, Arribas JR, Andrade-Villanueva J, et al; GS-US-292-0109 team. Switching from tenofovir disoproxil fumarate to tenofovir alafenamide in antiretroviral regimens for virologically suppressed adults with HIV-1 infection: a randomised, active-controlled, multicentre, open-label, phase 3, non-inferiority study. Lancet Infect Dis. 2016;16(1):43-52.
  6. Pozniak A, Arribas JR, Gathe J, et al; for GS-US-292-0112 Study Team. Switching to tenofovir alafenamide, coformulated with elvitegravir, cobicistat, and emtricitabine, in HIV-infected patients with renal impairment: 48-week results from a single-arm, multicenter, open-label phase 3 study. J Acquir Immune Defic Syndr. 2016;71(5):530-537.
  7. Pozniak A, Arribas JR, Gathe J, et al; for GS-US-292-0112 Study Team. Switching to tenofovir alafenamide, coformulated with elvitegravir, cobicistat, and emtricitabine, in HIV-infected patients with renal impairment: 48-week results from a single-arm, multicenter, open-label phase 3 study. [supplementary appendix]. J Acquir Immune Defic Syndr. 2016;71(5):530-537.

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