On February 7, 2018, FDA approved BIKTARVY (bictegravir, emtricitabine, and tenofovir alafenamide) which is a three drug fixed dose combination tablet indicated as a complete regimen for the treatment of HIV-1 infection in adults who have no antiretroviral treatment history or 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 for at least 3 months with no history of treatment failure and no known substitutions associated with resistance to the individual components of BIKTARVY.
Highlights from the product labeling include the following:
DOSAGE AND ADMINISTRATION
BIKTARVY is contraindicated to be co-administered with:
Most common adverse reactions (incidence greater than or equal to 5%, all grades) are diarrhea, nausea, and headache.
Clinical Trials in Adults with No Antiretroviral Treatment History
The primary safety assessment of BIKTARVY was based on Week 48 data from two randomized, double-blind, active-controlled trials, Trial 1489 and Trial 1490, that enrolled 1274 HIV-1 infected adult subjects with no antiretroviral treatment history. A total of 634 subjects received one tablet of BIKTARVY once daily [see Clinical Studies (14.2)].
The most common adverse reactions (all Grades) reported in at least 5% of subjects in the BIKTARVY group in either Trial 1489 or Trial 1490 were diarrhea, nausea, and headache. The proportion of subjects who discontinued treatment with BIKTARVY, abacavir [ABC]/dolutegravir [DTG]/ lamivudine [3TC]), or DTG + FTC/TAF, due to adverse events, regardless of severity, was 1%, 1%, and < 1%, respectively. Table 1 displays the frequency of adverse reactions (all Grades) greater than or equal to 2% in the BIKTARVY group.
Table 1 Adverse Reactionsa (All Grades) Reported in ≥ 2% of HIV-1 Infected Adults with No Antiretroviral Treatment History Receiving BIKTARVY in Trials 1489 or 1490 (Week 48 analysis)
a Frequencies of adverse reactions are based on all adverse events attributed to trial drugs by the investigator. No adverse reactions of Grade 2 or higher occurred in ≥ 1% of subjects treated with BIKTARVY.
Additional adverse reactions (all Grades) occurring in less than 2% of subjects administered BIKTARVY in Trials 1489 and 1490 included vomiting, flatulence, dyspepsia, abdominal pain, rash, and depression.
Suicidal ideation, suicide attempt, and depression suicidal occurred in < 1% of subjects administered BIKTARVY; all events were serious and primarily occurred in subjects with a preexisting history of depression, prior suicide attempt or psychiatric illness.
The majority (87%) of adverse events associated with BIKTARVY were Grade 1.
Clinical Trials in Virologically Suppressed Adults
The safety of BIKTARVY in virologically-suppressed adults was based on Week 48 data from 282 subjects in a randomized, double-blind, active-controlled trial (Trial 1844) in which virologically-suppressed subjects were switched from either DTG + ABC/3TC or ABC/DTG/3TC to BIKTARVY; and Week 48 data from 290 subjects in an open-label, active-controlled trial in which virologically-suppressed subjects were switched from a regimen containing atazanavir (ATV) (given with cobicistat or ritonavir) or darunavir (DRV) (given with cobicistat or ritonavir) plus either FTC/TDF or ABC/3TC, to BIKTARVY (Trial 1878). Overall, the safety profile in virologically suppressed adult subjects in Trials 1844 and 1878 was similar to that in subjects with no antiretroviral treatment history [see Clinical Studies (14.3)].
Laboratory Abnormalities
The frequency of laboratory abnormalities (Grades 3–4) occurring in at least 2% of subjects receiving BIKTARVY in Trials 1489 and 1490 are presented in Table 2.
Table 2 Laboratory Abnormalities (Grades 3–4) Reported in ≥ 2% of Subjects Receiving BIKTARVY in Trials 1489 or 1490 (Week 48 analysis)
ULN = Upper limit of normal
a Frequencies are based on treatment-emergent laboratory abnormalities.
Changes in Serum Creatinine: BIC has been shown to increase serum creatinine due to inhibition of tubular secretion of creatinine without affecting renal glomerular function [see Clinical Pharmacology (12.2)]. Increases in serum creatinine occurred by Week 4 of treatment and remained stable through Week 48. In Trials 1489 and 1490, median (Q1, Q3) serum creatinine increased by 0.10 (0.03, 0.17) mg per dL from baseline to Week 48 in the BIKTARVY group and was similar to the comparator groups who received ABC/DTG/3TC, or DTG + FTC/TAF. There were no discontinuations due to renal adverse events through Week 48 in BIKTARVY clinical trials.
Changes in Bilirubin: In Trials 1489 and 1490, total bilirubin increases were observed in 12% of subjects administered BIKTARVY through Week 48. Increases were primarily Grade 1 (1.0 to 1.5 x ULN) (9%) and Grade 2 (1.5 to 2.5 x ULN) (3%). Graded bilirubin increases in the ABC/DTG/3TC, and DTG + FTC/TAF groups, were 4% and 6%, respectively. Increases were primarily Grade 1 (3% ABC/DTG/3TC and 5% DTG + FTC/TAF) or Grade 2 (1% ABC/DTG/3TC and 1% DTG + FTC/TAF). There were no discontinuations due to hepatic adverse events through Week 48 in BIKTARVY clinical studies.
DRUG INTERACTIONS
Other Antiretroviral Medications
Because BIKTARVY is a complete regimen, coadministration with other antiretroviral medications for the treatment of HIV-1 infection is not recommended [see Indications and Usage (1)]. Comprehensive information regarding potential drug-drug interactions with other antiretroviral medications is not provided because the safety and efficacy of concomitant HIV-1 antiretroviral therapy is unknown.
Potential for BIKTARVY to Affect Other Drugs
BIC inhibits organic cation transporter 2 (OCT2) and multidrug and toxin extrusion transporter 1 (MATE1)in vitro. Coadministration of BIKTARVY with drugs that are substrates of OCT2 and MATE1 (e.g., dofetilide) may increase their plasma concentrations (see Table 3).
Potential Effect of Other Drugs on One or More Components of BIKTARVY
BIC is a substrate of CYP3A and UGT1A1. A drug that is a strong inducer of CYP3A and also an inducer of UGT1A1 can substantially decrease the plasma concentrations of BIC which may lead to loss of therapeutic effect of BIKTARVY and development of resistance [see Clinical Pharmacology (12.3)].
The use of BIKTARVY with a drug that is a strong inhibitor of CYP3A and also an inhibitor of UGT1A1 may significantly increase the plasma concentrations of BIC (see Table 3).
TAF is a substrate of P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP). Co-administration of drugs that inhibit P-gp and BCRP may increase the absorption and plasma concentrations of TAF [see Clinical Pharmacology (12.3)]. Co-administration of drugs that induce P-gp activity are expected to decrease the absorption of TAF, resulting in decreased plasma concentration of TAF, which may lead to loss of therapeutic effect of BIKTARVY and development of resistance (see Table 3).
Drugs Affecting Renal Function
Because FTC and tenofovir are primarily excreted by the kidneys by a combination of glomerular filtration and active tubular secretion, coadministration of BIKTARVY with drugs that reduce renal function or compete for active tubular secretion may increase concentrations of FTC, tenofovir, and other renally eliminated drugs and this may increase the risk of adverse reactions. Some examples of drugs that are eliminated by active tubular secretion include, but are not limited to, acyclovir, cidofovir, ganciclovir, valacyclovir, valganciclovir, aminoglycosides (e.g., gentamicin), and high-dose or multiple NSAIDs [see Warnings and Precautions (5.4)].
Established and Potentially Significant Drug Interactions
Table 3 provides a listing of established or potentially clinically significant drug interactions with recommended prevention or management strategies. The drug interactions described are based on studies conducted with either BIKTARVY, the components of BIKTARVY (BIC, FTC, and TAF) as individual agents, or are drug interactions that may occur with BIKTARVY [see Contraindications (4), Warnings and Precautions (5.2), and Clinical Pharmacology (12.3)].
Highlights from the product labeling include the following:
DOSAGE AND ADMINISTRATION
- Testing: Prior to or when initiating BIKTARVY test for hepatitis B virus infection. Prior to or when initiating BIKTARVY, and during treatment, assess serum creatinine, estimated creatinine clearance, urine glucose, and urine protein in all patients as clinically appropriate. In patients with chronic kidney disease, also assess serum phosphorus.
- Recommended dosage: One tablet taken once daily with or without food.
- Renal impairment: BIKTARVY is not recommended in patients with estimated creatinine clearance below 30 mL per minute.
- Hepatic impairment: BIKTARVY is not recommended in patients with severe hepatic impairment.
BIKTARVY is contraindicated to be co-administered with:
- dofetilide
- rifampin
- Severe Acute Exacerbation of Hepatitis B in Patients Coinfected with HIV-1 and HBV
- The BIKTARVY label also includes a Box Warning regarding Post Treatment Acute Exacerbation of Hepatitis B
- Risk of adverse reactions or loss of virologic response due to drug interactions
- Immune reconstitution syndrome: May necessitate further evaluation and treatment.
- New onset or worsening renal impairment: Assess serum creatinine, estimated creatinine clearance, urine glucose and urine protein when initiating BIKTARVY and during therapy as clinically appropriate in all patients. Also assess serum phosphorus in patients with chronic kidney disease.
- Lactic acidosis/severe hepatomegaly with steatosis: Discontinue treatment in patients who develop symptoms or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity.
Most common adverse reactions (incidence greater than or equal to 5%, all grades) are diarrhea, nausea, and headache.
Clinical Trials in Adults with No Antiretroviral Treatment History
The primary safety assessment of BIKTARVY was based on Week 48 data from two randomized, double-blind, active-controlled trials, Trial 1489 and Trial 1490, that enrolled 1274 HIV-1 infected adult subjects with no antiretroviral treatment history. A total of 634 subjects received one tablet of BIKTARVY once daily [see Clinical Studies (14.2)].
The most common adverse reactions (all Grades) reported in at least 5% of subjects in the BIKTARVY group in either Trial 1489 or Trial 1490 were diarrhea, nausea, and headache. The proportion of subjects who discontinued treatment with BIKTARVY, abacavir [ABC]/dolutegravir [DTG]/ lamivudine [3TC]), or DTG + FTC/TAF, due to adverse events, regardless of severity, was 1%, 1%, and < 1%, respectively. Table 1 displays the frequency of adverse reactions (all Grades) greater than or equal to 2% in the BIKTARVY group.
Table 1 Adverse Reactionsa (All Grades) Reported in ≥ 2% of HIV-1 Infected Adults with No Antiretroviral Treatment History Receiving BIKTARVY in Trials 1489 or 1490 (Week 48 analysis)
| Trial 1489 | Trial 1490 | |||
| Adverse Reactions | BIKTARVY N=314 | ABC/DTG/3TC N=315 | BIKTARVY N=320 | DTG + FTC/TAF N=325 |
| Diarrhea | 6% | 4% | 3% | 3% |
| Nausea | 5% | 17% | 3% | 5% |
| Headache | 5% | 5% | 4% | 3% |
| Fatigue | 3% | 3% | 2% | 2% |
| Abnormal dreams | 3% | 3% | < 1% | 1% |
| Dizziness | 2% | 3% | 2% | 1% |
| Insomnia | 2% | 3% | 2% | < 1% |
a Frequencies of adverse reactions are based on all adverse events attributed to trial drugs by the investigator. No adverse reactions of Grade 2 or higher occurred in ≥ 1% of subjects treated with BIKTARVY.
Additional adverse reactions (all Grades) occurring in less than 2% of subjects administered BIKTARVY in Trials 1489 and 1490 included vomiting, flatulence, dyspepsia, abdominal pain, rash, and depression.
Suicidal ideation, suicide attempt, and depression suicidal occurred in < 1% of subjects administered BIKTARVY; all events were serious and primarily occurred in subjects with a preexisting history of depression, prior suicide attempt or psychiatric illness.
The majority (87%) of adverse events associated with BIKTARVY were Grade 1.
Clinical Trials in Virologically Suppressed Adults
The safety of BIKTARVY in virologically-suppressed adults was based on Week 48 data from 282 subjects in a randomized, double-blind, active-controlled trial (Trial 1844) in which virologically-suppressed subjects were switched from either DTG + ABC/3TC or ABC/DTG/3TC to BIKTARVY; and Week 48 data from 290 subjects in an open-label, active-controlled trial in which virologically-suppressed subjects were switched from a regimen containing atazanavir (ATV) (given with cobicistat or ritonavir) or darunavir (DRV) (given with cobicistat or ritonavir) plus either FTC/TDF or ABC/3TC, to BIKTARVY (Trial 1878). Overall, the safety profile in virologically suppressed adult subjects in Trials 1844 and 1878 was similar to that in subjects with no antiretroviral treatment history [see Clinical Studies (14.3)].
Laboratory Abnormalities
The frequency of laboratory abnormalities (Grades 3–4) occurring in at least 2% of subjects receiving BIKTARVY in Trials 1489 and 1490 are presented in Table 2.
Table 2 Laboratory Abnormalities (Grades 3–4) Reported in ≥ 2% of Subjects Receiving BIKTARVY in Trials 1489 or 1490 (Week 48 analysis)
| Trial 1489 | Trial 1490 | |||
|---|---|---|---|---|
| Laboratory Parameter Abnormalitya | BIKTARVY N=314 | ABC/DTG/3TC N=315 | BIKTARVY N=320 | DTG + FTC/TAFN=325 |
| Amylase (> 2.0 x ULN) | 2% | 2% | 2% | 2% |
| ALT (> 5.0 × ULN) | 1% | 1% | 2% | 1% |
| AST (> 5.0 × ULN) | 2% | 1% | 1% | 3% |
| Creatine Kinase (≥10.0 × ULN) | 4% | 3% | 4% | 2% |
| Neutrophils (< 750 mm3) | 2% | 3% | 2% | 1% |
| LDL-cholesterol (fasted) (> 190 mg/dL) | 2% | 3% | 3% | 3% |
a Frequencies are based on treatment-emergent laboratory abnormalities.
Changes in Serum Creatinine: BIC has been shown to increase serum creatinine due to inhibition of tubular secretion of creatinine without affecting renal glomerular function [see Clinical Pharmacology (12.2)]. Increases in serum creatinine occurred by Week 4 of treatment and remained stable through Week 48. In Trials 1489 and 1490, median (Q1, Q3) serum creatinine increased by 0.10 (0.03, 0.17) mg per dL from baseline to Week 48 in the BIKTARVY group and was similar to the comparator groups who received ABC/DTG/3TC, or DTG + FTC/TAF. There were no discontinuations due to renal adverse events through Week 48 in BIKTARVY clinical trials.
Changes in Bilirubin: In Trials 1489 and 1490, total bilirubin increases were observed in 12% of subjects administered BIKTARVY through Week 48. Increases were primarily Grade 1 (1.0 to 1.5 x ULN) (9%) and Grade 2 (1.5 to 2.5 x ULN) (3%). Graded bilirubin increases in the ABC/DTG/3TC, and DTG + FTC/TAF groups, were 4% and 6%, respectively. Increases were primarily Grade 1 (3% ABC/DTG/3TC and 5% DTG + FTC/TAF) or Grade 2 (1% ABC/DTG/3TC and 1% DTG + FTC/TAF). There were no discontinuations due to hepatic adverse events through Week 48 in BIKTARVY clinical studies.
DRUG INTERACTIONS
Other Antiretroviral Medications
Because BIKTARVY is a complete regimen, coadministration with other antiretroviral medications for the treatment of HIV-1 infection is not recommended [see Indications and Usage (1)]. Comprehensive information regarding potential drug-drug interactions with other antiretroviral medications is not provided because the safety and efficacy of concomitant HIV-1 antiretroviral therapy is unknown.
Potential for BIKTARVY to Affect Other Drugs
BIC inhibits organic cation transporter 2 (OCT2) and multidrug and toxin extrusion transporter 1 (MATE1)in vitro. Coadministration of BIKTARVY with drugs that are substrates of OCT2 and MATE1 (e.g., dofetilide) may increase their plasma concentrations (see Table 3).
Potential Effect of Other Drugs on One or More Components of BIKTARVY
BIC is a substrate of CYP3A and UGT1A1. A drug that is a strong inducer of CYP3A and also an inducer of UGT1A1 can substantially decrease the plasma concentrations of BIC which may lead to loss of therapeutic effect of BIKTARVY and development of resistance [see Clinical Pharmacology (12.3)].
The use of BIKTARVY with a drug that is a strong inhibitor of CYP3A and also an inhibitor of UGT1A1 may significantly increase the plasma concentrations of BIC (see Table 3).
TAF is a substrate of P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP). Co-administration of drugs that inhibit P-gp and BCRP may increase the absorption and plasma concentrations of TAF [see Clinical Pharmacology (12.3)]. Co-administration of drugs that induce P-gp activity are expected to decrease the absorption of TAF, resulting in decreased plasma concentration of TAF, which may lead to loss of therapeutic effect of BIKTARVY and development of resistance (see Table 3).
Drugs Affecting Renal Function
Because FTC and tenofovir are primarily excreted by the kidneys by a combination of glomerular filtration and active tubular secretion, coadministration of BIKTARVY with drugs that reduce renal function or compete for active tubular secretion may increase concentrations of FTC, tenofovir, and other renally eliminated drugs and this may increase the risk of adverse reactions. Some examples of drugs that are eliminated by active tubular secretion include, but are not limited to, acyclovir, cidofovir, ganciclovir, valacyclovir, valganciclovir, aminoglycosides (e.g., gentamicin), and high-dose or multiple NSAIDs [see Warnings and Precautions (5.4)].
Established and Potentially Significant Drug Interactions
Table 3 provides a listing of established or potentially clinically significant drug interactions with recommended prevention or management strategies. The drug interactions described are based on studies conducted with either BIKTARVY, the components of BIKTARVY (BIC, FTC, and TAF) as individual agents, or are drug interactions that may occur with BIKTARVY [see Contraindications (4), Warnings and Precautions (5.2), and Clinical Pharmacology (12.3)].
Steve Morin
Office of Health and Constituent Affairs
Food and Drug Administration
Food and Drug Administration
Kimberly Struble
Division of Antiviral Products
Food and Drug Administration
Division of Antiviral Products
Food and Drug Administration
Visit the FDA Patient Network for more Information about the HIV Liaison Program
.png)
No hay comentarios:
Publicar un comentario