Drug Information

Drug Interaction:

DRUG INTERACTIONS

Because BIKTARVY is a complete regimen, coadministration with other antiretroviral medications for the treatment of HIV-1 infection is not recommended.

Consult the Full Prescribing Information prior to and during treatment for important drug interactions.

Indication:

BRIEF SUMMARY

BICTEGRAVIR,EMBITCITABINE,TENOFOVIR ALAFINAMIDE-(Feb 2018)

Indn- To treat infection in adults who have no antiretroviral treatment history or to replace the current antiretrviral regimen

Comp- Tablets: 50 mg of bictegravir (equivalent to 52.5 mg of bictegravir sodium), 200 mg of emtricitabine, and 25 mg of tenofovir alafenamide (equivalent to 28 mg of tenofovir alafenamide fumarate). One tablet taken once daily with or without food.

ADR- diarrhea, nausea, and headache.

CI- BIKTARVY is contraindicated to be co-administered with:

dofetilide.

rifampin.

WARNINGS-

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 and during therapy as clinically appropriate in all patients. Also assess serum phosphorus in patients with chronic kidney disease.

Pat Inform- Post-treatment Acute Exacerbation of Hepatitis B in Patients with HBV Coinfection-

Severe acute exacerbations of hepatitis B have been reported in patients who are coinfected with HBV and HIV-1 and have discontinued products containing FTC and/or TDF, and may likewise occur with discontinuation of BIKTARVY.

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U.S. FDA APPROVED DRUGS DURING 2018

Sr.No- 2

Name of the Drug- BIKTARVY

Active Ingredient - Bictegravir,Embitccitabine, Tenofovir Alafenamide

Pharmacological Classification-

To treat infection in adults who have no antiretroviral treatment

history or to replace the current antiretrviral regimen

Date of Approval- 2-7-2018

(Ref- FDA approved List 2018)

HIGHLIGHTS OF PRESCRIBING INFORMATION

These highlights do not include all the information needed to use

BIKTARVY safely and effectively.

See full prescribing information for BIKTARVY.

BIKTARVY® (bictegravir, emtricitabine, and tenofovir alafenamide) tablets, for oral use

Initial U.S. Approval: 2018

WARNING:

POST TREATMENT ACUTE EXACERBATION OF HEPATITIS B

See full prescribing information for complete boxed warning.

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 (FTC) and/or tenofovir disoproxil fumarate (TDF), and may occur with discontinuation of BIKTARVY. Closely monitor hepatic function in these patients. If appropriate, anti-hepatitis B therapy may be warranted.

INDICATIONS AND USAGE

BIKTARVY is a three-drug combination of bictegravir (BIC), a human immunodeficiency virus type 1 (HIV-1) integrase strand transfer inhibitor (INSTI), and emtricitabine (FTC) and tenofovir alafenamide (TAF), both HIV-1 nucleoside analog reverse transcriptase inhibitors (NRTIs),

and is 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.

Adverse Reaction:

ADVERSE REACTIONS-

Most common adverse reactions

(incidence greater than or equal to 5%, all grades) are

diarrhea, nausea, and headache.

Contra-Indications:

CONTRAINDICATIONS-

BIKTARVY is contraindicated to be co-administered with:

dofetilide.

rifampin.

WARNINGS AND PRECAUTIONS

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.

Dosages/ Overdosage Etc:

INDICATIONS AND USAGE-

BIKTARVY is a three-drug combination of bictegravir (BIC), a human immunodeficiency virus type 1 (HIV-1) integrase strand transfer inhibitor (INSTI), and emtricitabine (FTC) and tenofovir alafenamide (TAF), both HIV-1 nucleoside analog reverse transcriptase inhibitors (NRTIs), and is indicated as a complete regimen for the treatment of HIV-1 infection in adults

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.

DOSAGE FORMS AND STRENGTHS-

Tablets: 50 mg of bictegravir (equivalent to 52.5 mg of bictegravir sodium), 200 mg of emtricitabine, and 25 mg of tenofovir alafenamide (equivalent to 28 mg of tenofovir alafenamide fumarate).

Patient Information:

PATIENT COUNSELING INFORMATION-

Advise the patient to read the FDA-approved patient labeling (Patient Information).

Post-treatment Acute Exacerbation of Hepatitis B in Patients with HBV Coinfection-

Severe acute exacerbations of hepatitis B have been reported in patients who are coinfected with HBV and HIV-1 and have discontinued products containing FTC and/or TDF, and may likewise occur with discontinuation of BIKTARVY.

Advise the patient to not discontinue BIKTARVY without first informing their healthcare provider.

Drug Interactions-

BIKTARVY may interact with certain drugs; therefore, advise patients to report to their healthcare provider the use of any other prescription or non-prescription medication or herbal products including St. John’s wort

Immune Reconstitution Syndrome-

Advise patients to inform their healthcare provider immediately of any symptoms of infection, as in some patients with advanced HIV infection (AIDS), signs and symptoms of inflammation from previous infections may occur soon after anti-HIV treatment is started

Renal Impairment-

Advise patients to avoid taking BIKTARVY with concurrent or recent use of nephrotoxic agents. Renal impairment including cases of acute renal failure has been reported in association with the use of tenofovir prodrugs

Lactic Acidosis and Severe Hepatomegaly-

Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with use of drugs similar to BIKTARVY.

Advise patients that they should stop BIKTARVY if they develop clinical symptoms suggestive of lactic acidosis or pronounced hepatotoxicity.

Missed Dosage

Inform patients that it is important to take BIKTARVY on a regular dosing schedule with or without food and to avoid missing doses as it can result in development of resistance

Pregnancy Registry-

Inform patients that there is an antiretroviral pregnancy registry to monitor fetal outcomes of pregnant women exposed to BIKTARVY

Lactation-

Instruct women with HIV-1 infection not to breastfeed because HIV-1 can be passed to the baby in breast milk

BIKTARVY is a trademark of Gilead Sciences, Inc., or its related companies.

Pharmacology/ Pharmacokinetics:

CLINICAL PHARMACOLOGY-

1. Mechanism of Action-

BIKTARVY is a fixed dose combination of antiretroviral drugs bictegravir (BIC), emtricitabine (FTC), and tenofovir alafenamide (TAF)

2. Pharmacodynamics Cardiac Electrophysiology

In a thorough QT/QTc trial in 48 healthy subjects, BIC at doses 1.5 and 6 times the recommended dose did not affect the QT/QTc interval and did not prolong the PR interval. In a thorough QT/QTc trial in 48 healthy subjects,

TAF at the recommended dose or at a dose 5 times the recommended dose, did not affect the QT/QTc interval and did not prolong the PR interval. The effect of FTC on the QT interval is not known.

Effects on Serum Creatinine-

Mean change from baseline in serum creatinine in healthy subjects who received BIC 75 mg (1.5 times the approved recommended dosage) once daily with food for 14 days was 0.1 mg per dL on Days 7 and 14 compared to placebo.

BIC did not have a significant effect on the estimated creatinine clearance or on the actual glomerular filtration rate (determined by the clearance of probe drug, iohexol).

3. Pharmacokinetics-

The pharmacokinetic (PK) properties of BIKTARVY components are provided below

The multiple dose PK parameters of BIKTARVY components (based on population pharmacokinetic analysis) are-

Pharmacokinetic Properties of the Components of BIKTARVY Bictegravir (BIC) Emtricitabine (FTC) Tenofovir Alafenamide (TAF)

Absorption- Tmax (h)a 2.0–4.0 1.5–2.0 0.5–2.0 Effect of high-fat meal (relative to fasting)b AUC ratio 1.24 (1.16, 1.33) 0.96 (0.93, 0.99) 1.63 (1.43, 1.85) Cmax ratio 1.13 (1.06, 1.20) 0.86 (0.78, 0.93) 0.92 (0.73, 1.14)

Distribution- % bound to human plasma proteins >99 <4 ~80 Blood-to-plasma ratio 0.64 0.6 1.0 Elimination t1/2 (h)c 17.3 (14.8, 20.7) 10.4 (9.0, 12.0) 0.51 (0.45, 0.62)c

Metabolism Metabolic pathway(s)-CYP3A UGT1A1 Not significantly metabolized Cathepsin Ad (PBMCs) CES1 (hepatocytes)

Excretion- Major route of elimination Metabolism Glomerular filtration and active tubular secretion Metabolism % of dose excreted in urinee 35 70 <1 % of dose excreted in fecese 60.3 13.7 31.7 PBMCs=peripheral blood mononuclear cells; CES1=carboxylesterase 1

a. Values reflect administration of BIKTARVY with or without food.

b. Values refer to geometric mean ratio [high-fat meal/ fasting] in PK parameters and (90% confidence interval)

High fat meal is approximately 800 kcal, 50% fat. c. t1/2 values refer to median (Q1, Q3) terminal plasma half-life. Note that the active metabolite of TAF, tenofovir diphosphate, has a half-life of 150-180 hours within PBMCs. d. In vivo,

Pregnancy and lactation:

USE IN SPECIFIC POPULATIONS-

1. Pregnancy Pregnancy Exposure Registry-

There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to BIKTARVY during pregnancy. Healthcare providers are encouraged to register patients by calling the Antiretroviral Pregnancy Registry (APR) at 1-800-2584263.

Risk Summary-

There are insufficient human data on the use of BIKTARVY during pregnancy to inform a drug-associated risk of birth defects and miscarriage.

Available data from the APR show no difference in the overall risk of major birth defects for FTC 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)

The estimated background rate of miscarriage in the clinically recognized pregnancies in the U.S. general population is 15-20%. Methodological limitations of the APR include the use of MACDP as the external comparator group.

3. Lactation Risk Summary-

The Centers for Disease Control and Prevention recommend that HIV-1-infected mothers in the United States not breastfeed their infants to avoid risking postnatal transmission of HIV-1 infection.

Because of the potential for 1) HIV transmission (in HIV-negative infants);

2) developing viral resistance (in HIV-positive infants); and

3) adverse reactions in a breastfed infant similar to those seen in adults,

instruct mothers not to breastfeed if they are receiving BIKTARVY.

3.Pediatric Use-

Safety and effectiveness of BIKTARVY in pediatric patients less than 18 years of age have not been established.

4. Geriatric Use-

Clinical trials of BIKTARVY did not include sufficient numbers of subjects aged 65 and

over to determine whether they respond differently from younger subjects.

5. Renal Impairment-

BIKTARVY is not recommended in patients with severe renal impairment (estimated creatinine clearance (CLcr) below 30 mL per minute, estimated by Cockcroft-Gault (CG).

No dosage adjustment of BIKTARVY is recommended in patients with CLcr greater than or equal to 30 mL per minute [see Dosage and Administration (2.3)]. 8.7 Hepatic Impairment

No dosage adjustment of BIKTARVY is recommended in patients with mild (Child-Pugh Class A) or moderate (Child-Pugh Class B) hepatic impairment. BIKTARVY has not been studied in patients with severe hepatic impairment (Child-Pugh Class C).

Therefore, BIKTARVY is not recommended for use in patients with severe hepatic impairment.

OVERDOSAGE

No data are available on overdose of BIKTARVY in patients.

If overdose occurs, monitor the patient for evidence of toxicity. Treatment of overdose with BIKTARVY consists of general supportive measures including monitoring of vital signs as well as observation of the clinical status of the patient.

Hemodialysis treatment removes approximately 30% of the FTC dose over a 3-hour dialysis period starting within 1.5 hours of FTC dosing (blood flow rate of 400 mL per minute and a dialysate flow rate of 600 mL per minute).

It is not known whether FTC can be removed by peritoneal dialysis. Tenofovir is efficiently removed by hemodialysis with an extraction coefficient of approximately 54%.

2/18. Bictegravir,Embitcitabine,Tenofovir Alafenamide - (BIFENAMIDEKTARYVY)-@- (Feb- 2018)- to treat infection in adults who have no antiretrovral treatment

Drug Interaction

Indication

Adverse Reaction

Contra-Indications

Dosages/ Overdosage Etc

Patient Information

Pharmacology/ Pharmacokinetics

Pregnancy and lactation