GENVOYA FILM-COATED TABLET 150mg/150mg/200mg/10mg

Cobicistat
Elvitegravir
Emtricitabine
Tenofovir Alafenamide

Source of information: Drugbank (External Link). Last updated on: 3rd July 18
*Trade Name used in the content below may not be the same as the HSA-registered product.

Active Ingredient / Synonyms

1,3-thiazol-5-ylmethyl [(2R,5R)-5-{[(2S)-2-({[(2-isopropyl-1,3-thiazol-4-yl)methyl](methyl)carbamoyl}amino)-4-(morpholin-4-yl)butanoyl]amino}-1,6-diphenylhexan-2-yl]carbamate | Cobicistat |

Description

Cobicistat, trade name Tybost (formerly GS-9350), is a licensed drug for use in the treatment of infection with human immunodeficiency virus (HIV). Although it does not have any anti-HIV activity, cobicistat acts as a pharmacokinetic enhancer by inhibiting cytochrome P450 3A isoforms (CYP3A) and therefore increases the systemic exposure of coadministered agents that are metabolized by CYP3A enzymes. More specifically, cobicistat is indicated to increase systemic exposure of atazanavir or darunavir (once daily dosing regimen) in combination with other antiretroviral agents in the treatment of HIV-1 infection. Increasing systemic exposure of anti-retrovirals (ARVs) without increasing dosage allows for better treatment outcomes and a decreased side effect profile.

Indication

Cobicistat is a CYP3A inhibitor indicated to increase systemic exposure of atazanavir or darunavir (once daily dosing regimen) in combination with other antiretroviral agents in the treatment of HIV-1 infection. It is not interchangeable with ritonavir to increase systemic exposure of darunavir 600 mg twice daily, fosamprenavir, saquinavir, or tipranavir due to lack of exposure data. The use of cobicistat is not recommended with darunavir 600 mg twice daily, fosamprenavir, saquinavir or tipranavir. Complex or unknown mechanisms of drug interactions preclude extrapolation of ritonavir drug interactions to certain cobicistat interactions. Cobicistat and ritonavir when administered with either atazanavir or darunavir may result in different drug interactions when used with concomitant medications.

Mechanism of Action

Cobicistat is a mechanism-based inhibitor of cytochrome P450 3A (CYP3A) isoforms. Inhibition of CYP3A-mediated metabolism by cobicistat increases the systemic exposure of CYP3A substrates atazanavir and darunavir and therefore enables increased anti-viral activity at a lower dosage. Cobicistat does not have any anti-HIV activity on its own.

Pharmacodynamics

Not Available

Pharmacokinetics

Absorption:

Median peak plasma concentrations were observed at 3.5 hours post-dose.

Distribution:

Not Available

Metabolism:

Cobicistat is metabolized by CYP3A and to a minor extent by CYP2D6 enzymes and does not undergo glucuronidation.

Elimination:

With single dose administration of [14C] cobicistat after multiple dosing of cobicistat for six days, the mean percent of the administered dose excreted in feces and urine was 86.2% and 8.2%, respectively.

Half-life

The terminal plasma half-life of cobicistat is approximately 3 to 4 hours.

Clearance

Not Available

Toxicity

The most common adverse reactions reported during clinical trials were jaundice (13%), ocular icterus (15%), and nausea (12%).

Source of information: Drugbank (External Link). Last updated on: 3rd July 18
*Trade Name used in the content below may not be the same as the HSA-registered product.

Active Ingredient / Synonyms

6-(3-chloro-2-fluorobenzyl)-1-[(2S)-1-hydroxy-3-methylbutan-2-yl]-7-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid | elvitégravir | EVG | GS 9137 | Elvitegravir |

Description

Elvitegravir is a human immunodeficiency virus type 1 (HIV-1) integrase strand transfer inhibitor (INSTI) used for the treatment of HIV-1 infection in antiretroviral treatment-experienced adults. Because integrase is necessary for viral replication, inhibition prevents the integration of HIV-1 DNA into the host genome and thereby blocks the formation of the HIV-1 provirus and resulting propagation of the viral infection. Although available as a single dose tablet, elvitegravir must be used in combination with an HIV protease inhibitor coadministered with ritonavir and another antiretroviral drug. It was developed by the pharmaceutical company Gilead Sciences, which licensed EVG from Japan Tobacco in March 2008. The drug gained approval by the U.S. Food and Drug Administration on August 27, 2012 for use in adult patients starting HIV treatment for the first time as part of the fixed dose combination known as Stribild. On September 24, 2014 the FDA approved Elvitegravir (tradename Vitekta) as a single pill formulation.

Indication

Elvitegravir in combination with an HIV protease inhibitor coadministered with ritonavir and with other antiretroviral drug(s) is indicated for the treatment of HIV-1 infection in antiretroviral treatment-experienced adults.

Mechanism of Action

Elvitegravir is an HIV-1 integrase strand transfer inhibitor (INSTI). Integrase is an HIV-1 encoded enzyme that is required for viral replication. Inhibition of integrase prevents the integration of HIV-1 DNA into host genomic DNA, blocking the formation of the HIV-1 provirus and propagation of the viral infection. Elvitegravir does not inhibit human topoisomerases I or II.

Pharmacodynamics

Not Available

Pharmacokinetics

Absorption:

Following oral administration of elvitegravir and ritonavir with food, in HIV-1 infected subjects, peak elvitegravir plasma concentrations were observed approximately 4 hours post-dose.

Distribution:

Not Available

Metabolism:

Elvitegravir undergoes primarily oxidative metabolism via CYP3A, and is secondarily glucuronidated via UGT1A1/3 enzymes. Metabolites are found in the plasma at very low concentrations, displayed considerably lower anti-HIV activity, and did not contribute to the overall antiviral activity of elvitegravir.

Elimination:

Following oral administration of [14C]elvitegravir/ritonavir, 94.8% of the dose was recovered in feces, while 6.7% was recovered in urine as metabolites.

Half-life

The median terminal plasma half-life following administration of elvitegravir and ritonavir was approximately 8.7 hours.

Clearance

Not Available

Toxicity

The most common adverse reactions reported for elvitegravir use during clinical trials include nausea, vomiting, and diarrhea. Less common side effects occurring in <2% of patients, include abdominal pain, dyspepsia, fatigue, insomnia, rash, depression, suicidal ideation, and suicidal attempt.

Source of information: Drugbank (External Link). Last updated on: 3rd July 18
*Trade Name used in the content below may not be the same as the HSA-registered product.

Active Ingredient / Synonyms

(−)-(2R,5S)-5-fluoro-1-[2-(hydroxymethyl)-1,3-oxathiolan-5-yl]cytosine | (−)-2'-deoxy-5-fluoro-3'-thiacytidine | (−)-cis-4-amino-5-fluoro-1-(2-hydroxymethyl-1,3-oxathiolan-5-yl)-(1H)-pyrimidin-2-one | (−)-FTC | (−)-β-2',3'-dideoxy-5-fluoro-3'-thiacytidine | (2R-cis)-4-amino-5-fluoro-1-(2-(hydroxymethyl)-1,3-oxathiolan-5-yl)-2(1H)-pyrimidinone | 4-amino-5-fluoro-1-((2R,5S)-2-(hydroxymethyl)-1,3-oxathiolan-5-yl)pyrimidin-2(1H)-one | 4-Amino-5-fluoro-1-((2R,5S)-2-hydroxymethyl-[1,3]oxathiolan-5-yl)-1H-pyrimidin-2-one | 5-fluoro-1-((2R,5S)-2-(hydroxymethyl)-1,3-oxathiolan-5-yl)cytosine | Emtricitabin | Emtricitabina | Emtricitabine | Emtricitabinum | Emtricitabine |

Description

Emtricitabine is a nucleoside reverse transcriptase inhibitor (NRTI) for the treatment of HIV infection in adults. Emtricitabine is an analogue of cytidine. The drug works by inhibiting reverse transcriptase, the enzyme that copies HIV RNA into new viral DNA.

Indication

Indicated, in combination with other antiretroviral agents, for the treatment of HIV-1 infection in adults and for postexposure prophylaxis of HIV infection in health care workers and others exposed occupationally or nonoccupationally via percutaneous injury or mucous membrane or nonintact skin contact with blood, tissues, or other body fluids associated with risk for transmission of the virus.

Mechanism of Action

Emtricitabine works by inhibiting reverse transcriptase, the enzyme that copies HIV RNA into new viral DNA. Emtricitabine is a synthetic nucleoside analogue of cytidine. It is phosphorylated by cellular enzymes to form emtricitabine 5'-triphosphate, which is responsible for the inhibition of HIV-1 reverse transcriptase. It competes with the natural substrate deoxycytidine 5'-triphosphate and incorporates into nascent viral DNA, resulting in early chain termination. Therefore emtricitabine inhibits the activity of HIV-1 reverse transcriptase (RT) both by competing with the natural substrate deoxycytidine 5'-triphosphate and by its incorporation into viral DNA. By inhibiting HIV-1 reverse transcriptase, emtricitabine can help to lower the amount of HIV, or "viral load", in a patient's body and can indirectly increase the number of immune system cells (called T cells or CD4+ T-cells). Both of these changes are associated with healthier immune systems and decreased likelihood of serious illness.

Pharmacodynamics

Emtricitabine is a nucleoside reverse transcriptase inhibitor (NRTI) with activity against Human Immunodeficiency Virus Type 1 (HIV-1). Emtricitabine helps to block HIV reverse transcriptase, a chemical in your body (enzyme) that is needed for HIV to multiply. Emtricitabine is always used with other anti-HIV medicines to treat people with HIV infection. Emtricitabine may lower the amount of HIV in the blood (viral load). Emtricitabine may also help to increase the number of T cells called CD4 cells. Lowering the amount of HIV in the blood lowers the chance of death or infections that happen when your immune system is weak (opportunistic infections). People taking emtricitabine may still get opportunistic infections or other conditions that happen with HIV infection.

Pharmacokinetics

Absorption:

Rapidly absorbed (mean absolute bioavailability of 93% for capsules, and 75% for solution). Food does not effect absorption.

Distribution:

Not Available

Metabolism:

Minimally transformed (13%), most appears unchanged in urine (86%). The biotransformation of emtricitabine includes oxidation of the thiol moiety to form the 3′-sulfoxide diastereomers (~ 9% of dose) and conjugation with glucuronic acid to form 2′-O-glucuronide (~ 4% of dose). In vitro studies indicate emtricitabine is not an inhibitor or cytochrome P450 enzymes.

Elimination:

The renal clearance of emtricitabine is greater than the estimated creatinine clearance, suggesting elimination by both glomerular filtration and active tubular secretion.

Half-life

10 hours

Clearance

* 302 +/- 94 mL/min [Renal Function Creatinine Clearance>80 ml/min] * 168 +/- 10 mL/min [Renal Function Creatinine Clearance 50-80 ml/min] * 138 +/- 28 mL/min [Renal Function Creatinine Clearance 30-49 ml/min] * 99 +/- 6 mL/min [Renal Function Creatinine Clearance<30 ml/min] * 64 +/- 12 mL/min [ESRD patients requiring dialysis]

Toxicity

Symptoms of overdose include serious liver problems (hepatotoxicity, with liver enlargement and fat in the liver called steatosis) or a lactic acidosis (buildup of an acid in the blood).

Source of information: Drugbank (External Link). Last updated on: 3rd July 18
*Trade Name used in the content below may not be the same as the HSA-registered product.

Active Ingredient / Synonyms

Tenofovir alafenamide | Tenofovir alafenamide |

Description

Tenofovir alafenamide fumarate (TAF) is a nucleotide reverse transcriptase inhibitor (NRTI) and a novel ester prodrug of the antiretroviral tenofovir. Following oral administration, TAF is converted in vivo to tenofovir, an acyclic nucleoside phosphonate (nucleotide) analog of adenosine 5′-monophosphate. Tenofovir mimics normal DNA building blocks but is lacking a 3'-OH molecule required for phosphodiester bond linkage. By competing with regular nucleotides for incorporation into proviral DNA and prevention of the formation of the 5' to 3' phosphodiester linkage required for DNA elongation, tenofovir causes early chain termination and prevents proviral DNA transcription. Although tenofovir (available as tenofovir disoproxil fumarate) has a good safety profile and efficacy, and is currently a cornerstone of HIV antiviral treatment, its use has been associated with nephrotoxicity and reduced bone mineral density. In comparison, TAF has been shown to have improved antiviral efficacy, enhanced delivery of TFV into peripheral blood mononuclear cells (PBMCs) and lymphatic tissues, a higher barrier to resistance, and an improved safety profile. Improved renal safety is likely attributable to lower circulating plasma concentrations of tenofovir and therefore less exposure and damage to bone and the kidneys, where tenofovir is metabolized. Because HIV antiretroviral therapy is usually life-long, reduced toxicity and improved efficacy results in better patient outcomes and improved adherence in the long term. Tenofovir alafenamide fumarate is currently available in two fixed dose combination products: Odefsey (emtricitabine, rilpivirine, and tenofovir alafenamide), and Descovy (emtricitabine and tenofovir alafenamide). Both products are indicated for the treatment of HIV-1 infection in adults and pediatric patients 12 years of age and older.

Indication

For use in the treatment of HIV infection and chronic hepatitis B.

Mechanism of Action

Tenofovir alafenamide fumarate (TAF) is a nucleotide reverse transcriptase inhibitor (NRTI) and a novel ester prodrug of the antiretroviral tenofovir. Following oral administration, TAF is converted in vivo to tenofovir, an acyclic nucleoside phosphonate (nucleotide) analog of adenosine 5′-monophosphate. Tenofovir mimics normal DNA building blocks but is lacking a 3'-OH molecule required for phosphodiester bond linkage. By competing with regular nucleotides for incorporation into proviral DNA and prevention of the formation of the 5' to 3' phosphodiester linkage required for DNA elongation, tenofovir causes early chain termination and prevents proviral DNA transcription.

Pharmacodynamics

In a thorough QT/QTc study in 48 healthy subjects, TAF at the recommended dose and at a dose approximately 5 times the recommended dose, did not affect the QT/QTc interval and did not prolong the PR interval.

Pharmacokinetics

Absorption:

Tmax is observed at 1 hour post oral administration.

Distribution:

Not Available

Metabolism:

In vivo, TAF is hydrolyzed within cells to form tenofovir (major metabolite), which is phosphorylated to the active metabolite, tenofovir diphosphate. In vitro studies have shown that TAF is metabolized to tenofovir by cathepsin A (also known as Lysosomal Protective Protein) in peripheral blood mononuclear cells (PBMCs) and macrophages; and by Carboxylesterase 1 (CES1) in hepatocytes.

Elimination:

Not Available

Half-life

0.51 h

Clearance

Not Available

Toxicity

Not Available

References

  1. Health Science Authority of Singapore - Reclassified POM
  2. Drugbank

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Approval Information

GENVOYA FILM-COATED TABLET 150mg/150mg/200mg/10mg was registered with Health Science Authority of Singapore by GILEAD SCIENCES SINGAPORE PTE LTD. It is marketed with the registration number of SIN15165P with effective from 2017-01-20.

This product contains 150mg of Cobicistat, 150mg of Elvitegravir, 200mg of Emtricitabine, and 10mg of Tenofovir Alafenamide in the form of TABLET, FILM-COATED.

The medicine was manufactured by Patheon Inc. in CANADA

It is a Presciption Only Medicine which can only be obtained from a doctor or a dentist, or from a pharmacist with a prescription from a Singapore-registered doctor or dentist.

Anatomical Therapeutic Chemical (ATC) Classification

ATC Code: J05AR18

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