Genvoya^® (Tablets) Instructions for Use

Marketing Authorization Holder

Gilead Sciences International, Ltd. (United Kingdom)

Manufactured By

Gilead Sciences Ireland, UC (Ireland)

Or

Patheon Inc. (Canada)

Primary Packaging

GILEAD SCIENCES IRELAND, UC (Ireland)

Or

PATHEON Inc. (Canada)

Secondary Packaging

GILEAD SCIENCES IRELAND, UC (Ireland)

Or

PATHEON Inc. (Canada)

Or

PHARMSTANDARD-LEKSREDSTVA, JSC (Russia)

Quality Control Release

GILEAD SCIENCES IRELAND, UC (Ireland)

Or

PHARMSTANDARD-LEKSREDSTVA, JSC (Russia)

ATC Code

J05AR18 (Cobicistat, Tenofovir alafenamide, Elvitegravir and Emtricitabine)

Dosage Form

Genvoya®

Film-coated tablets, 150 mg+10 mg+150 mg+200 mg: 30 pcs.

Dosage Form, Packaging, and Composition

Film-coated tablets green, capsule-shaped, engraved “GSI” on one side and “510” on the other.

* Cobicistat sodium on silicon dioxide 288.5 mg.
** Tenofovir alafenamide fumarate 11.2 mg.

Excipients: lactose monohydrate, microcrystalline cellulose, hypromellose (hydroxypropylcellulose), sodium lauryl sulfate, croscarmellose sodium, magnesium stearate.

Coating composition Opadry II Green 85F110095, containing polyvinyl alcohol, titanium dioxide, macrogol 3350, talc, indigo carmine FD&C Blue 2, yellow iron oxide.

30 pcs. – white bottles, capacity 100 ml made of high-density polyethylene (1) – cardboard packs.
30 pcs. – white bottles, capacity 100 ml made of high-density polyethylene (1) – cardboard packs with first opening control*.

* During secondary packaging of the drug at “Pharmstandard-Leksredstva” JSC.

Clinical-Pharmacological Group

Antiviral drug active against HIV

Pharmacotherapeutic Group

Systemic antiviral agents; direct-acting antiviral agents; antiviral agents for the treatment of HIV infection, combinations

Pharmacological Action

Combined antiviral agent with a fixed dose of cobicistat, tenofovir alafenamide, elvitegravir and emtricitabine.

Elvitegravir – HIV-1 integrase inhibitor. Integrase is an enzyme encoded by HIV-1, necessary for viral replication. Inhibition of integrase prevents the integration of HIV-1 DNA into the host’s genomic DNA, blocking the formation of the HIV-1 provirus and the spread of viral infection.

Cobicistat – selective irreversible inhibitor of CYP3A subfamily enzymes. Cobicistat inhibits CYP3A-mediated metabolism, which enhances the systemic exposure of cytochrome CYP3A substrates, such as Elvitegravir, whose bioavailability is limited and T_1/2 is shortened during metabolism involving CYP3A.

Emtricitabine – nucleoside reverse transcriptase inhibitor and analog of the nucleoside 2′-deoxycytidine; phosphorylated by cellular enzymes to form emtricitabine triphosphate. Emtricitabine triphosphate inhibits HIV replication by being incorporated into viral DNA by HIV reverse transcriptase, leading to DNA chain termination. Emtricitabine is active against HIV-1, HIV-2 and hepatitis B virus.

Tenofovir alafenamide – nucleotide reverse transcriptase inhibitor, represented by a phosphonamidate which is a prodrug of tenofovir (an analog of 2′-deoxyadenosine monophosphate). Tenofovir alafenamide is able to penetrate cells and, due to increased stability in plasma and intracellular activation via hydrolysis by cathepsin A, Tenofovir alafenamide is more effective than tenofovir disoproxil fumarate at the concentration of tenofovir in peripheral blood mononuclear cells (including lymphocytes and other HIV target cells) and in macrophages. Intracellular tenofovir is subsequently phosphorylated to the pharmacologically active metabolite tenofovir diphosphate. Tenofovir diphosphate inhibits HIV replication by being incorporated into viral DNA by HIV reverse transcriptase, leading to DNA chain termination. Tenofovir has antiviral activity against HIV-1, HIV-2 and hepatitis B virus.

In vitro antiviral activity

Elvitegravir, Emtricitabine and Tenofovir alafenamide demonstrated synergistic antiviral activity in cell culture. Antiviral synergy persisted when elvitegravir, emtricitabine and tenofovir alafenamide were studied in the presence of cobicistat.

The antiviral activity of elvitegravir against laboratory and clinical isolates of HIV-1 was evaluated in lymphoblastoid cells, monocytes/macrophages and peripheral blood lymphocytes, with 50% effective concentration (EC₅₀) values ranging from 0.02-1.7 nM. Elvitegravir showed antiviral activity in cell culture against HIV-1 clades A, B, C, D, E, F, G and O (EC₅₀ values ranged from 0.1-1.3 nM), as well as activity against HIV-2 (EC₅₀ 0.53 nM).

Cobicistat has no definable antiviral activity against HIV-1 and is not an antagonist to the antiviral effects of elvitegravir, emtricitabine or tenofovir.

The antiviral activity of emtricitabine against laboratory and clinical isolates of HIV-1 was evaluated in lymphoblastoid cell lines, MAGI CCR5 cell line and PBMC. EC₅₀ values for emtricitabine ranged from 0.0013-0.64 µM. Emtricitabine showed antiviral activity in cell culture against HIV-1 clades A, B, C, D, E, F and G (EC₅₀ values ranged from 0.007-0.075 µM), and also demonstrated strain-specific activity against HIV-2 (EC₅₀ values ranged from 0.007-1.5 µM).

The antiviral activity of tenofovir alafenamide against laboratory and clinical isolates of HIV-1 subtype B was evaluated in lymphoblastoid cell lines, PBMC, primary monocytes/macrophages and CD4+ T-lymphocytes. EC₅₀ values for tenofovir alafenamide ranged from 2.0-14.7 nM. Tenofovir alafenamide showed antiviral activity in cell culture against all groups of HIV-1 (M, N and O), including subtypes A, B, C, D, E, F and G (EC₅₀ values ranged from 0.1-12 nM), and also demonstrated strain-specific activity against HIV-2 (EC₅₀ values ranged from 0.91-2.63 nM).

Resistance

Reduced susceptibility to elvitegravir is most often associated with primary integrase mutations T66I, E92Q and Q148R. Additional integrase mutations identified during cell culture selection included H51Y, F121Y, S147G, S153Y, E157Q and R263K. HIV-1 with raltegravir-induced substitutions T66A/K, Q148H/K and N155H showed cross-resistance to elvitegravir.

In vitro resistance to cobicistat cannot be demonstrated due to the lack of antiviral activity of this drug.

Reduced susceptibility to emtricitabine is associated with M184V/I mutations in HIV-1 reverse transcriptase.

HIV-1 isolates with reduced susceptibility to tenofovir alafenamide express the K65R mutation in HIV-1 reverse transcriptase; in addition, the K70E mutation in HIV-1 reverse transcriptase was temporarily observed. HIV-1 isolates with the K65R mutation have a slight decrease in susceptibility to abacavir, emtricitabine, tenofovir and lamivudine.

Pharmacokinetics

Elvitegravir

After oral administration with food in HIV-1-infected patients, C_max in plasma was observed approximately 4 hours later. Mean steady-state values of C_max, AUC_tau and C_trough (mean ± SD) in HIV-1-infected patients were 1.7±0.39 µg/ml, 23±7.5 µg×h/ml and 0.45±0.26 µg/ml, respectively. Elvitegravir provides an inhibitory quotient of approximately 10 (ratio of C_trough to the protein-binding adjusted IC95 for wild-type HIV-1 virus). C_max and AUC values increased by 22% and 36% when taken with a light meal and by 56% and 91% when taken with a high-fat meal compared to fasting. Elvitegravir is 98-99% bound to plasma proteins, binding is concentration-independent in the range from 1 ng/ml to 1.6 µg/ml. The mean ratio of elvitegravir concentrations in plasma to blood was 1.37. Elvitegravir initially undergoes oxidative metabolism via cytochrome CYP3A, followed by secondary glucuronidation by UGT 1A1/3 enzymes. After oral administration of labeled [¹⁴C]-elvitegravir, it was the predominant drug in plasma, accounting for approximately 94% of circulating radioactive compounds. Metabolites of aromatic and aliphatic hydroxylation or glucuronidation are present in very low concentrations, reflecting significantly lower anti-HIV-1 activity and no contribution to the overall antiviral activity of elvitegravir. After oral administration of [¹⁴C]-elvitegravir/ritonavir, 94.8% of the dose was excreted in feces, consistent with hepatobiliary excretion of elvitegravir; 6.7% of the administered dose was excreted in urine. The median terminal T_1/2 of elvitegravir from plasma after administration of E/C/F/TDF is approximately 12.9 hours.

Cobicistat

After oral administration with food in HIV-1-infected patients, C_max in plasma was observed approximately 3 hours later. At steady state, mean values of C_max, AUC_tau and C_trough (mean ± SD) in HIV-1-infected patients were 1.1±0.4 µg/ml, 8.3±3.8 µg×h/ml and 0.05±0.13 µg/ml, respectively. Cobicistat exposures were not altered by a light meal and, despite a slight 24% and 18% decrease in C_max and AUC, respectively, when taken with a high-fat meal, no differences in its ability to enhance the pharmacological effect of cobicistat were observed. Cobicistat is 97-98% bound to plasma proteins, the mean ratio of plasma concentration to blood concentration was 2. Cobicistat is metabolized by cytochrome CYP3A-mediated (major) and cytochrome CYP2D6-mediated (minor) oxidation and does not undergo glucuronidation. After oral administration of [¹⁴C]-cobicistat, 99% of circulating radioactive compounds in plasma were unchanged cobicistat; 86% and 8.2% of the dose were excreted in feces and urine, respectively. The median terminal T_1/2 of cobicistat from plasma after administration of this combination is approximately 3.5 hours, and the associated cobicistat exposures provide approximately a 10-fold increase in the C_trough of elvitegravir relative to the protein-binding adjusted IC95 for wild-type HIV-1 virus.

Emtricitabine

After oral administration with food in HIV-1-infected patients, C_max in plasma was observed approximately 3 hours later. Corresponding mean steady-state values of C_max, AUC_tau and C_trough (mean ± SD) were 1.9±0.5 µg/ml, 13±4.5 µg×h/ml and 0.14±0.25 µg/ml for emtricitabine. Emtricitabine exposures were not altered by a light meal or a high-fat meal. In vitro binding of emtricitabine to human plasma proteins was <4% and was concentration-independent in the range of 0.02-200 µg/ml. At plasma C_max, the mean ratio of drug concentration in plasma to blood concentration was approximately 1.0, and the mean ratio of drug concentration in semen to plasma concentration was approximately 4.0. In vitro studies show that Emtricitabine is not an inhibitor of human cytochrome CYP enzymes. Biotransformation of emtricitabine includes oxidation of the thiol moiety to form 3′-sulfoxide diastereomers (approximately 9% of the dose) and conjugation with glucuronic acid to form 2′-O-glucuronide (approximately 4% of the dose). Emtricitabine is primarily excreted by the kidneys with complete recovery of the administered dose in urine (approximately 86%) and feces (approximately 14%). Thirteen percent of the emtricitabine dose was detected in urine as three metabolites. The total clearance of emtricitabine averaged 307 ml/min. After oral administration, the T_1/2 of emtricitabine is approximately 10 hours.

Tenofovir alafenamide

After oral administration with food in HIV-1-infected patients, C_max in plasma was observed approximately 1 hour later. Mean steady-state values of C_max and AUC_tau were 0.16±0.08 µg/ml and 0.21±0.15 µg×h/ml, respectively. Compared to taking the drug on an empty stomach, taking this combination with a light meal (approximately 400 kcal, 20% fat) or with a high-fat meal (approximately 800 kcal, 50% fat) generally does not affect tenofovir alafenamide exposures in a clinically significant manner (when taken with a light meal or a high-fat meal, AUC is approximately 15% and 18% higher compared to fasting, respectively). The binding of tenofovir to human plasma proteins in vitro is <0.7% and is concentration-independent in the range of 0.01-25 µg/ml. The binding of tenofovir alafenamide to human plasma proteins ex vivo in samples collected during clinical studies was approximately 80%. For humans, metabolism is the primary route of elimination of tenofovir alafenamide, accounting for >80% of the oral dose. In vitro studies have shown that Tenofovir alafenamide is metabolized to tenofovir (the main metabolite) by cathepsin A in PBMC (including lymphocytes and other HIV target cells) and macrophages; and by carboxylesterase-1 in hepatocytes. In vivo, Tenofovir alafenamide is hydrolyzed intracellularly to form tenofovir (the main metabolite), which is phosphorylated to form the active metabolite tenofovir diphosphate. In vitro, Tenofovir alafenamide is not metabolized by cytochrome CYP1A2, CYP2C8, CYP2C9, CYP2C19 or CYP2D6. Tenofovir alafenamide is minimally metabolized via cytochrome CYP3A4. Renal excretion of unchanged tenofovir alafenamide is a minor pathway, with less than 1% of the dose excreted in urine. Tenofovir alafenamide is largely eliminated after metabolism to tenofovir. The median T_1/2 of tenofovir alafenamide and tenofovir from plasma are 0.51 and 32.37 hours, respectively. Tenofovir is eliminated from the body by the kidneys, involving two mechanisms – glomerular filtration and active tubular secretion.

Pharmacokinetics in special patient groups

The mean systemic exposure of emtricitabine in patients with severe renal impairment (CrCl <30 ml/min) was higher (33.7 µg×h/ml) than in patients with normal renal function (11.8 µg×h/ml).

Results from a prospective post-registration study showed that therapy with regimens containing Cobicistat and Elvitegravir during pregnancy leads to lower exposures of elvitegravir and cobicistat.

Indications

Treatment of HIV-1 infection in the absence of any mutations associated with resistance to integrase inhibitor class drugs, emtricitabine or tenofovir, in adults and children over 12 years of age and weighing at least 35 kg, as well as in children over 6 years of age and weighing at least 25 kg, for whom alternative treatment regimens are not suitable due to toxicity.

ICD codes

Dosage Regimen

Take one tablet once daily with food.

Swallow the tablet whole; do not crush or chew.

Administer to adults and pediatric patients weighing at least 35 kg.

Administer to pediatric patients 6 years and older weighing at least 25 kg only if alternative regimens are unsuitable due to toxicity.

Confirm absence of resistance mutations to integrase inhibitors, emtricitabine, or tenofovir prior to initiation.

No dose adjustment is required for patients with mild to moderate hepatic impairment (Child-Pugh Class A or B).

No dose adjustment is required for patients with mild or moderate renal impairment (CrCl ≥30 mL/min).

Do not administer to patients with severe renal impairment (CrCl <30 mL/min).

Do not administer to patients with severe hepatic impairment (Child-Pugh Class C).

Assess creatinine clearance, serum creatinine, urine glucose, and urine protein before initiating therapy and during treatment as clinically indicated.

Monitor patients co-infected with hepatitis B virus (HBV) for several months after discontinuation due to risk of severe hepatitis exacerbation.

If a dose is missed and it is less than 18 hours since the usual administration time, take the missed dose immediately with food and resume the normal schedule.

If a dose is missed and it is more than 18 hours since the usual administration time, skip the missed dose and resume the normal schedule with the next dose.

Do not take a double dose to make up for a missed dose.

Adverse Reactions

From the hematopoietic system uncommon – anemia.

Mental disorders common – unusual dreams; uncommon – depression.

From the nervous system common – headache, dizziness.

From the digestive system very common – nausea; common – diarrhea, vomiting, abdominal pain, flatulence; uncommon – dyspepsia.

From the skin and subcutaneous tissue common – rash; uncommon – pruritus.

Allergic reactions uncommon – angioedema.

Other common – fatigue.

Contraindications

Hypersensitivity to cobicistat, tenofovir alafenamide, elvitegravir, emtricitabine or any other component of the drug; children under 6 years of age and weighing less than 25 kg; children under 12 years of age and weighing less than 35 kg with impaired renal function; severe hepatic impairment (Child-Pugh class C); severe renal failure (CrCl<30 ml/min); pregnancy, breastfeeding period; concomitant use with drugs that are metabolized primarily by cytochrome CYP3A and for which an increase in plasma concentration is associated with the possibility of developing serious or life-threatening adverse reactions (alpha₁-adrenergic blockers /alfuzosin/; antiarrhythmic drugs /amiodarone, quinidine/; ergot derivatives /dihydroergotamine, ergometrine, ergotamine/; drugs stimulating gastrointestinal motility /cisapride/; HMG-CoA reductase inhibitors /lovastatin, simvastatin/; neuroleptics/antipsychotic drugs /pimozide, lurasidone/; PDE5 inhibitors /sildenafil for the treatment of pulmonary arterial hypertension/; sedatives/hypnotics /midazolam, triazolam for oral administration/); concomitant use with drugs that are strong inducers of cytochrome CYP3A (anticonvulsants /carbamazepine, phenobarbital, phenytoin/; antituberculosis drugs /rifampicin/; herbal medicinal products /St. John’s wort/; concomitant use with dabigatran etexilate, a substrate of P-glycoprotein.

With caution history of liver disease, including chronic active hepatitis B or C; patients with co-infection of HIV and HBV; simultaneously with antifungal drugs (ketoconazole, itraconazole, voriconazole, posaconazole, fluconazole), macrolide antibiotics (telithromycin), hypoglycemic drugs (metformin), oral contraceptive drugs containing drospirenone as a progestogen, antiarrhythmic agents (digoxin, disopyramide, flecainide, systemic lidocaine, mexiletine, propafenone), endothelin receptor blockers (bosentan); hypolipidemic agents (HMG-CoA reductase inhibitors – atorvastatin, pitavastatin); tadalafil for the treatment of pulmonary arterial hypertension.

Use in Pregnancy and Lactation

The use of the drug is contraindicated during pregnancy and lactation.

Use in Hepatic Impairment

Contraindicated in severe hepatic impairment.

No dose adjustment is required for patients with mild or moderate hepatic impairment.

It should be prescribed with caution to patients with a history of liver disease.

Use in Renal Impairment

Contraindicated in severe renal impairment (CrCl <30 ml/min).

No dose adjustment is required for CrCl >30 ml/min.

Pediatric Use

Contraindicated in children under 6 years of age and weighing less than 25 kg, as well as in children under 12 years of age and weighing less than 35 kg with renal impairment.

Geriatric Use

No dose adjustment is required for elderly patients.

Special Precautions

Patients with chronic hepatitis B or C receiving antiretroviral therapy are at an increased risk of severe or potentially fatal adverse liver reactions.

Tenofovir alafenamide is active against the hepatitis B virus.

Discontinuation of treatment with this combination in patients co-infected with HIV and hepatitis B virus may be associated with severe exacerbations of hepatitis.

Patients co-infected with HIV and hepatitis B virus who discontinue this combination should be carefully monitored with both clinical and laboratory follow-up for at least several months after treatment cessation.

Patients with pre-existing liver dysfunction, including chronic active hepatitis, have an increased frequency of liver function abnormalities during combination antiretroviral therapy and should be monitored according to standard practice.

If signs of worsening liver disease appear in such patients, interruption or discontinuation of treatment should be considered.

During antiretroviral therapy, increases in body weight and concentrations of blood lipids and glucose may occur.

These changes may be partly related to disease control and lifestyle.

In some cases, increased lipid concentrations indicate treatment efficacy, while convincing evidence linking weight gain to any particular treatment regimen is lacking.

For the management of blood lipid and glucose levels, refer to HIV treatment guidelines.

Lipid metabolism disorders should be managed using established clinical practices.

Nucleos(t)ide analogues can affect mitochondrial function to varying degrees, which is most pronounced with stavudine, didanosine, and zidovudine.

There have been reports of mitochondrial dysfunction in HIV-negative infants exposed to nucleoside analogues in utero and/or postnatally; this primarily concerns regimens including zidovudine.

The main adverse reactions reported are hematological disorders (anemia, neutropenia) and metabolic disorders (hyperlactatemia, hyperlipasemia).

These complications are often transient.

Late-onset neurological disorders (hypertension, seizures, abnormal behavior) are rarely reported.

These findings should be considered for any child exposed in utero to nucleos(t)ide analogues who presents with serious clinical manifestations of unknown etiology, particularly of a neurological nature.

In HIV-infected patients with severe immunodeficiency, the initiation of combination antiretroviral therapy may cause an inflammatory reaction to non-pathogenic or residual opportunistic microorganisms, leading to severe clinical conditions or exacerbation of symptoms.

Such reactions are usually observed within the first few weeks or months after starting combination antiretroviral therapy.

Relevant examples include cytomegalovirus retinitis, generalized and/or focal mycobacterial infections, and Pneumocystis jirovecii pneumonia.

Any inflammatory symptoms should be evaluated and treated as necessary.

Cases of autoimmune disorders (such as Graves’ disease and autoimmune hepatitis) have also been reported in the context of immune reconstitution; however, the reported time of onset varied greatly, and these cases could occur many months after starting treatment.

Patients receiving this combination or any other antiretroviral therapy may continue to develop opportunistic infections and other complications of HIV infection; therefore, they must remain under close clinical supervision by physicians experienced in treating patients with associated HIV diseases.

Although the etiology is considered multifactorial (including corticosteroid use, alcohol consumption, severe immunosuppression, increased BMI), cases of osteonecrosis have been reported, particularly in patients with advanced HIV disease and/or on long-term combination antiretroviral therapy.

Patients should be informed to seek medical attention if they experience joint pain and aches, joint stiffness, or difficulty moving.

The potential risk of nephrotoxicity due to long-term exposure to low levels of tenofovir when using tenofovir alafenamide cannot be ruled out.

Women of childbearing potential should use either a hormonal contraceptive containing at least 30 mcg of ethinyl estradiol and drospirenone or norgestimate as the progestogen, or an alternative reliable method of contraception.

Effect on Ability to Drive and Operate Machinery

Cases of dizziness have been reported during treatment with this combination, which should be considered when driving vehicles and performing work requiring increased concentration and speed of psychomotor reactions.

Drug Interactions

Concomitant use of this combination with other antiretroviral drugs, as well as drugs containing Tenofovir alafenamide, tenofovir disoproxil, lamivudine, or adefovir dipivoxil used for the treatment of viral hepatitis B, should be avoided.

Concomitant use of this combination with anti-tuberculosis drugs (rifabutin), corticosteroids that are metabolized by cytochrome CYP3A (including betamethasone, budesonide, fluticasone, mometasone, prednisone, triamcinolone), anticoagulants (apixaban, rivaroxaban, edoxaban), and inhaled beta-agonists (salmeterol) is not recommended.

Concomitant use with oral contraceptive preparations containing a progestogen other than drospirenone or norgestimate should be avoided.

Concomitant use of this combination with colchicine is not recommended in patients with renal or hepatic impairment.

Elvitegravir is primarily metabolized by cytochrome CYP3A, and drugs that are inducers or inhibitors of cytochrome CYP3A may affect the action of elvitegravir.

Concomitant use of the drug containing this combination with drugs that are inducers of cytochrome CYP3A may lead to decreased plasma concentrations of elvitegravir and reduced therapeutic effect of this combination.

Elvitegravir may induce cytochrome CYP2C9 enzymes and/or inducible uridine diphosphate-glucuronosyltransferase (UGT); therefore, the plasma concentrations of substrates of these enzymes may decrease.

Cobicistat is a strong, irreversible inhibitor of cytochrome CYP3A and is also a substrate of cytochrome CYP3A.

Cobicistat is a weak inhibitor of cytochrome CYP2D6 and is minimally metabolized by cytochrome CYP2D6.

Drugs that inhibit cytochrome CYP3A may reduce the clearance of cobicistat, leading to increased plasma concentrations of cobicistat.

Drugs that are highly dependent on CYP3A metabolism and have a high first-pass metabolism in the liver are most susceptible to a significant increase in exposure when co-administered with cobicistat.

Cobicistat is an inhibitor of the following transporters: P-glycoprotein (P-gp), Breast Cancer Resistance Protein (BCRP), Organic Anion Transporting Polypeptide (OATP) 1B1 and OATP1B3.

Concomitant use with drugs that are substrates of P-gp, BCRP, OATP1B1, and OATP1B3 may lead to increased plasma concentrations of these drugs.

Concomitant use of emtricitabine with drugs that are eliminated by active tubular secretion may increase the concentrations of emtricitabine and/or the co-administered drug.

Drugs that reduce renal function may increase the concentrations of emtricitabine.

Tenofovir alafenamide is transported by P-gp and BCRP.

Use of drugs that significantly affect the activity of P-gp and BCRP may lead to changes in the absorption of tenofovir alafenamide.

However, when co-administered with cobicistat as part of this fixed combination, near-maximal inhibition of P-gp by cobicistat is achieved, leading to increased availability of tenofovir alafenamide, resulting in exposures comparable to 25 mg of tenofovir alafenamide as a monotherapy.

Therefore, no additional increase in tenofovir alafenamide exposures is expected after administration of this fixed combination in conjunction with another P-gp and/or BCRP inhibitor.

Tenofovir alafenamide is a substrate of OATP in vitro.

Storage Conditions

Store at 2°C (36°F) to 30°C (86°F). Keep in original packaging, protected from light. Keep out of reach of children.

Dispensing Status

Rx Only

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.