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Darunavir, Cobicistat, Emtricitabine, And Tenofovir Alafenamide

FDA Drug Information • Also known as: Symtuza

Brand Names
Symtuza
Dosage Form
TABLET, FILM COATED
Product Type
DRUG FOR FURTHER PROCESSING

⚠ Boxed Warning (Black Box)

WARNING: POST TREATMENT ACUTE EXACERBATION OF HEPATITIS B Severe acute exacerbations of hepatitis B (HBV) 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 SYMTUZA. Closely monitor hepatic function with both clinical and laboratory follow-up for at least several months in patients who are coinfected with HIV-1 and HBV and discontinue SYMTUZA. If appropriate, anti-hepatitis B therapy may be warranted [see Warnings and Precautions (5.1) ] . WARNING: POST TREATMENT ACUTE EXACERBATION OF HEPATITIS B See full prescribing information for complete boxed warning. Severe acute exacerbations of hepatitis B (HBV) 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 SYMTUZA. Hepatic function should be monitored closely in these patients. If appropriate, anti-hepatitis B therapy may be warranted. ( 5.1 )

Description

11. DESCRIPTION SYMTUZA ® (darunavir, cobicistat, emtricitabine, and tenofovir alafenamide) is a fixed-dose combination tablet. Darunavir is an inhibitor of the HIV-1 protease. Cobicistat is a mechanism-based inhibitor of cytochrome P450 (CYP) enzymes of the CYP3A family. Emtricitabine, a synthetic nucleoside analog of cytidine, is an HIV nucleoside analog reverse transcriptase inhibitor (HIV NRTI). Tenofovir alafenamide, an HIV NRTI, is converted in vivo to tenofovir, an acyclic nucleoside phosphonate (nucleotide) analog of adenosine 5′-monophosphate. SYMTUZA tablets are for oral administration. Each tablet contains darunavir ethanolate equivalent to 800 mg of darunavir, 150 mg of cobicistat, 200 mg of emtricitabine, and 11.2 mg of tenofovir alafenamide fumarate equivalent to 10 mg of tenofovir alafenamide. The tablets include the following inactive ingredients: colloidal silicon dioxide, croscarmellose sodium, magnesium stearate, and microcrystalline cellulose. The tablets are film-coated with a coating material containing polyethylene glycol (macrogol), polyvinyl alcohol (partially hydrolyzed), talc, titanium dioxide, and yellow ferric oxide. Darunavir : Darunavir, in the form of darunavir ethanolate, has the following chemical name: [(1 S ,2 R )-3-[[(4-aminophenyl)sulfonyl](2-methylpropyl)amino]-2-hydroxy-1-(phenylmethyl)propyl]-carbamic acid (3 R ,3a S ,6a R )-hexahydrofuro[2,3- b ]furan-3-yl ester monoethanolate. Its molecular formula is C 27 H 37 N 3 O 7 S ∙ C 2 H 5 OH and its molecular weight is 593.73. Darunavir ethanolate has the following structural formula: Chemical Structure Cobicistat : Cobicistat is adsorbed onto silicon dioxide. The chemical name for cobicistat is 1,3-thiazol-5-ylmethyl[(2 R ,5 R )-5-{[(2 S )-2-[(methyl{[2-(propan-2-yl)-1,3-thiazol-4-yl]methyl}carbamoyl)amino]-4-(morpholin-4yl)butanoyl]amino}-1,6-diphenylhexan-2-yl]carbamate. It has a molecular formula of C 40 H 53 N 7 O 5 S 2 and a molecular weight of 776.02. It has the following...

What Is Darunavir, Cobicistat, Emtricitabine, And Tenofovir Alafenamide Used For?

1. INDICATIONS AND USAGE SYMTUZA is indicated as a complete regimen for the treatment of human immunodeficiency virus type 1 (HIV-1) infection in adults and pediatric patients weighing at least 40 kg: who have no prior antiretroviral treatment history or who are virologically suppressed (HIV-1 RNA less than 50 copies per mL) on a stable antiretroviral regimen for at least 6 months and have no known substitutions associated with resistance to darunavir or tenofovir. SYMTUZA is a four-drug combination of darunavir (DRV), a human immunodeficiency virus (HIV-1) protease inhibitor, cobicistat (COBI), a CYP3A inhibitor, and emtricitabine (FTC) and tenofovir alafenamide (TAF), both HIV-1 nucleoside analog reverse transcriptase inhibitors, and is indicated as a complete regimen for the treatment of HIV-1 infection in adults and pediatric patients weighing at least 40 kg: who have no prior antiretroviral treatment history or who are virologically suppressed (HIV-1 RNA less than 50 copies per mL) on a stable antiretroviral regimen for at least 6 months and have no known substitutions associated with resistance to darunavir or tenofovir. ( 1 )

Dosage and Administration

2. DOSAGE AND ADMINISTRATION Testing : Prior to or when initiating SYMTUZA, test patients for HBV infection. Prior to or when initiating SYMTUZA, and during treatment with SYMTUZA, on a clinically appropriate schedule, assess serum creatinine, estimated creatinine clearance, urine glucose, and urine protein in all patients. In patients with chronic kidney disease, also assess serum phosphorus. ( 2.1 ) Recommended dosage : One tablet taken once daily with food in adults and pediatric patients, weighing at least 40 kg. ( 2.2 ) Renal Impairment: SYMTUZA is not recommended in patients with estimated creatinine clearance below 30 mL/min. ( 2.3 ) Hepatic Impairment : SYMTUZA is not recommended in patients with severe hepatic impairment. ( 2.4 ) 2.1 Testing Prior to Initiation of SYMTUZA Prior to or when initiating SYMTUZA, test patients for hepatitis B (HBV) virus infection [see Warnings and Precautions (5.1) ] . Prior to or when initiating SYMTUZA, and during treatment with SYMTUZA, on a clinically appropriate schedule, assess serum creatinine, estimated creatinine clearance, urine glucose, and urine protein in all patients. In patients with chronic kidney disease, also assess serum phosphorus [see Warnings and Precautions (5.6) ] . 2.2 Recommended Dosage SYMTUZA is a four-drug fixed-dose combination product containing 800 mg of darunavir (DRV), 150 mg of cobicistat (COBI), 200 mg of emtricitabine (FTC), and 10 mg of tenofovir alafenamide (TAF). The recommended dosage of SYMTUZA is one tablet taken orally once daily with food in adults and pediatric patients weighing at least 40 kg. For patients who are unable to swallow the whole tablet, SYMTUZA may be split into two pieces using a tablet-cutter, and the entire dose should be consumed immediately after splitting [see Clinical Pharmacology (12.3) ] . 2.3 Not Recommended in Patients with Severe Renal Impairment SYMTUZA is not recommended in patients with creatinine clearance below 30 mL per minute [see Use in Specific Populations (8.6) ] . 2.4 Not Recommended in Patients with Severe Hepatic Impairment SYMTUZA is not recommended for use in patients with severe hepatic impairment (Child-Pugh Class C) [see Use in Specific Populations (8.7) ] . 2.5 Not Recommended During Pregnancy SYMTUZA is not recommended during pregnancy because of substantially lower exposures of darunavir and cobicistat during the second and third trimesters [see Use in Specific Populations (8.1) and Clinical Pharmacology (12.3)] . SYMTUZA should not be initiated in pregnant individuals. An alternative regimen is recommended for those who become pregnant during therapy with SYMTUZA.

Side Effects (Adverse Reactions)

6. ADVERSE REACTIONS The following adverse reactions are discussed in other sections of the labeling: Severe acute exacerbations of hepatitis B [see Warnings and Precautions (5.1) ] Hepatotoxicity [see Warnings and Precautions (5.2) ] Severe skin reactions [see Warnings and Precautions (5.3) ] Immune reconstitution syndrome [see Warnings and Precautions (5.5) ] New onset or worsening renal impairment [see Warnings and Precautions (5.6) ] Lactic acidosis/severe hepatomegaly with steatosis [see Warnings and Precautions (5.8) ] The most common adverse reactions (all grades, incidence greater than or equal to 2%) were diarrhea, rash, nausea, fatigue, headache, abdominal discomfort, and flatulence. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Janssen Products, LP at 1-800-JANSSEN (1-800-526-7736) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Clinical Trials in Adults Adverse Reactions in Adults with No Prior Antiretroviral Treatment History The safety profile of SYMTUZA in HIV-1 infected adults with no prior antiretroviral treatment history is based on Week 48 data from the AMBER trial, a randomized, double-blind, active-controlled trial where a total of 362 subjects received SYMTUZA once daily and 363 subjects received a combination of PREZCOBIX ® (fixed-dose combination of darunavir and cobicistat) and fixed-dose combination of emtricitabine and tenofovir disoproxil fumarate (FTC/TDF). The proportion of subjects who discontinued treatment with SYMTUZA or PREZCOBIX+FTC/TDF due to adverse events, regardless of severity, were 2% and 4% respectively. An overview of the most frequent (occurring in at least 2% of subjects) adverse reactions irrespective of severity reported in AMBER are presented in Table 1. An overview of the most frequent laboratory abnormalities of at least Grade 2 severity reported in AMBER are presented in Table 2. Changes from baseline in lipid parameters for patients receiving SYMTUZA and those receiving PREZCOBIX + FTC/TDF are presented in Table 3. Most adverse reactions during treatment with SYMTUZA were grade 1 or 2 in severity. One grade 3 adverse reaction was reported and no grade 4 adverse reactions were reported during treatment with SYMTUZA. Table 1: Adverse Reactions Reported in ≥2% of HIV-1 Infected Adults With No Prior Antiretroviral Treatment History in AMBER (Week 48 Analysis) SYMTUZA (N=362) PREZCOBIX+FTC/TDF (N=363) All Grades At least Grade 2 All Grades At least Grade 2 Diarrhea 9% 2% 11% 2% Rash Includes pooled reported terms: dermatitis, dermatitis allergic, erythema, photosensitivity reaction, rash, rash generalized, rash macular, rash maculo-papular, rash morbilliform, rash pruritic, toxic skin eruption, urticaria 8% 4% 7% 5% Nausea 6% 1% 10% 3% Fatigue 4% 1% 4% 1% Headache 3% 1% 2% 1% Abdominal discomfort 2% - 4% <1% Flatulence 2% <1% 1% - Adverse Reactions in Virologically-Suppressed Adults The safety profile of SYMTUZA in virologically-suppressed HIV-1 infected adults is based on Week 48 data from 1,141 subjects in the EMERALD trial, a randomized, open-label, active-controlled trial where 763 subjects with a stable antiretroviral regimen consisting of a boosted protease inhibitor (bPI) [either darunavir once daily or atazanavir (both boosted with ritonavir or cobicistat), or lopinavir with ritonavir] combined with FTC/TDF switched to SYMTUZA, and 378 subjects who continued their treatment regimen of a bPI with FTC/TDF. Overall, the safety profile of SYMTUZA in subjects in this study was similar to that in subjects with no prior antiretroviral treatment history. The proportion of subjects who discontinued treatment with SYMTUZA due to adverse events, regardless of severity, was 1%....

Drug Interactions

7. DRUG INTERACTIONS Co-administration of SYMTUZA with other drugs can alter the concentration of other drugs and other drugs may alter the concentrations of SYMTUZA components. Consult the full prescribing information prior to and during treatment for potential drug interactions. ( 4 , 5.4 , 7 , 12.3 ) 7.1 Not Recommended With Other Antiretroviral Medications SYMTUZA is a complete regimen for HIV-1 infection and co-administration with other antiretroviral medications for the treatment of HIV-1 infection is not recommended. For this reason, information regarding potential drug-drug interactions with other antiretroviral medications is not provided. 7.2 Potential for SYMTUZA to Affect Other Drugs Darunavir co-administered with cobicistat is an inhibitor of CYP3A and CYP2D6. Cobicistat inhibits the following transporters: P-glycoprotein (P-gp), BCRP, MATE1, OATP1B1 and OATP1B3. Therefore, co-administration of SYMTUZA with drugs that are primarily metabolized by CYP3A and/or CYP2D6, or are substrates of P-gp, BCRP, MATE1, OATP1B1 or OATP1B3 may result in increased plasma concentrations of such drugs, which could increase or prolong their therapeutic effect and can be associated with adverse events. Co-administration of SYMTUZA with drugs that have active metabolite(s) formed by CYP3A may result in reduced plasma concentrations of these active metabolite(s), potentially leading to loss of their therapeutic effect (see Table 4 ). 7.3 Potential for Other Drugs to Affect SYMTUZA Darunavir is metabolized by CYP3A. Cobicistat is metabolized by CYP3A and, to a minor extent, by CYP2D6. Co-administration of drugs that induce CYP3A activity are expected to increase the clearance of darunavir and cobicistat, resulting in lowered plasma concentrations which may lead to loss of therapeutic effect and development of resistance. Co-administration of SYMTUZA with other drugs that inhibit CYP3A may result in increased plasma concentrations of darunavir and cobicistat (see Table 4 ). Tenofovir alafenamide (TAF) is a substrate of P-gp, BCRP, OATP1B1, and OATP1B3. Drugs that strongly affect P-gp activity may lead to changes in TAF absorption. Drugs that induce P-gp activity are expected to decrease the absorption of TAF, resulting in decreased plasma concentrations of TAF, which may lead to loss of therapeutic effect of SYMTUZA and development of resistance. Co-administration of SYMTUZA with other drugs that inhibit P-gp may increase the absorption and plasma concentrations of TAF (see Table 4 ). 7.4 Drugs Affecting Renal Function Because emtricitabine and tenofovir are primarily excreted by the kidneys through glomerular filtration and active tubular secretion, co-administration of SYMTUZA with drugs that reduce renal function or compete for active tubular secretion may increase concentrations of emtricitabine, tenofovir, and other renally eliminated drugs and this may increase the risk of adverse reactions. Some examples of drugs that are eliminated by active...

Contraindications

4. CONTRAINDICATIONS Darunavir and cobicistat are both inhibitors of the cytochrome P450 3A (CYP3A) isoform. SYMTUZA should not be co-administered with medicinal products that are highly dependent on CYP3A for clearance and for which increased plasma concentrations are associated with serious and/or life-threatening events (narrow therapeutic index). Darunavir and cobicistat are both substrates of the cytochrome P450 3A (CYP3A) isoform. Co-administration of SYMTUZA with CYP3A inducers is expected to lower plasma concentrations of darunavir and cobicistat which may lead to loss of efficacy of darunavir and development of resistance. Examples of drugs that are contraindicated for co-administration with SYMTUZA due to the potential for serious and/or life-threatening events or loss of therapeutic effect [see Drug Interactions (7.5) ] are listed below. Alpha 1-adrenoreceptor antagonist: alfuzosin Anticonvulsants: carbamazepine, phenobarbital, phenytoin Anti-gout: colchicine, in patients with renal and/or hepatic impairment Antimycobacterial: rifampin Antipsychotics: lurasidone, pimozide Cardiac Disorders: dronedarone, ivabradine, ranolazine Ergot derivatives, e.g., dihydroergotamine, ergotamine, methylergonovine Herbal product: St. John's wort ( Hypericum perforatum ) Hepatitis C direct acting antiviral: elbasvir/grazoprevir Lipid modifying agents: lomitapide, lovastatin, simvastatin Opioid Antagonist: naloxegol PDE-5 inhibitor: sildenafil when used for treatment of pulmonary arterial hypertension Sedatives/hypnotics: orally administered midazolam, triazolam SYMTUZA is contraindicated to be co-administered with certain drugs for which altered plasma concentrations are associated with serious and/or life-threatening events or which may lead to loss of therapeutic effect of SYMTUZA and development of resistance. ( 4 )

Pregnancy and Breastfeeding

8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in individuals exposed to SYMTUZA during pregnancy. Healthcare providers are encouraged to register patients by calling the Antiretroviral Pregnancy Registry (APR) at 1-800-258-4263. Risk Summary SYMTUZA is not recommended during pregnancy because of substantially lower exposures of darunavir and cobicistat during the second and third trimesters [see Dosage and Administration (2.5) ] . A study evaluating the pharmacokinetics of antiretrovirals during pregnancy demonstrated substantially lower exposures of darunavir and cobicistat in the second and third trimesters compared to the post-partum period (see Data ) and [see Clinical Pharmacology (12.3) ]. Prospective pregnancy data from the APR are not sufficient to adequately assess the risk of birth defects or miscarriage. However, available data from the APR show no statistically significant difference in the overall risk of major birth defects for darunavir, cobicistat, emtricitabine, or tenofovir alafenamide (TAF) 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) (see Data ) . The rate of miscarriage is not reported in the APR. The estimated background rate of miscarriage in clinically recognized pregnancies in the U.S. general population is 15–20%. The background risk of major birth defects and miscarriage for the indicated population is unknown. In animal reproduction studies, no adverse developmental effects were observed when the components of SYMTUZA were administered separately at darunavir exposures less than 1- (mice and rabbits) and 2.6-times (rats) higher, at cobicistat exposures 1.7- and 4.1-times higher (rats and rabbits respectively), at emtricitabine exposures 88- and 7.3- times higher (mice and rabbits, respectively), and tenofovir alafenamide exposures equal to or 85- times...

Overdosage

10. OVERDOSAGE Human experience of acute overdose with SYMTUZA is limited. There is no specific antidote for overdose with SYMTUZA. Treatment of overdose with SYMTUZA consists of general supportive measures including monitoring of vital signs and observation of the clinical status of the patient. Since darunavir and cobicistat are highly bound to plasma proteins, it is unlikely that they will be significantly removed by hemodialysis or peritoneal dialysis. Hemodialysis treatment removes approximately 30% of the emtricitabine dose over a 3-hour dialysis period starting within 1.5 hours of emtricitabine dosing (blood flow rate of 400 mL/min and a dialysate flow rate of 600 mL/min). Tenofovir is efficiently removed by hemodialysis with an extraction coefficient of approximately 54%. It is not known whether emtricitabine or tenofovir can be removed by peritoneal dialysis.

How Supplied

16. HOW SUPPLIED/STORAGE AND HANDLING SYMTUZA ® (darunavir, cobicistat, emtricitabine, and tenofovir alafenamide) tablets are supplied as yellow to yellowish-brown, capsule-shaped, film-coated tablets debossed with "8121" on one side and "JG" on the other side. SYMTUZA is packaged in bottles of 30 tablets (NDC 59676-800-30), with a silica gel desiccant and child-resistant closure. Storage Store at 20°C–25°C (between 68°F–77°F); with excursions permitted to 15°C–30°C (59°F–86°F). Dispense only in the original container. Keep container tightly closed with desiccant inside to protect from moisture. Keep SYMTUZA out of reach of children.

About This Information

This drug information is sourced from FDA-approved labeling via the openFDA database. It is intended for educational and reference purposes only. This is not medical advice. Always consult your healthcare provider before making decisions about medication. Drug information may be updated by the FDA; check with your pharmacist for the most current information.

What are side effects?

Side effects are unwanted reactions that can occur when taking a medication. They range from mild (headache, nausea) to severe (allergic reactions, organ damage). Not everyone experiences side effects, and severity varies. Report any concerning side effects to your doctor.

What are drug interactions?

Drug interactions occur when a medication is affected by another drug, food, or supplement. Interactions can make medications less effective or cause dangerous side effects. Always tell your doctor about all medications and supplements you take.