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.

5.1 Severe Acute Exacerbation of Hepatitis B in Patients Coinfected with HIV-1 and HBV

Patients with HIV-1 should be tested for the presence of chronic hepatitis B virus before initiating antiretroviral therapy [see Dosage and Administration (2.1)] . Severe acute exacerbations of hepatitis B (e.g., liver decompensation and liver failure) have been reported in patients who are coinfected with HIV-1 and HBV and have discontinued products containing emtricitabine and/or tenofovir disoproxil fumarate, and may occur with discontinuation of SYMTUZA. Patients coinfected with HIV-1 and HBV who discontinue SYMTUZA should be closely monitored with both clinical and laboratory follow-up for at least several months after stopping treatment. If appropriate, anti-hepatitis B therapy may be warranted, especially in patients with advanced liver disease or cirrhosis, since post-treatment exacerbation of hepatitis may lead to hepatic decompensation and liver failure.

5.2 Hepatotoxicity

Drug-induced hepatitis (e.g., acute hepatitis, cytolytic hepatitis) has been reported in clinical trials with darunavir, a component of SYMTUZA. Patients with pre-existing liver dysfunction, including chronic active hepatitis B or C, have an increased risk for liver function abnormalities including severe hepatic adverse reactions.

Post-marketing cases of liver injury, including some fatalities, have been reported with darunavir. These have generally occurred in patients with advanced HIV-1 disease taking multiple concomitant medications, having co-morbidities including hepatitis B or C co-infection, and/or developing immune reconstitution syndrome. A causal relationship with darunavir therapy has not been established.

Appropriate laboratory testing should be conducted prior to initiating therapy with SYMTUZA and patients should be monitored during treatment as clinically appropriate. Increased AST/ALT monitoring should be considered in patients with underlying chronic hepatitis, cirrhosis, or in patients who have pre-treatment elevations of transaminases, especially during the first several months of SYMTUZA treatment.

Evidence of new or worsening liver dysfunction (including clinically significant elevation of liver enzymes and/or symptoms such as fatigue, anorexia, nausea, jaundice, dark urine, liver tenderness, hepatomegaly) should prompt consideration of interruption or discontinuation of SYMTUZA.

5.3 Severe Skin Reactions

In patients receiving darunavir, a component of SYMTUZA, severe skin reactions may occur. These include conditions accompanied by fever and/or elevations of transaminases. Stevens-Johnson syndrome was reported with darunavir co-administered with cobicistat in clinical trials at a rate of 0.1%. During darunavir post-marketing experience, toxic epidermal necrolysis, drug rash with eosinophilia and systemic symptoms (DRESS), and acute generalized exanthematous pustulosis have been reported. Discontinue SYMTUZA immediately if signs or symptoms of severe skin reactions develop. These can include but are not limited to severe rash or rash accompanied with fever, general malaise, fatigue, muscle or joint aches, blisters, oral lesions, conjunctivitis, hepatitis, and/or eosinophilia.

Rash events of any cause and any grade occurred in 15% of subjects with no prior antiretroviral treatment history treated with SYMTUZA in the AMBER trial [see Adverse Reactions (6.1)] . Rash events were mild-to-moderate, often occurring within the first four weeks of treatment and resolving with continued dosing. The discontinuation rate due to rash in subjects using SYMTUZA was 2%.

5.4 Risk of Serious Adverse Reactions or Loss of Virologic Response Due to Drug Interactions

The concomitant use of SYMTUZA and other drugs may result in known or potentially significant drug interactions which may lead to [see Contraindications (4)and Drug Interactions (7.5)] :

• Clinically significant adverse reactions from greater exposures of concomitant drugs.
• Clinically significant adverse reactions from greater exposures of SYMTUZA.
• Loss of therapeutic effect of the concomitant drugs from lower exposures of active metabolite(s).
• Loss of therapeutic effect of SYMTUZA and possible development of resistance from lower exposures of SYMTUZA.

See Table 4for steps to prevent or manage these possible and known significant drug interactions, including dosing recommendations. Consider the potential for drug interactions prior to and during SYMTUZA therapy; review concomitant medications during SYMTUZA therapy; and monitor for the adverse reactions associated with concomitant medications [see Contraindications (4)and Drug Interactions (7)] .

When used with concomitant medications, SYMTUZA, which contains darunavir boosted with cobicistat, may result in different drug interactions than those observed or expected with darunavir co-administered with ritonavir. Complex or unknown mechanisms of drug interactions preclude extrapolation of drug interactions with darunavir co-administered with ritonavir to certain SYMTUZA interactions [see Drug Interactions (7)and Clinical Pharmacology (12.3)] .

5.5 Immune Reconstitution Syndrome

Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy. During the initial phase of combination antiretroviral treatment, patients whose immune systems respond may develop an inflammatory response to indolent or residual opportunistic infections (such as Mycobacterium aviuminfection, cytomegalovirus, Pneumocystis jiroveciipneumonia [PCP], or tuberculosis), which may necessitate further evaluation and treatment.

Autoimmune disorders (such as Graves' disease, polymyositis, Guillain-Barré syndrome, and autoimmune hepatitis) have also been reported to occur in the setting of immune reconstitution; however, the time to onset is more variable, and can occur many months after initiation of antiretroviral treatment.

5.6 New Onset or Worsening Renal Impairment

Postmarketing cases of renal impairment, including acute renal failure, proximal renal tubulopathy (PRT), and Fanconi syndrome have been reported with TAF-containing products; while most of these cases were characterized by potential confounders that may have contributed to the reported renal events, it is also possible these factors may have predisposed patients to tenofovir-related adverse events [see Adverse Reactions (6.1, 6.2)] . SYMTUZA is not recommended in patients with estimated creatinine clearance below 30 mL per minute.

Patients taking tenofovir prodrugs who have impaired renal function and those taking nephrotoxic agents including non-steroidal anti-inflammatory drugs are at increased risk of developing renal-related adverse reactions.

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. Discontinue SYMTUZA in patients who develop clinically significant decreases in renal function or evidence of Fanconi syndrome.

Cobicistat, a component of SYMTUZA, produces elevations of serum creatinine due to inhibition of tubular secretion of creatinine without affecting glomerular filtration. This effect should be considered when interpreting changes in estimated creatinine clearance in patients initiating SYMTUZA, particularly in patients with medical conditions or receiving drugs needing monitoring with estimated creatinine clearance. The elevation is typically seen within 2 weeks of starting therapy and is reversible after discontinuation. Patients who experience a confirmed increase in serum creatinine of greater than 0.4 mg/dL should be closely monitored for renal safety.

5.7 Sulfa Allergy

Darunavir contains a sulfonamide moiety. Monitor patients with a known sulfonamide allergy after initiating SYMTUZA. In clinical studies with darunavir co-administered with ritonavir, the incidence and severity of rash were similar in subjects with or without a history of sulfonamide allergy.

5.8 Lactic Acidosis/Severe Hepatomegaly with Steatosis

Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogs, including emtricitabine, a component of SYMTUZA, and TDF, another prodrug of tenofovir, alone or in combination with other antiretrovirals. Treatment with SYMTUZA should be suspended in any patient who develops clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity (which may include hepatomegaly and steatosis even in the absence of marked transaminase elevations).

5.9 Diabetes Mellitus/Hyperglycemia

New onset diabetes mellitus, exacerbation of pre-existing diabetes mellitus, and hyperglycemia have been reported during postmarketing surveillance in HIV infected patients receiving HIV protease inhibitor (PI) therapy. Some patients required either initiation or dose adjustments of insulin or oral hypoglycemic agents for treatment of these events. In some cases, diabetic ketoacidosis has occurred. In those patients who discontinued PI therapy, hyperglycemia persisted in some cases. Because these events have been reported voluntarily during clinical practice, estimates of frequency cannot be made and causal relationships between HIV PI therapy and these events have not been established.

5.10 Fat Redistribution

Redistribution/accumulation of body fat, including central obesity, dorsocervical fat enlargement (buffalo hump), peripheral wasting, facial wasting, breast enlargement, and "cushingoid appearance" have been observed in patients receiving antiretroviral therapy. The mechanism and long-term consequences of these events are currently unknown. A causal relationship has not been established.

5.11 Hemophilia

There have been reports of increased bleeding, including spontaneous skin hematomas and hemarthrosis in patients with hemophilia type A and B treated with HIV protease inhibitors (PIs). In some patients, additional factor VIII was given. In more than half of the reported cases, treatment with HIV PIs was continued or reintroduced if treatment had been discontinued. A causal relationship between PI therapy and these episodes has not been established.

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.

6.2 Postmarketing Experience

The following adverse reactions have been identified during post-approval use of darunavir. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

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 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 (5.6)] .

7.5 Significant Drug Interactions

Table 4 provides examples of established or potentially clinically significant drug interactions with SYMTUZA and recommended steps to prevent or manage these interactions. These recommendations are based on drug interaction trials conducted with the components of SYMTUZA, as individual agents or in combination, or are predicted interactions. No drug interaction trials have been performed with SYMTUZA or with all the components administered together. Drug interaction trials have been conducted with darunavir co-administered with ritonavir or cobicistat or with emtricitabine and tenofovir prodrugs. The table includes potentially significant interactions but is not all inclusive ,and therefore the label of each drug that is co- administered with SYMTUZA should be consulted for information related to the route of metabolism, interaction pathways, potential risks, and specific actions to be taken with regard to co- administration.

8.1 Pregnancy

8.2 Lactation

8.4 Pediatric Use

The safety and effectiveness of SYMTUZA for the treatment of HIV-1 infection in pediatric patients weighing at least 40 kg was established through studies with components of SYMTUZA. Use of SYMTUZA in this group is supported by evidence from adequate and well-controlled studies of SYMTUZA in adults with additional pharmacokinetic, safety, and virologic data from studies of components of SYMTUZA (Trials GS-US-216-0128 and GS-US-292-0106) in pediatric subjects with HIV-1 infection aged 12 to less than 18 years [see Adverse Reactions (6.1), Clinical Pharmacology (12.3), and Clinical Studies (14.3)] .

The safety and effectiveness of SYMTUZA have not been established in pediatric patients weighing less than 40 kg.

Darunavir, a component of SYMTUZA is not recommended in pediatric patients below 3 years of age because of toxicity and mortality observed in juvenile rats dosed with darunavir.

8.5 Geriatric Use

Clinical trials of SYMTUZA included 35 subjects aged above 65 years of which 26 received SYMTUZA. No differences in safety or efficacy have been observed between elderly subjects and those aged 65 years or less. In general, caution should be exercised in the administration and monitoring of SYMTUZA in elderly patients, reflecting the greater frequency of decreased hepatic function and of concomitant disease or other drug therapy [see Clinical Pharmacology (12.3)] .

8.6 Renal Impairment

SYMTUZA is not recommended in patients with severe renal impairment (creatinine clearance below 30 mL per minute). No dosage adjustment of SYMTUZA is required in patients with creatinine clearance greater than or equal to 30 mL per minute [see Clinical Pharmacology (12.3)] .

Cobicistat has been shown to decrease creatinine clearance without affecting actual renal glomerular function. Dosing recommendations are not available for drugs that require dosage adjustment for renal impairment when used in combination with SYMTUZA [see Warnings and Precautions (5.6)] .

8.7 Hepatic Impairment

No dosage adjustment of SYMTUZA is required in patients with mild (Child-Pugh Class A) or moderate (Child-Pugh Class B) hepatic impairment. SYMTUZA has not been studied in patients with severe hepatic impairment (Child-Pugh Class C) and there are only limited data regarding the use of SYMTUZA components in this population. Therefore, SYMTUZA is not recommended for use in patients with severe hepatic impairment [see Clinical Pharmacology (12.3)] .

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 27H 37N 3O 7S ∙ C 2H 5OH and its molecular weight is 593.73. Darunavir ethanolate has the following structural formula:

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 40H 53N 7O 5S 2and a molecular weight of 776.02. It has the following structural formula:

Emtricitabine: The chemical name of emtricitabine is 4-amino-5-fluoro-1-(2 R-hydroxymethyl-[1,3]-oxathiolan-5 S-yl)-(1H)-pyrimidin-2-one. Emtricitabine is the (-)enantiomer of a thio analog of cytidine, which differs from other cytidine analogs in that it has a fluorine in the 5 position. Emtricitabine has a molecular formula of C 8H 10FN 3O 3S and a molecular weight of 247.24. It has the following structural formula:

Tenofovir alafenamide: The chemical name of tenofovir alafenamide fumarate drug substance is L-alanine, N-[( S)-[[(1 R)-2-(6-amino-9 H-purin-9-yl)-1-methylethoxy]methyl]phenoxyphosphinyl]-,1-methylethyl ester, (2 E)-2-butenedioate (2:1). Tenofovir alafenamide fumarate has a molecular formula of C 21H 29O 5N 6P∙½(C 4H 4O 4) and a formula weight of 534.50. It has the following structural formula:

12.1 Mechanism of Action

SYMTUZA is a fixed-dose combination of antiretroviral drugs darunavir (plus the CYP3A inhibitor cobicistat), emtricitabine, and tenofovir alafenamide [see Microbiology (12.4)] .

12.2 Pharmacodynamics

12.3 Pharmacokinetics

12.4 Microbiology

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

13.2 Animal Toxicology and/or Pharmacology

Minimal to slight infiltration of mononuclear cells in the posterior uvea was observed in dogs with similar severity after 3 and 9 month administration of tenofovir alafenamide; reversibility was seen after a 3-month recovery period. No eye toxicity was observed in the dog at systemic exposures of 3.5 (TAF) and 0.62 (tenofovir) times the exposure seen in humans with the recommended daily dose of TAF in SYMTUZA.

14.1 Clinical Trial Results in Subjects with HIV-1 Infection with no Prior Antiretroviral Treatment History

The efficacy of SYMTUZA in HIV-1 subjects with no prior antiretroviral treatment history was evaluated in the Phase 3 trial TMC114FD2HTX3001 [NCT02431247, (AMBER)] in which subjects were randomized in a 1:1 ratio to receive either SYMTUZA (N=362) or a combination of PREZCOBIX and FTC/TDF (N=363) once daily. The median age was 34.0 years (range 18–71), 88.3% were male, 83% White, 11% Black, and 2% Asian. The mean baseline plasma HIV-1 RNA was 4.5 log 10copies/mL (range 1.3–6.7), and 18% had a baseline viral load ≥100,000 copies/mL. The median baseline CD4+ cell count was 453 cells/mm 3(range 38 to 1456 cells/mm 3).

Virologic outcomes at 48 weeks of treatment are presented in Table 11.

The mean increase from baseline in CD4+ cell count at Week 48 was 189 and 174 cells/mm 3in the SYMTUZA and PREZCOBIX + FTC/TDF groups, respectively.

14.2 Clinical Trial Results in Virologically-Suppressed Subjects with HIV-1 Infection Who Switched to SYMTUZA

Phase 3 trial TMC114IFD3013 [NCT02269917, (EMERALD)] evaluated the efficacy of SYMTUZA in virologically-suppressed (HIV-1 RNA less than 50 copies/mL) subjects with HIV-1 infection. Subjects were virologically suppressed for at least 2 months and no more than once had a viral load elevation above 50 HIV-1 RNA copies/mL during the year prior to enrollment. Subjects were on a stable antiretroviral regimen (for at least 6 months), consisting of a bPI [either darunavir once daily or atazanavir (both boosted with ritonavir or cobicistat), or lopinavir with ritonavir] combined with emtricitabine and TDF. Subjects had no history of failure on darunavir treatment and no known or suspected darunavir resistance-associated substitutions. Emtricitabine or tenofovir resistance-associated substitutions were not specifically excluded by the protocol. They either switched to SYMTUZA (N=763) or continued their treatment regimen (N=378) (randomized 2:1). Subjects had a median age of 46 years (range 19–78), 82% were male, 75% White, 21% Black, and 2% Asian. The median baseline CD4+ cell count was 628 cells/mm 3(range 111–1921 cells/mm 3). Overall, 15% (N=169) of subjects had prior virologic failure. Five subjects had archived tenofovir resistance-associated substitutions and 53 subjects had archived emtricitabine resistance-associated substitutions, mainly at RT position M184. All of these subjects with emtricitabine resistance-associated substitutions had HIV-1 RNA<50 copies/mL at Week 48 (N=50) or at the last on-treatment viral load (N=3). Virologic outcomes are presented in Table 12. Prior virologic failure did not impact treatment outcomes.

The mean increase from baseline in CD4+ cell count at Week 48 was 20 cells/mm 3in subjects who switched to SYMTUZA and 8 cells/mm 3in subjects who stayed on their baseline PI + FTC/TDF.

14.3 Clinical Trial Results in Pediatric Subjects with HIV-1 Infection

The pharmacokinetic profile, safety, and antiviral activity of the components of SYMTUZA were evaluated in open-label clinical trials in pediatric subjects with HIV-1 infection aged 12 to less than 18 years: GS-US-216-0128 (N=7) and GS-US-292-0106 (N=50).

In the Phase 2/3 trial GS-US-216-0128, darunavir 800 mg and cobicistat 150 mg once daily with 2 NRTIs were evaluated in 7 virologically suppressed pediatric subjects aged 12 to less than 18 years and weighing at least 40 kg. Subjects had a median (range) age of 14 (12–16) years and a median (range) weight of 57 (45–78) kg. At baseline, plasma HIV-1 RNA was <50 copies/mL in all subjects, and the median (range) CD4+ cell count was 1,117 (658–2,416) cells/mm 3. At Week 48, the proportion of subjects who maintained HIV-1 RNA <50 copies/mL was 86%, and the median change in CD4+ cell count from baseline was -342 cells/mm 3(range -1,389 to 210 cells/mm 3). All 6 subjects with available data had CD4+ cell counts above 800 cells/mm 3at Week 48.

In the Phase 2/3 trial GS-US-292-0106, cobicistat 150 mg, emtricitabine 200 mg, and tenofovir alafenamide 10 mg, as part of a fixed-dose combination regimen together with elvitegravir 150 mg, were evaluated in 50 treatment-naïve pediatric subjects with HIV-1 aged 12 to less than 18 years and weighing at least 35 kg. Subjects had a median (range) age of 15 (12–17) years. At baseline, median (range) plasma HIV-1 RNA was 4.7 (3.3–6.5) log 10copies/mL, median (range) CD4+ cell count was 456 (95–1,110) cells/mm 3, and 22% had baseline plasma HIV-1 RNA >100,000 copies/mL). At Week 48, the proportion of subjects who had HIV-1 RNA <50 copies/mL was 92%, and the median increase in CD4+ cell count from baseline was 220 cells/mm 3.

The use of SYMTUZA in pediatric patients weighing less than 40 kg has not been established [see Use in Specific Populations (8.4)].

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.

Instructions for Use

Advise patients to take SYMTUZA with food every day on a regular dosing schedule, as missed doses can result in development of resistance. Inform patients not to alter the dose of SYMTUZA or discontinue therapy with SYMTUZA without consulting their physician. For patients who are unable to swallow tablets whole, SYMTUZA may be split using a tablet-cutter, and the entire dose should be consumed immediately after splitting [see Dosage and Administration (2.2)] .

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

Severe acute exacerbations of hepatitis B have been reported in patients who are coinfected with HBV and HIV-1 and have discontinued products containing emtricitabine and/or TDF, and may likewise occur with discontinuation of SYMTUZA [see Warnings and Precautions (5.1)] . Advise the patient to not discontinue SYMTUZA without first informing their healthcare provider.

Hepatotoxicity

Inform patients that drug-induced hepatitis (e.g., acute hepatitis, cytolytic hepatitis) and liver injury, including some fatalities, could potentially occur with SYMTUZA. Advise patients to contact their healthcare provider immediately if signs and symptoms of liver problems develop [see Warnings and Precautions (5.2)] .

Severe Skin Reactions

Inform patients that skin reactions ranging from mild to severe, including Stevens-Johnson syndrome, drug rash with eosinophilia and systemic symptoms, and toxic epidermal necrolysis, could potentially occur with SYMTUZA. Advise patients to contact their healthcare provider immediately if signs or symptoms of severe skin reactions develop, including but not limited to severe rash or rash accompanied with fever, general malaise, fatigue, muscle or joint aches, blisters, oral lesions, and/or conjunctivitis [see Warnings and Precautions (5.3)] .

Pregnancy

Advise patients that SYMTUZA is not recommended during pregnancy and to alert their healthcare provider if they get pregnant while taking SYMTUZA. Inform patients that there is an antiretroviral pregnancy registry to monitor fetal outcomes of pregnant individuals exposed to SYMTUZA [see Use in Specific Populations (8.1)] .

Lactation

Instruct individuals with HIV-1 infection not to breastfeed because HIV-1 can be passed to the baby in breast milk [see Use in Specific Populations (8.2)] .

Drug Interactions

SYMTUZA may interact with many drugs; therefore, inform patients of the potential serious drug interactions with SYMTUZA, and that some drugs are contraindicated with SYMTUZA and other drugs may require dosage adjustment. Advise patients to report to their healthcare provider the use of any other prescription or nonprescription medication or herbal products, including St. John's wort [see Contraindications (4), Warnings and Precautions (5.4), and Drug Interactions (7)] .

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 [see Warnings and Precautions (5.5)] .

Renal Impairment

Advise patients to avoid taking SYMTUZA 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 [see Warnings and Precautions (5.6)] .

Lactic Acidosis and Severe Hepatomegaly

Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with use of drugs similar to SYMTUZA. Advise patients that they should stop SYMTUZA if they develop clinical symptoms suggestive of lactic acidosis or pronounced hepatotoxicity [see Warnings and Precautions (5.8)] .

Fat Redistribution

Inform patients that redistribution or accumulation of body fat may occur in patients receiving antiretroviral therapy, including SYMTUZA, and that the cause and long-term health effects of these conditions are not known at this time [see Warnings and Precautions (5.10)] .