`HIGHLIGHTS OF PRESCRIBING INFORMATION
`These highlights do not include all the information needed to use
`SYMTUZA safely and effectively. See full prescribing information for
`SYMTUZA.
`
`SYMTUZA® (darunavir, cobicistat, emtricitabine, and tenofovir
`alafenamide) tablets, for oral use
`Initial U.S. Approval: 2018
`
`
`WARNING: POST TREATMENT ACUTE EXACERBATION OF
`HEPATITIS B
`See full prescribing information for complete boxed warning.
`
`Severe acute exacerbations of hepatitis B (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)
`
`---------------------------RECENT MAJOR CHANGES---------------------------
`Contraindications (4) 04/2022
`Warnings and Precautions,
`New Onset or Worsening Renal Impairment (5.6)
`
` 06/2021
`
`-----------------------------INDICATIONS AND USAGE--------------------------
`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----------------------
`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)
`
`
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`
`WARNING: POST TREATMENT ACUTE EXACERBATION OF
`HEPATITIS B
`1.
`INDICATIONS AND USAGE
`2. DOSAGE AND ADMINISTRATION
`2.1 Testing Prior to Initiation of SYMTUZA
`2.2 Recommended Dosage
`2.3 Not Recommended in Patients with Severe Renal
`Impairment
`2.4 Not Recommended in Patients with Severe
`Hepatic Impairment
`2.5 Not Recommended During Pregnancy
`3. DOSAGE FORMS AND STRENGTHS
`4. CONTRAINDICATIONS
`5. WARNINGS AND PRECAUTIONS
`5.1 Severe Acute Exacerbation of Hepatitis B in
`Patients Coinfected with HIV-1 and HBV
`
`----------------------DOSAGE FORMS AND STRENGTHS---------------------
`Tablets: 800 mg of darunavir, 150 mg of cobicistat, 200 mg of emtricitabine,
`and 10 mg of tenofovir alafenamide (equivalent to 11.2 mg of tenofovir
`alafenamide fumarate). (3)
`-----------------------------CONTRAINDICATIONS--------------------------------
`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)
`-------------------------WARNINGS AND PRECAUTIONS----------------------
`• Drug-induced hepatitis (e.g., acute hepatitis, cytolytic hepatitis) including
`some fatalities can occur with SYMTUZA. Monitor liver function before
`and during therapy, especially in patients with underlying chronic
`hepatitis, cirrhosis, or in patients who have pre-treatment elevations of
`transaminases. (5.2)
`• Severe skin reactions, including Stevens-Johnson syndrome, toxic
`epidermal necrolysis, drug rash with eosinophilia and systemic symptoms,
`and acute generalized exanthematous pustulosis may occur with
`SYMTUZA. Discontinue treatment if severe skin reaction develops. (5.3)
`• Patients receiving SYMTUZA may develop new onset or exacerbations of
`immune reconstitution syndrome. (5.5)
`• Monitor in patients with a known sulfonamide allergy. (5.7)
`• Discontinue treatment in patients who develop symptoms or laboratory
`findings suggestive of lactic acidosis or pronounced hepatotoxicity. (5.8)
`• Patients receiving SYMTUZA may develop new onset or exacerbation of
`diabetes mellitus/hyperglycemia and redistribution/accumulation of body
`fat. (5.9, 5.10)
`• Patients with hemophilia may develop increase bleeding events. (5.11)
`------------------------------ADVERSE REACTIONS-------------------------------
`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.
`--------------------------------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)
`-----------------------USE IN SPECIFIC POPULATIONS------------------------
`• Pregnancy: SYMTUZA is not recommended during pregnancy due to
`substantially lower exposures of darunavir and cobicistat during
`pregnancy. (2.5, 8.1, 12.3)
`• Lactation: Breastfeeding is not recommended. (8.2)
`• Pediatrics: Not recommended for pediatric patients weighing less than
`40 kg (8.4)
`
`
`See 17 for PATIENT COUNSELING INFORMATION and FDA-
`approved patient labeling.
`
`Revised: 04/2022
`
`5.2 Hepatotoxicity
`5.3 Severe Skin Reactions
`5.4 Risk of Serious Adverse Reactions or Loss of
`Virologic Response Due to Drug Interactions
`5.5
`Immune Reconstitution Syndrome
`5.6 New Onset or Worsening Renal Impairment
`5.7 Sulfa Allergy
`5.8
`Lactic Acidosis/Severe Hepatomegaly with
`Steatosis
`5.9 Diabetes Mellitus/Hyperglycemia
`5.10 Fat Redistribution
`5.11 Hemophilia
`6. ADVERSE REACTIONS
`6.1 Clinical Trials Experience
`6.2 Postmarketing Experience
`7. DRUG INTERACTIONS
`
`1
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`7.1 Not Recommended With Other Antiretroviral
`Medications
`7.2 Potential for SYMTUZA to Affect Other Drugs
`7.3 Potential for Other Drugs to Affect SYMTUZA
`7.4 Drugs Affecting Renal Function
`7.5 Significant Drug Interactions
`8. USE IN SPECIFIC POPULATIONS
`8.1 Pregnancy
`8.2
`Lactation
`8.4 Pediatric Use
`8.5 Geriatric Use
`8.6 Renal Impairment
`8.7 Hepatic Impairment
`10. OVERDOSAGE
`11. DESCRIPTION
`12. CLINICAL PHARMACOLOGY
`12.1 Mechanism of Action
`12.2 Pharmacodynamics
`12.3 Pharmacokinetics
`12.4 Microbiology
`
`13. NONCLINICAL TOXICOLOGY
`13.1 Carcinogenesis, Mutagenesis, Impairment of
`Fertility
`13.2 Animal Toxicology and/or Pharmacology
`14. CLINICAL STUDIES
`14.1 Clinical Trial Results in Subjects with HIV-1
`Infection with no Prior Antiretroviral Treatment
`History
`14.2 Clinical Trial Results in Virologically-Suppressed
`Subjects with HIV-1 Infection Who Switched to
`SYMTUZA
`14.3 Clinical Trial Results in Pediatric Subjects with
`HIV-1 Infection
`16. HOW SUPPLIED/STORAGE AND HANDLING
`17. PATIENT COUNSELING INFORMATION
`
`*Sections or subsections omitted from the full prescribing information are not
`listed.
`
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`FULL PRESCRIBING INFORMATION
`
`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)].
`
`INDICATIONS AND USAGE
`1.
`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.
`DOSAGE AND ADMINISTRATION
`2.
`Testing Prior to Initiation of SYMTUZA
`2.1
`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)].
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`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.
`3.
`DOSAGE FORMS AND STRENGTHS
`Each SYMTUZA tablet contains darunavir ethanolate equivalent to 800 mg of darunavir, 150 mg
`of cobicistat, 200 mg of emtricitabine (FTC), and tenofovir alafenamide fumarate equivalent to
`10 mg of tenofovir alafenamide (TAF). The yellow to yellowish-brown, capsule-shaped,
`film-coated tablet is debossed with “8121” on one side and “JG” on the other side.
`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
`
`4
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`•
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`•
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`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
`•
`WARNINGS AND PRECAUTIONS
`5.
`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.
`
`Reference ID: 4968697
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`5
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`

`
`Severe Skin Reactions
`5.3
`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 4 for 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)].
`
`Reference ID: 4968697
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`Immune Reconstitution Syndrome
`5.5
`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 avium infection, cytomegalovirus, Pneumocystis
`jirovecii pneumonia [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.
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`Reference ID: 4968697
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`Lactic Acidosis/Severe Hepatomegaly with Steatosis
`5.8
`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.
`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)]
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`Lactic acidosis/severe hepatomegaly with steatosis [see Warnings and Precautions (5.8)]
`•
`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).
`treatment with SYMTUZA or
`subjects who discontinued
`The proportion of
`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
`PREZCOBIX+FTC/TDF
`(N=362)
`(N=363)
`All Grades
`At least Grade
`All Grades
`At least Grade
`2
`2
`11%
`2%
`2%
`9%
`Diarrhea
`7%
`4%
`5%
`8%
`Rasha
`10%
`1%
`3%
`6%
`Nausea
`4%
`1%
`1%
`4%
`Fatigue
`2%
`1%
`1%
`3%
`Headache
`4%
`-
`<1%
`2%
`Abdominal discomfort
`1%
`<1%
`-
`2%
`Flatulence
`a
`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
`
`
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`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%.
`
`Less Frequent Adverse Reactions
`The following adverse reactions occurred in less than 2% of adults with no antiretroviral treatment
`history or virologically suppressed subjects receiving SYMTUZA, or are from studies described
`in the prescribing information of the individual component PREZISTA (darunavir).
`Gastrointestinal Disorders: dyspepsia, pancreatitis (acute), vomiting
`Skin and Subcutaneous Tissue Disorders: angioedema, pruritus, Stevens-Johnson syndrome
`Metabolism and Nutrition Disorders: anorexia, diabetes mellitus, lipodystrophy
`Reproductive System and Breast Disorders: gynecomastia
`Musculoskeletal and Connective Tissue Disorders: myalgia, osteonecrosis
`Psychiatric Disorders: abnormal dreams
`Immune System Disorders: (drug) hypersensitivity, immune reconstitution inflammatory
`syndrome
`Hepatobiliary Disorders: acute hepatitis
`
`Laboratory Abnormalities
`Table 2:
`Laboratory Abnormalities (Grade 2-4) Reported in ≥2% of Adults With No Prior
`Antiretroviral Treatment History in AMBER (Week 48 Analysis)
`
`Laboratory Parameter
`Grade
`Creatinine
`Grade 2
`Grade 4
`Triglycerides
`Grade 2
`Grade 3
`Grade 4
`Total Cholesterol
`Grade 2
`Grade 3
`
`Limit
`
`>1.3 to 1.8 x ULN
`≥3.5x ULN
`
`301-500 mg/dL
`501-1,000 mg/dL
`>1,000 mg/dL
`
`240-<300 mg/dL
`≥ 300 mg/dL
`
`SYMTUZA
`N=362
`
`4%
`<1%
`
`7%
`1%
`<1%
`
`17%
`2%
`
`PREZCOBIX+FTC/TDF
`N=363
`
`14%
`0
`
`4%
`1%
`<1%
`
`4%
`1%
`
`10
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`Reference ID: 4968697
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`Lipoprotein
`
`
`
`
`
`
`
`Low-Density
`Cholesterol
`Grade 2
`Grade 3
`Elevated Glucose Levels
`Grade 2
`Grade 3
`
`160-189 mg/dL
`≥190 mg/dL
`
`126-250 mg/dL
`251-500 mg/dL
`
`9%
`5%
`
`6%
`<1%
`
`4%
`1%
`
`6%
`0
`
`
`ALT and/or AST elevations (Grade 2-4 combined) occurred in 2% of adult subjects receiving
`SYMTUZA with no antiretroviral treatment history in AMBER (Week 48 Analysis). Results were
`consistent in subjects receiving PREZCOBIX+FTC/TDF.
`
`
`Table 3:
`
`
`
`Lipid Values, Mean Change from Baseline, Reported in Adults With No Prior
`Antiretroviral Treatment History in AMBER (Week 48 Analysis)
`SYMTUZA
`PREZCOBIX+FTC/TDF
`N=362
`N=363
`
`Baseline
`mg/dL
`
`N=304c
`
`Week 48
`Change
`
`Baseline
`mg/dL
`
`Week 48
`Change
`
`N=290
`
`Meana
`
`Nb
`+11
`164
`+30
`168
`Total cholesterol
`+2
`44
`+6
`45
`HDL cholesterol
`+5
`98
`+19
`100
`LDL cholesterol
`+21
`112
`+34
`117
`Triglycerides
`0.1
`4.0
`0.2
`4.1
`Total cholesterol to HDL ratio
`a The change from baseline is the mean of within-subject changes from baseline for subjects with both baseline and Week 48 values, or the
`last value carried forward prior to initiating lipid-lowering agent post-baseline.
`b N corresponds to the number of subjects with paired values and not on a lipid-lowering agent at screening/baseline. Subjects on lipid-
`lowering agents at screening/baseline were excluded from the analysis (6 out of 362 subjects on SYMTUZA, 8 out of 363 subjects on
`PREZCOBIX+FTC/TDF). Subjects initiating a lipid-lowering agent post-baseline had their last fasted on-treatment value (prior to
`starting the agent) carried forward (6 on SYMTUZA, 2 on PREZCOBIX+FTC/TDF).
`c One subject did not have a Week 48 result for LDL cholesterol (n=303).
`
`
`The percentage of subjects starting any lipid lowering drug during treatment in the SYMTUZA
`and PREZCOBIX + FTC/TDF arm were 1.7% (n=6) and 0.6% (n=2), respectively.
`
`Renal Laboratory Tests
`In the AMBER trial, which enrolled 725 adults with no prior antiretroviral treatment history,
`subjects had a median baseline eGFR (estimated glomerular filtration rate) of 119 mL/min
`(SYMTUZA) and 118 mL/min (PREZCOBIX + FTC/TDF). From baseline to Week 48, mean
`(SD) serum creatinine increased by 0.05 (0.10) mg/dL in the SYMTUZA group and by 0.09
`(0.11) mg/dL in the PREZCOBIX + FTC/TDF group. Median serum creatinine was 0.90 mg/dL
`(SYMTUZA) and 0.89 mg/dL (PREZCOBIX + FTC/TDF) at baseline and 0.95 mg/dL
`(SYMTUZA) and 0.97 mg/dL (PREZCOBIX +FTC/TDF) at Week 48. Increases in serum
`creatinine occurred by Week 2 of treatment and remained stable. Median urine protein-to-
`creatinine ratio (UPCR) was 47 mg/g (SYMTUZA) and 51 mg/g (PREZCOBIX + FTC/TDF) at
`baseline and 30 mg/g (SYMTUZA) and 34 mg/g (PREZCOBIX + FTC/TDF) at Week 48.
`In the EMERALD trial which had 1,141 virologically-suppressed adults treated with an HIV
`protease inhibitor and TDF containing regimen with a median baseline eGFR of 104 mL/min
`(SYMTUZA) and 103 mL/min (bPI+FTC/TDF) who were randomized to continue their treatment
`
`11
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`Reference ID: 4968697
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`regimen or switch to SYMTUZA, at Week 48, mean serum creatinine was similar to baseline for
`both those continuing baseline treatment and those switching to SYMTUZA. Mean (SD) serum
`creatinine was 0.98 (0.18) mg/dL (SYMTUZA) and 0.98 (0.19) mg/dL (bPI+FTC/TDF) at
`baseline and 0.99 (0.18) mg/dL (SYMTUZA) and 0.99 (0.21) mg/dL (bPI+FTC/TDF) at Week 48.
`Median serum creatinine was 0.97 mg/dL (SYMTUZA) and 0.98 mg/dL (bPI+FTC/TDF) at
`baseline and 1.0 mg/dL (SYMTUZA) and 0.97 mg/dL (bPI+FTC/TDF) at Week 48. Median
`UPCR was 62 mg/g (SYMTUZA) and 63 mg/g (bP