`
` 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)
`
`
`
`
`
`
`
`
`
`
`-----------------------------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, 5.6, 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)
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` See 17 for PATIENT COUNSELING INFORMATION and FDA-
`
` approved patient labeling.
`
`
`
`
`
`
`
`
`
` Revised: 07/2018
`
`
`
`
`
`
`
`
`
`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
`
`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
`
`
`
`
`
` -----------------------------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:
`
`
`
`
`
`
`
`
`
`
`
`• 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. (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)
`
`
`
`
`
`
`
` ----------------------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)
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` FULL PRESCRIBING INFORMATION: CONTENTS*
`
`
`
`
` WARNING: POST TREATMENT ACUTE
`
` EXACERBATION OF HEPATITIS B
`
`
`
`
`
` INDICATIONS AND USAGE
`1.
`
`
`
`
` 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
`
`
`
`
`
`
`5.2 Hepatotoxicity
`
`
`5.3
` Severe Skin Reactions
`
`
`
`5.4
`
`
`
`
`
` Risk of Serious Adverse Reactions or Loss of
`
`
`
` Virologic Response Due to Drug Interactions
`
`
`
`
`
` Immune Reconstitution Syndrome
`
`
`
`
`
`
`
`
`
`
`5.5
`
`Reference ID: 4292588
`
`
`
` 1
`
`
`
`
`
`
`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 HIV-1 Subjects with no Prior
`
`
`
`
`
`
`
`
`
`Antiretroviral Treatment History
`
`
`
`
`14.2 Clinical Trial Results in HIV-1 Virologically-
`
`
`
`
`
`
`Suppressed Subjects Who Switched to SYMTUZA
`
`
`
`
`
`
`
`
` 16. HOW SUPPLIED/STORAGE AND HANDLING
`
`
`
`
` 17. PATIENT COUNSELING INFORMATION
`
`
` *Sections or subsections omitted from the full prescribing information are not
`
` listed.
`
`
`
`
`
`
`
`
`
`
`
`Reference ID: 4292588
`
`
`
` 2
`
`
`
`
`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)].
`
`
`
`
`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:
`
`
`
`
`
` 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.
`
`
`
`
`2.
`
`
`
` DOSAGE AND ADMINISTRATION
`
`
`
` 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. 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)].
`
`
`
`Reference ID: 4292588
`
`
`
` 3
`
`
`
`
` 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 pregnancy [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
`
` SYMTUZA is contraindicated with the following co-administered drugs due to the potential for
`
`
`
`
` serious and/or life-threatening events or loss of therapeutic effect [see Drug Interactions (7.5)].
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` Alpha 1-adrenoreceptor antagonist: alfuzosin
`
`
`
` Antianginal: ranolazine
`
`
`
` Antiarrhythmic: dronedarone
`
`
`
` Anticonvulsants: carbamazepine, phenobarbital, phenytoin
`
`
`
` Anti-gout: colchicine, in patients with renal/and or hepatic impairment
`
`
`
`
`
` Antimycobacterial: rifampin
`
`
`
` Antipsychotics: lurasidone, pimozide
`
`
`
` Ergot derivatives, e.g., dihydroergotamine, ergotamine, methylergonovine
`
`
`
`
`
` GI motility agent: cisapride
`
`
`
`
`
` Herbal product: St. John’s wort (Hypericum perforatum)
`
`
`
` Hepatitis C direct acting antiviral: elbasvir/grazoprevir
`
`
`
`
`
` HMG-CoA reductase inhibitors: lovastatin, simvastatin
`
`
`
` PDE-5 inhibitor: sildenafil when used for treatment of pulmonary arterial hypertension
`
`
`
`Reference ID: 4292588
`
`
`
` 4
`
`
`
`
`
`
`
`
`
` Sedatives/hypnotics: orally administered midazolam, triazolam
`
`5. WARNINGS AND PRECAUTIONS
`
`
`
`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
` therapy [see Dosage and Administration (2.1)]. Severe acute
`
`
`
`
`
`
` initiating antiretroviral
` 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
`
`
`
`
`
` 5
`
`Reference ID: 4292588
`
`
`
`
`
`
`
`
`
`
` 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, some of which may lead to [see Contraindications (4) and Drug
`
`
`
`
` Interactions (7.5)]:
`
`
`
`
` Loss of therapeutic effect of SYMTUZA and possible development of resistance.
`
`
`
`
`
`
`
`
`
` Possible clinically significant adverse reactions from greater exposures of concomitant
`
` drugs.
`
`
`
`
`
`
`
` 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)].
`
`
`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
`
`
`
`
`
`
` (such as Mycobacterium avium
`
`infections
` opportunistic
`infection, cytomegalovirus,
`
`
` Pneumocystis jirovecii pneumonia [PCP], or tuberculosis), which may necessitate further
`
`
`
` evaluation and treatment.
`
`
`Autoimmune disorders (such as Graves’ disease, polymyositis, and Guillain-Barré syndrome)
`
`
`
` 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.
`
`
`Reference ID: 4292588
`
`
`
` 6
`
`
`
`
` 5.6
`
`
`
`
`
` New Onset or Worsening Renal Impairment
`
`
`
`
`
`
` Renal impairment, including cases of acute renal failure and Fanconi syndrome (renal tubular
`
`
` injury with severe hypophosphatemia), has been reported with the use of tenofovir prodrugs in
`
`
`
`
` both animal toxicology studies and human trials. In clinical trials of SYMTUZA, there were no
`
`
`
`
`
`
`
`
` cases of proximal renal tubulopathy (PRT), including Fanconi syndrome, reported in the
`
`
`
`
` SYMTUZA group through Week 48. SYMTUZA is not recommended in patients with 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
`
`
`
`
`
` 7
`
`Reference ID: 4292588
`
`
`
`
`
`
`
`
`
` 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)]
`
`
`
`
`
`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.
`
`
`
`
`
`
` 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
`
`
`
`
`
`
`
`
`
`Reference ID: 4292588
`
`
`
` 8
`
`
`
`Table 1:
`
`
`
`
`
`
`
`
`
`
`
`
`
` Adverse Reactions Reported in ≥2% of HIV-1 Infected Adults With No Prior Antiretroviral
`
` Treatment History in AMBER (Week 48 Analysis)
`
`
`
` PREZCOBIX+FTC/TDF
` SYMTUZA
`
`
` (N=363)
`
` (N=362)
`
`
` At least Grade 2
`
` All Grades
`
`
` At least Grade 2
`
` All Grades
`
` Diarrhea
`
`
` 11%
` 2%
`
` 2%
`
` 9%
`
` Rasha
` 7%
`
` 5%
`
`
` 8%
`
` 4%
` Nausea
`
` 10%
`
` 3%
`
`
` 6%
`
` 1%
`Fatigue
`
` 4%
`
` 1%
`
`
` 4%
`
` 1%
` Headache
`
` 2%
`
` 1%
`
` 3%
`
` 1%
`
`
`
` 4%
` <1%
`
` 2%
`
`Abdominal discomfort
`-
`
` 1%
`
`
` 2%
` <1%
`
`
` 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
`
`
`
`
`
`
`
` 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
` The proportion of
`
`subjects who discontinued
`
`
`
` 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 and F/TDF are presented in Table 3.
`
`
`
`
`
`
`
`
` Most adverse reactions during treatment with SYMTUZA were grade 1 or 2 in severity. One
`
`
` grade 3 reaction was reported and no grade 4 adverse reactions were reported during treatment
`
`
`
`
`
`
` with SYMTUZA.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` 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 [either darunavir once daily or atazanavir (both boosted with ritonavir or
`
`
`
`
` cobicistat), or lopinavir with ritonavir] combined with FTC and TDF switched to SYMTUZA,
`
`
`
`
`and 378 subjects who continued their treatment regimen of a boosted protease inhibitor with FTC
`
`
`
`
`
` and 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).
`
`
`
`Reference ID: 4292588
`
`
`
` 9
`
`
`
`
` 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
`
` Low-Density Lipoprotein Cholesterol
`
` Grade 2
`
` Grade 3
` Elevated Glucose Levels
`
` 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
`
`
`
`
`
` 160-189 mg/dL
`≥ 190 mg/dL
`
`
`
`
`
`
` 126-250 mg/dL
`
`
` 251-500 mg/dL
`
`
`
`
`
`
`
`
`
` SYMTUZA
`
` N=362
`
` 4%
`
`
` <1%
`
`
` 7%
`
` 1%
`
` <1%%
`
`
` 17%
`
` 2%
`
`
` 9%
`
` 5%
`
` 6%
`
`
` <1%
`
` PREZCOBIX+FTC/TDF
`
`
` N=363
`
`
` 14%
`
` 0
`
`
` 4%
`
` 1%
`
` <1%
`
`
` 4%
`
` 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)a
`
`
`
`
`
`
`
`
`
`
`
`
`
` Meanb
`
`
`
`
` SYMTUZA
`
` N=356
`
`
` Baseline
`
` mg/dL
`
`
`
` Week 48
`
` Change
`
`
`
` N=304c
`
`
`
` PREZCOBIX+FTC/TDF
`
` N=355
`
`
` Baseline
`
` mg/dL
`
`
`
` Week 48
`
` Change
`
`
`
` N=290
`
`
`
` 10
`
`Reference ID: 4292588
`
`
`
`
`
` Total cholesterol
`
` +11
`
` 164
`
` +30
`
` 168
`
`
` HDL cholesterol
`
` +2
` 44
`
`
` +6
` 45
`
`
` LDL cholesterol
`
`
` +5
`
` 98
`
` +19
` 199
`
` Triglycerides
`
`
` +21
` 112
`
`
` +34
`
` 117
` Total cholesterol to HDL ratio
`
` 0.1
`
` 4.0
`
` 0.2
`
` 4.1
`
`
`
`a
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`