`
`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)
`
`
`
`-----------------------------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
`
`
`
`
`
`1.
`INDICATIONS AND USAGE
`
`
`2. DOSAGE AND ADMINISTRATION
`
`
`
`Testing Prior to Initiation of SYMTUZA
`2.1
`
`
`
`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
`
`Severe Acute Exacerbation of Hepatitis B in Patients
`5.1
`
`
`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
`
`
`5.5
`Immune Reconstitution Syndrome
`
`
`
`-----------------------------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)
`
`
`
`
`See 17 for PATIENT COUNSELING INFORMATION and FDA-
`approved patient labeling.
`
`
`
`
`
`Revised: 01/2019
`
`
`
`
`
`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
`
`
`Clinical Trials Experience
`6.1
`
`
`Postmarketing Experience
`6.2
`
`
`7. DRUG INTERACTIONS
`
`7.1 Not Recommended With Other Antiretroviral
`
`
`Medications
`
`
`
`7.2
`Potential for SYMTUZA to Affect Other Drugs
`
`
`Potential for Other Drugs to Affect SYMTUZA
`7.3
`
`
`7.4 Drugs Affecting Renal Function
`
`
`7.5
`Significant Drug Interactions
`
`
`8. USE IN SPECIFIC POPULATIONS
`
`8.1 Pregnancy
`
`
`8.2
`Lactation
`
`
`Pediatric Use
`8.4
`
`
`8.5 Geriatric Use
`
`
`8.6
`Renal Impairment
`
`
`8.7 Hepatic Impairment
`
`
`
` 1
`
`Reference ID: 4381545
`
`
`
`
`
`
`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: 4381545
`
`
`
` 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)].
`
`
`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:
`
`
`
`• 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. 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)].
`
`Not Recommended in Patients with Severe Renal Impairment
`2.3
`
`
`SYMTUZA is not recommended in patients with creatinine clearance below 30 mL per minute
`
`
`
`
`[see Use in Specific Populations (8.6)].
`
`
`
`
` 3
`
`Reference ID: 4381545
`
`
`
`
`
`
`Not Recommended in Patients with Severe Hepatic Impairment
`2.4
`
`
`
`SYMTUZA is not recommended for use in patients with severe hepatic impairment (Child-Pugh
`
`
`Class C) [see Use in Specific Populations (8.7)].
`
`
`Not Recommended During Pregnancy
`2.5
`
`
`
`
`
`
`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.
`
`
`DOSAGE FORMS AND STRENGTHS
`3.
`
`
`
`
`
`
`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.
`
`
`CONTRAINDICATIONS
`4.
`
`
`
`
`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
`
`
`Lipid modifying agents: lomitapide, lovastatin, simvastatin
`
`
`PDE-5 inhibitor: sildenafil when used for treatment of pulmonary arterial hypertension
`
`
`
` 4
`
`Reference ID: 4381545
`
`
`
`
`
`
` Sedatives/hypnotics: orally administered midazolam, triazolam
`
`•
`
` 5. WARNINGS AND PRECAUTIONS
`
`Severe Acute Exacerbation of Hepatitis B in Patients Coinfected with HIV-1 and
` 5.1
`
`
` 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
`
`
`
` 5
`
`Reference ID: 4381545
`
`
`
`
`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%.
`
`Risk of Serious Adverse Reactions or Loss of Virologic Response Due to Drug
`5.4
`
`
`
`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
`
`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, 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: 4381545
`
`
`
` 6
`
`
`
`
`New Onset or Worsening Renal Impairment
`5.6
`
`
`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.
`
`
`
`
`
`Sulfa Allergy
`5.7
`
`
`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.
`
`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).
`
`
`Diabetes Mellitus/Hyperglycemia
`5.9
`
`
`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
`
`
`
`
`
`
` 7
`
`Reference ID: 4381545
`
`
`
`
`
`
` 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.
`
`
`
`
`
` ADVERSE REACTIONS
` 6.
` 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
`received a combination of PREZCOBIX® (fixed-dose combination of darunavir and cobicistat)
`
`
`
`and fixed-dose combination of emtricitabine and tenofovir disoproxil fumarate (FTC/TDF).
`
`
`
` 8
`
`Reference ID: 4381545
`
`
`
`
`subjects who discontinued
`The proportion of
`
` treatment with SYMTUZA or
`
` PREZCOBIX+FTC/TDF due to adverse events, regardless of severity, were 2% and 4%
`
` respectively.
`An overview of the most frequent (occurring in at least 2% of subjects) adverse reactions
`
`
`
`
`
`
` irrespective of severity reported in AMBER are presented in Table 1. An overview of the most
` frequent laboratory abnormalities of at least Grade 2 severity reported in AMBER are presented
`
`
`
` in Table 2. Changes from baseline in lipid parameters for patients receiving SYMTUZA and those
`
`
` receiving PREZCOBIX + FTC/TDF are presented in Table 3.
`
`
`
`
` Most adverse reactions during treatment with SYMTUZA were grade 1 or 2 in severity. One grade
`
`
` 3 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)
`
` At least Grade
` At least Grade
`
`
`
` All Grades
`
` All Grades
`
`
` 2
` 2
`
` Diarrhea
`
`
` 2%
` 2%
`
` 11%
`
` 9%
`
` Rasha
`
` 5%
`
` 4%
` 7%
`
`
` 8%
`
` Nausea
`
` 1%
`
` 3%
` 10%
`
`
` 6%
`
` Fatigue
`
` 1%
`
` 1%
` 4%
`
`
` 4%
` Headache
`
` 1%
`
` 1%
`
` 2%
`
` 3%
`
`
` <1%
`
`
` 4%
`
` 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
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` 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/TDF switched to SYMTUZA, and
`
`378 subjects who continued their treatment regimen of a boosted protease inhibitor 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
`
`Reference ID: 4381545
`
`
`
` 9
`
`
`
`
`
`
`
`
`
`
`
`
` 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
`
`
`
`
`
` Laboratory Abnormalities (Grade 2-4) Reported in ≥2% of Adults With No Prior
` Table 2:
`
`
`
` 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
`
` Cholesterol
`
` Grade 2
`
` Grade 3
`
` Elevated Glucose Levels
`
` Grade 2
`
` Grade 3
`
`
`
`
`
`
`
`
`
` Lipoprotein
`
`
`
`
`
`
` 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%
`
`
`
`
`
` 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)a
`
`
`
`
`
`
` SYMTUZA
` PREZCOBIX+FTC/TDF
`
`
`
` N=356
` N=355
`
`
`
`
`
`
`
`
`
`
`
`
` Meanb
`
`
`
` Total cholesterol
`
`
` HDL cholesterol
` LDL cholesterol
`
`
`
` Baseline
`
` mg/dL
`
` 168
`
` 45
`
` 100
`
`
`
`
` N=304c
`
`
` Week 48
`
` Change
`
`
` +30
` +6
`
` +19
`
`
`
` Baseline
`
` mg/dL
`
`
` 164
`
` 44
`
` 98
`
`
`
` N=290
`
`
` Week 48
`
` Change
`
`
` +11
` +2
`
`
` +5
`
`
`
` 10
`
`Reference ID: 4381545
`
`
`
`
`
` Triglycerides
`
`
` +21
`
` 112
`
` +34
` 117
`
` Total cholesterol to HDL ratio
`
` 0.1
`
` 4.0
`
` 0.2
`
` 4.1
`
`
`
`
`a
`
` 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).
`
` b 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.
`
`
`
` 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 had 670 adults with no prior antiretroviral treatment history with a
`
` median baseline eGFR (estimated glomerular filtration rate) of 119 mL/min (SYMTUZA) and 118
`
`
`
` mL/min (PREZCOBIX + FTC/TDF), 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 from
`
`
` baseline to Week 48. 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