Applies to cobicistat / darunavir / emtricitabine / tenofovir alafenamide: oral tablet.

Serious side effects

Along with its needed effects, cobicistat/darunavir/emtricitabine/tenofovir alafenamide may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Check with your doctor immediately if any of the following side effects occur while taking cobicistat / darunavir / emtricitabine / tenofovir alafenamide:

More common

• Rash

Less Common

• Blistering, peeling, or loosening of the skin
• bloating
• blurred vision
• chills
• constipation
• cough
• dark urine
• diarrhea
• dry mouth
• fast heartbeat
• fever
• flushed, dry skin
• fruit-like breath odor
• general tiredness and weakness
• heavy jaw feeling
• increased hunger
• increased thirst
• increased urination
• indigestion
• itching
• joint or muscle pain
• large, hive-like swelling on the face, eyelids, lips, tongue, throat, hands, legs, feet, or genitals
• light-colored stools
• loosening of a tooth
• loss of appetite
• loss of consciousness
• nausea
• pain, swelling, or numbness in the mouth or jaw
• pains in the stomach, side, or abdomen, possibly radiating to the back
• red skin lesions, often with a purple center
• red, irritated eyes
• sore throat
• sores, ulcers, or white spots in the mouth or on the lips
• stomachache
• sweating
• trouble breathing
• unexplained weight loss
• unusual tiredness or weakness
• upper right abdominal or stomach pain
• vomiting
• yellow eyes or skin

Incidence not known

• Lower back pain
• muscle cramps, spasms, or stiffness
• pain or burning while urinating
• sudden decrease in amount of urine

Other side effects

Some side effects of cobicistat / darunavir / emtricitabine / tenofovir alafenamide may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects.

Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

Less common

• Abnormal dreams
• belching
• difficulty in moving
• excess air or gas in the stomach or bowels
• headache
• heartburn
• passing gas
• redistribution or accumulation of body fat
• stomach discomfort, upset, or pain
• swelling of the breasts or breast soreness in both females and males
• swollen joints
• weight loss

For Healthcare Professionals

Applies to cobicistat / darunavir / emtricitabine / tenofovir alafenamide: oral tablet.

General

In clinical trials, the most common side effects reported in therapy-naive patients were diarrhea, headache, rash, nausea, fatigue, and abdominal pain; in suppressed therapy-experienced patients, diarrhea, headache, arthralgia, abdominal pain, fatigue, and rash were reported most often. This drug was discontinued due to side effects in 2% and up to 1% of therapy-naive and therapy-experienced patients, respectively.^[Ref]

Gastrointestinal

Very common (10% or more): Diarrhea (up to 22.6%)

Common (1% to 10%): Abdominal pain, vomiting, nausea, abdominal discomfort, abdominal distension, dyspepsia, flatulence, elevated amylase

Uncommon (0.1% to 1%): Acute pancreatitis, increased pancreatic enzymes, elevated lipase^[Ref]

Elevated amylase (1.5 to less than 3 times the upper limit of normal [1.5 to less than 3 x ULN]: up to 4.2%; 3 to less than 5 x ULN: 0.4%; at least 5 x ULN: up to 0.3%) and lipase (greater than 1.5 to less than 3 x ULN: 0.3%; 1.5 to less than 3 x ULN: 0.4%; 3 to less than 5 x ULN: up to 0.4%; at least 5 x ULN: up to 0.3%) have been reported.^[Ref]

Other

Very common (10% or more): Elevated total cholesterol (up to 21%), elevated low-density lipoprotein (LDL) cholesterol

Common (1% to 10%): Fatigue, asthenia, elevated triglycerides, lipid-lowering drug started

Uncommon (0.1% to 1%): Elevated alkaline phosphatase

Frequency not reported: Elevated high-density lipoprotein (HDL), total cholesterol to HDL ratio increased

Darunavir-containing regimen:

-Frequency not reported: Asthenia

Antiretroviral therapy:

-Frequency not reported: Increased weight, increased blood lipids^[Ref]

Elevated total cholesterol (240 to less than 300 mg/dL [6.19 to less than 7.77 mmol/L]: up to 21%; at least 300 mg/dL [at least 7.77 mmol/L]: up to 3.7%), LDL cholesterol (160 to 189 mg/dL [4.12 to less than 4.9 mmol/L]: up to 15.6%; at least 190 mg/dL [at least 4.9 mmol/L]: up to 6.3%), triglycerides (301 to 500 mg/dL [greater than 3.42 to 5.7 mmol/L]: up to 7%; 501 to 1000 mg/dL [greater than 5.7 to 11.4 mmol/L]: up to 1.4%; greater than 1000 mg/dL [greater than 11.4 mmol/L]: less than 1%), and alkaline phosphatase (2.5 to less than 5 x ULN: up to 0.3%) have been reported.^[Ref]

Musculoskeletal

Very common (10% or more): Decreased bone mineral density (BMD) (up to 16%)

Common (1% to 10%): Myalgia, arthralgia

Uncommon (0.1% to 1%): Osteonecrosis

Darunavir-containing regimen:

-Postmarketing reports: Rhabdomyolysis (associated with coadministration with HMG-CoA reductase inhibitors)

HIV protease inhibitors:

-Rare (0.01% to 0.1%): Rhabdomyolysis

-Frequency not reported: Increased creatine phosphokinase, myalgia, myositis^[Ref]

In therapy-naive patients, BMD decreases of at least 5% at the lumbar spine were reported in 16% of patients using this drug and 22% of patients using cobicistat-darunavir plus emtricitabine-tenofovir disoproxil fumarate (DF); BMD decreases of at least 7% at the femoral neck were reported in 2% of patients using this drug and 15% of patients using cobicistat-darunavir plus emtricitabine-tenofovir DF. In boosted protease inhibitor and tenofovir DF-treated patients, BMD decreases of at least 5% at the lumbar spine were reported in 2% of patients using this drug and 9% of patients using cobicistat-darunavir plus emtricitabine-tenofovir DF; BMD decreases of at least 7% at the femoral neck were reported in no patients using this drug and 2% of patients using cobicistat-darunavir plus emtricitabine-tenofovir DF.^[Ref]

Dermatologic

Very common (10% or more): Rash (included dermatitis, allergic dermatitis, erythema, photosensitivity reaction, rash, erythematous rash, generalized rash, macular rash, maculopapular rash, morbilliform rash, papular rash, pruritic rash, toxic skin eruption, urticaria; up to 12.7%)

Common (1% to 10%): Pruritus, urticaria

Uncommon (0.1% to 1%): Angioedema, lipodystrophy

Darunavir-containing regimen:

-Rare (0.01% to 0.1%): Stevens-Johnson syndrome, drug rash with eosinophilia and systemic symptoms (DRESS)

-Frequency not reported: Severe skin reactions (included conditions accompanied by fever and/or transaminase elevations)

-Postmarketing reports: Toxic epidermal necrolysis, acute generalized exanthematous pustulosis, DRESS^[Ref]

Rash was commonly reported with darunavir; rashes were generally mild-to-moderate, often occurring within the first 4 weeks of therapy and resolving with continued use. In trials in therapy-naive patients, 12.7% of those using this drug reported rash (most were grade 1) and 1.5% of patients discontinued therapy due to rash (1 due to rash and hypersensitivity). In the trial in suppressed therapy-experienced patients, 5.1% of patients using this drug reported rash (most were grade 1) and no patients discontinued therapy due to rash.^[Ref]

Nervous system

Very common (10% or more): Headache (up to 13.1%)

Common (1% to 10%): Dizziness^[Ref]

Metabolic

Elevated glucose levels/hyperglycemia (126 to 250 mg/dL [6.95 to less than 13.89 mmol/L]: up to 6.9%; 251 to 500 mg/dL [13.89 to less than 27.75 mmol/L]: up to 1%) have been reported.

Lactic acidosis and severe hepatomegaly with steatosis (including fatal cases) have been reported with the use of nucleoside analogs.^[Ref]

Common (1% to 10%): Elevated glucose levels/hyperglycemia, anorexia, diabetes mellitus, hypercholesterolemia, hypertriglyceridemia, hyperlipidemia, dyslipidemia

Darunavir-containing regimen:

-Frequency not reported: Anorexia

-Postmarketing reports: Redistribution of body fat

Emtricitabine and tenofovir DF:

-Frequency not reported: Lactic acidosis

HIV protease inhibitors:

-Postmarketing reports: New onset diabetes mellitus, exacerbation of preexisting diabetes mellitus, hyperglycemia, diabetic ketoacidosis

Antiretroviral therapy:

-Frequency not reported: Increased glucose, redistribution/accumulation of body fat (including central obesity, dorsocervical fat enlargement, peripheral wasting, facial wasting, breast enlargement, "cushingoid appearance")^[Ref]

Renal

Common (1% to 10%): Elevated creatinine

Frequency not reported: Decreased urine protein-to-creatinine ratio (UPCR)

Cobicistat:

-Frequency not reported: Increased serum creatinine

Tenofovir prodrugs:

-Frequency not reported: Renal impairment (including acute renal failure, Fanconi syndrome)^[Ref]

Elevated creatinine (greater than 1.3 to 1.8 x ULN [or increased greater than 0.3 mg/dL above baseline]: up to 5.4%; greater than 1.8 to less than 3.5 x ULN [or increased 1.5 to less than 2 x above baseline]: up to 0.3%; at least 3.5 x ULN [or increased at least 2 x above baseline]: less than 1%) has been reported.

In a trial in therapy-naive HIV-1-infected patients (median estimated glomerular filtration rate [eGFR] 119 mL/min at baseline), mean serum creatinine increased by 0.05 mg/dL from baseline to week 48; median serum creatinine was 0.9 mg/dL at baseline at 0.95 mg/dL at week 48. Serum creatinine increased and eGFR (according to Cockcroft-Gault) decreased by week 2 of therapy and remained stable through 96 weeks; the median change in eGFR (according to Cockcroft-Gault) was -5.5 and -5.2 mL/min at 48 and 96 weeks, respectively. Median UPCR was 47 mg/g at baseline and 30 mg/g at week 48.

In a trial in virologically-suppressed patients treated with an HIV protease inhibitor and tenofovir DF-containing regimen (mean eGFR 104 mL/min at baseline) who switched to this drug or who remained on initial regimen (mean eGFR 103 mL/min at baseline), mean serum creatinine was similar to baseline for both at week 48; median UPCR was 62 mg/g at baseline and 37 mg/g at week 48 in those who switched to this drug and 63 mg/g at baseline and 53 mg/g at week 48 in those who remained on initial regimen.^[Ref]

Hepatic

Common (1% to 10%): Elevated ALT, elevated AST, increased hepatic enzyme

Frequency not reported: Acute hepatitis

Darunavir-containing regimen:

-Uncommon (0.1% to 1%): Acute hepatitis, cytolytic hepatitis

-Frequency not reported: Drug-induced hepatitis

-Postmarketing reports: Liver injury

Emtricitabine and/or tenofovir DF:

-Frequency not reported: Severe hepatomegaly with steatosis, severe acute exacerbations of hepatitis B, liver decompensation, liver failure^[Ref]

Elevated ALT (greater than 2.5 to less than 5 x ULN: up to 2.4%; 5 to less than 10 x ULN: up to 1.1%; at least 10 x ULN: up to 0.4%) and AST (greater than 2.5 to less than 5 x ULN: up to 1.6%; greater than 5 to less than 10 x ULN: up to 1.1%; at least 10 x ULN: up to 0.5%) have been reported.

Severe acute exacerbations of hepatitis B (e.g., liver decompensation and liver failure) have been reported in patients coinfected with HIV-1 and hepatitis B virus after discontinuation of products containing emtricitabine and/or tenofovir DF.

Lactic acidosis and severe hepatomegaly with steatosis (including fatal cases) have been reported with the use of nucleoside analogs.^[Ref]

Hematologic

Common (1% to 10%): Anemia

HIV protease inhibitors:

-Frequency not reported: Increased bleeding (including spontaneous skin hematomas, hemarthrosis) in hemophiliacs^[Ref]

Psychiatric

Common (1% to 10%): Abnormal dreams^[Ref]

Hypersensitivity

Common (1% to 10%): Drug hypersensitivity^[Ref]

Immunologic

Uncommon (0.1% to 1%): Immune reconstitution inflammatory syndrome

Darunavir-containing regimen:

-Frequency not reported: Immune reconstitution inflammatory syndrome

Combination antiretroviral therapy:

-Frequency not reported: Immune reconstitution syndrome, autoimmune disorders in the setting of immune reconstitution (e.g., Graves' disease, polymyositis, Guillain-Barre syndrome, autoimmune hepatitis)^[Ref]

Endocrine

Darunavir-containing regimen:

-Uncommon (0.1% to 1%): Gynecomastia^[Ref]