Applies to cobicistat / darunavir: oral tablet, tablet oral.

Serious side effects

Along with its needed effects, cobicistat/darunavir 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:

Incidence not known

• Agitation
• blistering, peeling, or loosening of the skin
• chills
• clay-colored stools
• confusion
• cough
• dark urine
• decreased appetite
• decreased awareness or responsiveness
• decreased urine output
• depression
• diarrhea
• dizziness
• fever
• headache
• irritability
• itching, skin rash
• joint or muscle pain
• loss of appetite
• loss of consciousness
• lower back pain
• muscle cramps, spasms, stiffness, or twitching
• nausea
• pain or burning while urinating
• rapid weight gain
• red skin lesions, often with a purple center
• red, irritated eyes
• seizures
• severe sleepiness
• sore throat
• sores, ulcers, or white spots in the mouth or on the lips
• stomach pain or tenderness
• swelling of the face, hands, feet, lower legs, or ankles
• unusual drowsiness, dullness, tiredness, weakness, or feeling of sluggishness
• vomiting
• yellow eyes or skin

Other side effects

Some side effects of cobicistat / darunavir 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:

Incidence not known

• Increased amount of fat in the upper back and neck, or around the chest and stomach area

For Healthcare Professionals

Applies to cobicistat / darunavir: oral tablet.

General

In clinical trials, safety of this drug was evaluated in therapy-naive and therapy-experienced patients using the individual components with other antiretrovirals. Safety data was also provided from clinical trials and postmarketing experience of darunavir/ritonavir and cobicistat in combination with other antiretrovirals. In the pooled data of a trial using darunavir 800 mg plus cobicistat 150 mg once a day with other antiretrovirals and an arm of a trial using this drug once a day with other antiretrovirals, the most common side effects were diarrhea, nausea, rash, and headache; serious side effects were diabetes mellitus, drug hypersensitivity, immune reconstitution inflammatory syndrome, rash, Stevens-Johnson syndrome, and vomiting. In clinical trials and postmarketing experience with darunavir 600 mg plus ritonavir 100 mg twice a day, the most common side effects were diarrhea, nausea, rash, headache, and vomiting; the most common serious side effects were acute renal failure, myocardial infarction, immune reconstitution inflammatory syndrome, thrombocytopenia, osteonecrosis, diarrhea, hepatitis, and pyrexia.

The manufacturer product information for cobicistat and darunavir should be consulted.^[Ref]

Gastrointestinal

Very common (10% or more): Diarrhea (up to 23%), nausea (up to 17%)

Common (1% to 10%): Increased pancreatic amylase, increased lipase, vomiting, abdominal pain, abdominal distension, flatulence, dyspepsia

Uncommon (0.1% to 1%): Acute pancreatitis, increased pancreatic enzymes

Darunavir/ritonavir:

-Common (1% to 10%): Abdominal pain, diarrhea, nausea, vomiting, increased pancreatic amylase, increased pancreatic lipase, increased pancreatic enzyme

-Uncommon (0.1% to 1%): Acute pancreatitis, dyspepsia, flatulence

-Frequency not reported: Abdominal distension

-Postmarketing reports: Pancreatitis, relapsing pancreatitis, rectal hemorrhage, gastritis, esophageal candidiasis^[Ref]

Increased pancreatic amylase (grade 2: 6.5%; grade 3: 2.6%) and lipase (grade 2: 3.9%; grade 3: 1%; grade 4: 1.3%) were reported.^[Ref]

Dermatologic

In clinical trials with darunavir/ritonavir and darunavir/cobicistat, rashes were generally mild-to-moderate, often occurring within the first 4 weeks of therapy and resolving with continued use. The pooled data of a trial using darunavir 800 mg plus cobicistat 150 mg once a day with other antiretrovirals and an arm of a trial using this drug once a day with other antiretrovirals, therapy was discontinued due to rash in 1.9% of patients.^[Ref]

Very common (10% or more): Rash (included allergic dermatitis, drug eruption, erythema, rash, erythematous rash, generalized rash, macular rash, maculopapular rash, pruritic rash, papular rash, skin reaction, papular urticaria; up to 15.7%)

Common (1% to 10%): Pruritus

Uncommon (0.1% to 1%): Stevens-Johnson syndrome, angioedema, urticaria

Darunavir:

-Postmarketing reports: Toxic epidermal necrolysis, acute generalized exanthematous pustulosis, drug rash with eosinophilia and systemic symptoms (DRESS)

Darunavir/ritonavir:

-Common (1% to 10%): Pruritus, rash

-Uncommon (0.1% to 1%): Lipodystrophy (lipohypertrophy, lipodystrophy, lipoatrophy), Stevens-Johnson syndrome, severe skin reactions (sometimes with fever and/or transaminase elevations)

-Rare (less than 0.1%): DRESS

-Postmarketing reports: Swelling face, toxic epidermal necrolysis, acute generalized exanthematous pustulosis, urticaria, angioedema^[Ref]

Other

Increased LDL cholesterol (grade 2: 10.9%; grade 3: 4.8%), total cholesterol (grade 2: 10.6%; grade 3: 1%), triglycerides (grade 2: 1.4%; grade 3: 1.4%), and alkaline phosphatase (grade 2: 1%) were reported.^[Ref]

Very common (10% or more): Increased low-density lipoprotein (LDL) cholesterol (up to 10.9%), increased total cholesterol (up to 10.6%)

Common (1% to 10%): Fatigue, asthenia, increased triglycerides

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

Darunavir/ritonavir:

-Very common (10% or more): Increased total cholesterol (up to 22.9%), increased LDL cholesterol (up to 14.1%)

-Common (1% to 10%): Increased alkaline phosphatase, increased triglycerides

-Uncommon (0.1% to 1%): Asthenia, fatigue

-Postmarketing reports: Increased blood alkaline phosphatase, clostridial infection, cryptosporidiosis infection, sepsis, drug toxicity

Antiretroviral therapy:

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

Nervous system

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

Darunavir/ritonavir:

-Common (1% to 10%): Headache

-Postmarketing reports: Cytomegalovirus encephalitis, progressive multifocal leukoencephalopathy, altered state of consciousness, cerebrovascular accident, dizziness, facial palsy, grand mal convulsion, ischemic cerebral infarction, nervous system disorder, neuromyopathy, petit mal epilepsy^[Ref]

Metabolic

Common (1% to 10%): Increased glucose, anorexia, hypercholesterolemia, hypertriglyceridemia

Uncommon (0.1% to 1%): Diabetes mellitus, dyslipidemia, hyperglycemia, hyperlipidemia

Darunavir:

-Postmarketing reports: Redistribution of body fat

Darunavir/ritonavir:

-Very common (10% or more): Increased glucose (up to 10.8%)

-Common (1% to 10%): Anorexia

-Uncommon (0.1% to 1%): Diabetes mellitus

-Frequency not reported: Hypercholesterolemia, hyperglycemia, hypertriglyceridemia

-Postmarketing reports: Dehydration, hyperkalemia, metabolic acidosis, redistribution of body fat

HIV protease inhibitors:

-Postmarketing reports: New onset diabetes mellitus, exacerbation of preexisting diabetes, 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"), metabolic abnormalities (such as hypertriglyceridemia, hypercholesterolemia, insulin resistance, hyperglycemia, hyperlactatemia)^[Ref]

Increased glucose (grade 2: 6.5%) was reported.^[Ref]

Hepatic

Increased AST (grade 2: 6.1%; grade 3: 2.3%; grade 4: 0.6%) and ALT (grade 2: 3.2%; grade 3: 1.9%; grade 4: 1%) were reported.

In patients using darunavir/ritonavir, hepatic transaminase elevations were reported more often in those coinfected with HIV and hepatitis B and/or C virus than in patients infected with HIV only.^[Ref]

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

Darunavir/ritonavir:

-Common (1% to 10%): Increased ALT, increased AST

-Uncommon (0.1% to 1%): Drug-induced hepatitis, hepatitis, cytolytic hepatitis, acute hepatitis

-Frequency not reported: Hyperbilirubinemia, hepatic transaminase elevations

-Postmarketing reports: Bile duct obstruction, hepatic cirrhosis, hepatic failure, hepatotoxicity, jaundice, hepatitis B, increased blood bilirubin, abnormal liver function test, liver injury (including fatalities)^[Ref]

Renal

Common (1% to 10%): Increased creatinine

Cobicistat:

-Frequency not reported: Decreased estimated CrCl, increased serum creatinine, renal tubular secretion of creatinine inhibited (actual renal glomerular function not affected), decreased estimated glomerular filtration rate (based on CrCl), renal impairment (including acute renal failure, Fanconi syndrome)

Darunavir/ritonavir:

-Postmarketing reports: Acute renal failure, renal tubular necrosis, decreased creatinine renal clearance, decreased glomerular filtration rate, renal failure^[Ref]

Increased creatinine (grade 2) was reported in 3.2% of patients.

Within 7 days after starting cobicistat 150 mg in a phase I trial, estimated glomerular filtration rate (eGFR) change from baseline averaged -9.9 mL/min in patients with normal renal function (eGFR at least 80 mL/min [calculated by Cockcroft-Gault method]) and -11.9 mL/min in patients with mild to moderate renal dysfunction (eGFR 50 to 79 mL/min [calculated by Cockcroft-Gault method]). These eGFR decreases were reversible after cobicistat was discontinued and did not affect the actual glomerular filtration rate.

In a phase III trial using darunavir 800 mg plus cobicistat 150 mg once a day with other antiretrovirals, eGFR (calculated by Cockcroft-Gault method) change from baseline averaged -9.6 mL/min at week 2, -11.5 mL/min at week 24, and -9.6 mL/min at week 48. In an arm of a phase III trial using this drug once a day with other antiretrovirals, eGFR (calculated by Cockcroft-Gault method) change from baseline averaged -11.1 mL/min at week 48; eGFR (based on cystatin C) change from baseline averaged +2.9 mL/min/1.73 m2 at week 48.

Renal impairment (including acute renal failure and Fanconi syndrome) has been reported when cobicistat was used in a regimen containing tenofovir.^[Ref]

Hypersensitivity

Common (1% to 10%): Drug hypersensitivity

Darunavir/ritonavir:

-Postmarketing reports: Drug hypersensitivity^[Ref]

Musculoskeletal

Increased CPK, myalgia, myositis, and rarely, rhabdomyolysis have been reported with HIV protease inhibitors, especially when coadministered with nucleoside reverse transcriptase inhibitors.

Osteonecrosis has been reported, particularly with commonly known risk factors (e.g., corticosteroid use, alcohol use, severe immunosuppression, higher body mass index), advanced HIV disease, or long-term combination antiretroviral therapy.^[Ref]

Common (1% to 10%): Myalgia

Darunavir:

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

Darunavir/ritonavir:

-Uncommon (0.1% to 1%): Myalgia, osteonecrosis

-Postmarketing reports: Myositis, rhabdomyolysis, sensation of heaviness, arthritis, bone pain, pain in extremities, arthropathy

HIV protease inhibitors:

-Rare (0.01% to 0.1%): Rhabdomyolysis

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

Psychiatric

Common (1% to 10%): Abnormal dreams

Darunavir/ritonavir:

-Uncommon (0.1% to 1%): Abnormal dreams

-Postmarketing reports: Completed suicide, anxiety, depression^[Ref]

Immunologic

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

Darunavir/ritonavir:

-Uncommon (0.1% to 1%): Immune reconstitution 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/ritonavir:

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

Cardiovascular

Darunavir/ritonavir:

-Postmarketing reports: Bradycardia, myocarditis^[Ref]

Hematologic

Darunavir/ritonavir:

-Postmarketing reports: Anemia, pancytopenia, thrombocytopenia, neutropenia

HIV protease inhibitors:

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

Respiratory

Darunavir/ritonavir:

-Postmarketing reports: Acute respiratory distress syndrome, pharyngeal lesion, pneumothorax, respiratory failure, pulmonary edema, epistaxis^[Ref]

Genitourinary

Darunavir/ritonavir:

-Postmarketing reports: Hematuria, proteinuria^[Ref]

Oncologic

Darunavir/ritonavir:

-Postmarketing reports: Diffuse large B-cell neoplasm, malignant hepatic neoplasm, lymphoma^[Ref]

Ocular

Darunavir/ritonavir:

-Postmarketing reports: Eye swelling, uveitis, maculopathy, blurred vision^[Ref]