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Cobicistat / darunavir Side Effects

For the Consumer

Applies to cobicistat / darunavir: oral tablet, tablet oral

In addition to its needed effects, some unwanted effects may be caused by cobicistat / darunavir. In the event that any of these side effects do occur, they may require medical attention.

Major Side Effects

You should check with your doctor immediately if any of these side effects occur when taking cobicistat / darunavir:

Rare
  • Blistering, peeling, or loosening of the skin
  • chills
  • cough
  • diarrhea
  • itching
  • joint or muscle pain
  • 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
  • unusual tiredness or weakness
Incidence not known:
  • Abdominal or stomach pain or tenderness
  • agitation
  • clay colored stools
  • coma
  • confusion
  • dark urine
  • decreased appetite
  • decreased urine output
  • depression
  • dizziness
  • fever
  • headache
  • hostility
  • irritability
  • lethargy
  • loss of appetite
  • muscle twitching
  • nausea and vomiting
  • rapid weight gain
  • seizures
  • skin rash
  • stupor
  • swelling of the face, ankles, or hands
  • swelling of the feet or lower legs
  • yellow eyes or skin

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 a clinical trial with darunavir and cobicistat, the most common side effects were diarrhea, nausea, and rash; the most common serious side effects were diabetes mellitus, drug hypersensitivity, immune reconstitution syndrome, rash, 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 syndrome, thrombocytopenia, osteonecrosis, diarrhea, hepatitis, and pyrexia. The manufacturer product information for cobicistat and darunavir should be consulted.[Ref]

Gastrointestinal

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.

Darunavir/ritonavir: Abdominal pain, diarrhea, nausea, and vomiting were reported in at least 1% of patients. Abdominal distension, acute pancreatitis, dyspepsia, and flatulence were reported in less than 1% of patients.[Ref]

Very common (10% or more): Diarrhea (up to 28%), nausea (up to 23%)
Common (1% to 10%): Increased pancreatic amylase, increased lipase, vomiting, abdominal pain, abdominal distension, flatulence, dyspepsia, increased pancreatic enzymes
Uncommon (0.1% to 1%): Acute pancreatitis

Darunavir (with ritonavir):
-Frequency not reported: Abdominal pain, diarrhea, nausea, vomiting, abdominal distension, acute pancreatitis, dyspepsia, flatulence, increased pancreatic amylase, increased pancreatic lipase, increased pancreatic enzyme
-Postmarketing reports: Pancreatitis, relapsing pancreatitis, rectal hemorrhage, gastritis, esophageal candidiasis[Ref]

Dermatologic

Very common (10% or more): Rash (up to 16%; included allergic dermatitis, drug eruption, erythema, rash, erythematous rash, generalized rash, macular rash, maculopapular rash, pruritic rash, papular rash, skin reaction, papular urticaria)
Common (1% to 10%): Pruritus, angioedema, urticaria

Darunavir (with ritonavir):
-Common (1% to 10%): Lipodystrophy (lipohypertrophy, lipodystrophy, lipoatrophy)
-Uncommon (0.1% to 1%): Severe skin reactions (sometimes with fever and/or transaminase elevations)
-Rare (less than 0.1%): Stevens-Johnson syndrome, drug reaction with eosinophilia and systemic symptoms
-Frequency not reported: Pruritus, rash, urticaria, angioedema
-Postmarketing reports: Swelling face, toxic epidermal necrolysis, acute generalized exanthematous pustulosis[Ref]

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. In a trial using darunavir 800 mg plus cobicistat 150 mg once a day with other antiretrovirals, therapy was discontinued due to rash in 2.2% of patients.

Darunavir/ritonavir: Pruritus, rash, and urticaria were reported in at least 1% of patients. Angioedema was reported in less than 1% of patients. Angioedema, rash, Stevens-Johnson syndrome, drug reaction with eosinophilia and systemic symptoms, and urticaria have also been reported during postmarketing experience.[Ref]

Nervous system

Very common (10% or more): Headache

Darunavir (with ritonavir):
-Frequency not reported: 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]

Darunavir/ritonavir: Headache was reported in at least 1% of patients.[Ref]

Metabolic

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%): Increased glucose, increased triglycerides, anorexia, diabetes mellitus, hypercholesterolemia, hypertriglyceridemia, hyperlipidemia
Uncommon (0.1% to 1%): Increased alkaline phosphatase (ALP)

Darunavir (with ritonavir):
-Frequency not reported: Anorexia, diabetes mellitus, increased ALP, increased glucose, increased LDL cholesterol, increased total cholesterol, increased triglycerides, hypercholesterolemia, hyperglycemia, hypertriglyceridemia, increased LDL
-Postmarketing reports: Increased blood ALP, dehydration, hyperkalemia, metabolic acidosis, redistribution of body fat

Combination antiretroviral therapy:
-Frequency not reported: 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)

HIV protease inhibitor therapy:
-Postmarketing reports: New onset diabetes mellitus, exacerbation of preexisting diabetes, hyperglycemia, diabetic ketoacidosis[Ref]

Increased LDL cholesterol (grade 2: 10.9%; grade 3: 1.8%), total cholesterol (grade 2: 10.6%; grade 3: 1%), glucose (grade 2: 6.5%), triglycerides (grade 2: 1.4%; grade 3: 1.4%), and ALP (grade 2: 1%) were reported.

Darunavir/ritonavir: Anorexia (at least 1%) and diabetes mellitus (less than 1%) were 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.

Darunavir/ritonavir: Acute hepatitis was reported in less than 1% of patients; hepatitis has also been reported during postmarketing experience. Increased hepatic enzymes were reported more often in patients 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 (with ritonavir):
-Uncommon (0.1% to 1%): Hepatitis, cytolytic hepatitis
-Frequency not reported: Acute hepatitis, increased ALT, increased AST, hyperbilirubinemia, increased hepatic enzyme
-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 (with 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.

Serum creatinine increase due to inhibitory effect of cobicistat usually does not exceed 0.4 mg/dL from baseline.

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) and -11.9 mL/min in patients with mild to moderate renal dysfunction (eGFR 50 to 79 mL/min). These eGFR decreases were reversible after cobicistat was discontinued and did not affect the actual glomerular filtration rate.

In a phase III trial, eGFR (based on CrCl) 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.

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 (with ritonavir):
-Frequency not reported: Drug hypersensitivity[Ref]

Darunavir/ritonavir: Drug hypersensitivity was reported in less than 1% of patients; it has also been reported during postmarketing experience.[Ref]

Other

Common (1% to 10%): Fatigue
Uncommon (0.1% to 1%): Asthenia

Darunavir (with ritonavir):
-Frequency not reported: Asthenia, fatigue
-Postmarketing reports: Clostridial infection, cryptosporidiosis infection, sepsis, drug toxicity[Ref]

Darunavir/ritonavir: Asthenia and fatigue were reported in less than 1% of patients.[Ref]

Musculoskeletal

Darunavir/ritonavir: Myalgia was reported in less than 1% of patients. Osteonecrosis has also been reported during postmarketing experience.

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 (with ritonavir):
-Common (1% to 10%): Osteonecrosis
-Frequency not reported: Myalgia
-Postmarketing reports: Myositis, rhabdomyolysis, sensation of heaviness, arthritis, bone pain, pain in extremities, arthropathy

HIV protease inhibitor therapy:
-Frequency not reported: Increased creatine phosphokinase (CPK), myalgia, myositis, rhabdomyolysis[Ref]

Psychiatric

Darunavir/ritonavir: Abnormal dreams were reported in less than 1% of patients.[Ref]

Common (1% to 10%): Abnormal dreams

Darunavir (with ritonavir):
-Frequency not reported: Abnormal dreams
-Postmarketing reports: Completed suicide, anxiety, depression[Ref]

Immunologic

Darunavir/ritonavir: Immune reconstitution syndrome was reported in less than 1% of patients; it has also been reported during postmarketing experience.[Ref]

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

Darunavir (with ritonavir):
-Frequency not reported: 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)[Ref]

Endocrine

Darunavir (with ritonavir):
-Uncommon (0.1% to 1%): Gynecomastia[Ref]

Cardiovascular

Darunavir (with ritonavir):
-Postmarketing reports: Bradycardia, myocarditis[Ref]

Hematologic

Darunavir (with ritonavir):
-Postmarketing reports: Anemia, pancytopenia, thrombocytopenia, neutropenia

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

Respiratory

Darunavir (with ritonavir):
-Postmarketing reports: Acute respiratory distress syndrome, pharyngeal lesion, pneumothorax, respiratory failure, pulmonary edema, epistaxis[Ref]

Genitourinary

Darunavir (with ritonavir):
-Postmarketing reports: Hematuria, proteinuria[Ref]

Oncologic

Darunavir (with ritonavir):
-Postmarketing reports: Diffuse large B-cell neoplasm, malignant hepatic neoplasm, lymphoma[Ref]

Ocular

Darunavir (with ritonavir):
-Postmarketing reports: Eye swelling, uveitis, maculopathy, blurred vision[Ref]

References

1. "Product Information. Prezcobix (cobicistat-darunavir)." Janssen Pharmaceuticals, Titusville, NJ.

2. Cerner Multum, Inc. "UK Summary of Product Characteristics." O 0

3. EMEA. European Medicines Agency "EPARs. European Union Public Assessment Reports. Available from: URL: http://www.ema.europa.eu/ema/index.jsp?curl=pages/includes/medicines/medicines_landingpage.jsp&mid."

4. "Product Information. Prezista (darunavir)." Ortho Biotech Inc, Bridgewater, NJ.

Not all side effects for cobicistat / darunavir may be reported. You should always consult a doctor or healthcare professional for medical advice. Side effects can be reported to the FDA here.

Disclaimer: Every effort has been made to ensure that the information provided is accurate, up-to-date and complete, but no guarantee is made to that effect. In addition, the drug information contained herein may be time sensitive and should not be utilized as a reference resource beyond the date hereof. This material does not endorse drugs, diagnose patients, or recommend therapy. This information is a reference resource designed as supplement to, and not a substitute for, the expertise, skill , knowledge, and judgement of healthcare practitioners in patient care. The absence of a warning for a given drug or combination thereof in no way should be construed to indicate safety, effectiveness, or appropriateness for any given patient. Drugs.com does not assume any responsibility for any aspect of healthcare administered with the aid of materials provided. The information contained herein is not intended to cover all possible uses, directions, precautions, warnings, drug interactions, allergic reactions, or adverse effects. If you have questions about the substances you are taking, check with your doctor, nurse, or pharmacist.

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