Summary

More frequently reported side effects include: first degree atrioventricular block. Continue reading for a comprehensive list of adverse effects.

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

Serious side effects

Along with its needed effects, atazanavir/cobicistat 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 atazanavir / cobicistat:

More common

• Chills
• clay-colored stools
• dark urine
• dizziness
• fever
• headache
• itching, skin rash
• loss of appetite
• nausea
• stomach pain
• unpleasant breath odor
• unusual tiredness or weakness
• vomiting of blood
• yellow eyes or skin

Incidence not known

• Black, tarry stools
• blistering, peeling, or loosening of the skin
• blood in the urine
• chest pain
• decreased appetite
• diarrhea
• gaseous stomach pain
• joint or muscle pain
• pain in the groin or genitals
• painful or difficult urination
• recurrent fever
• red skin lesions, often with a purple center
• red, irritated eyes
• sharp back pain just below the ribs
• sore throat
• sores, ulcers, or white spots in the mouth or on the lips
• stomach fullness or tenderness
• swelling of the feet or lower legs
• swollen glands
• unusual bleeding or bruising

For Healthcare Professionals

Applies to atazanavir / cobicistat: oral tablet.

General

In a clinical trial (based on week 144 data), safety of this drug was evaluated in HIV-1-infected, antiretroviral therapy-naive patients using the individual components with other antiretrovirals. In this trial, patients received atazanavir and cobicistat with emtricitabine-tenofovir disoproxil fumarate (DF) (cobicistat-boosted group) or atazanavir and ritonavir with emtricitabine-tenofovir DF (ritonavir-boosted group). In the cobicistat-boosted group, the most commonly reported side effects were associated with elevated bilirubin levels; the most common side effects (grades 2 to 4) were jaundice and rash. Study treatment was discontinued due to side effects in 11% of patients in both the cobicistat- and the ritonavir-boosted groups. Most of the side effects included from clinical trials were of at least moderate intensity (grade 2 or higher).

The manufacturer product information for atazanavir and cobicistat should be consulted for additional safety information.^[Ref]

Hepatic

In 1 study through 144 weeks of therapy, hyperbilirubinemia was reported in 97.7% and 97.4% of patients in the cobicistat-boosted and ritonavir-boosted groups, respectively; however, more patients in the cobicistat-boosted group had increases in total bilirubin greater than 2 times the upper limit of normal (2 x ULN) than patients in the ritonavir-boosted group (88% versus 80.9%). Study drug was discontinued due to bilirubin-related side effects in 4.9% and 4% of patients in the cobicistat-boosted and ritonavir-boosted groups, respectively. Increased ALT or AST greater than 3 x ULN was reported in 12.8% and 9% of patients in the cobicistat-boosted and ritonavir-boosted groups, respectively.

Increases in total bilirubin greater than 2.5 x ULN was reported in 73% and 66% of patients in the cobicistat-boosted and ritonavir-boosted groups, respectively. Increased ALT (greater than 5 x ULN), AST (greater than 5 x ULN), and GGT (greater than 5 x ULN) were reported in 6%, 4%, and 4% of patients in the cobicistat-boosted group, respectively, and 3%, 3%, and 2% of patients in the ritonavir-boosted group, respectively.

Jaundice (grades 2 to 4) was reported in 6% and 3% of patients in the cobicistat-boosted and ritonavir-boosted groups, respectively.

Most patients taking atazanavir experienced asymptomatic elevations in indirect (unconjugated) bilirubin related to inhibition of UGT. This hyperbilirubinemia was reversible upon discontinuation of atazanavir.^[Ref]

Very common (10% or more): Hyperbilirubinemia (97.7%), increased total bilirubin (up to 88%), jaundice (up to 13%), increased ALT or AST (12.8%)

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

Uncommon (0.1% to 1%): Hepatitis

Rare (0.01% to 0.1%): Hepatosplenomegaly

Atazanavir:

-Very common (10% or more): Elevated indirect (unconjugated) bilirubin/hyperbilirubinemia, UGT inhibited, jaundice, increased total bilirubin

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

-Postmarketing reports: Hepatic function abnormalities, cholelithiasis, cholecystitis, cholestasis^[Ref]

Gastrointestinal

Nausea and diarrhea were reported in 2% and 2% of patients in the cobicistat-boosted group, respectively, and 2% and 1% of patients in the ritonavir-boosted group, respectively.

Increased serum amylase (greater than 2 x ULN) was reported in 4% and 2% of patients in the cobicistat-boosted and ritonavir-boosted groups, respectively.

If serum amylase was greater than 1.5 x ULN, lipase was also measured. Increased lipase (grades 3 to 4) was reported in 7% and 3% of patients in the cobicistat-boosted and ritonavir-boosted groups, respectively.^[Ref]

Very common (10% or more): Nausea (up to 12%)

Common (1% to 10%): Increased lipase, increased serum amylase, diarrhea, vomiting, dyspepsia, abdominal pain, abdominal distension, flatulence, dry mouth

Uncommon (0.1% to 1%): Pancreatitis, gastritis, aphthous stomatitis

Frequency not reported: Upper abdominal pain

Atazanavir:

-Very common (10% or more): Nausea, diarrhea

-Common (1% to 10%): Increased lipase, increased serum amylase

-Postmarketing reports: Pancreatitis^[Ref]

Ocular

Ocular icterus (grades 2 to 4) was reported in 4% and 2% of patients in the cobicistat-boosted and ritonavir-boosted groups, respectively.^[Ref]

Very common (10% or more): Ocular icterus^[Ref]

Dermatologic

Common (1% to 10%): Rash (rash events included allergic dermatitis, drug hypersensitivity, generalized pruritus, eosinophilic pustular folliculitis, rash, generalized rash, macular rash, maculopapular rash, morbilliform rash, papular rash, urticaria)

Uncommon (0.1% to 1%): Pruritus, urticaria, alopecia

Rare (0.01% to 0.1%): Vesiculobullous rash, eczema, vasodilatation

Atazanavir:

-Common (1% to 10%): Rash events

-Frequency not reported: Stevens-Johnson syndrome, erythema multiforme, toxic skin eruptions, drug rash with eosinophilia and systemic symptoms (DRESS) syndrome, mild-to-moderate maculopapular skin eruptions

-Postmarketing reports: Alopecia, maculopapular rash, pruritus, angioedema^[Ref]

Rash events (grades 2 to 4) were reported in 5% and 4% of patients in the cobicistat-boosted and ritonavir-boosted groups, respectively.^[Ref]

Musculoskeletal

Common (1% to 10%): Increased creatine kinase

Uncommon (0.1% to 1%): Myalgia, muscle atrophy, arthralgia

Rare (0.01% to 0.1%): Myopathy

Frequency not reported: Rhabdomyolysis, osteonecrosis

Atazanavir:

-Common (1% to 10%): Increased creatine kinase

-Postmarketing reports: Arthralgia^[Ref]

Increased creatine kinase (at least 10 x ULN) was reported in 8% and 9% of patients in the cobicistat-boosted and ritonavir-boosted groups, respectively.^[Ref]

Renal

In 1 study, serum creatinine increases and estimated CrCl decreases occurred early during therapy in the cobicistat-boosted group, after which they stabilized. After 144 weeks of therapy, eGFR (by Cockcroft-Gault method) change averaged -15.1 mL/min in the cobicistat-boosted group and -8 mL/min in the ritonavir-boosted group.

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

In clinical trials over 144 weeks (n=692), 10 (2.9%) patients using atazanavir, cobicistat, and tenofovir DF discontinued therapy due to a renal side effect; 7 patients had laboratory findings consistent with proximal renal tubulopathy. One patient had baseline renal dysfunction (e.g., estimated CrCl less than 70 mL/min). Laboratory findings in these 7 patients improved but did not completely resolve in all patients when therapy was stopped. No patients required renal replacement therapy.

Postmarketing reports of chronic kidney disease in HIV-infected patients using atazanavir (with or without ritonavir) included biopsy-proven cases of granulomatous interstitial nephritis associated with deposition of atazanavir crystals in renal parenchyma.^[Ref]

Uncommon (0.1% to 1%): Interstitial nephritis

Rare (0.01% to 0.1%): Kidney pain

Frequency not reported: Decreased estimated CrCl, increased serum creatinine, decreased estimated glomerular filtration rate (eGFR; by Cockcroft-Gault method), nephropathy, Fanconi syndrome acquired, nephrolithiasis, laboratory findings consistent with proximal renal tubulopathy

Atazanavir:

-Frequency not reported: Decreased eGFR

-Postmarketing reports: Nephrolithiasis, interstitial nephritis, granulomatous interstitial nephritis, chronic kidney disease

Cobicistat:

-Frequency not reported: Decreased estimated CrCl, increased serum creatinine, tubular secretion of creatinine inhibited (actual renal glomerular function not affected), decreased eGFR, renal impairment (including acute renal failure, Fanconi syndrome)^[Ref]

Genitourinary

Increased urine RBC (greater than 75 RBC/high power field) and urine glucose (at least 1000 mg/dL) were reported in 6% and 3% of patients in the cobicistat-boosted group, respectively, and 3% and 3% of patients in the ritonavir-boosted group, respectively.^[Ref]

Common (1% to 10%): Hematuria (increased urine RBC), glycosuria (increased urine glucose)

Uncommon (0.1% to 1%): Proteinuria, pollakiuria

Atazanavir:

-Common (1% to 10%): Increased urine RBC, increased urine glucose^[Ref]

Metabolic

Increased serum glucose (at least 250 mg/dL) was reported in 2% and 2% of patients in the cobicistat-boosted and ritonavir-boosted groups, respectively.^[Ref]

Common (1% to 10%): Hyperglycemia (increased serum glucose), increased appetite

Uncommon (0.1% to 1%): Anorexia

Atazanavir:

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

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")

Antiretroviral therapy:

-Frequency not reported: Increased glucose levels^[Ref]

Nervous system

Common (1% to 10%): Headache, dizziness, somnolence, dysgeusia

Uncommon (0.1% to 1%): Peripheral neuropathy, syncope, amnesia^[Ref]

Headache (grades 2 to 4) was reported in 2% and 1% of patients in the cobicistat-boosted and ritonavir-boosted groups, respectively.^[Ref]

Other

Common (1% to 10%): Fatigue

Uncommon (0.1% to 1%): Decreased weight, weight gain, pyrexia, asthenia, chest pain, malaise

Rare (0.01% to 0.1%): Edema, gait disturbance

Frequency not reported: Increased fasted total cholesterol, increased fasted high-density lipoprotein cholesterol, increased fasted low-density lipoprotein cholesterol, increased fasted triglycerides

Atazanavir:

-Postmarketing reports: Edema

Antiretroviral therapy:

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

Psychiatric

Common (1% to 10%): Abnormal dreams, insomnia

Uncommon (0.1% to 1%): Depression, sleep disorder, disorientation, anxiety^[Ref]

Hematologic

Decreased neutrophils (less than 750/mm3) were reported in 3% and 2% of patients in the cobicistat-boosted and ritonavir-boosted groups, respectively.^[Ref]

Common (1% to 10%): Decreased neutrophils

Atazanavir:

-Common (1% to 10%): Decreased neutrophils

Protease inhibitor therapy:

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

Cardiovascular

Uncommon (0.1% to 1%): Hypertension

Rare (0.01% to 0.1%): Palpitation

Atazanavir:

-Common (1% to 10%): First-degree atrioventricular (AV) block

-Frequency not reported: Prolongation of the PR interval, abnormalities in AV conduction, other conduction abnormalities

-Postmarketing reports: Second-degree AV block, third-degree AV block, left bundle branch block, QTc prolongation, torsades de pointes^[Ref]

Hypersensitivity

Uncommon (0.1% to 1%): Hypersensitivity

Respiratory

Uncommon (0.1% to 1%): Dyspnea

Endocrine

Uncommon (0.1% to 1%): Gynecomastia

Immunologic

Atazanavir:

-Frequency not reported: Immune reconstitution syndrome

Combination antiretroviral therapy:

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