Cobicistat

Before taking cobicistat, tell your doctor about all of your medical conditions. Especially tell your doctor if you:

• are allergic to cobicistat or to any of its ingredients
• have kidney problems
• have liver problems
• are pregnant or breastfeeding

Tell your doctor about all the medicines you take including prescription and non-prescription medicines, vitamins, and herbal supplements.

Cobicistat reduces the action of enzymes in your liver that break down certain antiviral medicines. This allows the antiviral medicines to be used more safely and effectively at lower doses.

Cobicistat is given together with atazanavir (Reyataz) or darunavir (Prezista) to treat human immunodeficiency virus (HIV) in adults. HIV is the virus that causes acquired immunodeficiency syndrome (AIDS).

Cobicistat is not an antiviral medicine and will not treat HIV or AIDS. Cobicistat is given only to help increase your blood levels of atazanavir or darunavir.

Cobicistat may also be used for purposes not listed in this medication guide.

Seek emergency medical attention or call the Poison Help line at 1-800-222-1222.

Cobicistat is a mechanism-based inhibitor of cytochrome P450 3A (CYP3A).1

Mechanism of Action

Cobicistat is a mechanism-based inhibitor of cytochrome P450 3A (CYP3A). Inhibition of CYP3A-mediated metabolism by cobicistat increases the systemic exposure of CYP3A substrates such as atazanavir and darunavir.1

Microbiology

Cobicistat does not inhibit recombinant HIV-1 protease in a biochemical assay and has no detectable antiviral activity in cell culture against HIV-1, HBV, or HCV. The antiviral activity of selected HIV-1 antiretroviral drugs in cell cultures was not antagonized by cobicistat.1

In an analysis of treatment-failure subjects who received cobicistat coadministered with atazanavir and the fixed combination of emtricitabine and tenofovir DF (Truvada) in Study 114 through Week 144, evaluable genotypic data from paired baseline and treatment-failure isolates from subjects who had HIV-1 RNA greater than or equal to 400 copies/mL were available for all 21 virologic failures in the cobicistat group [6%, 21/344]. Among the 21 subjects, 3 developed the emtricitabine-associated resistance substitution M184V. No subject developed the tenofovir-associated resistance substitution K65R or K70E, or any primary resistance substitution associated with protease inhibitors. In the ritonavir group, evaluable genotypic data were available for all 19 virologic failures [5%, 19/348]. Among the 19 patients, 1 developed the emtricitabine-associated resistance substitution M184V with no tenofovir or protease inhibitor associated resistance substitutions.1

Your doctor will want to check your progress at regular visits, especially during the first few weeks that you take cobicistat. Blood and urine tests may be needed to check for any unwanted effects.

Do not use cobicistat together with atazanavir or darunavir if you are also using any of the following: alfuzosin (Uroxatral®), carbamazepine (Tegretol®), cisapride (Propulsid®), colchicine (Colcrys®), dronedarone (Multaq®), indinavir (Crixivan®), irinotecan (Camptosar®), lovastatin (Altoprev®, Mevacor®), lurasidone (Latuda®), midazolam (Versed®), nevirapine (Viramune®), phenobarbital (Luminal®), phenytoin (Dilantin®), pimozide (Orap®), ranolazine (Ranexa®), rifampin (Rifadin®), sildenafil (Revatio®), simvastatin (Simcor®, Zocor®), St. John's wort, triazolam (Halcion®), or ergot medicines (eg, dihydroergotamine, ergotamine, methylergonovine, Cafergot®, Migranal®). Doing so may cause serious unwanted effects.

Using cobicistat together with tenofovir DF may cause kidney problems (including Fanconi syndrome). Tell your doctor right away if you have bloody urine, decreased frequency or amount of urine, increased thirst, loss of appetite, lower back or side pain, nausea, vomiting, swelling of the face, fingers, or lower legs, troubled breathing, unusual tiredness or weakness, or weight gain.

cobicistat does not decrease the risk of transmitting the HIV infection to others through sexual contact or by contaminated blood. Make sure you understand and practice safe sex, even if your partner also has HIV. Avoid sharing needles with anyone.

Do not take other medicines unless they have been discussed with your doctor. This includes prescription or nonprescription (over-the-counter [OTC]) medicines and herbal or vitamin supplements.

If you think there has been an overdose, call your poison control center or get medical care right away. Be ready to tell or show what was taken, how much, and when it happened.

All adverse reactions are from trials using cobicistat coadministered with atazanavir, emtricitabine + tenofovir unless otherwise noted.

Frequency not always defined.

Central nervous system: Headache (2%), abnormal dreams (<2%), depression (<2%), fatigue (<2%), insomnia (<2%)

Dermatologic: Skin rash (5%)

Endocrine & metabolic: Increased gamma-glutamyl transferase (>5 x ULN: 4%), glycosuria (3%), Fanconi's syndrome (<2%), increased HDL cholesterol, increased LDL cholesterol, increased serum cholesterol, increased serum triglycerides

Gastrointestinal: Increased serum amylase (>2 x ULN: 4% to 7%), diarrhea (2%), nausea (2%), upper abdominal pain (<2%), vomiting (<2%)

Genitourinary: Hematuria (6%), proximal tubular nephropathy (2%)

Hepatic: Hyperbilirubinemia (>2.5 x ULN: 73%), increased serum ALT (>5 x ULN: 6%), jaundice (6%), increased serum AST (>5 x ULN: 4%)

Neuromuscular & skeletal: Increased creatine phosphokinase (8%), rhabdomyolysis (<2%)

Ophthalmic: Scleral icterus (4%)

Renal: Nephrolithiasis (<2%), renal disease (<2%), decreased creatinine clearance (no effect on renal glomerular function in patients with normal renal function), increased serum creatinine, renal insufficiency

CBC with differential, reticulocyte count, CD4 count, HIV RNA plasma levels, and serum creatinine at baseline and when clinically indicated during therapy; when coadministered with tenofovir disoproxil fumarate, serum creatinine, urine glucose and urine protein prior to initiation and as clinically indicated during therapy; assess serum phosphorus in patients with or at risk for renal impairment. Patients who experience a confirmed increase in serum creatinine >0.4 mg/dL from baseline should have renal function monitored closely. Testing for HBV is recommended prior to the initiation of antiretroviral therapy.

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience nausea. Have patient report immediately to prescriber signs of kidney problems (urinary retention, hematuria, change in amount of urine passed, or weight gain) or jaundice (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for health care professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience, and judgment in diagnosing, treating, and advising patients.

Applies to cobicistat: oral tablet

General

In a clinical trial, safety of this drug was evaluated in therapy-naive patients using cobicistat-boosted atazanavir with emtricitabine-tenofovir. The most commonly reported side effects were associated with elevated bilirubin levels including jaundice, ocular icterus, and nausea. Study drug was discontinued due to side effects in 7% of patients in the cobicistat-boosted group; 4.9% discontinued due to bilirubin-related side effects.[Ref]

Hepatic

In 1 clinical trial, hyperbilirubinemia (greater than 1 times the upper limit of normal [1 x ULN]) was reported in 97.7% of patients in the cobicistat-boosted atazanavir group and 97.4% in the ritonavir-boosted atazanavir group. Increases in total bilirubin greater than 2 x ULN was reported in 85.7% of patients in the cobicistat-boosted group and 77.7% in the ritonavir-boosted group. Increases in total bilirubin greater than 2.5 x ULN was reported in 65% of patients in the cobicistat-boosted group and 56% in the ritonavir-boosted group. Increased ALT or AST (greater than 3 x ULN) was reported in 12% of patients in the cobicistat-boosted group and 8.7% in the ritonavir-boosted group. Increased ALT (greater than 5 x ULN), AST (greater than 5 x ULN), and GGT (greater than 5 x ULN) were reported in 3%, 3%, and 2% of patients in the cobicistat-boosted group, respectively.[Ref]

Very common (10% or more): Hyperbilirubinemia, increased total bilirubin, jaundice (up to 13%), increased ALT or AST
Common (1% to 10%): Increased ALT, increased AST, increased GGT[Ref]

Ocular

Very common (10% or more): Ocular icterus (up to 15%)[Ref]

Gastrointestinal

Increased serum amylase (greater than 2 x ULN) was reported in up to 4% of patients in the cobicistat-boosted group.

If serum amylase was greater than 1.5 x ULN, lipase was also measured. Increased lipase (grades 3 to 4) was reported in up to 9% of patients in the cobicistat-boosted group.[Ref]

Very common (10% or more): Nausea (up to 12%)
Common (1% to 10%): Vomiting, diarrhea, dyspepsia, abdominal pain, abdominal distension, flatulence, dry mouth, increased lipase, increased serum amylase
Frequency not reported: Upper abdominal pain[Ref]

Musculoskeletal

Common (1% to 10%): Increased creatine kinase
Uncommon (0.1% to 1%): Myalgia
Frequency not reported: Rhabdomyolysis[Ref]

Increased creatine kinase (at least 10 x ULN) was reported in up to 6% of patients in the cobicistat-boosted group.[Ref]

Genitourinary

Increased urine RBC (greater than 75 RBC/high power field) and urine glucose (at least 1000 mg/dL) have been reported in up to 4% and 3% of patients in the cobicistat-boosted group, respectively.[Ref]

Common (1% to 10%): Hematuria (increased urine RBC), glycosuria (increased urine glucose)
Uncommon (0.1% to 1%): Proteinuria[Ref]

Renal

Nephrolithiasis has been reported with atazanavir. In clinical trials, nephrolithiasis was reported in 2% of patients in the cobicistat-boosted group and no patients in the ritonavir-boosted group. Onset of nephrolithiasis was about 24 weeks.

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

Common (1% to 10%): Nephrolithiasis
Frequency not reported: Decreased estimated CrCl, increased serum creatinine, tubular secretion of creatinine inhibited (actual renal glomerular function not affected), renal impairment (including acute renal failure, Fanconi syndrome), nephropathy, Fanconi syndrome acquired[Ref]

Nervous system

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

Metabolic

Common (1% to 10%): Hyperglycemia, increased appetite
Frequency not reported: Increased fasted total cholesterol, increased fasted high-density lipoprotein cholesterol, increased fasted low-density lipoprotein cholesterol, increased fasted triglycerides[Ref]

Other

Common (1% to 10%): Fatigue
Uncommon (0.1% to 1%): Pyrexia, asthenia[Ref]

Psychiatric

Common (1% to 10%): Insomnia, abnormal dreams
Uncommon (0.1% to 1%): Depression, sleep disorder[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[Ref]

Some side effects of cobicistat may not be reported. Always consult your doctor or healthcare specialist for medical advice. You may also report side effects to the FDA.