Tybost

Tell your doctor if you are breastfeeding or plan to breastfeed.

It is not known if Tybost crosses into human milk. The Centers for Disease Control and Prevention recommend that HIV-infected mothers not breastfeed their infants, to avoid risking postnatal transmission of HIV. Because of both the potential for HIV transmission and the potential for serious adverse reactions in nursing infants, HIV-infected mothers should not breastfeed.

Take Tybost exactly as prescribed.

This medication comes in tablet form and is taken once a day, with food.

If you miss a dose of Tybost with atazanavir or Tybost with darunavir and you remember within 12 hours, take the missed dose of Tybost with atazanavir or darunavir right away. The next dose of Tybost with atazanavir or darunavir should be taken together as usual. If you miss a dose of Tybost with atazanavir or Tybost with darunavir and it has been more than 12 hours, wait and take the next dose at the usual time. If a dose of Tybost with atazanavir or darunavir is skipped, do not double the next dose of Tybost with atazanavir or darunavir.

Cobicistat is usually taken once per day with atazanavir or darunavir. Follow all directions on your prescription label. Do not take this medicine in larger or smaller amounts or for longer than recommended.

Take your HIV medicines with food at the same time each day to be sure you do not miss a dose.

If you take cobicistat with atazanavir, your doctor may also prescribe a medicine to reduce stomach acid. If so, follow these recommendations, unless your doctor tells you otherwise:

• If you take an antacid: Take the antacid at least 2 hours before or 2 hours after you take cobicistat and atazanavir.

• If you take a medicine such as cimetidine, ranitidine, Tagamet, Axid, Zantac, Pepcid, and others: You may either take the stomach medicine at the same time you take cobicistat and atazanavir; or wait at least 10 hours after taking the stomach medicine to take your cobicistat and atazanavir doses.

• If you take a proton pump inhibitor such as omeprazole, esomeprazole, Nexium, Prevacid, Prilosec, Protonix: Wait at least 12 hours after taking the stomach medicine to take your cobicistat and atazanavir doses.

While using cobicistat, your blood may need to be tested often. Your kidney function may also need to be tested.

HIV/AIDS is usually treated with a combination of drugs. Use all medications as directed by your doctor. Read the medication guide or patient instructions provided with each medication. Do not change your doses or medication schedule without your doctor's advice. Every person with HIV or AIDS should remain under the care of a doctor.

Store in the original container at room temperature, away from moisture and heat. Keep the bottle tightly closed when not in use.

Specific Drugs

It is essential that the manufacturer’s labeling be consulted for more detailed information on interactions with this drug, including possible dosage adjustments. Interaction highlights:

Cobicistat, coadministered with atazanavir or darunavir, can alter the concentrations of drugs metabolized by CYP3A or CYP2D6. Drugs that induce CYP3A can alter the concentrations of cobicistat, atazanavir, and darunavir. Consult the full prescribing information prior to and during treatment for potential drug interactions.1

Recommended Dosage

Administer Tybost in conjunction with atazanavir or darunavir and other antiretroviral agents in the treatment of adults with HIV-1 infection. The recommended dosages of Tybost and atazanavir or darunavir given with food are presented in Table 1. Tybost must be coadministered at the same time as atazanavir or darunavir [see Drug Interactions (7)]. Consult the prescribing information for atazanavir or darunavir.

Testing Prior to Initiation of Tybost

Prior to starting Tybost, assess estimated creatinine clearance because Tybost decreases estimated creatinine clearance due to inhibition of tubular secretion of creatinine without affecting actual renal glomerular function [see Warnings and Precautions (5.1)]. When coadministering Tybost with tenofovir disoproxil fumarate (tenofovir DF), assess estimated creatinine clearance, urine glucose, and urine protein at baseline [see Warnings and Precautions 5.2].

Renal Impairment

Tybost coadministered with tenofovir DF is not recommended in patients who have an estimated creatinine clearance below 70 mL/min because dose adjustment of tenofovir DF is required below 50 mL/min and such dose adjustments have not been established for coadministration with Tybost [see Warnings and Precautions (5.2) and Adverse Reactions (6.1)].

Orange, round, biconvex, film-coated tablets debossed with "GSI" on one side and plain faced on the other side providing 150 mg of cobicistat.

The following adverse reaction is described in greater detail in another section of the labeling:

• New Onset or Worsening Renal Impairment When Used with Tenofovir Disoproxil Fumarate [see Warnings and Precautions (5.2)]

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The safety of Tybost is based on Week 144 data from a Phase 3 trial, Study 114, in which 692 HIV-1 infected, antiretroviral treatment-naïve subjects received:

• Tybost coadministered with atazanavir and tenofovir DF/emtricitabine (administered as TRUVADA) (N=344) or;
• ritonavir coadministered with atazanavir and tenofovir DF/emtricitabine (administered as TRUVADA) (N=348).

The most common adverse reactions (Grades 2–4) and reported in >5% of subjects in the Tybost group were jaundice (6%) and rash (5%). The proportion of subjects who discontinued study treatment due to adverse events, regardless of severity, was 11% in both the Tybost and ritonavir groups. Table 3 displays the frequency of adverse reactions (Grades 2–4) occurring in at least 2% of subjects in the Tybost group in Study 114.

Less Common Adverse Reactions

Selected adverse reactions of at least moderate severity (≥Grade 2) occurring in less than 2% of subjects receiving Tybost coadministered with atazanavir and TRUVADA are listed below. These events have been included because of the investigator's assessment of potential causal relationship and were considered serious or have been reported in more than one subject treated with Tybost and with greater frequency compared with ritonavir.

Gastrointestinal Disorders: vomiting, upper abdominal pain

General Disorders and Administration Site Conditions: fatigue

Musculoskeletal and Connective Tissue Disorders: rhabdomyolysis

Psychiatric Disorders: depression, abnormal dreams, insomnia

Renal and Urinary Disorders: nephropathy, Fanconi syndrome acquired, nephrolithiasis

Refer to the prescribing information for atazanavir or darunavir for information regarding adverse reactions with these drugs.

Laboratory Abnormalities: The frequency of laboratory abnormalities (Grades 3–4) occurring in at least 2% of subjects in the Tybost group in Study 114 is presented in Table 4.

Increase in Serum Creatinine: Tybost causes increases in serum creatinine and decreases in estimated creatinine clearance due to inhibition of tubular secretion of creatinine without affecting actual renal glomerular function [see Warnings and Precautions (5.1) and Clinical Pharmacology (12.2)]. In Study 114, increases in serum creatinine and decreases in estimated creatinine clearance occurred early in treatment with Tybost, after which they stabilized. The mean (± SD) change in estimated glomerular filtration rate (eGFR) by Cockcroft-Gault method after 144 weeks of treatment was –15.1 ± 16.5 mL/min in the Tybost group and –8.0 ± 16.8 mL/min in the ritonavir group.

Serum Lipids: Changes from baseline in total cholesterol, HDL-cholesterol, LDL-cholesterol, and triglycerides are presented in Table 5. In both groups, mean values for serum lipids remained within the study reference range for each laboratory test. The clinical significance of these changes is unknown.

Cobicistat is not a complete treatment and must be used in combination with other antiviral medicines your doctor has prescribed. However, there are certain antiviral medicines that should not be taken in combination with Tybost. Follow your doctor's medication and dosing instructions very carefully.

Tybost is recommended for use only with atazanavir or darunavir. You should not take Tybost with other protease inhibitor HIV medicines, such as fosamprenavir, nelfinavir, saquinavir, or tipranavir.

You should not take Tybost with darunavir if you are taking darunavir twice daily. You should not take Tybost with atazanavir if you also take indinavir, irinotecan, or nevirapine.

Many drugs can interact with cobicistat and some should not be used at the same time, especially: alfuzosin, cisapride, dronedarone, lovastatin, simvastatin, oral midazolam, triazolam, pimozide, rifampin, sildenafil (for treating pulmonary arterial hypertension), St. John's wort, or ergot medicine (dihydroergotamine, ergotamine, ergonovine, methylergonovine). Tell your doctor about all your current medicines and any you start or stop using.

Taking this medication will not prevent you from passing HIV to other people. Do not have unprotected sex or share razors or toothbrushes. Talk with your doctor about safe ways to prevent HIV transmission during sex. Sharing drug or medicine needles is never safe, even for a healthy person.

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