darunavir/cobicistat (Rx)

Brand and Other Names:Prezcobix
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Dosing & Uses

AdultPediatric

Dosage Forms & Strengths

darunavir/cobicistat

tablet

  • 800mg/150mg

HIV-1 Infection

Indicated in combination with other antiretroviral agents in naïve and treatment-experienced patients without darunavir resistance-associated mutations

1 tablet (800 mg/150 mg) PO qDay with food

Dosage Modifications

CrCl <70 mL/min: Coadministration with tenofovir disoproxil fumarate (DF) is not recommended

Severe hepatic impairment: Not recommended

Dosing Considerations

Not recommended for use in pregnant women because of substantially lower exposures of darunavir and cobicistat during pregnancy

HIV genotypic testing recommended for treatment-experienced patients

Obtain laboratory values initiating

  • Creatinine clearance (CrCl): Before initiating, assess estimated CrCl because cobicistat decreases eCrCl owing to inhibition of tubular secretion of creatinine, without affecting actual renal glomerular function
  • Coadministration with tenofovir DF: Assess eCrCl, urine glucose, and urine protein at baseline

Dosage Forms & Strengths

darunavir/cobicistat

tablet

  • 800mg/150mg

HIV-1 Infection

Indicated in combination with other antiretroviral agents for HIV in treatment-naïve and treatment-experienced patients weighing at least 40 kg with no darunavir resistance-associated substitutions

<40 kg: Safety and efficacy not established

≥40 kg: 1 tablet (800 mg/150 mg) PO qDay with food

Dosage Modifications

CrCl <70 mL/min: Coadministration with tenofovir disoproxil fumarate (DF) is not recommended

Severe hepatic impairment: Not recommended

Dosing Considerations

Indication for pediatrics supported by evidence from adequate and well-controlled studies in adults with additional pharmacokinetic, safety, and virologic data from a study of children with HIV-1 infection aged 12 to less than 18 years

Not recommended for use in pregnant females because of substantially lower exposures of darunavir and cobicistat during pregnancy

HIV genotypic testing recommended for treatment-experienced patients

Obtain laboratory values initiating

  • Creatinine clearance (CrCl): Before initiating, assess estimated CrCl because cobicistat decreases eCrCl owing to inhibition of tubular secretion of creatinine, without affecting actual renal glomerular function
  • Coadministration with tenofovir DF: Assess eCrCl, urine glucose, and urine protein at baseline
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Interactions

Interaction Checker

and darunavir/cobicistat

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            Adverse Effects

            >10% (darunavir)

            Increased total cholesterol (10-25%)

            >10% (cobicistat)

            Total bilirubin, >2.5 x ULN (65%)

            Ocular icterus, all grades (15%)

            Jaundice, all grades (13%)

            Nausea, all grades (12%)

            1-10% (darunavir)

            Increased triglycerides (3-10%)

            Diarrhea (9%)

            Headache (7%)

            Rash (6%)

            Abdominal pain (6%)

            Nausea (4%)

            Vomiting (2%)

            Anorexia (2%)

            1-10% (cobicistat)

            Creatine kinase, >10 x ULN (5%)

            Jaundice, grades 2-4 (5%)

            Rash, grades 2-4 (5%)

            Serum amylase, >2 x ULN (4%) ALT or AST, >5 x ULN (3%)

            Glycosuria, >1000 mg/dL (3%)

            Urine RBC, >75 RBC/HPF (3%)

            Ocular icterus, grades 2-4 (3%)

            GGT, >5 x ULN (2%)

            Nausea, grades 2-4 (2%)

            Postmarketing Reports

            Metabolism and nutrition disorders: Redistribution of body fat

            Musculoskeletal and connective tissue disorders: Rhabdomyolysis (associated with co-administration with HMG-CoA reductase inhibitors)

            Skin and subcutaneous tissue disorders: Toxic epidermal necrolysis, acute generalized exanthematous pustulosis, drug rash with eosinophilia and systemic symptoms

            Immune reconstitution syndrome

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            Warnings

            Contraindications

            Alfuzosin, dronedarone, ivabradine, ranolazine, naloxegol, CYP inducers (rifampin, St. John’s wort), cisapride, pimozide, lurasidone, ergot derivatives (dihydroergotamine, ergotamine, methylergonovine), HMG-CoA reductase inhibitors (lomitapide, lovastatin, simvastatin), PDE5 inhibitors (long-term administration [eg, sildenafil as Revatio for PAH]), triazolam, midazolam, anticonvulsants (carbamazepine, phenobarbital, phenytoin), hepatitis C direct-acting antiviral (elbasvir/grazoprevir), colchicine (in patients with renal/and or hepatic impairment)

            Cautions

            Hepatotoxicity reported; monitor liver enzymes at baseline and during treatment; consider interrupting or discontinuing treatment with evidence of new or worsening liver dysfunction (including clinically significant elevation of liver enzymes and/or symptoms [eg, fatigue, anorexia, nausea, jaundice, dark urine, liver tenderness, hepatomegaly])

            Severe skin reactions accompanied by fever and/or elevations of transaminases; Stevens-Johnson syndrome rarely; mild-to-moderate rash reported to occur within first 4 weeks of treatment and resolved with continued dosing

            Assess eCrCl before initiating therapy; cobicistat decreases estimated creatinine clearance without affecting actual renal glomerular function by inhibiting tubular secretion of creatinine

            Sulfa allergy: Darunavir contains a sulfa moiety; monitor patients with a known sulfonamide allergy

            New-onset diabetes mellitus, exacerbation of pre-existing diabetes mellitus, and hyperglycemia reported during postmarketing surveillance in HIV-infected patients receiving protease inhibitors

            Redistribution/accumulation of body fat, including central obesity, dorsocervical fat enlargement (buffalo hump), peripheral wasting, facial wasting, breast enlargement, and cushingoid appearance have been observed in patients receiving ARTs

            Increased bleeding, including spontaneous skin hematomas and hemarthrosis, reported in patients with hemophilia type A and B treated with HIV protease inhibitors

            Not recommended for use in pregnant women because of substantially lower exposures of darunavir and cobicistat during pregnancy

            Immune reconstitution

            • Reported during initial phase of combination ART treatment
            • Patients whose immune systems become active may develop an inflammatory reaction to indolent or residual opportunistic infections (eg, Mycobacterium avium infection, CMV, Pneumocystis jirovecii pneumonia [PCP], or tuberculosis), which may necessitate further evaluation and treatment
            • Autoimmune disorders (eg, Graves disease, polymyositis, Guillan-Barre syndrome, autoimmune hepatitis) also reported

            Renal impairment

            • Renal impairment, including cases of acute renal failure and Fanconi syndrome, reported when cobicistat was used in an ART regimen that contained tenofovir DF
            • Document urine glucose and urine protein at baseline and perform routine monitoring of eCrCl, urine glucose, and urine protein during treatment
            • Coadministration of darunavir/cobicistat plus tenofovir DF in combination with concomitant or recent use of a nephrotoxic agent is not recommended

            Drug interaction overview

            • Also see Contraindications and Drug Interaction Checker
            • When evaluated separately, darunavir and cobicistat both inhibited CYP3A and CYP2D6
            • Cobicistat inhibits the following transporters: P-glycoprotein (P-gp), BCRP, OATP1B1, and OATP1B3
            • Drugs that are metabolized by CYP3A and CYP2D6, or are substrates of the transporters P-gp, BCRP, OATP1B1, or OATP1B3, may show increased systemic exposure if coadministered with darunavir/cobicistat

            ART agents that are not recommended

            • Not recommended in combination with other ART drugs that require pharmacokinetic boosting (ie, another protease inhibitor or elvitegravir)
            • Dosing recommendations for such combinations not established; coadministration may result in decreased plasma concentrations of ART agents, leading to loss of therapeutic effect and development of resistance
            • Darunavir/cobicistat is not recommended in combination with products containing the individual components (darunavir and cobicistat) or with ritonavir
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            Pregnancy & Lactation

            Pregnancy

            Not recommended for use in pregnant women because of substantially lower exposures of darunavir and cobicistat during pregnancy

            There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to therapy during pregnancy; healthcare providers are encouraged to register patients by calling the Antiretroviral Pregnancy Registry (APR) 1-800-258-4263

            There are insufficient data from the APR to inform a drug-associated risk of pregnancy outcomes; rate of miscarriage is not reported in the APR; the background risk of major birth defects and miscarriage for the indicated population is unknown

            Contraception

            • Consider additional or alternative (non-hormonal) forms of contraception when estrogen- containing contraceptives are co-administered; for co-administration with drospirenone, clinical monitoring is recommended due to potential for hyperkalemia; no data are available to make recommendations on co-administration with other hormonal contraceptives

            Lactation

            There are no data on presence of darunavir or cobicistat in human milk, effects on breastfed infant, or on milk production; darunavir and cobicistat are secreted into milk of lactating rats; because of potential for (1) HIV transmission (in HIV- negative infants), (2) developing viral resistance (in HIV-positive infants), and (3) serious adverse reactions in breastfed infants, instruct mothers not to breastfeed if receiving therapy

            Pregnancy Categories

            A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

            B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

            C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

            D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

            X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

            NA: Information not available.

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            Pharmacology

            Mechanism of Action

            Darunavir: Protease inhibitor; selectively inhibits cleavage of Gag-Pol polyprotein precursors, thereby preventing the formation of mature virus particles

            Cobicistat: CYP3A4 inhibitor; mechanism-based pharmacokinetic enhancer, increases the systemic exposure of darunavir (a CYP3A4 substrate)

            Absorption

            Peak plasma time: 4-4.5 hr (darunavir); 4-5 hr (cobicistat)

            Trough concentration (darunavir): 1875 ng/mL

            AUC (darunavir): 100,152 ng⋅hr/mL High-fat meal increases absorption; darunavir/cobicistat should be taken with food

            Distribution

            Protein bound: 95% (darunavir); 97-98% (cobicistat)

            Metabolism

            Darunavir: Primarily undergoes oxidative metabolism; extensively metabolized by CYP enzymes, primarily by CYP3A

            Cobicistat: Metabolized by CYP3A and to a minor extent by CYP2D6 enzymes and does not undergo glucuronidation

            Elimination

            Half-life: 7 hr (darunavir); 4 hr (cobicistat)

            Excretion

            • Darunavir: 79.5% feces (41.2% unchanged); 13.9% urine (7.7% unchanged)
            • Cobicistat: 86.2% feces; 8.2% urine

            Pharmacogenomics

            HIV genotypic testing is recommended for ART treatment-experienced patients

            However, when HIV genotypic testing is not feasible, darunavir/cobicistat can be used in protease inhibitor-naïve patients, but is not recommended in protease inhibitor-experienced patients

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            Administration

            Instructions

            Take once daily with food (improves absorption)

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            Images

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            Formulary

            FormularyPatient Discounts

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            Tier Description
            1 This drug is available at the lowest co-pay. Most commonly, these are generic drugs.
            2 This drug is available at a middle level co-pay. Most commonly, these are "preferred" (on formulary) brand drugs.
            3 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs.
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            5 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
            6 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
            NC NOT COVERED – Drugs that are not covered by the plan.
            Code Definition
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            Drugs that require prior authorization. This restriction requires that specific clinical criteria be met prior to the approval of the prescription.
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