Darunavir Ethanolate And Cobicistat

FDA Drug Information • Also known as: Prezcobix, Prezcobix Ped

Brand Names: Prezcobix, Prezcobix Ped
Drug Class: Cytochrome P450 3A Inhibitor [EPC]
Route: ORAL
Dosage Form: TABLET, FOR SUSPENSION
Product Type: HUMAN PRESCRIPTION DRUG

Description

11 DESCRIPTION PREZCOBIX ® is a fixed-dose combination tablet containing darunavir and cobicistat. Darunavir is an inhibitor of the human immunodeficiency virus (HIV-1) protease. Cobicistat is a mechanism-based inhibitor of cytochrome P450 (CYP) enzymes of the CYP3A family. PREZCOBIX tablets are for oral administration. Each tablet contains darunavir ethanolate equivalent to 800 mg of darunavir and 150 mg of cobicistat. The tablets include the following inactive ingredients: colloidal silicon dioxide, crospovidone, hypromellose, magnesium stearate, and silicified microcrystalline cellulose. The tablets are film-coated with a coating material containing iron oxide black, iron oxide red, polyethylene glycol, polyvinyl alcohol (partially hydrolyzed), talc, and titanium dioxide. Darunavir : Darunavir, in the form of darunavir ethanolate, has the following chemical name: [(1 S ,2 R )-3-[[(4-aminophenyl)sulfonyl](2-methylpropyl)amino]-2-hydroxy-1-(phenylmethyl)propyl]-carbamic acid (3 R ,3a S ,6a R )-hexahydrofuro[2,3- b ]furan-3-yl ester monoethanolate. Its molecular formula is C 27 H 37 N 3 O 7 S ∙ C 2 H 5 OH and its molecular weight is 593.73. Darunavir ethanolate has the following structural formula: Chemical Structure Cobicistat : Cobicistat is adsorbed onto silicon dioxide. The chemical name for cobicistat is 1,3-thiazol-5-ylmethyl[(2 R ,5 R )-5-{[(2 S )2-[(methyl{[2-(propan-2-yl)-1,3-thiazol-4-yl]methyl}carbamoyl)amino]-4-(morpholin-4yl)butanoyl]amino}-1,6-diphenylhexan-2-yl]carbamate. It has a molecular formula of C 40 H 53 N 7 O 5 S 2 and a molecular weight of 776.0. It has the following structural formula: Chemical Structure

What Is Darunavir Ethanolate And Cobicistat Used For?

1 INDICATIONS AND USAGE PREZCOBIX is indicated in combination with other antiretroviral agents for the treatment of human immunodeficiency virus (HIV-1) infection in treatment-naïve and treatment-experienced adults and pediatric patients weighing at least 40 kg with no darunavir resistance-associated substitutions (V11I, V32I, L33F, I47V, I50V, I54L, I54M, T74P, L76V, I84V, L89V). PREZCOBIX is a two-drug combination of darunavir, a human immunodeficiency virus (HIV-1) protease inhibitor, and cobicistat, a CYP3A inhibitor, and is indicated for the treatment of HIV-1 infection in treatment-naïve and treatment-experienced adults and pediatric patients weighing at least 40 kg with no darunavir resistance-associated substitutions (V11I, V32I, L33F, I47V, I50V, I54L, I54M, T74P, L76V, I84V, L89V). ( 1 )

Dosage and Administration

2 DOSAGE AND ADMINISTRATION Recommended dosage: One tablet taken once daily with food in adults and pediatric patients weighing at least 40 kg. ( 2.1 ) Testing Prior to Initiation: HIV genotypic testing is recommended for antiretroviral treatment experienced patients. Assess estimated creatinine clearance in all patients prior to starting PREZCOBIX. When used with tenofovir DF: Assess urine glucose and urine protein at baseline and monitor creatinine clearance, urine glucose, and urine protein. Monitor serum phosphorus in patients with or at risk for renal impairment. ( 2.2 ) 2.1 Recommended Dosage PREZCOBIX is a fixed-dose combination product containing 800 mg of darunavir and 150 mg of cobicistat. In treatment-naïve and treatment-experienced adults and pediatric patients weighing at least 40 kg with no darunavir resistance-associated substitutions, the recommended dosage of PREZCOBIX is one tablet taken once daily orally with food. Administer PREZCOBIX in conjunction with other antiretroviral agents. 2.2 Testing Prior to Initiation of PREZCOBIX HIV Genotypic Testing HIV genotypic testing is recommended for antiretroviral treatment-experienced patients. However, when HIV genotypic testing is not feasible, PREZCOBIX can be used in protease inhibitor-naïve patients, but is not recommended in protease inhibitor-experienced patients. Creatinine Clearance Prior to starting PREZCOBIX, assess estimated creatinine clearance because cobicistat decreases estimated creatinine clearance due to inhibition of tubular secretion of creatinine without affecting actual renal glomerular function [see Warnings and Precautions (5.3) ] . When co-administering PREZCOBIX with tenofovir disoproxil fumarate (tenofovir DF) assess estimated creatinine clearance, urine glucose, and urine protein at baseline [see Warnings and Precautions (5.4) ] . 2.3 Not Recommended in Severe Renal Impairment PREZCOBIX co-administered with tenofovir DF is not recommended in patients who have an estimated creatinine clearance below 70 mL per minute [see Warnings and Precautions (5.4) and Adverse Reactions (6.1) ] . 2.4 Not Recommended in Severe Hepatic Impairment PREZCOBIX is not recommended for use in patients with severe hepatic impairment [see Use in Specific Populations (8.6) and Clinical Pharmacology (12.3) ] . 2.5 Not Recommended During Pregnancy PREZCOBIX is not recommended during pregnancy because of substantially lower exposures of darunavir and cobicistat during the second and third trimesters [see Use in Specific Populations (8.1) and Clinical Pharmacology (12.3) ] . PREZCOBIX should not be initiated in pregnant individuals. An alternative regimen is recommended for those who become pregnant during therapy with PREZCOBIX.

Side Effects (Adverse Reactions)

6 ADVERSE REACTIONS The following adverse reactions are discussed in other sections of the labeling: Hepatotoxicity [see Warnings and Precautions (5.1) ] Severe skin reactions [see Warnings and Precautions (5.2) ] Effects on serum creatinine [see Warnings and Precautions (5.3) ] New onset or worsening renal impairment when used with tenofovir DF [see Warnings and Precautions (5.4) ] Immune Reconstitution Syndrome [see Warnings and Precautions (5.10) ] The most common adverse reactions to darunavir, a component of PREZCOBIX (incidence greater than or equal to 5%) of at least moderate severity (greater than or equal to Grade 2) were diarrhea, nausea, rash, headache, abdominal pain, and vomiting. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Janssen Products, LP at 1-800-JANSSEN (1-800-526-7736) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 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 clinical practice. Clinical Trials in Adults During the darunavir clinical development program, where darunavir was co-administered with ritonavir 100 mg once or twice daily, the most common clinical adverse reactions (incidence greater than or equal to 5%) of at least moderate intensity (greater than or equal to Grade 2) were diarrhea, nausea, rash, headache, abdominal pain, and vomiting. See the darunavir full prescribing information for additional information on adverse reactions reported with darunavir co-administered with ritonavir. See cobicistat full prescribing information for clinical trial information on adverse reactions reported with cobicistat. One single arm clinical trial was conducted with darunavir and cobicistat administered as single entities in 313 subjects with HIV-1 infection. Adverse reactions evaluated through Week 24 did not differ substantially from those reported in clinical trials with darunavir co-administered with ritonavir. Clinical Trials in Pediatric Patients No clinical trials with PREZCOBIX were performed in pediatric patients. However, the safety of the components of PREZCOBIX, darunavir and cobicistat, co-administered with two nucleoside reverse transcriptase inhibitors, was evaluated in pediatric subjects of 12 to less than 18 years of age with HIV-1 infection through clinical trial GS-US-216-0128 (virologically-suppressed, N=7 with weight ≥40 kg) through Week 48. Safety analyses of this trial in these pediatric subjects did not identify new safety concerns compared to the known safety profile of PREZCOBIX in adult subjects [see Clinical Studies (14.2) ] . 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of darunavir. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Metabolism and Nutrition Disorders Redistribution of body fat Musculoskeletal and Connective Tissue Disorders Rhabdomyolysis (associated with co-administration with HMG-CoA reductase inhibitors) Renal and Urinary Disorders Crystal nephropathy, crystalluria Skin and Subcutaneous Tissue Disorders Toxic epidermal necrolysis, acute generalized exanthematous pustulosis, drug rash with eosinophilia and systemic symptoms [see Warnings and Precautions (5.2) ] .

Drug Interactions

7 DRUG INTERACTIONS Co-administration of PREZCOBIX with other drugs can alter the concentration of other drugs and other drugs may alter the concentrations of darunavir or cobicistat. Consult the full prescribing information prior to and during treatment for potential drug interactions. ( 4 , 5.6 , 7 , 12.3 ) 7.1 Potential for PREZCOBIX to Affect Other Drugs Darunavir co-administered with cobicistat is an inhibitor of CYP3A and CYP2D6. Cobicistat inhibits the following transporters: P-glycoprotein (P-gp), BCRP, MATE1, OATP1B1 and OATP1B3. Therefore, co-administration of PREZCOBIX with drugs that are primarily metabolized by CYP3A and/or CYP2D6 or are substrates of P-gp, BCRP, MATE1, OATP1B1 or OATP1B3 may result in increased plasma concentrations of such drugs, which could increase or prolong their therapeutic effect and can be associated with adverse events. Co-administration of PREZCOBIX with drugs that have active metabolite(s) formed by CYP3A may result in reduced plasma concentrations of these active metabolite(s), potentially leading to loss of their therapeutic effect (see Table 1 ). 7.2 Potential for Other Drugs to Affect PREZCOBIX Darunavir is metabolized by CYP3A. Cobicistat is metabolized by CYP3A, and to a minor extent, by CYP2D6. Co-administration of PREZCOBIX and drugs that induce CYP3A activity are expected to increase the clearance of darunavir and cobicistat, resulting in lowered plasma concentrations of darunavir and cobicistat which may lead to loss of therapeutic effect and development of resistance. Co-administration of PREZCOBIX and other drugs that inhibit CYP3A may result in increased plasma concentrations of darunavir and cobicistat (see Table 1 ). 7.3 Established and Other Potentially Significant Drug Interactions Table 1 provides dosing recommendations for expected clinically relevant interactions with PREZCOBIX (this table is not all inclusive). These recommendations are based on either drug interaction trials or predicted interactions due to the expected magnitude of interaction and potential for serious adverse events or loss of therapeutic effect. The table includes examples of potentially significant interactions but is not all inclusive , and therefore the label of each drug that is co-administered with PREZCOBIX should be consulted for information related to the route of metabolism, interaction pathways, potential risks, and specific actions to be taken with regard to co-administration. For the list of examples of contraindicated drugs, [see Contraindications (4) ] . Table 1: Established and Other Potentially Significant this table is not all inclusive Drug Interactions: Alterations in Dose or Regimen May Be Recommended Concomitant Drug Class: Drug Name Examples Effect on Concentration of Darunavir, Cobicistat, or Concomitant Drug Clinical Comment HIV-1 antiviral agents: Nucleoside Reverse Transcriptase Inhibitors (NRTIs) didanosine ↔ darunavir ↔ cobicistat ↔ didanosine Didanosine should be administered one hour...

Contraindications

4 CONTRAINDICATIONS Darunavir and cobicistat are both inhibitors of the cytochrome P450 3A (CYP3A) isoform. PREZCOBIX should not be co-administered with medicinal products that are highly dependent on CYP3A for clearance and for which increased plasma concentrations are associated with serious and/or life threatening events (narrow therapeutic index). Darunavir and cobicistat are both substrates of the cytochrome P450 3A (CYP3A) isoform. Co-administration of PREZCOBIX with CYP3A inducers may lead to lower exposures of darunavir and cobicistat and potential loss of efficacy of darunavir and possible resistance. Examples of drugs that are contraindicated for co-administration with PREZCOBIX [see Drug Interactions (7.3) and Clinical Pharmacology (12.3) ] are listed below. Alpha 1-adrenoreceptor antagonist: alfuzosin Anticonvulsants: carbamazepine, phenobarbital, phenytoin Anti-gout: colchicine, in patients with renal and/or hepatic impairment Antimycobacterial: rifampin Antipsychotics: lurasidone, pimozide Cardiac Disorders: dronedarone, ivabradine, ranolazine Ergot derivatives, e.g. dihydroergotamine, ergotamine, methylergonovine Herbal product: St. John's wort ( Hypericum perforatum ) Hepatitis C direct acting antiviral: elbasvir/grazoprevir Lipid modifying agents: lomitapide, lovastatin, simvastatin Opioid Antagonist: naloxegol PDE-5 inhibitor: sildenafil when used for treatment of pulmonary arterial hypertension Sedatives/hypnotics: orally administered midazolam, triazolam PREZCOBIX is contraindicated in patients receiving certain co-administered drugs for which altered plasma concentrations are associated with serious and/or life-threatening events or loss of therapeutic effect. ( 4 , 7.2 )

Pregnancy and Breastfeeding

8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in individuals exposed to PREZCOBIX during pregnancy. Healthcare providers are encouraged to register patients by calling the Antiretroviral Pregnancy Registry (APR) 1-800-258-4263. Risk Summary PREZCOBIX is not recommended during pregnancy because of substantially lower exposures of darunavir and cobicistat during the second and third trimesters [see Dosage and Administration (2.5) ] . A study evaluating the pharmacokinetics of antiretrovirals during pregnancy demonstrated substantially lower exposures of darunavir and cobicistat in the second and third trimesters compared to the post-partum period (see Data ) and [see Clinical Pharmacology (12.3) ]. Prospective pregnancy data from the APR are not sufficient to adequately assess the risk of birth defects or miscarriage. However, available data from the APR show no statistically significant difference in the overall risk of major birth defects for darunavir and cobicistat compared with the background rate for major birth defects of 2.7% in a U.S. reference population of the Metropolitan Atlanta Congenital Defects Program (MACDP) (see Data ) . The rate of miscarriage is not reported in the APR. The estimated background rate of miscarriage in clinically recognized pregnancies in the U.S. general population is 15–20%. The background risk of major birth defects and miscarriage for the indicated population is unknown. In animal reproduction studies, no adverse developmental effects were observed when the components of PREZCOBIX were administered separately at darunavir exposures less than 1 (mice and rabbits) and 3-times (rats), and at cobicistat exposures 1.6 (rats) and 3.8 (rabbits) times human exposures at the recommended daily dose of these components in PREZCOBIX (see Data ) . No adverse developmental effects were seen when cobicistat was administered to rats through lactation at cobicistat exposures up...

Overdosage

10 OVERDOSAGE Human experience of acute overdose with PREZCOBIX is limited. No specific antidote is available for overdose with PREZCOBIX. Treatment of overdose with PREZCOBIX consists of general supportive measures including monitoring of vital signs and observation of the clinical status of the patient. Since both darunavir and cobicistat are highly protein bound, dialysis is unlikely to be beneficial in significant removal of the active substance.

How Supplied

16 HOW SUPPLIED/STORAGE AND HANDLING Product: 50090-1723 NDC: 50090-1723-0 30 TABLET, FILM COATED in a BOTTLE

About This Information

This drug information is sourced from FDA-approved labeling via the openFDA database. It is intended for educational and reference purposes only. This is not medical advice. Always consult your healthcare provider before making decisions about medication. Drug information may be updated by the FDA; check with your pharmacist for the most current information.

What are side effects?

Side effects are unwanted reactions that can occur when taking a medication. They range from mild (headache, nausea) to severe (allergic reactions, organ damage). Not everyone experiences side effects, and severity varies. Report any concerning side effects to your doctor.

What are drug interactions?

Drug interactions occur when a medication is affected by another drug, food, or supplement. Interactions can make medications less effective or cause dangerous side effects. Always tell your doctor about all medications and supplements you take.