Darunavir ethanolate and cobicistat
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Shivani Chaparala M.B.B.S [2]
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Overview
Darunavir ethanolate and cobicistat is a combination of darunavir, a human immunodeficiency virus (HIV-1) protease inhibitor and cobicistat, a CYP3A inhibitor that is FDA approved for the treatment of HIV-1 infection in adult patients.. Common adverse reactions include Darunavir: diarrhea, nausea, rash, headache, abdominal pain, and vomiting..
Adult Indications and Dosage
FDA-Labeled Indications and Dosage (Adult)
- 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 with no darunavir resistance-associated substitutions. Recommended dosage: One tablet taken once daily with food. Tablets: 800 mg of darunavir and 150 mg of cobicistat.
Off-Label Use and Dosage (Adult)
Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Darunavir ethanolate and cobicistat in adult patients.
Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Darunavir ethanolate and cobicistat in adult patients.
Pediatric Indications and Dosage
FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding Darunavir ethanolate and cobicistat FDA-Labeled Indications and Dosage (Pediatric) in the drug label.
Off-Label Use and Dosage (Pediatric)
Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Darunavir ethanolate and cobicistat in pediatric patients.
Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Darunavir ethanolate and cobicistat in pediatric patients.
Contraindications
There is limited information regarding Darunavir ethanolate and cobicistat Contraindications in the drug label.
Warnings
Hepatotoxicity
- During the darunavir clinical development program (N=3063), where darunavir was co-administered with ritonavir 100 mg once or twice daily, drug-induced hepatitis (e.g., acute hepatitis, cytolytic hepatitis) was reported in 0.5% of subjects.
- Patients with pre-existing liver dysfunction, including chronic active hepatitis B or C, have an increased risk for liver function abnormalities including severe hepatic adverse reactions.
- Post-marketing cases of liver injury, including some fatalities, have also been reported with darunavir co-administered with ritonavir.
- These have generally occurred in patients with advanced HIV-1 disease taking multiple concomitant medications, having co-morbidities including hepatitis B or C co-infection, and/or developing immune reconstitution syndrome.
- A causal relationship with darunavir co-administered with ritonavir has not been established.
- Appropriate laboratory testing should be conducted prior to initiating therapy with PREZCOBIX and patients should be monitored during treatment.
- Increased AST/ALT monitoring should be considered in patients with underlying chronic hepatitis, cirrhosis, or in patients who have pre-treatment elevations of transaminases, especially during the first several months of PREZCOBIX treatment.
- Evidence of new or worsening liver dysfunction (including clinically significant elevation of liver enzymes and/or symptoms such as fatigue, anorexia, nausea, jaundice, dark urine, liver tenderness, hepatomegaly) in patients on PREZCOBIX should prompt consideration of interruption or discontinuation of treatment.
Severe Skin Reactions
- During the darunavir clinical development program (n=3063), where darunavir was co-administered with ritonavir 100 mg once or twice daily, severe skin reactions, accompanied by fever and/or elevations of transaminases in some cases, was reported in 0.4% of subjects.
- Stevens-Johnson Syndrome was rarely (less than 0.1%) reported during the clinical development program.
- During post-marketing experience toxic epidermal necrolysis, drug rash with eosinophilia and systemic symptoms, and acute generalized exanthematous pustulosis have been reported.
- Discontinue PREZCOBIX immediately if signs or symptoms of severe skin reactions develop.
- These can include but are not limited to severe rash or rash accompanied with fever, general malaise, fatigue, muscle or joint aches, blisters, oral lesions, conjunctivitis, hepatitis and/or eosinophilia.
- Mild-to-moderate rash was also reported and often occurred within the first four weeks of treatment and resolved with continued dosing.
Effects on Serum Creatinine
- Cobicistat decreases estimated creatinine clearance due to inhibition of tubular secretion of creatinine without affecting actual renal glomerular function.
- This effect should be considered when interpreting changes in estimated creatinine clearance in patients initiating PREZCOBIX, particularly in patients with medical conditions or receiving drugs needing monitoring with estimated creatinine clearance.
- Prior to initiating therapy with PREZCOBIX, assess estimated creatinine clearance.
- Dosage recommendations are not available for drugs that require dosage adjustments in PREZCOBIX-treated patients with renal impairment.
- Consider alternative medications that do not require dosage adjustments in patients with renal impairment.
- Although cobicistat may cause modest increases in serum creatinine and modest declines in estimated creatinine clearance without affecting renal glomerular function, patients who experience a confirmed increase in serum creatinine of greater than 0.4 mg/dL from baseline should be closely monitored for renal safety.
New Onset or Worsening Renal Impairment when used with Tenofovir Disoproxil Fumarate
- Renal impairment, including cases of acute renal failure and Fanconi syndrome, has been reported when cobicistat, a component of PREZCOBIX, was used in an antiretroviral regimen that contained tenofovir DF.
- Co-administration of PREZCOBIX and tenofovir DF is not recommended in patients who have an estimated creatinine clearance below 70 mL/min.
- Document urine glucose and urine protein at baseline and perform routine monitoring of estimated creatinine clearance, urine glucose, and urine protein during treatment when PREZCOBIX is used with tenofovir DF. * Measure serum phosphorus in patients with or at risk for renal impairment when used with tenofovir DF.
- Co-administration of PREZCOBIX and tenofovir DF in combination with concomitant or recent use of a nephrotoxic agent is not recommended.
Risk of Serious Adverse Reactions or Loss of Virologic response due to Drug Interactions
- Initiation of PREZCOBIX, which inhibits CYP3A, in patients receiving medications metabolized by CYP3A, or initiation of medications metabolized by CYP3A in patients already receiving PREZCOBIX may increase plasma concentrations of medications metabolized by CYP3A.
- Initiation of medications that inhibit or induce CYP3A may respectively increase or decrease concentrations of PREZCOBIX.
- Increased concentrations may lead to: clinically significant adverse reactions, potentially leading to severe, life threatening, or fatal events from higher exposures of concomitant medications.
- Clinically significant adverse reactions from higher exposures of PREZCOBIX.
- Decreased antiretroviral concentrations may lead to: loss of therapeutic effect of PREZCOBIX and possible development of resistance.
- See TABLE 2 for steps to prevent or manage these possible and known significant drug interactions, including dosing recommendations.
- Consider the potential for drug interactions prior to and during PREZCOBIX therapy; review concomitant medications during PREZCOBIX therapy; and monitor for the adverse reactions associated with concomitant medications.
- When used with concomitant medications, PREZCOBIX may result in different drug interactions than those observed or expected with darunavir co-administered with ritonavir.
- Complex or unknown mechanisms of drug interactions preclude extrapolation of drug interactions with darunavir co-administered with ritonavir to certain PREZCOBIX interactions.
Antiretrovirals not Recommended
- PREZCOBIX is not recommended in combination with other antiretroviral drugs that require pharmacokinetic boosting (i.e., another protease inhibitor or elvitegravir) because dosing recommendations for such combinations have not been established and co-administration may result in decreased plasma concentrations of the antiretroviral agents, leading to loss of therapeutic effect and development of resistance.
- PREZCOBIX is not recommended in combination with products containing the individual components of PREZCOBIX (darunavir and cobicistat) or with ritonavir.
Sulfa Allergy
- Darunavir contains a sulfonamide moiety.
- Monitor patients with a known sulfonamide allergy after initiating PREZCOBIX.
- In clinical studies with darunavir co-administered with ritonavir, the incidence and severity of rash were similar in subjects with or without a history of sulfonamide allergy.
Diabetes Mellitus/Hyperglycemia
- New onset diabetes mellitus, exacerbation of pre-existing diabetes mellitus, and hyperglycemia have been reported during postmarketing surveillance in HIV infected patients receiving HIV protease inhibitor (PI) therapy.
- Some patients required either initiation or dose adjustments of insulin or oral hypoglycemic agents for treatment of these events.
- In some cases, diabetic ketoacidosis has occurred.
- In those patients who discontinued PI therapy, hyperglycemia persisted in some cases.
- Because these events have been reported voluntarily during clinical practice, estimates of frequency cannot be made and causal relationships between HIV PI therapy and these events have not been established.
Fat Redistribution
- 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 antiretroviral therapy.
- The mechanism and long-term consequences of these events are currently unknown.
- A causal relationship has not been established.
Immune Reconstitution Syndrome
- Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including PREZCOBIX.
- During the initial phase of combination antiretroviral treatment, patients whose immune systems respond may develop an inflammatory response to indolent or residual opportunistic infections (such as Mycobacterium avium infection, cytomegalovirus, Pneumocystis jirovecii pneumonia [PCP], or tuberculosis), which may necessitate further evaluation and treatment.
- Autoimmune disorders (such as Graves' disease, polymyositis, and Guillain-Barré syndrome) have also been reported to occur in the setting of immune reconstitution; however, the time to onset is more variable, and can occur many months after initiation of antiretroviral treatment.
Hemophilia
- There have been reports of increased bleeding, including spontaneous skin hematomas and hemarthrosis in patients with hemophilia type A and B treated with HIV PIs.
- In some patients, additional factor VIII was given.
- In more than half of the reported cases, treatment with HIV PIs was continued or reintroduced if treatment had been discontinued.
- A causal relationship between PI therapy and these episodes has not been established.
Adverse Reactions
Clinical Trials Experience
There is limited information regarding Darunavir ethanolate and cobicistat Clinical Trials Experience in the drug label.
Postmarketing Experience
There is limited information regarding Darunavir ethanolate and cobicistat Postmarketing Experience in the drug label.
Drug Interactions
There is limited information regarding Darunavir ethanolate and cobicistat Drug Interactions in the drug label.
Use in Specific Populations
Pregnancy
Pregnancy Category (FDA):
There is no FDA guidance on usage of Darunavir ethanolate and cobicistat in women who are pregnant.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Darunavir ethanolate and cobicistat in women who are pregnant.
Labor and Delivery
There is no FDA guidance on use of Darunavir ethanolate and cobicistat during labor and delivery.
Nursing Mothers
There is no FDA guidance on the use of Darunavir ethanolate and cobicistat in women who are nursing.
Pediatric Use
There is no FDA guidance on the use of Darunavir ethanolate and cobicistat in pediatric settings.
Geriatic Use
There is no FDA guidance on the use of Darunavir ethanolate and cobicistat in geriatric settings.
Gender
There is no FDA guidance on the use of Darunavir ethanolate and cobicistat with respect to specific gender populations.
Race
There is no FDA guidance on the use of Darunavir ethanolate and cobicistat with respect to specific racial populations.
Renal Impairment
There is no FDA guidance on the use of Darunavir ethanolate and cobicistat in patients with renal impairment.
Hepatic Impairment
There is no FDA guidance on the use of Darunavir ethanolate and cobicistat in patients with hepatic impairment.
Females of Reproductive Potential and Males
There is no FDA guidance on the use of Darunavir ethanolate and cobicistat in women of reproductive potentials and males.
Immunocompromised Patients
There is no FDA guidance one the use of Darunavir ethanolate and cobicistat in patients who are immunocompromised.
Administration and Monitoring
Administration
There is limited information regarding Darunavir ethanolate and cobicistat Administration in the drug label.
Monitoring
There is limited information regarding Darunavir ethanolate and cobicistat Monitoring in the drug label.
IV Compatibility
There is limited information regarding the compatibility of Darunavir ethanolate and cobicistat and IV administrations.
Overdosage
There is limited information regarding Darunavir ethanolate and cobicistat overdosage. If you suspect drug poisoning or overdose, please contact the National Poison Help hotline (1-800-222-1222) immediately.
Pharmacology
There is limited information regarding Darunavir ethanolate and cobicistat Pharmacology in the drug label.
Mechanism of Action
There is limited information regarding Darunavir ethanolate and cobicistat Mechanism of Action in the drug label.
Structure
There is limited information regarding Darunavir ethanolate and cobicistat Structure in the drug label.
Pharmacodynamics
There is limited information regarding Darunavir ethanolate and cobicistat Pharmacodynamics in the drug label.
Pharmacokinetics
There is limited information regarding Darunavir ethanolate and cobicistat Pharmacokinetics in the drug label.
Nonclinical Toxicology
There is limited information regarding Darunavir ethanolate and cobicistat Nonclinical Toxicology in the drug label.
Clinical Studies
There is limited information regarding Darunavir ethanolate and cobicistat Clinical Studies in the drug label.
How Supplied
There is limited information regarding Darunavir ethanolate and cobicistat How Supplied in the drug label.
Storage
There is limited information regarding Darunavir ethanolate and cobicistat Storage in the drug label.
Images
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Patient Counseling Information
There is limited information regarding Darunavir ethanolate and cobicistat Patient Counseling Information in the drug label.
Precautions with Alcohol
Alcohol-Darunavir ethanolate and cobicistat interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
Brand Names
There is limited information regarding Darunavir ethanolate and cobicistat Brand Names in the drug label.
Look-Alike Drug Names
There is limited information regarding Darunavir ethanolate and cobicistat Look-Alike Drug Names in the drug label.
Drug Shortage Status
Price
References
The contents of this FDA label are provided by the National Library of Medicine.