Darunavir Ethanolate

Trade Names:
Prezista
- Tablets 75 mg (as base)
- Tablets 150 mg (as base)
- Tablets 300 mg (as base)
- Tablets 400 mg (as base)
- Tablets 600 mg (as base)

Pharmacology

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Inhibits HIV-1 protease, the enzyme required to form functional proteins in HIV-infected cells.

Pharmacokinetics

Absorption

The T _max of darunavir is approximately 2.5 to 4 h when administered with ritonavir 100 mg. Oral bioavailability is 37% and 82% when administered alone and with ritonavir, respectively. C _max and AUC are approximately 30% higher when taken with food.

Distribution

Protein binding is approximately 95%. Primarily bound to alpha-1 acid glycoprotein.

Metabolism

Extensively metabolized by CYP enzymes, primarily CYP3A. At least 3 active metabolites have been identified; all show activity that is at least 90% less than darunavir.

Elimination

When coadministered with ritonavir, approximately 79.5% and 13.9% of the administered darunavir dose was eliminated in the feces and urine, respectively. Unchanged drug accounted for approximately 41.2% and 7.7% of the drug elimination in the feces and urine, respectively. Terminal elimination half-life is 15 h when combined with ritonavir. The Cl of darunavir administered alone and coadministered with ritonavir 100 mg was 32.8 and 5.9 L/h, respectively.

Special Populations

Pharmacokinetics not affected in patients with moderate renal function impairment (CrCl 30 to 60 mL/min). Pharmacokinetic data are not available for patients with severe renal function impairment or end-stage renal disease; however, a decrease in total body Cl of darunavir is not expected.

No dose adjustment is needed for patients with mild or moderate hepatic function impairment. No pharmacokinetic data are available for use in patients with severe hepatic function impairment; however, administration is not recommended.

No significant differences in patients 18 to 75 years of age.

Pharmacokinetics of darunavir plus ritonavir in children 6 yr of age and older and weighing at least 20 kg (44 lb) are comparable with those of treatment-experienced adults.

Mean exposure is higher in HIV-infected women compared with men; however, the difference is not clinically important.

Does not appear to affect the pharmacokinetics.

Indications and Usage

Treatment of HIV infection in adults and children in combination with ritonavir and other antiretroviral agents.

Contraindications

Coadministration with drugs that are highly dependent on CYP3A for Cl and drugs for which elevated plasma levels are associated with serious and/or life-threatening events (eg, cisapride, dihydroergotamine, ergonovine, ergotamine, lovastatin, methylergonovine, midazolam, pimozide, rifampin, simvastatin, St. John's wort, triazolam); hypersensitivity to any component of the product.

Dosage and Administration

Darunavir 600 mg/ritonavir 100 mg twice daily.

PO Coadminister darunavir 375 mg and ritonavir 50 mg twice daily with food.

PO Coadminister darunavir 450 mg and ritonavir 60 mg twice daily with food.

PO Coadminister darunavir 600 mg and ritonavir 100 mg twice daily with food.

Safety and efficacy have not been established in children 3 to younger than 6 yr of age.

Do not use in children younger than 3 yr of age.

PO 600 mg twice daily with ritonavir 100 mg twice daily with food.

PO 800 mg with ritonavir 100 mg once daily with food.

General Advice

• Administer with food.
• Administer with ritonavir.
• Do not use once-daily dosing in children.
• Pediatric dose should be selected based on body weight and should not exceed the recommended dose for treatment-experienced adults.

Storage/Stability

Store at 59° to 86°F.

Drug Interactions

Plasma levels may be elevated by darunavir/ritonavir, increasing the risk of adverse reactions; careful monitoring and/or dosage adjustment are warranted.

Carbamazepine levels may be elevated while darunavir levels may be decreased, resulting in antiretroviral treatment failure.

Darunavir levels may be decreased. Do not administer lopinavir/ritonavir with darunavir/ritonavir.

Because didanosine is administered on an empty stomach, give didanosine 1 h before or 2 h after darunavir/ritonavir.

Coadministration with darunavir/ritonavir is contraindicated.

Plasma levels may be reduced by darunavir/ritonavir, decreasing the efficacy.

Fluticasone plasma levels may be increased. Consider alternative therapy.

When administered with food, the C _max and AUC of darunavir, coadministered with ritonavir, are approximately 30% higher compared with the fasting state. Always administer darunavir, coadministered with ritonavir, with food.

Indinavir and darunavir plasma levels may be elevated; however, appropriate doses in combination have not been established.

Darunavir plasma levels may be elevated. Itraconazole and ketoconazole levels may be increased; do not increase the daily dose of itraconazole or ketoconazole above 200 mg.

Coadministration may decrease darunavir plasma levels and clinical efficacy may be reduced. Efavirenz and nevirapine concentrations may be increased while etravine concentrations may be decreased.

Rifabutin and darunavir plasma levels may be elevated. Decrease the rifabutin dose by at least 75% of the usual dose.

Darunavir plasma levels may be decreased; therefore, coadministration is not recommended.

Do not coadminister with darunavir/ritonavir unless an assessment of the benefit/risk ratio justifies the use.

Warfarin plasma levels may be decreased; INR monitoring is recommended.

Laboratory Test Interactions

None well documented.

Adverse Reactions

CNS

Headache (5%); asthenia (3%); fatigue (1%).

Dermatologic

Rash (6%); Stevens-Johnson syndrome.

GI

Diarrhea (12%); nausea (7%); abdominal pain (adults, 5%; children, 10%); vomiting (adults, 4%; children, 13%); abdominal distension, dyspepsia (2%); anorexia (1%).

Hypersensitivity

Hypersensitivity, including facial edema (postmarketing).

Lab Tests

Increased total cholesterol (24%); increased LDL (13%); increased triglycerides (11%); increased glucose levels (8%); increased ALT and AST, increased pancreatic amylase (6%); increased pancreatic lipase (2%); increased hyperbilirubinemia, increased alkaline phosphatase (1%).

Musculoskeletal

Myalgia (1%); rhabdomyolysis (postmarketing).

Precautions

Pregnancy

Category C .

Lactation

Undetermined. Per the CDC, HIV-infected women should not breast-feed.

Children

Safety and efficacy not established in children younger than 6 yr of age. Do not administer in children younger than 3 yr of age.

Elderly

Use with caution because of the greater frequency of decreased hepatic, renal, or cardiac function, and concomitant diseases or other drug therapy.

Renal Function

Pharmacokinetics not affected by moderate renal function impairment (CrCl of 30 to 60 mL/min). Pharmacokinetic data are not available for patients with severe renal function impairment or end-stage renal disease; however, a decrease in total body Cl is not expected.

Hepatic Function

No dose adjustment is needed for patients with mild or moderate hepatic function impairment. No pharmacokinetic data are available for use in patients with severe hepatic function impairment; however, administration is not recommended.

Sulfite Sensitivity

Darunavir contains a sulfonamide moiety; use with caution in patients with a sulfonamide allergy.

Diabetes mellitus/hyperglycemia

New-onset diabetes mellitus, exacerbation of preexisting diabetes mellitus, and hyperglycemia have been reported.

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.

Hemophilia

There have been reports of increased bleeding, including spontaneous skin hematomas and hemarthrosis, in patients with hemophilia types A and B treated with protease inhibitors.

Hepatotoxicity

Has been reported. During postmarketing experience, liver damage, including fatalities, has been reported. The risk may be increased in patients with preexisting liver dysfunction, including chronic active hepatitis B or C.

Immune reconstitution syndrome

During initial phase of treatment, patients may develop an inflammatory response to indolent or residual opportunistic infections.

Skin rash

Skin rash accompanied by fever and/or elevated transaminases has been reported. Rarely, Stevens-Johnson syndrome has been reported. Discontinue treatment if severe rash occurs.

Overdosage

Symptoms

Oral doses of up to 3,200 mg have been administered without untoward effects.

Patient Information

• Advise patient to read the patient information leaflet before using darunavir for first time and with each refill.
• Advise patient to take with food and ritonavir daily as prescribed.
• Inform patient that darunavir is not a cure for HIV infection and that opportunistic infections and other complications associated with HIV may continue to develop.
• Advise patient to take this medication exactly as prescribed.
• Instruct patients receiving estrogen-based contraceptive to use additional or alternate contraceptive measures.
• Inform patients that redistribution or accumulation of body fat may occur.
• Instruct patient to inform health care provider of any medical condition, including hemophilia or liver disease.

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