Darunavir Ethanolate

Pronunciation: dar-UE-na-vir ETH-a-NOLE-ate
Class: Protease inhibitor

Trade Names

Prezista
- Tablets, oral 75 mg
- Tablets, oral 150 mg
- Tablets, oral 400 mg
- Tablets, oral 600 mg
- Suspension, oral 100 mg/mL

Pharmacology

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

Slideshow: Flashback: FDA Drug Approvals 2013

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 40% 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 showed activity that was at least 90% less than activity of 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

Renal Function Impairment

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

Hepatic Function Impairment

The steady-state pharmacokinetic parameters of darunavir were similar after multiple-dose coadministration of darunavir 600 mg and ritonavir 100 mg twice daily to subjects with healthy hepatic function, mild hepatic impairment (Child-Pugh class A), and moderate hepatic impairment (Child-Pugh class B). No pharmacokinetic data are available for use in patients with severe hepatic impairment.

Elderly

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

Children

Pharmacokinetics of darunavir plus ritonavir in children 3 y and older and weighing at least 10 kg are comparable with those of treatment-experienced adults.

Gender

Mean exposure is higher in HIV-1–infected women compared with men; however, the difference is not clinically important.

Race

Does not appear to affect pharmacokinetics.

Indications and Usage

Treatment of HIV-1 infection in adults and children 3 y and older 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, alfuzosin, cisapride, dihydroergotamine, ergonovine, ergotamine, lovastatin, methylergonovine, oral midazolam, pimozide, rifampin, sildenafil for the treatment of pulmonary arterial hypertension, simvastatin, St. John's wort, triazolam).

Dosage and Administration

HIV Infection
Treatment-naive adults

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

Treatment-experienced adults

PO For antiretroviral treatment-experienced patients, genotypic testing is recommended: darunavir 800 mg with ritonavir 100 mg once daily with food in patients with no darunavir resistance-associated substitutions or darunavir 600 mg with ritonavir 100 mg twice daily with food in patients with 1 or more darunavir resistance-associated substitutions. When genotypic testing is not feasible, darunavir 600 mg with ritonavir 100 mg twice daily is recommended.

Children 3 to younger than 18 y weighing at least 10 kg Weight 10 kg to less than 11 kg

PO Darunavir 200 mg with ritonavir 32 mg twice daily with food.

Weight 11 kg to less than 12 kg

PO Darunavir 220 mg with ritonavir 32 mg twice daily with food.

Weight 12 kg to less than 13 kg

PO Darunavir 240 mg with ritonavir 40 mg twice daily with food.

Weight 13 kg to less than 14 kg

PO Darunavir 260 mg with ritonavir 40 mg twice daily with food.

Weight 14 kg to less than 15 kg

PO Darunavir 280 mg with ritonavir 48 mg twice daily with food.

Weight 15 kg to less than 30 kg

PO Darunavir 375 mg (if using darunavir oral suspension, round off dose to 380 mg) with ritonavir 50 mg twice daily with food.

Weight 30 kg to less than 40 kg

PO Darunavir 450 mg (if using darunavir oral suspension, round off dose to 460 mg) with ritonavir 60 mg twice daily with food.

Weight 40 kg or more

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

Missed dose Once-daily dosing

If a dose of darunavir or ritonavir is missed by more than 12 h, instruct patient to wait and take the next dose of darunavir and ritonavir at the regularly scheduled time. If a dose of darunavir or ritonavir is missed by less than 12 h, darunavir and ritonavir should be taken immediately, and the next dose of darunavir and ritonavir should be taken at the regularly scheduled time.

Twice-daily dosing

If a dose of darunavir or ritonavir is missed by more than 6 h, instruct patient to wait and take the next dose of darunavir and ritonavir at the regularly scheduled time. If a dose of darunavir or ritonavir is missed by less than 6 h, darunavir and ritonavir should be taken immediately, and the next dose of darunavir and ritonavir should be taken at the regularly scheduled time.

Skipped dose

If a dose of darunavir or ritonavir is skipped, instruct patient not to double the next dose.

General Advice

  • Darunavir must be coadministered with ritonavir and food to exert its therapeutic effect. Failure to correctly coadminister darunavir with ritonavir will result in plasma levels of darunavir that will be insufficient to achieve the desired antiviral effect and will alter some drug interactions.
  • Do not use once-daily dosing in children.
  • Shake suspension well before administering the dose. Use supplied dosing syringe when withdrawing the dose.
  • An 8 mL dose of the suspension should be taken as two 4 mL administrations.

Storage/Stability

Store between 59° and 86°F. Do not refrigerate or freeze the suspension and avoid exposure to excessive heat. Store the suspension in the original container.

Drug Interactions

Alpha-1 adrenoreceptor antagonists (eg, alfuzosin)

The risk for potential serious and/or life-threatening reactions may be increased. Coadministration is contraindicated.

Amiodarone, atorvastatin, bepridil, buprenorphine, clarithromycin, cyclosporine, desipramine, dextromethorphan, digoxin, felodipine, fentanyl, flecainide, lidocaine (systemic), metoprolol, midazolam (parenteral), nicardipine, nifedipine, pravastatin, propafenone, quetiapine, quinidine, risperidone, rosuvastatin, sildenafil, sirolimus, tacrolimus, tadalafil, thioridazine, timolol, trazodone, vardenafil

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

Bosentan

Bosentan plasma concentrations may be elevated, increasing the pharmacologic effect and risk of adverse reactions. For patients who have been receiving darunavir/ritonavir for at least 10 days, start bosentan at 62.5 mg once daily or every other day based on individual tolerability. In patients on bosentan, discontinue bosentan at least 36 hours before starting darunavir/ritonavir. At least 10 days after starting darunavir/ritonavir, resume bosentan at 62.5 mg once daily or every other day based on individual tolerability.

Carbamazepine

Carbamazepine levels may be elevated while darunavir levels may be decreased, resulting in antiretroviral treatment failure. Close clinical monitoring is indicated if concomitant use cannot be avoided. Consider alternative therapy for carbamazepine.

Clarithromycin

Concurrent darunavir use may increase clarithromycin levels. Dosage adjustment is not needed in patients with healthy renal function. For patients with a CrCl of 30 to 60 mL/min, decrease clarithromycin dose by 50%. For patients with a CrCl of less than 30 mL/min, decrease clarithromycin dose by 75%.

Colchicine

Colchicine and darunavir/ritonavir should not be given to patients with hepatic or renal impairment.

Treatment of gout flares

Coadminister colchicine 0.6 mg followed by 0.3 mg 1 hour later. Dose to be repeated no earlier than 3 days.

Prophylaxis of gout flares

If the original colchicine regimen was colchicine 0.6 mg twice daily, adjust the dosage to 0.3 mg once daily. If the original colchicine dosage was 0.6 mg once daily, adjust the regimen to colchicine 0.3 mg every other day.

Treatment of familial Mediterranean fever

Coadminister colchicine at a maximum daily dosage of 0.3 mg twice a day.

Dexamethasone, lopinavir/ritonavir

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

Didanosine

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

Dronedarone

Plasma concentrations and pharmacologic effects of dronedarone may be increased by darunavir. Coadministration of dronedarone with darunavir and ritonavir is contraindicated.

Drugs that are highly dependent on CYP3A for Cl and have a narrow therapeutic index (eg, cisapride, dihydroergotamine, ergonovine, ergotamine, lovastatin, methylergonovine, oral midazolam, pimozide, rifampin, simvastatin, St. John's wort, triazolam)

Coadministration with darunavir and ritonavir is contraindicated.

Ethinyl estradiol, norethindrone

Plasma levels may be reduced by darunavir and ritonavir, decreasing the efficacy. Use alternative or additional contraceptive measures when estrogen-containing contraceptives are coadministered.

Fluticasone inhalation

Fluticasone plasma levels may be increased. Consider alternative therapy, especially for long-term use.

Iloperidone

Plasma concentrations and pharmacologic effects of iloperidone may be increased by darunavir. Reduce the dose of iloperidone by one-half when coadministered with darunavir. If therapy with darunavir is discontinued, increase the dose of iloperidone to the original dose.

Indinavir

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

Itraconazole, ketoconazole

Darunavir plasma levels may be elevated. Itraconazole and ketoconazole levels may be increased. When coadministered with darunavir, do not increase the daily dose of itraconazole or ketoconazole above 200 mg.

Maraviroc

Concomitant use may increase plasma concentrations of maraviroc. When used in combination, the maraviroc dosage should be 150 mg twice daily.

Methadone

During concurrent use, monitor patients for opiate abstinence syndrome. Methadone dosage may need to be increased.

Midazolam

Concomitant use of IV midazolam with darunavir and ritonavir may increase plasma concentrations of midazolam. Closely monitor for respiratory function and prolonged sedation. Consider midazolam dose reduction, especially if more than a single IV midazolam dose is administered. Administration of darunavir and oral midazolam is contraindicated.

NRTIs/NNRTIs

Etravirine and nevirapine may increase darunavir AUC, while efavirenz may decrease darunavir AUC. Darunavir may increase the AUC of efavirenz and nevirapine, and decrease the etravirine AUC. However, no dosage adjustment appears to be needed for any of these drugs.

Omeprazole

Omeprazole plasma concentrations may be decreased, reducing the efficacy. Monitor the patient. If an interaction is suspected, it may be necessary to increase the omeprazole dose.

Opioid analgesics (eg, buprenorphine, buprenorphine/naloxone)

No dosage adjustment for buprenorphine or buprenorphine/naloxone is needed with coadministration of darunavir/ritonavir. However, clinical monitoring is recommended.

Phenobarbital, phenytoin

Coadministration may decrease darunavir plasma concentrations, resulting in a loss of therapeutic effect. If coadministration cannot be avoided, monitor phenytoin and phenobarbital concentrations and adjust the dose as needed.

Phosphodiesterase type 5 (PDE5) inhibitors (eg, sildenafil, tadalafil, vardenafil)

Coadministration of darunavir and sildenafil for the treatment of pulmonary arterial hypertension is contraindicated. Coadministration may result in an increase in PDE5 inhibitor–associated adverse reactions, including hypotension, visual changes, and priapism.

For use in patients with pulmonary arterial hypertension, who have received darunavir/ritonavir for at least 1 week

Start tadalafil at 20 mg once daily. The tadalafil dosage may be increased to 40 mg once daily based on individual tolerability. Avoid tadalafil during initiation of darunavir/ritonavir. Stop tadalafil at least 24 h prior to starting darunavir/ritonavir. After at least 1 week following the start of darunavir/ritonavir, resume tadalafil at 20 mg once daily. The tadalafil dosage may be increased to 40 mg once daily based on individual tolerability.

For the treatment of erectile dysfunction

Use with caution at reduced dosages and increase monitoring for adverse events. Limit dosage of sildenafil to 25 mg in 48 h, tadalafil to 10 mg in 72 h, or vardenafil to no more than 2.5 mg every 72 h.

Raltegravir

The risk of a rash may be increased. Instruct patients to contact their health care provider if a rash develops.

Rifabutin

Rifabutin and darunavir plasma levels may be elevated. Concomitant use of rifabutin and darunavir in the presence of ritonavir is expected to increase rifabutin plasma concentrations and decrease darunavir plasma concentrations. Administer rifabutin 150 mg once every other day when coadministered with darunavir and ritonavir. Increase monitoring for adverse reactions; further rifabutin dose reductions may be necessary.

Rilpivirine

Coadministration may decrease the darunavir AUC and increase the rilpivirine AUC. However, no dosage adjustment is needed for either drug.

Salmeterol

Salmeterol concentrations may be elevated, increasing the risk of CV events, including QT prolongation, palpitations, and sinus tachycardia. Coadministration is not recommended.

Saquinavir

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

SSRIs (eg, paroxetine, sertraline)

The SSRI dose may need to be carefully titrated based on antidepressant response.

Telaprevir

Steady-state exposure to both darunavir and telaprevir may be reduced. Coadministration is not recommended.

Voriconazole

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

Warfarin

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

Adverse Reactions

Adverse reactions are for darunavir with ritonavir and other antiviral agents.

CNS

Headache (9%); asthenia, fatigue (3%); abnormal dreams (less than 2%).

Dermatologic

Rash (10%); angioedema, pruritus, Stevens-Johnson syndrome, urticaria (less than 2%); TEN (postmarketing).

GI

Diarrhea (19%); vomiting (14%); abdominal pain (10%); nausea (7%); abdominal distension, anorexia, dyspepsia (2%); acute hepatitis, acute pancreatitis, flatulence (less than 2%).

Hypersensitivity

Hypersensitivity (less than 2%).

Lab Tests

Increased total cholesterol (25%); increased LDL (14%); increased glucose levels, increased triglycerides (10%); increased ALT (9%); increased AST, increased pancreatic amylase (6%); increased pancreatic lipase (3%); increased alkaline phosphatase (1%).

Miscellaneous

Diabetes mellitus (2%); myalgia, immune reconstitution syndrome, osteonecrosis (less than 2%); redistribution of body fat, rhabdomyolysis (postmarketing).

Precautions

Monitor

Conduct appropriate laboratory testing prior to initiating therapy and monitor patients during treatment. Assess liver function prior to starting therapy and monitor during treatment. Consider more frequent AST/ALT monitoring in patients with underlying chronic hepatitis or cirrhosis, or in patients who have pretreatment elevations in transaminases. Monitor patients for new-onset diabetes mellitus, exacerbation of preexisting diabetes mellitus, and hyperglycemia.


Pregnancy

Category C .

Lactation

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

Children

Do not administer in children younger than 3 y. Do not administer darunavir with ritonavir once daily in children.

Elderly

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

Hepatic Function

Administration is not recommended in patients with severe hepatic impairment.

Sulfite Sensitivity

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

Dermatologic effects

Severe skin reactions, accompanied by fever and/or elevations of transaminases in some cases, have been reported. Stevens-Johnson syndrome was rarely reported during the clinical development program. During postmarketing experience, TEN has been reported.

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

Drug-induced hepatitis (eg, acute hepatitis, cytolytic hepatitis) has been reported. Postmarketing cases of liver injury, including some fatalities, have been reported. These have generally occurred in patients with advanced HIV-1 disease taking multiple concomitant medications, having comorbidities (eg, hepatitis B or C coinfection), and/or developing immune reconstitution syndrome.

Immune reconstitution syndrome

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

Overdosage

Symptoms

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

Patient Information

  • Inform patients that darunavir is not a cure for HIV infection and that they may continue to develop opportunistic infections and other complications associated with HIV disease. Inform patients that there are currently no data demonstrating that therapy with darunavir can reduce the risk of transmitting HIV to others.
  • Inform patients that sustained decreases in plasma HIV RNA have been associated with a reduced risk of progression to AIDS and death. Instruct patients to remain under the care of a health care provider while using darunavir.
  • Advise patients to take darunavir and ritonavir with food every day as prescribed. Instruct patients to swallow the tablets whole with a drink, such as water or milk. Darunavir must always be used with ritonavir 100 mg in combination with other antiretroviral drugs. Instruct patients not to alter the dose of darunavir or ritonavir, discontinue ritonavir, or discontinue therapy with darunavir without consulting their health care provider.
  • In patients taking darunavir once daily, if the patient misses a dose of darunavir or ritonavir by more than 12 h, instruct the patient to wait and then take the next dose of darunavir and ritonavir at the regularly scheduled time. If the patient misses a dose of darunavir or ritonavir by less than 12 h, instruct the patient to take darunavir and ritonavir immediately, and then take the next dose of darunavir and ritonavir at the regularly scheduled time. If a dose of darunavir or ritonavir is skipped, advise the patient not to double the next dose. Inform the patient not to take more or less than the prescribed dose of darunavir or ritonavir.
  • In patients taking darunavir twice daily, if the patient misses a dose of darunavir or ritonavir by more than 6 h, instruct the patient to wait and then take the next dose of darunavir and ritonavir at the regularly scheduled time. If the patient misses a dose of darunavir or ritonavir by less than 6 h, instruct the patient to take darunavir and ritonavir immediately, and then take the next dose of darunavir and ritonavir at the regularly scheduled time. If a dose of darunavir or ritonavir is skipped, instruct the patient not to double the next dose. Instruct the patient not to take more or less than the prescribed dose of darunavir or ritonavir at any one time.
  • Darunavir and ritonavir may interact with many drugs; therefore, advise patients to report to their health care provider the use of any other prescription or nonprescription medication or herbal products, including St. John's wort.
  • Instruct patients receiving estrogen-based contraceptives to use alternate contraceptive measures during therapy with darunavir and ritonavir because hormonal levels may decrease.
  • Inform patients that redistribution or accumulation of body fat may occur in patients receiving antiretroviral therapy, including darunavir and ritonavir, and that the cause and long-term health effects of these conditions are not known at this time.
  • Inform patients that drug-induced hepatitis has been reported with darunavir coadministered with ritonavir. Inform patients of the signs and symptoms of liver problems (eg, jaundice of the skin or eyes; dark, tea-colored urine; pale-colored stools; nausea; vomiting; loss of appetite; pain, aching, or sensitivity in the right upper quadrant of the abdomen).
  • Inform patients that skin reactions ranging from mild to severe, including Stevens-Johnson syndrome and TEN, have been reported.

Copyright © 2009 Wolters Kluwer Health.

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