Darunavir

Indications

Darunavir is used for: HIV Infection

Adult Dose

HIV Infection Coadministered with ritonavir and in combination with other antiretroviral agents for HIV infection Treatment-naive or antiretroviral treatment-experienced (with no darunavir resistance associated substitutions): 800 mg + ritonavir 100 mg PO qDay with food Treatment-experienced (with at least 1 DRV mutation) or genotyping not obtained: 600 mg + ritonavir 100 mg PO q12hr with food Pregnant females Recommended: 600 mg + ritonavir 100 mg PO q12hr with food 800 mg + ritonavir 100 mg PO qDay should only be considered in certain pregnant patients who are already on a stable darunavir 800 mg + ritonavir 100 mg qDay regimen prior to pregnancy, are virologically suppressed (ie, HIV-1 RNA <50 copies/mL), and in whom a change to the twice daily regimen may compromise tolerability or compliance

Child Dose

HIV Infection Coadministered with ritonavir and in combination with other antiretroviral agents for HIV infection <3 years or <10 kg: Safety and efficacy not established Treatment-naive or antiretroviral treatment-experienced (with no darunavir resistance associated substitutions) NOTE: The HIV treatment guidelines differ from the prescribing information and recommend that once-daily darunavir dosing should NOT be used as initial therapy in children <12 yr; a switch to once-daily therapy may be considered in patients who have undetectable viral loads on twice-daily therapy to enhance ease of use and support compliance Weight 10 kg to <15 kg Use oral suspension >10 kg to <11 kg: 350 mg (3.6 mL)* + ritonavir 64 mg (0.8 mL) PO qDay >11 kg to <12 kg: 385 mg (4 mL)* + ritonavir 64 mg (0.8 mL) PO qDay >12 kg to <13 kg: 420 mg (4.2 mL) + ritonavir 80 mg (1 mL) PO qDay >13 kg to <14 kg: 455 mg (4.6 mL)* + ritonavir 80 mg (1 mL) PO qDay >14 kg to <15 kg: 490 mg (5 mL)* + ritonavir 96 mg (1.2 ml) PO qDay *NOTE: Doses that were rounded up to nearest measurable suspension dose Weight >15 kg >15 kg to <30 kg: 600 mg + ritonavir 100 mg PO qDay >30 kg to <40 kg: 675 mg + ritonavir 100 mg PO qDay >40 kg: 800 mg + ritonavir 100 mg PO qDay Antiretroviral treatment-experienced with at least 1 darunavir resistance associated substitution Weight 10 kg to <15 kg Use oral suspension >10 kg to <11 kg: 200 mg (2 mL) + ritonavir 32 mg (0.4 mL) PO BID >11 kg to <12 kg: 220 mg (2.2 mL) + ritonavir 40 mg (0.4 mL) PO BID >12 kg to <13 kg: 240 mg (2.4 mL) + ritonavir 32 mg (0.5 mL) PO BID >13 kg to <14 kg: 260 mg (2.6 mL) + ritonavir 40 mg (0.5 mL) PO BID >14 kg to <15 kg: 280 mg (2.8 mL) + ritonavir 48 mg (0.6 mL) PO BID Weight >15 kg >15 kg to <30 kg: 375 mg + ritonavir 48 mg PO BID >30 kg to <40 kg: 450 mg + ritonavir 60 mg PO BID >40 kg: 600 mg + ritonavir 100 mg PO BID

Renal Dose

Renal impairment Mild-to-moderate (> 30 mL/min): No dosage adjustment required Severe (< 30 mL/min): Data not available, but renal clearance is limited and decreased total body clearance not expected

Administration

Swallow tablet whole; do not chew, crush, or split Must take with food; food increases the area under the curve (AUC) and maximum plasma concentration (Cmax) by 30% Assess ability to swallow; use oral suspension for adults or children who cannot swallow the tablet whole

Contra Indications

Hypersensitivity

Precautions

Must be taken with ritonavir and food, since dose is based on the fact that darunavir is metabolized by CYP3A4 and ritonavir is a potent CYP3A4 inhibitor Severe skin reactions, accompanied by fever and/or elevations of transaminases reported (0.4%); Stevens-Johnson Syndrome (<0.1%), toxic epidermal necrolysis, drug rash with eosinophilia and systemic symptoms, and acute generalized exanthematous pustulosis also reported Caution with elderly patients Caution with hepatic impairment (not recommended if severe) Contains a sulfa moiety; monitor patients with a known sulfonamide allergy Increase in total cholesterol and triglycerides reported; screen before therapy and throughout treatment Pancreatitis reported; use caution in patients at risk for pancreatitis (those with elevated triglycerids, history of pancreatitis, or advanced HIV disease Risk of immune reconstitution syndrome 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 Patients may develop new onset diabetes mellitus or hyperglycemia; initiation or dose adjustments of insulin or oral hypoglycemic agents may be required Patients with hemophilia may develop increased bleeding events Not for use in patients < 3 years of age; toxicity may occur Hepatoxicity Risk of hepatotoxicity including drug induced hepatitis: acute hepatitis, cytolytic hepatitis Especially with preexisting liver dysfunction (chronic hepatitis B or C) Interrupt or discontinue treatment if new/worsening liver dysfunction develops

Pregnancy-Lactation

Pregnancy: The recommended dosage in pregnant patients is 600 mg taken with ritonavir 100 mg twice daily with food; darunavir 800 mg taken with ritonavir 100 mg once daily should only be considered in certain pregnant patients who are already on a stable darunavir 800 mg with ritonavir 100 mg once daily regimen prior to pregnancy, are virologically suppressed (HIV-1 RNA less than 50 copies per mL), and in whom a change to twice daily darunavir 600 mg with ritonavir 100 mg may compromise tolerability or compliance Use of darunavir may reduce the efficacy of combined hormonal contraceptives and the progestin only pill; advise patients using combined hormonal contraceptives or the progestin only pill to use an effective alternative contraceptive method or add a barrier method of contraception; for co-administration with drospirenone, clinical monitoring recommended due to potential for hyperkalemia Lactation: The Centers for Disease Control and Prevention recommend that HIV-infected mothers not breastfeed their infants to avoid risking postnatal transmission of HIV There are no data on the presence of darunavir in human milk, the effects on the breastfed infant, or the effects on milk production; because of the potential for (1) HIV transmission (in HIV-negative infants), (2) developing viral resistance (in HIV-positive infants) and (3) serious adverse reactions in a breastfed infant, instruct mothers not to breastfeed if they are receiving darunavir

Interactions

Adverse Effects

Side effects of Darunavir : >10% Increased total cholesterol (10-25%) Increased triglycerides (3-10%) 1-10% Diarrhea (9%) Headache (7%) Rash (6%) Abdominal pain (6%) Nausea (4%) Vomiting (2%) Anorexia (2%) <1% Fatigue Frequency Not Defined Gastrointestinal disorders: Acute pancreatitis, dyspepsia, flatulence General disorders and administration site Conditions: Asthenia Hepatobiliary disorders: Acute hepatitis (eg, cytolytic hepatitis, hepatotoxicity) Immune dystem disorders: Hypersensitivity, immune reconstitution syndrome Metabolism and nutrition disorders: Diabetes mellitus/hyperglycemia, fat distribution Musculoskeletal and connective tissue disorders: Myalgia, osteonecrosis Psychiatric disorders: Abnormal dreams Skin and subcutaneous tissue disorders: Angioedema, pruritus, Stevens-Johnson Syndrome, urticaria

Mechanism of Action

Protease Inhibitor; inhibits cleavage of Gag-Pol polyprotein precursors, which in turn causes the formation of immature, noninfectious viral particles.