darunavir (Rx)

Brand and Other Names:Prezista
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Dosing & Uses

AdultPediatric

Dosage Forms & Strengths

tablet

  • 75mg
  • 150mg
  • 400mg
  • 600mg
  • 800mg

oral suspension

  • 100mg/mL

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

Dosage Modifications

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

Hepatic impairment

  • Mild-to-moderate impairment (Child-Pugh class A or B): No dosage adjustment required
  • Severe (Child-Pugh class C): Not recommended

Dosing Considerations

In treatment-experienced patients, treatment history, genotypic and/or phenotypic testing is recommended to assess drug susceptibility of the HIV-1 virus

Obtain appropriate laboratory testing (eg, serum liver biochemistries) before initiating darunavir

Patients with underlying chronic hepatitis, cirrhosis, or those who have pretreatment liver enzyme should be monitored for elevated transaminases, especially during the first several months

Dosage Forms & Strengths

tablet

  • 75mg
  • 150mg
  • 400mg
  • 600mg
  • 800mg

oral suspension

  • 100mg/mL

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

Must take with food

Also see Administration

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
    • &ge:30 kg to <40 kg: 450 mg + ritonavir 60 mg PO BID
    • ≥40 kg: 600 mg + ritonavir 100 mg PO BID

Dosage Modifications

Renal impairment

  • Mild-to-moderate: No dosage adjustment required
  • Severe: Data not available, but renal clearance is limited and decreased total body clearance not expected

Hepatic impairment

  • Mild-to-moderate impairment: No dosage adjustment required
  • Severe: Not recommended

Dosing Considerations

In treatment-experienced patients, treatment history, genotypic and/or phenotypic testing is recommended to assess drug susceptibility of the HIV-1 virus

Administer BID only in patients with at least 1 darunavir-associated mutation (eg, V11I, V32I, L33F, I47V, I50V, I54L, I54M, T74P, L76V, I84V, and L89V)

Obtain appropriate laboratory testing (eg, serum liver biochemistries) before initiating darunavir

Patients with underlying chronic hepatitis, cirrhosis, or those who have pretreatment liver enzyme should be monitored for elevated transaminases, especially during the first several months

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Interactions

Interaction Checker

and darunavir

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            Adverse Effects

            >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

            Postmarketing Reports

            Body fat redistribution

            Rhabdomyolysis (associated with statin coadministration)

            Toxic epidermal necrolysis and acute generalized exanthematous pustulosis

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            Warnings

            Contraindications

            Hypersensitivity

            Coadministration of darunavir/ritonavir

            • Concomitant CYP3A4 substrates that are toxic in excess
            • Concurrent strong CYP3A4 inducers (eg, St John's wort, rifampin)
            • Alpha-1 antagonist: Alfuzosin
            • Cardiovascular agents: Ranolazine, ivabradine, dronedarone
            • Antigout: Colchicine (in patients with renal/and or hepatic impairment)
            • Antimycobacterial: Rifampin
            • Antipsychotics: Lurasidone, pimozide
            • Ergot derivatives (eg, dihydroergotamine, ergotamine, methylergonovine)
            • GI motility agent: Cisapride
            • Herbal product: St. John’s wort (Hypericum perforatum)
            • Hepatitis C direct acting antiviral: Elbasvir/grazoprevir
            • Lipid modifying agents: Lomitapide, lovastatin, simvastatin
            • PDE-5 inhibitor: Sildenafil (used for treatment of pulmonary arterial hypertension)
            • Sedatives/hypnotics: PO midazolam, triazolam
            • Opioid antagonist: Naloxegol

            Cautions

            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
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            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

            Pregnancy Categories

            A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

            B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

            C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

            D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

            X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

            NA: Information not available.

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            Pharmacology

            Mechanism of Action

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

            Pharmacokinetics

            Bioavailability: with ritonavir: 82%; without ritonavir: 37%

            Peak Plasma Time: 2.5-4 hr

            Protein Bound: 95%

            Metabolism: CYP3A4

            Half-life, elimination: 15 hr

            Excretion: Urine (14%) feces (80%)

            Pharmacogenomics

            Genotyping is recommended to determine if darunavir resistance mutations are present in treatment experienced patients

            Increase dose if 1 of the following resistance associated substitutions is present: V11I, V32I, L33F, I47V, I50V, I54L, I54M, T74P, L76V, I84V, and L89V

            Genetic testing laboratories

            • The following companies provide genetic testing for antiretrovirals
            • Monogram Biosciences (http://www.monogrambio.com/200HIVProducts.aspx)
            • Virco (http://www.vircolab.com/)
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            Administration

            Oral 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

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            Formulary

            FormularyPatient Discounts

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            The above information is provided for general informational and educational purposes only. Individual plans may vary and formulary information changes. Contact the applicable plan provider for the most current information.

            Tier Description
            1 This drug is available at the lowest co-pay. Most commonly, these are generic drugs.
            2 This drug is available at a middle level co-pay. Most commonly, these are "preferred" (on formulary) brand drugs.
            3 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs.
            4 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
            5 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
            6 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
            NC NOT COVERED – Drugs that are not covered by the plan.
            Code Definition
            PA Prior Authorization
            Drugs that require prior authorization. This restriction requires that specific clinical criteria be met prior to the approval of the prescription.
            QL Quantity Limits
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