darunavir/cobicistat

General

Genetic Implications: Genetic Implications

Pronunciation:
da-roo-na-veer/koe-bik-i-stat/


Trade Name(s)

  • Prezcobix

Ther. Class.
antiretrovirals
pharmacoenhancers

Pharm. Class.
protease inhibitors
enzyme inhibitors

Indications

Treatment of HIV–1 infection in combination with other agents in patients who have no darunavir resistance.

Action

  • Darunavir–Inhibits HIV-1 protease, selectively inhibiting the cleavage of HIV-encoded specific polyproteins in infected cells. This prevents the formation of mature virus particles.
  • Genetic implicationCobicistat–Strongly inhibits CYP3A enzymes, enhancing systemic exposure to darunavir.

Therapeutic Effect(s):

Increased CD4 cell counts and decreased viral load with subsequent slowed progression of HIV infection and its sequelae.

Pharmacokinetics

Darunavir

Absorption: Food enhances oral absorption.

Distribution: Unknown.

Protein Binding: 95% bound to plasma proteins.

Metabolism and Excretion: Extensively metabolized by CYP3A enzyme system. 41% eliminated unchanged in feces, 8% in urine.

Half-life: 15 hr.

Cobicistat

Absorption: Absorption follows oral administration.

Distribution: Unknown.

Protein Binding: 97–98%.

Metabolism and Excretion: Metabolized by CYP3A and to a small extent by CYP2D6; 86.2 eliminated in feces, 8.2% in urine.

Half-life: 3–4 hr.

TIME/ACTION PROFILE

ROUTEONSETPEAKDURATION
darunavir unknown2.5–4 hr12 hr
cobicistat unknown3 hr24 hr

Contraindication/Precautions

Contraindicated in:

  • Concurrent use of other drugs for which changes in blood levels are associated with serious toxicity or loss of effectiveness;
  • Concurrent alfuzosin, dronedarone, colchicine (in renal/hepatic impairment), elbasvir/grazoprevir, ergot derivatives, lovastatin, lurasidone, midazolam (PO), pimozide, ranolazine, rifampin, sildenafil (Revatio), simvastatin, triazolam, or St. John's wort;
  • Concurrent alfuzosin, dronedarone, colchicine (in renal/hepatic impairment), elbasvir/grazoprevir, ergot derivatives, lovastatin, lurasidone, midazolam (PO), pimozide, ranolazine, rifampin, sildenafil (Revatio), simvastatin, triazolam, or St. John's wort;
  • Lactation: HIV may be transmitted in human milk, breastfeeding is not recommended.

Use Cautiously in:

  • Hepatic impairment;
  • Sulfonamide allergy;
  • Geri: Consider age-related impairment in hepatic function, concurrent chronic disease states and drug therapy;
  • OB: Use only if maternal benefit outweighs fetal risk;
  • Pedi: Safe and effective use in children <18 yr has not been established.

Adverse Reactions/Side Effects

CNS: headache

GI: HEPATOTOXICITY, abdominal pain, diarrhea, nausea, vomiting

Derm: STEVENS-JOHNSON SYNDROME, rash

Endo: hyperglycemia

Misc: redistribution of body fat

* CAPITALS indicate life-threatening.
Underline indicate most frequent.

Interactions

Drug-Drug

  • ↑ blood levels and risk of toxicity from alfuzosin, dronedarone, elbasvir/grazoprevir, ergot derivatives (dihydroergotamine, ergotamine, methylergonovine), lovastatin, lurasidone, midazolam (oral), pimozide, ranolazine, sildenafil (Revatio), simvastatin, and triazolam; concurrent use contraindicated.
  • Rifampin ↑ metabolism and may ↓ antiretroviral effectiveness, concurrent use is contraindicated.
  • ↑ levels and risk of myopathy from atorvastatin, fluvastatin, pitavastatin, pravastatin, or rosuvastatin; use lowest dose of these agents; do not exceed atorvastatin or rosuvastatin dose of 20 mg/day.
  • Concurrent use with indinavir in a regimen containing atazanavir ↑ risk of hyperbilirubinemia and is contraindicated.
  • Concurrent use of more than one antiretroviral that requires another agent to ↑ blood levels, such as two protease inhibitors or a protease inhibitor in conjunction with elvitegravir may ↓ antiretroviral effectiveness; concurrent use is not recommended.
  • Concurrent use of darunavir with efavirenz, nevirapine, or etravirine may ↓ antiretroviral effectiveness and ↑ risk of resistance; concurrent use is not recommended.
  • Concurrent use of darunavir at a dose of 600 mg twice daily may ↓ antiretroviral effectiveness and ↑ risk of resistance; concurrent use at that dose is not recommended.
  • Concurrent use of other protease inhibitors, including fosamprenavir, saquinavir, tipranavir may ↓ antiretroviral effectiveness and ↑ risk of resistance; concurrent use is not recommended.
  • Should not be used concurrently with other cobicistat-containing fixed-dose combinations or ritonavir-containing regimens or fixed-dose combinationsdue to cumulative effects on CYP3A.
  • ↑ levels of maraviroc(when used concurrently ↓ maraviroc dose to 150 mg twice daily).
  • ↑ level/risk of toxicity/adverse reactions with antiarrhythmics including amiodarone, digoxin, disopyrramide, flecainide, mexiletine, propafenone, and quindine; careful monitoring and titration is recommended.
  • Clarithromycin and erythromycin may ↑ levels of darunavir and cobicistat; consider alternative anti-infectives.
  • ↑ blood levels/risk of toxicity with dasatinib, nilotinib, vinblastine, and vincristine; careful monitoring for toxicity and dose adjustments recommended.
  • May ↑ bleeding risk with rivaroxaban; avoid concurrent use.
  • May ↑ bleeding risk with dabigatranin patients with renal impairment; avoid concurrent use.
  • Effect on warfarin is not known; monitor INR.
  • Carbamazepine and oxcarbazepine ↓ levels of cobicistat; consider alternative anticonvulsants or antiretroviral.
  • May ↑ levels of clonazepam and carbamazepine; careful anticonvulsant monitoring recommended.
  • May ↑ levels/effects of tricyclic antidepressants and trazodone; careful dosing of antidepressants recommended (effect on SSRIs in unknown).
  • Concurrent use with itraconazole, ketoconazole, and voriconazole may result in ↑ levels of itraconazole and ketoconazole (effect on voriconazole is unknown) and ↑ levels of cobicistat and darunavir; voriconazole use not recommended.
  • ↑ levels/risk of adverse reactions with colchicine; concurrent use in patients with renal/hepatic impairment contraindicated, for others ↓ dose (for gout flare–0.6 mg followed by 0.3 mg one hr later, may repeat no sooner than 3 days, for prophylaxis of flare–if dose was originally 0.6 mg twice daily, decrease to 0.3 mg once daily, if original regimen was 0.6 mg once daily, ↓ to 0.3 mg every other day, treatment of familial Mediterranean fever–daily dose should not exceed 0.6 mg or 0.3 mg twice daily).
  • ↑ levels/effects/risk of adverse reaction including neutropenia and uveitis with rifabutin; lower rifabutin dose to 150 mg every other day.
  • ↑ levels/effects of metoprolol, carvedilol, timolol, or any other beta-blockers metabolized by CYP2D6; clinical monitoring recommended.
  • ↑ levels/effects of amlodipine, diltiazem, felodipine, nifedipine, verapamil, or any other calcium channel blocker metabolized by CYP3A; careful monitoring recommended.
  • Dexamethasone may ↓ levels/effects; consider use of alternative corticosteroid, such as beclomethasone or prednisolone.
  • May ↑ levels of systemic, inhaled, nasal, or ophthalmic corticosteroids (betamethasone, budesonide, ciclesonide, dexamethasone, fluticasone, methylprednisolone, mometasone, prednisone, or triamcinolone; consider alternative corticosteroid such as beclomethasone or prednisolone.
  • Concurrent use with bosentan may result in ↑ levels/toxicity of bosentan and ↓ levels darunavir and cobicistat; dose alteration is required (initiating bosentan in patients already receiving cobicistat with darunavir for 10 days or more–bosentan 62.5 mg daily or every other day, depending on toleranceinitiating cobicistat with darunavir in patient already receiving bosentan –discontinue bosentan for 10 days, resume bosentan at 62.5 mg daily or every other day, depending on tolerance).
  • H2-receptor antagonists including famotidine may decrease levels/effectiveness and ↑ risk of resistance; administer simultaneously or at least 10 hr after H2–receptor antagonist (dose of H2–receptor antagonist should not exceed famotidine 40 mg [or equivalent] twice daily in treatment-naïve patients or famotidine 20 mg [or equivalent] twice daily in treatment-experienced patients.
  • ↑ levels/risk of toxicity from immunosuppressants metabolized by CYP3A including cyclosporine, everolimus, sirolimus, and tacrolimus; therapeutic monitoring recommended.
  • ↑ levels of salmeterol and may ↑risk of serious adverse cardiovascular events; concurrent use is not recommended.
  • May ↑ levels/risk of respiratory depression with opioids including buprenorphine, buprenorphine/naloxone, fentanyl, and tramadol; carefully monitor opioid effects when cobicistat with darunavir is initiated, dose adjustment of opioid may be necessary.
  • May ↑ levels/effects of neuroleptics that are metabolized by CYP3A or CYP2D6 including perphenazine, risperidone, and thioridazine; ↓ dose of neuroleptic may be necessary.
  • May ↑ levels and risk of adverse cardiovascular, ophthalmic and genitourinary effects of PDE-5 inhibitors including avanafil, sildenafil, tadalafil, and vardenafilavanafil use is not recommended, sildenafil –use for pulmonary hypertension is contraindicated, when used for erectile dysfunction single dose should not exceed 25 mg/48 hr, tadalafil –for pulmonary hypertension-initiating tadalafil in patients receiving cobicistat with atazanavir and darunavir for at least 7 days– 20 mg once daily initially, may be titrated to 40 mg once daily, initiating cobicistat with darunavir in patients receiving tadalafil– discontinue tadalafil 24 hr prior to initiating cobicistat with darunavir, after 7 days reinstitute tadalafil at 20 mg once daily, may be increased to 40 mg once daily, for erectile dysfunction single dose should not exceed 10 mg/72 hrvardenafil–for erectile dysfunction single dose should not exceed 2.5 mg/72 hr.
  • Proton-pump inhibitors including omeprazole ↓ levels/effectiveness and ↑risk of resistance; in treatment–naïve patients, administer cobicistat with darunavir at least 12 hr after proton-pump inhibitors, dose of proton-pump inhibitor should not exceed omeprazole 20 mg daily or equivalent, in treatment-experienced patients concurrent use with proton-pump inhibitors is not recommended.
  • ↑ levels/ effects and risk of excess sedation/respiratory depression from some sedative/hypnotics metabolized by CYP3A including buspirone, diazepam, and parenteral midazolam; concurrent use with oral midazolam is contraindicated, concurrent with other sedative/hypnotics metabolized by CYP3A should be undertaken with caution, dose reduction may be necessary.
  • Effects are unknown with artemether/lumefantrine; monitor for ↓ antimalarial activity or QT prolongation.
  • Rifapentine↓ darunavir levels; concurrent use is not recommended.
  • Didanosine should be administered 1 hr before or 2 hr after darunavir/cobicistat.
  • May ↑ levels of quetiapine; if taking quetiapine when initiating therapy, consider alternative antiretroviral therapy or ↓ quetiapine dose to 1/6 of the original dose and monitor for adverse effects.
  • ↑ risk of hyperkalemia from drosperinone/ethinyl estradiol when used in a regimen containing atazanavir and cobicistat; concurrent use contraindicated.
  • May ↑ ticagrelor levels; concurrent use not recommended.

Drug-Natural Products:

St. John's wort may ↓ blood levels and antiretroviral effectiveness; concurrent use is contraindicated.

Route/Dosage

PO: (Adults)One tablet (darunavir 800 mg/cobicistat 150 mg) once daily.

Availability

Tablets: darunavir 800 mg/cobicistat 150 mg

Assessment

  • Assess patient for change in severity of HIV symptoms and for symptoms of opportunistic infections during therapy.
  • Assess for allergy to sulfonamides.
  • Monitor patient for development of rash; usually maculopapular and self-limited during first 4 wk. May cause Stevens-Johnson syndrome or toxic epidermal necrolysis. Discontinue therapy if severe or if accompanied with fever, general malaise, fatigue, muscle or joint aches, blisters, oral lesions, conjunctivitis, hepatitis, and/or eosinophilia.

Lab Test Considerations:

Genetic implicationObtain HIV genotypic testing for antiretroviral treatment experienced patients prior to starting therapy.

  • Monitor viral load and CD4 counts regularly during therapy.
  • May cause ↑ serum AST, ALT, GGT, total bilirubin, alkaline phosphatase, pancreatic amylase, pancreatic lipase, triglycerides, total cholesterol, and uric acid concentrations. Monitor hepatic function prior to and periodically during therapy. Hepatotoxicity may require interruption or discontinuation of therapy.
  • Assess CCr before starting therapy.
  • If administered with tenofovir, assess urine glucose and urine protein at baseline and monitor CCr, urine glucose, and urine protein. Monitor serum phosphorus in patients with or at risk for renal impairment

Potential Diagnoses

Implementation

  • PO: Administer once daily with food.

Patient/Family Teaching

  • Explain purpose of cobicistat/darunavir (Prezcobix) to patient; must be taken with other antiretroviral medications. Instruct patient to take Prezcobix as directed with food. Take missed doses as soon as remembered if within 12 hr; if more than 12 hr, skip dose and take next dose as scheduled; do not double doses. Do not stop taking Prezcobix without consulting health care professional. Advise patient to read Patient Information prior to starting therapy and with each Rx refill in case of change.
  • Instruct patient that Prezcobix should not be shared with others.
  • Instruct patient to notify health care professional of all Rx or OTC medications, vitamins, or herbal products being taken and consult health care professional before taking any new medications, especially St. John's Wort.
  • Inform patient that Prezcobix does not cure AIDS or prevent associated or opportunistic infections. Darunavir does not reduce the risk of transmission of HIV to others through sexual contact or blood contamination. Caution patient to use a condom during sexual contact and to avoid sharing needles or donating blood to prevent spreading the AIDS virus to others. Advise patient that the long-term effects of Prezcobix are unknown at this time.
  • Inform patient that Prezcobix may cause hyperglycemia, hepatotoxicity, and severe skin reactions. Advise patient to notify health care professional promptly if signs of hyperglycemia (increased thirst or hunger; unexplained weight loss; increased urination; fatigue; or dry, itchy skin), immune reconstitution syndrome (signs and symptoms of inflammation from previous infections [Mycobacterium avium infection, cytomegalovirus, Pneumocystis jirovecii pneumonia [PCP, or tuberculosis]), hepatotoxicity (unexplained fatigue, anorexia, nausea, jaundice, abdominal pain, or dark urine), or rash occur.
  • Inform patient that redistribution and accumulation of body fat may occur, causing central obesity, dorsocervical fat enlargement (buffalo hump), peripheral wasting, breast enlargement, and cushingoid appearance. The cause and long-term effects are not known.
  • Rep: Instruct females using hormonal contraceptives to use an alternative nonhormonal method of contraception. Advise patient to notify health care professional if pregnancy is planned or suspected and to avoid breastfeeding. If pregnant patient is exposed to Prezcobix, register patient in Antiretroviral Pregnancy Registry by calling 1-800-258-4263.
  • Emphasize the importance of regular follow-up exams and blood counts to determine progress and monitor for side effects.

Evaluation/Desired Outcomes

  • Delayed progression of AIDS and decreased opportunistic infections in patients with HIV.
  • Decrease in viral load and improvement in CD4 cell counts.
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