darunavir/cobicistat

da-ROO-na-veer/koe-BIK-i-stat/

Therapeutic Classification: antiretrovirals, pharmacoenhancers

Pharmacologic Classification: protease inhibitors, enzyme inhibitors

REMS

HIV–1 infection in patients who have no darunavir resistance (in combination with other antiretroviral agents) .

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.
Cobicistat: Strongly inhibits CYP3A enzymes, enhancing systemic exposure to darunavir.

Therapeutic effects:

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

Darunavir

Absorption: Food enhances oral absorption.

Distribution: Unknown.

Protein Binding: 95% bound to plasma proteins.

Metabolism/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/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.

ROUTE	ONSET	PEAK	DURATION
darunavir	unknown	2.5–4 hr	12 hr
cobicistat	unknown	3 hr	24 hr

Contraindicated in:

Concurrent use of alfuzosin, dronedarone, colchicine (in renal/hepatic impairment), elbasvir/grazoprevir, ergot derivatives, ivabradine, lomitapide, lovastatin, lurasidone, midazolam (PO), naloxegol, pimozide, ranolazine, rifampin, sildenafil (Revatio), simvastatin, triazolam, or St. John's wort;
OB: Not recommended in pregnancy (significantly lower concentrations of darunavir and cobicistat during 2nd and 3rd trimesters);
Lactation: Breastfeeding not recommended in mothers with HIV.

Use Cautiously in:

Hepatic impairment;
Sulfonamide allergy;
Pedi: Children <40 kg (safety and effectiveness not established);
Geri: Consider age-related impairment in hepatic function, concurrent chronic disease states and drug therapy in older adults.

Derm: rash, STEVENS-JOHNSON SYNDROME

Endo: Graves' disease, hyperglycemia

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

MS: polymyositis

Neuro: Guillain-Barré syndrome, headache

Misc: immune reconstitution syndrome, redistribution of body fat

Drug-drug:

↑blood levels and risk of toxicity from alfuzosin, dronedarone, elbasvir/grazoprevir, ergot derivatives (dihydroergotamine, ergotamine, methylergonovine), ivabradine, lomitapide, lovastatin, lurasidone, midazolam (oral), pimozide, ranolazine, sildenafil (Revatio), simvastatin, and triazolam; concurrent use contraindicated.
May ↑ naloxegol levels which can precipitate opioid withdrawal symptoms; 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 of more than one antiretroviral that requires another agent to ↑ blood levels, such as two protease inhibitors 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, 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, disopyramide, 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 apixaban, dabigatran, edoxabanrivaroxaban; concurrent use with rivaroxaban not recommended.
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).
May ↑ levels of ketoconazole, isavuconazole, and itraconazole; effect on voriconazole unknown; concurrent use with voriconazole not recommended.
Ketoconazole, isavuconazole, itraconazole, and posaconazolemay ↑ levels.
↑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 corticosteroids (all routes of administration) primarily metabolized by the CYP3A isoenzyme (e.g. betamethasone, budesonide, ciclesonide, fluticasone, methylprednisolone, mometasone, or triamcinolone which may ↑ the risk of Cushing's disease and adrenal suppression; consider alternative corticosteroid such as beclomethasone, prednisone, 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 tolerance; initiating 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 ↓ 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.
May ↑ levels of irinotecan; discontinue darunavir/cobicistat ≥1 week before starting irinotecan therapy.
↑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 vardenafil; avanafil 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 hr; vardenafil: 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.
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.
May ↓ levels and contraceptive efficacy of some combined hormonal contraceptives (additional or alternative methods of nonhormonal contraception recommended).
May ↑ risk of hyperkalemia when used with drospirenone.
May ↑ levels of glecaprevir/pibrentasvir; concurrent use not recommended.
May ↑ ticagrelor levels and risk of bleeding; concurrent use not recommended.
May ↓ antiplatelet effects of clopidogrel; concurrent use not recommended.
May ↑ fesoterodine and solifenacin levels; should not exceed fesoterodine dose of 4 mg once daily or solifenacin dose of 5 mg once daily.

Drug-Natural Products:

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

PO (Adults and Children ≥40 kg): One tablet (darunavir 800 mg/cobicistat 150 mg) once daily.

Tablets: darunavir 800 mg/cobicistat 150 mg

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:

Obtain 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

PO: Administer once daily with food with other antiviral agents.

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 may 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.
Advise patient to notify health care professional if signs and symptoms of immune reconstitution syndrome (signs and symptoms of an infection) occur.
Rep: Instruct females of reproductive potential 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 to monitor pregnancy outcomes.
Emphasize the importance of regular follow-up exams and blood counts to determine progress and monitor for side effects.

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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