darunavir/cobicistat/emtricitabine/tenofovir alafenamide

Darunavir

Absorption: Food enhances oral absorption.

Distribution: Unknown.

Protein Binding: 95%.

Metabolism/Excretion: Extensively metabolized by the liver via the CYP3A isoenzyme; 41% excreted unchanged in feces, 8% in urine.

Half-Life: 9.4 hr.

Cobicistat

Absorption: Absorption follows oral administration.

Distribution: Unknown.

Protein Binding: 97–98%.

Metabolism/Excretion: Metabolized by the liver primarily by the CYP3A isoenzyme and to a lesser extent by the CYP2D6 isoenzyme; 86.2% excreted in feces, 8.2% in urine.

Half-Life: 3.2 hr.

Emtricitabine

Absorption: 93% absorbed following oral administration.

Distribution: Unknown.

Metabolism/Excretion: Not significantly metabolized; 86% excreted in urine, 14% in feces.

Half-Life: 7.5 hr.

Tenofovir Alafenamide

Absorption: Tenofovir alafenamide is a prodrug, which is hydrolyzed into tenofovir, the active component; absorption enhanced by high-fat meals.

Distribution: Unknown.

Metabolism/Excretion: Tenofovir is phosphorylated to tenofovir diphosphate (active metabolite); 32% excreted in feces, <1% in urine.

Half-Life: 0.5 hr.

Time/Action Profile ⬆ ⬇

(plasma concentrations)

ROUTE	ONSET	PEAK	DURATION
Darunavir (PO)	unknown	3 hr	24 hr
Cobicistat (PO)	unknown	3 hr	24 hr
Emtricitabine (PO)	rapid	1.5 hr	24 hr
Tenofovir (PO)	unknown	0.5 hr	24 hr

Contraind./Precautions ⬆ ⬇

Contraindicated in:

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

Use Cautiously in:

Hepatitis B virus (HBV) or hepatitis C virus infection;
Sulfonamide allergy;
Hemophilia (↑ risk of bleeding);
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.

Adv. Reactions/Side Effects ⬆ ⬇

Derm: rash, ACUTE GENERALIZED EXANTHEMATOUS PUSTULOSIS, DRUG REACTION WITH EOSINOPHILIA AND SYSTEMIC SYMPTOMS (DRESS), STEVENS-JOHNSON SYNDROME (SJS), TOXIC EPIDERMAL NECROLYSIS (TEN)

Endo: Graves' disease, hyperglycemia

GI: abdominal pain, ACUTE EXACERBATION OF HBV, autoimmune hepatitis, diarrhea, flatulence, HEPATOTOXICITY, LACTIC ACIDOSIS/HEPATOMEGALY WITH STEATOSIS, nausea

GU: acute renal failure, Fanconi syndrome, proximal renal tubulopathy

Metab: body fat redistribution, hyperlipidemia

MS: polymyositis

Neuro: Guillain-Barré syndrome, fatigue, headache

Misc: immune reconstitution syndrome

Interactions ⬆ ⬇

Drug-drug:

↑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.
Strong CYP3A4 inducers, including carbamazepine, phenobarbital, phenytoin, and rifampin may ↓ cobicistat, darunavir, and tenofovir levels and their effectiveness; concurrent use contraindicated.
↑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 1 hr later, may repeat no sooner than 3 days, for prophylaxis of gout flare: if dose was originally 0.6 mg twice daily, ↓ to 0.3 mg once daily, if original regimen was 0.6 mg once daily, ↓ to 0.3 mg every other day, for treatment of familial Mediterranean fever: dose should not exceed 0.6 mg once daily or 0.3 mg twice daily).
Clarithromycin and erythromycin may ↑ levels of darunavir and cobicistat; consider alternative anti-infectives.
↑levels/risk of toxicity with dasatinib, nilotinib, vinblastine, and vincristine; careful monitoring for toxicity and dose adjustments recommended.
May ↑ bleeding risk with apixaban and rivaroxaban; may need to adjust apixaban dose; avoid concurrent use with rivaroxaban.
Effect on warfarin is not known; monitor INR.
Oxcarbazepine and eslicarbazepine may ↓ cobicistat and tenofovir levels and their effectiveness; consider alternative anticonvulsant or antiretroviral therapy.
May ↑ levels of clonazepam; careful anticonvulsant monitoring recommended.
May ↑ levels/effects of tricyclic antidepressants and trazodone; careful dosing of antidepressants recommended (effect on SSRIs is unknown).
May ↑ levels of ketoconazole, isavuconazonium, and itraconazole; effect on voriconazole unknown; concurrent use with voriconazole not recommended.
Effects are unknown with artemether/lumefantrine; monitor for ↓ antimalarial activity or QT prolongation.
↑levels/effects/risk of adverse reaction including neutropenia and uveitis with rifabutin; lower rifabutin dose to 150 mg every other day.
Rifapentine↓ darunavir and tenofovir levels; concurrent use not recommended.
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 of quetiapine; if taking quetiapine when initiating therapy, consider alternative antiretroviral therapy or ↓ quetiapine dose to ⅙ of the original dose and monitor for adverse effects.
↑levels/effects of beta blockers metabolized by CYP2D6, including metoprolol, carvedilol, and timolol; clinical monitoring recommended.
↑levels/effects of calcium channel blockers metabolized by CYP3A, including amlodipine, diltiazem, felodipine, nifedipine, or verapamil; careful monitoring recommended.
↑level and risk of toxicity with antiarrhythmics including amiodarone, disopyramide, flecainide, mexiletine, propafenone, and quinidine; careful monitoring and titration is recommended.
May ↑ levels and risk of toxicity with digoxin; closely monitor digoxin levels and adjust dose as needed.
Dexamethasone may ↓ levels of cobicistat and darunavir; consider use of alternative corticosteroid, such as prednisone 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 darunavir/cobicistat/emtricitabine/tenofovir alafenamide for ≥10 days: bosentan 62.5 mg daily or every other day, depending on tolerance; initiating darunavir/cobicistat/emtricitabine/tenofovir alafenamide in patient already receiving bosentan: discontinue bosentan for 10 days, resume bosentan at 62.5 mg daily or every other day, depending on tolerance).
May ↑ levels of glecaprevir/pibrentasvir; concurrent use not recommended.
Nephrotoxic agents, including NSAIDs, ↑ risk of nephrotoxicity; avoid concurrent use.
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.
↑levels and risk of toxicity from immunosuppressants metabolized by CYP3A, including cyclosporine, everolimus, sirolimus, and tacrolimus; therapeutic monitoring recommended.
May ↑ levels of irinotecan; discontinue darunavir/cobicistat/emtricitabine/tenofovir alafenamide ≥1 wk before starting irinotecan therapy.
↑levels of salmeterol and may ↑ risk of serious adverse cardiovascular events; concurrent use is not recommended.
↑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.
May ↑ levels/risk of respiratory depression with opioids, including buprenorphine, buprenorphine/naloxone, fentanyl, oxycodone, and tramadol; carefully monitor for opioid effects, dose adjustment of opioid 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 darunavir/cobicistat/emtricitabine/tenofovir alafenamide for ≥7 days—20 mg once daily initially, may be titrated to 40 mg once daily, initiating darunavir/cobicistat/emtricitabine/tenofovir alafenamide in patients receiving tadalafil—discontinue tadalafil 24 hr prior to initiating therapy, after 7 days reinstitute tadalafil at 20 mg once daily, may be ↑ 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.
May ↑ levels and risk of bleeding with ticagrelor; concurrent use not recommended.
May ↓ antiplatelet effects of clopidogrel; concurrent use 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 with other sedative/hypnotics metabolized by CYP3A should be undertaken with caution; dose ↓ may be necessary.
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 ↓ cobicistat, darunavir, and tenofovir levels and their effectiveness; concurrent use contraindicated.

Route/Dosage ⬆ ⬇

PO (Adults and Children ≥40 kg): One tablet (darunavir 800 mg/cobicistat 150 mg/emtricitabine 200 mg/tenofovir alafenamide 10 mg) once daily.

Availability ⬆ ⬇

Tablets: darunavir 800 mg/cobicistat 150 mg/emtricitabine 200 mg/tenofovir alafenamide 10 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 for development of rash. May cause SJS or TEN. 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:

Monitor viral load and CD4 count before and routinely during therapy to determine response.
- Assess for HBV. Symtuza is not approved for administration in patients with HIV and HBV. If therapy is discontinued, may cause severe exacerbation of HBV. Monitor liver function in coinfected patients for several mo after stopping therapy.
- Monitor liver function tests prior to, during, and following therapy. May cause ↑ LDL cholesterol, total cholesterol, and triglyceride concentrations. Lactic acidosis may occur with hepatic toxicity causing hepatic steatosis; may be fatal, especially in women. Discontinue therapy if symptoms occur.
- Monitor serum creatinine, CCr, urine glucose, and urine protein prior to and periodically during therapy and when clinically indicated. In patients with chronic kidney disease, assess serum creatinine, creatinine clearance, serum phosphorus, urine glucose, and urine protein prior to and periodically during therapy. May cause hypophosphatemia in patients with renal impairment.
- May cause hyperglycemia and glycosuria.

Implementation ⬆ ⬇

PO: Administer once daily with food. For patients who are unable to swallow the whole tablet, may be split into two pieces using a tablet cutter, and consume entire dose immediately after splitting.

Patient/Family Teaching ⬆ ⬇

Instruct patient on the importance of taking medication as directed, even if feeling better. Do not take more than prescribed amount and do not stop taking without consulting health care professional. Discontinuing therapy may lead to severe exacerbations. Take missed doses as soon as remembered unless almost time for next dose; do not double doses. Advise patient to read Patient Information prior to starting therapy and with each Rx refill in case of changes. Caution patient not to share or trade Symtuza with others.
Inform patient of importance of HBV testing before starting antiretroviral therapy.
Inform patient that Symtuza does not cure AIDS and may reduce the risk of transmission of HIV to others through sexual contact or blood contamination. Caution patient to use a condom and avoid sharing needles or donating blood to prevent spreading HIV to others.
Advise patient to notify health care professional immediately if symptoms of lactic acidosis (nausea, vomiting, unusual or unexpected stomach discomfort, unusual muscle pain, difficulty breathing, feeling cold, especially in arms and legs, dizziness, fast or irregular heartbeat, and weakness or tiredness), liver problems (yellow skin or whites of eyes, dark urine, light colored stools, loss of appetite, nausea, stomach pain), or signs of immune reconstitution syndrome (signs and symptoms of an infection or inflammation) occur.
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 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: Advise females of reproductive potential to notify health care professional if pregnancy is planned or suspected. Encourage pregnant women to enroll in the Antiretroviral Pregnancy Registry by calling 1-800-258-4263 to monitor pregnancy outcomes. Advise female patient that pregnancy is not recommended during Symtuza and avoid breastfeeding during therapy.
Emphasize the importance of regular follow-up exams and blood counts to determine progress and monitor for side effects.

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Pronunciation ⬇

Classifications ⬆ ⬇

Indications ⬆ ⬇

Action ⬆ ⬇

Pharmacokinetics ⬆ ⬇

Time/Action Profile ⬆ ⬇

Contraind./Precautions ⬆ ⬇

Adv. Reactions/Side Effects ⬆ ⬇

Interactions ⬆ ⬇

Route/Dosage ⬆ ⬇

Availability ⬆ ⬇

Assessment ⬆ ⬇

Implementation ⬆ ⬇

Patient/Family Teaching ⬆ ⬇

Evaluation/Desired Outcomes ⬆ ⬇

US Brand Names ⬆