Classes
DEA Class; Rx
Common Brand Names; Symtuza
- HIV, ART Combos
Description
Darunavir: Protease inhibitor; selectively inhibits cleavage of Gag-Pol polyprotein precursors, thereby preventing the formation of mature virus particles
Cobicistat: CYP3A4 inhibitor; mechanism-based pharmaco-enhancer; first product to be developed and submitted solely as pharmacokinetic booster; enhances the systemic exposure of CYP3A substrates (eg, darunavir), where bioavailability is limited and half-life is shortened by CYP3A-dependent metabolism
Emtricitabine: Nucleoside reverse transcriptase inhibitor (NRTI); following phosphorylation, interferes with HIV viral DNA polymerase and inhibits viral replication; cytosine analogue
Tenofovir alafenamide (AF): NRTI prodrug of tenofovir; compared with tenofovir disoproxil fumarate (tenofovir DF, Viread), tenofovir AF is a more targeted form of tenofovir that has demonstrated high antiviral efficacy at a dose that is 10 times lower than tenofovir DF, as well as an improved renal and bone safety profile; inhibits HIV-1 RT by competing with the natural substrate deoxyadenosine 5′-triphosphate and, after incorporation into DNA, by DNA chain termination
Indications
Complete regimen indicated for treatment of HIV-1 infection in adults weighing at least 40 kg who have no prior antiretroviral (ART) treatment history or who are virologically suppressed (HIV-1 RNA <50 copies/mL) on a stable ART regimen for at least 6 months and have no known substitutions associated with resistance to darunavir or tenofovir
Contraindications
Coadministration of the following drugs due to the potential for serious and/or life-threatening events or loss of therapeutic effect
- Alpha 1-adrenoreceptor antagonist: Alfuzosin
- Anticonvulsants: Carbamazepine, phenobarbital, phenytoin
- Anti-gout: Colchicine, in patients with renal and/or hepatic impairment
- Antimycobacterial: Rifampin
- Antipsychotics: Lurasidone, pimozide
- Cardiac disorders: Dronedarone, ivabradine, ranolazine
- Ergot derivative (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
- Opioid Antagonist: Naloxegol
- PDE-5 inhibitor: Sildenafil for treatment of pulmonary arterial hypertension
- Sedatives/hypnotics: Midazolam PO, triazolam
- CYP3A4 substrates with narrow therapeutic index
Adverse Effects
The following includes all grades unless otherwise specified
- Total cholesterol, Grade 2 (17%)
- LDL cholesterol, Grade 2 (9%)
- Rash (8%)
- Triglycerides, Grade 2 (7%)
- Nausea (6%)
- Elevated glucose levels, Grade 2 (6%)
- LDL cholesterol, Grade 3 (5%)
- Fatigue (4%)
- Creatinine, Grade 2 (4%)
- Headache (3%)
- Abdominal discomfort (2%)
- Flatulence (2%)
- Total cholesterol, Grade 3 (2%)
- Triglycerides, Grade 3 (1%)
- Gastrointestinal disorders: Dyspepsia, pancreatitis (acute), vomiting
- Skin and subcutaneous tissue disorders: Angioedema, pruritus, Stevens-Johnson syndrome
- Metabolism and nutrition disorders: Anorexia, diabetes mellitus, lipodystrophy
- Reproductive system and breast disorders: Gynecomastia
- Musculoskeletal and connective-tissue disorders: Myalgia, osteonecrosis
- Psychiatric disorders: Abnormal dreams
- Immune system disorders: Drug hypersensitivity, immune reconstitution inflammatory syndrome
- Hepatobiliary disorders: Acute hepatitis
Warnings
Severe, acute exacerbation of hepatitis B in patients coinfected with HBV and HIV-1 reported (see Black Box Warnings and Dosing Considerations); test HIV-1 patients for the presence of chronic hepatitis B virus before initiating therapy
Drug-induced hepatitis (eg, acute hepatitis, cytolytic hepatitis) reported in clinical trials with darunavir; patients with preexisting liver dysfunction, including chronic active hepatitis B or C, are at increased risk for liver function abnormalities, including severe hepatic adverse reactions
Rare reports of severe skin reactions, accompanied by fever and/or elevations of transaminases; Stevens-Johnson syndrome, toxic epidermal necrolysis, drug rash with eosinophilia and systemic symptoms, and acute generalized exanthematous pustulosis have been reported
Immune reconstitution syndrome reported in patients treated with combination antiretroviral therapy; autoimmune disorders (such as Graves’ disease, polymyositis, Guillain-Barré syndrome, and autoimmune hepatitis) reported
Postmarketing cases of renal impairment, including acute renal failure, proximal renal tubulopathy (PRT), and Fanconi syndrome (renal tubular injury with severe hypophosphatemia), reported with use of tenofovir prodrugs
Darunavir contains a sulfonamide moiety; monitor patients with a known sulfonamide allergy after initiating
Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, reported with the use of nucleoside analogs, including emtricitabine
New-onset diabetes mellitus, exacerbation of preexisting diabetes mellitus, and hyperglycemia reported during postmarketing surveillance in HIV-infected patients receiving HIV protease inhibitor therapy
Redistribution/accumulation of body fat, including central obesity, dorsocervical fat enlargement (buffalo hump), peripheral wasting, facial wasting, breast enlargement, and cushingoid appearance, observed in patients receiving ARTs
Reports of increased bleeding, including spontaneous skin hematomas and hemarthrosis in patients with hemophilia type A and B treated with HIV protease inhibitors
Pregnancy and Lactation
Not recommended during pregnancy because of substantially lower exposures of darunavir and cobicistat during pregnancy
The CDC recommends that HIV-infected mothers in the United States are not to breastfeed their infants to avoid risking postnatal HIV-1 infection transmission
Maximum Dosage
1 tablet (ie, darunavir 800 mg/cobicistat 150 mg/emtricitabine 200 mg/tenofovir AF 10 mg) PO qDay
How supplied
darunavir/cobicistat/emtricitabine/tenofovir AF (tenofovir alafenamide)
tablet
- 800mg/150mg/200mg/10mg