darunavir/cobicistat/emtricitabine/tenofovir alafenamide

General

Genetic Implications: Genetic Implications

Pronunciation:
da-roo-na-veer/koe-bik-i-stat/em-tri-si-ti-been/te-noe-fo-veer al-a-fen-a-mide


Trade Name(s)

  • Symtuza

Ther. Class.

antiretrovirals

pharmacoenhancers

Pharm. Class.

protease inhibitors

enzyme inhibitors

nucleoside reverse transcriptase inhibitors

Indications

HIV-1 infection in patients who have no prior antiretroviral treatment history or who are virologically suppressed (HIV-1 RNA <50 copies/mL) on a stable antiretroviral regimen for ≥6 mo and have no known substitutions associated with resistance to darunavir or tenofovir.

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.  Cobicistat:  Strongly inhibits CYP3A enzymes, enhancing systemic exposure to darunavir.  Emtricitabine:  Phosphorylated intracellularly, where it inhibits HIV reverse transcriptase, resulting in viral DNA chain termination.  Tenofovir alafenamide:  Phosphorylated intracellularly, where it inhibits HIV reverse transcriptase, resulting in disruption of DNA synthesis.

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%.

Metabolism and 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 and 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 and 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 and 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)

ROUTEONSETPEAKDURATION
Darunavir (PO)unknown3 hr24 hr
Cobicistat (PO)unknown3 hr24 hr
Emtricitabine (PO)rapid1.5 hr 24 hr
Tenofovir (PO)unknown0.5 hr24 hr

Contraindication/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:

  • Black Box:  Chronic hepatitis B virus (HBV) infection (may exacerbate following discontinuation);
  • Sulfonamide allergy;
  • Hemophilia (↑ risk of bleeding);
  • Pedi:  Children <40 kg (safety and effectiveness not established);
  • Geri:  Consider age-related impairment in hepatic function and concurrent chronic disease states and drug therapy in older adults.

Adverse 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

Metabolic: body fat redistribution, hyperlipidemia

MS: polymyositis

Neuro: Guillain-Barré syndrome, fatigue, headache

Misc: immune reconstitution syndrome

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

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 ↓ levels and effectiveness of cobicistat, darunavir, and tenofovir; concurrent use contraindicated.
  • May ↑ levels and risk of toxicity of  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:  not to exceed 0.6 mg once daily or 0.3 mg twice daily).
  •  Clarithromycin  and  erythromycin  may ↑ levels and risk of toxicity of darunavir and cobicistat; consider alternative anti-infectives.
  • May ↑ levels and risk of toxicity of  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 ↓ levels and effectiveness of cobicistat and tenofovir; consider alternative anticonvulsant or antiretroviral therapy.
  • May ↑ levels and risk of toxicity of  clonazepam ; careful anticonvulsant monitoring recommended.
  • May ↑ levels and risk of toxicity of  tricyclic antidepressants  and  trazodone ; careful dosing of antidepressants recommended (effect on  SSRIs  is unknown).
  • May ↑ levels and risk of toxicity 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 interval prolongation.
  • May ↑ levels and risk of toxicity of  rifabutin ; ↓ rifabutin dose to 150 mg every other day.
  •  Rifapentine  may ↓ levels and effectiveness of darunavir and tenofovir; concurrent use not recommended.
  • May ↑ levels and risk of toxicity of  neuroleptics metabolized by CYP3A or CYP2D6, including  perphenazine,  risperidone, and  thioridazine ; ↓ dose of neuroleptic may be necessary.
  • May ↑ levels and risk of toxicity 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.
  • May ↑ levels and risk of toxicity of  beta blockers metabolized by CYP2D6, including  metoprolol,  carvedilol, and  timolol ; clinical monitoring recommended.
  • May ↑ levels and risk of toxicity of  calcium channel blockers metabolized by CYP3A, including  amlodipine,  diltiazem,  felodipine,  nifedipine, or  verapamil ; careful monitoring recommended.
  • May ↑ levels and risk of toxicity of  antiarrhythmics, including  amiodarone,  disopyramide,  flecainide,  mexiletine,  propafenone, and  quinidine ; careful monitoring and titration is recommended.
  • May ↑ levels and risk of toxicity of  digoxin ; closely monitor digoxin levels and adjust dose as needed.
  •  Dexamethasone  may ↓ levels and effectiveness 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 disease and adrenal suppression; consider alternative corticosteroid, such as beclomethasone, prednisone, or prednisolone.
  •  Bosentan  may ↑ levels and risk of toxicity of bosentan and ↓ levels and effectiveness of 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 and risk of toxicity 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.
  • May ↑ levels and risk of toxicity of  immunosuppressants metabolized by CYP3A, including  cyclosporine,  everolimus,  sirolimus, and  tacrolimus ; therapeutic monitoring recommended.
  • May ↑ levels and risk of toxicity of  irinotecan ; discontinue darunavir/cobicistat/emtricitabine/tenofovir alafenamide ≥1 wk before starting irinotecan therapy.
  • May ↑ levels and risk of toxicity of  salmeterol ; concurrent use not recommended.
  • May ↑ 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 and 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 toxicity 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.
  • May ↑ levels 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 ↑ levels and risk of toxicity of  fesoterodine  and  solifenacin ; 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 ↓ levels and effectiveness of cobicistat, darunavir, and tenofovir levels; 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, 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 months after stopping therapy.
  • Black Box:  Monitor liver function tests prior to, during, and following therapy.
  • Lactic acidosis may occur with hepatotoxicity causing hepatic steatosis; may be fatal, especially in women. Discontinue therapy if symptoms occur.
  • May ↑ LDL-C, total cholesterol, and triglycerides.
  • Monitor serum creatinine, CCr, urine glucose, and urine protein before and periodically during therapy and when clinically indicated. In patients with chronic kidney disease, assess serum creatinine, CCr, serum phosphorus, urine glucose, and urine protein before 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; consume entire dose immediately after splitting.

Patient/Family Teaching

  • Explain purpose and side effects of medication to patient. Advise to read  Patient Information  before starting therapy and with each Rx refill in case of changes. Instruct patient to take as directed, even if feeling better. Black Box:  Do not take more than prescribed amount, and do not stop taking without consulting health care provider. Discontinuing therapy may lead to severe exacerbations. Take missed doses as soon as remembered unless almost time for next dose; do not double doses. Caution patient not to share or trade tablets with others.
  • Instruct patient to notify health care provider of all Rx or OTC medications, vitamins, or herbal products being taken and consult health care provider before taking any new medications, especially St. John's wort.
  • Inform patient of importance of HBV testing before starting antiretroviral therapy.
  • Inform patient that  Symtuza  does not cure HIV and may ↓ 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 provider 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; 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.
  • 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.
  • Emphasize the importance of regular follow-up exams and blood counts to determine progress.
  • Rep:  Advise women of reproductive potential to notify health care provider 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 patient that pregnancy is not recommended during treatment and to avoid breastfeeding during therapy.

Evaluation/Desired Outcomes

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

darunavir/cobicistat/emtricitabine/tenofovir alafenamideis the Pediatrics Central Word of the day!