Atazanavir-Cobicistat

Atazanavir-Cobicistat is a combination medication used for the treatment ofhuman immunodeficiency virustype 1 (HIV-1) infection in combination with otherantiretroviralagents.

• Atazanavir-Cobicistat is available under the following different brand names: Evotaz

Common side effects of Atazanavir-Cobicistat include:

• yellowing of the skin or eyes (jaundice)
• itching and rash
• hives
• nausea
• diarrhea
• vomiting
• abdominal pain
• fatigue
• muscle tissue breakdown (rhabdomyolysis)
• headache
• depressionabnormal or strangedreams
• insomnia
• kidney disease

Serious side effects of Atazanavir-Cobicistat include:

• irregular heartbeat
• dizziness
• feeling faint or light-headedness
• vision changes
• yellowing of skin or eyes (especially in newborn infants)
• pain in the back or low stomach area
• pain with urination
• blood in urine
• vomiting
• loss of appetite
• decreased urination
• dark-colored urine
• 浅色的排便

Rare side effects of Atazanavir-Cobicistat include:

none

Seek medical care or call 911 at once if you have the following serious side effects:

• Severe headache, confusion, slurred speech, arm or leg weakness, trouble walking, coordination loss, unsteady, very stiff muscles, high fever, profuse sweating, or tremors
• Serious eye symptoms such as sudden vision loss, blurred vision,tunnel vision, eye pain or swelling, or seeing halos around lights
• Serious heart symptoms include fast, irregular, or pounding heartbeats; fluttering in the chest; shortness of breath; sudden dizziness, light-headedness, or passing out

This is not a complete list of side effects and other serious side effects or health problems that may occur because of the use of this drug. Call your doctor for medical advice about serious side effects or adverse reactions. You may report side effects or health problems to FDA at 1-800-FDA-1088.

Adult and pediatric dosage

HIV-1 Infection

• Adult dosage
  • One tablet (300 mg/150 mg) orally once a day with food
• Pediatric dosage
  • Children weighing less than 35 kg: Safety and efficacy not established
  • Children weighing 35 kg and more
  • 1 tablet (300 mg/150 mg) orally once a day with food

Dosage Considerations – Should be Given as Follows:

• See “Dosages”

If your medical doctor is using this medicine to treat your pain, your doctor or pharmacist may already be aware of any possible drug interactions and may be monitoring you for them. Do not start, stop, or change the dosage of any medicine before checking with your doctor, healthcare provider, or pharmacist first.

• Atazanavir-Cobicistat has severe interactions with at least 59 other drugs.
• Atazanavir-Cobicistat has serious interactions with at least 247 other drugs.
• Atazanavir-Cobicistat has moderate interactions with at least 405 other drugs.
• Atazanavir-Cobicistat has minor interactions with at least 99 other drugs.

This information does not contain all possible interactions or adverse effects. Visit the RxList Drug Interaction Checker for any drug interactions. Therefore, before using this product, tell your doctor or pharmacist about all the products you use. Keep a list of all your medications with you and share this information with your doctor and pharmacist. Check with your healthcare professional or doctor for additional medical advice, health questions, or concerns.

Contraindications

• Previously demonstrated clinically significant hypersensitivity (eg,Stevens-Johnson syndrome,erythema multiforme, or toxic skin eruptions)
• Coadministration with drugs that are highly dependent on CYP3A or UGT1A1 for clearance and for which elevated plasma concentrations of the interacting drugs are associated with serious and/or life-threatening events
• Coadministration with drugs that strongly induce CYP3A and may lead to lower exposure and loss of efficacy of Atazanavir-Cobicistat
• Contraindicated drugs
  • Alfuzosin: Potential for increased alfuzosin concentrations, which can result in serious or life-threatening reactions (eg,hypotension)
  • Dronedarone, ranolazine: Potential for increased dronedarone and ranolazine concentrations that may result in prolonged QT interval
  • Colchicine: Contraindicated in patients with renal and/or hepatic impairment owing to the potential for serious and/or life-threatening reactions
  • CYP inducers (rifampin, St. John’s wort): Rifampin is a potent inducer of CYPmetabolism, and coadministration may cause a significant decrease in the plasma concentrations of darunavir and result in loss of therapeutic effect and development of resistance
  • Carbamazepine: Potential for decreased atazanavir plasma concentrations, which may result in loss of therapeutic effect and development of resistance
  • Cisapride, pimozide, lurasidone: Potential for serious and/or life-threatening reactions (eg, cardiac arrhythmias)
  • Elbasvir / grazoprevir: Atazanavir OATP1B1/3抑制ion may cause a significant increase in grazoprevir levels and, therefore, increase the risk for elevated ALT
  • Ergotderivatives (dihydroergotamine, ergotamine, methylergonovine): Potential for serious and/or life-threatening reactions (eg, acute ergot toxicity characterized by peripheral vasospasm andischemiaof the extremities and other tissues)
  • Lipid-modifying agents, lovastatin, simvastatin, lomitapide: Potential for serious reactions (eg,myopathy, including rhabdomyolysis)
  • Indinavir: Both atazanavir and indinavir are associated with indirect (unconjugated)hyperbilirubinemia
  • Irinotecan: UGT1A1 inhibition by atazanavir may interfere with the metabolism of irinotecan, resulting in increased toxicity
  • 奈韦拉平:奈韦拉平ata大幅减少zanavir exposure which may result in loss of therapeutic effect and development of resistance; potential risk for nevirapine-associated adverse reactions owing to increased nevirapine exposures
  • Phosphodiesterase type 5 inhibitors (long-term administration [eg, sildenafil as Revatio forPAH]): Potential for sildenafil-associated adverse reactions (eg, visual disturbances, hypotension,priapism,syncope)
  • Phenobarbital, phenytoin: Potential for decreased atazanavir plasma concentrations may result in loss of therapeutic effect and development of resistance
  • Triazolam and midazolam orally: These are extensively metabolized by CYP3A4; potential for prolonged or increased sedation orrespiratory depression

Effects of drug abuse

• none

Short-Term Effects

• See "What Are Side Effects Associated with Using Atazanavir-Cobicistat?"

Long-Term Effects

• See "What Are Side Effects Associated with Using Atazanavir-Cobicistat?"

Cautions

• Atazanavir prolongs the PR interval of theelectrocardiogramin healthy subjects, and in subjects with HIV-1 infection treated with atazanavir, abnormalities inatrioventricular(AV) conduction wereasymptomaticand generally limited to first-degree AV block; reports of second-degree AV block and other conduction abnormalities
• Cases of Stevens-Johnson syndrome,erythemamultiforme, and toxic skin eruptions, including drug rash,eosinophilia, and systemic symptoms syndrome, have been reported; mild-to-moderate maculopapular skin eruptions have also been reported in atazanavir clinical trials and generally did not result in treatment discontinuation
• Effects on serum creatinine: Assess eCrCl before initiating; cobicistat decreases estimated creatinine clearance, owing to an inhibition of tubular secretion of creatinine, without affecting actual renalglomerularfunction
• Chronic kidney disease in HIV-infected patients treated with atazanavir, with or without ritonavir reported; consider alternatives to therapy in patients at high risk for renal disease or with preexisting renal disease; renal laboratory testing (including serum creatinine, estimated creatinine clearance, andurinalysiswithmicroscopicexamination) should be conducted in all patients before initiating therapy and continued during treatment
• Cases ofnephrolithiasisand/orcholelithiasishave been reported during postmarketing surveillance in patients receiving atazanavir
• Patients with underlyinghepatitis Bor C viral infections or marked elevations in transaminases may be at increased risk of developing further transaminase elevations or hepatic decompensation
• Most patients taking atazanavir experience asymptomatic elevations in indirect (unconjugated) bilirubin related to inhibition ofUDP-glucuronosyltransferase
• New-onsetdiabetes mellitus, exacerbation of preexistingdiabetes相关知识,hyperglycemiareported during postmarketing surveillance in HIV-infected patients receivingproteaseinhibitors
• Redistribution/accumulation of body fat, including centralobesity, dorsocervical fat enlargement (buffalo hump), peripheralwasting, facial wasting, breast enlargement, andcushingoidappearance have been observed in patients receivingantiretroviral therapy(ART)
• Immune reconstitution syndrome reported in patients treated with combination ART; during the initial phase of combination ART treatment, patients whose immune systems respond may develop aninflammatory responseto indolent orresidualopportunistic infections (eg,Mycobacterium aviuminfection,Cytomegalovirus,Pneumocystisjiroveciipneumonia, ortuberculosis), which may necessitate further evaluation and treatment;autoimmunedisorders (eg, Graves disease,polymyositis,autoimmune hepatitis, Guillan-Barre syndrome) have also been reported
• Increased bleeding, including spontaneous skin hematomas andhemarthrosis, was reported in patients withhemophiliatype A and B treated with HIV protease inhibitors
• Renal impairment
  • Renal impairment, including cases ofacute renal failureand Fanconi syndrome, was reported when cobicistat was used in an ART regimen that contained tenofovir DF
  • Do not use with tenofovir DF if CrCl is below 70 mL/min
  • Document urine glucose and urine protein at baseline and perform routine monitoring of eCrCl, urine glucose, and urine protein during treatment
  • Measure serumphosphorusin patients at risk for renal impairment
  • Coadministration of Atazanavir-Cobicistat plus tenofovir DF in combination with concomitant or recent use of anephrotoxicagent is not recommended
• Drug interaction overview
  • Drugs that induce CYP3A4 may lead to lower exposure of atazanavir and loss of virologic response
  • Atazanavir inhibits CYP3A4 and is a substrate for CYP3A4
  • Cobicistat inhibits CYP3A and CYP2D6
  • Cobicistat inhibits the following transporters: P-glycoprotein(P-gp), BCRP, OATP1B1, and OATP1B3
  • Drugs that are metabolized by CYP3A and CYP2D6, or are substrates of the transporters P-gp, BCRP, OATP1B1, or OATP1B3, may show increased systemic exposure if coadministered with darunavir/cobicistat
  • Atazanavir solubility decreases as pH increases; reduced plasma concentrations of atazanavir are expected if proton-pump inhibitors, antacids, buffered medications, or H2-receptor antagonists are administered
• ART agents that are not recommended
  • Not recommended in combination with other ART drugs that require pharmacokinetic boosting (ie, anotherprotease inhibitoror elvitegravir) because dosing recommendations for such combinations have not been established and coadministration may result in decreased plasma concentrations of the ART agents, leading to loss of therapeutic effect and development of resistance
  • Not recommended in combination with products containing the individual components (atazanavir and cobicistat) or with ritonavir

Pregnancy and Lactation

• Cases oflactic acidosissyndrome, sometimes fatal, and symptomatic hyperlactatemia have occurred in pregnant women using atazanavir in combination with nucleoside analogs
• Nucleoside analogs are associated with an increased risk for lacticacidosissyndrome
• Hyperbilirubinemia occurs frequently in patients who take atazanavir, including pregnant women
• All infants, including neonates exposed to atazanavir in utero, should be monitored for the development of severe hyperbilirubinemia during the first few days of life
• Not recommended for use during pregnancy and should not be initiated in pregnant individuals; an alternative regimen is recommended for individuals who become pregnant during therapy
• Components of drug combination interact with certain oral contraceptives; nonhormonal forms of contraceptives should be considered
• Lactation
  • The CDC recommends that HIV-infected mothers in the United States not breastfeed their infants to avoid risking postnatal transmission of HIV to infants
  • Unknown whether atazanavir or cobicistat are secreted in human milk