Reyataz

Reyataz

atazanavir

Manufacturer:

Bristol-Myers Squibb

Distributor:

DKSH
Full Prescribing Info
Contents
Atazanavir sulfate.
Action
Azapeptide inhibitor of HIV-1 protease.
Pharmacology: Resistance/Cross-Resistance: Resistance in Cell Culture: Atazanavir susceptibility was evaluated in clinical isolates from patients without prior atazanavir exposure and exhibiting a wide array of genotypic and phenotypic patterns. There was a clear trend toward decreased susceptibility to atazanavir as isolates exhibited high resistance levels to multiple protease inhibitors. In general, susceptibility to atazanavir was retained among isolates resistant to 1-2 protease inhibitors, despite the presence of primary substitutions associated with resistance to protease inhibitors.
Resistance In Vivo: Treatment-Naive Patients: Reyataz 400 mg without Ritonavir: The I50L substitution, sometimes in combination with an A71V change, is the signature resistance change for atazanavir. Of the 25 resistant isolates emerging in treatment-naive patient studies, 23 had an I50L susbstitution emerge on atazanavir therapy. There was no evidence of cross-resistance between atazanavir and amprenavir. Phenotypic analysis of the I50L-containing isolates showed atazanavir-specific resistance, which coincided with increased susceptibility to other protease inhibitors.
Reyataz 300 mg with Ritonavir 100 mg: In a study of treatment-naive patients comparing the efficacy of atazanavir plus ritonavir to lopinavir plus ritonavir, after 96 weeks of treatment, of the 30 isolates from patients with virologic failure without baseline substitutions, only 1/28 displayed phenotypic resistance to ATV (>5.2) with multipe PI substitutions (L10F, V32I, K43T, M46I, A71I, G73S, I85I/V, and L90M) without emergence of I50L.
Treatment-Experienced Patients: Reyataz with or without Ritonavir: Approximately 80% and 100% of atazanavir-resistant isolates from experienced patients treated with atazanavir or the combination of atazanavir plus saquinavir, respectively, showed no evidence of the emergence of the I50L substitution, instead displaying decreased susceptibility to multiple protease inhibitors, which coincided with the accumulation of several additional amino acid substitutions, including I84V.
In studies of treatment-experienced patients treated with ATV/RTV, most ATV resistant isolates from patients who experienced virologic failure through 48 weeks developed substitutions that were associated with resistance to multiple PIs and displayed decreased susceptibility to multiple PIs. The most common protease substitutions (>10% frequency) to develop in the viral isolates of patients who failed treatment with ATV 300 mg once daily and RTV 100 mg once daily [together with tenofovir and an nucleoside reverse transcriptase inhibitor (NRTI)] included L10F, K20I/M/V, V32I, M36I/L, M46I/L, I54V, A71V/T/I, G73S/T/C and V82A/T/L. Other substitutions that developed on ATV/RTV treatment including L24I, L33F/I/V, G48V, I50L/V, I84V and L90M occurred in <10% of patient isolates.
Pharmacokinetics: The pharmacokinetics of atazanavir were evaluated in healthy adult volunteers and in HIV-infected patients.
Absorption: Multiple dosing of Reyataz 400 mg once daily with a light meal produced peak steady-state atazanavir plasma concentrations approximately 2.7 hrs after administration. Steady state for atazanavir was achieved between day 4 and day 8.
Food Effect: Administration of Reyataz with food enhances bioavailability and reduces pharmacokinetic variability. Administration of Reyataz plus ritonavir with food optimizes the bioavailability of atazanavir.
Distribution: Atazanavir is 86% bound to human serum proteins.
Metabolism: Atazanavir is principally metabolized by the cytochrome P-450 3A4 (CYP3A4) isozyme to oxygenated metabolites. Metabolites are then excreted in the bile as either free or glucuronidated metabolites.
Elimination: Following a single  14C-atazanavir 400-mg dose, 79% and 13% of the total radioactivity was recovered in the feces and urine, respectively. Unchanged drug accounted for approximately 20% and 7% of the administered dose in the feces and urine, respectively. The mean elimination half-life of atazanavir in healthy volunteers and HIV-infected adult patients was approximately 7 hrs.
Adolescents and Children: There are insufficient data at this time to recommend a dose (see Dosage & Administration: Adolescents and Children).
Toxicology: Nonclinical Safety: Carcinogenesis, Mutagenesis & Impairment of Fertility: Carcinogenicity studies with atazanavir were conducted in mice and rats. Mice were administered doses of 20, 40 and 80 mg/kg/day in males and 40, 120 and 360 mg/kg/day in females. In female mice, there was an increase in the incidence of benign hepatocellular adenomas at the highest dose. The exposure in female mice at the high dose is approximately 7 times exposure in humans given atazanavir 400 mg once daily.
No increase in the incidence of tumors was observed in female mice at lower doses or male mice at any dose. Exposures in male and female mice at nontumorigenic doses are approximately 4 times human exposure at 400 mg/day. In rats administered doses of 100, 350 and 1200 mg/kg/day, there was no increased incidence of any tumor type. Exposures in rats at the high dose are approximately 2 (males) and 6 (females) times exposure in humans given atazanavir 400 mg once daily. The increased incidence of benign hepatic adenomas in high-dose female mice was likely the result of increased hepatocellular proliferation secondary to cytotoxic liver changes (single-cell necrosis) and is considered to have no clinical relevance at human therapeutic exposures.
Atazanavir was negative in an Ames reverse-mutation assay but did induce chromosomal aberrations in vitro in both the absence and presence of metabolic activation. In in vivo studies in rats, atazanavir did not induce micronuclei in bone marrow, DNA damage in duodenum (comet assay) or unscheduled DNA repair in liver at plasma and tissue concentrations exceeding those that were clastogenic in vitro.
Atazanavir produced no effects on mating, fertility or early embryonic development in rats at doses that provided exposures equivalent to (males) and at least 2 times (females) exposure in humans given 400 mg once daily.
Indications/Uses
In combination with other antiretroviral agents for the treatment of HIV-1 infection.
The efficacy of Reyataz has been demonstrated in antiretroviral-naive and treatment-experienced patients.
Dosage/Direction for Use
Efficacy and safety of Reyataz with ritonavir in doses >100 mg once daily have not been established. The use of higher ritonavir doses might alter the safety profile of atazanavir (cardiac effects, hyperbilirubinemia) and, therefore, is not recommended.
Recommended Dosage: Treatment-Naive Patients: 400 mg once daily taken with food, or 300 mg once daily with ritonavir 100 mg once daily taken with food.
Treatment-Experienced Patients: 300 mg once daily with ritonavir 100 mg once daily taken with food.
Reyataz without ritonavir is not recommended for treatment-experienced patients with prior virologic failure.
Concomitant Therapy: Didanosine: It is recommended that all didanosine formulations be administered on an empty stomach and that Reyataz be taken with food; therefore, didanosine should be taken 2 hrs after Reyataz (taken with food).
Tenofovir: When co-administered with tenofovir, it is recommended that Reyataz 300 mg be given with ritonavir 100 mg and tenofovir 300 mg, all as a single daily dose with food. Reyataz without ritonavir should not be co-administered with tenofovir.
Adolescents and Children: The optimal dosing regimen for use of Reyataz in pediatric patients has not been established. Reyataz should not be administered to pediatric patients <3 months.
Elderly: Clinical studies of Reyataz did not include sufficient numbers of patients ≥65 years to determine whether they respond differently than younger patients. Based on pharmacokinetic comparisons, a dose adjustment for age is not recommended.
Renal Impairment: For patients with renal impairment, including those with severe renal impairment who are not managed by hemodialysis, no dose adjustment is required for Reyataz. For treatment-naive patients managed with hemodialysis, administration of Reyataz 300 mg with ritonavir 100 mg is recommended. Reyataz should not be administered to HIV-treatment-experienced patients with severe renal impairment managed with hemodialysis.
Hepatic Impairment: Reyataz should be used with caution in patients with mild to moderate hepatic impairment. A dose reduction to 300 mg once daily should be considered for patients with moderate hepatic impairment. Reyataz should not be used in patients with severe hepatic impairment. Reyataz in combination with ritonavir has not been studied in subjects with hepatic impairment and should be used with caution in patients with mild hepatic impairment. Reyataz with ritonavir is not recommended for patients with moderate to severe impairment.
Overdosage
Human experience of acute overdose with Reyataz is limited. Single doses up to 1200 mg have been taken by healthy volunteers without symptomatic untoward effects. A single self-administered overdose of Reyataz 29.2 g  in an HIV-infected patient (73 times the 400-mg recommended dose) was associated with asymptomatic bifascicular block and PR interval prolongation. These events resolved spontaneously. At high doses that lead to high drug exposures, jaundice, predominantly due to indirect (unconjugated) hyperbilirubinemia (without associated liver function test changes) or PR interval prolongation may be observed.
Treatment of overdosage with Reyataz should consist of general supportive measures, including monitoring of vital signs and electrocardiogram, and observations of the patient's clinical status. If indicated, elimination of unabsorbed atazanavir should be achieved by emesis or gastric lavage. Administration of activated charcoal may also be used to aid removal of unabsorbed drug. There is no specific antidote for overdose with Reyataz. Since atazanavir is extensively metabolized by the liver and is highly protein-bound, dialysis is unlikely to be beneficial in significant removal of Reyataz.
Contraindications
Known hypersensitivity to any of the ingredients of Reyataz, including atazanavir. Reyataz is contraindicated when co-administered with drugs that are highly dependent on CYP3A4 for clearance, and for which elevated plasma concentrations are associated with serious and/or life-threatening events. Severe hepatic insufficiency.
Alpha 1-adrenoreceptor Antagonist: Alfuzosin: Potential for increased alfuzosin concentrations which can result in hypotension.
Antiarrhythmics: Quinidine:
Contraindicated if Reyataz is co-administered with ritonavir due to potential for serious and/or life-threatening reactions eg, cardiac arrhythmias.
Calcium-Channel Blockers: Bepridil: Potential for serious and/or life-threatening adverse events. Contraindicated if Reyataz is co-administered with ritonavir.
Ergot Derivatives: Dihydroergotamine, Ergotamine, Ergonovine, Methylergonovine: Potential for serious and/or life-threatening events eg, acute ergot toxicity characterized by peripheral vasospasm and ischemia of the extremities and other tissues.
GI Motility Agent: Cisapride: Potential for serious and/or life-threatening reactions eg, cardiac arrhythmias.
HMG-CoA Reductase Inhibitors: Lovastatin, Simvastatin: There may be potential for serious reactions eg, myopathy including rhabdomyolysis. (See HMG-CoA Reductase Inhibitors: Atorvastatin, Cerivastatin as follows.)
Herbal Products: St. John's Wort (Hypericum perforatum): Patients taking Reyataz should not use products containing St. John's wort because co-administration may be expected to reduce plasma concentrations of atazanavir. This may result in loss of therapeutic effect and development of resistance.
Neuroleptic: Pimozide: Potential for serious and/or life-threatening reactions eg, cardiac arrhythmias.
Sedative Hypnotics: Orally-Administered Midazolam, Triazolam: Potential for increased concentrations of the sedative hypnotic and increased risk of prolonged sedation or respiratory depression.
PDE5 Inhibitor: Sildenafil when used for the treatment of pulmonary arterial hypertension: A safe and effective dose in combination with Reyataz has not been established for sildenafil when used for the treatment of pulmonary hypertension. There is increased potential for sildenafil-associated adverse events (which include visual disturbances, hypotension, priapism and syncope).
Special Precautions
Drug Class-Specific Warnings and Precautions: Diabetes Mellitus/Hyperglycemia: New-onset diabetes mellitus, exacerbation of preexisting diabetes mellitus and hyperglycemia have been reported during post-marketing surveillance in HIV-infected patients receiving protease inhibitor therapy. In some cases, diabetic ketoacidosis has occurred.
Hemophilia: There have been reports of increased bleeding, including spontaneous skin hematomas and hemarthrosis, in patients with hemophilia type A and B treated with protease inhibitors. In some patients, additional factor VIII was given. In most reported cases, treatment with protease inhibitors was continued or reintroduced.
Fat Redistribution: Redistribution/accumulation of body fat including central obesity, dorsocervical fat enlargement (buffalo hump), peripheral wasting, facial wasting, breast enlargement and "cushingoid appearance" have been observed in patients receiving antiretroviral therapy.
Immune Reconstitution Syndrome: Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including Reyataz. During the initial phase of combination antiretroviral treatment, patients whose immune system respond may develop an inflammatory response to indolent or residual opportunistic infections [eg, Mycobacterium avium infection, cytomegalovirus, Pneumocystis jiroveci pneumonia (PCP) or tuberculosis], which may necessitate further evaluation and treatment.
Product-Specific Warnings and Precautions: PR Interval Prolongation: Atazanavir has the potential to prolong the PR interval of the electrocardiogram in some patients. Reyataz should be used with caution in patients with preexisting conduction system disease. Caution should be used when co-administering Reyataz with medicinal products known to induce PR interval prolongation.
Hyperbilirubinemia: Reversible elevations in indirect (unconjugated) bilirubin related to inhibition of UDP-glucuronosyl transferase (UGT) have occurred in patients receiving Reyataz. Hepatic transaminase elevations that occur with elevated bilirubin in patients receiving Reyataz should be evaluated for alternative etiologies. No long-term safety data are available for patients experiencing persistent elevations in bilirubin >5 times the upper limit of normal (ULN). Alternative antiretroviral therapy to Reyataz may be considered if jaundice or scleral icterus associated with bilirubin elevations presents cosmetic concerns for patients. Dose reduction of Reyataz is not recommended since long-term efficacy of reduced doses has not been established.
Rash:
Rashes are usually mild to moderate maculopapular skin eruptions that occur within the first 3 weeks of initiating therapy with Reyataz. In most patients, rash resolves within 2 weeks while continuing Reyataz therapy. Reyataz should be discontinued if severe rash develops. Cases of Stevens-Johnson syndrome, erythema multiforme and toxic skin eruptions have been reported in patients receiving Reyataz.
Hepatic Impairment and Toxicity: Atazanavir is principally metabolized by the liver; caution should be exercised when administering Reyataz to patients with hepatic impairment because atazanavir concentrations may be increased (see Dosage & Administration: Hepatic Impairment). Patients with underlying hepatitis B or C viral infections or marked elevations in transaminases prior to treatment may be at increased risk for developing further transaminase elevations.
Nephrolithiasis: Cases of nephrolithiasis have been reported during post-marketing surveillance in HIV-infected patients receiving Reyataz therapy. If signs and symptoms of nephrolithiasis occur, temporary interruption or discontinuation of therapy may be considered.
Use in pregnancy & lactation: No teratogenic effects were observed in rats or rabbits at maternally toxic doses producing maternal exposures (AUC) 2 times (rats) and comparable to (rabbits) exposure in humans given 400 mg once daily. In the pre- and postnatal development assessment in rats, atazanavir produced transient body weight loss or gain suppression in the offspring at a maternally toxic dose. Offspring were unaffected at a lower dose which produced maternal exposure equivalent to that observed in humans given 400 mg once daily.
In clinical trial AI424-182, Reyataz/ritonavir (300/100 mg or 400/100 mg) in combination with zidovudine/lamivudine was administered to 41 pregnant women during the 2nd or 3rd trimester. Among the 39 women who completed the study, 38 women achieved an HIV RNA <50 copies/mL at time of delivery. Six (6) of 20 (30%) women on Reyataz/ritonavir 300/100 mg and 13 of 21 (62%) women on Reyataz/ritonavir 400/100 mg experienced grades 3-4 hyperbilirubinemia. There were no cases of lactic acidosis observed in the clinical trial AI424-182.
Forty (40) infants had test result that were negative for HIV-1 DNA at the time of delivery and/or during the first 6 months postpartum. All 40 infants received antiretroviral prophylactic treatment containing zidovudine. Three (3) of 20 infants (15%) born to women treated with Reyataz/ritonavir 300/100 mg and 4 of 20 infants (20%) born to women treated with Reyataz/ritonavir 400/100 mg experienced grade 3-4 bilirubin. There was no evidence of pathologic jaundice and 6 of 40 infants in this study received phototherapy for a maximum of 4 days. There were no reported cases of kernicterus in neonates.
No dosage adjustment is required if used during pregnancy.
Reyataz should be used during pregnancy only if the potential benefit justifies the potential risk.
It is not known whether atazanavir is secreted in human milk. A study in lactating rats demonstrated that atazanavir is secreted in milk. Because of both the potential for HIV transmission and the potential for serious adverse reactions in nursing infants, mothers should be instructed not to breastfeed if they are receiving Reyataz.
Post-Marketing Data: As of December 2009, there were 315 identified cases with prospective 1st trimester exposure to atazanavir and known outcome in the post-marketing database. There was no association between atazanavir and specific birth defects observed in the post-marketing data.
Antiretroviral Pregnancy Registry Data: As of January 2010, the Antiretroviral Pregnancy Registry (APR) has received prospective reports of 635 exposures to atazanavir-containing regimens (425 exposed in the 1st trimester and 160 and 50 exposed in 2nd and 3rd trimester, respectively). Birth defects occurred in 9 of 393 (2.3%) live births (1st trimester exposure) and 5 of 212 (2.4%) live births (2nd/3rd trimester exposure). There was no association between atazanavir and specific birth defects observed in the APR.
Labor and Delivery: Hyperbilirubinemia occurred frequently during treatment with Reyataz. It is not known whether Reyataz administered to the mother during pregnancy will exacerbate physiological hyperbilirubinemia and lead to kernicterus in neonates and young infants. In the prepartum period, additional monitoring should be considered.
Use In Pregnancy & Lactation
No teratogenic effects were observed in rats or rabbits at maternally toxic doses producing maternal exposures (AUC) 2 times (rats) and comparable to (rabbits) exposure in humans given 400 mg once daily. In the pre- and postnatal development assessment in rats, atazanavir produced transient body weight loss or gain suppression in the offspring at a maternally toxic dose. Offspring were unaffected at a lower dose which produced maternal exposure equivalent to that observed in humans given 400 mg once daily.
In clinical trial AI424-182, Reyataz/ritonavir (300/100 mg or 400/100 mg) in combination with zidovudine/lamivudine was administered to 41 pregnant women during the 2nd or 3rd trimester. Among the 39 women who completed the study, 38 women achieved an HIV RNA <50 copies/mL at time of delivery. Six (6) of 20 (30%) women on Reyataz/ritonavir 300/100 mg and 13 of 21 (62%) women on Reyataz/ritonavir 400/100 mg experienced grades 3-4 hyperbilirubinemia. There were no cases of lactic acidosis observed in the clinical trial AI424-182.
Forty (40) infants had test result that were negative for HIV-1 DNA at the time of delivery and/or during the first 6 months postpartum. All 40 infants received antiretroviral prophylactic treatment containing zidovudine. Three (3) of 20 infants (15%) born to women treated with Reyataz/ritonavir 300/100 mg and 4 of 20 infants (20%) born to women treated with Reyataz/ritonavir 400/100 mg experienced grade 3-4 bilirubin. There was no evidence of pathologic jaundice and 6 of 40 infants in this study received phototherapy for a maximum of 4 days. There were no reported cases of kernicterus in neonates.
No dosage adjustment is required if used during pregnancy.
Reyataz should be used during pregnancy only if the potential benefit justifies the potential risk.
It is not known whether atazanavir is secreted in human milk. A study in lactating rats demonstrated that atazanavir is secreted in milk. Because of both the potential for HIV transmission and the potential for serious adverse reactions in nursing infants, mothers should be instructed not to breastfeed if they are receiving Reyataz.
Post-Marketing Data: As of December 2009, there were 315 identified cases with prospective 1st trimester exposure to atazanavir and known outcome in the post-marketing database. There was no association between atazanavir and specific birth defects observed in the post-marketing data.
Antiretroviral Pregnancy Registry Data: As of January 2010, the Antiretroviral Pregnancy Registry (APR) has received prospective reports of 635 exposures to atazanavir-containing regimens (425 exposed in the 1st trimester and 160 and 50 exposed in 2nd and 3rd trimester, respectively). Birth defects occurred in 9 of 393 (2.3%) live births (1st trimester exposure) and 5 of 212 (2.4%) live births (2nd/3rd trimester exposure). There was no association between atazanavir and specific birth defects observed in the APR. Labor and Delivery: Hyperbilirubinemia occurred frequently during treatment with Reyataz. It is not known whether Reyataz administered to the mother during pregnancy will exacerbate physiological hyperbilirubinemia and lead to kernicterus in neonates and young infants. In the prepartum period, additional monitoring should be considered.
Adverse Reactions
Clinical Trial Experiences: Body System List of Events: Reyataz has been evaluated for safety and tolerability in combination therapy with other antiretroviral medications in controlled clinical trials in adult patients, receiving Reyataz 400 mg once daily or Reyataz 300 mg once daily plus ritonavir 100 mg once daily.
The more frequent adverse events of any severity with at least a possible relationship to regimens containing Reyataz and ≥1 NRTIs were nausea (20%), jaundice (13%) and diarrhea (10%). Jaundice was reported within a few days to a few months after the initiation of treatment and resulted in discontinuation of treatment in <1% of patients.
Lipodystrophy, of moderate intensity or greater, was reported in regimens containing Reyataz and ≥1 NRTIs, as at least possibly related to the regimen, in 5% of patients.
The following adverse reactions of moderate intensity or greater with at least a possible relationship to regimens containing Reyataz and ≥1 NRTIs have been reported: Cardiac Disorders: Uncommon: Syncope. Rare: Oedema, palpitation.
Nervous System Disorders: Common: Headache. Uncommon: Peripheral neurologic symptoms, amnesia, somnolence, dizziness, dysgeusia.
Eye Disorders: Common: Scleral icterus.
Respiratory, Thoracic and Mediastinal Disorders: Uncommon: Dyspnea.
Gastrointestinal Disorders: Common: Abdominal pain, diarrhoea, dyspepsia, nausea, vomiting. Uncommon: Dry mouth, flatulence, gastritis, pancreatitis, aphthous stomatitis, abdominal distention.
Renal and Urinary Disorders: Uncommon: Hematuria, pollakiuria, proteinuria, nephrolithiasis. Rare: Kidney pain.
Skin and Subcutaneous Tissue Disorders: Common: Rash. Uncommon: Alopecia, pruritus, urticaria. Rare: Vasodilatation, vesiculobullous rash, eczema.
Musculoskeletal and Connective Tissue Disorders: Uncommon: Arthralgia, muscle atrophy, myalgia. Rare: Myopathy.
Metabolism and Nutrition Disorders: Uncommon: Anorexia, increased appetite, decreased weight, weight gain.
Vascular Disorders: Uncommon: Hypertension.
General Disorders and Administration Site Conditions: Common: Asthenia, fatigue. Uncommon: Chest pain, fever, malaise, gait disturbance.
Immune System Disorders: Uncommon: Allergic reaction.
Hepatobiliary Disorders: Common: Jaundice. Uncommon: Hepatitis. Rare: Hepatosplenomegaly.
Reproductive System and Breast Disorders: Uncommon: Gynecomastia.
Psychiatric Disorders: Uncommon: Anxiety, depression, sleep disorder, insomnia, abnormal dream, disorientation.
Patients Co-infected with Hepatitis B and/or C Virus: The frequency of treatment-emergent hepatitis or transaminase elevations in co-infected patients was comparable between Reyataz and comparator regimens. No differences in frequency of bilirubin elevations were observed.
Laboratory Findings: Adult Patients: The most frequently reported laboratory abnormality in patients receiving regimens containing Reyataz and ≥1 NRTIs was elevated total bilirubin reported predominantly as elevated indirect (unconjugated) bilirubin (87% Grade 1, 2, 3 or 4). Grade 3 or 4 elevation of total bilirubin was noted in 37% (6% Grade 4).
Other marked clinical laboratory abnormalities (Grade 3 or 4) reported in ≥2% of patients receiving regimens containing Reyataz and ≥1 NRTIs included: Elevated creatinine kinase (CK) (7%), elevated ALT/SGPT (5%), low neutrophils (5%), elevated AST/SGOT (3%) and elevated lipase (3%).
In clinical studies, the observed magnitude of dyslipidemia was less with Reyataz than with comparators.
Post-marketing Experience: The following events have been identified during post-approval use of Reyataz. Because they are reported voluntarily from a population of unknown size, estimates of frequency cannot be made. These events have been chosen for inclusion due to the seriousness, frequency of reporting or causal connection to Reyataz or a combination of these factors.
Cardiac and Vascular Disorders: Second- and third-degree atrioventicular block, QTc prolongation, torsades de pointes.
Metabolism and Nutrition Disorders: Hyperglycemia, diabetes mellitus.
Renal and Urinary Disorders: Nephrolithiasis.
Hepatobiliary Disorders: Cholelithiasis, cholecystitis, cholestasis.
Drug Interactions
Atazanavir is metabolized in the liver by the cytochrome P-450 enzyme system, and is an inhibitor of CYP3A4. Co-administration of Reyataz and drugs primarily metabolized by CYP3A4 [eg, calcium channel blockers, HMG-CoA reductase inhibitors, immunosuppressants and phosphodiesterase (PDE5) inhibitors] may result in increased plasma concentrations of the other drug that could increase or prolong both its therapeutic and adverse effects. Co-administration of Reyataz and drugs that induce CYP3A4 eg, rifampin, may decrease atazanavir plasma concentrations and reduce its therapeutic effect. Co-administration of Reyataz and drugs that inhibit CYP3A4 may increase atazanavir plasma concentrations.
The magnitude of CYP3A4-mediated drug interactions (effect on atazanavir or on co-administered drug) may change when Reyataz is co-administered with ritonavir, a potent CYP3A4 inhibitor. The prescribing information for ritonavir should be consulted for information on drug interactions with ritonavir.
Caution should be used when co-administering Reyataz with medicinal products known to induce PR interval prolongation (see Precautions).
Drugs that Should Not be Co-Administered with Reyataz: Antimycobacterial: Rifampin substantially decreases plasma concentrations of atazanavir, which may result in loss of therapeutic effect and development of resistance.
Antineoplastic: Irinotecan: Atazanavir inhibits UGT and may interfere with the metabolism of irinotecan, resulting in increased irinotecan toxicities.
Inhaled β-Agonists: Salmeterol: Concomitant use of salmeterol and Reyataz may result in increased cardiovascular adverse events associated with salmeterol, including QT prolongation, palpitations and sinus tachycardia. Co-administration of salmeterol and Reyataz is not recommended.
Protease Inhibitor: Indinavir: Both Reyataz and indinavir are associated with hyperbilirubinemia. Co-administration of Reyataz and indinavir is not recommended.
Alteration in dose or regimen of the following drugs may be recommended based on drug interaction studies or predicted interactions: HIV Antiviral Agents: NRTIs: Didanosine: Co-administration of didanosine buffered tablets and Reyataz markedly decreased exposure to atazanavir (presumably due to the increase in gastric pH caused by buffers in the didanosine tablets). Co-administration with Reyataz did not alter exposure to didanosine. Administration of enteric-coated didanosine formulation with Reyataz or Reyataz/ritonavir and a light meal decreased exposure to didanosine (see Dosage & Administration: Concomitant Therapy).
Tenofovir: Exposure to atazanavir is decreased when tenofovir is co-administered with Reyataz (see Dosage & Administration: Concomitant Therapy). Atazanavir increases tenofovir concentrations. Higher tenofovir concentrations could potentiate tenofovir-associated adverse events, including renal disorders. Patients receiving atazanavir and tenofovir should be monitored for tenofovir-associated adverse events.
Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs): Efavirenz: Exposure to atazanavir is decreased when efavirenz is co-administered with Reyataz. Co-administration of Reyataz with efavirenz is not recommended. If co-administration of Reyataz with efavirenz cannot be avoided, the following recommendations may be used for treatment-naive patients only. Reyataz 400 mg with ritonavir 100 mg both administered as a single dose with food, and efavirenz administered on an empty stomach, preferable at bedtime.
Reyataz should not be co-administered with efavirenz to treatment-experienced patients.
Nevirapine: Nevirapine, an inducer of CYP3A4, decreases atazanavir exposure. There is a potential risk for nevirapine-associated toxicity due to the increased nevirapine exposures. Do not co-administer Reyataz with nevirapine.
Protease Inhibitors: Saquinavir (Soft Gelatin Capsules): Exposure to saquinavir is increased when it is co-administered with Reyataz. Appropriate dosing recommendations for this combination, with respect to efficacy and safety, have not been established.
Ritonavir: Exposure to atazanavir is increased when ritonavir is co-administered with Reyataz (see Dosage & Administration: Recommended Dosage).
Other Protease Inhibitors: Although not studied, the co-administration of Reyataz plus ritonavir with other protease inhibitors would be expected to increase exposure to the other protease inhibitor and is not recommended.
Other Agents: Antacids and Buffered Medications: Reduced plasma concentrations of atazanavir may result if antacids, including buffered medications, are administered with Reyataz. Reyataz should be administered 2 hrs before or 1 hr after these medications.
Antiarrhythmics: Amiodarone, Lidocaine (Systemic), Quinidine: Concentrations may be increased when co-administered with Reyataz. Caution is warranted and therapeutic concentration monitoring is recommended when available. Quinidine is contraindicated when Reyataz is co-administered with ritonavir.
Anticoagulants: Warfarin: Co-administration with Reyataz has the potential to produce serious and/or life-threatening bleeding due to increased exposure to warfarin and has not been studied. It is recommended that International Normalization Ratio (INR) be monitored.
Antidepressants: Tricyclic Antidepressants: Co-administration of tricyclic antidepressants with Reyataz has the potential to produce serious and/or life-threatening adverse events due to increased exposure to these agents and has not been studied. Concentration monitoring of these drugs is recommended if they are used concomitantly with Reyataz.
Trazodone: Concomitant use of trazodone and Reyataz with or without ritonavir may increase plasma concentrations of trazodone. Adverse events of nausea, dizziness, hypotension and syncope have been observed following co-administration of trazodone and ritonavir. If trazodone is used with a CYP3A4 inhibitor eg, Reyataz, the combination should be used with caution and a lower dose of trazodone should be considered.
Antifungals: High doses of ketoconazole and itraconazole (>200 mg/day) should be used cautiously with Reyataz and ritonavir. Voriconazole should not be administered to patients receiving Reyataz and ritonavir.
Antigout: Colchicine: Exposure to colchicine may be increased when co-administered with Reyataz. Colchicine is a CYP3A4 substrate (see Contraindications).
Antimycobacterials: Rifabutin: Exposure to rifabutin is increased when co-administered with Reyataz. A rifabutin dose reduction of up to 75% (eg, 150 mg every other day or 3 times/week) is recommended. Increased monitoring for adverse reactions is warranted in patients receiving the combination of rifabutin and Reyataz with or without ritonavir. Further dosage reduction of rifabutin may be necessary.
Beta-Adrenergic Blockers: Atenolol: Co-administration of atenolol with Reyataz in healthy subjects resulted in no clinically important increase in exposure to atenolol and no change in the pharmacokinetics of atazanavir. No clinically relevant pharmacokinetic interactions requiring dose adjustment are expected with β-adrenergic blockers.
Calcium Channel Blockers: Diltiazem: Exposure to diltiazem and a metabolite, desacetyl-diltiazem, is increased when diltiazem is co-administered with Reyataz. A dose reduction of diltiazem by 50% should be considered and electrocardiogram monitoring is recommended.
Other Calcium Channel Blockers eg, Verapamil: Caution is warranted. Dose titration of the calcium channel blocker should be considered. Electrocardiogram monitoring is recommended.
Endothelin Receptor Antagonists: Bosentan: Bosentan is metabolised by CYP3A4. Plasma concentrations of atazanavir may be decreased when bosentan is administered with Reyataz without ritonavir. Co-administration of bosentan and Reyataz without ritonavir is not recommended.
PDE5 Inhibitors (Sildenafil, Tadalafil, Vardenafil): Co-administration of a protease inhibitor with a PDE5 inhibitor is expected to substantially increase PDE5 inhibitor concentrations and may result in an increase in PDE5 inhibitor-associated adverse events. Use with caution and monitor for adverse events. The use of sildenafil for the treatment of pulmonary arterial hypertension is contraindicated with Reyataz (see Contraindications).
Proton-Pump Inhibitors: Plasma concentrations of atazanavir were substantially decreased when Reyataz 400 mg or Reyataz 300 mg/ritonavir 100 mg once daily was administered with omeprazole 40 mg once daily, which may result in loss of therapeutic effect and development of resistance. An increased dose of Reyataz 400 mg/ritonavir 100 mg may be administered with omeprazole at a maximum dose of 20 mg once daily (or comparable dose of an alternative proton-pump inhibitor) to HIV-infected patients without suspected or documented evidence of decreased susceptibility to atazanavir. Doses of omeprazole exceeding 20 mg daily (or comparable dose of an alternative proton-pump inhibitor) are not recommended.
H2-Receptor Antagonists: Plasma concentrations of atazanavir were substantially decreased when Reyataz 400 mg once daily was administered simultaneously with famotidine 40 mg twice daily, which may result in loss of therapeutic effect and development of resistance.
In Treatment-Naive Patients: Reyataz 400 mg once daily with food should be administered at least 2 hrs before and at least 10 hrs after a dose of the H2-receptor antagonist. No single dose of the H2-receptor antagonist should exceed a dose comparable to famotidine 20 mg, and the total daily dose should not exceed a dose comparable to famotidine 40 mg; or Reyataz 300 mg with ritonavir 100 mg once daily with food should be administered simultaneously with, and or at least 2 hrs before and at least 10 hrs after, a dose of the H2-receptor antagonist.
In Treatment-Experienced Patients: Reyataz 300 mg with ritonavir 100 mg should be administered once daily with food at least 2 hrs before and at least 12 hrs after the H2-receptor antagonist at a single daily dose comparable to famotidine 40 mg; or Reyataz 300 mg with ritonavir 100 mg once daily with food may be administered simultaneously with, or at least 2 hrs before and at least 10 hrs after, a dose of an H2-receptor antagonist not to exceed a dose comparable to famotidine 20 mg administered once or twice daily.
For treatment-exprienced patients taking Reyataz/ritonavir and tenofovir with an H2-receptor antagonist, it is recommended that Reyataz 400 mg with ritonavir 100 mg once daily be administered.
HMG-CoA Reductase Inhibitors: Atorvastatin, Cerivastatin: Exposure to atorvastatin and cerivastatin may be increased when they are co-administered with Reyataz. The risk of myopathy including rhabdomyolysis may be increased when protease inhibitors, including Reyataz, are used in combination with these drugs. Caution should be exercised (see also previous text).
Immunosuppressants: Cyclosporin, Tacrolimus, Sirolimus: Exposure to cyclosporin, tacrolimus and sirolimus may be increased when they are co-administered with Reyataz. Therapeutic concentration monitoring is recommended for immunosuppressant agents when co-administered with Reyataz.
Inhaled/Nasal Corticosteroids (Interaction with Ritonavir): In healthy volunteers, ritonavir significantly increased plasma fluticasone propionate exposures, resulting in significantly decreased serum cortisol concentrations. Concomitant use of Reyataz/ritonavir with fluticasone propionate is expected to produce the same effects. Systemic corticosteroid effects including Cushing's syndrome and adrenal suppression have been reported when ritonavir was co-administered with inhaled or intranasally-administered fluticasone propionate. These effects could also occur with other corticosteroids metabolized via the CYP4503A pathway eg, budesonide. Therefore, concomitant use of Reyataz/ritonavir and fluticasone propionate or other glucocorticoids that are metabolized by CYP3A4 is not recommended unless the potential benefit of treatment outweighs the risk of systemic corticosteroid effects. Concomitant use of fluticasone propionate and Reyataz (without ritonavir) may increase plasma concentrations of fluticasone propionate. Use with caution. Consider alternatives to fluticasone propionate, particularly for long-term use.
Macrolide Antibiotics: Clarithromycin: Exposure to clarithromycin is increased when it is co-administered with Reyataz. Increased concentrations of clarithromycin may cause QTc prolongations; therefore, a dose reduction of clarithromycin by 50% should be considered when it is co-administered with Reyataz.
Benzodiazepines: Midazolam: Midazolam is extensively metabolised by CYP3A4, Although not studied, co-administration of midazolam with Reyataz may cause a large increase in the concentration of this benzodiazepine. Increases in benzodiazepine concentration are expected to be significantly higher with oral administration of the benzodiazepine, relative to parenteral. Therefore, Reyataz should not be co-administered with orally-administered midazolam, whereas caution should be used with co-administration of Reyataz and parenteral midazolam.
If Reyataz is co-administered with parenteral midazolam, a close clinical monitoring for respiratory depression and/or prolonged sedation should be exercised and dosage adjustment should be considered.
Opioids: Buprenorphine: Concentrations of buprenorphine and norbuprenorphine were increased when buprenorphine was co-administered with Reyataz with or without ritonavir due to CYP3A4 and UGT1A1 inhibition. Concentrations of Reyataz are not significantly affected. Co-administration warrants clinical monitoring for sedation and cognitive effects. A dose reduction of buprenorphine may be considered. There was no significant effect on atazanavir plasma concentration when Reyataz plus ritonavir were co-administered with buprenorphine. Co-administration of buprenorphine and Reyataz without ritonavir may substantially decrease atazanavir plasma concentrations. Reyataz without ritonavir should not be co-administered with buprenorphine.
Oral Contraceptives: Ethinyl Estradiol, Norethindrone and Norgestimate: Mean concentrations of ethinyl estradiol and norethindrone are increased when they are co-administered with Reyataz.
Administration of Reyataz/ritonavir with ethinyl estradiol and norgestimate decreases the mean concentration of ethinyl estradiol and increases the mean concentration of 17-deacetyl norgestimate, the active metabolite of norgestimate. If an oral contraceptive is administered with Reyataz plus ritonavir, it is recommended that the oral contraceptive contain at least 30 mcg of ethinyl estradiol. If Reyataz is administered without ritonavir, the oral contraceptive should contain no more than 30 mcg of ethinyl estradiol. Use with caution as the effect of increases in concentration of the progestational agent are unknown and could increase the risk of acne, dyslipidemia and insulin resistance.
Co-administration of Reyataz or Reyataz/ritonavir with other hormonal contraceptives (eg, contraceptive patch, contraceptive vaginal ring or injectable contraceptives) or oral contraceptives containing progestagens other than norethindrone or norgestimate or ethinyl estradiol <25 mcg have not been studied; therefore, alternative methods of contraception are recommended.
Effect on Other Cytochrome P-450 (CYP) Enzymes: Atazanavir is a weak inhibitor of CYP2C8. Caution should be used when Reyataz without ritonavir is co-administered with drugs highly dependent on CYP2C8 with narrow therapeutic indicies.
Storage
Store below 25°C (77°F).
MIMS Class
ATC Classification
J05AE08 - atazanavir ; Belongs to the class of protease inhibitors. Used in the systemic treatment of viral infections.
Presentation/Packing
Cap 200 mg x 60's. 300 mg x 30's.
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