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Atazanavir (Reyataz): new PI
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As you know the new protease inhibitor, atazanavir (ATV) was FDA approved and is expected to be in the pharmacy soon. My unconfirmed information is that the drug will be in the pharmacy on July 2. Here is relevant excerpted information printed in advance copy of the Product Information document available in your pharmacy.
ATV capsules are available for oral administration in strengths containing the equivalent of 100 mg, 150, mg, and 200 mg of ATV as ATV sulfate.
Atazanavir is a protease inhibitor taken once daily at a dose of 400 mg (2 capsules of 200 mg). In study 034 ATV was compared with efavirenz and the results of the study showed ATV was equivalent. The study results are available at the link I will provide after this paragraph. In studies so far ATV has not shown increases in lipids including triglycerides and cholesterol. One study 045 has compared 300 mg of ATV plus 100 mg of ritonavir (used to boost ATV levels) in patients with PI resistance. The study results are not included in this Package Insert because the data was not submitted soon enough for the review process by the FDA. The link following this paragraph will provide a report on this. Week 24 study results from 045 will be presented at the IAS Conference in Paris in July.
Atazanavir in PI-Experienced Patients (study 045)
http://www.natap.org/2003/june/060203_2.htm
Atazanavir Reports 1 and 2: lipids, study results, antiviral activity
http://www.natap.org/2003/may/051403_1.htm
http://www.natap.org/2003/may/051403_2.htm
DOSAGE AND ADMINISTRATION
Adults--The recommended dose of REYATAZ (atazanavir sulfate) is 400 mg (two 200-mg capsules) once daily taken with food.
ATV is recommended to be taken with food. Administration of ATV with food enhances bioavailability and reduces pharmacokinetic variability. Administration of a single dose of 400-mg ATV with a light meal (357 K-cal, 8.2 g fat, 10.6 g protein) resulted in a 70% increase in AUC and 57% increase in Cmax relative to fasting state. (note: In other words a light mean increases blood levels, and without this light meal ATV blood levels may be inadequate). Potency of ATV will be less without food. Administration of a single dose of 400-mg ATV with a high-fat meal (721 K-cal, 37.3 g fat, 29.4 g protein) resulted in a mean increase in AUC of 35% with no change in Cmax relative to the fasting state.
EFAVRIENZ. If REYATAZ is to be coadministered with efavirenz, which
decreases atazanavir exposure, it is recommended that REYATAZ 300 mg with ritonavir 100 mg be coadministered with efavirenz 600 mg (all as a single daily dose with food), as this combination results in atazanavir exposure that approximates the mean exposure to atazanavir produced by 400 mg of REYATAZ alone. REYATAZ without ritonavir should not be coadministered with efavirenz.
RITONAVIR. Coadministration of REYATAZ and ritonavir is currently under
clinical investigation. If REYATAZ is coadministered with ritonavir, it is recommended that REYATAZ 300 mg once daily be given with ritonavir 100 mg once daily with food.
DDI. Coadministration with REYATAZ did not alter exposure to didanosine; however, exposure to atazanavir was markedly decreased by coadministration of REYATAZ with didanosine buffered tablets (presumably due to the increase in gastric pH caused by buffers in the didanosine tablets). In addition, it is
recommended that didanosine be administered on an empty stomach; therefore, REYATAZ should be given (with food) 2 h before or 1 h after didanosine buffered formulations. (Although no interaction is expected with didanosine EC capsules, because didanosine EC capsules are to be given on an empty stomach and REYATAZ is to be given with food, they should be
administered at different times.)
RESISTANCE IN VIVO
HIV-1 isolates with reduced susceptibility to ATV (93 to 183 fold resistant) from 3 different viral strains were selected in vitro by 5 months. The mutations in these HIV-1 viruses appeared to contribute to ATV resistance included N88S, I50L, I84V, A71V, and M46I. Changes were also observed at the protease cleavage sites following drug selection. The I50L substitution, with or without an A71V substitution, conferred ATV resistance in recombinant viral clones in a variety of genetic backgrounds. Recombinant viruses containing the I50L mutation were growth impaired and showed increased susceptibility to other protease inhibitors (amprenavir, indinavir, lopinavir, nelfinavir, ritonavir, and saquinavir).
CROSS-RESISTANCE IN VITRO
ATV susceptibility was evaluated in vitro using a diverse panel of 551 clinical isolates from patients without prior ATV exposure. These isolates exhibited resistance to at least one approved PI, with resistance defined as 2.5 fold change or greater in EC50 relative to a reference strain. Greater than 80% of the isolates resistant to 1 or 2 protease inhibitors (with the majority resistant to nelfinavir) retained susceptibility to ATV despite the presence of key mutations (eg, D30N) associated with PI resistance. Of 104 isolates displaying nelfinavir-specific resistance, 84 retained susceptibility to ATV. There was a clear trend toward decreased ATV susceptibility as isolates exhibited resistance to multiple protease inhibitors. Baseline genotypic and phenotypic analysis of clinical isolates from ATV clinical trials of PI-experienced subjects showed that isolates cross-resistant to multiple protease inhibitors were also highly resistant (61%-95%) to ATV. Greater than 90% of the isolates containing I84V or G48V were resistant to ATV. Greater than 60% of isolates containing L90M, A71V/T, M46I, or a change at V82 were resistant to ATV, and 38% of isolates containing a D30N, mutation in addition to other changes were resistant to ATV. ATV-resistant isolates were highly cross-resistant (51%-100%) to other protease inhibitors (amprenavir, indinavir, lopinavir, nelfinavir, ritonavir, and saquinavir). The I50L and I50V substitutions yielded selective resistance to ATV and amprenavir, respectively, and did not appear to confer cross-resistance.
RESISTANCE IN VIVO
ATV-resistant isolates have been obtained from patients experiencing virologic failure on ATV therapy. There were 14 ATV-resistant isolates from studies of treatment-naive patients (n=96 evaluable isolates) that showed decreases in susceptibilty levels from baseline, and all had an I50L substitution emerge on atazanavir therapy (after an average of 50 weeks of therapy) often in combination with an A71V mutation. Phenotypic analysis of the isolates containing the signature mutation I50L showed atazanavir-specific resistance, which coincided with increased susceptibility to other protease inhibitors (amprenavir, indinavir, lopinavir, nelfinavir, ritonavir, and saquinavir). In contrast, 89% (32 of 36) of atazanavir-resistant isolates from studies of treat-ment-experienced patients (n=67 evaluable isolates) treated with atazanavir (n=26) or atazanavir plus saquinavir (n=10) showed no evidence of the emergence of the I50L substitution. (I think BMS has reported some patients taking ATV+SQV had the I50L). Instead, these isolates displayed decreased susceptibility to multiple protease inhibitors and contained mutations associated with resistance to multiple protease inhibitors. These mutations included I84V, L90M, A71V/T, N88S/D, and M46I, which conferred atazanavir resistance and reduced the clinical response to atazanavir. Generally, if protease inhibitor mutations were present in the HIV-1 of the patient at baseline, atazanavir resistance developed through mutations associated with resistance to other protease inhibitors instead of the I50L mutation. These mutations conferred high cross-resistance to other protease inhibitors with 100% of the isolates resistant to nelfinavir, >80% of the isolates resistant to indinavir, ritonavir, and saquinavir, and >35% of the isolates resistant to amprenavir and lopinavir. Genotypic and/or phenotypic analysis of baseline virus may aid in determining atazanavir susceptibility before initiation of atazanavir therapy.
Effects on Electrocardiogram
Concentration- and dose-dependent prolongation of the PR interval in the electrocardiogram has been observed in healthy volunteers receiving atazanavir. In a placebo-controlled study (AI424-076), the mean (±SD) maximum change in PR interval from the predose value was 24 (±15) msec following oral dosing with 400 mg of atazanavir (n=65) compared to 13 (±11) msec following dosing with placebo (n=67). The PR interval prolongations in this study were asymptomatic. There is limited information on the potential for a pharmacodynamic interaction in humans between atazanavir and other drugs that prolong the PR interval of the electrocardiogram.
Electrocardiographic effects of atazanavir were determined in a clinical pharmacology study of 72 healthy subjects. Oral doses of 400 mg and 800 mg were compared with placebo; there was no concentration-dependent effect of atazanavir on the QTc interval (using FridericiaÕs correction). In 1793 HIV-infected patients receiving antiretroviral regimens, QTc prolongation was comparable in the atazanavir and comparator regimens. No atazanavir-treated healthy subject or HIV-infected patient had a QTc interval >500 msec.
PR Interval Prolongation
Atazanavir has been shown to prolong the PR interval of the electrocardiogram in some patients. In healthy volunteers and in patients, abnormalities in atrioventricular (AV) conduction were asymptomatic and limited to first-degree AV block with rare exceptions. In clinical trials, asymptomatic first-degree AV block was observed in 5.9% of atazanavir-treated patients (n=920), 5.2% of lopinavir/ritonavir-treated patients (n=252), 10.4% of nelfinavir-treated patients (n=48), and in 3.0% of efavirenz-treated patients (n=329). There has been no second- or third-degree AV block. Because of limited clinical experience, atazanavir should be used with caution in patients with preexisting conduction system disease (eg, marked first-degree AV block or second-or
third-degree AV block).
In a pharmacokinetic study between atazanavir 400 mg once daily and diltiazem 180 mg once daily, a CYP3A substrate, there was a 2-fold increase in the diltiazem plasma concentration and an additive effect on the PR interval. When used in combination with atazanavir, a dose reduction of diltiazem by one half should be considered and ECG monitoring is recommended. In a
pharmacokinetic study between atazanavir 400 mg once daily and atenolol 50 mg once daily, there was no substantial additive effect of atazanavir and atenolol on the PR interval. When used in combination with atazanavir, there is no need to adjust the dose of atenolol.
Pharmacokinetic studies between atazanavir and other drugs that prolong the PR interval including beta blockers (other than atenolol), verapamil, and digoxin have not been performed. An additive effect of atazanavir and these drugs cannot be excluded; therefore, caution should be exercised when atazanavir is given concurrently with these drugs, especially those that are
metabolized by CYP3A (eg, verapamil).
ANTIARRYTHIMCS. Coadministration with REYATAZ has the potential to produce
serious and/or life-threatening adverse events and has not been
studied. Concentration monitoring of these drugs is recommended
if they are used concomitantly with REYATAZ.
Hyperbilirubinemia
Most patients taking REYATAZ experience asymptomatic elevations in indirect (unconjugated) bilirubin related to inhibition of UDP-glucuronosyl transferase (UGT). This hyperbilirubinemia is reversible upon discontinuation of REYATAZ.
Hepatic transaminase elevations that occur with hyperbilirubinemia should be evaluated for alternative etiologies. No long-term safety data are avail-able
for patients experiencing persistent elevations in total bilirubin >5 times 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 atazanavir is not recommended since long-term efficacy of reduced doses has not been established. (note: In phase III study 043 at week 24, 22% of patients receiving ATV 400mg daily plus 2 NRTIs had total bilirubin 2.6 x ULN or greater. In study 045 (300mg ATV+100mg RTV once daily at week 15, 40% of patients had bilirubion 2.6 x ULN or greater).
Impaired Hepatic Function
Atazanavir is metabolized and eliminated primarily by the liver. REYATAZ has been studied in adult subjects with moderate to severe hepatic impairment (14 Child-Pugh B and 2 Child-Pugh C subjects) after a single 400-mg dose. The mean AUC(0-o) was 42% greater in subjects with impaired hepatic function than in healthy volunteers. The mean half-life of atazanavir in hepatically
impaired subjects was 12.1 hours compared to 6.4 hours in healthy volunteers. Increased concentrations of atazanavir are expected in patients with moderately or severely impaired hepatic function.
Patients with Hepatic Impairment
REYATAZ should be used with caution in patients with mild to moderate hepatic insufficiency. A dose reduction to 300 mg once daily should be considered for patients with moderate hepatic insufficiency (Child-Pugh Class B). REYATAZ
should not be used in patients with severe hepatic insufficiency (Child-Pugh Class C).
Patients Co-infected With Hepatitis B and/or Hepatitis C Virus
Liver function tests should be monitored in patients with a history of hepatitis B or C. In studies AI424-008 and AI424-034, 74 patients treated with 400 mg of REYATAZ (atazanavir sulfate) once daily, 58 who received efavirenz, and 12 who received nelfi-navir were seropositive for hepatitis B and/or C at study entry. AST levels >5 times the upper limit of normal (ULN) developed
in 9% of the REYATAZ-treated patients, 5% of the efavirenz-treated patients, and 17% of the nelfinavir-treated patients. ALT levels >5 times ULN developed in 15% of the REYATAZ-treated patients, 14% of the efavirenz-treated patients, and 17% of the nelfinavir- treated patients. Within atazanavir and control regimens, no difference in frequency of bilirubin elevations was noted between
seropositive and seronegative patients.
DOSAGE AND ADMINISTRATION
Adults
The recommended dose of REYATAZ (atazanavir sulfate) is 400 mg (two 200-mg capsules) once daily taken with food.
Important dosing information:
Efavirenz. When coadministered with efavirenz, it is recommended that REYATAZ 300 mg and ritonavir 100 mg be given with efavirenz 600 mg (all as a single daily dose with food). REYATAZ without ritonavir should not be coadministered with efavirenz.
Didanosine. When coadministered with didanosine buffered formulations, REYATAZ should be given (with food) 2 hours before or 1 hour after didanosine.
Antacids and buffered medications
Reduced plasma concentrations of atazanavir are expected if antacids, including buffered medications, medications antacids, are administered
with REYATAZ. REYATAZ should be administered 2 h before or 1 h after these medications.
Drug Interactions (see Package Insert and talk with your doctor for full discussion about potential drug-drug interactions)
Atazanavir is an inhibitor of CYP3A and UGT1A1. Coadministration of REYATAZ (atazanavir sulfate) and drugs primarily metab-olized by CYP3A (eg, calcium channel blockers, HMG-CoA reductase inhibitors, immunosuppressants, and sildenafil) or UGT1A1 (eg, irinotecan) may result in increased plasma concentrations of the other drug that could increase or prolong its therapeutic
and adverse effects.
Particular caution should be used when prescribing sildenafil (VIAGRA) in patients receiving protease inhibitors, including REYATAZ. Coadministration
of a protease inhibitor with sildenafil is expected to substantially increase sildenafil concentrations and may result in an increase in sildenafil-associated adverse events, including hypotension, visual changes, and priapism. (See complete prescribing information for sildenafil.)
Concomitant use of REYATAZ with lovastatin or simvastatin is not recommended. Caution should be exercised if HIV protease inhibitors, including REYATAZ, are used concurrently with other HMG-CoA reductase inhibitors that are also metabolized by the CYP3A pathway (eg, atorvastatin). The risk of myopathy, including rhabdomyolysis, may be increased when HIV protease inhibitors, including REYATAZ, are used in combination with these drugs.
Concomitant use of REYATAZ and St. John's wort (Hypericum perforatum), or products containing St. John's wort, is not recommended. Coadministration of protease inhibitors, including REYATAZ, with St. John's wort is expected to substantially decrease concentrations of the protease inhibitor and may result in suboptimal levels of atazanavir and lead to loss of virologic response and possible resistance to atazanavir or to the class of protease inhibitors. Patients taking REYATAZ should not use products containing St. John's wort
(Hypericum perforatum) because coadministration may be expected to reduce
plasma concentrations of atazanavir. This may result in loss of therapeutic
effect and development of resistance.
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