| |
Reyataz Drug Interactions: Tenofovir; Viagra/Cialis/Levitra; buffered ddI; Antacids: dosing recommendations from the FDA
|
| |
| |
Reported by Jules Levin
March 21, 2004
The FDA sent a notice out this past week regarding drug-drug interactions between Reyataz (atazanavir) and tenofovir (Viread) and also Viagra and similar drugs. Here is the information as it appears in the FDA Package Insert, also called the Label.
New drug interaction information has led to the following changes in theCLINICAL PHARMACOLOGY section of the REYATAZ (atazanavir sulfate) label -
Table 2: Drug Interactions: Pharmacokinetic Parameters for Atazanaivr inthe Presence of Coadministered Drugs and Table 3: Drug Interactions:Pharmacokinetic Parameters for Coadministered Drugs in the Presence ofREYATAZ were revised to include results from the tenofovir interactionstudies.
The following information was added to the PRECAUTION: Drug Interactionsection -
Table 9: Established and Other Potentially Significant Drug Interactions.Specifically the following statement was included
--Tenofovir decreases the AUC (area under the curve) and Cmin (minimumconcentration) of REYATAZ. When coadministered with tenofovir, it isrecommended that REYATAZ 300 mg is given with ritonavir 100 mg and tenofovir 300 mg (all as a single daily dose with food). REYATAZ without ritonavir should not be coadministered with tenofovir.
--REYATAZ increases tenofovir concentrations. The mechanism of thisinteraction is unknown. Higher tenofovir concentrations could potentiatetenofovir-associated adverse events, including renal disorders. Patientsreceiving REYATAZ and tenofovir should be monitored for tenofovir-associatedadverse events.
The following information was added to the DOSAGE AND ADMINISTRATIONsection.
--When coadministered with tenofovir, it is recommended that REYATAZ 300 mg is given with ritonavir 100 mg and tenofovir 300 mg (all as a single dailydose with food). REYATAZ without ritonavir should not be coadministered withtenofovir.
|
Table 3: Drug Interactions: Pharmacokinetic Parameters for Coadministered Drugs in the Presence of REYATAZ
|
Drug Pharmacokinetic Parameters with/without
REYATAZ;
No effect = 1.00
|
|
Coadministered drug dose/ schedule tenofovir
|
Reyataz dose/ schedule
|
n
|
Cmax
|
AUC
|
Cmin
|
|
300 mg QD d 9-16 and d 24-30
|
400 mg QD, d 2-16
|
33
|
1.14 (1.08,1.20)
|
1.24 (1.21, 1.28)
|
1.22 (1.15, 1.30)
|
|
Table 2: Drug Interactions: Pharmacokinetic Parameters for Atazanavir in the Presence of Coadministered Drugs
|
|
Tenofovir 300 mg QD d 9-16
|
Reyataz 400 mg QD d 2-16
|
34
|
0.79 (0.73,amp; 0.86)
|
0.75 (0.70,amp; 0.81)
|
0.60 (0.52,amp; 0.68)
|
|
300 mg QD d 15-42
|
300 mg/ritonavir 100 mg QD,amp; d 1-42
|
10
|
0.72f (0.50,amp; 1.05)
|
0.75 f (0.58,amp; 0.97)
|
0.77 f (0.54,amp; 1.10)
|
The data below compares Reyataz blood levels as 400mg monotherapy, 300mg boosted with 100mg RTV, and 300mg+100mg RTV+tenofovir. Although tenofovir reduces Reyataz blood levels when using boosting with 100mg RTV plus TDF this results in higher levels of Reyataz than when Reyataz is used as 400mg monotherapy without the RTV boost.
f-Ratio of atazanavir plus ritonavir plus tenofovir to atazanavir plus ritonavir. Atazanavir 300 mg plus ritonavir 100 mg results in higher atazanavir exposure than atazanavir 400 mg (see footnote d). The geometric mean values of atazanavir pharmacokinetic parameters when coadministered with ritonavir and tenofovir were: Cmax = 3190 ng/mL, AUC = 34459 ng·h/mL, and Cmin = 491 ng/mL.
d-Compared with atazanavir 400 mg QD historical data, administration of atazanavir/ritonavir 300/100 mg QD increased the atazanavir geometric mean values of Cmax, AUC, and Cmin by 18%, 103%, and 671%, respectively. The geometric mean values of atazanavir pharmacokinetic parameters when coadministered with ritonavir were: Cmax = 6129 ng/mL, AUC = 57039 ng·h/mL, and Cmin = 1227 ng/mL.
Table 1: Steady-State Pharmacokinetics of Atazanavir in HIV-Infected Patients in the Fed State After Atazanavir 400 mg Once Daily (geometric mean values): Cmax=2298 ng/mL, AUC= 14874 ng·h/mL, Cmin= 120 ng/mL.
VIAGRA, CIALIS, LEVITRA
Further, information regarding PDE5 inhibitors (sildenafil [Viagra],tadalafil [Cialis] and vardenafil [Levitra]) was added to the WARNINGS andPRECAUTION sections. The information included is consistent with therecently approved Invirase and Fortovase label.
In addition, the patient package insert was revised to include informationregarding tenofovir and PDE5 inhibitors (sildenafil, tadalafil, vardenafil).
PDE5 inhibitors:
Sildenafil (VIAGRA)
tadalafil
vardenafil
Coadministration with REYATAZ has not been studied but may result in an increase in PDE5 inhibitor-associated adverse events, including hypotension, visual changes, and priapism. Use sildenafil with caution at reduced doses of 25 mg every 48 hours with increased monitoring for adverse events. Use tadalafil with caution at reduced doses of 10 mg every 72 hours with increasedmonitoring for adverse events. Use vardenafil with caution at reduced doses of no more than 2.5 mg every 72 hours with increased monitoring for adverse events.
ADDITIONAL INFORMATION
Food Effect: take Reyataz with food
Administration of REYATAZ with food enhances bioavailability and reducespharmacokinetic variability. Administration of a single 400-mg dose of REYATAZ with a light meal (357 kcal, 8.2 g fat, 10.6 g protein) resulted in a 70% increase in AUC and 57% increase in Cmax relative to the fasting state. Administration of a single 400-mg dose of REYATAZ with a high-fat meal (721 kcal, 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. Administration of REYATAZ with either a light meal or high-fat meal decreased the coefficient of variation of AUC and Cmax by approximately one half compared to the fasting state (less variability in AUC).
Special Populations
Age/Gender
A study of the pharmacokinetics of atazanavir was performed in young (n=29; 18-40 years) and elderly (n=30; >=65 years) healthy subjects. There were no clinically important pharmacokinetic differences observed due to age or gender.
Race
There are insufficient data to determine whether there are any effects of race on the pharmacokinetics of atazanavir.
Pediatrics
The pharmacokinetics of atazanavir in pediatric patients are under investigation. There are insufficient data at this time to recommend a dose.
Impaired Renal Function
In healthy subjects, the renal elimination of unchanged atazanavir was approximately 7% of the administered dose. There are no pharmacokinetic data available on patients with impaired renal function.
Impaired Hepatic Function: Reyataz levels increased in patients with moderate to severe hepatic impairment
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-∞) 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.
Coadministration of REYATAZ with didanosine buffered tablets did not alter exposure to didanosine; however, exposure to atazanavir was markedly decreased (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. Because didanosine EC capsules are to be given on an empty stomach andREYATAZ is to be given with food, they should be administered at different times.
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.
ANTACIDS
Reduced plasma concentrations of atazanavir are expected if antacids, including buffered medications, are administered with REYATAZ. REYATAZ should be administered 2 h before or 1 h after these medications.
|
|
| |
| |
|
|
|
