Like other protease inhibitors, atazanavir (Reyataz) is metabolised
through the cytochrome P450 system, and is a specific inhibitor of the CYP3A4
enzyme. This means that it may interact with a wide variety of drugs also
metabolised through this pathway.
Many other drugs using the CYP3A4 enzyme should not be given with
atazanavir, as their levels may be increased in the body. These include:
- Alfuzosin
- Astemizole
- Bepridil
- Cisapride
- Colchicine in
people with renal or hepatic impairment
- Ergotamine
tartrate (Cafergot / Migril)
- Flecainide
acetate (Tambocor)
- Fluticasone
propionate (Flixotide)
- Halofantrine
- Hypericin (St
John’s wort)
- Lovastatin
- Lumefantrine
- Midazolam (Hypnovel)
- Pimozide (Orap)
- Propafenone (Arythmol)
- Quinidine (Kinidin
Durules)
- Rifampicin (Rifadin
/ Rimactane)
- Simvastatin (Zocor)
- Terfenadine
- Triazolam
- Voriconazole
(Vfend).
Atazanavir also inhibits P-glycoprotein and the multidrug
resistance-associated protein, which pump foreign substances, including some
drugs, out of cells. This could explain the observation that the blood
disorders caused by many chemotherapy drugs are more severe in people taking
protease inhibitors.
When atazanavir is taken with drugs to treat acid reflux disease and related
symptoms, the AUC of atazanavir decreases significantly. Studies have shown
that taking atazanavir with proton pump inhibitors such as omeprazole (Losec)
and esomeprazole (Nexium) or H2-receptor blockers (e.g. ranitidine/Zantac
and cimetidine/Dyspamet, Tagamet) results in lowered blood
atazanavir concentrations in HIV-negative people.
Proton pump inhibitors should not be used in treatment-experienced people
receiving atazanavir. In treatment-naive people, the proton pump inhibitor dose
should not exceed a dose comparable to omeprazole 20mg and must be taken
approximately 12 hours prior to the atazanavir/ritonavir 300/100mg dose.
According to the Bristol-Myers Squibb package insert, treatment-naive people
taking omeprazole (or other proton pump inhibitor drugs) with
an atazanavir-containing regimen decrease atazanavir exposure by
30 to 65%. When use of the two drugs is unavoidable, the drugs should be
taken 12 hours apart, close clinical monitoring is recommended, and an
increase in the atazanavir dose to 400mg boosted
with 100mg ritonavir is recommended.
In treatment-experienced people on an atazanavir-containing
regimen, the H2-receptor antagonist dose should not exceed the
dose-equivalent of 20mg famotidine taken twice daily. Atazanavir and
ritonavir should be administered simultaneously with, or at least 10 hours
after, the H2-receptor antagonist.
This advisory was issued despite an earlier study carried out in
HIV-positive people that failed to show reduced atazanavir levels when
combined with low-dose ritonavir.1 In
that study, proton pump inhibitors did not have a significant effect
on the outcomes of antiretroviral therapy containing ritonavir-boosted
atazanavir.2
The study investigators claim that the effects of omeprazole may be less
important in people with HIV because of possible reduced stomach acid
levels. Differences in study design and variability in drug levels may have
also led to confusion over the relationship between these drugs.3
When atazanavir is dosed with efavirenz (Sustiva), atazanavir levels
are reduced by around 70%. Adding low-dose ritonavir counteracts this effect in
HIV-negative volunteers, but a small study has found that this may not be the
case in people with HIV.4 5 6 A similar effect
of nevirapine has also been seen in a small study. Both drugs are CYP3A4
inducers, which means that they speed up metabolism of other drugs metabolised
by the same route.7
Combining atazanavir with tenofovir (Viread) may put an individual at
risk of treatment failure, since tenofovir can reduce atazanavir levels by up
to 40%.8 9 Atazanavir can also increase the likelihood of
tenofovir-associated adverse events, including kidney disorders. Doctors should
consider boosting atazanavir levels with ritonavir, if atazanavir and tenofovir
must be used together, although studies have shown that this is not always
successful in restoring atazanavir levels.10
Sildenafil is contraindicated when used for treatment of pulmonary arterial
hypertension.
Atazanavir is contraindicated for use with the hepatitis C direct-antiviral
combination elbasvir/grazoprevir (Zepatier).
Use of simeprevir (Olysio) with
atazanavir is not recommended. The daily dose of daclatasvir (Daklinza) should be reduced to 30mg when
used with atazanavir.
Some drugs require dose adjustments when taken with atazanavir. The
following drugs need to be taken at lower doses:
- Clarithromycin
(Klaricid / Klaricid EC): the dose should be halved.
- Diltiazem
(Tildiem / Angiozem / Optil): the dose should be halved.
- Rifabutin
(Mycobutin): the dose should be reduced by up to 75% (150mg every
day or three times a week) when atazanavir is dosed at 400mg once daily.11
Atazanavir has been observed to increase levels of the hormonal
contraceptives ethinylestradiol and norethindrone. No guidance is available at
present on appropriate dose reductions or interactions with other
contraceptives. There have also been at least three case reports of elevated
levels of buprenorphine, which is used to treat opiate addiction, in people
taking atazanavir.12 A dose reduction may be necessary. In contrast,
no dose adjustment of methadone (Methadose) is needed.13