on is likely to result in increased plasma concentrations of clorazepate, diazepam, estazolam and flurazepam and is therefore contraindicated (see section 4.3).
Midazolam is extensively metabolised by CYP3A4. Co-administration with Norvir may cause a large increase in the concentration of this benzodiazepine. No medicinal product interaction study has been performed for the co-administration of Norvir with benzodiazepines. Based on data for other CYP3A4 inhibitors, plasma concentrations of midazolam are expected to be significantly higher when midazolam is given orally. Therefore, Norvir should not be co-administered with orally administered midazolam (see section 4.3), whereas caution should be used with co-administration of Norvir and parenteral midazolam. Data from concomitant use of parenteral midazolam with other protease inhibitors suggest a possible 3 – 4 fold increase in midazolam plasma levels. If Norvir is co-administered with parenteral midazolam, it should be done in an intensive care unit (ICU) or similar setting which ensures close clinical monitoring and appropriate medical management in case of respiratory depression and/or prolonged sedation. Dosage adjustment for midazolam should be considered, especially if more than a single dose of midazolam is administered.
Triazolam
0.125, single dose
200, 4 doses
↑ > 20 fold
↑ 87%
Ritonavir co-administration is likely to result in increased plasma concentrations of triazolam and is therefore contraindicated (see section 4.3).
Pethidine
Norpethidine metabolite
50, oral single dose
500 q12h
62%
↑ 47%
59%
↑ 87%
The use of pethidine and ritonavir is contraindicated due to the increased concentrations of the metabolite, norpethidine, which has both analgesic and CNS stimulant activity. Elevated norpethidine concentrations may increase the risk of CNS effects (eg, seizures), see section 4.3.
Alprazolam
1, single dose
200 q12h, 2 days
↑2.5 fold
↔
500 q12h, 10 days
12%
16%
Alprazolam metabolism was inhibited following the introduction of ritonavir. After ritonavir use for 10 days, no inhibitory effect of ritonavir was observed. Caution is warranted during the first several days when alprazolam is co-administered with ritonavir dosed as an antiretroviral agent or as a pharmacokinetic enhancer, before induction of alprazolam metabolism develops.
Buspirone
Ritonavir dosed as a pharmacokinetic enhancer or as an antiretroviral agent inhibits CYP3A and as a result is expected to increase the plasma concentrations of buspirone. Careful monitoring of therapeutic and adverse effects is recommended when buspirone concomitantly administered with ritonavir.
Sleeping agent
Zolpidem
5
200, 4 doses
↑ 28%
↑ 22%
Zolpidem and ritonavir may be co-administered with careful monitoring for excessive sedative effects.
Smoke cessation
Bupropion
150
100 q12h
22%
21%
150
600 q12h
66%
62%
Bupropion is primarily metabolised by CYP2B6. Concurrent administration of bupropion with repeated doses of ritonavir is expected to decrease bupropion levels. These effects are though |
