The following dose adjustments are recommended for use of tadalafil (AdcircaTM) with ritonavir:

Co-administration of ADCIRCA in patients on ritonavir:

In patients receiving ritonavir for at least one week, start ADCIRCA at 20 mg once daily. Increase to 40 mg once daily based upon individual tolerability.

Co-administration of ritonavir in patients on ADCIRCA:

Avoid use of ADCIRCA during the initiation of ritonavir. Stop ADCIRCA at least 24 hours prior to starting ritonavir. After at least one week following the initiation of ritonavir, resume ADCIRCA at 20 mg once daily. Increase to 40 mg once daily based upon individual tolerability.

Use of PDE5 inhibitors for the treatment of erectile dysfunction:

It is recommended not to exceed the following doses:

Sildenafil: 25 mg every 48 hours
Tadalafil: 10 mg every 72 hours
Vardenafil: 2.5 mg every 72 hours.

Use with increased monitoring for adverse events.
Sedative/hypnotics:
buspirone, clorazepate, diazepam, estazolam, flurazepam, zolpidem  ↑ sedative/hypnotics  A dose decrease may be needed for these drugs when co-administered with ritonavir.
Sedative/hypnotics:
Parenteral midazolam ↑ midazolam Co-administration of oral midazolam with NORVIR is CONTRAINDICATED. Concomitant use of parenteral midazolam with NORVIR may increase plasma concentrations of midazolam. Co-administration should be done in a setting which ensures close clinical monitoring and appropriate medical management in case of respiratory depression and/or prolonged sedation. Dosage reduction for midazolam should be considered, especially if more than a single dose of midazolam is administered.
Steroids:
dexamethasone, fluticasone, prednisone   A dose decrease may be needed for these drugs when co-administered with ritonavir.
Stimulant:
methamphetamine ↑ methamphetamine Use with caution. A dose decrease of methamphetamine may be needed when co-administered with ritonavir.

Carcinogenesis and Mutagenesis
Carcinogenicity studies in mice and rats have been carried out on ritonavir. In male mice, at levels of 50, 100 or 200 mg/kg/day, there was a dose dependent increase in the incidence of both adenomas and combined adenomas and carcinomas in the liver. Based on AUC measurements, the exposure at the high dose was approximately 0.3-fold for males that of the exposure in humans with the recommended therapeutic dose (600 mg twice-daily). There were no carcinogenic effects seen in females at the dosages tested. The exposure at the high dose was approximately 0.6-fold for the females that of the exposure in humans. In rats dosed at levels of 7, 15 or 30 mg/kg/day there were no carcinogenic effects. In this study, the exposure at the high dose was approximately 6% that of the exposure in humans with the recommended therapeutic dose. Based on the exposures achieved in the animal studies, the significance of the observed effects is not known. However, ritonavir was found to be negative for mutagenic or clastogenic activity in a battery of in vitro and in vivo assays including the Ames bacterial reverse mutation assay using S. typhimurium and E. coli, the mouse lymphoma assay, the mouse micronucleus test and chromosomal aberration assays in human lymphocytes.

Pregnancy, Fertility, and Re