ral therapy (CART). The frequency of this is unknown (see section 4.4).
4.9 Overdose
Human experience of acute overdose with ritonavir is limited. One patient in clinical trials took ritonavir 1500 mg/day for two days and reported paraesthesia, which resolved after the dose was decreased. A case of renal failure with eosinophilia has been reported.
The signs of toxicity observed in animals (mice and rats) included decreased activity, ataxia, dyspnoea and tremors.
There is no specific antidote for overdose with ritonavir. Treatment of overdose with ritonavir should consist of general supportive measures including monitoring of vital signs and observation of the clinical status of the patient. Due to the solubility characteristics and possibility of transintestinal elimination, it is proposed that management of overdose could entail gastric lavage and administration of activated charcoal. Since ritonavir is extensively metabolised by the liver and is highly protein bound, dialysis is unlikely to be beneficial in significant removal of the medicine.
5. PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Pharmaco-therapeutic group: antiviral for systemic use, protease inhibitors ATC code: J05AE03
Ritonavir dosed as a pharmacokinetic enhancer
Pharmacokinetic enhancement by ritonavir is based on ritonavir's activity as a potent inhibitor of CYP3A- mediated metabolism. The degree of enhancement is related to the metabolic pathway of the co-administered protease inhibitor and the impact of the co-administered protease inhibitor on the metabolism of ritonavir. Maximal inhibition of metabolism of the co-administered protease inhibitor is generally achieved with ritonavir doses of 100 mg daily to 200 mg twice daily, and is dependent on the co-administered protease inhibitor. For additional information on the effect of ritonavir on co-administered protease inhibitor metabolism, see section 4.5 and refer to the Summary of Product Characteristics of the particular co-administered PIs.
Ritonavir dosed as an antiretroviral agent
Ritonavir is an orally active peptidomimetic inhibitor of the HIV-1 and HIV-2 aspartyl proteases. Inhibition of HIV protease renders the enzyme incapable of processing the gag-pol polyprotein precursor which leads to the production of HIV particles with immature morphology that are unable to initiate new rounds of infection. Ritonavir has selective affinity for the HIV protease and has little inhibitory activity against human aspartyl proteases.
Ritonavir was the first protease inhibitor (approved in 1996) for which efficacy was proven in a study with clinical endpoints. However, due to ritonavir's metabolic inhibitory properties its use as a pharmacokinetic enhancer of other protease inhibitors is the preva lent use of ritonavir in clinical practice (see section 4.2).
Effects on the Electrocardiogram
QTcF interval was eva luated in a randomised, placebo and active (moxifloxacin 400 mg once daily) controlled crossover study in 45 healthy adults, with 10 measurements over 12 hours on Day 3. The maximum mean (95% upper confidence bound) difference in QTcF from placebo was 5.5 (7.6) for 400 mg twice daily ritonavir. The Day 3 ritonavir exposure was approximately 1.5 fold higher than that observed with the 600 mg twice daily dose at steady state. No subject experienced an increase in QTcF of 60 msec from baseline or a QTcF interval exceeding the potentially clinically relevant t |
