Source: European Medicines Agency (EU) Revision Year: 2019 Publisher: Mylan S.A.S., 117 Allée des Parcs, Saint-Priest, 69800, France
Ritonavir is indicated in combination with other antiretroviral agents for the treatment of HIV-1 infected patients (adults and children of 2 years of age and older).
Ritonavir Mylan should be administered by physicians who are experienced in the treatment of HIV infection.
When ritonavir is used as a pharmacokinetic enhancer with other protease inhibitors the Summary of Product Characteristics for the particular protease inhibitor must be consulted.
The following HIV-1 protease inhibitors have been approved for use with ritonavir as a pharmacokinetic enhancer at the noted doses.
Adults:
Amprenavir 600 mg twice daily with ritonavir 100 mg twice daily.
Atazanavir 300 mg once daily with ritonavir 100 mg once daily.
Fosamprenavir 700 mg twice daily with ritonavir 100 mg twice daily.
Lopinavir co-formulated with ritonavir (lopinavir/ritonavir) 400 mg/100 mg or 800 mg/200 mg.
Saquinavir 1,000 mg twice daily with ritonavir 100 mg twice daily in ART experienced patients. Initiate treatment with saquinavir 500 mg twice daily with ritonavir 100 mg twice daily for the first 7 days, then saquinavir 1,000 mg twice daily with ritonavir 100 mg twice daily in ART-naïve patients.
Tipranavir 500 mg twice daily with ritonavir 200 mg twice daily. Tipranavir with ritonavir should not be used in treatment-naïve patients.
Darunavir 600 mg twice daily with ritonavir 100 mg twice daily in antiretroviral treatment. (ART) experienced patients. Darunavir 800 mg once daily with ritonavir 100 mg once daily may be used in some ART experienced patients. Refer to the darunavir Summary of Product Characteristics for further information on once daily dosing in ART experienced patients.
Darunavir 800 mg once daily with ritonavir 100 mg once daily in ART-naïve patients.
Children and adolescents:
Ritonavir is recommended for children 2 years of age and older. For further dosage recommendations, refer to the product information of other Protease Inhibitors approved for co-administration with ritonavir.
Renal impairment:
As ritonavir is primarily metabolised by the liver, ritonavir may be appropriate for use with caution as a pharmacokinetic enhancer in patients with renal insufficiency depending on the specific protease inhibitor with which it is co-administered. However, since the renal clearance of ritonavir is negligible, the decrease in the total body clearance is not expected in patients with renal impairment. For specific dosing information in patients with renal impairment, refer to the Summary of Product Characteristics (SPC) of the co-administered protease inhibitor.
Hepatic impairment:
Ritonavir should not be given as a pharmacokinetic enhancer to patients with decompensated liver disease, (see section 4.3). In the absence of pharmacokinetic studies in patients with stable severe hepatic impairment (Child Pugh Grade C) without decompensation, caution should be exercised when ritonavir is used as a pharmacokinetic enhancer as increased levels of the co-administered PI may occur. Specific recommendations for use of ritonavir as a pharmacokinetic enhancer in patients with hepatic impairment are dependent on the protease inhibitor with which it is co-administered. The SPC of the co-administered PI should be reviewed for specific dosing information in this patient population.
The recommended dose of ritonavir is 600 mg (6 tablets) twice daily (total of 1,200 mg per day) by mouth.
Gradually increasing the dose of ritonavir when initiating therapy may help to improve tolerance. Treatment should be initiated at 300 mg (3 tablets) twice daily for a period of three days and increased by 100 mg (1 tablet) twice daily increments up to 600 mg twice daily over a period of no longer than 14 days. Patients should not remain on 300 mg twice daily for more than 3 days.
The recommended dosage of ritonavir in children is 350 mg/m 2 by mouth twice daily and should not exceed 600 mg twice daily. Ritonavir should be started at 250 mg/m 2 and increased at 2 to 3 day intervals by 50 mg/m 2 twice daily.
Other pharmaceutical forms/strengths may be more appropriate for administration to this population.
For older children it may be feasible to substitute tablets for the maintenance dose of other pharmaceutical forms.
Dosage conversion from oral solution to tablets for children:
| Oral solution dose | Tablet dose |
|---|---|
| 175 mg (2.2 ml) twice daily | 200 mg in the morning and 200 mg in the evening |
| 350 mg (4.4 ml) twice daily | 400 mg in the morning and 300 mg in the evening |
| 437.5 mg (5.5 ml) twice daily | 500 mg in the morning and 400 mg in the evening |
| 525 mg (6.6 ml) twice daily | 500 mg in the morning and 500 mg in the evening |
Ritonavir is not recommended in children below 2 years of age due to lack of data on safety and efficacy.
Pharmacokinetic data indicated that no dose adjustment is necessary for elderly patients (see section 5.2).
Currently, there are no data specific to this patient population and therefore specific dosage recommendations cannot be made. The renal clearance of ritonavir is negligible therefore; a decrease in the total body clearance is not expected in patients with renal impairment. Because ritonavir is highly protein bound it is unlikely that it will be significantly removed by haemodialysis or peritoneal dialysis.
Ritonavir is principally metabolised and eliminated by the liver. Pharmacokinetic data indicate that no dose adjustment is necessary in patients with mild to moderate hepatic impairment (see section 5.2). Ritonavir must not be given to patients with severe hepatic impairment (see section 4.3).
The safety and efficacy of ritonavir in children aged below 2 years has not been established. Currently available data are described in sections 5.1 and 5.2 but no recommendation on a posology can be made.
Ritonavir Mylan film-coated tablets are administered orally and should be ingested with food (see section 5.2).
Ritonavir Mylan film-coated tablets should be swallowed whole and not chewed, broken or crushed.
Human experience of acute overdose with ritonavir is limited. One patient in clinical trials took ritonavir 1,500 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.
Shelf-life: 2 years.
After first opening, use within 100 days.
Do not store above 30°C.
Store in the original bottle in order to protect from moisture.
HDPE bottle with polypropylene screw cap with inbuilt desiccant.
Pack sizes: 30, 90, 100 and multipack containing 90 (3 bottles of 30) film-coated tablets.
Not all pack sizes may be marketed.
No special requirements.
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