Ritonavir should be administered by physicians who are experienced in the treatment of HIV infection.
Norvir solution is administered orally and should preferably be ingested with food.
Ritonavir dosed as a pharmacokinetic enhancer
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.
Adult use:
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/200mg.
Saquinavir 1000 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 1000 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 SmPC for further information on once daily dosing in ART experienced patients.
Darunavir 800mg once daily with ritonavir 100 mg once daily in ART-naïve patients
Paediatric use: 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. Norvir is not recommended in children below 2 years of age due to lack of data on safety and efficacy.
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.
Ritonavir dosed as an antiretroviral agent
Adult use: The recommended dosage of Norvir solution is 600 mg (7.5 ml) twice daily by mouth.
Gradually increasing the dose of ritonavir when initiating therapy may help to improve tolerance. Treatment should be initiated at 300 mg (3.75 ml) twice daily for a period of three days and increased by 100 mg (1.25 ml) 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.
Paediatric use (2 years of age and above): the recommended dosage of Norvir solution in children is 350 mg/m2 by mouth twice daily and should not exceed 600 mg twice daily. Norvir should be started at 250 mg/m2 and increased at 2 to 3 day intervals by 50 mg/m2 twice daily. When possible, the dose should be administered using a calibrated dosing syringe.
Paediatric Dosage Guidelines
|
Body Surface area* (m2)
|
Twice daily dose 250 mg/m2
|
Twice daily dose 300 mg/m2
|
Twice daily dose 350 mg/m2
|
|
0.25
|
0.8 ml (62.5 mg)
|
0.9 ml (75 mg)
|
1.1 ml (87.5 mg)
|
|
0.50
|
1.6 ml (125 mg)
|
1.9 ml (150 mg)
|
2.2 ml (175 mg)
|
|
1.00
|
3.1 ml (250 mg)
|
3.8 ml (300 mg)
|
4.4 ml (350 mg)
|
|
1.25
|
3.9 ml (312.5 mg)
|
4.7 ml (375 mg)
|
5.5 ml (437.5 mg)
|
|
1.50
|
4.7 ml (375 mg)
|
5.6 ml (450 mg)
|
6.6 ml (525 mg)
|
* Body surface area can be calculated with the following equation
BSA (m2) = √(Height (cm) X Weight (kg) / 3600)
Doses for intermediate body surface areas not included in the above table can be calculated using the following equations:
To calculate the volume to be administered (in ml) the body surface area should be multiplied by a factor of: 3.1 for a dose of 250 mg/m2; 3.8 for one of 300 mg/m2; and by 4.4 for 350 mg/m2.
Ritonavir oral solution also contains propylene glycol (26.0% v/v). Total amounts of alcohol and propylene glycol from all medicines, including ritonavir oral solution, that are to be given to infants should be taken into account in order to avoid toxicity from these excipients (see section 4.4).
Renal impairment: 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.
Hepatic impairment: 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 should not be given to patients with severe hepatic impairment (see section 4.3).
Older People: Pharmacokinetic data indicated that no dose adjustment is necessary for older patients (see section 5.2).
The bitter taste of Norvir solution may be lessened if mixed with chocolate milk.
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
When ritonavir is used as a pharmacokinetic enhancer of other PIs, consult the Summary of Product Characteristics of the co-administered protease inhibitor for contraindications.
Ritonavir should not be given as a pharmacokinetic enhancer or as an antiretroviral agent to patients with decompensated liver disease.
In vitro and in vivo studies have demonstrated that ritonavir is a potent inhibitor of CYP3A- and CYP2D6- mediated biotransformations. The following medicines are contraindicated when used with ritonavir and unless otherwise noted, the contraindication is based on the potential for ritonavir to inhibit metabolism of the co-administered medicinal product, resulting in increased exposure to the co-administered medicinal product and risk of clinically significant adverse effects.
The enzyme-modulating effect of ritonavir may be dose dependent. For some products, contraindications may be more relevant when ritonavir is used as an antiretroviral agent than when ritonavir is used as a pharmacokinet
