Taking it

Ritonavir (Norvir) is available in 100mg capsules and in liquid formulations (80mg/ml). It was first formulated as a liquid or oral solution, but after complaints about its unpleasant taste, ritonavir capsules were developed. Once dispensed, ritonavir capsules can be stored out of a refrigerator for up to a month, as long as they are kept below 25°C.

A 100mg heat-stable ritonavir tablet, approved in the European Union in early 2010, does not require refrigeration.

Ritonavir should be used with at least two other antiretroviral drugs. However, ritonavir is now rarely dosed as the only protease inhibitor in a combination, due to problems with tolerability. Instead, it is usually used to boost levels of other protease inhibitors.

Controversially, in late 2003 Abbott increased the price of ritonavir fourfold in the United States, a move which has led many clinicians to boycott the company’s products and clinical trials. However, the company has agreed to supply the drug at the previous price to research studies of unlicensed products where it is needed for boosting, and free to patients without insurance coverage or who exceed their annual maximum budget for prescription drug costs.

The full adult dose of ritonavir, when taken as a single protease inhibitor, is 600mg twice a day. Patients taking this dose should begin at a lower dose, such as 300mg twice a day, before gradually building up to the full dose over two weeks.

Taking ritonavir within two hours of a meal reduces nausea and increases the amount of the drug that the body absorbs. It should be taken with food, if possible.

Liver disease may increase levels of ritonavir in the body substantially, although there is considerable individual variation. A dose reduction to 500mg twice a day may be considered for people with mild liver impairment. However, ritonavir should not be taken by people with severe liver problems.

The side-effects seen with the 600mg twice-daily dose of ritonavir have led some researchers and practitioners to consider dosing the drug at 400mg twice daily. Although preliminary results of a small study comparing the standard and low doses found similar proportions of people achieving undetectable viral loads, but with fewer side-effects in the lower dose, the trial design has been seriously criticised.¹ The lower dose is not currently recommended.

Ritonavir inhibits the activity of the gut and liver enzymes that break down protease inhibitors and clear them from the body. Taking a low dose of ritonavir alongside another protease inhibitor therefore increases the concentration of the other protease inhibitor in the blood and maintains it at effective levels in the blood for longer.

Combining ritonavir at a dose of 100 to 200mg once or twice a day with another protease inhibitor produces a stronger and more durable antiviral effect, which is of use in many anti-HIV drug combinations, including first-line and salvage therapy. Adding low-dose ritonavir can also make drug combinations easier to take. For example, ritonavir-boosted indinavir (Crixivan) is taken twice daily with food, whereas indinavir alone must be taken three times a day on an empty stomach.

The disadvantage of combining two protease inhibitors is the increased risk of short-term side-effects, such as nausea and diarrhoea, and long-term metabolic irregularities associated with protease inhibitors.

In adults, low-dose ritonavir can be administered with other protease inhibitors at the following doses: 

• Atazanavir (Reyataz): 300mg with 100mg ritonavir once a day.
• Darunavir (Prezista): 600mg with 100mg ritonavir twice a day.
• Fosamprenavir (Telzir): 700mg with 100mg ritonavir twice a day. In the United States, 1400mg fosamprenavir with 200mg ritonavir once a day is also approved.
• Indinavir is not licensed for combination with ritonavir, but 400mg with 100mg ritonavir or 600mg with 200mg ritonavir twice a day seem to be the best doses in terms of efficacy and side-effects.² Combining ritonavir and indinavir removes the need for the food restrictions normally associated with indinavir.
• Lopinavir is only approved for use in combination with ritonavir and is only available in a fixed-dose combination with ritonavir, marketed as Kaletra. The standard dose is 400mg lopinavir with 100mg ritonavir twice a day.
• Nelfinavir (Viracept) is not licensed for combination with ritonavir, but 500mg with 400mg ritonavir twice a day, and 2000mg with 200mg ritonavir once a day have been studied.
• Saquinavir (Invirase): 1000mg with 100mg ritonavir twice a day.
• Tipranavir (Aptivus): 500mg with 200mg ritonavir twice a day.³

Some pharmacokinetic studies have suggested that a 50 mg boosting dose of ritonavir  may be sufficient for some protease inhibitors and have encouraged clinical trials to investigate this dosing.⁴