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How ritonavir works
Ritonavir is a member of the group of drugs referred to as protease inhibitors (PIs). This class of drug combats viral replication of HIV by blocking HIV's protease protein. This protein or enzyme is used by HIV to break up large viral proteins into smaller particles from which new HIV particles can be formed. Protease inhibitors ensure that these new particles are immature and incapable of infecting new cells, thus inhibiting the HIV replication process.
HISTORY
Ritonavir was formerly known as ABT-538 and A-84,538. Ritonavir was first licensed in Europe and the USA in late 1996 as an oral solution. It was later developed into capsule formulation. Both formulations are still available. The licence was granted for the use of ritonavir in combination with other antiretroviral agents for the treatment of HIV-1 in adults and children of two years of age and older.
Combination therapy
Ritonavir is established as an effective component of combination antiretroviral therapy against an optimal antiretroviral background, it should not be used as monotherapy as resistant viruses rapidly emerge. Careful consideration needs to be applied when incorporating ritonavir into HIV combination therapy, as several interactions with other antiretrovirals have been observed.
If used in combination with the NNRTI efavirenz both levels are increased, increasing the likelihood of CNS side effects. If ritonavir is used alongside other protease inhibitors interactions should be carefully considered, for example when used with nelfinavir or saquinavir the nelfinavir or saquinavir levels are raised. Indinavir levels are also raised when used alongside ritonavir, increasing the likelihood of kidney stones. These interactions may indicate the necessity for dose modifications.
DOSING
Ritonavir is produced in two formulations - 100mg capsules and oral solution. The recommended adult daily dose of ritonavir is six 100mg capsules taken twice daily with food. The recommended dose of ritonavir capsules or oral solution for children two years or older is 350mg/m2 twice daily and should not exceed 600mg twice daily. Dosing should start at 250mg/m2 and be increased at 2 to 3 day intervals by 50mg/m2 twice daily.
Dosing restrictions
Ritonavir should be taken with food. Ritonavir is metabolised by the CYP3A4 enzyme. Any drug that inhibits or accelerates this process is likely to impact on the levels of ritonavir in the blood. Sub-optimal levels of ritonavir in the blood increase the risk of resistance developing. Similarly any drug that shares this metabolic pathway is likely to be affected by the co-administration of ritonavir, for this reason there are dosing restrictions or recommended dose modifications.
Drug interactions with ritonavir include:
St. John's Wort should not be taken with ritonavir as it reduces plasma levels of ritonavir and can therefore potentially reduce its efficacy
Caution should be taken when administering ritonavir alongside other PIs and NNRTIs, drug interactions should be considered
Levels of sildenafil (Viagra(r)) in the body are increased in the presence of ritonavir, a reduced dose of 25mg sildenafil is recommended
Co-administration of ritonavir with rifampicin (TB medication) results in decreased levels of ritonavir, alternatives should be sought
Ritonavir should not be administered alongside:
Certain painkillers (e.g. piroxicam), anti-arrhythmic drugs (e.g. amiodarone), anti-depressants (e.g. bupropion), anti-histamines (e.g. terfenadine), anti-psychotic (e.g. clozapine), anxiolytics (e.g.diazepam), anti-dyspepsia (e.g. cisapride) and certain sedatives (e.g.midazolam)
If using the antibiotic clarithromycin while on ritonavir, it may be necessary to reduce the clarithromycin dose in patients with kidney impairment
When ritonavir is administered alongside methadone, reductions in methadone levels have been observed and may require dose adjustment
The efficacy of the oral contraceptive is reduced if ritonavir is administered, other contraceptive methods are recommended.
Warfarin levels may be reduced in the presence of ritonavir
Side effects
Some of the common side effects of ritonavir are related to gastro-intestinal disturbance. These are likely to occur in the first few weeks after commencing treatment. Common side effects include:
Diarrhoea
Nausea
Vomiting
Abdominal pain
Dyspepsia
Loss of appetite
Taste perversion
Tingling or numbness
Fatigue
Headache
Rash
Other side effects associated with ritonavir and common to all the protease inhibitors include:
Lipodystrophy (although incidence and degree varies between all PIs)
Myopathy (muscle disease)
Increased bleeding in those with bleeding disorders
Increase in blood fats
Diabetes
Pancreatitis
Storage
Ritonavir capsules stored at room temperature should be used within 30 days. Stocks stored in the refrigerator should be used by the expiry date. Ritonavir oral solution should be stored at room temperature and not refrigerated. Oral solution should be shaken thoroughly before administering.
Pre-existing conditions
Ritonavir soft capsules and oral solution should not be used in patients with severe liver impairment, caution should be exercised in those with mild liver impairment.
All protease inhibitors, including ritonavir, have been associated with increased bleeding in patients with bleeding disorders, these patients may require additional clotting agents if protease inhibitors are included in their antiretroviral combination therapy.
Patients taking the anti-coagulant warfarin may experience reduced levels of warfarin if co-administered with ritonavir. Patients with TB should not be co-administered ritonavir and rifabutin. Women should not breastfeed if taking ritonavir.
Paediatric use
Ritonavir is licensed for use in children of two years or over. Both capsules and oral solution are available and follow the same dosing recommendations. The oral solution is more palatable if mixed with chocolate milk.
Use during pregnancy
There are no adequate and well-controlled studies of ritonavir in pregnant women. For this reason ritonavir should only be used during pregnancy if the benefits justify any potential risks. In addition, it is not known whether ritonavir is excreted into breast milk, mothers should be advised not to breastfeed their infants if receiving ritonavir.
Ritonavir-resistant HIV
It is widely accepted that all protease inhibitors experience an element of cross-resistance within the group.
