Tracy Barnes explains MK-639, L-735,524 - better known as indinavir or Crixivan® - one of the first licensed protease inhibitors and still widely used today.
Drug name:
Indinavir
Drug Class:
Protease inhibitors (PIs)
Brand Name:
Crixivan®
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How indinavir works:
Indinavir is a PI. This class of drug combats viral replication of HIV by blocking HIV protease (a protein or enzyme used by HIV to break up large viral proteins into smaller particles from which new HIV particles can be formed). PIs ensure that these new particles are immature and incapable of infecting new cells, thus inhibiting the HIV replication process.
History:
Indinavir was formerly known as MK-639 or L-735,524. It was first licensed in Europe in October 1996. The licence was granted for the use of indinavir in combination with antiretroviral nucleoside analogues for the treatment of HIV-1 in adults. This was more recently extended to include adolescents and children four years of age and older. (The benefit of indinavir therapy versus the increased risk of kidney stones should be particularly considered.)
Combination therapy:
Indinavir is established as an effective component of combination antiretroviral therapy. It should not be used as monotherapy as resistant viruses rapidly emerge. Careful consideration needs to be applied when incorporating indinavir into a regime, as there are several known interactions with other antiretrovirals.
Indinavir levels are reduced if it is used in combination with the non-nucleoside reverse transcriptase inhibitors efavirenz or nevirapine. A dosage increase of indinavir to 1,000mg every 8 hours should be considered if administered with nevirapine; relevant safety and efficacy data are not available for this combination. The use of indinavir with efavirenz should also consider the interaction of these two antiretrovirals. When indinavir is used with the NNRTI delavirdine, consideration should be given to reducing the indinavir dose to 400-600mg every 8 hours: again, safety and efficacy data are unavailable for this combination.
If indinavir is co-administered with didanosine (ddI), then they should be taken at least an hour apart on an empty stomach.
Co-administration of indinavir and ritonavir may lead to higher levels of indinavir with an increased risk of kidney stones developing, although there is insufficient data available to support a definite relationship between indinavir levels, efficacy and kidney stones.
Dosing:
Indinavir is produced in semi-transluscent white hard capsules of 100mg, 200mg, 333mg and 400mg strengths. Each capsule also contains lactose in quantities starting from 37.4mg in the 100mg capsule and rising to 149 mg in the 400 mg capsule. These quantities of lactose are unlikely to induce symptoms of lactose intolerance. Each capsule is coded with the trademark and the relevant dose in coloured print.
The recommended adult daily dose of indinavir is 800mg taken orally every eight hours in combination with other antiretrovirals, and should be swallowed whole. The recommended dose for four to 17-year-olds is 500mg/m2 (a calculation of body surface area) up to a maximum of 800mg every eight hours.
Dosing restrictions:
Indinavir capsules should be taken on an empty stomach, either 1 hour before or 2 hours after a meal. High fat food is not recommended as it decreases the absorption of indinavir. Alternatively, indinavir may be administered with a low-fat, light meal. It should be taken with water; it is recommended that a total of 1.5 litres of water should be consumed by adults daily to decrease the likelihood of kidney stones developing. Drinking water with the last dose of the day is especially important.
Indinavir is metabolised by the CYP3A4 enzyme. Any drug that accelerates or inhibits this process may influence the levels of indinavir in the blood. Sub-optimal levels of indinavir in the blood decreases efficacy and increases the risk of resistance developing.
Drugs that share this metabolic pathway may affect levels of indivavir; hence there are several recommended dosing restrictions or modifications.
In addition to considerations relating to the CYP3A4 enzyme, there are several drug interactions with indinavir that should be noted, these include the following:
St. John's Wort should not be taken alongside indinavir: it reduces plasma levels of indivavir and therefore can potentially reduce indinavir's efficacy
Levels of sildenafil in the body are increased in the presence of indinavir, a reduced dose of sildenafil is recommended
Co-administration of indinavir and rifabutin (TB medication) results in increased blood levels of rifabutin and decreased levels of indinavir: dosing adjustments for both drugs will be necessary
Indinavir should not be administered alongside alprazolam, pimozide, triazolam, cisapride, astemizole, terfenadine, ergotamine, midazolam or rifampicin as these drugs have a narrow therapeutic window and are substrates of CYP3A4
HMG-CoA reductase inhibitors (cholesterol lowering drugs), which are highly dependent on CYP3A4 metabolism, are expected to have increased plasma concentrations when co-administered with indinavir: this may cause myopathy (muscle disorder), so the combination of these drugs (e.g. lovastatin or simvastatin) with indinavir is not recommended. Atorvastation is less dependent on CYP3A4 for metabolism, but caution must be exercised. If treatment with a HMG-CoA reductase inhibitor is needed, pravastatin or fluvastatin is recommended as they are less dependent on CYP3A4
If indinavir is co-administered alongside itraconazole (treatment for thrush) then consider a reduced indinavir dose
Storage:
Indinavir capsules are sensitive to moisture and should be stored in their original container or pack.
Side effects:
A common side effect of indinavir requiring careful observation is the development of kidney stones or pain when urinating. This can occur when high concentrations of indinavir accumulates in the blood and is the reason why the consumption of large amounts of water is important, especially in children where the incidence of kidney stones is much higher.
Common side effects of indinavir include nausea; diarrhoea; headache; fatigue; dizziness; altered taste; rash; abdominal pain; dry skin; vomiting; kidney stones in children and dyspepsia.
Other common side effects include insomnia; flatulence; dry mouth; pins and needles; myalgia (muscle pain); itchy skin;kidney stones in adults; pain on urinating.
Other side effects associated with indinavir and common to all the protease inhibitors include:
Lipodystrophy (although incidence and degree varies between all PIs)
Myopathy (muscle disorder)
Increased bleeding in those with bleeding disorders
Increase in blood fats
Hyperglycaemia and diabetes
Pre-existing conditions:
Safety in patients with impaired renal function has not been studied; however, less than 20% of indinavir is excreted in the urine as unchanged drug or metabolites.
Patients with mild to moderate liver impairment due to cirrhosis will require a dose reduction of indinavir.
Paediatric use:
Indinavir is licensed for use in children over four years of age who can swallow tablets. No oral solution is available. Indinavir has not been studied in children under four years of age. Children who weigh less than 20kg should drink at least 75ml water per kg per day, children between 20kg and 40kg should drink at least 50ml of water per kg per day.
Use during pregnancy:
There are no adequate and well-controlled studies of indinavir in pregnant women. For this reason, indinavir should only be used during pregnancy if the benefits justify any potential risks. It is recommended that mothers do not breastfeed their infants if receiving indinavir.
Indinavir-resistant HIV:
It is widely accepted that all PIs experience an element of cross-resistance within the group. Resistance to indinavir is quick to develop if levels of the drug in the blood are sub-optimal or it is used as monotherapy. This is less likely to occur if indinavir is used in an effective antiretroviral combination.
