Ritonavir (Norvir)

Ritonavir (Norvir) is a protease inhibitor, an anti-HIV drug that reduces the amount of virus in the body. Anti-HIV drugs such as ritonavir slow down or prevent damage to the immune system, and reduce the risk of developing AIDS-related illnesses. Protease (or proteinase) is the enzyme that HIV uses to break up large viral proteins from which new HIV particles can be made. For more information about how protease inhibitors work, see Protease inhibitors.

Ritonavir was approved for use in combination with nucleoside reverse transcriptase inhibitors (NRTIs) for treating adults with advanced or progressing HIV disease in Europe and the United States in late 1996[ix] [ix] [ix].

Ritonavir is manufactured by Abbott, under the trade name Norvir. During early trials it was known as ABT-538 and A-84,538. A generic version of the drug is manufactured by Hetero/Genix under the trade name Ritovir.

Although it was originally developed for use as a protease inhibitor in its own right, today ritonavir is mainly used in low doses to boost the effect (blood levels) of one of the other protease inhibitors.

Effectiveness

Ritonavir (Norvir) is able to reduce HIV viral load and increase CD4 cell counts in the majority of people taking it in combination with at least two other antiretroviral drugs.

Ritonavir was approved after two main studies demonstrating its effectiveness in reducing AIDS-defining events and viral loads when added to an existing nucleoside reverse transcriptase inhibitor (NRTI) regimen (Study 247), and in reducing viral loads in treatment-naive patients (Study 245).[ref] Interestingly, the latter study showed equivalent effectiveness in patients treated with ritonavir plus AZT (zidovudine, Retrovir) and those treated with ritonavir alone, over 48 weeks. This was probably due to side-effects and poor adherence in the dual therapy arm.

Subsequent studies found that ritonavir-based HIV treatment was as effective as treatment based on indinavir (Crixivan) in patients with prior exposure to NRTIs. After over a year of treatment, similar numbers of patients taking each drug developed a new AIDS-defining condition or died, and CD4 cell count increases were similar.[ref]

Ritonavir does not cross the blood-brain barrier as well as NRTIs such as AZT or d4T (stavudine, Zerit).[ref] It also penetrates poorly into the semen.[ref]

There is some evidence that ritonavir also has anti-malarial activity, which may be of relevance in areas with high prevalence of HIV and malaria.[ref]

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.

Taking full-dose ritonavir

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.[ref] The lower dose is not currently recommended.

Taking low-dose ritonavir with other protease inhibitors

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.[ref] 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.[ref]

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.[ref]

Side-effects

Common side-effects of ritonavir (Norvir) include headache, nausea, vomiting, diarrhoea, dizziness, and tingling or numbness around the mouth. These are most likely to occur during the first weeks of treatment and there is evidence that women are more likely to suffer from these side-effects than men.[ref] [ref] Medicines to control nausea, diarrhoea and headache can be prescribed before starting ritonavir[ix] [ix] [ix] [ix] [ix].

As a class, protease inhibitors have been associated with a syndrome of fat and metabolic irregularities. This syndrome includes altered body fat distribution, high fat levels in the blood, diabetes, increased levels of blood sugar and increased bleeding in haemophiliacs. Ritonavir has been associated with a more rapid and severe form of body fat changes than other protease inhibitors in some studies. It is also particularly associated with elevated in blood lipids such as cholesterol and triglycerides, although genetic variation in two apolipoprotein genes determines the risk of triglyceride elevations, at least in part.[ref] Combining ritonavir with another protease inhibitors may produce greater increases in triglyceride levels than a single protease inhibitor.[ref] [ref] For more details, see Metabolic changes while on ART.

Kidney failure is a rare, serious side-effect of ritonavir.[ref] It is more likely in people with pre-existing kidney problems or who are taking other drugs that are toxic to the kidneys.

While liver toxicity is a side-effect of full-dose ritonavir, it is not associated with the low doses used to boost the levels of other protease inhibitors, even in patients with hepatitis C co-infection.[ref]

Low-dose ritonavir may also cause elevations of uric acid in the blood, which may lead to gout, particularly in patients with other risk factors.[ref]

Resistance

As ritonavir (Norvir) is now rarely given as the only protease inhibitor in an HIV treatment regimen, ritonavir resistance rarely develops. However, previous studies have found that mutations in the protease gene at codons 82 and 84 are associated with resistance to ritonavir, as well as mutations M46I/L, I50V, I54V and L90M. The I84V mutation reduces susceptibility to all available protease inhibitors, whereas V82A/T/F/S reduces susceptibility to indinavir and lopinavir.

HIV that is resistant to ritonavir is usually entirely cross-resistant to indinavir (Crixivan), and responses to nelfinavir (Viracept) and saquinavir (Invirase) tend to be poor.

Drug interactions

Because it inhibits the P450 liver enzymes, ritonavir (Norvir) interacts with a large number of other medicines.[ref] Some of these drug interactions may be life-threatening.

It is extremely important for patients taking ritonavir to check with their doctor before taking any other medications whatsoever. Abbott, ritonavir’s manufacturer, has produced a card listing all the drug’s possible interactions.

Patients taking ritonavir should not take the following drugs:

  • Alfuzosin
  • Amiodarone (Cordarone X)
  • Astemizole
  • Bepidril
  • Chlorazepate (Tranxene), due to a risk of sedation and breathing difficulties
  • Cisapride
  • Colchicine in patients with renal or hepatic impairment
  • Diazepam, due to a risk of sedation and breathing difficulties
  • Ergotamine tartrate (Cafergot / Migril), due to a risk of blood vessel constriction
  • Estazolam, due to a risk of sedation and breathing difficulties
  • Flecainide acetate (Tambocor)
  • Flurazepam (Dalmane), due to a risk of sedation and breathing difficulties
  • Halofantrine
  • Hypericin (St John’s wort)
  • Lovastatin
  • Lumefantrine
  • Midazolam (Hypnovel), due to a risk of sedation and breathing difficulties
  • Pethidine hydrochloride (Pamergan P100)[ref]
  • Pimozide (Orap)
  • Piroxicam (Feldene / Brexidol)
  • Propafenone (Arythmol)
  • Quinidine sulphate (Kinidin Dureles)
  • Simvastatin (Zocor)
  • Terfenadine
  • Triazolam, due to a risk of sedation and breathing difficulties[ref]
  • Vardenafil (Levitra)
  • Voriconazole (Vfend).

Co-administration of ritonavir with efavirenz (Sustiva) can increase the likelihood of side-effects such as dizziness, nausea and unusual skin sensations, as well as elevated liver enzymes.

Other drugs that should be used cautiously by people taking ritonavir include the following:

  • Amitriptyline (Tryptizol, Elavil, Lentizol) levels may be increased by ritonavir.
  • Atorvastatin (Lipitor) levels are increased by ritonavir.
  • Atovaquone (Wellvone) levels may be reduced by ritonavir.
  • Clomipramine (Anafranil) levels may be increased by ritonavir.
  • Codeine phosphate levels may be reduced by ritonavir.
  • Desipramine (Pertrofan) levels may be increased by ritonavir.
  • Fluoxetine (Prozac) levels may be increased by ritonavir.
  • Fluticasone propionate (Flixotide) levels are increased by ritonavir. This can cause symptoms of Cushing’s syndrome and suppression of the adrenal glands, including weight gain, weakening of the skin, sweating, facial hair growth and psychological disturbances.[ref] [ref]
  • Imipramine (Tofranil) levels may be increased by ritonavir.
  • Ketoconazole (Nizoral) levels are increased by ritonavir, increasing the incidence of side-effects.
  • Ketoprofen (Orudis / Oruvail) levels may be reduced by ritonavir.
  • Lorazepam levels may be reduced by ritonavir.
  • Maprotiline (Ludiomil) levels may be increased by ritonavir.
  • Methadone hydrochloride (Methadose) concentrations are reduced by ritonavir, requiring dose escalation to avoid the risk of withdrawal symptoms developing.
  • Morphine (Oramorph / Sevredol / Morcap SR / Morphegesic SR / MST Continus / MXL / Zomorph) levels may be reduced by ritonavir.
  • Naproxen (Naprosyn / Synflex) levels may be reduced by ritonavir.
  • Nefazodone (Dutonin) levels may be increased by ritonavir.
  • Nortryptiline (Allegron) levels may be increased by ritonavir.
  • Oxazepam levels may be reduced by ritonavir.
  • Paroxetine (Seroxat) levels may be increased by ritonavir.
  • Prednisolone levels are increased by ritonavir.[ref]
  • Propofol (Diprivan) levels may be reduced by ritonavir.
  • Rifabutin (Mycobutin): levels are increased by ritonavir, so it should be taken at the lower dose of 150mg two to three times a week.[ref]
  • Sertraline (Lustral) levels may be increased by ritonavir.
  • Sildenafil (Viagra) levels are increased eleven-fold by ritonavir, increasing the incidence of dangerous side-effects.[ref] The dose of sildenafil should be reduced to less than 25mg every 48 hours. Sildenafil is contraindicated if used for treatment of pulmonary arterial hypertension (due to dose required).
  • Tadalafil (Cialis) levels are increased by ritonavir, so it should be taken at a reduced dose.
  • Temazepam levels may be reduced by ritonavir.
  • Trazadone (Molipaxin) levels may be increased by ritonavir.
  • Venlafaxine (Effexor) levels may be increased by ritonavir.

Ritonavir decreases the blood concentrations of the oral contraceptive ethinylestradiol, so alternative forms of contraception should be used.

One case of reduced levels of valproic acid (Depakote) has also been reported in a patient taking ritonavir, resulting in re-emergence of symptoms of bipolar disorder.[ref] However, further data are required to confirm this link.

Ritonavir capsules and oral solution contain alcohol. They should therefore not be taken with the alcoholism treatment drug disulfiram (Antabuse) or medicines with similar modes of action, including the antibiotic metronidazole (Flagyl / Flagyl S / Metrolyl).

Children

Ritonavir (Norvir) is approved for use in children aged over two years in Europe and over one month in the United States[ix] [ix]. Body surface area is used for dosing in children at a recommended twice daily dose of 350mg/m2 twice daily, not exceeding 600mg twice daily. The starting dose is 250mg/m2, increasing by 50mg/m2 every two to three days until the final dose is reached.

Triple drug combinations including ritonavir are effective in children, with similar side-effect profiles to adults, even in those with prior treatment exposure.[ref] [ref] [ref] [ref] [ref] The approval of ritonavir for children aged as young as one month was based on good results of a combination of ritonavir, AZT (zidovudine, Retrovir) and 3TC (lamivudine, Epivir) in 50 HIV-positive children.[ref]

The liquid formulation of ritonavir is bitter. If children cannot stand the taste, it can be disguised by being given after peanut butter and followed with chocolate sauce or cheese. Alternatively, it can be mixed into chocolate milk.

Pregnancy

There are no formal comparative studies of ritonavir (Norvir) in pregnant women. However, animal studies and one study of ritonavir monotherapy in pregnant women suggest that the drug is relatively safe and effective, and that the risk of developmental abnormalities is low.[ref]