Ritonavir oral
- Drugs List
- Therapeutic Indications
- Dosage
- Contraindications
- Precautions and Warnings
- Pregnancy and Lactation
- Side Effects
- Monograph
Presentation
Oral formulations of ritonavir
Drugs List
Therapeutic Indications
Uses
HIV infection-combined with other antiretrovirals
Dosage
Ritonavir may be used as a pharmacokinetic enhancer to boost the effect of some other protease inhibitors.
Adults
Ritonavir as an antiretroviral agent
600 mg twice daily.
Gradually increasing the dose of ritonavir when initiating therapy may help improve tolerance.
Treatment should be initiated at 300 mg twice daily for 3 days then increase by 100 mg 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.
Ritonavir as a pharmacokinetic enhancer
When using ritonavir in combination with a protease inhibitor, please also consult the monograph of the relevant drug.
The following protease inhibitors have been approved for use with ritonavir as a pharmacokinetic enhancer at the following dosages:
Amprenavir
600 mg of amprenavir twice daily with ritonavir 100 mg twice daily.
Atazanavir
300 mg of atazanavir once daily with ritonavir 100 mg once daily.
Fosamprenavir
700 mg of fosamprenavir twice daily with ritonavir 100 mg twice daily.
Saquinavir
1000 mg of saquinavir twice daily with ritonavir 100 mg twice daily in antiretroviral treatment (ART) experienced patients.
Initiate treatment 500 mg of saquinavir twice daily with 100 mg ritonavir twice daily for the first 7 days. Then 1000 mg saquinavir twice daily with 100 mg ritonavir twice daily in ART-naive patients.
Tipranavir
500 mg of tipranavir twice daily with ritonavir 200 mg twice daily.
Darunavir
600 mg darunavir twice daily with ritonavir 100 mg twice daily ART experienced patients.
800 mg darunavir once daily with ritonavir 100 mg once daily in ART-naive patients.
Elderly
Pharmacokinetic data indicates that no dose adjustments are necessary for elderly patients (see Dosage; Adults).
Children
Under 2 years
Contraindicated in patients under 2 years old due to a lack of data on safety and efficacy.
2 years and above
Ritonavir as a pharmacokinetic enhancer
Specific dosage adjustment depends upon the protease inhibitor with which ritonavir is administered. The clinician should refer to the product documentation for the co-administered protease inhibitor.
Ritonavir as an antiretroviral agent
Starting dose 250 mg per square metre twice daily, increasing at 2 to 3 day intervals by 50 mg per square metre twice daily. Recommended dosage is 350 mg per square metre body surface area twice daily. It should not exceed 600 mg twice daily.
Body surface area can be calculated with the following equation:
BSA (square metre) = the square root of (Height (cm) X Weight (KG) / 3600)
Tablets
For older children it may be feasible to substitute tablets for the maintenance dose of the oral solution.
Dosage conversion from oral solution to tablets is as follows:
175 mg (2.2 ml) oral solution twice daily: 200 mg in the morning and 200 mg in the evening
350 mg (4.4 ml) oral solution twice daily: 400 mg in the morning and 300 mg in the evening
437.5 mg (5.5 ml) oral solution twice daily: 500 mg in the morning and 400 mg in the evening
525 mg (6.6 ml) oral solution twice daily: 500 mg in the morning and 500 mg in the evening
Oral Solution
Paediatric dosage guidelines are as follows:
Doses for intermediate body surface areas not included in the above recommendations 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 per square metre; 3.8 for one of 300 mg per square metre; and by 4.4 for 350 mg per square metre.
Body surface area of 0.25 square metre
Twice daily dose of 250 mg/square metre: 0.8 ml (62.5 mg) twice daily
Twice daily dose of 300 mg/square metre: 0.9 ml (75 mg) twice daily
Twice daily dose of 350 mg/square metre: 1.1 ml (87.5 mg) twice daily
Body surface area of 0.50 square metre
Twice daily dose of 250 mg/square metre: 1.6 ml (125 mg) twice daily
Twice daily dose of 300 mg/square metre: 1.9 ml (150 mg) twice daily
Twice daily dose of 350 mg/square metre: 2.2 ml (175 mg) twice daily
Body surface area of 1.00 square metre
Twice daily dose of 250 mg/square metre: 3.1 ml (250 mg) twice daily
Twice daily dose of 300 mg/square metre: 3.8 ml (300 mg) twice daily
Twice daily dose of 350 mg/square metre: 4.4 ml (350 mg) twice daily
Body surface area of 1.25 square metre
Twice daily dose of 250 mg/square metre: 3.9 ml (312.5 mg) twice daily
Twice daily dose of 300 mg/square metre: 4.7 ml (375 mg) twice daily
Twice daily dose of 350 mg/square metre: 5.5 ml (437.5 mg) twice daily
Body surface area of 1.50 square metre
Twice daily dose of 250 mg/square metre: 4.7 ml (375 mg) twice daily
Twice daily dose of 300 mg/square metre: 5.6 ml (450 mg) twice daily
Twice daily dose of 350 mg/square metre: 6.6 ml (525 mg) twice daily
Oral powder administered as oral suspension
Paediatric dosage guidelines are as follows when oral powder is administered as oral suspension prepared as 100 mg/10 ml. Some doses may have been adjusted to ensure recommended final dose and volume:
Doses for intermediate body surface areas not included in the above recommendations 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 25 for a dose of 250 mg per square metre; 30 for one of 300 mg per square metre; and by 35 for 350 mg per square metre.
Body surface area of 0.25 square metre
Twice daily dose of 250 mg/square metre: 6.4 ml (62.5 mg) twice daily
Twice daily dose of 300 mg/square metre: 7.6 ml (76 mg) twice daily
Twice daily dose of 350 mg/square metre: 8.8 ml (88 mg) twice daily
Body surface area of 0.50 square metre
Twice daily dose of 250 mg/square metre: 12.6 ml (126 mg) twice daily
Twice daily dose of 300 mg/square metre: 15 ml (150 mg) twice daily
Twice daily dose of 350 mg/square metre: 17.6 ml (176 mg) twice daily
Body surface area of 0.75 square metre
Twice daily dose of 250 mg/square metre: 18.8 ml (188 mg) twice daily
Twice daily dose of 300 mg/square metre: 22.6 ml (226 mg) twice daily
Twice daily dose of 350 mg/square metre: 26.4 ml (262.5 mg) twice daily
Body surface area of 1.00 square metre
Twice daily dose of 250 mg/square metre: 25 ml (250 mg) twice daily
Twice daily dose of 300 mg/square metre: 30 ml (300 mg) twice daily
Twice daily dose of 350 mg/square metre: 35 ml (350 mg) twice daily
Body surface area of 1.25 square metre
Twice daily dose of 250 mg/square metre: 31.4 ml (312.5 mg) twice daily
Twice daily dose of 300 mg/square metre: 37.6 ml (376 mg) twice daily
Twice daily dose of 350 mg/square metre: 43.8 ml (438 mg) twice daily
Body surface area of 1.50 square metre
Twice daily dose of 250 mg/square metre: 37.6 ml (376 mg) twice daily
Twice daily dose of 300 mg/square metre: 45 ml (450 mg) twice daily
Twice daily dose of 350 mg/square metre: 52.6 ml (526 mg) twice daily
Oral powder
If appropriate, the entire contents of the sachet may be poured over a small amount of soft food. All of the mixed soft food must be administered within 2 hours.
Patients with Renal Impairment
No dosage adjustment is necessary in patients with renal impairment or undergoing renal replacement therapies (see Dosage; Adults).
The renal clearance of ritonavir is negligible, therefore a decrease in total body clearance is not expected in patients with renal impairment.
It is unlikely that ritonavir will be significantly removed by haemodialysis or peritoneal dialysis.
Patients with Hepatic Impairment
Ritonavir is principally metabolised and eliminated by the liver.
Ritonavir as a pharmacokinetic enhancer
Specific dosage adjustment depends upon the protease inhibitor with which ritonavir is administered - the clinician should refer to the product documentation for the co-administered protease inhibitor.
Severe hepatic impairment (Child Pugh Grade C)
Use with caution in patients with severe hepatic impairment - increased levels of co-administered protease inhibitor may occur.
Decompensated liver disease
Contraindicated in these patients
Ritonavir as an antiretroviral agent
Patients with chronic hepatitis B or C who are treated with combination antiretroviral therapy have an increased risk of developing severe and potentially fatal hepatic adverse effects, and therefore should be closely monitored during treatment. The product literature relating to concurrent treatments for hepatitis B or C should be consulted. If hepatic disease worsens in these patients, interruption or discontinuation of therapy should be considered.
Severe hepatic impairment
Contraindicated in these patients.
Mild to moderate hepatic impairment
No dose adjustment is required.
Patients with pre-existing hepatic impairment, including chronic active hepatitis, have an increased risk of developing hepatic function abnormalities during therapy. These patients should be closely monitored and the interruption or discontinuation of treatment should be considered if hepatic disease worsens in these patients.
Decompensated liver disease
Contraindicated in these patients
Contraindications
Children under 2 years
Acute porphyria
Breastfeeding
Decompensated liver disease
Severe hepatic impairment - if used as antiretroviral agent
Precautions and Warnings
Diarrhoea
Cardiac conduction defects
Haemophilia
Hepatic impairment
Hepatitis
Hepatitis B
Hepatitis C
Pregnancy
Structural cardiac disorder
Treatment does not prevent risk of transmission of HIV
Advise ability to drive/operate machinery may be affected by side effects
Monitor TSH when starting/stopping treatment if concurrent levothyroxine
Must be used in combination with other antiretrovirals
Treatment to be initiated and supervised by a specialist
Some formulations contain castor oil polyoxyl which may cause diarrhoea
Some formulations contain sunset yellow (E110); may cause allergic reaction
Some formulations may contain alcohol
Advise patient to take with or after food
Autoimmune disorders can occur many months after initiation of treatment
Blood lipid and glucose levels may increase requiring treatment
Diarrhoea may compromise absorption and efficacy - monitor patient
May prolong PR interval
Monitor hepatic function in patients with hepatic impairment
Monitor renal function in patients with renal impairment
Monitor serum amylase in patients at risk of pancreatitis
Advise patient to seek medical advice if joint aches or pain occur
Advise patient to seek medical advice if movement becomes difficult
Inflammatory symptoms should be evaluated and treated appropriately
Risk of developing opportunistic infections
Discontinue if hepatic function deteriorates in pts with hepatic impairment
Discontinue if pancreatitis occurs
Advise patient not to take St John's wort concurrently
Female: Barrier or non-hormonal contraception advised during treatment
Female: Oral contraception may not be adequate during treatment
Advise haemophiliac patients of possibility of increased bleeding
Patients should be informed that ritonavir is not a cure for HIV infection and that they may continue to acquire illnesses associated with HIV infection, including opportunistic infections.
Must be used in combination with other antiretrovirals. The clinician should refer to the product documentation for the co-administered protease inhibitor.
Increased bleeding, including spontaneous skin haematomas and haemarthroses, have been reported in type A and B haemophiliac patients treated with protease inhibitors and additional factor VIII was required in some patients. A causal relationship has been suggested but the mechanism of action has not been determined. In more than half of all reported cases, treatment was continued or reintroduced after discontinuation.
When combination antiretroviral therapy is initiated in HIV-infected patients with severe immune deficiency, an inflammatory reaction to asymptomatic or residual opportunist pathogens may arise (Immune Reactivation Syndrome). This can lead to the aggravation of symptoms or other serious clinical conditions such as cytomegalovirus retinitis, mycobacterial infections or pneumocystis jiroveci pneumonia. These reactions are usually observed within the first few weeks or months after treatment initiation. Any inflammatory symptoms should be evaluated and treated appropriately.
Blood lipid and glucose levels may increase during antiretroviral therapy. This may be linked to disease control and lifestyle. Refer to established HIV treatment guidelines for monitoring and manage lipid and glucose level disorders as appropriate.
Pancreatitis has been observed in patients receiving ritonavir, including those who have developed hypertriglyceridaemia. In some cases fatalities have occurred. Patients with advanced HIV disease may be at risk of elevated triglycerides and pancreatitis. Pancreatitis should be considered if clinical symptoms (nausea, vomiting, abdominal pain) or abnormalities in laboratory tests (such as increased serum lipase or amylase values) suggestive of pancreatitis should occur. Ritonavir therapy should be discontinued if a diagnosis of pancreatitis is made.
Ritonavir is known to cause modest asymptomatic prolongation of the PR interval in healthy adult patients. Second and third degree atrioventricular block have been reported in patients with underlying structural heart disease and pre-existing conduction system abnormalities or patients receiving drugs known to prolong the PR interval. Ritonavir should be used in caution in these patients.
Pregnancy and Lactation
Pregnancy
Use ritonavir with caution in pregnancy.
Briggs suggests, in the incidence of pregnancy occurring during therapy of HIV-1, combined antiretroviral therapy should not be withheld. Treatment of the pregnant mother with monotherapy is considered inadequate. The manufacturer suggests ritonavir may be considered for use during pregnancy only when the benefits outweigh the risk to the foetus.
Limited data, at the time of writing, are available on the use of ritonavir in human pregnancy. The lack of data regarding the use of ritonavir during pregnancy prevents a reliable risk assessment.
Animal data suggests that the drug may represent a low risk to the developing foetus. Transplacental passage has been demonstrated in rats. An in vitro study using term perfused human placentas demonstrated that placental transfer is concentration dependant with a low clearance index.
No association between protease inhibitors and an increased risk of gestational diabetes has been discovered. However, pregnant women being treated with protease inhibitors such as ritonavir should be monitored for hyperglycaemia as this may lead to severe complications.
Briggs suggests the use of zidovudine during the intrapartum period regardless of current regimen, as this may prevent vertical transmission of HIV to the newborn.
The use of all medication in pregnancy should be avoided whenever possible; particularly in the first trimester. Non-drug treatments should also be considered. When essential, a medication with the best safety record over time should be chosen, employing the lowest effective dose for the shortest possible time. Polypharmacy should be avoided. Teratogens taken in the pre-embryonic period, often quoted as lasting until 14 to 17 days post-conception, are believed to have an all-or-nothing effect. Where drugs have a short half-life, and when the date of conception is certain, this may allow women to be reassured where drug exposure has occurred within this time frame. Further advice may be available from the UK National Teratology Information Service (NTIS) and through ToxBase, available via password on the internet ( www.toxbase.org ) or if this is unavailable at the backup site ( www.toxbasebackup.org ).
Lactation
HIV is known to be transmitted in milk. Therefore, HIV infected mothers should avoid breastfeeding in order to prevent transmission of the disease.
There are no data available on the use of ritonavir during breastfeeding. Due to the low molecular weight and prolonged elimination half-life, it is considered likely that ritonavir will be excreted in breast milk. Animal studies have demonstrated some effects on offspring development.
Neonates, infants born prematurely, those with low birth weight, those with an unstable gastrointestinal function or who have serious illnesses may require special consideration. For any infant, if a drug is prescribed to the nursing mother, it should be at the lowest practical dose and for the shortest time. When drug administration is unavoidable and breastfeeding is to continue, minimisation of exposure of the infant to the drug may sometimes be achieved by timing the maternal doses to just after a feeding episode. Infants exposed to drugs via breast milk should be monitored for unusual signs or symptoms. Interactions between the drug received by the infant from the mother's milk and medication prescribed for the infant should also be considered, for example, when the drug given to the infant may prevent metabolism of the drug received via breast milk.
Specialist advice is available from the UK Drugs in Lactation Advisory Service at https://www.midlandsmedicines.nhs.uk/content.asp?section=6&subsection=17&pageIdx=1
Counselling
Advise patient to avoid taking St John's wort concurrently.
Advise patient to seek medical advice if movement becomes difficult or joint aches or pain occurs.
Advise haemophiliac patients of possibility of increased bleeding.
Advise female patients barrier or non-hormonal contraception is advised during treatment. Oral contraception may not be adequate.
Advise patient ability to drive/operate machinery may be affected by side effects.
Oral solution
Advise patient to take with or after food. Advise patient bitter taste can be lessened if mixed with chocolate milk.
Oral powder
Advise patient to take with or after food. Mix with soft food or liquid before taking. Bitter taste can be lessened if soft food (e.g. peanut butter) or syrup taken after dose.
Tablets
Advise patient to take with or after food.
Side Effects
Abdominal pain
Acne
Acute renal failure
Anaphylaxis
Anorexia
Anxiety
Arthralgia
Asthenia
Attention disturbances
Autoimmune hepatitis
Blurred vision
Confusion
Cough increased
Creatine phosphokinase increased
Decrease in blood thyroxine values
Dehydration
Diabetes mellitus
Diarrhoea
Dizziness
Dry mouth
Dyspepsia
Electrolyte disturbances
Elevated amylase levels
Eosinophilia
Fatigue
Fever
Flatulence
Gamma glutamyl transferase (GGT) increased
Gastro-intestinal haemorrhage
Gastroesophageal reflux disease
Gout
Graves' disease
Haemoglobin decrease
Headache
Hepatitis
Hyperaesthesia
Hypercholesterolaemia
Hyperglycaemia
Hyperlactataemia
Hypermagnesaemia
Hypersensitivity reactions
Hypertension
Hypertriglyceridaemia
Hyperuricaemia
Hypotension
Immune Reactivation/Reconstitution Syndrome
Increase in alkaline phosphatase
Increase of liver transaminases
Increased spontaneous bleeding (haemophiliacs)
Increased urination
Insomnia
Insulin resistance
Jaundice
Leucopenia
Menorrhagia
Metabolic disorders
Mouth ulcers
Myalgia
Myocardial infarction
Myopathy
Myositis
Nausea
Neutropenia
Oedema
Orthostatic hypotension
Osteonecrosis
Pain
Pancreatitis
Paraesthesia
Peripheral coldness
Peripheral neuropathy
Pharyngitis
Prothrombin time increased
Pruritus
Raised neutrophil count
Rash
Renal impairment
Rhabdomyolysis
Seizures
Serum bilirubin increased
Somnolence
Stevens-Johnson syndrome
Sweating
Syncope
Taste disturbances
Throat irritation
Thrombocytopenia
Toxic epidermal necrolysis
Urticaria
Vasodilatation
Vomiting
Weight loss
Overdosage
It is strongly recommended that the UK National Poisons Information Service be consulted on cases of suspected or actual overdose where there is doubt over the degree of risk or about appropriate management.
The following number will direct the caller to the relevant local centre (0844) 892 0111
Information may be obtained if you have access to ToxBase the primary clinical toxicology database of the National Poisons Information Service. This is available via password on the internet ( www.toxbase.org ) or if this is unavailable at the backup site ( www.toxbasebackup.org ).
Further Information
Last Full Review Date: July 2016
Reference Sources
Drugs in Pregnancy and Lactation: A Reference Guide to Fetal and Neonatal Risk, 10th edition (2015) ed. Briggs, G., Freeman, R. Wolters Kluwer Health, Philadelphia.
Joint Formulary Committee. British National Formulary(online) London: BMJ Group and Pharmaceutical Press Accessed on 22 July, 2016.
Paediatric Formulary Committee. BNF for Children (online) London: BMJ Group, Pharmaceutical Press, and RCPCH Publications Accessed on 22 July, 2016.
Summary of Product Characteristics: Norvir 100 mg Film-Coated Tablets. AbbVie Limited. Revised October 2018.
Summary of Product Characteristics: Norvir Powder Oral Suspension. AbbVie Limited. Revised October 2018.
MHRA Drug Safety Update October 2018
Available at: https://www.mhra.gov.uk
Last accessed: 11/02/2019
US National Library of Medicine. Toxicology Data Network. Drugs and Lactation Database (LactMed).
Available at: https://toxnet.nlm.nih.gov/cgi-bin/sis/htmlgen?LACT
Ritonavir. Last revised: 7 July, 2016
Last accessed: 22 July, 2016
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