Adult: To enhance the efficacy of other HIV protease inhibitors and nirmatrelvir (SARS-CoV-2 main protease inhibitor): 100-400 mg daily in 1-2 divided doses, depending on the co-administered protease inhibitor (refer to specific product guidelines of the co-administered drug). Child: Refer to specific product guidelines of the co-administered protease inhibitor.
Oral HIV-1 infection
Adult: In combination with other antiretroviral agents: Initially, 300 mg bid for 3 days; increase gradually in increments of 100 mg bid for up to 14 days. Max: 600 mg bid. Child: >1 month In combination with other antiretroviral agents: Initially, 250 mg/m2 bid; increase by 50 mg/m2 bid at 2-3 day intervals up to 350-400 mg/m2 bid. Max: 600 mg bid. Dosage recommendations may vary among countries or individual products. Refer to specific product guidelines.
Administration
film-coated tab: Should be taken with food. Swallow whole, do not chew/break/crush. oral powd: Should be taken with food. May be mixed w/ soft food (eg, applesauce, vanilla pudding), water, chocolate milk or infant formula. oral soln: Should be taken with food. May be mixed w/ chocolate milk w/in 1 hr of dosing.
Patient with haemophilia A or B, pre-existing conduction system disease, ischaemic heart disease, cardiomyopathy, underlying structural heart disease, diabetes, increased triglycerides. Moderate to severe hepatic impairment (without decompensation). Children. Pregnancy. Ritonavir oral solution should not be administered to neonates before a postmenstrual age (1st day of the mother's last menstrual period to birth plus the time elapsed after birth) of 44 weeks has been attained. The oral powder should be used only for dosing increments of 100 mg. The use of ritonavir as a pharmacokinetic enhancer to nirmatrelvir for the treatment of COVID-19 has not been fully established, some data are available from several initial clinical trials in the US and other countries.
Adverse Reactions
Significant: Immune reconstitution syndrome, autoimmune disorders (e.g. Graves’ disease, autoimmune hepatitis), osteonecrosis, PR interval prolongation, increased total cholesterol and triglycerides, diabetes mellitus, hyperglycaemia, redistribution or accumulation of body fat (e.g. central obesity, dorsocervical fat enlargement, peripheral wasting, facial wasting, breast enlargement), increased bleeding (including spontaneous skin haematomas and haemarthrosis). Blood and lymphatic system disorders: Thrombocytopenia. Eye disorders: Blurred vision. Gastrointestinal disorders: Abdominal pain, nausea, diarrhoea, vomiting, dyspepsia, flatulence, mouth ulcer, gastrointestinal haemorrhage, GERD, dysgeusia. General disorders and administration site conditions: Fatigue, asthenia, fever. Immune system disorders: Hypersensitivity (e.g. urticaria, face oedema). Investigations: Increased or decreased weight, increased GGT, blood bilirubin, amylase, creatine phosphokinase, uric acid, eosinophils; decreased free and total thyroxin, WBC, Hb, neutrophils. Metabolism and nutrition disorders: Gout, oedema, peripheral oedema, dehydration, anorexia. Musculoskeletal and connective tissue disorders: Arthralgia, back pain, myositis, rhabdomyolysis, myalgia, myopathy. Nervous system disorders: Headache, dizziness, peripheral neuropathy, oral and peripheral paraesthesia, syncope, seizure. Psychiatric disorders: Insomnia, anxiety, confusion, attention disturbance. Renal and urinary disorders: Increased urination, renal impairment (e.g. oliguria, elevated creatinine). Reproductive system and breast disorders: Menorrhagia. Respiratory, thoracic and mediastinal disorders: Pharyngitis, oropharyngeal pain, cough. Skin and subcutaneous tissue disorders: Pruritus, erythematous or maculopapular rash, acne. Vascular disorders: Hypertension, hypotension, orthostatic hypotension, peripheral coldness. Potentially Fatal: Hepatotoxicity (e.g. hepatitis, jaundice, exacerbation of pre-existing hepatic dysfunction); pancreatitis; hypersensitivity reactions (e.g. anaphylaxis, toxic epidermal necrolysis, Stevens-Johnson syndrome, bronchospasm, angioedema).
Monitoring Parameters
Monitor liver function, total cholesterol and triglycerides before and during therapy; CBC, creatine phosphokinase, uric acid, viral load, CD4 count, glucose, serum amylase and lipase.
Overdosage
Symptoms: Paraesthesia, renal failure with eosinophilia. Management: Supportive treatment. Gastric lavage and administration of activated charcoal may be considered.
Drug Interactions
Increases the plasma concentrations of tadalafil, sildenafil (when used for erectile dysfunction), atorvastatin, rosuvastatin, digoxin, glucocorticoids (e.g. fluticasone, budesonide), trazodone. May reduce the effect and change the uterine bleeding profile when co-administered with estradiol-containing contraceptives. Increased risk of bleeding with rivaroxaban. May increase the exposure of riociguat, vorapaxar, bedaquiline, delamanid. Potentially Fatal: Increase the plasma concentrations of the following drugs, which may lead to severe adverse reactions: alfuzosin, pethidine, piroxicam, dextropropoxyphene, ranolazine, neratinib, apalutamide, venetoclax, amiodarone, bepridil, dronedarone, encainide, flecainide, propafenone, quinidine, fusidic acid, astemizole, terfenadine, rifabutin (at 500 mg bid ritonavir dose), blonanserin, lurasidone, clozapine, pimozide, quetiapine, salmeterol, ergot derivatives (e.g. ergotamine, dihydroergotamine, ergonovine, methylergonovine), cisapride, lovastatin, simvastatin, lomitapide, avanafil, sildenafil (when used for pulmonary arterial hypertension), vardenafil, clorazepate, diazepam, estazolam, flurazepam, oral midazolam, triazolam. Significantly reduces the plasma concentration which may lead to loss of antifungal response to voriconazole (ritonavir dose ≥400 mg bid). Potential for serious reactions with colchicine (in patients with renal and/or hepatic impairment).
Food Interaction
Decreased plasma concentrations and reduced clinical effects with St. John’s wort.
Action
Description: Mechanism of Action: Ritonavir is a selective, competitive and reversible inhibitor of HIV protease. It binds to the site of HIV-1 protease activity and inhibits the cleavage of viral Gag-Pol polyprotein precursors into individual functional proteins, resulting in the formation of immature, non-infectious viral particles. Pharmacokinetics: Absorption: Well absorbed. Increased absorption with food. Time to peak plasma concentration: Approx 2-4 hours. Distribution: Highest concentrations in the serum and lymph nodes; minimally penetrates the brain. Volume of distribution: 0.41 ± 0.25 L/kg. Plasma protein binding: Approx 98-99%, to α-1 acid glycoprotein and albumin. Metabolism: Extensively metabolised in the liver mainly by CYP3A4 and to a lesser extent by CYP2D6 isoenzymes into 5 metabolites; isopropylthiazole metabolite (M-2) as the major metabolite. Excretion: Mainly via faeces (approx 86%, 34% as unchanged drug); urine (approx 11%, 4% as unchanged drug). Elimination half-life: 3-5 hours.
Chemical Structure
Ritonavir Source: National Center for Biotechnology Information. PubChem Compound Summary for CID 392622, Ritonavir. https://pubchem.ncbi.nlm.nih.gov/compound/Ritonavir. Accessed Nov. 23, 2022.
Storage
Tab, oral susp or powder: Store at or below 30°C. Protect from light and moisture. Oral solution: Store between 20-25°C. Protect from heat.
J05AE03 - ritonavir ; Belongs to the class of protease inhibitors. Used in the systemic treatment of viral infections.
References
AbbVie Limited. Norvir 100 mg Tablets data sheet 29 April 2020. Medsafe. http://www.medsafe.govt.nz. Accessed 07/11/2022.Anon. Nirmatrelvir and Ritonavir. Lexicomp Online. Hudson, Ohio. Wolters Kluwer Clinical Drug Information, Inc. https://online.lexi.com. Accessed 11/11/2022.Anon. Ritonavir. AHFS Clinical Drug Information [online]. Bethesda, MD. American Society of Health-System Pharmacists, Inc. https://www.ahfscdi.com. Accessed 07/11/2022.Anon. Ritonavir. Lexicomp Online. Hudson, Ohio. Wolters Kluwer Clinical Drug Information, Inc. https://online.lexi.com. Accessed 07/11/2022.Buckingham R (ed). Ritonavir. Martindale: The Complete Drug Reference [online]. London. Pharmaceutical Press. https://www.medicinescomplete.com. Accessed 07/11/2022.Joint Formulary Committee. Nirmatrelvir with Ritonavir. British National Formulary [online]. London. BMJ Group and Pharmaceutical Press. https://www.medicinescomplete.com. Accessed 11/11/2022.Joint Formulary Committee. Ritonavir. British National Formulary [online]. London. BMJ Group and Pharmaceutical Press. https://www.medicinescomplete.com. Accessed 07/11/2022.Norvir 100 mg Powder for Oral Suspension (AbbVie Ltd). MHRA. https://products.mhra.gov.uk. Accessed 07/11/2022.Norvir Tablet, Film Coated; Solution; Powder (AbbVie Inc.). DailyMed. Source: U.S. National Library of Medicine. https://dailymed.nlm.nih.gov/dailymed. Accessed 07/11/2022.Norvir Tablets (Abbvie Sdn Bhd.). National Pharmaceutical Regulatory Agency - Ministry of Health Malaysia. https://www.npra.gov.my. Accessed 07/11/2022.Paxlovid (Pfizer Laboratories Div Pfizer Inc). DailyMed. Source: U.S. National Library of Medicine. https://dailymed.nlm.nih.gov/dailymed. Accessed 11/11/2022.Paxlovid 150 mg/100 mg Film-coated Tablets (Pfizer Limited). MHRA. https://products.mhra.gov.uk. Accessed 11/11/2022.Ritonavir 100 mg Tablet (Cipla USA Inc.). DailyMed. Source: U.S. National Library of Medicine. https://dailymed.nlm.nih.gov/dailymed. Accessed 07/11/2022.Ritonavir Mylan 100 mg Film-coated Tablets (Generics UK Limited t/a Mylan). MHRA. https://products.mhra.gov.uk. Accessed 07/11/2022.
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