Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection
The information in the brief version is excerpted directly from the full-text guidelines. The brief version is a compilation of the tables and boxed recommendations.
Last Updated: April 14, 2020; Last Reviewed: April 14, 2020
|Ritonavir (RTV, Norvir)|
Oral Powder: 100 mg per packet
Fixed-Dose Combination Tablets:
For additional information, see Drugs@FDA or DailyMed.
|Dosing Recommendations||Selected Adverse Events|
|Ritonavir as a Pharmacokinetic Enhancer:
Infant, Child, Adolescent, and Adult Dose:
- Metabolism: Ritonavir (RTV) is extensively metabolized by (and is one of the most potent inhibitors of) hepatic cytochrome P450 (CYP) 3A. Also, RTV is a CYP2D6 inhibitor and a CYP1A2, CYP2B6, CYP2C9, CYP2C19, and glucuronidation inducer. RTV inhibits the intestinal transporter P-glycoprotein. There is potential for multiple drug interactions with RTV.
- Before RTV is administered, a patient’s medication profile should be carefully reviewed for potential interactions with RTV and overlapping toxicities with other drugs.
- RTV and cobicistat are not interchangeable. The potential drug interactions for these drugs are different.2
- Avoid concomitant use of corticosteroids, including intranasal or inhaled fluticasone. Reduced elimination of steroids can increase steroid effects, leading to adrenal insufficiency.3,4 Use caution when prescribing RTV with other inhaled steroids. Limited data suggest that beclomethasone may be a suitable alternative to fluticasone when a patient who is taking RTV requires an inhaled or intranasal corticosteroid.5,6 Iatrogenic Cushing’s syndrome and suppression of the hypothalamic-pituitary axis secondary to the drug interaction between RTV and local injection of triamcinolone has occurred.7,8 See Drug Interactions between Protease Inhibitors and Other Drugs in the Adult and Adolescent Antiretroviral Guidelines for additional information.
- More common: Nausea, vomiting, diarrhea, headache, abdominal pain, anorexia, circumoral paresthesia, lipid abnormalities.
- Less common (more severe): Exacerbation of chronic liver disease, fat maldistribution.
- Rare: New-onset diabetes mellitus, hyperglycemia, ketoacidosis, exacerbation of preexisting diabetes mellitus, spontaneous bleeding in hemophiliacs, and pancreatitis. Cases of hepatitis, including life-threatening cases, have been reported. Allergic reactions, including bronchospasm, urticaria, and angioedema. Toxic epidermal necrolysis and Stevens-Johnson syndrome have occurred.9
Resistance to RTV is not clinically relevant when the drug is used as a pharmacokinetic (PK) enhancer of other antiretroviral (ARV) medications.
RTV has been approved by the Food and Drug Administration for use in the pediatric population.
Effectiveness in Practice
Use of RTV as the sole protease inhibitor (PI) in ARV therapy in children is not recommended. In both children and adults, RTV is recommended as a PK enhancer for use with other PIs. RTV is a CYP3A inhibitor and functions as a PK enhancer by slowing the metabolism of the PI.
Pediatric dosing regimens, including boosted darunavir, atazanavir, and the coformulation lopinavir/ritonavir (LPV/r), are available. For more information about individual PIs, see other sections of the Drug Appendix.
Full-dose RTV has been shown to prolong the PR interval in a study of healthy adults who were given RTV 400 mg twice daily.9 Potentially life-threatening arrhythmias have been reported in premature infants who were treated with LPV/r; the use of LPV/r is generally not recommended before a gestational age of 42 weeks (see the Lopinavir/Ritonavir section).10,11 Coadministration of RTV with other drugs that prolong the PR interval (e.g., macrolides, quinolones, methadone) should be undertaken with caution, because it is unknown how coadministering any of these drugs with RTV will affect the PR interval. In addition, RTV should be used with caution in patients who may be at increased risk of developing cardiac conduction abnormalities, such as patients who have underlying structural heart disease, conduction system abnormalities, ischemic heart disease, or cardiomyopathy.
- Morris JB, Tisi DA, Tan DCT, Worthington JH. Development and palatability assessment of norvir(R) (ritonavir) 100 mg powder for pediatric population. Int J Mol Sci. 2019;20(7). Available at: https://www.ncbi.nlm.nih.gov/pubmed/30959935.
- Marzolini C, Gibbons S, Khoo S, Back D. Cobicistat versus ritonavir boosting and differences in the drug-drug interaction profiles with co-medications. J Antimicrob Chemother. 2016;71(7):1755-1758. Available at: https://www.ncbi.nlm.nih.gov/pubmed/26945713.
- Bernecker C, West TB, Mansmann G, Scherbaum WA, Willenberg HS. Hypercortisolism caused by ritonavir associated inhibition of CYP 3A4 under inhalative glucocorticoid therapy. 2 case reports and a review of the literature. Exp Clin Endocrinol Diabetes. 2012;120(3):125-127. Available at: http://www.ncbi.nlm.nih.gov/pubmed/22328106.
- Peyro-Saint-Paul L, Besnier P, Demessine L, et al. Cushing's syndrome due to interaction between ritonavir or cobicistat and corticosteroids: a case-control study in the French Pharmacovigilance Database. J Antimicrob Chemother. 2019;74(11):3291-3294. Available at: https://www.ncbi.nlm.nih.gov/pubmed/31369085.
- Boyd SD, Hadigan C, McManus M, et al. Influence of low-dose ritonavir with and without darunavir on the pharmacokinetics and pharmacodynamics of inhaled beclomethasone. J Acquir Immune Defic Syndr. 2013;63(3):355-361. Available at: http://www.ncbi.nlm.nih.gov/pubmed/23535292.
- Saberi P, Phengrasamy T, Nguyen DP. Inhaled corticosteroid use in HIV-positive individuals taking protease inhibitors: a review of pharmacokinetics, case reports and clinical management. HIV Med. 2013;14(9):519-529. Available at: http://www.ncbi.nlm.nih.gov/pubmed/23590676.
- Dubrocq G, Estrada A, Kelly S, Rakhmanina N. Acute development of Cushing syndrome in an HIV-infected child on atazanavir/ritonavir based antiretroviral therapy. Endocrinol Diabetes Metab Case Rep. 2017;2017. Available at: https://www.ncbi.nlm.nih.gov/pubmed/29118985.
- Noe S, Jaeger H, Heldwein S. Adrenal insufficiency due to ritonavir-triamcinolone drug-drug interaction without preceding Cushing's syndrome. Int J STD AIDS. 2018;29(11):1136-1139. Available at: https://www.ncbi.nlm.nih.gov/pubmed/29749880.
- Changes to Norvir labeling. AIDS Patient Care STDS. 2008;22(10):834-835. Available at: http://www.ncbi.nlm.nih.gov/pubmed/18924248.
- Lopriore E, Rozendaal L, Gelinck LB, Bokenkamp R, Boelen CC, Walther FJ. Twins with cardiomyopathy and complete heart block born to an HIV-infected mother treated with HAART. AIDS. 2007;21(18):2564-2565. Available at: http://www.ncbi.nlm.nih.gov/pubmed/18025905.
- McArthur MA, Kalu SU, Foulks AR, Aly AM, Jain SK, Patel JA. Twin preterm neonates with cardiac toxicity related to lopinavir/ritonavir therapy. Pediatr Infect Dis J. 2009;28(12):1127-1129. Available at: http://www.ncbi.nlm.nih.gov/pubmed/19820426.