Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection

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Pharmacokinetic Enhancers

Ritonavir

Last Updated: April 27, 2017; Last Reviewed: April 27, 2017

Ritonavir (RTV, Norvir)
Ritonavir (RTV, Norvir)
For additional information see Drugs@FDA: http://www.accessdata.fda.gov/scripts/cder/daf/
Formulations
Oral Solution (Contains 43% Alcohol by Volume): 80 mg/mL
Tablets: 100 mg
Dosing Recommendations Selected Adverse Events
Ritonavir as a Pharmacokinetic (PK) Enhancera:
  • Ritonavir is used as a PK enhancer of other protease inhibitors (PIs). The recommended dose of ritonavir varies and is specific to the drug combination selected. See dosing information for specific PIs.
a Ritonavir has antiviral activity but is not used as an antiviral agent (see text).
  • Gastrointestinal intolerance, nausea, vomiting, diarrhea
  • Paresthesia (circumoral and extremities)
  • Hyperlipidemia, especially hypertriglyceridemia
  • Hepatitis
  • Asthenia
  • Taste perversion
  • Hyperglycemia
  • Fat maldistribution
  • Possible increased bleeding episodes in patients with hemophilia
  • Toxic epidermal necrolysis and Stevens-Johnson syndrome
Special Instructions
  • Administer ritonavir with food to increase absorption and reduce gastrointestinal adverse effects.
  • Do not administer ritonavir with cobicistat or drugs that contain cobicistat (e.g., Stribild, Genvoya, Prezcobix, Evotaz).
  • If ritonavir is prescribed with didanosine, administer the drugs 2 hours apart.
  • Do not refrigerate ritonavir oral solution; store at 68°F to 77°F (20°C to 25°C). Shake the solution well before use.
  • To Increase Tolerability of Ritonavir Oral Solution in Children:
    • Mix solution with milk, chocolate milk, or vanilla or chocolate pudding or ice cream.
    • Before administration, give a child ice chips, a Popsicle, or spoonfuls of partially frozen orange or grape juice concentrate to dull the taste buds, or give peanut butter to coat the mouth.
    • After administration, give a child strong-tasting foods such as maple syrup or cheese.
    • Check food allergy history before making these recommendations.
    • Counsel parents or patients that the bad taste will not be completely masked.
Metabolism/Elimination
  • Cytochrome P (CYP) 3A4 and CYP2D6 inhibitor; CYP1A2, CYP2B6, CYP2C9, CYP2C19, and glucuronidation inducer. 
  • Dosing of ritonavir in patients with hepatic impairment: Ritonavir is primarily metabolized by the liver. No dosage adjustment is necessary in patients with mild or moderate hepatic impairment. Data are unavailable on ritonavir dosing for adult or pediatric patients with severe hepatic impairment. Use caution when administering ritonavir to patients with moderate-to-severe hepatic impairment.

Drug Interactions (see also the Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents and http://iasusa.org/sites/default/files/tam/october_november_2015.pdf#page=10)

Metabolism: Ritonavir is extensively metabolized by and is one of the most potent inhibitors of hepatic cytochrome P450 3A (CYP3A). There is potential for multiple drug interactions with ritonavir.

  • Before ritonavir is administered, a patient’s medication profile should be carefully reviewed for potential interactions with ritonavir and overlapping toxicities with other drugs.
  • Ritonavir and cobicistat are not interchangeable and may result in different drug interactions.1
  • Avoid concomitant use of intranasal or inhaled fluticasone because of reports of adrenal insufficiency.2 Use caution when prescribing ritonavir with other inhaled steroids; limited data suggest that beclomethasone may be a suitable alternative to fluticasone when an inhaled/intranasal corticosteroid is required for a patient who is taking ritonavir.3,4

Major Toxicities

  • 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, pancreatitis, and hepatitis (life-threatening in rare cases). Allergic reactions, including bronchospasm, urticaria, and angioedema. Toxic epidermal necrolysis and Stevens-Johnson syndrome have occurred.5

Resistance

Resistance to ritonavir is not clinically relevant when the drug is used as a pharmacokinetic (PK) enhancer of other antiretroviral (ARV) medications.

Pediatric Use

Approval
Ritonavir has been approved by the Food and Drug Administration for use in the pediatric population. 

Efficacy: Effectiveness in Practice
Use of ritonavir as the sole protease inhibitor (PI) in antiretroviral therapy in children is not recommended. Although ritonavir has been well studied in children as an ARV agent, it is no longer used as a sole PI for therapy because ritonavir is associated with a higher incidence of gastrointestinal toxicity and has a greater potential for drug-drug interactions than other PIs. In addition, poor palatability of the liquid preparation and large pill burden with the tablets (adult dose is 6 tablets twice daily) limit its use as a sole PI. However, in both children and adults, ritonavir is recommended as a PK enhancer for use with other PIs. Ritonavir is a CYP3A4 inhibitor and functions as a PK enhancer by slowing the metabolism of the PIs.

Dosing
Pediatric dosing regimens including boosted fosamprenavir, tipranavir, darunavir, atazanavir and a PI co-formulation, lopinavir/ritonavir (LPV/r), are available (see individual PIs for more specific information). 

Toxicity
Full-dose ritonavir has been shown to prolong the PR interval in a study of healthy adults who were given ritonavir at 400 mg twice daily.5 Potentially life-threatening arrhythmias in premature newborn infants treated with LPV/r have been reported; the use of LPV/r is not recommended until the gestational age of 42 weeks.6,7 Co-administration of ritonavir with other drugs that prolong the PR interval (e.g., macrolides, quinolones, methadone) should be undertaken with caution because it is unknown how co-administering any of these drugs with ritonavir will affect the PR interval. In addition, ritonavir should be used with caution in patients who may be at increased risk of developing cardiac conduction abnormalities, such as those with underlying structural heart disease, conduction system abnormalities, ischemic heart disease, or cardiomyopathy.

References

  1. 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.
  2. 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.
  3. 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.
  4. 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.
  5. Changes to Norvir labeling. AIDS Patient Care STDS. 2008;22(10):834-835. Available at http://www.ncbi.nlm.nih.gov/pubmed/18924248.
  6. 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.
  7. 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.

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