Updated
April 11, 2023
Reviewed
April 11, 2023

Pharmacokinetic Enhancers

Ritonavir

Ritonavir (RTV, Norvir)
Formulations

Oral Powder: 100 mg per packet

Oral Solution: 80 mg/mL. Oral solution contains 43% (v/v) ethanol and approximately 27% (w/v) propylene glycol.

Tablets: 100 mg

Generic Formulation

  • 100-mg tablets

Fixed-Dose Combination (FDC) Solution

  • [Kaletra] Lopinavir 80 mg/ritonavir 20 mg/mL. Oral solution contains 42.4% (v/v) ethanol and 15.3% (w/v) propylene glycol.

FDC Tablets

  • [Kaletra] Lopinavir 100 mg/ritonavir 25 mg
  • [Kaletra] Lopinavir 200 mg/ritonavir 50 mg

When using FDC tablets or solution, refer to other sections of Appendix A: Pediatric Antiretroviral Drug Information for information about the individual components of the FDC. See also Appendix A, Table 2. Antiretroviral Fixed-Dose Combination Tablets: Minimum Body Weights and Considerations for Use in Children and Adolescents.

For additional information, see Drugs@FDA or DailyMed.

Dosing Recommendations Selected Adverse Events

Ritonavir as a Pharmacokinetic Enhancer

  • Ritonavir (RTV) is used as a pharmacokinetic (PK) enhancer of other protease inhibitors (PIs). The recommended dose of RTV varies and is specific to the drug combination selected. See other sections of Appendix A: Pediatric Antiretroviral Drug Information for information about the recommended doses of RTV to use with specific PIs. RTV has antiviral activity, but it is not used as an antiviral agent; instead, it is used as a PK enhancer of other PIs.

Formulation Considerations

  • The RTV oral solution contains propylene glycol and ethanol.
  • The oral powder is preferred over the oral solution for children who cannot swallow the tablets and who need a dose of at least RTV 100 mg because the oral powder does not contain propylene glycol or ethanol.
  • RTV oral powder should be used only for dosing increments of 100 mg and cannot be used for doses <100 mg.

[Kaletra] Lopinavir/Ritonavir

Infant, Child, Adolescent, and Adult Dose

See the Lopinavir/Ritonavir section of Appendix A: Pediatric Antiretroviral Drug Information for information.

  • Gastrointestinal (GI) intolerance, nausea, vomiting, diarrhea
  • Hyperlipidemia, especially hypertriglyceridemia
  • Hepatitis
  • Hyperglycemia
  • Fat maldistribution
Special Instructions
  • Administer RTV with food to increase absorption and reduce the likelihood and severity of GI adverse events.
  • Do not administer RTV with cobicistat (COBI) or drugs that contain COBI (e.g., Stribild, Genvoya, Prezcobix, Evotaz).
  • Do not refrigerate RTV oral solution; store at 68°F to 77°F (20°C to 25°C). Shake the solution well before use.
  • RTV oral powder should be mixed with a soft food (e.g., applesauce, vanilla pudding) or a liquid (e.g., water, chocolate milk, infant formula) to help mitigate the bitter taste. Administer or discard the mixture within 2 hours of mixing.

To Increase Tolerability of Ritonavir Oral Solution or Oral Powder in Children

  • Mix the solution or powder with milk, chocolate milk, ice cream, or vanilla or chocolate pudding.
  • Before administering RTV, give a child ice chips, a Popsicle, or spoonfuls of partially frozen orange or grape juice concentrate to dull the taste buds. Another option is to give a nonallergic child peanut butter or hazelnut chocolate spread to coat the mouth.1
  • After administration, give foods with strong tastes (e.g., maple syrup, cheese).
  • Check a child’s food allergy history before making these recommendations.
  • Counsel caregivers or patients that the bad taste will not be completely masked.
Metabolism/Elimination
  • Cytochrome P450 (CYP) 3A and CYP2D6 inhibitor; CYP1A2, CYP2B6, CYP2C9, CYP2C19, and glucuronidation inducer. RTV inhibits the intestinal transporter P-glycoprotein.

Ritonavir Dosing in Patients with Hepatic Impairment

  • RTV is primarily metabolized by the liver.
  • No dose adjustment is necessary in patients with mild or moderate hepatic impairment.
  • No data exist on RTV dosing for adult or pediatric patients with severe hepatic impairment. Use caution when administering RTV to patients with moderate-to-severe hepatic impairment.

Drug Interactions

Additional information about drug interactions is available in the Adult and Adolescent Antiretroviral Guidelines and the HIV Drug Interaction Checker.

  • 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 reviewed carefully 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 or inhaled budesonide. 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.

Major Toxicities

  • More common: Nausea, vomiting, diarrhea, headache, abdominal pain, anorexia, circumoral paresthesia, abnormal lipid levels
  • 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. Cases of hepatitis, including life-threatening cases, have been reported. Allergic reactions, including bronchospasm, urticaria, and angioedema have occurred. Toxic epidermal necrolysis and Stevens-Johnson syndrome have occurred.9

Resistance

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

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

Pediatric Use

Approval

RTV has been approved by the U.S. 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.

Dosing

Dosing regimens for RTV-boosted darunavir and atazanavir and coformulated lopinavir/ritonavir (LPV/r) are available for pediatric patients. For more information about individual PIs, see other sections of Appendix A: Pediatric Antiretroviral Drug Information.

Toxicity

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; therefore, the use of LPV/r is generally not recommended before a gestational age of 42 weeks (see Lopinavir/Ritonavir).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.

References

  1. Morris JB, Tisi DA, Tan DCT, Worthington JH. Development and palatability assessment of norvir (ritonavir) 100 mg powder for pediatric population. Int J Mol Sci. 2019;20(7):1718. Available at: https://www.ncbi.nlm.nih.gov/pubmed/30959935.
  2. 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.
  3. 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: https://www.ncbi.nlm.nih.gov/pubmed/22328106.
  4. 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.
  5. 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: https://www.ncbi.nlm.nih.gov/pubmed/23535292.
  6. 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: https://www.ncbi.nlm.nih.gov/pubmed/23590676.
  7. 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;2017:17-0076. Available at: https://www.ncbi.nlm.nih.gov/pubmed/29118985.
  8. 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.
  9. Changes to Norvir labeling. AIDS Patient Care STDS. 2008;22(10):834-835. Available at: https://www.ncbi.nlm.nih.gov/pubmed/18924248.
  10. 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: https://www.ncbi.nlm.nih.gov/pubmed/18025905.
  11. 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: https://www.ncbi.nlm.nih.gov/pubmed/19820426.

Pharmacokinetic Enhancers

Ritonavir

Ritonavir (RTV, Norvir)
Formulations

Oral Powder: 100 mg per packet

Oral Solution: 80 mg/mL. Oral solution contains 43% (v/v) ethanol and approximately 27% (w/v) propylene glycol.

Tablets: 100 mg

Generic Formulation

  • 100-mg tablets

Fixed-Dose Combination (FDC) Solution

  • [Kaletra] Lopinavir 80 mg/ritonavir 20 mg/mL. Oral solution contains 42.4% (v/v) ethanol and 15.3% (w/v) propylene glycol.

FDC Tablets

  • [Kaletra] Lopinavir 100 mg/ritonavir 25 mg
  • [Kaletra] Lopinavir 200 mg/ritonavir 50 mg

When using FDC tablets or solution, refer to other sections of Appendix A: Pediatric Antiretroviral Drug Information for information about the individual components of the FDC. See also Appendix A, Table 2. Antiretroviral Fixed-Dose Combination Tablets: Minimum Body Weights and Considerations for Use in Children and Adolescents.

For additional information, see Drugs@FDA or DailyMed.

Dosing RecommendationsSelected Adverse Events

Ritonavir as a Pharmacokinetic Enhancer

  • Ritonavir (RTV) is used as a pharmacokinetic (PK) enhancer of other protease inhibitors (PIs). The recommended dose of RTV varies and is specific to the drug combination selected. See other sections of Appendix A: Pediatric Antiretroviral Drug Information for information about the recommended doses of RTV to use with specific PIs. RTV has antiviral activity, but it is not used as an antiviral agent; instead, it is used as a PK enhancer of other PIs.

Formulation Considerations

  • The RTV oral solution contains propylene glycol and ethanol.
  • The oral powder is preferred over the oral solution for children who cannot swallow the tablets and who need a dose of at least RTV 100 mg because the oral powder does not contain propylene glycol or ethanol.
  • RTV oral powder should be used only for dosing increments of 100 mg and cannot be used for doses <100 mg.

[Kaletra] Lopinavir/Ritonavir

Infant, Child, Adolescent, and Adult Dose

See the Lopinavir/Ritonavir section of Appendix A: Pediatric Antiretroviral Drug Information for information.

  • Gastrointestinal (GI) intolerance, nausea, vomiting, diarrhea
  • Hyperlipidemia, especially hypertriglyceridemia
  • Hepatitis
  • Hyperglycemia
  • Fat maldistribution
Special Instructions
  • Administer RTV with food to increase absorption and reduce the likelihood and severity of GI adverse events.
  • Do not administer RTV with cobicistat (COBI) or drugs that contain COBI (e.g., Stribild, Genvoya, Prezcobix, Evotaz).
  • Do not refrigerate RTV oral solution; store at 68°F to 77°F (20°C to 25°C). Shake the solution well before use.
  • RTV oral powder should be mixed with a soft food (e.g., applesauce, vanilla pudding) or a liquid (e.g., water, chocolate milk, infant formula) to help mitigate the bitter taste. Administer or discard the mixture within 2 hours of mixing.

To Increase Tolerability of Ritonavir Oral Solution or Oral Powder in Children

  • Mix the solution or powder with milk, chocolate milk, ice cream, or vanilla or chocolate pudding.
  • Before administering RTV, give a child ice chips, a Popsicle, or spoonfuls of partially frozen orange or grape juice concentrate to dull the taste buds. Another option is to give a nonallergic child peanut butter or hazelnut chocolate spread to coat the mouth.1
  • After administration, give foods with strong tastes (e.g., maple syrup, cheese).
  • Check a child’s food allergy history before making these recommendations.
  • Counsel caregivers or patients that the bad taste will not be completely masked.
Metabolism/Elimination
  • Cytochrome P450 (CYP) 3A and CYP2D6 inhibitor; CYP1A2, CYP2B6, CYP2C9, CYP2C19, and glucuronidation inducer. RTV inhibits the intestinal transporter P-glycoprotein.

Ritonavir Dosing in Patients with Hepatic Impairment

  • RTV is primarily metabolized by the liver.
  • No dose adjustment is necessary in patients with mild or moderate hepatic impairment.
  • No data exist on RTV dosing for adult or pediatric patients with severe hepatic impairment. Use caution when administering RTV to patients with moderate-to-severe hepatic impairment.

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