Summary of Use during Lactation

Ritonavir is excreted into milk in measurable concentrations and low levels can be found in the blood of some breastfed infants. No adverse reactions in breastfed infants have been reported. Achieving and maintaining viral suppression with antiretroviral therapy decreases breastfeeding transmission risk to less than 1%, but not zero. Individuals with HIV who are on antiretroviral therapy with a sustained undetectable viral load and who choose to breastfeed should be supported in this decision. If a viral load is not suppressed, banked pasteurized donor milk or formula is recommended.[1,2]

Drug Levels

Maternal Levels. One study measured ritonavir in breastmilk samples from nursing mothers who had been randomized to receive the drug as part of a clinical trial to evaluate maternal-to-child transmission of HIV infection. The dosages, dosage regimens and times of breastmilk sample collection times were not reported. Ritonavir was not detected in any of 60 breastmilk samples.[3]

Nine mothers who were receiving lopinavir 400 mg plus ritonavir 100 mg twice daily as part of a combination antiretroviral regimen provided a total of 23 milk samples at birth, 1 month, 3 months and/or 6 months postpartum. Milk samples were collected at a median of 4.5 hours (range 3.5 to 6 hours) after the previous dose. The median breastmilk ritonavir concentration was 79 mcg/L (range 31 to 193 mcg/L).[4]

Thirty women were studied at 6, 12 or 24 weeks postpartum (10 at each time). Each mother was taking zidovudine 300 mg, lamivudine 150 mg, lopinavir 400 mg, and ritonavir 100 mg twice daily by mouth starting at delivery. On the study day, at a median of 14.9 hours after the previous evening's dose, maternal plasma and breastmilk samples were obtained prior to the morning dose and 2, 4 and 6 hours after the dose. One hundred twelve of the 121 breastmilk samples contained detectable quantities (10 mcg/L or greater) of ritonavir, with a median breastmilk concentration of 79 mcg/L over the 6 hours.[5]

Nine HIV-positive women about to undergo cesarean section received 3 doses of lopinavir 200 mg, ritonavir 150 mg, zidovudine 300 mg, lamivudine 50 mg at 3 hour intervals before the procedure. Breastmilk samples were collected at a mean of 25 hours postpartum. In the 8 women where it was quantified, the average milk concentration of ritonavir was 240 mcg/L (range 98 to 402 mcg/L).[6]

Infant Levels. Breastfed infants of 9 mothers who were receiving lopinavir 400 mg plus ritonavir 100 mg twice daily as part of a combination antiretroviral regimen had a total of 6 blood samples analyzed at 1 month, 3 months and/or 6 months postpartum. Samples were collected at a median of 4.5 hours (range 3.5 to 6 hours) after the previous maternal dose and a median of 30 minutes (range 20 to 60 minutes) after the previous nursing. The infants' median ritonavir plasma concentration was 7 mcg/L (range 0 to 138 mcg/L), which was a median of 12% (range 11 to 40%) of the maternal serum concentration.[4]

Ritonavir was measured in 117 breastfed (90% exclusive) infants whose mothers were taking lopinavir plus ritonavir for HIV infection during pregnancy and postpartum. At 8 and 12 weeks postpartum, none of the infants had detectable ritonavir in their plasma; 91% of infants had detectable ritonavir in their hair samples at 12 weeks postpartum at a mean concentration of 0.15 ng/mg of hair (range 0.03 to 0.42 ng/mg). The authors interpreted the results to mean that infants receive negligible exposure to ritonavir during breastfeeding.[7]

Thirty nursing mothers were studied at 6, 12 or 24 weeks postpartum (10 at each time). Each mother was taking ritonavir 100 mg twice daily by mouth starting at delivery. Infant plasma samples were obtained before their mother's first dose and at 2, 4 and 6 hours after the mother's dose. Infants were allowed to breastfeed ad libitum during the study period. Ritonavir was undetectable (<10 mcg/L) in all of the 115 infant plasma samples.[5]

Effects in Breastfed Infants

Relevant published information was not found as of the revision date.

Effects on Lactation and Breastmilk

Gynecomastia has been reported among men receiving highly active antiretroviral therapy. Gynecomastia is unilateral initially, but progresses to bilateral in about half of cases. No alterations in serum prolactin were noted and spontaneous resolution usually occurred within one year, even with continuation of the regimen.[8-10] Some case reports and in vitro studies have suggested that protease inhibitors might cause hyperprolactinemia and galactorrhea in some male patients,[11,12] although this has been disputed.[13] The relevance of these findings to nursing mothers is not known. The prolactin level in a mother with established lactation may not affect her ability to breastfeed.

References

1.

World Health Organization. Consolidated guidelines on HIV prevention, testing, treatment, service delivery and monitoring: recommendations for a public health approach. 2021. https://www​.who.int/publications​/i/item/9789240031593 [PubMed: 34370423]

2.

Department of Health and Human Services. Recommendations for the use of antiretroviral drugs during pregnancy and interventions to reduce perinatal HIV transmission in the United States. Infant feeding for individuals with HIV in the United States. 2023. https:​//clinicalinfohivgov​/en/guidelines​/perinatal/infant-feeding-individuals-hiv-united-states?view=full

3.

Rezk NL, White N, Bridges AS, et al. Studies on antiretroviral drug concentrations in breast milk: Validation of a liquid chromatography-tandem mass spectrometric method for the determination of 7 anti-human immunodeficiency virus medications. Ther Drug Monit 2008;30:611-9. [PMC free article: PMC2901847] [PubMed: 18758393]

4.

Palombi L, Pirillo MF, Andreotti M, et al. Antiretroviral prophylaxis for breastfeeding transmission in Malawi: drug concentrations, virological efficacy and safety. Antivir Ther 2012;17:1511-9. [PubMed: 22910456]

5.

Corbett AH, Kayira D, White NR, et al. Antiretroviral pharmacokinetics in mothers and breastfeeding infants from 6 to 24 weeks post-partum: Results of the BAN Study. Antivir Ther 2014;19:587-95. [PMC free article: PMC4110187] [PubMed: 24464632]

6.

Ramírez-Ramírez A, Sanchez-Serrano E, Loaiza-Flores G, et al. Simultaneous quantification of four antiretroviral drugs in breast milk samples from HIV-positive women by an ultra-high performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) method. PLoS One 2018;13:e0191236. [PMC free article: PMC5774716] [PubMed: 29351333]

7.

Gandhi M, Mwesigwa J, Aweeka F, et al. Hair and plasma data show that lopinavir, ritonavir, and efavirenz all transfer from mother to infant in utero, but only efavirenz transfers via breastfeeding. J Acquir Immune Defic Syndr 2013;63:578-84. [PMC free article: PMC3800282] [PubMed: 24135775]

8.

García-Benayas T, Blanco F, Martin-Carbonero L, et al. Gynecomastia in HIV-infected patients receiving antiretroviral therapy. AIDS Res Hum Retroviruses 2003;19:739-41. [PubMed: 14585204]

9.

Pantanowitz L, Evans D, Gross PD, Dezube BJ. HIV-related gynecomastia. Breast J 2003;9:131-2. [PubMed: 12603389]

10.

Evans DL, Pantanowitz L, Dezube BJ, Aboulafia DM. Breast enlargement in 13 men who were seropositive for human immunodeficiency virus. Clin Infect Dis 2002;35:1113-9. [PubMed: 12384846]

11.

Hutchinson J, Murphy M, Harries R, Skinner CJ. Galactorrhoea and hyperprolactinaemia associated with protease-inhibitors. Lancet 2000;356:1003-4. [PubMed: 11041407]

12.

Orlando G, Brunetti L, Vacca M. Ritonavir and saquinavir directly stimulate anterior pituitary prolactin secretion, in vitro. Int J Immunopathol Pharmacol 2002;15:65-8. [PubMed: 12593790]

13.

Montero A, Bottasso OA, Luraghi MR, et al. Galactorrhoea, hyperprolactinaemia, and protease inhibitors. Lancet 2001;357:473-5. [PubMed: 11273087]

Substance Name

Ritonavir

CAS Registry Number

155213-67-5

Drug Class

Breast Feeding

Lactation

Milk, Human

Anti-Infective Agents

Antiviral Agents

Anti-HIV Agents

Anti-Retroviral Agents

HIV Protease Inhibitors