Lamivudine use while Breastfeeding

Drugs containing Lamivudine: Combivir, Epivir, Triumeq, Epzicom, Trizivir, Epivir-HBV

Lamivudine Levels and Effects while Breastfeeding

Summary of Use during Lactation

Lamivudine has not been studied in HIV-negative nursing mothers being treated for hepatitis B infection, but the low doses used would not be expected to cause any serious adverse effects in breastfed infants. An expert review of available data concluded that there is currently no justification for contraindicating the use of tenofovir for hepatitis B therapy during breastfeeding.[1]

In the United States and other developed countries, HIV-infected mothers should generally not breastfeed their infants. In countries in which no acceptable, feasible, sustainable and safe replacement feeding is available, World Health Organization guidelines recommend that all women with an HIV infection who are pregnant or breastfeeding should be maintained on antiretroviral therapy for at least the duration of risk for mother-to-child transmission. Mothers should exclusively breastfeed their infants for the first 6 months of life; breastfeeding with complementary feeding should continue through 12 months of life. The first choice regimen for nursing mothers is tenofovir, efavirenz and either lamivudine or emtricitabine. If these drugs are unavailable, alternative regimens include: 1) zidovudine, lamivudine and efavirenz; 2) zidovudine, lamivudine and nevirapine; or 3) tenofovir, nevirapine and either lamivudine or emtricitabine. Exclusively breastfed infants should also receive 6 weeks of prophylaxis with nevirapine.[2][3]

Drug Levels

Maternal Levels. Milk samples were taken daily before breastfeeding from women receiving lamivudine from 2 groups of women. In the group (n = 10) receiving lamivudine 300 mg twice daily (n = 10), the average milk concentration was 1.2 mg/L (range <0.5 to 6.1 mg/L). In the group receiving 150 mg twice daily plus zidovudine (n = 10), the average milk lamivudine concentration was 0.9 mg/L (range <0.5 to 8.2 mg/L).[4]

Twenty women who were receiving oral lamivudine 150 mg twice daily as part of a combination antiretroviral regimen had their milk analyzed at either 2 or 5 months postpartum. Milk samples were provided at a median of 4 hours (range 1 to 8.5 hours) after the last dose. The median lamivudine concentration in breastmilk was 1.8 mg/L.[5]

Forty women were given postpartum prophylaxis with unstated dosages of lamivudine, nevirapine, and zidovudine (or stavudine if the hemoglobin <8 g/dL). Blood and milk samples were collected once during the first 3 days postpartum and once at 7 days postpartum. The median times after a dose that samples were collected were 5.3 hours (range 0 to 99 hours) for the first sample and 6 hours (range 4.3 to 20 hours) for the 7-day sample. Average breastmilk lamivudine concentrations were calculated only for samples that had detectable (>20 mcg/L) concentrations of nevirapine. The mean breastmilk concentrations were 0.4 (n = 20) and 0.4 mg/L (n = 30), respectively, at the two sampling times, which was 2.9 to 3.3 times the simultaneous maternal serum concentrations.[6]

Forty-seven samples of breastmilk and maternal serum were obtained at 6, 12 and 24 weeks postpartum from mothers taking lamivudine as part of a combination of antiretrovirals. The lamivudine dosage the mothers were taking was not stated in the abstract. The median breastmilk concentrations of lamivudine at a median of 14 hours after the last maternal dose were 510 (17 samples), 387 (17 samples) and 310 mcg/L (13 samples). Median milk concentrations were 2.6 times (interquartile range 1.1 to 3.5 times) the maternal plasma concentrations.[7] In a related study by the same authors, the lamivudine milk to plasma ratio was found to be 2.96 in 49 patients.[8]

Fifty-eight mothers who were taking a combination regimen of lamivudine, nevirapine and zidovudine had their serum and breastmilk analyzed for the presence of these drugs. Mothers took lamivudine 150 mg twice daily starting at 34 to 36 weeks postpartum and continuing until 6 months postpartum. Breastmilk was collected within 24 hours after delivery and at 2, 6, 14 and 24 weeks postpartum at variable times after the previous dose. The median breastmilk lamivudine concentration across all visits was 1214 mcg/L. The authors estimated that a fully breastfed infant would receive a daily dosage of 182 mcg/kg of lamivudine.[9]

Sixty-six mothers who were receiving lamivudine 150 mg twice daily as part of a combination antiretroviral regimen provided a total of 206 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 lamivudine concentration was 446 mcg/L (range 269 to 683 mcg/L).[10] In a continuation of the same study, 65 breastmilk samples obtained at 1, 3 and 6 months postpartum were analyzed for lamivudine after the same dose. The median concentration was 684 mcg/L (IRQ range 405 to 868 mcg/L). It is not clear if the latter study included some of the same patients as the first study.[11]

Fifteen women had been taking lamivudine 150 mg twice daily for 53 to 182 days as part of a drug combination that included either abacavir and zidovudine or lopinavir, ritonavir, and zidovudine. Breastmilk samples were collected at just before a dose at a median of 1 month postpartum. Whole breastmilk levels contained a median of 0.14 mg/L of lamivudine, which was a median of 74% of maternal blood levels.[12]

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 seven of the 121 breastmilk samples contained detectable quantities (10 mcg/L or greater) of lamivudine, with an median breastmilk concentration of 0.94 mg/L over the 6 hours.[13]

Infant Levels. Twenty nursing mothers were receiving oral lamivudine 150 mg twice daily as part of a combination antiretroviral regimen. Their infants had serum concentrations determined at either 2 or 5 months postpartum. Serum samples were provided at a median of 4 hours (range 1 to 8.5 hours) after the last dose. The median infant serum lamivudine concentration was 28 mcg/L (range <14 to 53 mcg/L). The average value was 5% of the IC50 for HIV.[5]

The infants of postpartum mothers taking nevirapine as part of a combination of antiretrovirals had undetectable serum nevirapine concentrations by HPLC/MS analysis. The lamivudine dosage the mothers were taking and times of infant plasma sampling were not stated in the abstract. Infant serum concentrations were measured at 6 (17 samples), 12 (17 samples), and 24 (13 samples) weeks of age at an average of 14 hours after the last maternal dose. Median infant serum lamivudine concentrations were 13, 10, and 5 mcg/L, respectively, which was 6% of the maternal serum concentration.[7]

Fifty-eight infants whose mothers were taking a combination regimen of lamivudine, nevirapine and zidovudine had their serum analyzed for the presence of these drugs. Mothers took lamivudine 150 mg twice daily starting at 34 to 36 weeks postpartum and continuing until 6 months postpartum and were instructed to exclusively breastfeed for 5.5 months. Serum samples were collected within 24 hours after delivery and at 2, 6, 14 and 24 weeks postpartum. The median infant dried blood spot lamivudine concentrations were 67 mcg/L at delivery, 32 mcg/L at week 2, 24 mcg/L at week 6, 20 mcg/L at week 14 and not measurable (<16 mcg/L) at week 24 postpartum.[9]

Breastfed infants of 66 mothers who were receiving lamivudine 150 mg twice daily as part of a combination antiretroviral regimen had a total of 64 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 medial infants' lamivudine plasma concentration was 18 mcg/L (range 7 to 35 mcg/L), which was a median of 2% (range 0 to 4%) of the maternal serum concentration.[10] In a continuation of the same study, 17 breastfed infants (extent not stated) donated 22 blood samples between 1 and 6 months for lamivudine analysis. Their mothers were taking lamivudine 150 mg twice daily as part of combination antiretroviral regimens. The median concentration was 29.2 mcg/L (IRQ range 12.2 to 58.7 mcg/L). It is not clear if the latter study included some of the same patients as the first study.[11]

Twenty-four infants were breastfed either partially or exclusively by their mothers who had been taking lamivudine 150 mg twice daily for 53 to 182 days as part of a drug combination that included either abacavir and zidovudine or lopinavir, ritonavir, and zidovudine. Infant blood was collected at a median of 1 month postpartum at 11 to 18 hours after the last dose and a median of 1 hour (range 6 minutes to 35 hours) after the last breastfeeding. All of the infant plasma samples had undetectable (<7 mcg/L) plasma levels of lamivudine.[12]

Thirty nursing mothers were studied at 6, 12 or 24 weeks postpartum (10 at each time). Each mother was taking lamivudine 150 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. Lamivudine was detectable (10 mcg/L or greater) in 107 of the 115 infant plasma samples, at a median concentration of 180 mcg/L.[13]

Effects in Breastfed Infants

A study assigned pregnant women to zidovudine alone or highly active antiretroviral therapy (HAART: zidovudine, lamivudine and nevirapine) to prevent maternal-to-child transmission of HIV infection. After delivery, All infants received one month of zidovudine prophylaxis; some infants were breastfed and others were formula fed. A higher percentage of infants in the HAART-exposed group had neutropenia than those in the unexposed group at 1 month of age (15.9% and 3.7%, respectively). Hematologic toxicity was transient and asymptomatic. From 2 to 6 months postpartum, no differences in hematologic toxicity were seen between breastfed and formula-fed infants. No statistical difference in hepatic toxicity was seen between the breastfed and formula-fed infants.[14]

Effects on Lactation and Breastmilk

Some case reports and in vitro studies have suggested that protease inhibitors might cause hyperprolactinemia and galactorrhea in some male patients,[15][16] although this has been disputed.[17] One case series found an incidence of gynecomastia of 2.4 cases per person annually among men receiving highly active antiretroviral therapy; 51% of the affected patients were taking lamivudine. Gynecomastia was unilateral initially, but progressed to bilateral in 53% of cases. No alterations in serum prolactin were noted and spontaneous resolution usually occurred within one year, even with continuation of the regimen.[18] 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.

Alternate Drugs to Consider

(Hepatitis B) Interferon Alfa, Tenofovir

References

1. Ehrhardt S, Xie C, Guo N, Nelson K, Thio CL. Breastfeeding while taking lamivudine or tenofovir disoproxil fumarate: a review of the evidence. Clin Infect Dis. 2014. PMID: 25313254

2. World Health Organization. HIV and infant feeding: update. 2007. http://whqlibdoc.who.int/publications/2007/9789241595964_eng.pdf

3. World Health Organization. Consolidated guidelines on the use of antiretroviral drugs for treating and preventing HIV infection. Geneva: World Health Organization. 2013.

4. Moodley J, Moodley D, Pillay K et al. Pharmacokinetics and antiretroviral activity of lamivudine alone or when coadministered with zidovudine in human immunodeficiency virus type 1-infected pregnant women and their offspring. J Infect Dis. 1998;178:1327-33. PMID: 9780252

5. Shapiro RL, Holland DT, Capparelli E et al. Antiretroviral concentrations in breast-feeding infants of women in Botswana receiving antiretroviral treatment. J Infect Dis. 2005;192:720-7. PMID: 16088821

6. Giuliano M, Guidotti G, Andreotti M et al. Triple antiretroviral prophylaxis administered during pregnancy and after delivery significantly reduces breast milk viral load study within the Drug Resource Enhancement Against AIDS and Malnutrition Program. J Acquir Immune Defic Syndr. 2006 ;14:459-60. PMID: 17146372

7. Corbett A, Kashuba A, Rezk N et al. Antiretroviral drug concentrations in breast milk and breastfeeding infants. 15th Annual Conference on Retroviruses and Opportunistic Infections (CROI) 2/3/2008 to 2/6/2008; Boston, MA. Poster # 648. 2008.

8. 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. PMID: 18758393

9. Mirochnick M , Thomas T, Capparelli E et al. Antiretroviral concentrations in breast-feeding infants of mothers receiving highly active antiretroviral therapy. Antimicrob Agents Chemother. 2009;53:1170-6. PMID: 19114673

10. 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. PMID: 22910456

11. Pirillo MF, Scarcella P, Andreotti M et al. Hepatitis B virus mother-to-child transmission among HIV-infected women receiving lamivudine-containing antiretroviral regimens during pregnancy and breastfeeding. J Viral Hepatitis. 2014. PMID: 25174900

12. Shapiro RL , Rossi S, Ogwu A et al. Therapeutic levels of lopinavir in late pregnancy and abacavir passage into breast milk, in the Mma Bana Study, Botswana. Antivir Ther. 2013;18:585-90. PMID: 23183881

13. 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. PMID: 24464632

14. Bae WH, Wester C, Smeaton LM et al. Hematologic and hepatic toxicities associated with antenatal and postnatal exposure to maternal highly active antiretroviral therapy among infants. AIDS. 2008;22:1633-40. PMID: 18670224

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

16. 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. PMID: 12593790

17. Montero A, Bottasso OA, Luraghi MR et al. Galactorrhoea, hyperprolactinaemia, and protease inhibitors. Lancet. 2001;357:473-4; author reply 475. PMID: 11273087

18. Garcia-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. PMID: 14585204

Lamivudine Identification

Substance Name

Lamivudine

CAS Registry Number

134678-17-4

Drug Class

Antiinfective Agents

Anti-HIV Agents

Antiviral Agents

Anti-Retroviral Agents

Reverse Transcriptase Inhibitors

Administrative Information

LactMed Record Number

646

Last Revision Date

20141107

Disclaimer

Information presented in this database is not meant as a substitute for professional judgment. You should consult your healthcare provider for breastfeeding advice related to your particular situation. The U.S. government does not warrant or assume any liability or responsibility for the accuracy or completeness of the information on this Site.

Disclaimer: This information is not intended as a substitute for professional judgment. You should consult your healthcare provider for breastfeeding advice related to your particular situation. Use of this website signifies your agreement to the Terms of Use and Online Privacy Policy.

Hide
(web2)