Isoniazid

Drug Levels and Effects:




Summary of Use during Lactation:


The Centers for Disease Control and Prevention and other professional organizations state that breastfeeding should not be discouraged in women taking isoniazid . Nursing mothers who are taking isoniazid should take 25 mg of oral pyridoxine daily.[1][2][3] Because of the low levels of isoniazid in breastmilk and safe administration directly to infants, it is unlikely to cause adverse reactions in infants, but infants should be monitored for rare instances jaundice. Giving the maternal once-daily dose before the infant's longest sleep period will decrease the dose the infant receives. The amount of isoniazid in milk is insufficient to treat tuberculosis in the breastfed infant.


Drug Levels:


Maternal Levels.

Thirty mothers (time postpartum not stated) were given a single oral dose of 200 mg of isoniazid and a single milk sample was taken from each mother at various times between 2 and 7 hours after the dose. An average peak milk level of 2.1 mg/L (range 1.7 to 2.3 mg/L) occurred in 6 women at 2 hours after the dose. By 7 hours after the dose the average milk level was 0.46 mg/L (range 0.3 to 0.6 mg/L) in 3 women.[4]

Three mothers were given single oral isoniazid doses of 300 mg (5 mg/kg) and 600 mg (10 mg/kg). Peak isoniazid levels occurred 3 hours after the dose in all cases. Peak levels were 5.4 to 5.5 mg/L after 300 mg and 9 to 10.6 mg/L after 600 mg. At 12 hours after the dose, milk levels were undetectable (<0.25 mg/L) after the 300 mg dose and 0.25 to 0.5 mg/L after the 600 mg dose.[5]

A lactating mother (time postpartum not stated) was given a single oral 300 mg dose of isoniazid after weaning. Breastmilk was collected at various times during the next 24 hours. Peak milk levels of 16.6 mg/L of isoniazid occurred at 3 hours and 3.8 mg/L of acetylisoniazid occurred at 5 hours after the dose. Both were still detectable in milk at 24 hours. Half-lives in milk were 5.9 hours for isoniazid and 13.5 hours for acetylisoniazid. The authors estimated that a total of 7 mg would be excreted into milk in 24 hours.[6]

Seven women with an average weight of 40 kg had been receiving isoniazid 300 mg once daily for at least 34 days. All women were also receivingrifampinand ethambutol. Blood and milk samples were collected at 0, 1, 2, 3, and 4 hours after a dose for analysis of isoniazid ; metabolites were not measured. Peak milk isoniazid concentrations of 2 to 6.7 mg/L occurred 1 hour after the dose and dropped by about half by 4 hours after the dose. The authors calculated that a fully breastfed infant would receive a dose of 89.9 mcg/kg daily compared to a recommended infant dosage of 10 mg/kg daily. This dose is equivalent to 1.2% of the maternal weight-adjusted dosage.[7]

The data in the studies above indicate that the infant would be expected to receive about 0.3 to 1.2% of the maternal weight-adjusted dosage of isoniazid .

Infant Levels.

Isoniazidwas detectable in the urine of 2 of 3 breastfed infants whose mothers were given a single oral dose of 600 mg. The total amount excreted by the infants over 24 hours was about 6.8 to 7 mg.[5] Metabolites were not measured.


Effects in Breastfed Infants:


In one uncontrolled study, 6-beta-hydroxycortisol levels were measured in 10 male infants whose mothers had tuberculosis and took ethambutol 1 gram daily plus isoniazid 300 mg daily and the infants of mothers (apparently without tuberculosis) who took no chronic drug therapy. The infants of mothers taking the antituberculars had consistently lower 6-beta-hydroxycortisol levels on 8 occasions at 15-day intervals from 90 to 195 days of age, but these differences were statistically significant on days 120 and 195 only. The authors attributed the lower levels to inhibition of hepatic metabolism of cortisol to 6-beta-hydroxycortisol by the antitubercular drugs in milk.[8] However, ethambutol is not known to inhibit drug metabolism, so if the effect occurs it is more likely caused by isoniazid .

One woman takingrifampin450 mg, isoniazid 300 mg and ethambutol 1200 mg daily during pregnancy andrifampin450 mg and isoniazid 300 mg for the first 7 months of lactation (extent not stated). The infant was born with mildly elevated serum liver enzymes which persisted for to 1 (alanine transferase) to 2 years (aspartate transaminase), but had no other adverse reactions.[9]

Isoniazidwas used as part of multi-drug regimens to treat 2 pregnant women with multidrug-resistant tuberculosis during the second and third trimesters of pregnancy and postpartum. Their two infants were breastfed (extent and duration not stated). At age 3.9 and 4.6 years, the children were developing normally except for a mild speech delay in one.[10]


Possible Effects on Lactation:


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


References:


1. Blumberg HM, Burman WJ, Chaisson RE et al. American Thoracic Society/Centers for Disease Control and Prevention/Infectious Diseases Society of America: treatment of tuberculosis. Am J Respir Crit Care Med. 2003;167:603-62. PMID:12588714
2. Anon. Treatment of tuberculosis. MMWR Recomm Rep. 2003;52:1-77. PMID:12836625
3. Bartlett JG. Guidelines section. Infect Dis Clin Pract. 2002;11:467-71.
4. Lass A, Bunger P. [Studies on the diffusion of isoniazid in the fetal circulation, the amniotic fluid and human milk]. Klin Wochenschr. 1953;31:606-8. PMID:13097858
5. Ricci G, Copaitich T. [Elimination of orally administered isoniazid in human milk]. Rass Clin Ter. 1954;53:209-14. PMID:14372127
6. Berlin CM Jr, Lee C.Isoniazidand acetylisoniazid disposition in human milk, saliva and plasma. Fed Proc. 1979;38 (part 1):426. Abstract.
7. Singh N, Golani A, Patel Z, Maitra A. Transfer of isoniazid from circulation to breast milk in lactating women on chronic therapy for tuberculosis. Br J Clin Pharmacol. 2007;65:418-22. PMID:18093257
8. Toddywalla VS, Patel S, Betrabet SS et al. Can chronic maternal drug therapy alter the nursing infant's hepatic drug metabolizing enzyme pattern? J Clin Pharmacol. 1995;35:1025-9. PMID:8568011
9. Peters C, Nienhaus A. [Case report--tuberculosis in a health care worker during pregnancy]. Pneumologie. 2008;62:695-8. PMID:18855309
10. Drobac PC, del Castillo H, Sweetland A J et al. Treatment of multidrug-resistant tuberculosis during pregnancy: long-term follow-up of 6 children with intrauterine exposure to second-line agents. Clin Infect Dis. 2005;40:1689-92. PMID:15889370



Substance Identification:




Substance Name:

Isoniazid

CAS Registry Number:

54-85-3

Drug Class:


  • Antitubercular Agents


  • Administrative Information:




    LactMed Record Number:


    461


    Last Revision Date:


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