Isoniazid Risk Summary

Risk Factor: C
Class: Anti-infectives / Antituberculosis

Fetal Risk Summary

Isoniazid is used in the prevention and treatment of pulmonary tuberculosis. Reproduction studies in mice, rats, and rabbits have not revealed teratogenic effects, but embryocidal effects were observed in rats and rabbits (1).

An official statement of the American Thoracic Society, published in 1986, recommends isoniazid as part of the treatment regimen for women who have tuberculosis during pregnancy (2). Other reviewers also consider isoniazid as part of the treatment of choice for tuberculosis occurring during pregnancy (3).



Isoniazid crosses the placenta to the fetus (4,5 and 6). In a 1955 study, 19 women in labor were given a single 100-mg dose of isoniazid 0.254.25 hours before delivery (4). The mean maternal serum concentration at birth was 0.32 g/mL compared with a cord blood level of 0.22 g/mL. The mean cord:maternal ratio was 0.73, but in 7 of the patients, cord blood concentrations exceeded those in the maternal plasma. Another study examined the placental transfer of isoniazid in two women who had been treated with 300 mg/day during the 3rd trimester (5). One hour before delivery, the women were given a single 300-mg IM dose. Mean cord blood and maternal serum concentrations were 4 and 6.5 g/mL, respectively, a ratio of 0.62. These studies and the elimination kinetics of intrauterine acquired isoniazid in the newborn were reviewed in 1987 (6).

Reports discussing fetal effects of isoniazid during pregnancy reflect multiple drug therapies. Early reports identified retarded psychomotor activity, psychic retardation, convulsions, myoclonia, myelomeningocele with spina bifida and talipes, and hypospadias as possible effects related to isoniazid therapy during pregnancy (7,8). The Collaborative Perinatal Project monitored 85 patients who received isoniazid during the 1st trimester (9, pp. 299, 313). They observed 10 malformations, an incidence almost twice the expected rate, but they cautioned that their findings required independent confirmation. For use anytime during pregnancy, 146 mother-child pairs were exposed to isoniazid, with malformations that may have been produced after the 1st trimester observed in 4 infants (9, p. 435). This was close to the expected frequency. Adverse outcomes in the fetus and newborn after intrauterine exposure to isoniazid have not been confirmed by other studies (10,11,12,13,14 and 15). Retrospective analysis of more than 4,900 pregnancies in which isoniazid was administered demonstrated rates of malformations similar to those in control populations (0.7%2.3%). A 1980 review also found no association between isoniazid and fetal anomalies (16).

In a surveillance study of Michigan Medicaid recipients involving 229,101 completed pregnancies conducted between 1985 and 1992, 11 newborns had been exposed to isoniazid during the 1st trimester (F. Rosa, personal communication, FDA, 1993). One (9.1%) major birth defect was observed (0.5 expected), a case of polydactyly.

A case report of a malignant mesothelioma in a 9-year-old child who was exposed to isoniazid in utero was published in 1980 (17). The authors suggested a possible carcinogenic effect of isoniazid because of the rarity of malignant mesotheliomas during the first decade and supportive animal data. However, an earlier study examined 660 children up to 16 years of age and found no association with carcinogenic effects (18).

An association between isoniazid and hemorrhagic disease of the newborn has been suspected in two infants (19). The mothers were also treated with rifampin and ethambutol and in a third case, only with these latter two drugs. Although other reports of this potentially serious reaction have not been found, prophylactic vitamin K1 is recommended at birth (see Phytonadione).

In summary, isoniazid does not appear to be a human teratogen. The American Thoracic Society recommends use of the drug for tuberculosis occurring during pregnancy because, Untreated tuberculosis represents a far greater hazard to a pregnant woman and her fetus than does treatment of the disease. (2)

Breast Feeding Summary

No reports of isoniazid-induced effects in the nursing infant have been located, but the potential for interference with nucleic acid function and for hepatotoxicity may exist (20,21). Both isoniazid and its metabolite, acetylisoniazid, are excreted in breast milk (21,22 and 23). A woman was given a single oral dose of 300 mg after complete weaning of her infant (21). Both isoniazid and the metabolite were present in her milk within 1 hour with peak levels of isoniazid (16.6 g/mL) occurring at 3 hours and those of the metabolite (3.76 g/mL) at 5 hours. At 5 and 12 hours after the dose, isoniazid levels in the milk were twice the levels in simultaneously obtained plasma. Levels of acetylisoniazid were similar in plasma and milk at 5 and 12 hours. The elimination half-life for milk isoniazid was calculated to be 5.9 hours, whereas that of the metabolite was 13.5 hours. Both were detectable in milk 24 hours after the dose. The 24-hour excretion of isoniazid was estimated to be 7 mg. Two other studies also reported substantial excretion of isoniazid into human milk (22,23). A milk:plasma ratio of 1.0 was reported in one of these studies (22). In another, milk levels 3 hours after a maternal dose of 5 mg/kg were 6 g/mL (23). Doubling the maternal dose doubled the milk concentration.

Based on the above information, at least one review concluded that women can safely breast-feed their infants while taking isoniazid if, among other precautions, the infant is periodically examined for signs and symptoms of peripheral neuritis or hepatitis (20). Moreover, the American Academy of Pediatrics considers isoniazid to be compatible with breast feeding (24).

References

  1. Product information. Rifamate. Hoechst Marion Roussel, 2000.
  2. American Thoracic Society. Treatment of tuberculosis and tuberculosis infection in adults and children. Am Rev Respir Dis 1986;134:35563.
  3. Medchill MT, Gillum M. Diagnosis and management of tuberculosis during pregnancy. Obstet Gynecol Surv 1989;44:814.
  4. Bromberg YM, Salzberger M, Bruderman I. Placental transmission of isonicotinic acid hydrazide. Gynaecologia 1955;140:1414.
  5. Miceli JN, Olson WA, Cohen SN. Elimination kinetics of isoniazid in the newborn infant. Dev Pharmacol Ther 1981;2:2359.
  6. Holdiness MR. Transplacental pharmacokinetics of the antituberculosis drugs. Clin Pharmacokinet 1987;13:1259.
  7. Weinstein L, Dalton AC. Host determinants of response to antimicrobial agents. N Engl J Med 1968;279:52431.
  8. Lowe CR. Congenital defects among children born to women under supervision or treatment for pulmonary tuberculosis. Br J Prev Soc Med 1964;18:146.
  9. Heinonen OP, Slone D, Shapiro S. Birth Defects and Drugs in Pregnancy. Littleton, MA:Publishing Sciences Group, 1977.
  10. Marynowski A, Sianozecka E. Comparison of the incidence of congenital malformations in neonates from healthy mothers and from patients treated because of tuberculosis. Ginekol Pol 1972;43:713.
  11. Jentgens H. Antituberkulose Chimotherapie und Schwangerschaft sabbruch. Prax Klin Pneumol 1973;27:479.
  12. Ludford J, Doster B, Woolpert SF. Effect of isoniazid on reproduction. Am Rev Respir Dis 1973;108:11704.
  13. Scheinhorn DJ, Angelillo VA. Antituberculosis therapy in pregnancy; risks to the fetus. West J Med 1977;127:1958.
  14. Good JT, Iseman MD, Davidson PT, Lakshminarayan S, Sahn SA. Tuberculosis in association with pregnancy. Am J Obstet Gynecol 1981;140:4928.
  15. Kingdom JCP, Kennedy DH. Tuberculous meningitis in pregnancy. Br J Obstet Gynaecol 1989;96:2335.
  16. Snider DE Jr, Layde PM, Johnson MW, Lyle MA. Treatment of tuberculosis during pregnancy. Am Rev Respir Dis 1980;122:6579.
  17. Tuman KJ, Chilcote RR, Gerkow RI, Moohr JW. Mesothelioma in child with prenatal exposure to isoniazid. Lancet 1980;2:362.
  18. Hammond DC, Silidoff IJ, Robitzek EH. Isoniazid therapy in relation to later occurrence of cancer in adults and in infants. Br Med J 1967;2:7925.
  19. Eggermont E, Logghe N, Van De Casseye W, Casteels-Van Daele M, Jaeken J, Cosemans J, Verstraete M, Renaer M. Haemorrhagic disease of the newborn in the offspring of rifampicin and isoniazid treated mothers. Acta Paediatr Belg 1976;29:8790.
  20. Snider DE Jr, Powell KE. Should women taking antituberculosis drugs breast-feed? Arch Intern Med 1984;144:58990.
  21. Berlin CM Jr, Lee C. Isoniazid and acetylisoniazid disposition in human milk, saliva and plasma. Fed Proc 1979;38:426.
  22. Vorherr H. Drugs excretion in breast milk. Postgrad Med 1974;56:97104.
  23. Ricci G, Copaitich T. Modalta di eliminazione dili'isoniazide somministrata per via orale attraverso il latte di donna. Rass Clin Ter 19545;209:534.
  24. Committee on Drugs, American Academy of Pediatrics. The transfer of drugs and other chemicals into human milk. Pediatrics 1994;93:13750.

Questions and Answers

Why is isoniazid is prescribed for the latent Tb?, If antibiotics work by attacking fast dividing bacteria then why in the case of latent TB (when bacteria are dormant) isoniazid is given to patients for 4-9 months?

T.B.bacilli grow at 4 speeds -fast slow and in between of these two ---speeds--- the fast ones are looked after-by rifamycin---and other slow SPEED growing ones are attacked isoniazid and ethambutal following this the futher slow growing ones tackled by pyrizinamide

Three isoniazid tablets for a day, and same dosage in the third day after?, A local health unit prescribed someone I know with isoniazid to cure latent TB, but three 300mg tablets all at once every three days? I'm taking it one pill a day, wouldn't 3 pills be toxic?

One of the problems with TB is that you have to take the drugs for so long that people don't finish the entire course. To fix that problem, the clinic will have the person physically come back to the clinic every few days to take the dose until the entire course is done.

If they are doing it every 3 days, then 900 mg is appropriate. Yes, they will need to keep an eye out for liver toxicity, but chances are good that there won't be any problems.

how does isoniazid causes hematologic dysfunction?, as per drug information about isoniazid, some of its adverse drug reactions is agranulocytosis, anemia, thrombocytopenia. how can it cause these hematologic dysfunctions?

GENERIC NAME: ISONIAZID ( INH)
BRAND NAME(S): Niazid
INH; Isonicotinic Acid Hydrazide

This medication is used to prevent and treat tuberculosis.

Rarely, this medication has caused severe (sometimes fatal) liver problems (e.g.,fatal hepatitis)
As with all drugs; it can cause enlargement of the liver or liver dysfunctions/problems. . This drug can cause hepatoxicity.

One of the main functions of the liver is clearance of waste products, drugs, and toxins. . In addition, the liver metabolizes most hormones and ingested drugs to either more or less active products.

Nearly all drugs are modified or degraded in the liver. In particular, oral drugs are absorbed by the gut and transported via the portal circulation to the liver. In the liver, drugs may undergo first-pass metabolism, a process in which they are modified, activated, or inactivated before they enter the systemic circulation, or they may be left unchanged.

Alcohol is primarily metabolized by the liver, and accumulation of its products can lead to cell injury and death.

In patients with liver disease, drug detoxification and excretion may be dangerously altered, resulting in drug concentrations that are too low or too high or the production of toxic drug metabolites. Therefore, medications that are metabolized by the liver must be used with caution in patients with hepatic disease; these patients may need lower doses of the drug.

Thus this drug may cause thrombocytopenia ( low platelet count) or agranulocytosis( low WBC count).and hemolysis or destruction of blood cells and low production of RBC ( RBC is produced in the liver ) resulting in anemia.

Why Refampicin and Isoniazid can cause decrease in vitamin B6?, its our assignment. PLEASE help me.

or you can give me links or other sources where you get your answer.

Well for isoniazid, it's because it combines with and inactivates it.

"Isoniazid may induce a state of pyridoxine (or vitamin b6) deficiency by combining with pyridoxine and generating inactive isoniazid-pyridoxal hydrozones, thus depleting the supply of pyridoxine."

How significant is the risk of drinking alcohol when taking Isoniazid?, Staring treatment for TB infection.

Alcohol can increase the toxicity of this drug. Drugs and alcohol don't mix because most all drugs are metabolized by the liver. If you are drinking while taking medications it can allow larger amounts of the drug to enter your blood stream than was intended because your liver is busy detoxifying the body of alcohol. Even Tylenol should not be taken while consuming alcohol.

What can you eat while taking isoniazid?, I asked this because while researching information on the drug I recieved a very long list on what not to eat...and most of it is what I eat on daily basis like tuna, bananas, cheese, avocados, etc.....Please help me I'm starving!!!!!!!

Hi, I don't know where you got that list but I think you can basically eat that foods you mentioned while you're in INH. SIde effects of the drugs are mainly on liver so you better take care of it and AVOID alcohol, over-the-counter drugs that contain alcohol like thos for colds (ephedrine).

All patients receiving isoniazid, or other TB drugs should be instructed to stop taking the medications and to immediately report any hepatitis-suggesting symptoms (nausea, loss of appetite, vomiting, persistently dark urine, yellowish skin)

I am on isoniazid and had a beer what will happen?, I had a half of a bud light, do you think anything will happen. I know you shouldn't drink on antibiotics, but i did. I also had cheese, and caffeine which you shouldn't mix with alcohol due to the increase of pressure put on your liver, is that true. So far I feel fine, do you think it will get worse? Thanks

Hey. Nothing will go wrong because of beer. But those tablets you are taking are very bad for liver. You need to stop taking it. Make sure that if you feel weak go to doctors. I was prescribed but since 4 of my friends all said they had bad experience then I just didn't take it. Good luck

How long after taking isoniazid can you consume alcohol?,

Isoniazid is hard on your liver so you should not have alcohol for a month after finishing you isoniazid prescription. I know, that could be many months.

Will the TB pill isoniazid tablets make the plan b pill less effective?, It says that it will reduce the effects of birth control pills but i dont know if it would with plan b

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