Antituberculosis agent (isonicotinic acid hydrazide)
Isoniazid is an antibiotic used to treat and prevent tuberculosis, always in combination with other drugs. It is effective, but can affect the liver and the nerves — it requires monitoring and vitamin B6 supplementation.
Also known as: INH, Isoniazid
Isoniazid inhibits Carbamazepine metabolism and may raise its levels — risk of toxicity.
Isoniazid inhibits the enzymes that metabolise carbamazepine (CYP2C19/CYP3A4) and can raise its concentrations to toxic levels (nystagmus, ataxia, sedation); in tuberculosis patients the effect can be clinically relevant in the first weeks. In addition, both drugs are hepatotoxic, with an additive risk of liver injury. Monitor carbamazepine levels and reduce the dose if needed, monitor transaminases and watch for intoxication symptoms.
Isoniazid + carbamazepine: isoniazid inhibits carbamazepine metabolism and raises its levels; both are hepatotoxic. Monitor levels and liver function.
CYP2C19/3A4 inhibition and possible epoxide hydrolase inhibition.
Carbamazepine levels, neurological signs.
Nystagmus, ataxia, drowsiness, diplopia.
Monitor carbamazepine levels and signs of toxicity.
DailyMed/FDA (NIH/NLM) — approved Isoniazid label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=93252cc8-c8d4-401b-bde5-ca8a3b57651e ; approved Carbamazepine label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=9f3d91cd-a959-4e07-a51b-8a4e9ba9ece2
Isoniazid (a CYP2E1 inducer) increases formation of the toxic paracetamol metabolite — higher risk of hepatotoxicity, especially at high doses or with alcohol.
The isoniazid label documents a report of severe paracetamol (acetaminophen) toxicity in a patient taking isoniazid and proposes the molecular basis: "isoniazid induces P-450IIE1, a mixed-function oxidase enzyme that appears to generate the toxic metabolites in the liver", causing a greater proportion of ingested paracetamol to be converted into the toxic metabolite (NAPQI); rat studies demonstrated that isoniazid pretreatment potentiates paracetamol hepatotoxicity. The combination is very common (isoniazid is used in tuberculosis and paracetamol is the first-line analgesic/antipyretic), and the risk is mainly of additive hepatotoxicity in patients with liver disease, alcohol users or with high/prolonged paracetamol doses. Recommendations: use the lowest effective paracetamol dose, avoid alcohol, monitor transaminases in at-risk patients and watch for signs of liver injury (nausea, anorexia, jaundice, right upper quadrant pain).
Isoniazid + paracetamol: isoniazid induces CYP2E1 and increases toxic paracetamol metabolites. Monitor liver function and avoid overdose.
CYP2E1 induction with increased NAPQI (hepatotoxic) metabolite production.
Liver function (ALT/AST) in at-risk patients; signs of hepatitis.
Jaundice, nausea, right upper quadrant pain.
Limit paracetamol dose (2-3 g/day) and avoid alcohol during treatment.
DailyMed/FDA (NIH/NLM) — approved Isoniazid label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=93252cc8-c8d4-401b-bde5-ca8a3b57651e ; approved Paracetamol label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=bf001b70-6164-1ec9-e053-2a95a90a1274
Isoniazid with Tramadol raises serotonergic risk and may lower the seizure threshold.
Isoniazid has some monoamine oxidase inhibiting activity (the isoniazid label states it has MAO-inhibiting activity, with interaction with tyramine-rich foods), and tramadol is a weak serotonin and norepinephrine reuptake inhibitor; together, the combination may increase the risk of serotonin syndrome, potentially life-threatening. The tramadol label warns about serotonin syndrome with serotonergic drugs and with drugs that impair the metabolism of serotonin or tramadol (such as MAO inhibitors). Monitor for serotonin symptoms (agitation, tachycardia, hyperthermia, hyperreflexia, myoclonus, rigidity), especially at treatment initiation, and consider alternatives if needed.
Isoniazid + tramadol: risk of serotonin syndrome (isoniazid has MAO-inhibiting activity). Monitor symptoms.
Weak MAO effect of isoniazid and serotonergic and seizure effects of tramadol.
Serotonergic and neurological signs.
Confusion, tremor, seizures, hyperthermia.
Avoid if possible; if used, watch for serotonin signs and seizures.
DailyMed/FDA (NIH/NLM) — approved Isoniazid label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=93252cc8-c8d4-401b-bde5-ca8a3b57651e ; approved Tramadol label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=552955e6-2bb3-8755-e063-6394a90ab21c
Isoniazid has a weak monoamine oxidase-inhibiting effect; with SSRIs (Sertraline) it may raise the risk of serotonin syndrome.
Isoniazid has some monoamine oxidase inhibiting activity (the isoniazid label states it has MAO-inhibiting activity, with interaction with tyramine-rich foods), and SSRIs such as sertraline increase serotonin availability; together, the combination may increase the risk of serotonin syndrome. The sertraline label warns about the increased risk with serotonergic drugs and with drugs that impair serotonin metabolism (such as MAO inhibitors). Monitor for serotonin symptoms (agitation, tachycardia, hyperthermia, hyperreflexia, myoclonus, rigidity), especially at treatment initiation or dose increases, and consider alternatives if needed.
Isoniazid + sertraline: risk of serotonin syndrome (isoniazid has MAO-inhibiting activity). Monitor symptoms.
Weak MAO inhibition by isoniazid and serotonin reuptake inhibition.
Signs of serotonin syndrome.
Agitation, tremor, hyperthermia, rigidity, diarrhoea.
Watch for serotonergic signs; use with caution.
DailyMed/FDA (NIH/NLM) — approved Isoniazid label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=93252cc8-c8d4-401b-bde5-ca8a3b57651e ; approved Sertraline label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=61835f25-bfe4-49ac-9dbf-3d6387866e78
Similar risk to other SSRIs: Isoniazid with Fluoxetine may precipitate serotonin syndrome.
Isoniazid has some monoamine oxidase inhibiting activity (the label states that "isoniazid has some monoamine oxidase inhibiting activity", with an interaction with tyramine-rich foods, and warns about the risk of interaction with MAO inhibitors), and fluoxetine is a selective serotonin reuptake inhibitor (SSRI) whose label contraindicates the combination with MAO inhibitors "because of an increased risk of serotonin syndrome". Combining an SSRI with a drug with MAO activity can cause serotonin syndrome (agitation, confusion, hyperthermia, hyperreflexia, myoclonus, diaphoresis, tachycardia) or a hypertensive crisis. Avoid whenever possible; if the combination is unavoidable (e.g. tuberculosis in a patient with depression), use the lowest effective dose, actively watch for serotonin signs and neurological toxicity, and instruct the patient to seek immediate help with agitation, fever or rigidity.
Isoniazid + fluoxetine: isoniazid has MAO-inhibiting activity — risk of serotonin syndrome with the SSRI. Watch for symptoms.
Weak MAO effect of isoniazid and serotonin reuptake inhibition, with long fluoxetine half-life.
Signs of serotonin syndrome.
Agitation, confusion, tremor, hyperthermia.
Watch for serotonergic signs; counsel the patient.
DailyMed/FDA (NIH/NLM) — approved Isoniazid label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=93252cc8-c8d4-401b-bde5-ca8a3b57651e ; approved Fluoxetine label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=09fb3100-1e06-4cdc-8016-7e4f5d097490
Combining Phenytoin with Isoniazid raises Phenytoin serum levels, with a risk of toxicity, especially in slow acetylators.
Isoniazid interferes with phenytoin metabolism (inhibition of the enzymes that metabolise it, namely CYP2C19), and the isoniazid label explicitly states that "isoniazid may increase serum levels of phenytoin" and that "to avoid phenytoin intoxication, appropriate adjustment of the anticonvulsant should be made"; the label repeats the caution in the overdosage section ("phenytoin should be used cautiously, because isoniazid interferes with the metabolism of phenytoin"). Phenytoin has non-linear kinetics and a narrow therapeutic window: raised levels can cause nystagmus, ataxia, dysarthria, drowsiness and, in severe cases, seizures or coma. When the combination is needed (e.g. tuberculosis in an epileptic patient), monitor phenytoin serum levels and clinical signs of toxicity at initiation and whenever the isoniazid dose changes, adjusting the anticonvulsant dose; consider transaminase monitoring, since both drugs are hepatotoxic.
Isoniazid + phenytoin: isoniazid inhibits phenytoin metabolism and raises its levels. Monitor and adjust the anticonvulsant dose.
Isoniazid inhibits Phenytoin metabolism, raising its concentrations; the risk is higher in patients who slowly acetylate Isoniazid.
Nystagmus, ataxia, diplopia or sedation after starting Isoniazid require level testing and adjustment.
Nystagmus, ataxia, diplopia or sedation require level testing and dose adjustment.
Monitor Phenytoin levels and signs of toxicity; consider reducing the Phenytoin dose when Isoniazid is started.
DailyMed/FDA (NIH/NLM) — approved Phenytoin label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=ef4e97a7-cd18-47a9-a016-2eca5481a87e ; approved Isoniazid label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=93252cc8-c8d4-401b-bde5-ca8a3b57651e — with additional reference: Prontuário Terapêutico do INFARMED, INFARMED (11th ed., 2012)
Isoniazid may enhance the effect of Warfarin — raised INR and bleeding risk.
Isoniazid inhibits several cytochrome P450 isoenzymes, including CYP2C9 and CYP3A4, and can reduce warfarin metabolism, raising the INR. The effect is variable and coexists with the complexity of antituberculosis regimens (which often include rifampicin, a potent inducer — the interaction network is complex and the INR can swing in both directions). The INR should be monitored frequently when starting, adjusting and stopping each component of the antituberculosis regimen, and the warfarin dose adjusted accordingly.
Isoniazid can inhibit warfarin metabolism and raise the INR. Monitor the INR during tuberculosis treatment and adjust the dose.
CYP2C9 inhibition, the main Warfarin metabolic pathway.
INR, signs of bleeding.
Bleeding, bruising, dark stools.
Monitor the INR when starting/stopping isoniazid and adjust the dose.
DailyMed/FDA (NIH/NLM) — approved Isoniazid label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=93252cc8-c8d4-401b-bde5-ca8a3b57651e ; approved Warfarin label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=541c9a70-adaf-4ef3-94ba-ad4e70dfa057
Isoniazid mildly inhibits monoamine oxidase and may potentiate the effects of tyramine (aged cheese, red wine).
Moderate intake of aged cheeses and red wine during treatment.
DailyMed/FDA (NIH/NLM) — approved Isoniazid label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=93252cc8-c8d4-401b-bde5-ca8a3b57651e
Alcohol adds hepatotoxicity to that of isoniazid and increases the risk of severe liver injury.
Avoid alcohol during treatment.
DailyMed/FDA (NIH/NLM) — approved Isoniazid label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=93252cc8-c8d4-401b-bde5-ca8a3b57651e
Isoniazid interferes with vitamin B6 metabolism and can cause peripheral neuropathy, especially in at-risk patients.
Supplement with vitamin B6 (pyridoxine) in at-risk patients (diabetes, alcoholism, pregnancy, malnutrition).
DailyMed/FDA (NIH/NLM) — approved Isoniazid label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=93252cc8-c8d4-401b-bde5-ca8a3b57651e
Isoniazid is hepatotoxic and the risk of severe liver injury increases in patients with prior liver disease.
Monitor transaminases monthly; stop if hepatitis symptoms occur.
DailyMed/FDA (NIH/NLM) — approved Isoniazid label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=93252cc8-c8d4-401b-bde5-ca8a3b57651e
Isoniazid crosses the placenta; it is not teratogenic, but is hepatotoxic and requires vitamin B6 supplementation in pregnancy.
Use for active tuberculosis in pregnancy; supplement pyridoxine and monitor transaminases.
Excreted into breast milk; compatible with breastfeeding under supervision.
No specific additional contraception.
DailyMed/FDA (NIH/NLM) — approved Isoniazid label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=93252cc8-c8d4-401b-bde5-ca8a3b57651e
Clinical and educational support tool. The information does not replace a medical prescription or the opinion of a qualified healthcare professional.
Bactericidal antituberculous agent. Produces peak blood levels 1 to 2 hours after oral administration, declining to 50% or less within 6 hours. It diffuses into all body fluids (CSF, pleural, ascitic), tissues, organs and excreta; it crosses the placenta and passes into milk. 50 to 70% of a dose is excreted in urine within 24 hours.
It inhibits the synthesis of mycolic acids, an essential component of the bacterial cell wall; at therapeutic levels it is bactericidal against actively growing Mycobacterium tuberculosis, intracellular and extracellular. Resistance develops rapidly in monotherapy (mutations in the katG, inhA, kasA and ahpC genes).
Rapid and complete gastrointestinal absorption; peak blood levels 1 to 2 hours after dosing. Bioavailability is significantly reduced when administered with food, so it should be taken while fasting.
Metabolised mainly by acetylation and dehydrazination; the rate of acetylation is genetically determined (about 50% of Blacks and Caucasians are slow inactivators; the majority of Eskimos and Orientals are rapid inactivators). Slow acetylation may lead to higher blood levels and more toxic reactions, including peripheral neuropathy.
Peak blood levels decline to 50% or less within 6 hours; half-life is longer in slow inactivators (who accumulate more drug) and in hepatic impairment. Supplement with pyridoxine (B6) in patients at risk of neuropathy (alcoholics, diabetics, malnourished).
Medicines from the same therapeutic group (ATC classification) or the same pharmacological class.
