Severe and sometimes fatal hepatitis associated with isoniazid therapy has been reported and may occur or may develop even after many months of treatment. The risk of developing hepatitis is age related. Approximate case rates by age are as follows: less than 1/1,000 for persons younger than 20 years of age, 3/1,000 for persons in the 20 to 34 year age group, 12/1,000 for persons in the 35 to 49 year age group, 23/1,000 for persons in the 50 to 64 year age group, and 8/1,000 for persons older than 65 years. The risk of hepatitis is increased with daily consumption of alcohol. Precise data to provide a fatality rate for isoniazid-related hepatitis are not available; however, in a US Public Health Service surveillance study of 13,838 persons taking isoniazid, there were 8 deaths among 174 cases of hepatitis.
Therefore, carefully monitor patients given isoniazid and interview patients at monthly intervals. For persons 35 years and older, in addition to monthly symptom reviews, measure hepatic enzymes (specifically, AST and ALT) prior to starting isoniazid therapy and periodically throughout treatment. Isoniazid-associated hepatitis usually occurs during the first 3 months of treatment. Usually, enzyme levels return to normal despite continuance of drug, but, in some cases, progressive liver dysfunction occurs. Other factors associated with an increased risk of hepatitis include daily use of alcohol, chronic liver disease, and injection drug use. A recent report suggests an increased risk of fatal hepatitis associated with isoniazid among women, particularly black and Hispanic women. The risk may also be increased during the postpartum period. Consider more careful monitoring in these groups, possibly including more frequent laboratory monitoring. If abnormalities of liver function exceed 3 to 5 times the upper limit of normal (ULN), strongly consider discontinuation of isoniazid. Liver function tests are not a substitute for a clinical evaluation at monthly intervals or for the prompt assessment of signs or symptoms of adverse reactions occurring between regularly scheduled evaluations. Instruct patients to immediately report signs or symptoms consistent with liver damage or other adverse reactions. These include any of the following: unexplained anorexia, nausea, vomiting, dark urine, icterus, rash, persistent paresthesia of the hands and feet, persistent fatigue, weakness or fever of greater than 3-day duration or abdominal tenderness, especially right upper quadrant discomfort. If these symptoms appear or if signs suggestive of hepatic damage are detected, promptly discontinue isoniazid, because continued use of the drug in these cases has been reported to cause a more severe form of liver damage.
Give patients with tuberculosis who have hepatitis attributed to isoniazid appropriate treatment with alternative drugs. If isoniazid must be reinstituted, do so only after symptoms and laboratory abnormalities have cleared. Restart the drug in very small and gradually increasing doses and withdraw immediately if there is any indication of recurrent liver involvement.
Defer preventive treatment in persons with acute hepatic diseases.
Note: Concomitant pyridoxine is recommended in patients at risk for isoniazid-induced neuropathy, including breastfeeding infants and patients who are pregnant or have HIV, diabetes, malnutrition, alcoholism, or chronic renal failure (ATS/CDC/IDSA [Nahid 2016]; WHO 2020).
Tuberculosis, active (drug-susceptible); treatment (ATS/CDC/IDSA [Nahid 2016]):
Note: Always use in combination with other antitubercular drugs. Any regimens using less than once-daily dosing should administer dosing as directly observed therapy (DOT). Some experts recommend DOT for all pediatric patients. Isoniazid dosing differs depending on frequency of dosing/treatment regimen selected; consult current guidelines for detailed information (ATS/CDC/IDSA [Nahid 2016]; Red Book [AAP 2018]).
Once daily or 5 times weekly (DOT):
Infants, Children, and Adolescents <15 years, weighing ≤40 kg: Oral, IM: 10 to 15 mg/kg/dose once daily (or 5 days/week by DOT); maximum dose: 300 mg/dose.
Children and Adolescents <15 years weighing >40 kg or Adolescents ≥15 years: Oral, IM: 5 mg/kg/dose once daily (or 5 days/week by DOT); typical dose: 300 mg/dose.
Three-times-weekly DOT: Note: Three-times-weekly DOT may be used as an alternative to daily therapy in patients without HIV with noncavitary and/or smear-negative disease. Though three-times-weekly regimen is preferred to twice-weekly, data to guide dosing are limited; suggested dosing based on twice-weekly regimen.
Infants, Children, and Adolescents <15 years, weighing ≤40 kg: Oral, IM: 20 to 30 mg/kg/dose three times weekly by DOT; maximum dose: 900 mg/dose.
Children and Adolescents <15 years weighing >40 kg or Adolescents ≥15 years: Oral, IM: 15 mg/kg/dose three times weekly by DOT (typical dose: 900 mg).
Twice-weekly DOT: Note: Regimen not generally recommended; do not use in HIV patients or those with smear-positive and/or cavitary disease, and only use after completion of a 2-week once-daily (or 5-times-weekly) regimen in the intensive phase. Missed doses result in the equivalent of once-weekly dosing which has been shown to be inferior and is associated with treatment failure, relapse, and development of drug resistance.
Infants, Children, and Adolescents <15 years, weighing ≤40 kg: Oral, IM: 20 to 30 mg/kg/dose twice weekly by DOT; maximum dose: 900 mg/dose.
Children and Adolescents <15 years weighing >40 kg or Adolescents ≥15 years: Oral, IM: 15 mg/kg/dose twice weekly by DOT; typical dose: 900 mg/dose.
Duration of therapy: Treatment regimens consist of an initial 2-month intensive phase of a 4-drug regimen, followed by a continuation phase of isoniazid and rifampin. Duration of continuation phase is ≥4 months; should be longer for cavitary disease with positive cultures at completion of intensive phase (7 months), bone and joint disease (≥4 to 7 months), and CNS disease (7 to 10 months).
Tuberculosis, active (drug-resistant); treatment: Note: Use should only be considered in patients with low-level isoniazid resistance; do not use in patients with high-level isoniazid resistance. Always use in combination with other antitubercular drugs; expert consultation for optimal regimen and duration of treatment is advised (ATS/CDC/ERS/IDSA [Nahid 2019]).
Infants, Children, and Adolescents: Oral, IM: 15 to 20 mg/kg/day as part of an appropriate combination regimen (ATS/CDC/ERS/IDSA [Nahid 2019]; Harausz 2018; WHO 2019). Administer in combination with pyridoxine (WHO 2019).
Tuberculosis, latent infection; treatment: Preferred regimen varies between guidelines and based on patient characteristics (HHS [OI adult 2019]; HHS [OI pediatric 2019]; NTCA/CDC [Sterling 2020]); regimens should not be used in patients known or presumed to be infected with resistant strains of tuberculosis (TB) (NTCA/CDC [Sterling 2020]).
Isoniazid combination therapy: Note: Preferred regimens (NTCA/CDC [Sterling 2020]):
Rifapentine combination: Independent of HIV status: Note: May be administered by DOT or self-administered therapy (SAT) at the clinician's discretion based on local practice, patient attributes/preferences, and other factors including risk for TB disease progression (CDC [Borisov 2018]). Only use in HIV-infected patients if antiretroviral therapy has acceptable drug-drug interactions with rifapentine (CDC [Borisov 2018]; NTCA/CDC [Sterling 2020]).
Children 2 to 11 years: Oral: Isoniazid 25 mg/kg/dose once weekly for 12 weeks (12 doses); maximum dose: 900 mg/dose (NTCA/CDC [Sterling 2020]).
Children ≥12 years and Adolescents: Oral: Isoniazid 15 mg/kg/dose once weekly for 12 weeks (12 doses), round dose up to nearest 50 or 100 mg; maximum dose: 900 mg/dose (NTCA/CDC [Sterling 2020]).
Rifampin combination: Independent of HIV status: Note: Only use in HIV-infected patients if antiretroviral therapy has acceptable drug-drug interactions with rifampin (CDC [Borisov 2018]; NTCA/CDC [Sterling 2020]).
Infants, Children, and Adolescents: Oral: Isoniazid 10 to 20 mg/kg/dose once daily (maximum dose: 300 mg/dose) for 3 months (NTCA/CDC [Sterling 2020]).
Isoniazid monotherapy: Note: Alternative regimen (NTCA/CDC [Sterling 2020]):
Infants, Children, and Adolescents; independent of HIV status:
Daily regimen: Oral: 10 to 20 mg/kg/dose once daily for 6 to 9 months; maximum dose: 300 mg/dose; while the CDC recommends a 6-month duration, 9 months may be considered; direct comparative efficacy data for 6 months versus 9 months are lacking and risk of hepatotoxicity is greater with longer durations (HHS [OI adult 2019]; HHS [OI pediatric 2019]; NTCA/CDC [Sterling 2020]). Note: Some organizations recommend an upper limit of 15 mg/kg/dose (maximum dose: 300 mg/dose) (HHS [OI pediatric 2019]; Red Book [AAP 2018]; WHO 2018).
Twice-weekly regimen: Oral: 20 to 40 mg/kg/dose twice weekly for 6 to 9 months; maximum dose: 900 mg/dose; must be administered by DOT; while the CDC recommends a 6-month duration, 9 months may be considered; direct comparative efficacy data are lacking for 6 months versus 9 months and risk of hepatotoxicity is greater with longer durations (HHS [OI adult 2019]; HHS [OI pediatric 2019]; NTCA/CDC [Sterling 2020]). Note: Some organizations recommend an upper limit of 30 mg/kg/dose (maximum dose: 900 mg/dose) (HHS [OI pediatric 2019]); Red Book [AAP 2018]; WHO 2018).
Pulmonary nontuberculous mycobacterial infection; treatment: Limited data available:
Children and Adolescents: Oral: 10 mg/kg/dose once daily as part of an appropriate combination regimen; maximum dose: 300 mg/dose (BTS [Haworth 2017]).
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
Infants, Children, and Adolescents:
Altered kidney function: No dosage adjustment necessary (ATS/CDC/IDSA [Nahid 2016]; ATS/CDC/ERS/IDSA [Nahid 2019]; WHO 2010).
Hemodialysis: Dialyzable. Based on experience in adults, no dosage adjustment necessary; administer after hemodialysis on dialysis days (ATS/CDC/IDSA [Nahid 2016]).
Infants, Children, and Adolescents:
Baseline hepatic impairment:
Acute liver disease or previous isoniazid-associated hepatic injury: Contraindicated. For latent tuberculosis infection, defer treatment with isoniazid.
Chronic liver disease: There are no dosage adjustments provided in the manufacturer's labeling; however, use with caution, may accumulate and additional liver damage may occur in patients with preexisting liver disease. Monitor laboratory and clinical parameters frequently (ATS/CDC/IDSA [Nahid 2016]).
Hepatotoxicity during therapy (ALT or AST >3 times the ULN): Discontinue or temporarily withhold treatment.
(For additional information see "Isoniazid: Drug information")
Note: Concomitant pyridoxine is recommended in any patient at risk for neuropathy (eg, patients with HIV infection, diabetes, alcoholism, nutritional deficiency, chronic renal failure, advanced age) and in pregnant or breastfeeding women (ATS/CDC/IDSA [Nahid 2016]; WHO 2020; manufacturer’s labeling).
Tuberculosis, active (drug susceptible): Oral, IM: Note: Always administer in combination with other antitubercular drugs.
ATS/CDC/IDSA Drug-susceptible tuberculosis guideline recommendations (ATS/CDC/IDSA [Nahid 2016]):
Dosing:
Once-daily therapy: 5 mg/kg/dose (usual dose: 300 mg) once daily Note: The preferred frequency of administration is once daily during the intensive and continuation phases; however, 5 days per week administration by directly observed therapy (DOT) is an acceptable alternative.
Three-times-weekly DOT: 15 mg/kg/dose (usual dose: 900 mg) administered 3 times weekly
Twice-weekly DOT: 15 mg/kg/dose (usual dose: 900 mg) administered twice weekly
Once-weekly DOT: 15 mg/kg/dose (usual dose: 900 mg) administered once weekly
Regimens: Treatment regimens for pulmonary tuberculosis and tuberculous meningitis consist of an initial 2-month phase of a 4-drug regimen, followed by a continuation phase of an additional 4 to 7 months of isoniazid and rifampin for pulmonary tuberculosis and a continuation phase of an additional 7 to 10 months of isoniazid and rifampin for tuberculous meningitis (optimal duration is not defined although continuation phase must continue for a minimum of 7 additional months). Adjunctive corticosteroid therapy (eg, dexamethasone, prednisolone) tapered over 6 to 8 weeks is also recommended for tuberculous meningitis. Isoniazid frequency and dosing differs depending on treatment regimen selected; consult current Drug-sensitive TB guidelines (ATS/CDC/IDSA [Nahid 2016]).
Tuberculosis, treatment (drug-resistant) (alternative agent): Note: Use should only be considered in patients with low-level isoniazid resistance; do not use in patients with high-level isoniazid resistance. Expert consultation for optimal regimen and duration of treatment is advised (ATS/CDC/ERD/IDSA [Nahid 2019]).
Oral, IM: 15 mg/kg once daily as part of an appropriate combination regimen (ATS/CDC/ERS/IDSA [Nahid 2019]; Dooley 2020; Schluger 2020; Walsh 2019; WHO 2020).
Tuberculosis, latent infection:
Isoniazid and rifapentine combination regimen: Oral: 15 mg/kg/dose (round up to nearest 50 or 100 mg; maximum dose: 900 mg/dose) once weekly in combination with rifapentine for 3 months by DOT (preferred) or self-administered therapy (CDC [Borisov 2018]; HHS [OI adult 2020]; NTCA/CDC [Sterling 2020]; Sterling 2011; Sterling 2016). Note: The once-weekly rifapentine-containing regimen may only be used in patients who are not pregnant and/or not expecting to become pregnant; if used in patients with HIV, it may only be used in those receiving antiretroviral therapy (ART) with acceptable drug-drug interactions with rifapentine (CDC [Borisov 2018]; HHS [OI adult 2020]; NTCA/CDC [Sterling 2020]).
Isoniazid and rifampin combination regimen: Oral: 5 mg/kg (maximum: 300 mg/dose) once daily in combination with rifampin for 3 months. Note: If used in patients with HIV, it may only be used in those receiving antiretroviral therapy with acceptable drug-drug interactions with rifampin (NTCA/CDC [Sterling 2020]).
Isoniazid monotherapy (alternative regimen): Oral, IM: 5 mg/kg (maximum: 300 mg/dose) once daily for 6 or 9 months or 15 mg/kg (maximum: 900 mg/dose) twice weekly under DOT for 6 or 9 months. Note: 9 months of daily isoniazid therapy may be more effective than 6 months, but no clinical trial data are available that directly compare the 2 durations (NTCA/CDC [Sterling 2020]).
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
The renal dosing recommendations are based upon the best available evidence and clinical expertise. Senior Editorial Team: Bruce Mueller, PharmD, FCCP, FASN, FNKF; Jason A. Roberts, PhD, BPharm (Hons), B App Sc, FSHP, FISAC; Michael Heung, MD, MS.
Note: Acetylator status (eg, slow vs rapid), rather than kidney function, is considered to be the primary contributor to isoniazid clearance (Weber 1979). Although no dosage adjustments of isoniazid are recommended in patients with end-stage kidney disease, including patients on dialysis, use with caution due to an increased risk of neurotoxicity (Chaitanya 2016; Cheung 1993; Constantinescu 2017; Low 2019; Si 2018); close monitoring and concomitant pyridoxine therapy is recommended (ATS/CDC/IDSA [Nahid 2016]; WHO 2020).
Oral, IM:
Altered kidney function: No dosage adjustment necessary for any degree of kidney dysfunction (ATS/CDC/ERS/IDSA [Nahid 2019]; ATS/CDC/IDSA [Nahid 2016]; Gold 1976; Weber 1979).
Hemodialysis, intermittent (thrice weekly): Slightly dialyzable (9.2%) (Malone 1999): No dosage adjustment necessary (ATS/CDC/IDSA [Nahid 2016]; Malone 1999); when scheduled dose falls on a dialysis day, administer after hemodialysis (ATS/CDC/IDSA [Nahid 2016]).
Peritoneal dialysis: Slightly dialyzable (CAPD accounts for 1.3% of total clearance): No dosage adjustment necessary (Ahn 2003).
CRRT: No dosage adjustment necessary (expert opinion).
PIRRT (eg, sustained, low-efficiency diafiltration): No dosage adjustment necessary (expert opinion).
There are no dosage adjustments provided in the manufacturer's labeling; however, use with caution, may accumulate and additional liver damage may occur in patients with preexisting liver disease. Contraindicated in patients with acute liver disease or previous isoniazid-associated hepatic injury. For ALT or AST >3 times the ULN: discontinue or temporarily withhold treatment. Treatment with isoniazid for latent tuberculosis infection should be deferred in patients with acute hepatic diseases.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Solution, Injection:
Generic: 100 mg/mL (10 mL)
Syrup, Oral:
Generic: 50 mg/5 mL (473 mL)
Tablet, Oral:
Generic: 100 mg, 300 mg
Yes
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Syrup, Oral:
Isotamine: 50 mg/5 mL (500 mL)
Generic: 50 mg/5 mL (500 mL)
Tablet, Oral:
Isotamine: 100 mg, 300 mg
Generic: 50 mg, 100 mg, 300 mg
Oral: Administer on an empty stomach (1 hour before or 2 hours after meals with water); if unable to swallow tablets, may crush tablet and mix in a soft food or liquid, or starch-based pudding (commercial chocolate pudding) and administer as a slurry (Cruz 2018; Peloquin 2007; Villarino 2015).
Parenteral: IM: May be administered IM in patients who are unable to either take or absorb oral therapy.
Oral: Do not administer with food (bioavailability is decreased).
Intramuscular: IM injection may be used for patients who are unable to either take or absorb oral therapy. Inject deep IM into a large muscle mass.
Tablet: Store at 20°C to 25°C (68°F to 77°F). Protect from moisture and light.
Oral solution: Store at 20°C to 25°C (68°F to 77°F); excursions are permitted between 15°C to 30°C (59°F to 86°F). Protect from light.
Injection: Store at 20°C to 25°C (68°F to 77°F). Protect from light. Isoniazid injection may crystallize at low temperatures. If this occurs, warm the vial to room temperature before use to redissolve the crystals.
Treatment of susceptible active tuberculosis (eg, Mycobacterium tuberculosis) infections in combination with other agents (FDA approved in children and adults); treatment of latent tuberculosis infection (LTBI) caused by M. tuberculosis (also referred to as prophylaxis or preventive therapy) (FDA approved in infants, children, and adults); has also been used for treatment of pulmonary nontuberculous mycobacterial infections.
Hydra [Japan] may be confused with Hydrea brand name for hydroxyurea [US, Canada, and multiple international markets]
The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified.
>10%: Hepatic: Increased serum transaminases (mild and transient 10% to 20%)
Frequency not defined.
Cardiovascular: Vasculitis
Central nervous system: Brain disease, memory impairment, paresthesia, peripheral neuropathy, psychosis, seizure
Dermatologic: Skin rash (morbilliform, maculopapular, pruritic, or exfoliative), toxic epidermal necrolysis
Endocrine & metabolic: Gynecomastia, hyperglycemia, metabolic acidosis, pellagra, pyridoxine deficiency
Gastrointestinal: Epigastric distress, nausea, pancreatitis, vomiting
Genitourinary: Bilirubinuria
Hematologic & oncologic: Agranulocytosis, anemia (sideroblastic, hemolytic, or aplastic), eosinophilia, lymphadenopathy, thrombocytopenia
Hepatic: Hepatitis (risk increases with age; 2% in patients ≥50 years), hyperbilirubinemia, jaundice
Immunologic: DRESS syndrome
Neuromuscular & skeletal: Lupus-like syndrome, rheumatic disease
Ophthalmic: Optic atrophy, optic neuritis
Miscellaneous: Fever
Postmarketing and/or case reports: Hepatotoxicity (idiosyncratic) (Chalasani 2014)
Hypersensitivity to isoniazid or any component of the formulation, including drug-induced hepatitis; acute liver disease; previous history of hepatic injury during isoniazid therapy; previous severe adverse reaction (drug fever, chills, arthritis) to isoniazid
Concerns related to adverse effects:
• Hepatitis: [US Boxed Warning]: Severe and sometimes fatal hepatitis may occur; usually occurs within the first 3 months of treatment, although may develop even after many months of treatment. The risk of developing hepatitis is age-related, although isoniazid-induced hepatotoxicity has been reported in children; daily ethanol consumption, chronic liver disease, or injection drug use may also increase the risk. Patients given isoniazid must be monitored carefully and interviewed at monthly intervals. Fatal hepatitis associated with isoniazid may be increased in women (particularly black and Hispanic and in any woman in the postpartum period). Closer monitoring may be considered in these groups. Patients ≥35 years should also have AST and ALT measured at baseline and periodically throughout treatment. Patients must report any prodromal symptoms of hepatitis, such as fatigue, paresthesias of hands and feet, weakness, dark urine, rash, anorexia, nausea, fever >3 days’ duration, and/or abdominal pain (especially right upper quadrant discomfort), icterus, or vomiting. Patients should be instructed to immediately hold therapy if any of these symptoms occur, and contact their prescriber. If abnormalities of liver function exceed 3 to 5 times the upper limit of normal (ULN), strongly consider discontinuation of isoniazid. If isoniazid must be reinstituted, wait for symptoms and laboratory abnormalities to resolve and use very small and gradual increasing doses, withdrawing therapy immediately if an indication of recurrent hepatic involvement.
• Peripheral neuropathies: Pyridoxine supplementation is recommended in individuals at risk for development of peripheral neuropathies (eg, HIV infection, nutritional deficiency, diabetes, alcoholism, chronic renal failure, advanced age) (ATS/CDC/IDSA [Nahid 2016]).
Disease-related concerns:
• Hepatic impairment: Use with caution in patients with hepatic impairment; contraindicated in patients with acute liver disease or previous isoniazid-associated hepatic injury. Treatment with isoniazid for latent tuberculosis infection (LTBI) should be deferred in patients with acute hepatic diseases.
• Renal impairment: Use with caution in patients with severe renal impairment.
Other warnings/precautions:
• Appropriate use: Multidrug regimens should be utilized for the treatment of active tuberculosis to prevent the emergence of drug resistance.
• Monitoring: Use should be carefully monitored in the following groups: Daily users of alcohol, active chronic liver disease, severe renal dysfunction, age >35 years, concurrent use of any chronically administered drug, history of previous isoniazid discontinuation, existence of or conditions predisposing to peripheral neuropathy, pregnancy, injection drug use, women in minority groups (particularly postpartum), HIV seropositive patients.
Substrate of CYP2E1 (minor); Note: Assignment of Major/Minor substrate status based on clinically relevant drug interaction potential; Inhibits CYP2E1 (moderate), CYP3A4 (weak); Induces CYP2E1 (weak)
Acetaminophen: Isoniazid may enhance the hepatotoxic effect of Acetaminophen. Isoniazid may increase the metabolism of Acetaminophen. Specifically, formation of the hepatotoxic NAPQI metabolite may be increased. Risk C: Monitor therapy
Alcohol (Ethyl): May enhance the hepatotoxic effect of Isoniazid. Risk C: Monitor therapy
ALPRAZolam: CYP3A4 Inhibitors (Weak) may increase the serum concentration of ALPRAZolam. Risk C: Monitor therapy
Antacids: May decrease the absorption of Isoniazid. Risk C: Monitor therapy
BCG (Intravesical): Antibiotics may diminish the therapeutic effect of BCG (Intravesical). Risk X: Avoid combination
BCG Vaccine (Immunization): Antibiotics may diminish the therapeutic effect of BCG Vaccine (Immunization). Risk C: Monitor therapy
CarBAMazepine: May enhance the hepatotoxic effect of Isoniazid. Isoniazid may increase the serum concentration of CarBAMazepine. Risk C: Monitor therapy
Chlorzoxazone: Isoniazid may increase the serum concentration of Chlorzoxazone. Isoniazid may decrease the serum concentration of Chlorzoxazone. Specifically, it may decrease chlorzoxazone concentrations below baseline after isoniazid discontinuation. Risk C: Monitor therapy
Cholera Vaccine: Antibiotics may diminish the therapeutic effect of Cholera Vaccine. Management: Avoid cholera vaccine in patients receiving systemic antibiotics, and within 14 days following the use of oral or parenteral antibiotics. Risk X: Avoid combination
Corticosteroids (Systemic): May decrease the serum concentration of Isoniazid. Risk C: Monitor therapy
CycloSERINE: Isoniazid may enhance the adverse/toxic effect of CycloSERINE. Specifically, CNS toxicity may be enhanced. Risk C: Monitor therapy
CycloSPORINE (Systemic): CYP3A4 Inhibitors (Weak) may increase the serum concentration of CycloSPORINE (Systemic). Risk C: Monitor therapy
CYP2E1 Inhibitors (Strong): May increase the serum concentration of Isoniazid. Risk C: Monitor therapy
Dofetilide: CYP3A4 Inhibitors (Weak) may increase the serum concentration of Dofetilide. Risk C: Monitor therapy
Ethionamide: May increase the serum concentration of Isoniazid. Risk C: Monitor therapy
Finerenone: CYP3A4 Inhibitors (Weak) may increase the serum concentration of Finerenone. Risk C: Monitor therapy
Flibanserin: CYP3A4 Inhibitors (Weak) may increase the serum concentration of Flibanserin. Risk C: Monitor therapy
Fosphenytoin: Isoniazid may increase the serum concentration of Fosphenytoin. Management: Consider alternatives. If concomitant therapy cannot be avoided, monitor for increased phenytoin concentrations/effects with isoniazid initiation/dose increase, or decreased concentrations/effects with isoniazid discontinuation/dose decrease. Risk D: Consider therapy modification
Immune Checkpoint Inhibitors: Antibiotics may diminish the therapeutic effect of Immune Checkpoint Inhibitors. Risk C: Monitor therapy
Itraconazole: Isoniazid may decrease the serum concentration of Itraconazole. Risk C: Monitor therapy
Ixabepilone: CYP3A4 Inhibitors (Weak) may increase the serum concentration of Ixabepilone. Risk C: Monitor therapy
Ketoconazole (Systemic): Isoniazid may decrease the serum concentration of Ketoconazole (Systemic). Risk C: Monitor therapy
Lactobacillus and Estriol: Antibiotics may diminish the therapeutic effect of Lactobacillus and Estriol. Risk C: Monitor therapy
Lemborexant: CYP3A4 Inhibitors (Weak) may increase the serum concentration of Lemborexant. Management: The maximum recommended dosage of lemborexant is 5 mg, no more than once per night, when coadministered with weak CYP3A4 inhibitors. Risk D: Consider therapy modification
Levodopa-Containing Products: Isoniazid may diminish the therapeutic effect of Levodopa-Containing Products. Risk C: Monitor therapy
Levoketoconazole: Isoniazid may decrease the serum concentration of Levoketoconazole. Risk X: Avoid combination
Lomitapide: CYP3A4 Inhibitors (Weak) may increase the serum concentration of Lomitapide. Management: Patients on lomitapide 5 mg/day may continue that dose. Patients taking lomitapide 10 mg/day or more should decrease the lomitapide dose by half. The lomitapide dose may then be titrated up to a max adult dose of 30 mg/day. Risk D: Consider therapy modification
Lonafarnib: CYP3A4 Inhibitors (Weak) may increase the serum concentration of Lonafarnib. Management: Avoid concurrent use of lonafarnib with weak CYP3A4 inhibitors. If concurrent use is unavoidable, reduce the lonafarnib dose to or continue at a dose of 115 mg/square meter. Monitor for evidence of arrhythmia, syncope, palpitations, or similar effects. Risk D: Consider therapy modification
Methoxyflurane: Isoniazid may increase the metabolism of Methoxyflurane. Specifically, this increased metabolism may lead to increased production of nephrotoxic metabolites. Risk X: Avoid combination
Midazolam: CYP3A4 Inhibitors (Weak) may increase the serum concentration of Midazolam. Risk C: Monitor therapy
NiMODipine: CYP3A4 Inhibitors (Weak) may increase the serum concentration of NiMODipine. Risk C: Monitor therapy
Phenytoin: Isoniazid may increase the serum concentration of Phenytoin. Management: Consider alternatives. If concomitant therapy cannot be avoided, monitor for increased phenytoin concentrations/effects with isoniazid initiation/dose increase, or decreased concentrations/effects with isoniazid discontinuation/dose decrease. Risk D: Consider therapy modification
Pimozide: CYP3A4 Inhibitors (Weak) may increase the serum concentration of Pimozide. Risk X: Avoid combination
Propacetamol: Isoniazid may enhance the hepatotoxic effect of Propacetamol. Isoniazid may increase the metabolism of Propacetamol. Specifically, formation of the hepatotoxic NAPQI metabolite may be increased. Risk C: Monitor therapy
Prothionamide: Isoniazid may increase the serum concentration of Prothionamide. Prothionamide may increase the serum concentration of Isoniazid. Management: Reduce the prothionamide dose by half (do not exceed 500 mg per day in adults) if combined with isoniazid. Additionally, monitor for increased isoniazid toxicities and ensure pyridoxine supplementation is provided if these drugs are combined. Risk D: Consider therapy modification
RifAMPin: Isoniazid may enhance the hepatotoxic effect of RifAMPin. Risk C: Monitor therapy
Safinamide: May enhance the adverse/toxic effect of Isoniazid. Specifically, there is an increased risk for hypertension. Risk C: Monitor therapy
Simvastatin: CYP3A4 Inhibitors (Weak) may increase serum concentrations of the active metabolite(s) of Simvastatin. CYP3A4 Inhibitors (Weak) may increase the serum concentration of Simvastatin. Risk C: Monitor therapy
Sirolimus (Conventional): CYP3A4 Inhibitors (Weak) may increase the serum concentration of Sirolimus (Conventional). Risk C: Monitor therapy
Sirolimus (Protein Bound): CYP3A4 Inhibitors (Weak) may increase the serum concentration of Sirolimus (Protein Bound). Management: Reduce the dose of protein bound sirolimus to 56 mg/m2 when used concomitantly with a weak CYP3A4 inhibitor. Risk D: Consider therapy modification
Sodium Picosulfate: Antibiotics may diminish the therapeutic effect of Sodium Picosulfate. Management: Consider using an alternative product for bowel cleansing prior to a colonoscopy in patients who have recently used or are concurrently using an antibiotic. Risk D: Consider therapy modification
Tacrolimus (Systemic): CYP3A4 Inhibitors (Weak) may increase the serum concentration of Tacrolimus (Systemic). Risk C: Monitor therapy
Theophylline Derivatives: Isoniazid may increase the serum concentration of Theophylline Derivatives. Risk C: Monitor therapy
Triazolam: CYP3A4 Inhibitors (Weak) may increase the serum concentration of Triazolam. Risk C: Monitor therapy
Typhoid Vaccine: Antibiotics may diminish the therapeutic effect of Typhoid Vaccine. Only the live attenuated Ty21a strain is affected. Management: Avoid use of live attenuated typhoid vaccine (Ty21a) in patients being treated with systemic antibacterial agents. Postpone vaccination until 3 days after cessation of antibiotics and avoid starting antibiotics within 3 days of last vaccine dose. Risk D: Consider therapy modification
Ubrogepant: CYP3A4 Inhibitors (Weak) may increase the serum concentration of Ubrogepant. Management: In patients taking weak CYP3A4 inhibitors, the initial and second dose (given at least 2 hours later if needed) of ubrogepant should be limited to 50 mg. Risk D: Consider therapy modification
Administration with food significantly reduces bioavailability. Management: Avoid administration with food.
Isoniazid may decrease folic acid absorption and alters pyridoxine metabolism. Management: Increase dietary intake of folate, niacin, and magnesium.
Tyramine-containing food: Isoniazid has weak monoamine oxidase inhibiting activity and may potentially inhibit tyramine metabolism. Several case reports of mild reactions (flushing, palpitations, headache, mild increase in blood pressure, diaphoresis) after ingestion of certain types of cheese or red wine, have been reported (Self 1999; Toutoungi, 1985). Management: Manufacturer’s labeling recommends avoiding tyramine-containing foods (eg, aged or matured cheese, air-dried or cured meats including sausages and salamis; fava or broad bean pods, tap/draft beers, Marmite concentrate, sauerkraut, soy sauce, and other soybean condiments). However, the clinical relevance of the tyramine reaction for the vast majority of patients receiving isoniazid has been questioned due to isoniazid’s weak MAO inhibition and the relatively few published case reports of the interaction. Although not fully investigated, it has been proposed that the reaction has a genetic component and may only be significant in poor or intermediate acetylators since isoniazid is primarily inactivated by acetylation (DiMartini 1995; Toutoungi 1985).
Histamine-containing food: Isoniazid may also inhibit diamine oxidase resulting in headache, sweating, palpitations, flushing, diarrhea, itching, wheezing, dyspnea or hypotension to histamine-containing foods (eg, skipjack, tuna, saury, other tropical fish). Management: Manufacturer’s labeling recommends avoiding histamine-containing foods; corticosteroids and antihistamines may be administered if histamine intoxication occurs (Miki 2005).
Do not take with food; avoid tyramine- and/or histamine-containing foods. Increase dietary intake of folate, niacin, magnesium.
Isoniazid crosses the human placenta.
Active tuberculosis (TB) infection is associated with adverse fetal outcomes including intrauterine growth restriction, low birth weight, preterm birth, and perinatal death (Esmail 2018; Miele 2020) as well as adverse maternal outcomes, including increased risks for anemia and cesarean delivery. Placental transmission may rarely occur with active maternal disease (Miele 2020).
Due to the risks of untreated TB, isoniazid is recommended as part of the initial treatment regimen of drug-susceptible active TB when the probability of maternal disease is moderate to high. Isoniazid is associated with an increased risk of severe maternal hepatotoxicity which may require temporary drug withdrawal in pregnant and postpartum patients (Beck-Friis 2020; Gupta 2019); monthly monitoring of transaminases (ALT/AST) is recommended (HHS [OI adult 2020]). Pregnancy may increase the risk of isoniazid-associated peripheral neurotoxicity in the mother; pyridoxine supplementation is recommended in pregnant patients during treatment (ATS/CDC/IDSA [Nahid 2016]; HHS [OI adult 2020]).
Treatment of latent tuberculosis infection (LTBI) (also known as prophylaxis or preventive therapy) with isoniazid is recommended for pregnant patients with HIV coinfection who are close household contacts of persons with TB infection (HHS [OI adult 2020]; WHO 2020). Treatment of LTBI can be delayed until after delivery in some cases, considering the risk of progression to active disease (HHS [OI adult 2020]).
Pregnancy-induced physiologic changes do not alter the pharmacokinetic properties of isoniazid in a clinically significant way; dose adjustment is not needed in pregnant patients (Abdelwahab 2020).
Baseline and periodic (more frequently in patients with higher risk for hepatitis or with previous abnormal results) liver function tests (ALT and AST); monitor for peripheral neuropathy and prodromal signs of hepatitis.
Isoniazid inhibits the synthesis of mycoloic acids, an essential component of the bacterial cell wall. At therapeutic levels isoniazid is bacteriocidal against actively growing intracellular and extracellular Mycobacterium tuberculosis organisms.
Note: Isoniazid is primarily metabolized by acetylation and dehydrazination. Rate of acetylation is genetically determined. Approximately 50% of Black and White patients are “slow acetylators” and the rest are “rapid acetylators.” Populations in which there is a high prevalence of “rapid acetylators” include Inuit patients (including native peoples from Alaska and Canada), East Asian patients, and patients from certain areas within Southeast Asia (eg, Thailand) (Clark 1985; Sabbagh 2011; manufacturer's labeling). Acetylation rate does not significantly alter the effectiveness, but slow acetylation may lead to higher blood levels and possibly an increase in adverse effects.
Absorption: Oral, IM: Rapid and complete; food reduces rate and extent of absorption
Distribution: All body tissues and fluids including CSF
Protein binding: 10% to 15%
Metabolism: Hepatic to acetylisoniazid with decay rate determined genetically by acetylation phenotype; undergoes further hydrolysis to isonicotinic acid and acetylhydrazine
Half-life: May be prolonged in patients with impaired hepatic function or severe renal impairment
Fast acetylators: 30 to 100 minutes
Slow acetylators: 2 to 5 hours
Time to peak, serum: 1 to 2 hours
Excretion: Urine (75% to 95% as unchanged drug and metabolites); small amounts excreted in feces and saliva
Note: Commercial oral solution is available (50 mg/5 mL)
10 mg/mL Oral Suspension:
A 10 mg/mL oral suspension may be made with tablets, purified water, and sorbitol. Crush ten 100 mg tablets in a mortar and reduce to a fine powder. Add 10 mL of purified water and mix to a uniform paste. Mix while adding sorbitol in incremental proportions to almost 100 mL; transfer to a graduated cylinder, rinse mortar with sorbitol, and add quantity of sorbitol sufficient to make 100 mL (do not use sugar-based solutions). Label "shake well" and "refrigerate". Stable for 21 days refrigerated.
Solution (Isoniazid Injection)
100 mg/mL (per mL): $35.21
Syrup (Isoniazid Oral)
50 mg/5 mL (per mL): $0.86
Tablets (Isoniazid Oral)
100 mg (per each): $0.15
300 mg (per each): $0.31 - $1.29
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