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standards of non-Merck sources.
ALERT: U.S. Boxed Warning
The FDA-approved labeling includes a boxed warning. See Warnings/Precautions section and/or refer to product labeling for additional detail.
Medication Safety Issues
International issues:
Hydra® [Japan] may be confused with Hydrea®
Pronunciation
(eye soe NYE a zid)
Index Terms
Generic Available
Yes
Canadian Brand Names
Pharmacologic Category
Pharmacologic Category Synonyms
Use: Labeled Indications
Treatment of susceptible tuberculosis infections; treatment of latent tuberculosis infection (LTBI)
Pregnancy Risk Factor
C
Pregnancy Considerations
Isoniazid was found to be embryocidal in animal studies; teratogenic effects were not noted. Isoniazid crosses the human placenta. Due to the risk of tuberculosis to the fetus, treatment is recommended when the probability of maternal disease is moderate to high. The CDC recommends isoniazid as part of the initial treatment regimen (CDC, 2003). Pyridoxine supplementation is recommended (25 mg/day).
Lactation
Enters breast milk/compatible
Breast-Feeding Considerations
Small amounts of isoniazid are excreted in breast milk. However, women with tuberculosis should not be discouraged from breast-feeding. Pyridoxine supplementation is recommended for the mother and infant.
Contraindications
Hypersensitivity to isoniazid or any component of the formulation; acute liver disease; previous history of hepatic damage during isoniazid therapy; previous severe adverse reaction (drug fever, chills, arthritis) to isoniazid
Warnings/Precautions
Boxed warnings:
• Hepatitis: See “Concerns related to adverse effects” below.
Concerns related to adverse effects:
• Hepatitis: [U.S. 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; daily ethanol consumption may also increase the risk. Patients must report any prodromal symptoms of hepatitis, such as fatigue, weakness, malaise, anorexia, nausea, or vomiting.
• Peripheral neuropathies: Pyridoxine (10-50 mg/day) is recommended in individuals at risk for development of peripheral neuropathies (eg, HIV infection, nutritional deficiency, diabetes, pregnancy).
Disease-related concerns:
• Hepatic impairment: Use with caution in patients with hepatic impairment. Treatment with isoniazid for latent tuberculosis infection 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.
• Ophthalmic exams: Periodic ophthalmic examinations are recommended even when usual symptoms do not occur.
Adverse Reactions
Frequency not defined.
Cardiovascular: Hypertension, palpitation, tachycardia, vasculitis
Central nervous system: Depression, dizziness, encephalopathy, fever, lethargy, memory impairment, psychosis, seizure, slurred speech
Dermatologic: Flushing, rash (morbilliform, maculopapular, pruritic, or exfoliative)
Endocrine & metabolic: Gynecomastia, hyperglycemia, metabolic acidosis, pellagra, pyridoxine deficiency
Gastrointestinal: Anorexia, nausea, stomach pain, vomiting
Hematologic: Agranulocytosis, anemia (sideroblastic, hemolytic, or aplastic), eosinophilia, thrombocytopenia
Hepatic: LFTs mildly increased (10% to 20%); hyperbilirubinemia, bilirubinuria, jaundice, hepatic dysfunction, hepatitis (may involve progressive liver damage; risk increases with age; 2.3% in patients >50 years)
Neuromuscular & skeletal: Arthralgia, hyper-reflexia, peripheral neuropathy (dose-related incidence, 10% to 20% incidence with 10 mg/kg/day), weakness
Ocular: Blurred vision, loss of vision, optic neuritis and atrophy
Miscellaneous: Lupus-like syndrome, lymphadenopathy, rheumatic syndrome
Metabolism/Transport Effects
Substrate of CYP2E1 (major); Inhibits CYP1A2 (weak), 2A6 (moderate), 2C9 (weak), 2C19 (strong), 2D6 (moderate), 2E1 (moderate), 3A4 (strong); Induces CYP2E1 (after discontinuation) (weak)
Drug Interactions
Acetaminophen: Isoniazid may enhance the adverse/toxic effect of Acetaminophen. Risk C: Monitor therapy
Alosetron: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Alosetron. Risk C: Monitor therapy
Antacids: May decrease the absorption of Isoniazid. Risk D: Consider therapy modification
Benzodiazepines (metabolized by oxidation): Isoniazid may decrease the metabolism of Benzodiazepines (metabolized by oxidation). Risk C: Monitor therapy
Carbamazepine: Isoniazid may decrease the metabolism of Carbamazepine. Risk D: Consider therapy modification
Chlorzoxazone: Isoniazid may decrease the metabolism of Chlorzoxazone. Risk C: Monitor therapy
Ciclesonide: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Ciclesonide. Specifically, concentrations of the active des-ciclesonide metabolite may be increased. Risk C: Monitor therapy
Codeine: CYP2D6 Inhibitors (Moderate) may diminish the therapeutic effect of Codeine. These CYP2D6 inhibitors may prevent the metabolic conversion of codeine to its active metabolite morphine. Risk C: Monitor therapy
Corticosteroids (Systemic): May decrease the serum concentration of Isoniazid. Risk C: Monitor therapy
CycloSERINE: May enhance the CNS depressant effect of Isoniazid. Risk D: Consider therapy modification
CYP2A6 Substrates: CYP2A6 Inhibitors (Moderate) may decrease the metabolism of CYP2A6 Substrates. Risk C: Monitor therapy
CYP2C19 Substrates: CYP2C19 Inhibitors (Strong) may decrease the metabolism of CYP2C19 Substrates. Risk D: Consider therapy modification
CYP2D6 Substrates: CYP2D6 Inhibitors (Moderate) may decrease the metabolism of CYP2D6 Substrates. Risk C: Monitor therapy
CYP2E1 Substrates: CYP2E1 Inhibitors (Moderate) may decrease the metabolism of CYP2E1 Substrates. Risk C: Monitor therapy
CYP3A4 Substrates: CYP3A4 Inhibitors (Strong) may decrease the metabolism of CYP3A4 Substrates. Risk D: Consider therapy modification
Eplerenone: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Eplerenone. Risk X: Avoid combination
Ixabepilone: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Ixabepilone. Risk D: Consider therapy modification
Maraviroc: CYP3A4 Inhibitors may increase the serum concentration of Maraviroc. Risk D: Consider therapy modification
Nebivolol: CYP2D6 Inhibitors (Moderate) may increase the serum concentration of Nebivolol. Risk C: Monitor therapy
Nilotinib: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Nilotinib. Risk X: Avoid combination
Nisoldipine: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Nisoldipine. Risk X: Avoid combination
Phenytoin: Isoniazid may decrease the metabolism of Phenytoin. Risk D: Consider therapy modification
Pimecrolimus: CYP3A4 Inhibitors (Strong) may decrease the metabolism of Pimecrolimus. Risk C: Monitor therapy
Ranolazine: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Ranolazine. Risk X: Avoid combination
Rifamycin Derivatives: May enhance the hepatotoxic effect of Isoniazid. Even so, this is a frequently employed combination regimen. Risk C: Monitor therapy
Salmeterol: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Salmeterol. Risk X: Avoid combination
Sorafenib: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Sorafenib. Risk C: Monitor therapy
Theophylline Derivatives: Isoniazid may decrease the metabolism of Theophylline Derivatives. Exceptions: Dyphylline. Risk D: Consider therapy modification
Thioridazine: CYP2D6 Inhibitors may decrease the metabolism of Thioridazine. Risk X: Avoid combination
Tramadol: CYP2D6 Inhibitors (Moderate) may diminish the therapeutic effect of Tramadol. These CYP2D6 inhibitors may prevent the metabolic conversion of tramadol to its active metabolite that accounts for much of its opioid-like effects. Risk C: Monitor therapy
Ethanol/Nutrition/Herb Interactions
Ethanol: Avoid ethanol (increases the risk of hepatitis).
Food: Isoniazid should not be taken with food; serum levels may be decreased if taken with food. Has some ability to inhibit tyramine metabolism; several case reports of mild reactions (flushing, palpitations) after ingestion of cheese (with or without wine). Reactions resembling allergic symptoms following ingestion of fish high in histamine content have been reported. Isoniazid decreases folic acid absorption. Isoniazid alters pyridoxine metabolism.
Storage
Tablet: Store at 20°C to 25°C (68°F to 77°F). Protect from light.
Oral solution: Store at 15°C to 30°C (59°F to 86°F). Protect from light.
Mechanism of Action
Unknown, but may include the inhibition of mycolic acid synthesis resulting in disruption of the bacterial cell wall
Pharmacodynamics/Kinetics
Absorption: Rapid and complete; rate can be slowed with food
Distribution: All body tissues and fluids including CSF; crosses placenta; enters breast milk
Protein binding: 10% to 15%
Metabolism: Hepatic with decay rate determined genetically by acetylation phenotype
Half-life elimination: Fast acetylators: 30-100 minutes; Slow acetylators: 2-5 hours; may be prolonged with hepatic or severe renal impairment
Time to peak, serum: 1-2 hours
Excretion: Urine (75% to 95%); feces; saliva
Dosage
Usual dosage ranges: Oral, I.M.:
Infants and Children: 10-15 mg/kg/day in 1-2 divided doses (maximum: 300 mg/day) or 20-40 mg/kg given 2-3 times per week (maximum: 900 mg/dose)
Adults: 5 mg/kg/day (usual: 300 mg/day) as a single daily dose or 15 mg/kg (maximum: 900 mg/dose) given 2-3 times per week
Indication-specific dosing: Oral, I.M.: Recommendations often change due to resistant strains and newly-developed information; consult MMWR for current CDC recommendations. Intramuscular injection is available for patients who are unable to either take or absorb oral therapy.
Infants and Children:
Tuberculosis, active:
Daily therapy: 10-15 mg/kg/day in 1-2 divided doses (maximum: 300 mg/day)
Twice weekly or 3 times/week directly observed therapy (DOT): 20-40 mg/kg (maximum: 900 mg)
Tuberculosis, latent infection (LTBI): 10 mg/kg/day as a single dose (maximum: 300 mg/day) or 20-30 mg/kg (maximum: 900 mg/dose) twice weekly for 9 months
Adults: Note: Concomitant administration of 10-50 mg/day pyridoxine is recommended in malnourished patients or those prone to neuropathy (eg, alcoholics, patients with diabetes).
Nontuberculous mycobacterium (
M. kansasii
) (unlabeled use): 5 mg/kg/day (maximum: 300 mg/day) for duration to include 12 months of culture-negative sputum; typically used in combination with ethambutol and rifampin
Tuberculosis, active:
Daily therapy: 5 mg/kg/day given daily (usual dose: 300 mg/day)
Twice weekly or 3 times/week directly observed therapy (DOT): 15 mg/kg (maximum: 900 mg). Note: CDC guidelines state that once-weekly therapy (15 mg/kg/dose) may be considered, but only after the first 2 months of initial therapy in HIV-negative patients, and only in combination with rifapentine.
Note: Treatment may be defined by the number of doses administered (eg, “six-month” therapy involves 182 doses of INH and rifampin, and 56 doses of pyrazinamide). Six months is the shortest interval of time over which these doses may be administered, assuming no interruption of therapy.
Tuberculosis, latent infection (LTBI): 300 mg/day or 900 mg twice weekly for 6-9 months in patients who do not have HIV infection (9 months is optimal, 6 months may be considered to reduce costs of therapy) and 9 months in patients who have HIV infection. Extend to 12 months of therapy if interruptions in treatment occur.
Dosing adjustment in renal impairment: No adjustment necessary
Hemodialysis: Dialyzable (50% to 100%); administer dose post dialysis
Dosing adjustment in hepatic impairment: No adjustment required, however, use with caution; may accumulate and additional liver damage may occur in patients with pre-existing liver disease. 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.
Administration: Oral
Should be administered 1 hour before or 2 hours after meals on an empty stomach.
Monitoring Parameters
Baseline and periodic (more frequently in patients with higher risk for hepatitis) liver function tests (ALT and AST); sputum cultures monthly (until 2 consecutive negative cultures reported); monitoring for prodromal signs of hepatitis
Reference Range
Therapeutic: 1-7 mcg/mL (SI: 7-51 ?mol/L); Toxic: 20-710 mcg/mL (SI: 146-5176 ?mol/L)
Test Interactions
False-positive urinary glucose with Clinitest®
Dietary Considerations
Should be taken 1 hour before or 2 hours after meals on an empty stomach; increase dietary intake of folate, niacin, magnesium. Avoid tyramine-containing foods. Avoid histamine-containing foods.
Patient Education
Do not take any new prescription, OTC medications, or herbal products during therapy unless approved by prescriber. Best if taken on an empty stomach, 1 hour before or 2 hours after meals. Avoid missing any dose and do not discontinue without notifying prescriber. Avoid excessive alcohol and tyramine-containing foods (eg, aged cheese, broad beans, dry sausage, preserved meats or sausages, liver pate, fish, soy bean, protein supplements, wine) and increase dietary intake of folate, niacin, and magnesium. May cause false test results with Clinitest®; use of another type of glucose testing is preferable. You will need to have frequent ophthalmic exams and periodic medical check-ups to evaluate drug effects. You may experience nausea, vomiting, or loss of appetite (small, frequent meals, frequent mouth care, chewing gum, or sucking lozenges may help). Report chest pain, rapid heart beat, or palpitations; tingling, numbness, or loss of sensation in hands or feet; unusual weakness or fatigue; persistent gastrointestinal upset; dark-colored urine or change in urinary pattern; yellowing skin or eyes; change in color of stool; change in vision; skin rash; or other persistent adverse effects. Pregnancy precaution: Inform prescriber if you are or intend to become pregnant.
Geriatric Considerations
Age has not been shown to affect the pharmacokinetics of INH since acetylation phenotype determines clearance and half-life, acetylation rate does not change significantly with age. Most strains of M. tuberculosis found the elderly should be susceptible to INH since most acquired their initial infection prior to INH's introduction.
Additional Information
The AAP recommends that pyridoxine supplementation (1-2 mg/kg/day) should be administered to malnourished patients, children or adolescents on meat or milk-deficient diets, breast-feeding infants, and those predisposed to neuritis to prevent peripheral neuropathy; administration of isoniazid syrup has been associated with diarrhea
Dental Health: Effects on Dental Treatment
Key adverse event(s) related to dental treatment: Xerostomia (normal salivary flow resumes upon discontinuation).
Dental Health: Vasoconstrictor/Local Anesthetic Precautions
No information available to require special precautions
Mental Health: Effects on Mental Status
May cause drowsiness or dizziness; may rarely cause depression or psychosis; reports of insomnia, restlessness, disorientation, hallucinations, delusions, obsessive-compulsive symptoms, and exacerbation of schizophrenia
Mental Health: Effects on Psychiatric Treatment
Isoniazid may impair the metabolism of carbamazepine and oxidatively metabolized benzodiazepines; monitor for adverse effects
Nursing: Physical Assessment/Monitoring
Use caution with pre-existing renal impairment or hepatic disease. Assess potential for interactions with other pharmacological or herbal agents patient may be taking (eg, risk of toxicity, decreased effects). Evaluate results of laboratory tests, therapeutic effectiveness, and adverse response (eg, nausea, vomiting, peripheral neuropathy, liver damage, CNS changes) at regular intervals during therapy. Advise patients with diabetes about use of Clinitest® (may cause false-positive results). Teach patient proper use, possible side effects/appropriate interventions (eg, diet [see Tyramine Foods List], ophthalmic examinations), and adverse symptoms to report.
Dosage Forms
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Injection, solution: 100 mg/mL (10 mL)
Oral solution: 50 mg/5 mL (473 mL) [orange flavor]
Tablet: 100 mg, 300 mg
Pricing: U.S. (www.drugstore.com)
Syrup (Isoniazid)
50 mg/5 mL (473): $68.73
Tablets (Isoniazid)
100 mg (30): $8.99
300 mg (90): $17.00
Extemporaneously Prepared
A 10 mg/mL oral suspension was stable for 21 days when refrigerated when compounded as follows:
Triturate ten 100 mg tablets in a mortar, reduce to a fine powder, then add 10 mL of purified water U.S.P. to make a paste; then transfer to a graduate and qs to 100 mL with sorbitol (do not use sugar-based solutions)
Shake well before using and keep in refrigerator
Nahata MC and Hipple TF, Pediatric Drug Formulations, 3rd ed, Cincinnati, OH: Harvey Whitney Books Co, 1997.
References
Ad Hoc Committee of the Scientific Assembly on Microbiology, Tuberculosis, and Pulmonary Infections, “Treatment of Tuberculosis and Tuberculosis Infection in Adults and Children,” Clin Infect Dis, 1995, 21:9-27.
American Academy of Pediatrics, Committee on Infectious Diseases, “Chemotherapy for Tuberculosis in Infants and Children,” Pediatrics, 1992, 89(1):161-5.
American Thoracic Society, “Targeted Tuberculin Testing and Treatment of Latent Tuberculosis Infection,” MMWR Recomm Rep, 2000, 49(RR-6):1-51.
Aronoff GR, Bennett WM, Berns JS, et al, “Drug Prescribing in Renal Failure: Dosing Guidelines for Adults and Children,” 5th ed. Philadelphia, PA: American College of Physicians; 2007.
Askgaard DS, Wilcke T, and Dossing M, “Hepatotoxicity Caused by the Combined Action of Isoniazid and Rifampicin,” Thorax, 1995, 50(2):213-4.
Bass JB Jr, Farer LS, Hopewell PC, et al, “Treatment of Tuberculosis and Tuberculosis Infection in Adults and Children,” Am J Respir Crit Care Med, 1994, 149(5):1359-74.
Blowey DL, Johnson D, and Verjee Z, “Isoniazid-Associated Rhabdomyolysis,” Am J Emerg Med, 1995, 13(5):543-4.
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International Brand Names
Lexi-Comp.com
Last full review/revision August 2008
Content last modified August 2008
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