isoniazid

Absorption: Well absorbed following PO/IM administration.

Distribution: Widely distributed; readily crosses the blood-brain barrier.

Metabolism/Excretion: 50% metabolized by the liver by N-acetyltransferase (rate of acetylation is genetically determined [slow acetylators have ↑ isoniazid levels and ↑ risk of toxicity; fast acetylators have ↓ isoniazid levels and ↑ risk for treatment failure]); 50% excreted unchanged by the kidneys.

Half-Life: 1–4 hr in patients with normal renal and hepatic function; 0.5–1.6 hr in fast acetylators; 2–5 hr in slow acetylators.

Time/Action Profile ⬆ ⬇

(plasma concentrations)

ROUTE	ONSET	PEAK	DURATION
PO	rapid	1–2 hr	up to 24 hr
IM	rapid	1–2 hr	up to 24 hr

Contraind./Precautions ⬆ ⬇

Contraindicated in:

Hypersensitivity;
Acute liver disease;
History of hepatitis from previous use.

Use Cautiously in:

History of liver damage, chronic alcohol ingestion, or use of illicit injectable drugs
;
Black and Hispanic women, women in the postpartum period, or patients >50 yr (↑ risk of drug-induced hepatitis);
Severe renal impairment (dose ↓ may be necessary);
Malnourished patients, patients with diabetes, or chronic alcoholics (↑ risk of neuropathy).

Adv. Reactions/Side Effects ⬆ ⬇

Derm: ACUTE GENERALIZED EXANTHEMATOUS PUSTULOSIS, DRUG REACTION WITH EOSINOPHILIA AND SYSTEMIC SYMPTOMS (DRESS), rash, STEVENS-JOHNSON SYNDROME, TOXIC EPIDERMAL NECROLYSIS

EENT: visual disturbances

Endo: gynecomastia

GI: HEPATOTOXICITY, nausea, vomiting

Hemat: blood dyscrasias

Neuro: peripheral neuropathy, cerebellar syndrome, psychosis, seizures

Misc: fever

Interactions ⬆ ⬇

Drug-drug:

Additive CNS toxicity with other antituberculars.
BCG vaccine may not be effective during isoniazid therapy.
Isoniazid may ↑ levels and risk of toxicity of phenytoin.
Aluminum-containing antacids may ↓ absorption.
Psychotic reactions and coordination difficulties may result with disulfiram.
Concurrent administration of pyridoxine may prevent neuropathy.
↑risk of hepatotoxicity with other hepatotoxic agents, including alcohol, acetaminophen, and rifampin
.
Isoniazid may ↓ levels and effectiveness of ketoconazole.
May ↑ carbamazepine levels and risk of hepatotoxicity.
May ↓ effectiveness of clopidogrel; avoid concurrent use.

Drug-Food:

Severe reactions may occur with ingestion of foods containing high concentrations of tyramine (see Food Sources for Specific Nutrients).

Route/Dosage ⬆ ⬇

PO IM (Adults ): 5 mg/kg/day (max dose = 300 mg once daily) or 15 mg/kg (max dose = 900 mg) 2–3 times weekly.
PO IM (Children <40 kg): Latent TB infection: 10–20 mg/kg/day (max dose = 300 mg once daily) or 20–40 mg/kg (max dose = 900 mg) 2 times weekly; Active TB infection: 10–15 mg/kg/day (max dose = 300 mg once daily) or 20–40 mg/kg (max dose = 900 mg) 2 times weekly.

Availability ⬆ ⬇

(Generic available)

Tablets: 100 mg; 300 mg
Oral solution orange, raspberry flavor: 50 mg/5 mL
Solution for injection: 100 mg/mL

Assessment ⬆ ⬇

Monitor for signs and symptoms of hypersensitivity reaction (fever, rash) including severe skin eruptions (morbilliform, maculopapular, purpuric, exfoliative).
Monitor for signs and symptoms of DRESS (fever, rash, lymphadenopathy, angioedema, hepatitis, nephritis, hematologic abnormalities, myocarditis, myositis) during therapy. If symptoms occur, discontinue isoniazid.
Assess for neurotoxicity (peripheral neuropathy, seizures, encephalopathy, optic neuritis, memory loss, psychosis) during therapy.

Lab Test Considerations:

Mycobacterial studies and susceptibility tests should be performed prior to and periodically during therapy to detect possible resistance. About 50–65% of White, Black, South Indian, and Mexican patients are slow acetylators at risk for toxicity, while 80–90% of Inuit, Japanese, and Chinese patients are rapid acetylators at risk for ↓ levels and treatment failure.
Monitor hepatic function prior to therapy, monthly throughout, and as indicated. If AST, ALT, or serum bilirubin >3–5 times upper limit of normal or if signs/symptoms of hepatotoxicity occur, hold and consider alternate drug. If isoniazid must be used, resume only after symptoms and lab values have returned to baseline. Restart in small, gradually ↑ doses and discontinue immediately if liver toxicity recurs. Black, Hispanic, pregnant, and postpartal women and patients ≥35 yr are at highest risk. Isoniazid-associated hepatotoxicity usually occurs during 1st 3 mo of treatment.
May cause agranulocytosis, anemia, thrombocytopenia, and eosinophilia.
May ↓ vitamin B₆ and vitamin B₃.
May cause hyperglycemia and metabolic acidosis.

Toxicity and Overdose:

If isoniazid overdose occurs, treat with pyridoxine and other supportive measures as indicated.

Implementation ⬆ ⬇

PO: Administer on an empty stomach.
IM: Medication may cause discomfort at injection site. Massage site after administration and rotate injection sites.
- Solution may form crystals at low temperatures; crystals will redissolve upon warming to room temperature.

Patient/Family Teaching ⬆ ⬇

Explain purpose and side effects of medication. Advise patient to read Patient Information before starting therapy.
Advise patient to take missed doses as soon as possible unless almost time for next dose; do not double doses. Emphasize the importance of continuing therapy even after symptoms have subsided. Therapy may be continued for 6 mo–2 yr.
Advise patient to notify health care provider of all Rx or OTC medications, vitamins, or herbal products being taken and to consult health care provider before taking other medications.
Advise patient to notify health care provider immediately if signs and symptoms of hepatotoxicity (yellow eyes and skin, nausea, vomiting, abdominal tenderness, anorexia, dark urine, rash, fatigue, weakness, or fever >3 days) occur.
Advise patient to notify health care provider immediately if signs and symptoms of peripheral neuritis (numbness, tingling, paresthesia) or visual changes (pain, blurred vision, ↓ acuity) occur. Pyridoxine may be used concurrently to prevent neuropathy.
Caution patient to avoid the use of alcohol during therapy, as this may ↑ risk of hepatotoxicity. Avoid ingestion of Swiss or Cheshire cheeses, fish (tuna, skipjack, sardines), and tyramine-containing foods (see Food Sources for Specific Nutrients).
Rep: Caution pregnant patient that isoniazid may ↑ risk of peripheral neurotoxicity and pyridoxine supplementation is recommended. Advise patient to notify health care provider and discontinue breastfeeding if jaundice occurs in the breastfed infant. Pyridoxine supplementation is recommended for breastfed infants.
Emphasize the importance of regular follow-up including laboratory tests, and physical and ophthalmic exams.

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Pronunciation ⬇

Classifications ⬆ ⬇

Indications ⬆ ⬇

Action ⬆ ⬇

Pharmacokinetics ⬆ ⬇