INFORMATION FOR HEALTH PROFESSIONALS
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White 3/8" normal convex tablet
Isoniazid is a hydrazide derivative which is the mainstay of primary treatment of pulmonary and extrapulmonary tuberculosis. It is administered with other antituberculous agents such as rifampicin and pyrazinamide. Isoniazid is also used in high risk subjects for the prophylaxis of tuberculosis and has been given in regimens for the treatment of opportunistic mycobacterial infections. The usual dose of Isoniazid in the daily regimens for treatment of tuberculosis is 5mg per kg body weight given daily for 6 months by mouth on an empty stomach as a single dose to a maximum of 300mg daily. A dose of 15mg per kg is given two or three times a week in intermittent treatment regimens. Once-weekly administration has also been tried but may be less effective in patients who are rapid acetylators of Isoniazid. Slow-release preparations of Isoniazid have also been used in such regiments in an attempt to achieve sustained therapeutic concentrations.
Similar doses to those used orally may be given by intramuscular injection when Isoniazid cannot be taken by mouth; it may also be given by intravenous injection. Isoniazid has also been given intrathecally and intrapleurally.
In tuberculosis prophylaxis, daily doses of 300mg have usually been given for up to 1 year, although 6 months may be adequate. It may be given with rifampicin.
Isoniazid is readily absorbed from the gastro-intestinal tract and following intramuscular injection. Peak concentrations of about 3 to 8mg per mL appear in blood 1 to 2 hours after a fasting dose of 300mg by mouth. Lower peak concentrations are attained when Isoniazid is given with food. Isoniazid is not considered to be bound appreciably to plasma proteins and diffuses into all body tissues and fluids, including the cerebrospinal fluid; it appears in foetal blood if given during pregnancy and in milk of nursing mothers.
The plasma half-life for Isoniazid ranges from about 1 to 4 hours, those who are fast acetylators (see below) having shorter half-lives. The primary metabolic route is the acetylation of Isoniazid to acetylisoniazid by N-acetyltransferase found in the liver and small intestine. Acetylisoniazid is then hydrolysed to isonicotinic acid and monoacetylhydrazine; isonicotinic acid is conjugated with glycine to isonicotyinyl glycine (isonicotinuric acid) and monoacetylhydrazine is further acetylated to diacetylhydrazine. Some unmetabolised Isoniazid is conjugated to hydrazones. The metabolites of Isoniazid have no tuberculostatic activity and apart possibly from monoacetylhydrazine they are also less toxic. The rate of acetylation of Isoniazid and monoacetylhydrazine is genetically determined and there is a bimodal distribution of persons who acetylate them either slowly or rapidly.
When Isoniazid is administered daily or 2 to 3 times weekly, clinical effectiveness is not influenced by acetylator status.
In patients with normal renal function, over 70% of a dose appears in the urine in 24 hours, mainly as metabolites. Small amounts of drug are also excreted in the faeces. Isoniazid is removed by dialysis.
Isoniazid is highly active against Mycobacterium tuberculosis which it inhibits in vitro at concentrations of 0.02 to 0.2mg per mL. Isoniazid may have activity against some strains of other mycobacteria including M. kansasii.
Although it is rapidly bactericidal against actively dividing M. tuberculosis it is considered to be only bacteriostatic against semi-dormant organisms and has less sterilising activity than rifampicin or pyrazinamide.
Recommended Isoniazid doses are 5mg per kg body-weight daily or 15mg per kg body-weight two or three times a week for clinical tuberculosis. Intermittent administration is used to improve compliance and reduce toxicity. Regimens in which Isoniazid is given two or three times weekly are effective, but once weekly administration is not clinically effective in rapid acetylators.
Doses of Isoniazid for children vary. For the treatment of clinical infection, International Union Against Tuberculosis and Lung Disease (IUAT) recommends the same doses as for adults. Higher doses of 10 to 20mg per kg daily to 20 to 40 mg per kg (maximum 900mg per dose) twice weekly are recommended by the American Thoracic society, although it is suggested that the dose be limited to 10mg per kg daily when Isoniazid is given in association with rifampicin.
Standard doses of Isoniazid may be given to patients with renal impairment, although those on dialysis should receive Isoniazid following the procedure as the drug is removed by dialysis. The dose may need to be reduced in patients with liver impairment.
The contraindications/medical problems included have been selected on the basis of their potential clinical significance (reasons given in parentheses where appropriate) - not necessarily inclusive (>> = major clinical significance).
Patients hypersensitive to ethionamide, pyrazinamide, niacin (nicotinic acid), or other chemically related medications may be hypersensitive to this medication also.
Isoniazid has been shown to cause pulmonary tumors in a number of strains of mice. However, Isoniazid has not been shown to be carcinogenic or tumorigenic in humans.
Pregnancy - Isoniazid crosses the placenta, resulting in foetal serum concentrations that may exceed maternal serum concentrations. Problems in humans have not been documented. The effects of combination therapy on the foetus are unknown and neonates should be carefully observed for evidence of adverse effect.
Isoniazid is excreted in breast milk. An estimated 0.75 to 2.3% of the daily adult dose could possibly be ingested by the infant. Neonates should be carefully observed for evidence of adverse effects.
Note:
Isoniazid has been reported to cause severe, and sometimes fatal, age-related hepatitis. If signs and symptoms of hepatotoxicity occur, isoniazid should be promptly discontinued. Patients with advanced HIV disease have been reported to have an increased incidence of adverse reactions to antitubercular medications. This was not found in HIV-seropositive patients being treated for tuberculosis.
The following side/adverse effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate) - not necessarily inclusive:
Hepatitis prodromal symptoms (loss of appetite, nausea or vomiting, unusual tiredness or weakness); hepatitis (dark urine, yellow eyes or skin); peripheral neuritis (clumsiness or unsteadiness; numbness, tingling, burning, or pain in hands and feet)
Blood dyscrasias (fever and sore throat, unusual bleeding and bruising, unusual tiredness or weakness); hypersensitivity (fever, joint pain, skin rash); neurotoxicity (seizures, mental depression, mood or other mental changes); optic neuritis (blurred vision or loss of vision, with or without eye pain).
The following drug interactions and/or related problems have been selected on the basis of their potential clinical significance (possible mechanism in parentheses where appropriate) - not necessarily inclusive (>> = major clinical significance):
Note: Combinations containing any of the following medications depending on the amount present, may also interact with medication.
Acetaminophen
(concurrent use of acetaminophen with Isoniazid may increase the potential for
hepatotoxicity and, possibly nephrotoxicity Isoniazid is thought to induce
cytochrome P-450 resulting in a greater proportion of acetaminophen being
converted to toxic metabolite)
>> Alcohol
(concurrent daily use of alcohol may result in increased incidence of
Isoniazid-induced hepatotoxicity and increased metabolism of Isoniazid; dosage
adjustments of Isoniazid may be necessary, patients should be monitored closely
for signs of hepatotoxicity and should be advised to restrict intake of
alcoholic beverages.
>> Alfentanil
(chronic preoperative or perioperative use of Isoniazid, a hepatic enzyme
inhibitor, may decrease the plasma clearance or prolong the duration of action
of alfentanil)
Antacids, especially aluminum-containing
(antacids may delay and decrease absorption and serum concentrations of orally
administered Isoniazid. Concurrent use should be avoided, or patients should be
advised to take oral Isoniazid at least 1 hour before aluminum-containing
antacids).
Anticoagulants
coumarin or indandione-derivative. (concurrent use with Isoniazid may result in
increased anticoagulant effect because of the inhibition of enzymatic metabolism
of anticoagulants)
Benzodiazepines
(Isoniazid may decrease the hepatic metabolism of benzodiazepines such as
diazepam, chlordiazepoxide flurazepam and prazepam, that are metabolized by
phase I reaction (N-de methylation and hydroxylation); it may also impair the
oxidation of triazolam, increasing plasma benzodiazepine concentrations.
Isoniazid may decrease first-pass metabolism and elimination of midazolam in the
liver, probably by competitive inhibition at the cytochrome P-450 binding sites,
increasing steady state plasma concentrations of midazolam)
Carbamazepine
(Concurrent use with Isoniazid increases serum carbamazepine levels and
toxicity, probably through inhibition of carbamezepine metabolism; also,
carbamazepine may induce microsomal metabolism of Isoniazid, increasing
formation of an INN - reactive intermediate metabolite, which may lead to
hepatoxicity).
Cheese, such as Swiss or Cheshire, or Fish, such as tuna, skipjack,
or Sardinella
(Concurrent ingestion with Isoniazid may result in redness or itching of the
skin, hot feeling, rapid or pounding heartbeat, sweating, chills or clammy
feeling, headache or lightheadedness. This is thought to be due to the
inhibition of plasma monoamine and diamine oxidase by Isoniazid, interfering
with the oxidase of metabolism tyramine and histamine found in fish and cheese).
Corticosteroids, glucocorticoid.
(concurrent use of prednisolone, and probably other related corticosteroids,
with isoniazid may increase hepatic metabolism and/or excretion of Isoniazid,
leading to decreased plasma concentrations and effectiveness of Isoniazid,
especially in patients who are rapid acetylators; Isoniazid dosage adjustments
may be required).
Cycloserine
(concurrent use may result in increased incidence of central nervous system
(CNS) effects such as dizziness or drowsiness; dosage adjustments may be
necessary and patients should be monitored closely for signs of CNS toxicity)
Disulfiram
(concurrent use in alcoholics may result in increased incidence of CNS effects
such dizziness, incoordination, irritability, or insomnia; reduced dosage or
discontinuation of disulfiram may be necessary)
Enflurane
(Isoniazid may increase formation of the potentially nephrotoxic inorganic
fluoride metabolite when used concurrently with enflurane)
Hepatotoxic medications
(concurrent use of other hepatotoxic medications with Isoniazid may increase the
potential for hepatotoxicity and should be avoided)
Ketoconazole or Miconazole, parenteral, or
Rifampin
(in 1 study, a significant decrease in ketoconazole serum concentrations was
found when Isoniazid was given concurrently with ketoconazole and 12 hours
before ketoconazole; when both Isoniazid and rifampin were used concurrently
with ketoconazole, serum concentrations of ketoconazole were reported to be
undetectable; because of the similarities among imidazaole derivatives,
concurrent use of Isoniazid with parenteral miconazole is not recommended)
(concurrent use of rifampin with Isoniazid may increase the risk of
hepatotoxicity, especially in patients with pre-existing hepatic impairment
and/or in fast acetylators is Isoniazid; patients should be monitored closely
for signs of hepatotoxicity during the first 3 months of therapy)
Neurotoxic medications, other
(concurrent use of other neurotoxic medications with Isoniazid may produce
additive neurotoxicity)
Phenytoin
(concurrent use with Isoniazid inhibits the metabolism of phenytoin, resulting
in increased phenytoin serum concentrations and toxicity; phenytoin dosage
adjustments may be necessary during and after Isoniazid therapy, especially in
slow acetylators of Isoniazid)
Pyridoxine
(Isoniazid may cause peripheral neuritis by acting as a pyridoxine antagonist or
increasing renal excretion of pyridoxine; requirements for pyridoxine may be
increased in patients receiving Isoniazid concurrently)
Theophylline
(concurrent use may reduce the metabolism of theophylline, increasing
theophylline plasma concentrations).
Gastrointestinal disturbances (nausea and vomiting); metabolic acidosis; neurotoxicity (dizziness, slurred speech, lethargy, disorientation, hyperreflexia, seizures, coma)
Note: Patients may be asymptomatic for 30 minutes to 2 hours after an acute overdose. Early symptoms include nausea and vomiting, dizziness, slurred speech, lethargy, disorientation, and hyperreflexia. Seizures usually occur within 1 to 3 hours after ingestion, and are often repetitive and refractory to usual anticonvulsants. Lactic acid accumulation produces an anion-gap metabolic acidosis within a few hours, which is often severe and refractory to sodium bicarbonate. Hyperglycemia, glycosuria, and ketonuria have also been reported.
Incidence more frequent
Gastrointestinal disturbances (diarrhoea, nausea and vomiting, stomach pain)
Store below 25° C.
Prescription Medicine
Glass bottles of 100 tablets.
Nil
PSM Healthcare Ltd
PO Box 76 401
Manukau City
Auckland
Phone 09-277-7751
June 1 1999