Isoniazid dosing

Kinzig-Schippers M et al Should we use A/-acetyltransferase type 2 genotyping to personalize isoniazid doses Antimicrob Agents Chemother 2005 49 1733. [PMID 15855489]... 

Acute poisoning with isoniazid in children (48) and adults (13,26,35) causes recurrent seizures, profound metabolic acidosis, coma, and even death. In adults, toxicity can occur with the acute ingestion of as little as 1.5 g of isoniazid. Doses larger than 30 mg/kg often produce seizures and 80-150 mg/kg or more can be rapidly fatal. The first signs and symptoms of isoniazid toxicity usually appear 0.5-2.0 hours after ingestion, by which time peak absorption occurs (49), and include nausea, vomiting, slurred speech, dizziness, tachycardia, and urinary... 

In nearly all patients, isoniazid and rifampin do not require dose modification in renal failure. They are eliminated primarily by the liver." " " In the unlikely event that peripheral neuropathies develop, the frequency of isoniazid dosing may be reduced. Pyrazinamide and ethambutol typically require a reduction in dosing frequency from daily to three times weekly " (Table 110-6). 

A number of reports surest that the toxicity of paracetamol may be increased by isoniazid so that normal analgesic dosages (4 g daily) may not be safe in some individuals. Pharmacokinetic studies surest that isoniazid usually inhibits the metabolism of paracetamol, but that metabolism to toxic metaboUtes may be induced shortly after stopping isoniazid, or late in the isoniazid dose-interval in fast acetylators of isoniazid. 

However, in a pharmacokinetic study in 10 healthy subjects of both slow and fast acetylator status, isoniazid 300 mg daily for 7 days modestly decreased the total clearance of a single 500-mg dose of paracetamol by 15%. Moreover, the clearance of paracetamol to oxidative metabolites was decreased Similarly, in a further study in 10 healthy slow acetylators of isoniazid, the formation of paracetamol thioether metabolites and oxidative metabolites was reduced by 63% and 49%, respectively, by isoniazid 300 mg daily. However, one day after stopping isoniazid, the formation of thioether metabolites was increased by 56%, and this returned to pretreatment values 3 days after the discontinuation of isoniazid. In yet another study in 10 healthy subjects taking isoniazid prophylaxis, the formation clearance of paracetamol to A -acetyl-p-benzo-quinone imine (NAPQI) was inhibited by 56% when the paracetamol was given simultaneously with the daily isoniazid dose, but when the paracetamol was taken 12 hours after the isoniazid, there was no difference in NAPQI formation clearance, compared with the control phase (1 to 2 weeks after isoniazid had been discontinued). However, when the results were analysed by acetylator status, it appeared that the NAPQI formation clearance was increased in fast acetylators taking paracetamol 12 hours after the isoniazid dose. ... 

Information is limited, but it would now seem prudent to consider warning patients taking isoniazid to limit their use of paracetamol because it seems that some individuals risk possible paracetamol-induced liver toxicity, even with normal reeommended doses. Pharmacokinetic studies suggest that it is possible that the risk is greatest shortly after stopping isoniazid. The risk may also be higher if paracetamol is taken late in the isoniazid dosing interval, partieularly in fast acetylators of isoniazid. More study is needed to elarify the situation. 

The incidence of adverse reactions appears to be higher when larger doses of isoniazid are prescribed. Adverse reactions include hypersensitivity reactions, hematologic changes, jaundice, fever, skin eruptions, nausea, vomiting, and epigastric distress. Severe, and sometimes fatal, hepatitis has been associated witii isoniazid tiierapy and may appear after many months of treatment. Peripheral neuropathy (numbness and tingling of the extremities) is the most common symptom of toxicity. 

Acetaminophen may alter blood glucose test results, causing falsely lower blood glucose values. Use with the barbiturates, hydantoins, isoniazid, and rifampin may increase the toxic effects and possibly decrease the therapeutic effects of acetaminophen. The effects of the loop diuretics may be decreased when administered with acetaminophen. Hepatotoxicity has occurred in chronic alcoholics who are taking moderate doses of acetaminophen. 

Antacids also have clinically significant drug interactions with tetracycline, ferrous sulfate, isoniazid, quinidine, sul-fonylureas, and quinolone antibiotics. Antacid-drug interactions are influenced by antacid composition, dose, dosage schedule, and formulation. 

Isoniazid is used for treating LTBI.2,6,12,28 Typically, isoniazid 300 mg daily (5-10 mg/kg of body weight) is given alone for 9 months. Lower doses usually are less effective.2,31 The treatment of LTBI reduces a person s lifetime risk of active TB from about 10% to about 1%20 (Table 72-2). Rifampin 600 mg... 

Because they are hepatically cleared, isoniazid and rifampin do not require dose modification in renal failure.31,36,39 Pyrazinamide and ethambutol typically are reduced to three times weekly to avoid accumulation of the parent drug (ethambutol) or metabolites (pyrazinamide).28,31 Renally cleared TB drugs include the aminoglycosides (e.g., amikacin, kanamycin, and streptomycin), capreomycin, ethambutol, cycloserine, and lev-ofloxacin.28,31,33,39 Dosing intervals need to be extended for... 

Supplemental doses of pyridoxine hydrochloride (vitamin B6), 50 mg/ day, are recommended to prevent the peripheral neuropathy associated with isoniazid administration. 

Concurrent administration of rifampin is recommended at doses of 10 to 20 mg/kg/day (maximum 600 mg/day) for children and 600 mg/day for adults. The addition ofpyrazinamide (children and adults, 15 to 30 mg/kg/ day maximum in both, 2 g/day) to the regimen of isoniazid and rifampin is now recommended. The duration of concomitant pyrazinamide therapy should be limited to 2 months to avoid hepatotoxicity. 

Isoniazid, rifampin, pyra- Seven days per week for 56 doses (8 weeks) la Isoniazid/rifampin Seven days per week for 126 doses (18 182-130(26 A(l) A (II)... 

The drug can likely be used safely in older children but should be used with caution in children less than 5 years of age, in whom visual acuity cannot be monitored. In younger children, ethambutol at the dose of 15 mg/kg per day can be used if there is suspected or proven resistance to isoniazid or rifampin. 

The long-term (more than several weeks) use of levofloxacin in children and adolescents has not been approved because of concerns about effects on bone and cartilage growth. However, most experts agree that the drug should be considered for children with tuberculosis caused by organisms resistant to both isoniazid and rifampin. The optimal dose is not known. 

Frequency 45-65% of Caucasians and African Americans 10-15% of Asians Slow inactivation of drugs such as isoniazid (for tuberculosis), dapsone (for leprosy), and hydralazine (for high blood pressure), leading to toxicity from the drug at doses well tolerated in people with rapid acetylator phenotype Clinical consequences depend on the specific side effects of the drugs... 

Interesting information stems from studies of the hepatotoxic effect of the concomitant administration of rifampicin, another antituberculostatic drug (and a potent inducer of cytochrome P450) often used in combination with isoniazid. Rifampicin alone is not hepatotoxic but increases significantly the incidence of hepatitis in patients simultaneously dosed with isoniazid. In human volunteers (6 slow and 8 rapid acetylators), daily administration of rifampicin increased the release of hydrazine from isoniazid [180], In slow acetylators, the proportion of the dose metabolized to hydrazine increased... 

Rifater Tuberculostatic Tab Rifampin 120 mg, isoniazid 50 mg, pyrazinamide 6 tabs once daily. Reduce dose to 5 tabs if <54 300 mg kg, and to 4 tabs if <441 ... 

Rifampicin appears to be particularly promising in the treatment of tuberculosis, especially in combination with isoniazid. The prolonged high blood levels attainable with a single daily dose should simplify therapy. 

HIV - The initial phase of a 6-month tuberculosis regimen consists of isoniazid, rifabutin, pyrazinamide, and ethambutol for patients receiving therapy with protease inhibitors or nonnucleoside reverse transcriptase inhibitors. These drugs are administered a) daily for at least the first 2 weeks, followed by twice weekly dosing for 6 weeks or b) daily for 8 weeks to complete the 2-month induction phase. The second phase of treatment consists of rifabutin and isoniazid administered twice weekly or daily for 4 months. 

Treat patients with tuberculosis who have hepatitis attributed to isoniazid with appropriate alternative drugs. Reinstitute isoniazid after symptoms and laboratory abnormalities have become normal. Restart the drug in very small doses gradually increase doses and withdraw immediately if there is any indication of recurrent liver involvement. 

Excretion - Approximately 50% to 70% of a dose of isoniazid is excreted as unchanged drug and metabolites by the kidneys in 24 hours. 

Toxic effects are usually encountered with higher doses of isoniazid the most frequent are those affecting the nervous system and the liver. 

Initial treatment In patients who have not received previous antituberculosis therapy, administer 15 mg/kg (7 mg/lb) as a single oral dose once every 24 hours. Isoniazid has been administered concurrently in a single, daily oral dose. 

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