Isoniazid

Class: Antituberculosis Agents
VA Class: AM500
CAS Number: 54-85-3
Brands: Rifamate, Rifater

• 
  

  Severe and sometimes fatal hepatitis reported; hepatitis usually develops during the first 3 months of therapy but may develop after many months.^{b c d}

  
  


• 
  

  Risk of developing hepatitis is age related.^{b c d} Approximate case rates by age are: <1 per 1000 in individuals <20 years of age; 3 per 1000 in individuals 20–34 years of age; 12 per 1000 in individuals 35–49 years of age; 23 per 1000 in individuals 50–64 years of age; 8 per 1000 in individuals >65 years of age.^{b c d}

  
  


• 
  

  Risk of hepatitis is increased by daily consumption of alcohol, chronic liver disease, and use of illicit injection drugs.^{b c d}

  
  


• 
  

  There may be an increased risk of fatal hepatitis in women, particularly black and Hispanic women.^{b c d} Risk also may be increased during the postpartum period.^{b c d}

  
  


• 
  

  Precise data on fatality rate for isoniazid-related hepatitis not available.^{b c d} There were 8 deaths among 174 cases of hepatitis in a US Public Health Service Surveillance Study that included 13,838 individuals.^{b c d}

  
  


• 
  

  Monitor and interview patients at monthly intervals.^{b c d} In addition, determine AST and ALT concentrations at baseline and periodically (monthly or more frequently as needed) in individuals ≥35 years of age and in individuals at increased risk of hepatitis.^{b c d}

  
  


• 
  

  Increases in serum transaminase concentrations occur in 10–20% of patients; these increases usually occur during the first few months of therapy but can occur at any time.^{b c d} Enzyme concentrations usually return to pretreatment values despite continued isoniazid therapy, but progressive liver dysfunction occurs in some cases.^{b c d}

  
  


• 
  

  Consider discontinuing isoniazid if liver function abnormalities are >3–5 times ULN.^{b c d}

  
  


• 
  

  Liver function tests are not a substitute for monthly clinical evaluations or for prompt assessment of signs or symptoms of adverse reactions that may occur between regularly scheduled evaluations.^{b c d}

  
  


• 
  

  Patients should be advised to immediately report prodromal symptoms of hepatitis to their clinician.^{b c d} (See Advice to Patients.)

  
  


• 
  

  Discontinue immediately if symptoms or signs suggestive of hepatic damage are detected; continued isoniazid use has been reported to cause a more severe form of liver damage.^{b c d}

  
  


• 
  

  Patients who have signs or symptoms of isoniazid-associated hepatic damage should be treated using alternative antituberculosis agents.^{b c d} If use of isoniazid is considered necessary, the drug should be restarted only after symptoms and laboratory abnormalities have cleared.^{b c d} In this situation, isoniazid should be restarted in very small dosages and gradually increased; discontinue immediately if there is any indication of recurrent liver involvement.^{b c d}

  
  


• 
  

  Use of isoniazid for treatment of latent tuberculosis infection (LTBI) should be deferred in patients with acute hepatic disease.^{b c d}

  
  

Introduction

Antituberculosis agent; synthetic isonicotinic acid derivative.^{a b c d}

Uses for Isoniazid

Tuberculosis

Treatment of active (clinical) tuberculosis (TB) in conjunction with other antituberculosis agents.^{145 176 b c d e j}

First-line agent for treatment of all forms of active TB caused by Mycobacterium tuberculosis known or presumed to be susceptible to the drug.^{145 176 j} Essential component of multiple-drug regimens used for the initial intensive treatment phase and the continuation treatment phase.^{145 176 j}

Fixed-combination preparation containing rifampin and isoniazid (Rifamate) is used for treatment of pulmonary TB.^{143 176} Isoniazid and rifampin both are used in the initial intensive treatment phase and the continuation treatment phase,¹⁷⁶ but manufacturer states that Rifamate is not recommended for initial therapy, and the fixed-combination preparation should be used only after the patient has been treated with the individual components and efficacy of these drugs has been established.¹⁴³

Fixed combination preparation containing rifampin, isoniazid, and pyrazinamide (Rifater) is used for treatment of pulmonary TB;^{141 176} designated an orphan drug by US FDA for this use.¹⁰⁴ Used only in the initial intensive treatment phase since pyrazinamide is not usually indicated for the continuation phase.^{141 176}

For initial treatment of active TB caused by drug-susceptible M. tuberculosis, recommended multiple-drug regimens consist of an initial intensive phase (2 months) and a continuation phase (4 or 7 months).^{145 176} Although the usual duration of treatment for drug-susceptible pulmonary and extrapulmonary TB (except disseminated infections and TB meningitis) is 6–9 months,^{145 176} ATS, CDC, and IDSA state that completion of treatment is determined more accurately by the total number of doses and should not be based solely on the duration of therapy.¹⁷⁶ A longer duration of treatment (e.g., 12–24 months) usually is necessary for infections caused by drug-resistant M. tuberculosis.^{145 176}

Patients with treatment failure or drug-resistant M. tuberculosis, including multidrug-resistant (MDR) TB (resistant to both isoniazid and rifampin) or extensively drug-resistant (XDR) TB (resistant to both isoniazid and rifampin and also resistant to a fluoroquinolone and at least one parenteral second-line antimycobacterial such as capreomycin, kanamycin, or amikacin), should be referred to or managed in consultation with experts in the treatment of TB as identified by local or state health departments or CDC.^{176 l}

Latent Tuberculosis Infection

Treatment of latent tuberculosis infection (LTBI).^{145 166 177 b c d g h i j}

LTBI is asymptomatic infection with M. tuberculosis; usually defined as a positive tuberculin skin test (TST) or Quantiferon-TB gold test (QFT-G) with no evidence of active (clinical) TB.^{145 166 177 j} LTBI is treated to decrease the risk of progression to active TB.^{145 166 g}

Regimen of choice for treatment of LTBI is isoniazid monotherapy, unless the patient has been in contact with an individual with drug-resistant TB.^{145 166 177 g h i j} Rifampin monotherapy is the preferred alternative and is especially useful in adults, adolescents, or children who have been exposed to isoniazid-resistant M. tuberculosis and those who cannot tolerate isoniazid.^{145 166 177 g h i j} Rifabutin is used in those who cannot receive rifampin because of intolerance or because they are receiving other drugs that have clinically important interactions with rifampin (e.g., HIV patients receiving certain antiretroviral agents).^{177 h j}

Treatment of LTBI in patients who have been exposed to a source case with drug-resistant TB, including MDR TB or XDR TB, should be managed in consultation with experts in the treatment of TB as identified by local or state health departments or CDC.^{145 166 g h i j}

Prior to initiating treatment of LTBI, clinical (active) TB must be excluded using appropriate testing (e.g., radiographs).^{145 166 177 b c d g h i j}

Mycobacterium avium Complex (MAC) Infections

Has been used for treatment of M. avium complex (MAC) infections† in conjunction with other antimycobacterials.^t

Although a multiple-drug regimen of isoniazid, rifampin, and ethambutol (with streptomycin during the initial 3–6 months) has been used for treatment of MAC pulmonary infections,^t isoniazid is not included in current ATS, CDC, NIH, or IDSA recommendations for treatment of MAC infections, including macrolide-resistant MAC.^{e f t}

Treatment of MAC infections is complicated and should be directed by clinicians familiar with mycobacterial diseases; consultation with a specialist is particularly important when the patient cannot tolerate first-line drugs or when the infection has not responded to prior therapy or is caused by macrolide-resistant MAC.^t

Mycobacterium kansasii and Other Mycobacterial Infections

Treatment of M. kansasii infections in conjunction with other antimycobacterials.^t ATS and IDSA recommend a regimen of isoniazid, rifampin, and ethambutol for treatment of pulmonary or disseminated infections caused by rifampin-susceptible M. kansasii.^t If rifampin-resistant M. kansasii are involved, ATS and IDSA recommend a 3-drug regimen based on results of in vitro susceptibility, including clarithromycin (or azithromycin), moxifloxacin, ethambutol, sulfamethoxazole, or streptomycin.^t

Treatment of M. xenopi† infections in conjunction with other antimycobacterials.¹⁰⁷ Optimum regimens not established; in vivo response may not correlate with in vitro susceptibility.¹⁰⁷ ATS and IDSA state that a regimen of clarithromycin, rifampin, and ethambutol has been used, although the rate of relapse is high.¹⁰⁷ A regimen of isoniazid, rifampin (or rifabutin), ethambutol, and clarithromycin (without or without streptomycin during initial treatment) also has been suggested.¹⁰⁷

Isoniazid Dosage and Administration

Administration

Administer orally.^{c d} May be given IM when oral therapy is not feasible.^b

Used in conjunction with other antimycobacterial agents for treatment of active (clinical) TB.^{176 b c d e} Used alone for treatment of LTBI.^{166 177 b c d}

Fixed-combination preparations (Rifamate containing rifampin and isoniazid; Rifater containing rifampin, isoniazid, and pyrazinamide) can be used for treatment of active TB infection to reduce the pill burden and ensure compliance, especially when directly observed (supervised) therapy (DOT) cannot be used.¹⁷⁶ A fixed-combination preparation should be used only when all drugs in the preparation are indicated.¹⁷⁶

Oral Administration

Administer orally in the fasting state.^{c d} Do not administer with food.^{c d} (See Food under Pharmacokinetics.)

Rifamate or Rifater: Administer orally with a full glass of water 1 hour before or 2 hours after a meal.^{141 143}

Dosage

Oral and IM dosage is the same.^a

Dosage of Rifamate is expressed as number of capsules;¹⁴³ dosage of Rifater is expressed as number of tablets.¹⁴¹

Concomitant administration of pyridoxine (vitamin B₆) is recommended in adults, adolescents, and pediatric patients who are malnourished (including those on meat- or milk-deficient diets) and in those predisposed to neuropathy (e.g., those with alcoholism, diabetes, HIV infection, seizure disorders, or renal failure).^{141 145 147 166 176 b c d f} Administration of pyridoxine also is recommended in pregnant or nursing women;^{145 176} breast-feeding infants do not require pyridoxine unless they are receiving isoniazid.^{145 166 176} (See Nervous System Effects under Cautions.)

Pediatric Patients

Tuberculosis

Treatment of Active (Clinical) Tuberculosis

Oral

Children: 10–15 mg/kg (up to 300 mg) once daily or 20–40 mg/kg (up to 900 mg) 2 or 3 times weekly recommended by the manufacturers.^{c d}

Children <15 years of age or weighing ≤40 kg: 10–15 mg/kg (up to 300 mg) once daily or 20–30 mg/kg (up to 900 mg) twice weekly recommended by ATS, CDC, IDSA, AAP, and others.^{145 176 f j}

Adolescents ≥15 years of age: 5 mg/kg (up to 300 mg) once daily or 15 mg/kg (up to 900 mg) 1–3 times weekly recommended by ATS, CDC, and IDSA.^{176 e}

Rifater in adolescents ≥15 years of age: 4 tablets once daily in those weighing ≤44 kg, 5 tablets once daily in those weighing 45–54 kg, or 6 tablets once daily in those weighing ≥55 kg.¹⁴¹ Used only in the initial phase of treatment.¹⁴¹

IM

Children: 10–15 mg/kg (up to 300 mg) once daily or 20–40 mg/kg (up to 900 mg) 2 or 3 times weekly.^b

Latent Tuberculosis Infection (LTBI)

Oral

Infants, children, and adolescents: 10–15 mg/kg (up to 300 mg) once daily or 20–30 mg/kg (up to 900 mg) 2 or 3 times weekly recommended by manufacturers, ATS, CDC, IDSA, AAP, USPHS, and others.^{145 147 166 b c i j}

The usual duration of isoniazid monotherapy for treatment of LTBI in children is 9 months, especially in HIV-infected individuals.^{145 147 166 i j} A 6-month regimen is not recommended for children.^{145 147 166}

ATS and CDC recommend that completion of therapy for LTBI be based on total number of administered doses rather duration of therapy alone.¹⁶⁶ When the 9-month once-daily isoniazid regimen is used, at least 270 doses should be administered within 12 months.¹⁶⁶ Ideally, patients should receive the drug on a regular dosing schedule until completed; in practice, some doses may be missed requiring the course to be lengthened.¹⁶⁶ If the regimen is resumed after an interruption of ≥2 months, a medical examination is indicated to rule out active TB.¹⁶⁶

IM

Children: 10 mg/kg (up to 300 mg) once daily or 20–30 mg/kg (up to 900 mg) twice weekly.^b

Adults

Tuberculosis

Treatment of Active (Clinical) Tuberculosis

Oral

5 mg/kg (up to 300 mg) once daily^{176 c d e j} or 15 mg/kg (up to 900 mg) 1–3 times weekly^{176 c d e j} recommended by manufacturers, ATS, CDC, IDSA, and others.

Rifamate: 2 capsules once daily.¹⁴³

Rifater: 4 tablets once daily in adults weighing ≤44 kg, 5 tablets once daily in adults weighing 45–54 kg, or 6 tablets once daily in adults weighing ≥55 kg.¹⁴¹ Used in the initial phase of treatment.¹⁴¹

IM

5 mg/kg (up to 300 mg) once daily or 15 mg/kg (up to 900 mg) 2 or 3 times weekly.^b

Latent Tuberculosis Infection (LTBI)

Oral

5 mg/kg (up to 300 mg) once daily or 15 mg/kg (up to 900 mg) twice weekly recommended by ATS, CDC, IDSA, USPHS, and others.^{124 147 166 j}

Adults weighing >30 kg: 300 mg once daily recommended by manufacturers.^c

The usual duration of isoniazid monotherapy for treatment of LTBI is 9 months.^{145 147 163 166 177 j} A 6-month regimen may be used in some adults,¹⁷⁷ but a 9-month regimen should be used in immunocompromised or HIV-infected individuals or those with fibrotic lesions on chest radiographs.^{145 147 163 166 177}

ATS and CDC recommend that completion of therapy for LTBI be based on total number of administered doses rather duration of therapy alone.¹⁶⁶ When the 9-month once-daily isoniazid regimen is used, at least 270 doses should be administered within 12 months.¹⁶⁶ When the 6-month once-daily isoniazid regimen is used, at least 180 doses should be administered within 9 months.¹⁶⁶ Ideally, patients should receive the drug on a regular dosing schedule until completed; in practice, some doses may be missed requiring the course to be lengthened.¹⁶⁶ If the regimen is resumed after an interruption of ≥2 months, a medical examination is indicated to rule out active TB.¹⁶⁶

IM

Adults weighing >30 kg: 300 mg once daily or 20–30 mg/kg (up to 900 mg) twice weekly.^b

Mycobacterium kansasii Infections†

Treatment of Pulmonary or Disseminated Infections Caused by Rifampin-susceptible M. kansasii†

Oral

5 mg/kg (up to 300 mg) daily in conjunction with ethambutol (15 mg/kg once daily) and rifampin (10 mg/kg [up to 600 mg] daily), and pyridoxine (50 mg daily) recommended by ATS and IDSA.^t

Continue until patient has been culture negative on treatment for 1 year.^t A longer duration may be needed in HIV-infected individuals with disseminated infections.^t

Prescribing Limits

Pediatric Patients

Active (Clinical) Tuberculosis or Latent Tuberculosis Infection (LTBI)

Oral

Maximum 300 mg per dose in once-daily regimens or 900 mg per dose in 2- or 3-times weekly regimens.^{145 166 176 c f}

When used in conjunction with rifampin, isoniazid dosage >10 mg/kg daily may increase the incidence of hepatotoxicity.^{145 f}

Adults

Active (Clinical) Tuberculosis or Latent Tuberculosis Infection (LTBI)

Oral

Maximum 300 mg per dose in once-daily regimens or 900 mg per dose in 2- or 3-times weekly regimens.^{166 176 e}

Special Populations

Hepatic Impairment

Risk of drug accumulation may be increased, but no specific dosage recommendations available.¹⁷⁶ (See Hepatic Impairment under Cautions.)

Renal Impairment

No dosage adjustment needed in patients with renal impairment, including end-stage renal disease; supplemental doses not necessary in hemodialysis patients.¹⁷⁶ (See Renal Impairment under Cautions.)

Cautions for Isoniazid

Contraindications

• 
  

  History of severe hypersensitivity reactions, including drug-induced hepatitis.^{b c d}

  
  


• 
  

  History of isoniazid-associated hepatic injury.^{b c d}

  
  


• 
  

  History of severe adverse reactions to isoniazid (e.g., drug fever, chills, arthritis).^{b c d}

  
  


• 
  

  Acute liver disease of any etiology.^{b c d}

  
  

Warnings/Precautions

Warnings

Hepatic Effects

Severe and sometimes fatal hepatitis reported.^{b c d} (See Boxed Warning.)

Sensitivity Reactions

Hypersensitivity Reactions

Hypersensitivity reactions, including fever, skin eruptions (morbilliform, maculopapular, purpuric, or exfoliative), lymphadenopathy, or vasculitis reported.^{b c d}

At first sign of hypersensitivity, discontinue all drugs and evaluate patient.^{b c d} If isoniazid must be reinstituted, the drug should be restarted only after symptoms have cleared.^{b c d} Isoniazid should be restarted in very small dosages and gradually increased; discontinue immediately if there is any indication of recurrent hypersensitivity reaction.^{b c d}

General Precautions

Nervous System Effects

Peripheral neuritis (usually preceded by paresthesia of the feet and hands) reported.^{b c} Appears to be dose-related^{176 b c} and is uncommon with recommended dosages.^{176 b} Occurs most frequently in those who are malnourished or predisposed to neuritis (e.g., alcoholics, diabetics, HIV-infected, renal failure)^{176 b c} and in those who are slow inactivators of isoniazid (see Elimination under Pharmacokinetics).^{b c}

Neuropathy may be prevented or relieved by pyridoxine (vitamin B₆).^{166 176 a} ATS, CDC, IDSA, AAP, and USPHS recommend pyridoxine supplementation in adults, adolescents, and children at increased risk of neuropathy (e.g., those with malnutrition, alcoholism, diabetes, HIV infection, seizure disorders, or renal failure), pregnant or breast-feeding women, and in breast-feeding infants receiving isoniazid.^{145 147 166 176} Multivitamin preparations contain variable amounts of pyridoxine and usually will not provide adequate supplementation in these patients.¹⁷⁶ Some experts recommend a pyridoxine dosage of 10–25 mg daily during isoniazid therapy;^{166 176} higher dosage may be recommended in HIV-infected adults.¹⁴⁷

Carefully monitor patients with peripheral neuropathy or conditions that predispose to neuropathy.^{b c}

Patient Monitoring

Because of risk of isoniazid-associated hepatitis, closely monitor and interview patients once monthly.^{b c d} Determine serum transaminase concentrations prior to and periodically during treatment in those at increased risk, including daily users of alcohol, patients >35 years of age, those with chronic liver disease, those who use illicit injection drugs, and women (particularly during the postpartum period and in those who belong to minority groups).^{b c d} (See Boxed Warning.)

Carefully monitor patients who are daily users of alcohol, those who are >35 years of age, those receiving long-term concomitant therapy, those who previously discontinued isoniazid, those who use illicit injection drugs, those with a history of peripheral neuropathy or conditions predisposing to neuropathy, those with active chronic liver disease or severe renal dysfunction, women who are pregnant or in the postpartum period, women who belong to minority groups, and HIV-infected individuals.^{b c d}

Perform periodic ophthalmologic examinations if visual symptoms occur during isoniazid therapy.^b

Use of Fixed Combinations

When the fixed-combination preparations (Rifamate containing rifampin and isoniazid or Rifater containing rifampin, isoniazid, and pyrazinamide) are used, observe the usual precautions and contraindications associated with all drugs in the preparation.^{141 143} Use these preparations only when all drugs contained in the fixed combination are indicated.¹⁷⁶

Precautions Related to Treatment of Tuberculosis

Should not be used alone for treatment of active TB; must be used in conjunction with other antituberculosis agents.^{176 b c d e}

Clinical specimens for microscopic examination and mycobacterial cultures and in vitro susceptibility testing should be obtained prior to initiation of antituberculosis therapy and periodically during treatment to monitor therapeutic response.¹⁷⁶ The antituberculosis regimen should be modified as needed.¹⁷⁶ Patients with positive cultures after 4 months of treatment should be considered to have failed treatment (usually as the result of noncompliance or drug-resistant TB).¹⁷⁶

Compliance with the full course of antituberculosis therapy and all drugs included in the multiple-drug regimen is critical.¹⁷⁶ Missed doses increase the risk of treatment failure and increase the risk that M. tuberculosis will develop resistance to the antituberculosis regimen.¹⁷⁶

To ensure compliance, ATS, CDC, IDSA, and AAP recommend that directly observed (supervised) therapy (DOT) be used for treatment of active (clinical) TB and for treatment of LTBI whenever possible, especially when intermittent regimens are used, when the patient is immunocompromised or infected with HIV, or when drug-resistant M. tuberculosis is involved.^{145 166 176 e f i}

Specific Populations

Pregnancy

Category C.^{b c d}

A regimen of isoniazid, rifampin, and ethambutol is recommended by ATS, CDC, IDSA, and AAP for treatment of active (clinical) TB in pregnant women.^{145 176} Consider that the risk of fatal isoniazid-associated hepatitis may be increased in women, especially during the postpartum period.¹⁷⁶ Carefully monitor when used during pregnancy and the postpartum period (especially in women belonging to minority groups).^{b c d}

Treatment for LTBI generally should be deferred until after delivery to avoid risk to the fetus.^{b c d}

If isoniazid is used during pregnancy, consider concomitant use of pyridoxine.^{145 176} (See Nervous System Effects under Cautions.) Neonates born to women who received isoniazid during pregnancy should be carefully observed for evidence of adverse effects.^{b c d}

Lactation

Distributed into milk, but manufacturers state that breast-feeding should not be discouraged.^{b c d} Consider use of pyridoxine in breast-feeding woman; her breast-fed infant does not require pyridoxine unless also receiving isoniazid.^{145 176} (See Nervous System Effects under Cautions.)

Isoniazid concentrations in breast milk are too low to be considered therapeutic for the infant.^{b c d}

Pediatric Use

Used in infants and children for treatment of active (clinical) TB and treatment of LTBI.^{145 166 176 b c d}

Rifamate: Safety and efficacy not established in pediatric patients.¹⁴³

Rifater: Safety and efficacy not established in children <15 years of age; the ratio of rifampin and isoniazid in this preparation may not be appropriate for this age group.¹⁴¹

Infants, children, and adolescents who experience paresthesias while receiving isoniazid and those who are malnourished (including those on meat- or milk-deficient diets) or have conditions that predispose to neuropathy (e.g., HIV infection, renal failure) should receive pyridoxine supplementation during isoniazid therapy.^{145 166 176} Breast-feeding infants receiving isoniazid also should receive pyridoxine supplementation.^{145 176} Routine administration of pyridoxine in other pediatric patients is not recommended.^{145 166}

Hepatic Impairment

Risk of drug accumulation and isoniazid-associated hepatitis may be increased.^{176 b c d} (See Boxed Warning.)

Carefully monitor patients with chronic liver disease.^{176 b c d} Contraindicated in patients with acute liver disease.^{b c d}

Renal Impairment

Carefully monitor patients with severe renal impairment.^{b c d}

Common Adverse Effects

Nervous system effects (peripheral neuropathy), hepatic effects (elevated transaminase concentrations).^{b c d}

Interactions for Isoniazid

Specific Drugs, Food, and Laboratory Tests

Drug	Interaction	Comments
Acetaminophen	Severe acetaminophen toxicity reportedb c d
Alcohol	Daily alcohol consumption associated with higher incidence of isoniazid-related hepatitisb c d	Monitor carefullyb c d
Aminosalicylic acid	Reduced rate of acetylation of isoniazid (especially in rapid acetylators) reported with some aminosalicylic acid preparations; appears to be dose relateda r Interaction not studied using commercially available aminosalicylic acid delayed-release granules (Paser);r the lower serum concentrations produced by the delayed-release preparation should result in a reduced effect on acetylation of isoniazidr	Not considered clinically importanta
Antacids, aluminum hydroxide gel	Decreased isoniazid absorptiona	Administer isoniazid at least 1 hour before the antacida
Antifungals, azoles (ketoconazole)	Potential pharmacokinetic interaction; decreased AUC of ketoconazoleb c d
BCG vaccine	Isoniazid inhibits multiplication of BCGa	Vaccine may not be effectivea
Carbamazepine	Increased carbamazepine concentrations; symptoms of carbamazepine toxicity reported120 121 122 b c d Increased risk of isoniazid-induced hepatotoxicity121	Determine carbamazepine concentrations prior to and during isoniazid therapy;b c d closely monitor for carbamazepine toxicityb c d and adjust carbamazepine dosage as needed120 122 176 b c d
Cycloserine	Adverse CNS effects (e.g., dizziness, drowsiness) may be additivea p	Use concomitantly with cautiona p and closely monitor for signs of CNS toxicity;p dosage adjustments may be necessaryp
Disulfiram	Adverse nervous system effects (coordination difficulties, psychotic episodes) reporteda	Concomitant use not recommendeda
Ethionamide	Increased isoniazid concentrationsq Additive adverse nervous system effectsa	Use concomitantly with cautiona q
Food, histamine-containing (skipjack, tuna, tropical fish)	Potential for monoamine poisoning176 or exaggerated response (e.g., headache, sweating, palpitations, flushing, hypotension) 141	Avoid histamine-containing food141
Food, tyramine-containing (cheese, red wine)	Potential for monoamine poisoning176	Avoid tyramine-containing food141
Phenytoin	Increased phenytoin concentrations;176 b c d phenytoin toxicity reporteda	Monitor phenytoin concentrations;176 adjust phenytoin dosage as needed176 b c d
Rifabutin	Pharmacokinetic interaction unlikelys
Rifampin	Increased risk of hepatotoxicityo	Closely monitor for signs and symptoms of hepatotoxicityo
Serotonergic agents	Potential for serotonin syndrome;a isoniazid has some MAO-inhibiting activity161
Test, urinary glucose	Isoniazid may cause false-positive results with cupric sulfate solution (Benedict's reagent, Clinitest)a
Theophylline	Increased theophylline concentrations; slight decrease in elimination of isoniazidb c d	Monitor theophylline concentrations; adjust theophylline dosage as neededb c d
Valproate	Increased plasma valproate concentrations b c d	Monitor plasma valproate concentrations; adjust dosage of valproate as neededb c d

Isoniazid Pharmacokinetics

Absorption

Bioavailability

Readily absorbed from GI tract; peak plasma concentrations achieved within 1–2 hours.^{b c d}

Readily absorbed from IM injection sites.^a

Food

Food reduces oral bioavailability.^{b c d}

Plasma Concentrations

Plasma concentrations in rapid isoniazid inactivators are 20–50% of those in slow isoniazid inactivators.^a

Distribution

Extent

Distributed into all body tissues and fluids, including pleural fluid, ascitic fluid, saliva, and sputum.^{b c d}

CSF concentrations are 90–100% of concurrent plasma concentrations.^{176 a}

Crosses the placenta.^{b c d}

Distributed into milk in concentrations comparable to those in plasma.^{176 b c d}

Plasma Protein Binding

Not substantially bound.^a

Elimination

Metabolism

Inactivated in the liver, mainly by acetylation and dehydrazination.^{b c d} The rate of acetylation is genetically determined,^{b c d} and usually is constant for each person.^a Rate of acetylation does not have a clinically im