Isoniazid (oral)

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# Black Box Warning

# Overview
Isoniazid (oral) is an antitubercular, anti-bacterial agent that is FDA approved for the treatment of all forms of tuberculosis in which organisms are susceptible. There is a Black Box Warning for this drug as shown here.  Common adverse reactions include increased liver enzymes, neuropathy, neurotoxicity.

# Adult Indications and Dosage

## FDA-Labeled Indications and Dosage (Adult)

### Active tuberculosis
- Dosing Information
- The treatment of adults with pulmonary tuberculosis caused by drug-susceptible organisms consists of an initial phase (2 months), which always includes the four-drug combination of isoniazid, rifampin, pyrazinamide, and ethambutol, followed by a continuation phase (lasting 4 to 7 months) which includes isoniazid and either rifampin or rifapentine.

### Active tuberculosis - HIV infection
- Dosing Information
- The recommended dose of isoniazid in the treatment of HIV-related tuberculosis (TB) is 5 mg/kg given orally, intravenously, or intramuscularly once daily (maximum 300 mg/dose) or 15 mg/kg 2 to 3 times a week (maximum, 900 mg/dose) in combination with other TB medications. Twice-weekly dosing is not recommended in HIV-patients with CD4 lymphocyte counts less than 100 cells/mm(3).

### HIV infection - Inactive tuberculosis
- Dosing Information
- The recommended dose of isoniazid for the prevention of active tuberculosis (TB) (ie, treatment of latent tuberculosis) in adults and adolescents with human immunodeficiency virus (HIV) is 300 mg orally daily. Alternatively, 900 mg orally may be given twice weekly.
- Pyridoxine 50 mg orally daily should always be administered concomitantly with isoniazid to minimize the risk of peripheral neuropathy. The recommended duration of prophylaxis with isoniazid is 9 months. Directly observed therapy is recommended with intermittent dosing regimens to maximize compliance rates.
- As an equal alternative to a 9-month isoniazid course for HIV-infected, nonpregnant adults who are otherwise healthy and are not receiving antiretroviral therapy, the CDC recommends a combination regimen of isoniazid plus rifapentine orally once weekly (given as directly observed therapy) for 12 weeks. The isoniazid dose is 15 mg/kg (rounded up to the nearest 50 or 100 mg; maximum, 900 mg) and the rifapentine dose is as follows: 300 mg (10 to 14 kg), 450 mg (14.1 to 25 kg), 600 mg (25.1 to 32 kg), 750 mg (32.1 to 49.9 kg), or 900 mg (50 kg or greater). Due to lack of drug interaction data, this regimen is not recommended in HIV-infected patients receiving antiretroviral therapy.

### Inactive tuberculosis
- Dosing Information
- 5 mg/kg (MAX, 300 mg) ORALLY once daily for 9 months OR 15 mg/kg (MAX, 900 mg) ORALLY twice weekly as directly observed therapy for 9 months (guideline recommendation).
- Alternative: 15 mg/kg (rounded up to the nearest 50 or 100 mg; MAX, 900 mg) ORALLY once weekly in combination with rifapentine ORALLY once weekly for 12 weeks (rifapentine dose: 300 mg (10 to 14 kg), 450 mg (14.1 to 25 kg), 600 mg (25.1 to 32 kg), 750 mg (32.1 to 49.9 kg), or 900 mg (50 kg or greater)); give only as directly observed therapy (guideline recommendation).

## Off-Label Use and Dosage (Adult)

### Guideline-Supported Use
- Dosing Information
- The Centers for Disease Control and Prevention (CDC), in association with the American Thoracic Society and the Infectious Diseases Society of America, recommends a 6-month treatment regimen for tuberculosis in HIV-infected patients on antiretroviral therapy. The treatment regimen consists of a 2-month initial phase of isoniazid, rifampin, pyrazinamide, and ethambutol, followed by a continuation phase of 4 to 7 months. For patients on directly observed therapy (DOT), 5 day-a-week dosing may be used to replace 7 day-a-week dosing (AIII). Rifabutin, which has fewer problematic drug interactions, may be used interchangeably with rifampin; dose adjustments to rifabutin and antiretroviral agents may be necessary. Ethambutol may be excluded if drug susceptibility results indicate that the organisms are fully susceptible to isoniazid and rifampin. If pyrazinamide cannot be included in the initial phase due to conditions such as severe liver disease, gout, or pregnancy, the initial phase should consist of isoniazid, rifampin, and ethambutol given once daily for 2 months. If isoniazid cannot be used, a 6-month regimen of rifampin, pyrazinamide, and ethambutol may be substituted (BI). If rifampin cannot be used, treatment with isoniazid and ethambutol for 12 to 18 months, with pyrazinamide during at least the initial phase is recommended. Completion of treatment should be determined by the total number of doses taken, and not solely on duration of therapy. The following is a list of 4 different regimens of initial and continuation phases that may be used for the treatment of tuberculosis in HIV-infected patients. Strength of recommendation and quality of evidence ratings are included at the end of this protocol.
- Regimen 1
- Initial Phase:
- Isoniazid, rifampin, pyrazinamide, and ethambutol administered once daily for 56 doses/8 weeks (AII), OR
- Isoniazid, rifampin, pyrazinamide, and ethambutol administered once daily for 5 days/week for 40 doses/8 weeks (AIII)
- Continuation Phase:
- Isoniazid and rifampin administered once daily for 126 doses/18 weeks (AII), OR
- Isoniazid and rifampin administered once daily for 5 days/week for 90 doses/18 weeks (AIII), OR
- Isoniazid and rifampin administered twice weekly for 36 doses/18 weeks (AII) (not recommended in HIV-infected patients with CD4+ counts less than 100 cells/milliliter)
- Regimen 2 (not recommended in HIV-infected patients with CD4+ counts less than 100 cells/milliliter)
- Initial Phase:
- Isoniazid, rifampin, pyrazinamide, and ethambutol administered once daily for at least the first 14 doses/2 weeks, followed by twice weekly dosing for 12 doses/6 weeks (BII), OR
- Isoniazid, rifampin, pyrazinamide, and ethambutol administered once daily for 5 days/week for 10 doses/2 weeks (AIII), followed by twice weekly dosing for 12 doses/6 weeks (BII)
- Continuation Phase:
- Isoniazid and rifampin administered twice weekly for 36 doses/18 weeks (BII)
- Regimen 3
- Initial Phase:
- Isoniazid, rifampin, pyrazinamide, and ethambutol administered 3 times weekly for 24 doses/8 weeks (BII)
- Continuation Phase:
- Isoniazid and rifampin administered 3 times weekly for 54 doses/18 weeks (BII)
- Regimen 4
- Initial Phase:
- Isoniazid, rifampin, and ethambutol administered once daily for 56 doses/8 weeks (CII), OR
- Isoniazid, rifampin, and ethambutol administered once daily for 5 days/week for 40 doses/8 weeks (AIII)
- Continuation Phase:
- Isoniazid and rifampin administered once daily for 217 doses/31 weeks (CII), OR
- Isoniazid and rifampin administered once daily for 5 days/week for 155 doses/31 weeks (AIII), OR
- Isoniazid and rifampin administered twice weekly for 62 doses/31 weeks (CII)

### NonGuideline-Supported Use
- There is limited information regarding Off-Label NonGuideline-Supported Use of Isoniazid (oral) in adult patients.

# Pediatric Indications and Dosage

## FDA-Labeled Indications and Dosage (Pediatric)
- Dosing Information
- The following is recommended dosing based on daily or twice weekly administration.
- Extrapulmonary tuberculosis should be managed with the dosing regimens outlined for pulmonary tuberculosis. However, for children with miliary TB, bone or joint TB, or tuberculosis meningitis, treatment should be continued for a minimum of 12 months.
- Dosing Information
- Intensive 8-week Phase:
- The recommended dose of oral isoniazid for the treatment of drug susceptible HIV-related TB in infants and children is 10 to 15 mg/kg daily (maximum dose 300 mg/day) in combination with rifampin (10 to 20 mg/kg ORALLY once daily, up to 600 mg/day), pyrazinamide (20 to 40 mg/kg ORALLY once daily, up to 2000 mg/day), and ethambutol (15 to 25 mg/kg ORALLY once daily, up to 2500 mg/day) for 8 weeks.
- Continuation 9 to 12 week Phase:
- After the 8 week initial intensive phase, once daily dosing of isoniazid and rifampin may be continued if susceptible. Alternatively, an intermittent regimen of isoniazid 20 to 30 mg/kg once daily (max 900 mg/day) 3 times per week in combination with rifampin 10 to 20 mg/kg once daily (max 600 mg/day) 3 times per week may be used. For patients older than 6 years who are not immunosuppressed (CD4 count greater than 25% or greater than 500 cells/microL), isoniazid and rifampin may be administered twice weekly; however, severely immunosuppressed patients should receive only a daily or 3 times weekly regimen due to increased rifampin resistance with a twice weekly regimen. Total treatment duration should be no less than 9 to 12 months. Longer treatment durations may be required for drug resistant cases and a minimum treatment course of 12 months is recommended for extrapulmonary disease involving the bones, joints, CNS, or miliary disease.

### Inactive tuberculosis
- Dosing Information
- The preferred regimen for the treatment of latent tuberculosis in children is isoniazid 10 to 20 mg/kg (maximum, 300 mg) orally once daily for 9 months OR 20 to 40 mg/kg (maximum, 900 mg) orally twice weekly as directly observed therapy for 9 months.
- As an equal alternative to isoniazid for children 12 years or older, the CDC recommends a combination regimen of isoniazid plus rifapentine orally once weekly (given as directly observed therapy) for 12 weeks. The isoniazid dose is 15 mg/kg (rounded up to the nearest 50 or 100 mg; maximum, 900 mg) and the rifapentine dose is as follows: 300 mg (10 to 14 kg), 450 mg (14.1 to 25 kg), 600 mg (25.1 to 32 kg), 750 mg (32.1 to 49.9 kg), or 900 mg (50 kg or greater).

### HIV infection - Inactive tuberculosis
- Dosing Information
- The recommended dose of isoniazid for the prevention of active tuberculosis (TB) (ie, treatment of latent tuberculosis) in children with human immunodeficiency virus (HIV) is 10 to 15 mg/kg (maximum, 300 mg) orally daily for 9 months. Alternatively, 20 to 30 mg/kg (maximum, 900 mg) orally may be given twice weekly for 9 months. Pyridoxine should always be administered concomitantly with isoniazid in children with symptomatic HIV infection.
- As an equal alternative to a 9-month isoniazid course for HIV-infected, nonpregnant adolescents (12 years or older) who are otherwise healthy and are not receiving antiretroviral therapy, the CDC recommends a combination regimen of isoniazid plus rifapentine orally once weekly (given as directly observed therapy) for 12 weeks. The isoniazid dose is 15 mg/kg (rounded up to the nearest 50 or 100 mg; maximum, 900 mg) and the rifapentine dose is as follows: 300 mg (10 to 14 kg), 450 mg (14.1 to 25 kg), 600 mg (25.1 to 32 kg), 750 mg (32.1 to 49.9 kg), or 900 mg (50 kg or greater). Due to lack of drug interaction data, this regimen is not recommended in HIV-infected patients receiving antiretroviral therapy.

## Off-Label Use and Dosage (Pediatric)

### Guideline-Supported Use
- There is limited information regarding Off-Label Guideline-Supported Use of Isoniazid (oral) in pediatric patients.

### NonGuideline-Supported Use
- There is limited information regarding Off-Label NonGuideline-Supported Use of Isoniazid (oral) in pediatric patients.

# Contraindications
- Isoniazid is contraindicated in patients who develop severe hypersensitivity reactions, including drug-induced hepatitis; previous isoniazid-associated hepatic injury; severe adverse reactions to isoniazid such as drug fever, chills, arthritis; and acute liver disease of any etiology.

# Warnings
- See the boxed WARNING.

### Precautions
General:
- All drugs should be stopped and an evaluation made at the first sign of a hypersensitivity reaction. If isoniazid therapy must be reinstituted, the drug should be given only after symptoms have cleared. The drug should be restarted in very small and gradually increasing doses and should be withdrawn immediately if there is any indication of recurrent hypersensitivity reaction.
- Use of isoniazid should be carefully monitored in the following:
- Daily users of alcohol. Daily ingestion of alcohol may be associated with a higher incidence of + isoniazid hepatitis.
- Patients with active chronic liver disease or severe renal dysfunction.
- Age > 35.
- Concurrent use of any chronically administered medication.
- History of previous discontinuation of isoniazid.
- Existence of peripheral neuropathy or conditions predisposing to neuropathy.
- Pregnancy.
- Injection drug use.
- Women belonging to minority groups, particularly in the postpartum period.
- HIV seropositive patients.
- Laboratory Tests:
- Because there is a higher frequency of isoniazid associated hepatitis among certain patient groups, including Age > 35, daily users of alcohol, chronic liver disease, injection drug use and women belonging to minority groups, particularly in the post-partum period, transaminase measurements should be obtained prior to starting and monthly during preventative therapy or more frequently as needed. If any of the values exceed three to five times the upper limit of normal, isoniazid should be temporarily discontinued and consideration given to restarting therapy.

# Adverse Reactions

## Clinical Trials Experience
- The most frequent reactions are those affecting the nervous system and the liver.
- Nervous System Reactions: Peripheral neuropathy is the most common toxic effect. It is dose-related, occurs most often in the malnourished and in those predisposed to neuritis (e.g., alcoholics and diabetics), and is usually preceded by paresthesias of the feet and hands. The incidence is higher in "slow inactivators".
- Other neurotoxic effects, which are uncommon with conventional doses, are convulsions, toxic encephalopathy, optic neuritis and atrophy, memory impairment, and toxic psychosis.
- Hepatic Reactions: See boxed WARNING. Elevated serum transaminase (SGOT; SGPT), bilirubinemia, bilirubinuria, jaundice, and occasionally severe and sometimes fatal hepatitis. The common prodromal symptoms of hepatitis are anorexia, nausea, vomiting, fatigue, malaise, and weakness. Mild hepatic dysfunction, evidenced by mild and transient elevation of serum transaminase levels occurs in 10% to 20% of patients taking isoniazid. This abnormality usually appears in the first 1 to 3 months of treatment but can occur at any time during therapy. In most instances, enzyme levels return to normal and generally, there is no necessity to discontinue medication during the period of mild serum transaminase elevation. In occasional instances, progressive liver damage occurs, with accompanying symptoms. If the SGOT value exceeds three to five times the upper limit of normal, discontinuation of the isoniazid should be strongly considered. The frequency of progressive liver damage increases with age. It is rare in persons under 20, but occurs in up to 2.3 percent of those over 50 years of age.
- Gastrointestinal Reactions: Nausea, vomiting and epigastric distress.
- Hematologic Reactions: Agranulocytosis; hemolytic, sideroblastic or aplastic anemia, thrombocytopenia; and eosinophilia.
- Hypersensitivity Reactions: Fever, skin eruptions (morbilliform, maculopapular, purpuric or exfoliative), lymphadenopathy and vasculitis.
- Metabolic and Endocrine Reactions: Pyridoxine deficiency, pellagra, hyperglycemia, metabolic acidosis and gynecomastia.
- Miscellaneous Reactions: Rheumatic syndrome and systemic lupus erythematosus-like syndrome.
- To report SUSPECTED ADVERSE REACTIONS, contact West-Ward Pharmaceutical Corp. at 1-877-233-2001, or the FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

## Postmarketing Experience
- There is limited information regarding Postmarketing Experience of Isoniazid (oral) in the drug label.

# Drug Interactions
- Food: Isoniazid should not be administered with food. Studies have shown that the bioavailability of isoniazid is reduced significantly when administered with food. Tyramine- and histamine-containing foods should be avoided in patients receiving isoniazid. Because isoniazid has some monoamine oxidase inhibiting activity, an interaction with tyramine-containing foods (cheese, red wine) may occur. Diamine oxidase may also be inhibited, causing exaggerated response (e.g., headache, sweating, palpitations, flushing, hypotension) to foods containing histamine (e.g., skipjack, tuna, other tropical fish).
Acetaminophen:
- A report of severe acetaminophen toxicity was reported in a patient receiving isoniazid. It is believed that the toxicity may have resulted from a previously unrecognized interaction between isoniazid and acetaminophen and a molecular basis for this interaction has been proposed. However, current evidence suggests that isoniazid does induce P-450IIE1, a mixed-function oxidase enzyme that appears to generate the toxic metabolites, in the liver. Furthermore it has been proposed that isoniazid resulted in induction of P-450IIE1 in the patient's liver which, in turn, resulted in a greater proportion of the ingested acetaminophen being converted to the toxic metabolites. Studies have demonstrated that pretreatment with isoniazid potentiates acetaminophen hepatotoxicity in rats1,2.
Carbamazepine:
- Isoniazid is known to slow the metabolism of carbamazepine and increase its serum levels. Carbamazepine levels should be determined prior to concurrent administration with isoniazid, signs and symptoms of carbamazepine toxicity should be monitored closely, and appropriate dosage adjustment of the anticonvulsant should be made3.
Ketoconazole:
- Potential interaction of ketoconazole and isoniazid may exist. When ketoconazole is given in combination with isoniazid and rifampin the AUC of ketoconazole is decreased by as much as 88% after 5 months of concurrent isoniazid and rifampin therapy4.
Phenytoin:
- Isoniazid may increase serum levels of phenytoin. To avoid phenytoin intoxication, appropriate adjustment of the anticonvulsant should be made5,6.
Theophylline:
- A recent study has shown that concomitant administration of isoniazid and theophylline may cause elevated plasma levels of theophylline, and in some instances a slight decrease in the elimination of isoniazid. Since the therapeutic range of theophylline is narrow, theophylline serum levels should be monitored closely and appropriate dosage adjustments of theophylline should be made7.
Valproate:
- A recent case study has shown a possible increase in the plasma level of valproate when co-administered with isoniazid. Plasma valproate concentration should be monitored when isoniazid and valproate are co-administered, and appropriate dosage adjustments of valproate should be made5.

# Use in Specific Populations

### Pregnancy
Pregnancy Category (FDA): C
Teratogenic Effects: Pregnancy Category C:
- Isoniazid has been shown to have an embryocidal effect in rats and rabbits when given orally during pregnancy. Isoniazid was not teratogenic in reproduction studies in mice, rats and rabbits. There are no adequate and well-controlled studies in pregnant women. Isoniazid should be used as a treatment for active tuberculosis during pregnancy because the benefit justifies the potential risk to the fetus. The benefit of preventive therapy also should be weighed against a possible risk to the fetus. Preventive therapy generally should be started after delivery to prevent putting the fetus at risk of exposure; the low levels of isoniazid in breast milk do not threaten the neonate. Since isoniazid is known to cross the placental barrier, neonates of isoniazid treated mothers should be carefully observed for any evidence of adverse affects.
Nonteratogenic effects:
- Since isoniazid is known to cross the placental barrier, neonates of isoniazid-treated mothers should be carefully observed for any evidence of adverse effects.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
- There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Isoniazid (oral) in women who are pregnant.

### Labor and Delivery
- There is no FDA guidance on use of Isoniazid (oral) during labor and delivery.

### Nursing Mothers
- The small concentrations of isoniazid in breast milk do not produce toxicity in the nursing newborn; therefore, breast feeding should not be discouraged. However, because levels of isoniazid are so low in breast milk, they can not be relied upon for prophylaxis or therapy of nursing infants.

### Pediatric Use
- There is no FDA guidance on the use of Isoniazid (oral) with respect to pediatric patients.

### Geriatic Use
- There is no FDA guidance on the use of Isoniazid (oral) with respect to geriatric patients.

### Gender
- There is no FDA guidance on the use of Isoniazid (oral) with respect to specific gender populations.

### Race
- There is no FDA guidance on the use of Isoniazid (oral) with respect to specific racial populations.

### Renal Impairment
- There is no FDA guidance on the use of Isoniazid (oral) in patients with renal impairment.

### Hepatic Impairment
- There is no FDA guidance on the use of Isoniazid (oral) in patients with hepatic impairment.

### Females of Reproductive Potential and Males
- There is no FDA guidance on the use of Isoniazid (oral) in women of reproductive potentials and males.

### Immunocompromised Patients
- There is no FDA guidance one the use of Isoniazid (oral) in patients who are immunocompromised.

# Administration and Monitoring

### Administration
- (See also INDICATIONS AND USAGE): NOTE: For preventive therapy of tuberculous infection and treatment of tuberculosis, it is recommended that physicians be familiar with the following publications: (1) the recommendations of the Advisory Council for the Elimination of Tuberculosis, published in the MMWR: vol 42; RR-4, 1993 and (2) Treatment of Tuberculosis and Tuberculosis Infection in Adults and Children, American Journal of Respiratory and Critical Care Medicine: vol 149; 1359-1374, 1994.
- For Treatment of Tuberculosis:
- Isoniazid is used in conjunction with other effective anti-tuberculosis agents. Drug susceptibility testing should be performed on the organisms initially isolated from all patients with newly diagnosed tuberculosis. If the bacilli becomes resistant, therapy must be changed to agents to which the bacilli are susceptible.
Usual Oral Dosage (depending on the regimen used):
Adults:
- 5 mg/kg up to 300 mg daily in a single dose; or
- 15 mg/kg up to 900 mg/day, two or three times/week
Chidren:
- 10 to 15 mg/kg up to 300 mg daily in a single dose; or
- 20 to 40 mg/kg up to 900 mg/day, two or three time/week
Patients with Pulmonary Tuberculosis Without HIV Infection:
- There are 3 regimen options for the initial treatment of tuberculosis in children and adults:
- Option 1: Daily isoniazid, rifampin, and pyrazinamide for 8 weeks followed by 16 weeks of isoniazid and rifampin daily or 2 to 3 times weekly. Ethambutol or streptomycin should be added to the initial regimen until sensitivity to isoniazid and rifampin is demonstrated. The addition of a fourth drug is optional if the relative prevalence of isoniazid-resistant Mycobacterium tuberculosis isolates in the community is less than or equal to four percent.
- Option 2: Daily isoniazid, rifampin, pyrazinamide, and streptomycin or ethambutol for 2 weeks followed by twice weekly administration of the same drugs for 6 weeks, subsequently twice weekly isoniazid and rifampin for 16 weeks.
- Option 3: Three times weekly with isoniazid, rifampin, pyrazinamide, and ethambutol or streptomycin for 6 months.
- All regimens given twice weekly or 3 times weekly should be administered by directly observed therapy (see also Directly Observed Therapy (DOT)).
- The above treatment guidelines apply only when the disease is caused by organisms that are susceptible to the standard antituberculous agents. Because of the impact of resistance to isoniazid and rifampin on the response to therapy, it is essential that physicians initiating therapy for tuberculosis be familiar with the prevalence of drug resistance in their communities. It is suggested that ethambutol not be used in children whose visual acuity cannot be monitored.
Patients with Pulmonary Tuberculosis and HIV Infection:
- The response of the immunologically impaired host to treatment may not be as satisfactory as that of a person with normal host responsiveness. For this reason, therapeutic decisions for the impaired host must be individualized. Since patients co-infected with HIV may have problems with malabsorption, screening of antimycobacterial drug levels, especially in patients with advanced HIV disease, may be necessary to prevent the emergence of MDRTB.
Patients with Extra Pulmonary Tuberculosis:
- The basic principles that underlie the treatment of pulmonary tuberculosis also apply to Extra pulmonary forms of the disease. Although there have not been the same kinds of carefully conducted controlled trials of treatment of Extra pulmonary tuberculosis as for pulmonary disease, increasing clinical experience indicates that a 6 to 9 month short-course regimen is effective. Because of the insufficient data, miliary tuberculosis, bone/joint tuberculosis, and tuberculous meningitis in infants and children should receive 12 months therapy.
- Bacteriologic evaluation of Extra pulmonary tuberculosis may be limited by the relative inaccessibility of the sites of disease. Thus, response to treatment often must be judged on the basis of clinical and radiographic findings.
- The use of adjunctive therapies such as surgery and corticosteroids is more commonly required in Extra pulmonary tuberculosis than in pulmonary disease. Surgery may be necessary to obtain specimens for diagnosis and to treat such processes as constrictive pericarditis and spinal cord compression from Potts Disease. Corticosteriods have been shown to be of benefit in preventing cardiac constriction from tuberculous pericarditis and in decreasing the neurologic sequelae of all stages of tuberculosis meningitis, especially when administered early in the course of the disease.
Pregnant Women with Tuberculosis:
- The options listed above must be adjusted for the pregnant patient. Streptomycin interferes with in utero development of the ear and may cause congenital deafness. Routine use of pyrazinamide is also not recommended in pregnancy because of inadequate teratogenicity data. The initial treatment regimen should consist of isoniazid and rifampin. Ethambutol should be included unless primary isoniazid resistance is unlikely (isoniazid resistance rate documented to be less than 4%).
Treatment of Patients with Multi-Drug Resistant Tuberculosis (MDRTB):
- Multiple-drug resistant tuberculosis (i.e., resistance to at least isoniazid and rifampin) presents difficult treatment problems. Treatment must be individualized and based on susceptibility studies. In such cases, consultation with an expert in tuberculosis is recommended.
Directly Observed Therapy (DOT):
- A major cause of drug-resistant tuberculosis is patient noncompliance with treatment. The use of DOT can help assure patient compliance with drug therapy. DOT is the observation of the patient by a health care provider or other responsible person as the patient ingests anti-tuberculosis medications. DOT can be achieved with daily, twice weekly or thrice weekly regimens, and is recommended for all patients.
For Preventative Therapy of Tuberculosis:
- Before isoniazid preventive therapy is initiated, bacteriologically positive or radiographically progressive tuberculosis must be excluded. Appropriate evaluations should be performed if Extra pulmonary tuberculosis is suspected.
- Adults over 30 Kg: 300 mg per day in a single dose.
- Infants and Children: 10 mg/kg (up to 300 mg daily) in a single dose. In situations where adherence with daily preventative therapy cannot be assured, 20 to 30 mg/kg (not to exceed 900 mg) twice weekly under the direct observation of a health care worker at the time of administration8.
- Continuous administration of isoniazid for a sufficient period is an essential part of the regimen because relapse rates are higher if chemotherapy is stopped prematurely. In the treatment of tuberculosis, resistant organisms may multiply and the emergence of resistant organisms during the treatment may necessitate a change in the regimen.
- For following patient compliance: the Potts-Cozart test9, a simple colorimetric6 method of checking for isoniazid in the urine, is a useful tool for assuring patient compliance, which is essential for effective tuberculosis control. Additionally, isoniazid test strips are also available to check patient compliance.
- Concomitant administration of pyridoxine (B6) is recommended in the malnourished and in those predisposed to neuropathy (e.g., alcoholics and diabetics).

### Monitoring
- Patients given isoniazid should be carefully monitored and interviewed at monthly intervals. For persons 35 and older, in addition to monthly symptom reviews, hepatic enzymes (specifically, AST and ALT (formerly SGOT and SGPT, respectively) should be measured prior to starting isoniazid therapy and periodically throughout treatment. Isoniazid-associated hepatitis usually occurs during the first three months of treatment. Usually, enzyme levels return to normal despite continuance of drug, but in some cases progressive liver dysfunction occurs. Other factors associated with an increased risk of hepatitis include daily use of alcohol, chronic liver disease and injection drug use. A recent report suggests an increased risk of fatal hepatitis associated with isoniazid among women, particularly Black and Hispanic women. The risk may also be increased during the post partum period. More careful monitoring should be considered in these groups, possibly including more frequent laboratory monitoring. If abnormalities of liver function exceed three to five times the upper limit of normal, discontinuation of isoniazid should be strongly considered.
- Use of isoniazid should be carefully monitored in the following:
- Daily users of alcohol. Daily ingestion of alcohol may be associated with a higher incidence of + isoniazid hepatitis.
- Patients with active chronic liver disease or severe renal dysfunction.
- Age > 35.
- Concurrent use of any chronically administered medication.
- History of previous discontinuation of isoniazid.
- Existence of peripheral neuropathy or conditions predisposing to neuropathy.
- Pregnancy.
- Injection drug use.
- Women belonging to minority groups, particularly in the postpartum period.
- HIV seropositive patients.
- Carbamazepine levels should be determined prior to concurrent administration with isoniazid, signs and symptoms of carbamazepine toxicity should be monitored closely, and appropriate dosage adjustment of the anticonvulsant should be made.
- Theophylline serum levels should be monitored closely and appropriate dosage adjustments of theophylline should be made as the therapeutic range of theophylline is narrow.
- Plasma valproate concentration should be monitored when isoniazid and valproate are co-administered, and appropriate dosage adjustments of valproate should be made.
- Patients with this degree of INH intoxication are likely to have hypoventilation. The administration of sodium bicarbonate under these circumstances can cause exacerbation of hypercarbia. Ventilation must be monitored carefully, by measuring blood carbon dioxide levels and supported mechanically, if there is respiratory insufficiency.

# IV Compatibility
- There is limited information regarding IV Compatibility of Isoniazid (oral) in the drug label.

# Overdosage
Signs and Symptoms:
- Isoniazid overdosage produces signs and symptoms within 30 minutes to 3 hours after ingestion. Nausea, vomiting, dizziness, slurring of speech, blurring of vision and visual hallucinations (including bright colors and strange designs) are among the early manifestations. With marked overdosage, respiratory distress and CNS depression, progressing rapidly from stupor to profound coma, are to be expected, along with severe, intractable seizures. Severe metabolic acidosis, acetonuria and hyperglycemia are typical laboratory findings.
Treatment:
- Untreated or inadequately treated cases of gross isoniazid overdosage, 80 mg/kg to 150 mg/kg, can cause neurotoxicity6 and terminate fatally, but good response has been reported in most patients brought under adequate treatment within the first few hours after drug ingestion.
For the Asymptomatic Patient:
- Absorption of drugs from the GI tract may be decreased by giving activated charcoal. Gastric emptying should also be employed in the asymptomatic patient. Safeguard the patient"s airway when employing these procedures. Patients who acutely ingest > 80 mg/kg should be treated with intravenous pyridoxine on a gram per gram basis equal to the isoniazid dose. If an unknown amount of isoniazid is ingested, consider an initial dose of 5 grams of pyridoxine given over 30 to 60 minutes in adults or 80 mg/kg of pyridoxine in children.
For the Symptomatic Patient:
- Ensure adequate ventilation, support cardiac output, and protect the airway while treating seizures and attempting to limit absorption. If the dose of isoniazid is known, the patient should be treated initially with a slow intravenous bolus of pyridoxine, over 3 to 5 minutes, on a gram per gram basis, equal to the isoniazid dose. If the quantity of isoniazid ingestion is unknown, then consider an initial intravenous bolus of pyridoxine of 5 grams in the adult or 80 mg/kg in the child. If seizures continue, the dosage of pyridoxine may be repeated. It would be rare that more than 10 grams of pyridoxine would need to be given. The maximum safe dose for pyridoxine in isoniazid intoxication is not known. If the patient does not respond to pyridoxine, diazepam may be administered. Phenytoin should be used cautiously, because isoniazid interferes with the metabolism of phenytoin.
General:
- Obtain blood samples for immediate determination of gases, electrolytes, BUN, glucose, etc.; type and cross-match blood in preparation for possible hemodialysis.
Rapid control of metabolic acidosis:
- Patients with this degree of INH intoxication are likely to have hypoventilation. The administration of sodium bicarbonate under these circumstances can cause exacerbation of hypercarbia. Ventilation must be monitored carefully, by measuring blood carbon dioxide levels and supported mechanically, if there is respiratory insufficiency.
Dialysis:
- Both peritoneal and hemodialysis have been used in the management of isoniazid overdosage. These procedures are probably not required if control of seizures and acidosis is achieved with pyridoxine, diazepam and bicarbonate.
- Along with measures based on initial and repeated determination of blood gases and other laboratory tests as needed, utilize meticulous respiratory and other intensive care to protect against hypoxia, hypotension, aspiration, pneumonitis, etc.

# Pharmacology

## Mechanism of Action
- Isoniazid inhibits the synthesis of mycoloic acids, an essential component of the bacterial cell wall. At therapeutic levels isoniazid is bacteriocidal against actively growing intracellular and extracellular Mycobacterium tuberculosis organisms.

## Structure
- Isoniazid is an antibacterial available as 100 mg and 300 mg tablets for oral administration. Each tablet also contains as inactive ingredients: anhydrous lactose, calcium stearate, colloidal silicon dioxide, microcrystalline cellulose, and stearic acid.
- Isoniazid is chemically known as isonicotinyl hydrazine or isonicotinic acid hydrazide. It has an empirical formula of C6H7N3O and a molecular weight of 137.14. It has the following structure:
- Isoniazid is odorless, and occurs as a colorless or white crystalline powder or as white crystals. It is freely soluble in water, sparingly soluble in alcohol, and slightly soluble in chloroform and in ether. Isoniazid is slowly affected by exposure to air and light.

## Pharmacodynamics
- There is limited information regarding Pharmacodynamics of Isoniazid (oral) in the drug label.

## Pharmacokinetics
- Within 1 to 2 hours after oral administration, isoniazid produces peak blood levels which decline to 50 percent or less within 6 hours. It diffuses readily into all body fluids (cerebrospinal, pleural, and ascitic fluids), tissues, organs, and excreta (saliva, sputum, and feces). The drug also passes through the placental barrier and into milk in concentrations comparable to those in the plasma. From 50 to 70 percent of a dose of isoniazid is excreted in the urine in 24 hours.
- Isoniazid is metabolized primarily by acetylation and dehydrazination. The rate of acetylation is genetically determined. Approximately 50 percent of Blacks and Caucasians are "slow inactivators" and the rest are "rapid inactivators"; the majority of Eskimos and Orientals are rapid inactivators.
- The rate of acetylation does not significantly alter the effectiveness of isoniazid. However, slow acetylation may lead to higher blood levels of the drug and, thus, to an increase in toxic reactions.
- Pyridoxine (vitamin B6), deficiency is sometimes observed in adults with high doses of isoniazid and is considered probably due to its competition with pyridoxal phosphate for the enzyme apotryptophanase.
- Isoniazid resistant Mycobacterium tuberculosis bacilli develop rapidly when isoniazid monotherapy is administered.
- Microbiology:
- Two standardized in vitro susceptibility methods are available for testing isoniazid against Mycobacterium tuberculosis organisms. The agar proportion method (CDC or NCCLS M24-P) utilizes middlebrook 7H10 medium impregnated with isoniazid at two final concentrations, 0.2 and 1.0 mcg/mL. MIC99 values are calculated by comparing the quantity of organisms growing in the medium containing drug to the control cultures. Mycobacterial growth in the presence of drug  1% of the control indicates resistance.
- The radiometric broth method employs the BACTEC 460 machine to compare the growth index from untreated control cultures to cultures grown in the presence of 0.2 and 1.0 mcg/mL of isoniazid. Strict adherence to the manufacturer's instructions for sample processing and data interpretation is required for this assay.
- Mycobacterium tuberculosis isolates with an MIC99  0.2 mcg/mL are considered to be susceptible to isoniazid. Susceptibility test results obtained by the two different methods discussed above cannot be compared unless equivalent drug concentrations are evaluated.
- The clinical relevance of in vitro susceptibility for mycobacterium species other than M. tuberculosis using either the BACTEC or the proportion method has not been determined.

## Nonclinical Toxicology
Carcinogenesis and Mutagenesis:
- Isoniazid has been shown to induce pulmonary tumors in a number of strains of mice. Isoniazid has not been shown to be carcinogenic in humans. (Note: a diagnosis of mesothelioma in a child with prenatal exposure to isoniazid and no other apparent risk factors has been reported). Isoniazid has been found to be weakly mutagenic in strains TA 100 and TA 1535 of Salmonella typhimurium (Ames assay) without metabolic activation.

# Clinical Studies
- There is limited information regarding Clinical Studies of Isoniazid (oral) in the drug label.

# How Supplied
- Isoniazid Tablets, USP 300 mg: White, Round Tablets; Debossed "West-ward 261" on one side and Scored on the other side.
- Bottle of 30 - 68788-9116-3
- Bottle of 60 - 68788-9116-6
- Bottle of 90 - 68788-9116-9
- Bottle of 100 - 68788-9116-1

## Storage
- Store at 20 to 25C (68 to 77F) . Protect from light and moisture.
- Dispense in a tight, light-resistant container as defined in the USP using a child-resistant closure.

# Images

## Drug Images

## Package and Label Display Panel

# Patient Counseling Information
- There is limited information regarding Patient Counseling Information of Isoniazid (oral) in the drug label.

# Precautions with Alcohol
- Alcohol-Isoniazid (oral) interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.

# Brand Names
- Nydrazid

# Look-Alike Drug Names
- A  B

# Drug Shortage Status

# Price