Niazitol

Ethambutol:

• Description
• Clinical pharmacology
• Animal pharmacology
• Indications and usage
• Contraindications
• Warnings
• Precautions
• Adverse reactions
• Dosage and administration
• How supplied
• Myambutol (ethambutol hydrochloride) tablet, film coated
• Niazitol (Ethambutol) reviews

DESCRIPTION

Niazitol (Ethambutol) Niazitol (Ethambutol) hydrochloride is an oral chemotherapeutic agent which is specifically effective against actively growing microorganisms of the genus Mycobacterium, including M. tuberculosis. The structural formula is:

Niazitol (Ethambutol) 100 and 400 mg tablets contain the following inactive ingredients: Gelatin, Hydroxypropyl Methylcellulose, Magnesium Stearate, Sodium Lauryl Sulfate, Sorbitol, Stearic Acid, Sucrose, Titanium Dioxide and other ingredients.

Structural Formula

CLINICAL PHARMACOLOGY

Niazitol (Ethambutol), following a single oral dose of 25 mg/kg of body weight, attains a peak of 2 to 5 mg/mL in serum 2 to 4 hours after administration. When the drug is administered daily for longer periods of time at this dose, serum levels are similar. The serum level of Niazitol (Ethambutol) falls to undetectable levels by 24 hours after the last dose except in some patients with abnormal renal function. The intracellular concentrations of erythrocytes reach peak values approximately twice those of plasma and maintain this ratio throughout the 24 hours.

During the 24-hour period following oral administration of Niazitol (Ethambutol) approximately 50 percent of the initial dose is excreted unchanged in the urine, while an additional 8 to 15 percent appears in the form of metabolites. The main path of metabolism appears to be an initial oxidation of the alcohol to an aldehydic intermediate, followed by conversion to a dicarboxylic acid. From 20 to 22 percent of the initial dose is excreted in the feces as unchanged drug. No drug accumulation has been observed with consecutive single daily doses of 25 mg/kg in patients with normal kidney function, although marked accumulation has been demonstrated in patients with renal insufficiency.

Niazitol (Ethambutol) diffuses into actively growing mycobacterium cells such as tubercle bacilli. Niazitol (Ethambutol) appears to inhibit the synthesis of one or more metabolites, thus causing impairment of cell metabolism, arrest of multiplication, and cell death. No cross resistance with other available antimycobacterial agents has been demonstrated.

Niazitol (Ethambutol) has been shown to be effective against strains of Mycobacterium tuberculosis but does not seem to be active against fungi, viruses, or other bacteria. Mycobacterium tuberculosis strains previously unexposed to Niazitol (Ethambutol) have been uniformly sensitive to concentrations of 8 or less mcg/mL, depending on the nature of the culture media. When Niazitol (Ethambutol) has been used alone for treatment of tuberculosis, tubercle bacilli from these patients have developed resistance to Niazitol (Ethambutol) (ethambutol hydrochloride) by in-vitro susceptibility tests; the development of resistance has been unpredictable and appears to occur in a step-like manner. No cross resistance between Niazitol (Ethambutol) and other antituberculous drugs has been reported. Niazitol (Ethambutol) has reduced the incidence of the emergence of mycobacterial resistance to isoniazid when both drugs have been used concurrently.

An agar diffusion microbiologic assay, based upon inhibition of Mycobacterium smegmatis (ATCC 607) may be used to determine concentrations of Niazitol (Ethambutol) in serum and urine.

ANIMAL PHARMACOLOGY

Toxicological studies in dogs on high prolonged doses produced evidence of myocardial damage and failure, and depigmentation of the tapetum lucidum of the eyes, the significance of which is not known. Degenerative changes in the central nervous system, apparently not dose-related, have also been noted in dogs receiving Niazitol (Ethambutol) hydrochloride over a prolonged period.

In the rhesus monkey, neurological signs appeared after treatment with high doses given daily over a period of several months. These were correlated with specific serum levels of Niazitol (Ethambutol) and with definite neuroanatomical changes in the central nervous system. Focal interstitial carditis was also noted in monkeys which received Niazitol (Ethambutol) hydrochloride in high doses for a prolonged period.

INDICATIONS AND USAGE

Niazitol (Ethambutol) is indicated for the treatment of pulmonary tuberculosis. It should not be used as the sole antituberculous drug, but should be used in conjunction with at least one other antituberculous drug. Selection of the companion drug should be based on clinical experience, considerations of comparative safety, and appropriate in-vitro susceptibility studies. In patients who have not received previous antituberculous therapy, ie, initial treatment, the most frequently used regimens have been the following:

Niazitol (Ethambutol) plus isoniazid

Niazitol (Ethambutol) plus isoniazid plus streptomycin.

In patients who have received previous antituberculous therapy, mycobacterial resistance to other drugs used in initial therapy is frequent. Consequently, in such retreatment patients, Niazitol (Ethambutol) should be combined with at least one of the second line drugs not previously administered to the patient and to which bacterial susceptibility has been indicated by appropriate in-vitro studies. Antituberculous drugs used with Niazitol (Ethambutol) have included cycloserine, ethionamide, pyrazinamide, viomycin and other drugs. Isoniazid, aminosalicylic acid, and streptomycin have also been used in multiple drug regimens. Alternating drug regimens have also been utilized.

CONTRAINDICATIONS

Niazitol (Ethambutol) is contraindicated in patients who are known to be hypersensitive to this drug. It is also contraindicated in patients with known optic neuritis unless clinical judgment determines that it may be used. Niazitol (Ethambutol) is contraindicated in patients who are unable to appreciate and report visual side effects or changes in vision (e.g., young children, unconscious patients).

WARNINGS

Niazitol (Ethambutol) may produce decreases in visual acuity which appear to be due to optic neuritis. This effect may be related to dose and duration of treatment. This effect is generally reversible when administration of the drug is discontinued promptly. However, irreversible blindness has been reported. (See PRECAUTIONS and ADVERSE REACTIONS ).

Liver toxicities including fatalities have been reported. Baseline and periodic assessment of hepatic function should be performed.

PRECAUTIONS

Niazitol Niazitol (Ethambutol) hydrochloride is not recommended for use in pediatric patients under thirteen years of age since safe conditions for use have not been established.

Patients with decreased renal function need the dosage reduced as determined by serum levels of Niazitol (Ethambutol), since the main path of excretion of this drug is by the kidneys.

Because this drug may have adverse effects on vision, physical examination should include ophthalmoscopy, finger perimetry and testing of color discrimination. In patients with visual defects such as cataracts, recurrent inflammatory conditions of the eye, optic neuritis, and diabetic retinopathy, the evaluation of changes in visual acuity is more difficult, and care should be taken to be sure the variations in vision are not due to the underlying disease conditions. In such patients, consideration should be given to relationship between benefits expected and possible visual deterioration since evaluation of visual changes is difficult. (For recommended procedures, see next paragraphs under ADVERSE REACTIONS ).

As with any potent drug, baseline and periodic assessment of organ system functions, including renal, hepatic, and hematopoietic, should be performed.

Drug Interactions:

The results of a study of coadministration of Niazitol (Ethambutol) (50mg/kg) with an aluminum hydroxide containing antacid to 13 patients with tuberculosis showed a reduction of mean serum concentrations and urinary excretion of Niazitol (Ethambutol) of approximately 20% and 13%, respectively, suggesting that the oral absorption of Niazitol (Ethambutol) may be reduced by these antacid products. It is recommended to avoid concurrent administration of Niazitol (Ethambutol) with aluminum hydroxide containing antacids for at least 4 hours following Niazitol (Ethambutol) administration.

Pregnancy:

Teratogenic Effects: Pregnancy Category C.

There are no adequate and well-controlled studies in pregnant women. There are reports of ophthalmic abnormalities occurring in

infants born to women on antituberculous therapy that included Niazitol. Niazitol (Ethambutol) should be used during pregnancy

only if the benefit justifies the potential risk to the fetus.

Niazitol (Ethambutol) has been shown to be teratogenic in pregnant mice and rabbits when given in high doses. When pregnant mice or

rabbits were treated with high doses of Niazitol (Ethambutol) hydrochloride, fetal mortality was slightly but not significantly (P>0.05) increased.

Female rats treated with Niazitol (Ethambutol) hydrochloride displayed slight but insignificant (P>0.05) decreases in fertility and litter size.

In fetuses born of mice treated with high doses of Niazitol (Ethambutol) during pregnancy, a low incidence of cleft palate, exencephaly

and abnormality of the vertebral column were observed. Minor abnormalities of the cervical vertebra were seen in the newborn of

rats treated with high doses of Niazitol (Ethambutol) hydrochloride during pregnancy. Rabbits receiving high doses of Niazitol (Ethambutol) during

pregnancy gave birth to two fetuses with monophthalmia, one with a shortened right forearm accompanied by bilateral wrist-joint

contracture and one with hare lip and cleft palate.

Nursing Mothers:

Niazitol (Ethambutol) is excreted into breast milk. The use of Niazitol (Ethambutol) should be considered only if the expected benefit to the mother outweighs the potential risk to the infant.

Pediatric Use:

Niazitol (ethambutol hydrochloride) is not recommended for use in pediatric patients under thirteen years of age since safe conditions for use have not been established.

Geriatric Use:

There are limited data on the use of ethambutol in the elderly. One study of 101 patients, 65 years and older, on multiple drug antituberculosis regimens included 94 patients on Niazitol (Ethambutol). No differences in safety or tolerability were observed in these patients compared with that reported in adults in general. Other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

ADVERSE REACTIONS

Niazitol (Ethambutol) may produce decreases in visual acuity, including irreversible blindness, which appear to be due to optic neuritis. Optic neuropathy including optic neuritis or retrobulbar neuritis occurring in association with Niazitol (Ethambutol) therapy may be characterized by one or more of the following events: decreased visual acuity, scotoma, color blindness, and/or visual defect. These events have also been reported in the absence of a diagnosis of optic or retrobulbar neuritis.

Patients should be advised to report promptly to their physician any change of visual acuity.

The change in visual acuity may be unilateral or bilateral and hence each eye must be tested separately and both eyes tested together. Testing of visual acuity should be performed before beginning Niazitol (Ethambutol) therapy and periodically during drug administration, except that it should be done monthly when a patient is on a dosage of more than 15 mg per kilogram per day. Snellen eye charts are recommended for testing of visual acuity. Studies have shown that there are definite fluctuations of one or two lines of the Snellen chart in the visual acuity of many tuberculous patients not receiving Niazitol (Ethambutol).

The following table may be useful in interpreting possible changes in visual acuity attributable to Niazitol (Ethambutol).

In general, changes in visual acuity less than those indicated under “Significant Number of Lines” and “Decrease Number of Points” may be due to chance variation, limitations of the testing method, or physiologic variability. Conversely, changes in visual acuity equaling or exceeding those under “Significant Number of Lines” and “Decrease Number of Points” indicate need for retesting and careful evaluation of the patient's visual status. If careful evaluation confirms the magnitude of visual change and fails to reveal another cause, Niazitol (Ethambutol) should be discontinued and the patient reevaluated at frequent intervals. Progressive decreases in visual acuity during therapy must be considered to be due to Niazitol (Ethambutol).

If corrective glasses are used prior to treatment, these must be worn during visual acuity testing. During 1 to 2 years of therapy, a refractive error may develop which must be corrected in order to obtain accurate test results. Testing the visual acuity through a pinhole eliminates refractive error. Patients developing visual abnormality during Niazitol (Ethambutol) treatment may show subjective visual symptoms before, or simultaneously with, the demonstration of decreases in visual acuity, and all patients receiving Niazitol (Ethambutol) should be questioned periodically about blurred vision and other subjective eye symptoms.

Recovery of visual acuity generally occurs over a period of weeks to months after the drug has been discontinued. Some patients have received Niazitol (Ethambutol) (ethambutol hydrochloride) again after such recovery without recurrence of loss of visual acuity.

Other adverse reactions reported include: hypersensitivity, anaphylactic/anaphylactoid reaction, dermatitis, erythema multiforme, pruritus, and joint pain; anorexia, nausea, vomiting, gastrointestinal upset, and abdominal pain; fever, malaise, headache, and dizziness; mental confusion, disorientation, and possible hallucinations; thrombocytopenia, leucopenia, and neutropenia. Numbness and tingling of the extremities due to peripheral neuritis have been reported.

Elevated serum uric acid levels occur and precipitation of acute gout has been reported. Pulmonary infiltrates, with or without eosinophilia, also have been reported during Niazitol (Ethambutol) therapy. Liver toxicities, including fatalities, have been reported (See WARNINGS. ) Since Niazitol (Ethambutol) is recommended for therapy in conjunction with one or more other antituberculous drugs, these changes may be related to the concurrent therapy. Hypersensitivity syndrome consisting ot cutaneous reaction (such as rash or exfoliative dermatitis), eosinophilia, and one or more of the following: hepatitis, pneumonitis, nephritis, myocarditis, pericarditis. Fever and lymphadenopathy may be present.

DOSAGE AND ADMINISTRATION

Niazitol should not be used alone, in initial treatment or in retreatment. Niazitol (Ethambutol) should be administered on a once every 24-hour basis only. Absorption is not significantly altered by administration with food. Therapy, in general, should be continued until bacteriological conversion has become permanent and maximal clinical improvement has occurred.

Niazitol (Ethambutol) is not recommended for use in pediatric patients under thirteen years of age since safe conditions for use have not been established.

Initial Treatment:

Initial Treatment:

In patients who have not received previous antituberculous therapy, administer Niazitol (Ethambutol) 15 mg/kg (7 mg/ lb) of body weight, as a single oral dose once every 24 hours. In the more recent studies, isoniazid has been administered concurrently in a single, daily, oral dose.

Retreatment:

Retreatment:

In patients who have received previous antituberculous therapy, administer Niazitol (Ethambutol) 25 mg/kg (11 mg/lb) of body weight, as a single oral dose once every 24 hours. Concurrently administer at least one other antituberculous drug to which the organisms have been demonstrated to be susceptible by appropriate in-vitro tests. Suitable drugs usually consist of those not previously used in the treatment of the patient. After 60 days of Niazitol (Ethambutol) administration, decrease the dose to 15 mg/kg (7mg/ lb) of body weight, and administer as a single oral dose once every 24 hours.

During the period when a patient is on a daily dose of 25 mg/kg, monthly eye examinations are advised.

See Table for easy selection of proper weight-dose tablet(s).

HOW SUPPLIED

Product: 50090-0417

NDC: 50090-0417-2 98 TABLET, FILM COATED in a BOTTLE

Niazitol (ETHAMBUTOL HYDROCHLORIDE) TABLET, FILM COATED

Isoniazid:

• Indications and usage
• Contraindications
• Warnings
• Precautions
• Adverse reactions
• Overdosage
• Dosage and administration
• How supplied
• References
• Niazitol (Isoniazid) reviews

INDICATIONS AND USAGE

Niazitol (Isoniazid) is recommended for all forms of tuberculosis in which organisms are susceptible. However, active tuberculosis must be treated with multiple concomitant antituberculosis medications to prevent the emergence of drug resistance. Single-drug treatment of active tuberculosis with Niazitol (Isoniazid), or any other medication, is inadequate therapy.

Niazitol (Isoniazid) is recommended as preventive therapy for the following groups, regardless of age. (Note: the criterion for a positive reaction to a skin test (in millimeters of induration) for each group is given in parenthesis):

• Persons with human immunodeficiency virus (HIV) infection (≥ 5 mm) and persons with risk factors for HIV infection whose HIV infection status is unknown but who are suspected of having HIV infection.
  

  Preventive therapy may be considered for HIV infected persons who are tuberculin-negative but belong to groups in which the prevalence of tuberculosis infection is high. Candidates for preventive therapy who have HIV infection should have a minimum of 12 months of therapy.

• Close contacts of persons with newly diagnosed infectious tuberculosis (≥ 5 mm). In addition, tuberculin-negative (< 5 mm) children and adolescents who have been close contacts of infectious persons within the past 3 months are candidates for preventive therapy until a repeat tuberculin skin test is done 12 weeks after contact with the infectious source. If the repeat skin test is positive (> 5 mm), therapy should be continued.
• Recent converters, as indicated by a tuberculin skin test (≥ 10 mm increase within a 2-year period for those < 35 years old; ≥ 15 mm increase for those ≥ 35 years of age). All infants and children younger than 4 years of age with a > 10 mm skin test are included in this category.
• Persons with abnormal chest radiographs that show fibrotic lesions likely to represent old healed tuberculosis (≥ 5 mm). Candidates for preventive therapy who have fibrotic pulmonary lesions consistent with healed tuberculosis or who have pulmonary silicosis should have 12 months of Niazitol (Isoniazid) or 4 months of Niazitol (Isoniazid) and rifampin, concomitantly.
• Intravenous drug users known to be HIV-seronegative (> 10 mm).
• Persons with the following medical conditions that have been reported to increase the risk of tuberculosis (≥ 10 mm): silicosis; diabetes mellitus; prolonged therapy with adrenocorticosteroids; immunosuppressive therapy; some hematologic and reticuloendothelial diseases, such as leukemia or Hodgkin's disease; end-stage renal disease; clinical situations associated with substantial rapid weight loss or chronic undernutrition (including: intestinal bypass surgery for obesity, the postgastrectomy state (with or without weight loss), chronic peptic ulcer disease, chronic malabsorption syndromes, and carcinomas of the oropharynx and upper gastrointestinal tract that prevent adequate nutritional intake). Candidates for preventive therapy who have fibrotic pulmonary lesions consistent with healed tuberculosis or who have pulmonary silicosis should have 12 months of Niazitol (Isoniazid) or 4 months of Niazitol (Isoniazid) and rifampin, concomitantly.

Additionally, in the absence of any of the above risk factors, persons under the age of 35 with a tuberculin skin test reaction of 10 mm or more are also appropriate candidates for preventive therapy if they are a member of any of the following high-incidence groups:

• Foreign-born persons from high-prevalence countries who never received BCG vaccine.
• Medically underserved low-income populations, including high-risk racial or ethnic minority populations, especially blacks, Hispanics, and Native Americans.
• Residents of facilities for long-term care (e.g., correctional institutions, nursing homes, and mental institutions).

Children who are less than 4 years old are candidates for Niazitol (Isoniazid) preventive therapy if they have >10 mm induration from a PPD Mantoux tuberculin skin test.

Finally, persons under the age of 35 who a) have none of the above risk factors (1-6); b) belong to none of the high-incidence groups; and c) have a tuberculin skin test reaction of 15 mm or more, are appropriate candidates for preventive therapy.

The risk of hepatitis must be weighed against the risk of tuberculosis in positive tuberculin reactors over the age of 35. However, the use of Niazitol (Isoniazid) is recommended for those with the additional risk factors listed above (1-6) and on an individual basis in situations where there is likelihood of serious consequences to contacts who may become infected.

CONTRAINDICATIONS

Niazitol (Isoniazid) is contraindicated in patients who develop severe hypersensitivity reactions, including drug-induced hepatitis; previous isoniazid-associated hepatic injury; severe adverse reactions to Niazitol (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 Niazitol 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 Niazitol (Isoniazid) should be carefully monitored in the following:

• Daily users of alcohol. Daily ingestion of alcohol may be associated with a higher incidence of + Niazitol (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 Niazitol (Isoniazid).
• Existence of peripheral neuropathy or conditions predisposing to neuropathy.
• Pregnancy.
• Injection drug use.
• Women belonging to minority groups, particularly in the post-partum period.
• HIV seropositive patients.

Laboratory Tests

Because there is a higher frequency of Niazitol (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, Niazitol (Isoniazid) should be temporarily discontinued and consideration given to restarting therapy.

Drug Interactions

Food

Niazitol should not be administered with food. Studies have shown that the bioavailability of Niazitol (Isoniazid) is reduced significantly when administered with food. Tyramine- and histamine-containing foods should be avoided in patients receiving Niazitol (Isoniazid). Because Niazitol (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 Niazitol (Isoniazid). It is believed that the toxicity may have resulted from a previously unrecognized interaction between Niazitol (Isoniazid) and acetaminophen and a molecular basis for this interaction has been proposed. However, current evidence suggests that Niazitol (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 Niazitol (Isoniazid) resulted in induction of P-450IIE1 in the patients 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 Niazitol (Isoniazid) potentiates acetaminophen hepatotoxicity in rats^1,2.

Carbamazepine

Niazitol is known to slow the metabolism of carbamazepine and increase its serum levels. Carbamazepine levels should be determined prior to concurrent administration with Niazitol (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 Niazitol (Isoniazid) may exist. When ketoconazole is given in combination with Niazitol (Isoniazid) and rifampin the AUC of ketoconazole is decreased by as much as 88% after 5 months of concurrent Niazitol (Isoniazid) and rifampin therapy⁴.

Phenytoin

Niazitol may increase serum levels of phenytoin. To avoid phenytoin intoxication, appropriate adjustment of the anticonvulsant should be made^5,6.

Theophylline

A recent study has shown that concomitant administration of Niazitol (Isoniazid) and theophylline may cause elevated plasma levels of theophylline, and in some instances a slight decrease in the elimination of Niazitol (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 Niazitol. Plasma valproate concentration should be monitored when Niazitol (Isoniazid) and valproate are co-administered, and appropriate dosage adjustments of valproate should be made⁸.

Carcinogenesis and Mutagenesis:

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

Pregnancy

Teratogenic effects: Pregnancy Category C

Niazitol has been shown to have an embryocidal effect in rats and rabbits when given orally during pregnancy. Niazitol (Isoniazid) was not teratogenic in reproduction studies in mice, rats and rabbits. There are no adequate and well-controlled studies in pregnant women. Niazitol (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 Niazitol (Isoniazid) in breast milk do not threaten the neonate. Since Niazitol (Isoniazid) is known to cross the placental barrier, neonates of Niazitol (Isoniazid) treated mothers should be carefully observed for any evidence of adverse affects.

Nonteratogenic effects

Since Niazitol (Isoniazid) is known to cross the placental barrier, neonates of isoniazid-treated mothers should be carefully observed for any evidence of adverse effects.

Nursing Mothers

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

ADVERSE REACTIONS

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 Niazitol (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 Niazitol (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, and the FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

OVERDOSAGE

Signs and Symptoms

Niazitol 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 Niazitol (Isoniazid) overdosage, 80 mg/kg - 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 Niazitol dose. If an unknown amount of Niazitol (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 Niazitol (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 Niazitol (Isoniazid) dose. If the quantity of Niazitol (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 Niazitol (Isoniazid) intoxication is not known. If the patient does not respond to pyridoxine, diazepam may be administered. Phenytoin should be used cautiously, because Niazitol (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 Niazitol (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.

DOSAGE AND ADMINISTRATION

: 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 - Niazitol (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 become 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

• Children: 10-15 mg/kg up to 300 mg daily in a single dose; or
  

  20-40 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 Niazitol (Isoniazid), rifampin, and pyrazinamide for 8 weeks followed by 16 weeks of Niazitol (Isoniazid) and rifampin daily or 2-3 times weekly. Ethambutol or streptomycin should be added to the initial regimen until sensitivity to Niazitol (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 Niazitol (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 Niazitol (Isoniazid) and rifampin for 16 weeks.

Option 3: Three times weekly with Niazitol (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.

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 Niazitol (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 Pott's 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 Niazitol and rifampin. Ethambutol should be included unless primary Niazitol (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 Niazitol (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

A major cause of drug-resistant tuberculosis is patient non-compliance 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 Niazitol (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, 20-30 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 Niazitol (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 Niazitol (Isoniazid) in the urine, is a useful tool for assuring patient compliance, which is essential for effective tuberculosis control. Additionally, Niazitol (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).

HOW SUPPLIED

Niazitol (Isoniazid) Tablets, USP 100 mg: White, Round Tablets; Debossed "West-ward" on one side and "260" on the Scored side.

• Bottles of 100 tablets
• Bottles of 1000 tablets
• Unit Dose Boxes of 100 tablets

Niazitol (Isoniazid) Tablets, USP 300 mg: White, Round Tablets; Debossed "West-ward 261" on one side and Scored on the other side.

• Bottles of 30 tablets
• Bottles of 100 tablets
• Bottles of 1000 tablets
• Unit Dose Boxes of 100 tablets

Store at 20-25°C (68-77°F). Protect from light and moisture.

Dispense in a tight, light-resistant container as defined in the USP using a child-resistant closure.

References

• Murphy, R., et al: Annuals of Internal Medicine; 1990: November 15; volume 113:799-800.
• Burke, R.F., et al: Res Commun Chem Pathol Pharmacol. 1990;J uly; vol. 69; 115-118.
• Fleenor, M.F., et al: Chest (United States) Letter; 1991: June; 99(6): 1554.
• Baciewicz, A.M. and Baciewicz,Jr. F.A.,: Arch Int Med 1993, September; volume 153;1970-1971.
• Jonville, A.P., et al: European Journal of Clinical Pharmacol (Germany), 1991: 40(2) p198.
• American Thoracic Society/Centers for Disease Control: Treatment of Tuberculosis and Tuberculosis Infection in
  

  Adults and Children. Amer. J. Respir Crit Care Med.1994; 149: p 1359-1374.

• Hoglund P.,et al: European Journal of Respir Dis (Denmark) 1987: February; 70(2) p110-116.
• Committee on Infectious Diseases American Academy of Pediatrics: 1994, Red Book: Report of the
  

  Committee on Infectious Diseases; 23^rd edition; p487.

• Schraufnagel, DE; Testing for Niazitol (Isoniazid); Chest (United States) 1990, August: 98(2) p314-316.

Manufactured by:

West-ward Pharmaceutical Corp.

Eatontown, NJ 07724

Revised February 2011

Niazitol (Isoniazid) 300mg Tablet

Structural Formula