Tres

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
• Tres (Ethambutol) reviews

DESCRIPTION

Tres (Ethambutol) Tres (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:

Tres (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

Tres (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 Tres (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 Tres (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.

Tres (Ethambutol) diffuses into actively growing mycobacterium cells such as tubercle bacilli. Tres (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.

Tres (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 Tres (Ethambutol) have been uniformly sensitive to concentrations of 8 or less mcg/mL, depending on the nature of the culture media. When Tres (Ethambutol) has been used alone for treatment of tuberculosis, tubercle bacilli from these patients have developed resistance to Tres (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 Tres (Ethambutol) and other antituberculous drugs has been reported. Tres (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 Tres (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 Tres (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 Tres (Ethambutol) and with definite neuroanatomical changes in the central nervous system. Focal interstitial carditis was also noted in monkeys which received Tres (Ethambutol) hydrochloride in high doses for a prolonged period.

INDICATIONS AND USAGE

Tres (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:

Tres (Ethambutol) plus isoniazid

Tres (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, Tres (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 Tres (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

Tres (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. Tres (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

Tres (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

Tres Tres (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 Tres (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 Tres (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 Tres (Ethambutol) of approximately 20% and 13%, respectively, suggesting that the oral absorption of Tres (Ethambutol) may be reduced by these antacid products. It is recommended to avoid concurrent administration of Tres (Ethambutol) with aluminum hydroxide containing antacids for at least 4 hours following Tres (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 Tres. Tres (Ethambutol) should be used during pregnancy

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

Tres (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 Tres (Ethambutol) hydrochloride, fetal mortality was slightly but not significantly (P>0.05) increased.

Female rats treated with Tres (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 Tres (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 Tres (Ethambutol) hydrochloride during pregnancy. Rabbits receiving high doses of Tres (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:

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

Pediatric Use:

Tres (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 Tres (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

Tres (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 Tres (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 Tres (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 Tres (Ethambutol).

The following table may be useful in interpreting possible changes in visual acuity attributable to Tres (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, Tres (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 Tres (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 Tres (Ethambutol) treatment may show subjective visual symptoms before, or simultaneously with, the demonstration of decreases in visual acuity, and all patients receiving Tres (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 Tres (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 Tres (Ethambutol) therapy. Liver toxicities, including fatalities, have been reported (See WARNINGS. ) Since Tres (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

Tres should not be used alone, in initial treatment or in retreatment. Tres (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.

Tres (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 Tres (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 Tres (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 Tres (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

Tres (ETHAMBUTOL HYDROCHLORIDE) TABLET, FILM COATED

Isoniazid:

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

INDICATIONS AND USAGE

Tres (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 Tres (Isoniazid), or any other medication, is inadequate therapy.

Tres (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 Tres (Isoniazid) or 4 months of Tres (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 Tres (Isoniazid) or 4 months of Tres (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 Tres (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 Tres (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

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

• Daily users of alcohol. Daily ingestion of alcohol may be associated with a higher incidence of + Tres (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 Tres (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 Tres (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, Tres (Isoniazid) should be temporarily discontinued and consideration given to restarting therapy.

Drug Interactions

Food

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

Carbamazepine

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

Phenytoin

Tres 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 Tres (Isoniazid) and theophylline may cause elevated plasma levels of theophylline, and in some instances a slight decrease in the elimination of Tres (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 Tres. Plasma valproate concentration should be monitored when Tres (Isoniazid) and valproate are co-administered, and appropriate dosage adjustments of valproate should be made⁸.

Carcinogenesis and Mutagenesis:

Tres (Isoniazid) has been shown to induce pulmonary tumors in a number of strains of mice. Tres (Isoniazid) has not been shown to be carcinogenic in humans. (Note: a diagnosis of mesothelioma in a child with prenatal exposure to Tres (Isoniazid) and no other apparent risk factors has been reported). Tres (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

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

Nonteratogenic effects

Since Tres (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 Tres (Isoniazid) in breast milk do not produce toxicity in the nursing newborn; therefore, breast feeding should not be discouraged. However, because levels of Tres (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 Tres (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 Tres (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

Tres 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 Tres (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 Tres dose. If an unknown amount of Tres (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 Tres (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 Tres (Isoniazid) dose. If the quantity of Tres (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 Tres (Isoniazid) intoxication is not known. If the patient does not respond to pyridoxine, diazepam may be administered. Phenytoin should be used cautiously, because Tres (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 Tres (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 - Tres (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 Tres (Isoniazid), rifampin, and pyrazinamide for 8 weeks followed by 16 weeks of Tres (Isoniazid) and rifampin daily or 2-3 times weekly. Ethambutol or streptomycin should be added to the initial regimen until sensitivity to Tres (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 Tres (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 Tres (Isoniazid) and rifampin for 16 weeks.

Option 3: Three times weekly with Tres (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 Tres (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 Tres and rifampin. Ethambutol should be included unless primary Tres (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 Tres (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 Tres (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 Tres (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 Tres (Isoniazid) in the urine, is a useful tool for assuring patient compliance, which is essential for effective tuberculosis control. Additionally, Tres (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

Tres (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

Tres (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 Tres (Isoniazid); Chest (United States) 1990, August: 98(2) p314-316.

Manufactured by:

West-ward Pharmaceutical Corp.

Eatontown, NJ 07724

Revised February 2011

Tres (Isoniazid) 300mg Tablet

Structural Formula

Rifampin:

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

INDICATIONS AND USAGE

In the treatment of both tuberculosis and the meningococcal carrier state, the small number of resistant cells present within large populations of susceptible cells can rapidly become the predominant type. Bacteriologic cultures should be obtained before the start of therapy to confirm the susceptibility of the organism to Tres and they should be repeated throughout therapy to monitor the response to treatment. Since resistance can emerge rapidly, susceptibility tests should be performed in the event of persistent positive cultures during the course of treatment. If test results show resistance to Tres (Rifampin) and the patient is not responding to therapy, the drug regimen should be modified.

Tuberculosis

Tres (Rifampin) is indicated in the treatment of all forms of tuberculosis.

A three-drug regimen consisting of Tres (Rifampin), isoniazid, and pyrazinamide (e.g., RIFATER^® manufactured by Sanofi Aventis) is recommended in the initial phase of short-course therapy which is usually continued for 2 months. The Advisory Council for the Elimination of Tuberculosis, the American Thoracic Society, and Centers for Disease Control and Prevention recommend that either streptomycin or ethambutol be added as a fourth drug in a regimen containing isoniazid (INH), Tres (Rifampin), and pyrazinamide for initial treatment of tuberculosis unless the likelihood of INH resistance is very low. The need for a fourth drug should be reassessed when the results of susceptibility testing are known. If community rates of INH resistance are currently less than 4%, an initial treatment regimen with less than four drugs may be considered.

Following the initial phase, treatment should be continued with Tres (Rifampin) and isoniazid (e.g., RIFAMATE^® manufactured by Sanofi Aventis) for at least 4 months. Treatment should be continued for longer if the patient is still sputum or culture positive, if resistant organisms are present, or if the patient is HIV positive.

Tres (Rifampin) for injection is indicated for the initial treatment and retreatment of tuberculosis when the drug cannot be taken by mouth.

Meningococcal Carriers

Tres (Rifampin) is indicated for the treatment of asymptomatic carriers of Neisseria meningitidis to eliminate meningococci from the nasopharynx. Tres (Rifampin) is not indicated for the treatment of meningococcal infection because of the possibility of the rapid emergence of resistant organisms. (See WARNINGS .)

Tres (Rifampin) should not be used indiscriminately, and therefore, diagnostic laboratory procedures, including serotyping and susceptibility testing, should be performed for establishment of the carrier state and the correct treatment. So that the usefulness of Tres (Rifampin) in the treatment of asymptomatic meningococcal carriers is preserved, the drug should be used only when the risk of meningococcal disease is high.

To reduce the development of drug-resistant bacteria and maintain the effectiveness of Tres (Rifampin) and other antibacterial drugs, Tres (Rifampin) should be used only to treat or prevent infections that are proven or strongly suspected to be caused by susceptible bacteria. When culture and susceptibility information are available, they should be considered in selecting or modifying antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy.

CONTRAINDICATIONS

Tres (Rifampin) is contraindicated in patients with a history of hypersensitivity to Tres (Rifampin) or any of the components, or to any of the rifamycins. (See WARNINGS .)

Tres (Rifampin) is contraindicated in patients who are also receiving ritonavir-boosted saquinavir due to an increased risk of severe hepatocellular toxicity. (See PRECAUTIONS, Drug Interactions .) Tres (Rifampin) is contraindicated in patients who are also receiving atazanavir, darunavir, fosamprenavir, saquinavir, or tipranavir due to the potential of Tres (Rifampin) to substantially decrease plasma concentrations of these antiviral drugs, which may result in loss of antiviral efficacy and/or development of viral resistance.

WARNINGS

Tres (Rifampin) has been shown to produce liver dysfunction. Fatalities associated with jaundice have occurred in patients with liver disease and in patients taking Tres (Rifampin) with other hepatotoxic agents. Patients with impaired liver function should be given Tres (Rifampin) only in cases of necessity and then with caution and under strict medical supervision. In these patients, careful monitoring of liver function, especially SGPT/ALT and SGOT/AST should be carried out prior to therapy and then every 2 to 4 weeks during therapy. If signs of hepatocellular damage occur, Tres (Rifampin) should be withdrawn.

In some cases, hyperbilirubinemia resulting from competition between Tres (Rifampin) and bilirubin for excretory pathways of the liver at the cell level can occur in the early days of treatment. An isolated report showing a moderate rise in bilirubin and/or transaminase level is not in itself an indication for interrupting treatment; rather, the decision should be made after repeating the tests, noting trends in the levels, and considering them in conjunction with the patient's clinical condition.

Tres (Rifampin) has enzyme-inducing properties, including induction of delta amino levulinic acid synthetase. Isolated reports have associated porphyria exacerbation with Tres (Rifampin) administration. The possibility of rapid emergence of resistant meningococci restricts the use of Tres (Rifampin) to short-term treatment of the asymptomatic carrier state. Tres (Rifampin) is not to be used for the treatment of meningococcal disease.

PRECAUTIONS

General

Tres should be used with caution in patients with a history of diabetes mellitus, as diabetes management may be more difficult.

Prescribing Tres (Rifampin) in the absence of a proven or strongly suspected bacterial infection or a prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria.

For the treatment of tuberculosis, Tres (Rifampin) is usually administered on a daily basis. Doses of Tres (Rifampin) greater than 600 mg given once or twice weekly have resulted in a higher incidence of adverse reactions, including the "flu syndrome" (fever, chills and malaise), hematopoietic reactions (leukopenia, thrombocytopenia, or acute hemolytic anemia), cutaneous, gastrointestinal, and hepatic reactions, shortness of breath, shock, anaphylaxis, and renal failure. Recent studies indicate that regimens using twice-weekly doses of Tres (Rifampin) 600 mg plus isoniazid 15 mg/kg are much better tolerated.

Tres (Rifampin) is not recommended for intermittent therapy; the patient should be cautioned against intentional or accidental interruption of the daily dosage regimen since rare renal hypersensitivity reactions have been reported when therapy was resumed in such cases.

Tres (Rifampin) has enzyme induction properties that can enhance the metabolism of endogenous substrates including adrenal hormones, thyroid hormones, and vitamin D. Tres (Rifampin) and isoniazid have been reported to alter vitamin D metabolism. In some cases, reduced levels of circulating 25-hydroxy vitamin D and 1,25-dihydroxy vitamin D have been accompanied by reduced serum calcium and phosphate, and elevated parathyroid hormone.

Tres (Rifampin) for Injection

For intravenous infusion only. Must not be administered by intramuscular or subcutaneous route. Avoid extravasation during injection: local irritation and inflammation due to extravascular infiltration of the infusion have been observed. If these occur, the infusion should be discontinued and restarted at another site.

Information for Patients

Patients should be counseled that antibacterial drugs including Tres should only be used to treat bacterial infections. They do not treat viral infections (e.g., the common cold). When Tres (Rifampin) is prescribed to treat a bacterial infection, patients should be told that although it is common to feel better early in the course of therapy, the medication should be taken exactly as directed. Skipping doses or not completing the full course of therapy may (1) decrease the effectiveness of the immediate treatment and (2) increase the likelihood that bacteria will develop resistance and will not be treatable by Tres (Rifampin) or other antibacterial drugs in the future.

The patient should be told that Tres (Rifampin) may produce a reddish coloration of the urine, sweat, sputum, and tears, and the patient should be forewarned of this. Soft contact lenses may be permanently stained.

The patient should be advised that the reliability of oral or other systemic hormonal contraceptives may be affected; consideration should be given to using alternative contraceptive measures.

Patients should be instructed to notify their physicians promptly if they experience any of the following: fever, loss of appetite, malaise, nausea and vomiting, darkened urine, yellowish discoloration of the skin and eyes, and pain or swelling of the joints.

Compliance with the full course of therapy must be emphasized, and the importance of not missing any doses must be stressed.

Laboratory Tests

Adults treated for tuberculosis with Tres (Rifampin) should have baseline measurements of hepatic enzymes, bilirubin, serum creatinine, a complete blood count, and a platelet count (or estimate). Baseline tests are unnecessary in pediatric patients unless a complicating condition is known or clinically suspected.

Patients should be seen at least monthly during therapy and should be specifically questioned concerning symptoms associated with adverse reactions. All patients with abnormalities should have follow-up, including laboratory testing, if necessary. Routine laboratory monitoring for toxicity in people with normal baseline measurements is generally not necessary.

Drug Interactions

Healthy subjects who received Tres 600 mg once daily concomitantly with saquinavir 1000 mg/ritonavir 100 mg twice daily (ritonavir-boosted saquinavir) developed severe hepatocellular toxicity. Therefore, concomitant use of these medications is contraindicated. (See CONTRAINDICATIONS.)

Enzyme Induction

Tres (Rifampin) is known to induce certain cytochrome P-450 enzymes. Administration of Tres (Rifampin) with drugs that undergo biotransformation through these metabolic pathways may accelerate elimination of coadministered drugs. To maintain optimum therapeutic blood levels, dosages of drugs metabolized by these enzymes may require adjustment when starting or stopping concomitantly administered Tres (Rifampin).

Tres (Rifampin) has been reported to substantially decrease the plasma concentrations of the following antiviral drugs: atazanavir, darunavir, fosamprenavir, saquinavir, and tipranavir. These antiviral drugs must not be co-administered with Tres (Rifampin). (See CONTRAINDICATIONS .)

Tres (Rifampin) has been reported to accelerate the metabolism of the following drugs: anticonvulsants (e.g., phenytoin), digitoxin, antiarrhythmics (e.g., disopyramide, mexiletine, quinidine, tocainide), oral anticoagulants, antifungals (e.g., fluconazole, itraconazole, ketoconazole), barbiturates, beta-blockers, calcium channel blockers (e.g., diltiazem, nifedipine, verapamil), chloramphenicol, clarithromycin, corticosteroids, cyclosporine, cardiac glycoside preparations, clofibrate, oral or other systemic hormonal contraceptives, dapsone, diazepam, doxycycline, fluoroquinolones (e.g., ciprofloxacin), haloperidol, oral hypoglycemic agents (sulfonylureas), levothyroxine, methadone, narcotic analgesics, progestins, quinine, tacrolimus, theophylline tricyclic antidepressants (e.g., amitriptyline, nortriptyline) and zidovudine. It may be necessary to adjust the dosages of these drugs if they are given concurrently with Tres (Rifampin).

Patients using oral or other systemic hormonal contraceptives should be advised to change to nonhormonal methods of birth control during Tres (Rifampin) therapy.

Tres (Rifampin) has been observed to increase the requirements for anticoagulant drugs of the coumarin type. In patients receiving anticoagulants and Tres (Rifampin) concurrently, it is recommended that the prothrombin time be performed daily or as frequently as necessary to establish and maintain the required dose of anticoagulant.

Other Interactions

When the two drugs were taken concomitantly, decreased concentrations of atovaquone and increased concentrations of Tres were observed.

Concurrent use of ketoconazole and Tres (Rifampin) has resulted in decreased serum concentrations of both drugs. Concurrent use of Tres (Rifampin) and enalapril has resulted in decreased concentrations of enalaprilat, the active metabolite of enalapril. Dosage adjustments should be made if indicated by the patient's clinical condition.

Concomitant antacid administration may reduce the absorption of Tres (Rifampin). Daily doses of Tres (Rifampin) should be given at least 1 hour before the ingestion of antacids.

Probenecid and cotrimoxazole have been reported to increase the blood level of Tres (Rifampin).

When Tres (Rifampin) is given concomitantly with either halothane or isoniazid, the potential for hepatotoxicity is increased. The concomitant use of Tres (Rifampin) and halothane should be avoided. Patients receiving both Tres (Rifampin) and isoniazid should be monitored close for hepatotoxicity.

Plasma concentrations of sulfapyridine may be reduced following the concomitant administration of sulfasalazine and Tres (Rifampin). This finding may be the result of alteration in the colonic bacteria responsible for the reduction of sulfasalazine to sulfapyridine and mesalamine.

Drug/Laboratory Interactions

Cross-reactivity and false-positive urine screening tests for opiates have been reported in patients receiving Tres (Rifampin) when using the KIMS (Kinetic Interaction of Microparticles in Solution) method (e.g., Abuscreen OnLine opiates assay; Roche Diagnostic Systems). Confirmatory tests, such as gas chromatography/mass spectrometry, will distinguish Tres (Rifampin) from opiates.

Therapeutic levels of Tres (Rifampin) have been shown to inhibit standard microbiological assays for serum folate and vitamin B₁₂. Thus, alternate assay methods should be considered. Transient abnormalities in liver function tests (e.g., elevation in serum bilirubin, alkaline phosphatase, and serum transaminases) and reduced biliary excretion of contrast media used for visualization of the gallbladder have also been observed. Therefore, these tests should be performed before the morning dose of Tres (Rifampin).

Carcinogenesis, Mutagenesis, Impairment of Fertility

A few cases of accelerated growth of lung carcinoma have been reported in man, but a causal relationship with the drug has not been established. Hepatomas were increased in female mice dosed for 60 weeks with rifampicin followed by an observation period of 46 weeks, at 20 to 120 mg/kg (equivalent to 0.1 to 0.5 times the maximum dosage used clinically, based on body surface area comparisons). There was no evidence of tumorigenicity in male C3Hf/DP mice or in similar studies in BALB/c mice, or in two year studies in Wistar rats.

There was no evidence of mutagenicity in both prokaryotic (Salmonella typhi, Escherichia coli) and eukaryotic (Saccharomyces cerevisiae) bacteria, Drosophila melanogaster, or ICR/Ha Swiss mice. An increase in chromatid breaks was noted when whole blood cell cultures were treated with Tres (Rifampin). Increased frequency of chromosomal aberrations was observed in vitro in lymphocytes obtained from patients treated with combinations of Tres (Rifampin), isoniazid, and pyrazinamide and combinations of streptomycin, Tres (Rifampin), isoniazid, and pyrazinamide.

Pregnancy

Teratogenic Effects

Category C

Tres has been shown to be teratogenic in rodents. Congenital malformations, primarily spina bifida were increased in the offspring of pregnant rats given Tres (Rifampin) during organogenesis at oral doses of 150 to 250 mg/kg/day (about 1 to 2 times the maximum recommended human dose based on body surface area comparisons). Cleft palate was increased in a dose-dependent fashion in fetuses of pregnant mice treated at oral doses of 50 to 200 mg/kg (about 0.2 to 0.8 times the maximum recommended human dose based on body surface area comparisons). Imperfect osteogenesis and embryotoxicity were also reported in pregnant rabbits given Tres (Rifampin) at oral doses up to 200 mg/kg/day (about 3 times the maximum recommended human dose based on body surface area comparisons). There are no adequate and well-controlled studies of Tres (Rifampin) in pregnant women. Tres (Rifampin) has been reported to cross the placental barrier and appear in cord blood. Tres (Rifampin) should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Pregnancy

Non-Teratogenic Effects

When administered during the last few weeks of pregnancy, Tres can cause post-natal hemorrhages in the mother and infant for which treatment with vitamin K may be indicated.

Nursing Mothers

Because of the potential for tumorigenicity shown for Tres (Rifampin) in animal studies, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric Use

See CLINICAL PHARMACOLOGY– Pediatrics ; see also DOSAGE AND ADMINISTRATION .

Geriatric Use

Clinical studies of Tres (Rifampin) did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. Caution should therefore be observed in using Tres (Rifampin) in elderly patients. (See WARNINGS ).

ADVERSE REACTIONS

Gastrointestinal

Heartburn, epigastric distress, anorexia, nausea, vomiting, jaundice, flatulence, cramps, and diarrhea have been noted in some patients. Although Clostridium difficile has been shown in vitro to be sensitive to Tres, pseudomembranous colitis has been reported with the use of Tres (Rifampin) (and other broad spectrum antibiotics). Therefore, it is important to consider this diagnosis in patients who develop diarrhea in association with antibiotic use.

Hepatic

Transient abnormalities in liver function tests (e.g., elevations in serum bilirubin,, alkaline phosphatase, serum transaminases) have been observed. Rarely, hepatitis or a shock-like syndrome with hepatic involvement and abnormal liver function tests has been reported.

Hematologic

Thrombocytopenia has occurred primarily with high dose intermittent therapy, but has also been noted after resumption of interrupted treatment. It rarely occurs during well supervised daily therapy. This effect is reversible if the drug is discontinued as soon as purpura occurs. Cerebral hemorrhage and fatalities have been reported when Tres administration has been continued or resumed after the appearance of purpura.

Rare reports of disseminated intravascular coagulation have been observed.

Leukopenia, hemolytic anemia, and decreased hemoglobin have been observed.

Agranulocytosis has been reported very rarely.

Central Nervous System

Headache, fever, drowsiness, fatigue, ataxia, dizziness, inability to concentrate, mental confusion, behavioral changes, muscular weakness pains in extremities, and generalized numbness have been observed.

Psychoses have been rarely reported.

Rare reports of disseminated intravascular coagulation have been observed.

Ocular

Visual disturbances have been observed.

Endocrine

Menstrual disturbances have been observed.

Rare reports of adrenal insufficiency in patients with compromised adrenal function have been observed.

Renal

Elevations in BUN and serum uric acid have been reported. Rarely, hemolysis, hemoglobinuria, hematuria, interstitial nephritis, acute tubular necrosis, renal insufficiency, and acute renal failure have been noted. These are generally considered to be hypersensitivity reactions. They usually occur during intermittent therapy or when treatment is resumed following intentional or accidental interruption of a daily dosage regimen, and are reversible when Tres is discontinued and appropriate therapy instituted.

Dermatologic

Cutaneous reactions are mild and self-limiting and do not appear to be hypersensitivity reactions. Typically, they consist of flushing and itching with or without a rash. More serious cutaneous reactions which may be due to hypersensitivity occur but are uncommon.

Hypersensitivity Reactions

Occasionally, pruritus, urticaria, rash, pemphigoid reaction, erythema multiforme including Stevens-Johnson Syndrome, toxic epidermal necrolysis, vasculitis, eosinophilia, sore mouth, sore tongue, and conjunctivitis have been observed.

Anaphylaxis has been reported rarely.

Miscellaneous

Edema of the face and extremities has been reported. Other reactions reported to have occurred with intermittent dosage regimens include "flu syndrome" (such as episodes of fever, chills, headache, dizziness, and bone pain), shortness of breath, wheezing, decrease in blood pressure and shock. The "flu syndrome" may also appear if Tres (Rifampin) is taken irregularly by the patient or if daily administration is resumed after a drug free interval.

OVERDOSAGE

Signs and Symptoms

Nausea, vomiting, abdominal pain, pruritus, headache, and increasing lethargy will probably occur within a short time after ingestion; unconsciousness may occur when there is severe hepatic disease. Transient increases in liver enzymes and/or bilirubin may occur. Brownish-red or orange discoloration of the skin, urine, sweat, saliva, tears, and feces will occur, and its intensity is proportional to the amount ingested.

Liver enlargement, possibly with tenderness, can develop within a few hours after severe overdosage; bilirubin levels may increase and jaundice may develop rapidly. Hepatic involvement may be more marked in patients with prior impairment of hepatic function. Other physical findings remain essentially normal. A direct effect upon the hematopoietic system, electrolyte levels, or acid-base balance is unlikely.

Facial or periorbital edema has also been reported in pediatric patients. Hypotension, sinus tachycardia, ventricular arrhythmias, seizures and cardiac arrest were reported in some fatal cases.

Acute Toxicity

The minimum acute lethal or toxic dose is not well established. However, nonfatal acute overdoses in adults have been reported with doses ranging from 9 to 12 gm Tres. Fatal acute overdoses in adults have been reported with doses ranging from 14 to 60 gm. Alcohol or a history of alcohol abuse was involved in some of the fatal and nonfatal reports. Nonfatal overdoses in pediatric patients ages 1 to 4 years old of 100 mg/kg for one to two doses has been reported.

Treatment

Intensive support measures should be instituted and individual symptoms treated as they arise. The airway should be secured and adequate respiratory exchange established. Since nausea and vomiting are likely to be present, gastric lavage within the first 2 to 3 hours after ingestion is probably preferable to induction of emesis. Following evacuation of the gastric contents, the instillation of activated charcoal slurry into the stomach may help absorb any remaining drug from the gastrointestinal tract. Antiemetic medication may be required to control severe nausea and vomiting.

Active diuresis (with measured intake and output) will help promote excretion of the drug.

For severe cases, extracorporeal hemodialysis may be required. If this is not available, peritoneal dialysis can be used along with forced diuresis.

DOSAGE AND ADMINISTRATION

Tres can be administered by IV infusion (see INDICATIONS AND USAGE ).

See CLINICAL PHARMACOLOGY for dosing information in patients with renal failure.

Tuberculosis

Adults: 10 mg/kg, in a single daily administration, not to exceed 600 mg/day, IV

Pediatric Patients: 10–20 mg/kg, not to exceed 600 mg/day, IV

Tres (Rifampin) is indicated in the treatment of all forms of tuberculosis. A three-drug regimen consisting of Tres (Rifampin), isoniazid, and pyrazinamide (e.g., RIFATER^® manufactured by Sanofi Aventis) is recommended in the initial phase of short-course therapy which is usually continued for 2 months. The Advisory Council for the Elimination of Tuberculosis, the American Thoracic Society, and the Centers for Disease Control and Prevention recommend that either streptomycin or ethambutol be added as a fourth drug in a regimen containing isoniazid (INH), Tres (Rifampin) and pyrazinamide for initial treatment of tuberculosis unless the likelihood of INH resistance is very low. The need for a fourth drug should be reassessed when the results of susceptibility testing are known. If community rates of INH resistance are currently less than 4%, an initial treatment regimen with less than four drugs may be considered.

Following the initial phase, treatment should be continued with Tres (Rifampin) and isoniazid (e.g., RIFAMATE^® manufactured by Sanofi Aventis) for at least 4 months. Treatment should be continued for longer if the patient is still sputum or culture positive, if resistant organisms are present, or if the patient is HIV positive.

Preparation of Solution for IV Infusion

Reconstitute the lyophilized powder by transferring 10 mL of sterile water for injection to a vial containing 600 mg of Tres for injection. Swirl vial gently to completely dissolve the antibiotic. The reconstituted solution contains 60 mg Tres (Rifampin) per mL and is stable at room temperature for 24 hours. Prior to administration, withdraw from the reconstituted solution a volume equivalent to the amount of Tres (Rifampin) calculated to be administered and add to 500 mL of infusion medium. Mix well and infuse at a rate allowing for complete infusion within 3 hours. Alternatively, the amount of Tres (Rifampin) calculated to be administered may be added to 100 mL of infusion medium and infused in 30 minutes.

Dilutions in dextrose 5% for injection (D5W) are stable at room temperature for up to 4 hours and should be prepared and used within this time. Precipitation of Tres (Rifampin) from the infusion solution may occur beyond this time. Dilutions in normal saline are stable at room temperature for up to 24 hours and should be prepared and used within this time. Other infusion solutions are not recommended.

Incompatibilities

Physical incompatibility (precipitate) was observed with undiluted (5 mg/mL) and diluted (1 mg/mL in normal saline) diltiazem hydrochloride and Tres (Rifampin) (6 mg/mL in normal saline) during simulated Y-site administration.

Meningococcal Carriers

Adults: For adults, it is recommended that 600 mg Tres (Rifampin) be administered twice daily for two days.

Pediatric Patients: Pediatric patients 1 month of age or older: 10 mg/kg (not to exceed 600 mg per dose) every 12 hours for two days.

Pediatric patients under 1 month of age: 5 mg/kg every 12 hours for two days.

HOW SUPPLIED

Tres for injection, USP is available in glass vials containing 600 mg Tres (Rifampin) (NDC 0069-0112-01).

Storage

Store at 25°C (77°F); excursions permitted to 15–30°C (59–86°F). Avoid excessive heat (temperatures above 40°C or 104°F). Protect from light.

References

• Clinical Laboratory Standards Institute, Susceptibility Testing of Mycobacteria, Nocardiae, and Other Aerobic Actinomycetes; Approved Standard CLSI Document M24-A, Vol. 23, No. 18, CLSI, Villanova, PA, 2003.
• Clinical Laboratory Standards Institute. Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria that Grow Aerobically -- Eighth Edition. Approved Standard CLSI Document M7-A8, Vol. 29, No. 2, CLSI, Villanova, PA, January 2009.
• Clinical Laboratory Standards Institute. Performance Standards for Antimicrobial Disk Susceptibility Tests -- Tenth Edition. Approved Standard CLSI Document M2-A10, Vol. 29, No. 41,, CLSI, Villanova, PA, January 2009.
• Clinical Laboratory Standards Institute. Performance Standards for Antimicrobial Susceptibility Testing; Twentieth Informational Supplement, CLSI Document M100-S20, Vol. 30, No. 1, CLSI, Villanova, PA, January 2010.

Logo

LAB-0463-1.0

March 2013

NDC 0069-0112-01

1 Vial

Tres (Rifampin) for

Injection, USP

600 mg/vial

Sterile

For IV Infusion Only

Pfizer Injectables

Rx only