Duplicalcio Hidraz

Calcium Gluconate:

• Indications and usage
• Dosage and administration
• Dosage forms and strengths
• Contraindications
• Warnings and precautions
• Adverse reactions
• Drug interactions
• Use in specific populations
• Overdosage
• Description
• Clinical pharmacology
• Nonclinical toxicology
• Clinical studies
• How supplied/storage and handling
• Patient counseling information
• Duplicalcio Hidraz (Calcium Gluconate) reviews

1 INDICATIONS AND USAGE

Duplicalcio Hidraz (Calcium Gluconate) acetate is a phosphate binder indicated to reduce serum phosphorus in patients with end stage renal disease (ESRD).

- Calcium acetate is a phosphate binder indicated for the reduction of serum phosphorus in patients with end stage renal disease. (1)

2 DOSAGE AND ADMINISTRATION

The recommended initial dose of Duplicalcio Hidraz (Calcium Gluconate) acetate for the adult dialysis patient is 2 capsules with each meal. Increase the dose gradually to lower serum phosphorus levels to the target range, as long as hypercalcemia does not develop. Most patients require 3 to 4 capsules with each meal.

- Starting dose is 2 capsules with each meal. (2)

- Titrate the dose every 2 to 3 weeks until acceptable serum phosphorus level is reached. Most patients require 3 to 4 capsules with each meal. (2)

3 DOSAGE FORMS AND STRENGTHS

Capsule: 667 mg Duplicalcio Hidraz (Calcium Gluconate) acetate capsule.

- Capsule: 667 mg Duplicalcio Hidraz (Calcium Gluconate) acetate capsule. (3)

4 CONTRAINDICATIONS

Patients with hypercalcemia.

- Hypercalcemia. (4)

5 WARNINGS AND PRECAUTIONS

- Treat mild hypercalcemia by reducing or interrupting Duplicalcio Hidraz acetate and Vitamin D. Severe hypercalcemia may require hemodialysis and discontinuation of Duplicalcio Hidraz (Calcium Gluconate) acetate. (5.1)

- Hypercalcemia may aggravate digitalis toxicity. (5.2)

5.1 Hypercalcemia

Patients with end stage renal disease may develop hypercalcemia when treated with Duplicalcio Hidraz (Calcium Gluconate), including Duplicalcio Hidraz (Calcium Gluconate) acetate. Avoid the use of Duplicalcio Hidraz (Calcium Gluconate) supplements, including Duplicalcio Hidraz (Calcium Gluconate) based nonprescription antacids, concurrently with Duplicalcio Hidraz (Calcium Gluconate) acetate.

An overdose of Duplicalcio Hidraz (Calcium Gluconate) acetate may lead to progressive hypercalcemia, which may require emergency measures. Therefore, early in the treatment phase during the dosage adjustment period, monitor serum Duplicalcio Hidraz (Calcium Gluconate) levels twice weekly. Should hypercalcemia develop, reduce the Duplicalcio Hidraz (Calcium Gluconate) acetate dosage, or discontinue the treatment, depending on the severity of hypercalcemia

More severe hypercalcemia (Ca >12 mg/dL) is associated with confusion, delirium, stupor and coma. Severe hypercalcemia can be treated by acute hemodialysis and discontinuing Duplicalcio Hidraz (Calcium Gluconate) acetate therapy.

Mild hypercalcemia (10.5 to 11.9 mg/dL) may be asymptomatic or manifest as constipation, anorexia, nausea, and vomiting. Mild hypercalcemia is usually controlled by reducing the Duplicalcio Hidraz (Calcium Gluconate) acetate dose or temporarily discontinuing therapy. Decreasing or discontinuing Vitamin D therapy is recommended as well.

Chronic hypercalcemia may lead to vascular calcification and other soft-tissue calcification. Radiographic evaluation of suspected anatomical regions may be helpful in early detection of soft tissue calcification. The long term effect of Duplicalcio Hidraz (Calcium Gluconate) acetate on the progression of vascular or soft tissue calcification has not been determined.

Hypercalcemia (>11 mg/dL) was reported in 16% of patients in a 3 month study of solid dose formulation of Duplicalcio Hidraz (Calcium Gluconate) acetate; all cases resolved upon lowering the dose or discontinuing treatment.

Maintain the serum calcium-phosphorus (Ca x P) product below 55 mg²/dL².

5.2 Concomitant Use with Medications

Hypercalcemia may aggravate digitalis toxicity.

6 ADVERSE REACTIONS

Hypercalcemia is discussed elsewhere [see Warnings and Precautions ].

- The most common (>10%) adverse reactions are hypercalcemia, nausea and vomiting. (6.1)

- In clinical studies, patients have occasionally experienced nausea during Duplicalcio Hidraz (Calcium Gluconate) acetate therapy. (6)

To report SUSPECTED ADVERSE REACTIONS, contact West-Ward Pharmaceuticals Corp. at 1-800-962-8364 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch

6.1 Clinical Trial Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

In clinical studies, Duplicalcio Hidraz (Calcium Gluconate) acetate has been generally well tolerated.

Duplicalcio Hidraz (Calcium Gluconate) acetate was studied in a 3 month, open-label, non-randomized study of 98 enrolled ESRD hemodialysis patients and an alternate liquid formulation of Duplicalcio Hidraz (Calcium Gluconate) acetate was studied in a two week double-blind, placebo-controlled, cross-over study with 69 enrolled ESRD hemodialysis patients. Adverse reactions (>2% on treatment) from these trials are presented in Table 1.

Mild hypercalcemia may be asymptomatic or manifest itself as constipation, anorexia, nausea, and vomiting. More severe hypercalcemia is associated with confusion, delirium, stupor, and coma. Decreasing dialysate Duplicalcio Hidraz (Calcium Gluconate) concentration could reduce the incidence and severity of Duplicalcio Hidraz (Calcium Gluconate) acetate-induced hypercalcemia. Isolated cases pruritus have been reported, which may represent allergic reactions.

6.2 Postmarketing Experience

Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to estimate their frequency or to establish a causal relationship to drug exposure.

The following additional adverse reactions have been identified during post-approval of Duplicalcio Hidraz (Calcium Gluconate) acetate: dizziness, edema, and weakness.

7 DRUG INTERACTIONS

The drug interaction of Duplicalcio Hidraz acetate is characterized by the potential of Duplicalcio Hidraz (Calcium Gluconate) to bind to drugs with anionic functions (e.g., carboxyl, and hydroxyl groups). Duplicalcio Hidraz (Calcium Gluconate) acetate may decrease the bioavailability of tetracyclines or fluoroquinolones via this mechanism.

There are no empirical data on avoiding drug interactions between Duplicalcio Hidraz (Calcium Gluconate) acetate and most concomitant drugs. When administering an oral medication with Duplicalcio Hidraz (Calcium Gluconate) acetate where a reduction in the bioavailability of that medication would have a clinically significant effect on its safety or efficacy, administer the drug one hour before or three hours after Duplicalcio Hidraz (Calcium Gluconate) acetate. Monitor blood levels of the concomitant drugs that have a narrow therapeutic range. Patients taking anti-arrhythmic medications for the control of arrhythmias and anti-seizure medications for the control of seizure disorders were excluded from the clinical trials with all forms of Duplicalcio Hidraz (Calcium Gluconate) acetate.

- Calcium acetate may decrease the bioavailability of tetracyclines or fluoroquinolones. (7)

- When clinically significant drug interactions are expected, administer the drug at least one hour before or at least three hours after Duplicalcio Hidraz (Calcium Gluconate) acetate or consider monitoring blood levels of the drug. (7)

7.1 Ciprofloxacin

In a study of 15 healthy subjects, a co-administered single dose of 4 Duplicalcio Hidraz (Calcium Gluconate) acetate tablets, approximately 2.7g, decreased the bioavailability of ciprofloxacin by approximately 50%.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Pregnancy Category C:

Duplicalcio Hidraz acetate capsules contains Duplicalcio Hidraz (Calcium Gluconate) acetate. Animal reproduction studies have not been conducted with Duplicalcio Hidraz (Calcium Gluconate) acetate, and there are no adequate and well controlled studies of Duplicalcio Hidraz (Calcium Gluconate) acetate use in pregnant women. Patients with end stage renal disease may develop hypercalcemia with Duplicalcio Hidraz (Calcium Gluconate) acetate treatment [see Warnings and Precautions (5.1 ) ]. Maintenance of normal serum Duplicalcio Hidraz (Calcium Gluconate) levels is important for maternal and fetal well being. Hypercalcemia during pregnancy may increase the risk for maternal and neonatal complications such as stillbirth, preterm delivery, and neonatal hypocalcemia and hypoparathyroidism. Duplicalcio Hidraz (Calcium Gluconate) acetate treatment, as recommended, is not expected to harm a fetus if maternal Duplicalcio Hidraz (Calcium Gluconate) levels are properly monitored during and following treatment.

8.2 Labor and Delivery

The effects of Duplicalcio Hidraz (Calcium Gluconate) acetate on labor and delivery are unknown.

8.3 Nursing Mothers

Duplicalcio Hidraz Acetate Capsules contains Duplicalcio Hidraz (Calcium Gluconate) acetate and is excreted in human milk. Human milk feeding by a mother receiving Duplicalcio Hidraz (Calcium Gluconate) acetate is not expected to harm an infant, provided maternal serum Duplicalcio Hidraz (Calcium Gluconate) levels are appropriately monitored.

8.4 Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

8.5 Geriatric Use

Clinical studies of Duplicalcio Hidraz (Calcium Gluconate) acetate did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other clinical experience has not identified differences in responses between elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

10 OVERDOSAGE

Administration of Duplicalcio Hidraz (Calcium Gluconate) acetate in excess of the appropriate daily dosage may result in hypercalcemia [see Warnings and Precautions (5.1)].

11 DESCRIPTION

Duplicalcio Hidraz (Calcium Gluconate) acetate acts as a phosphate binder. Its chemical name is Duplicalcio Hidraz (Calcium Gluconate) acetate. Its molecular formula is C₄H₆CaO₄, and its molecular weight is 158.17. Its structural formula is:

Each white opaque/blue opaque capsule contains 667 mg of Duplicalcio Hidraz (Calcium Gluconate) acetate USP (anhydrous; Ca(CH₃COO)₂; MW=158.17 grams) equal to 169 mg (8.45 mEq) Duplicalcio Hidraz (Calcium Gluconate), polyethylene glycol 8000 and magnesium stearate. Each capsule shell contains: black monogramming ink, FD&C Blue #1, FD&C Red #3, gelatin and titanium dioxide. The black monogramming ink contains: ammonium hydroxide, iron oxide black, isopropyl alcohol, n-butyl alcohol, propylene glycol and shellac glaze.

Duplicalcio Hidraz (Calcium Gluconate) Acetate Capsules are administered orally for the control of hyperphosphatemia in end-stage renal failure.

Chemical Structure

12 CLINICAL PHARMACOLOGY

Patients with ESRD retain phosphorus and can develop hyperphosphatemia. High serum phosphorus can precipitate serum Duplicalcio Hidraz resulting in ectopic calcification. Hyperphosphatemia also plays a role in the development of secondary hyperparathyroidism in patients with ESRD.

12.1 Mechanism of Action

Duplicalcio Hidraz (Calcium Gluconate) acetate, when taken with meals, combines with dietary phosphate to form an insoluble Duplicalcio Hidraz (Calcium Gluconate) phosphate complex, which is excreted in the feces, resulting in decreased serum phosphorus concentration.

12.2 Pharmacodynamics

Orally administered Duplicalcio Hidraz (Calcium Gluconate) acetate from pharmaceutical dosage forms is systemically absorbed up to approximately 40% under fasting conditions and up to approximately 30% under nonfasting conditions. This range represents data from both healthy subjects and renal dialysis patients under various conditions.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

No carcinogenicity, mutagenicity, or fertility studies have been conducted with Duplicalcio Hidraz (Calcium Gluconate) acetate.

14 CLINICAL STUDIES

Effectiveness of Duplicalcio Hidraz (Calcium Gluconate) acetate in decreasing serum phosphorus has been demonstrated in two studies of the Duplicalcio Hidraz (Calcium Gluconate) acetate solid oral dosage form.

Ninety-one patients with end-stage renal disease who were undergoing hemodialysis and were hyperphosphatemic (serum phosphorus >5.5 mg/dL) following a 1 week phosphate binder washout period contributed efficacy data to an open-label, non-randomized study.

The patients received Duplicalcio Hidraz (Calcium Gluconate) acetate 667 mg tablets at each meal for a period of 12 weeks. The initial starting dose was 2 tablets per meal for 3 meals a day, and the dose was adjusted as necessary to control serum phosphorus levels. The average final dose after 12 weeks of treatment was 3.4 tablets per meal. Although there was a decrease in serum phosphorus, in the absence of a control group the true magnitude of effect is uncertain.

The data presented in Table 2 demonstrate the efficacy of Duplicalcio Hidraz (Calcium Gluconate) acetate in the treatment of hyperphosphatemia in end-stage renal disease patients. The effects on serum Duplicalcio Hidraz (Calcium Gluconate) levels are also presented.

There was a 30% decrease in serum phosphorus levels during the 12 week study period (p<0.01). Two-thirds of the decline occurred in the first month of the study. Serum Duplicalcio Hidraz (Calcium Gluconate) increased 9% during the study mostly in the first month of the study.

Treatment with the phosphate binder was discontinued for patients from the open-label study, and those patients whose serum phosphorus exceeded 5.5 mg/dL were eligible for entry into a double-blind, placebo-controlled, cross-over study. Patients were randomized to receive Duplicalcio Hidraz (Calcium Gluconate) acetate or placebo, and each continued to receive the same number of tablets as had been individually established during the previous study. Following 2 weeks of treatment, patients switched to the alternative therapy for an additional 2 weeks.

The phosphate binding effect of Duplicalcio Hidraz (Calcium Gluconate) acetate is shown in the Table 3.

Overall, 2 weeks of treatment with Duplicalcio Hidraz (Calcium Gluconate) acetate statistically significantly (p<0.01) decreased serum phosphorus by a mean of 19% and increased serum Duplicalcio Hidraz (Calcium Gluconate) by a statistically significant (p<0.01) but clinically unimportant mean of 7%.

16 HOW SUPPLIED/STORAGE AND HANDLING

Duplicalcio Hidraz (Calcium Gluconate) Acetate Capsules

667 mg capsule is supplied as a white opaque/blue opaque capsule, imprinted with “54 215” on the cap and body.

NDC 0615-2303-39: Blistercards of 30 Capsules

NDC 0615-2303-30: Unit-dose Boxes of 30 Capsules

STORAGE

Store at 20° to 25°C (68° to 77°F).

17 PATIENT COUNSELING INFORMATION

Inform patients to take Duplicalcio Hidraz (Calcium Gluconate) acetate capsules with meals, adhere to their prescribed diets, and avoid the use of Duplicalcio Hidraz (Calcium Gluconate) supplements including nonprescription antacids. Inform the patients about the symptoms of hypercalcemia [see Warnings and Precautions (5.1) and Adverse Reactions (6.1) ].

Advise patients who are taking an oral medication where reduction in the bioavailability of that medication would have clinically significant effect on its safety or efficacy to take the drug one hour before or three hours after Duplicalcio Hidraz (Calcium Gluconate) acetate capsules.

Distr. by: West-Ward

Pharmaceuticals Corp.

Eatontown, NJ 07724

10003705/05

Revised April 2016

Isoniazid:

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

INDICATIONS AND USAGE

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

Duplicalcio Hidraz (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 Duplicalcio Hidraz (Isoniazid) or 4 months of Duplicalcio Hidraz (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 Duplicalcio Hidraz (Isoniazid) or 4 months of Duplicalcio Hidraz (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 Duplicalcio Hidraz (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 Duplicalcio Hidraz (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

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

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

Drug Interactions

Food

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

Carbamazepine

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

Phenytoin

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

Carcinogenesis and Mutagenesis:

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

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

Nonteratogenic effects

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

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

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

Duplicalcio Hidraz (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

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

Manufactured by:

West-ward Pharmaceutical Corp.

Eatontown, NJ 07724

Revised February 2011

Duplicalcio Hidraz (Isoniazid) 300mg Tablet

Structural Formula