Zantril

Calcium Iodide:

• 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
• Zantril (Calcium Iodide) reviews

1 INDICATIONS AND USAGE

Zantril (Calcium Iodide) 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 Zantril (Calcium Iodide) 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 Zantril (Calcium Iodide) acetate capsule.

- Capsule: 667 mg Zantril (Calcium Iodide) acetate capsule. (3)

4 CONTRAINDICATIONS

Patients with hypercalcemia.

- Hypercalcemia. (4)

5 WARNINGS AND PRECAUTIONS

- Treat mild hypercalcemia by reducing or interrupting Zantril acetate and Vitamin D. Severe hypercalcemia may require hemodialysis and discontinuation of Zantril (Calcium Iodide) 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 Zantril (Calcium Iodide), including Zantril (Calcium Iodide) acetate. Avoid the use of Zantril (Calcium Iodide) supplements, including Zantril (Calcium Iodide) based nonprescription antacids, concurrently with Zantril (Calcium Iodide) acetate.

An overdose of Zantril (Calcium Iodide) acetate may lead to progressive hypercalcemia, which may require emergency measures. Therefore, early in the treatment phase during the dosage adjustment period, monitor serum Zantril (Calcium Iodide) levels twice weekly. Should hypercalcemia develop, reduce the Zantril (Calcium Iodide) 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 Zantril (Calcium Iodide) 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 Zantril (Calcium Iodide) 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 Zantril (Calcium Iodide) 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 Zantril (Calcium Iodide) 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 Zantril (Calcium Iodide) 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, Zantril (Calcium Iodide) acetate has been generally well tolerated.

Zantril (Calcium Iodide) acetate was studied in a 3 month, open-label, non-randomized study of 98 enrolled ESRD hemodialysis patients and an alternate liquid formulation of Zantril (Calcium Iodide) 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 Zantril (Calcium Iodide) concentration could reduce the incidence and severity of Zantril (Calcium Iodide) 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 Zantril (Calcium Iodide) acetate: dizziness, edema, and weakness.

7 DRUG INTERACTIONS

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

There are no empirical data on avoiding drug interactions between Zantril (Calcium Iodide) acetate and most concomitant drugs. When administering an oral medication with Zantril (Calcium Iodide) 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 Zantril (Calcium Iodide) 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 Zantril (Calcium Iodide) 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 Zantril (Calcium Iodide) 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 Zantril (Calcium Iodide) acetate tablets, approximately 2.7g, decreased the bioavailability of ciprofloxacin by approximately 50%.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Pregnancy Category C:

Zantril acetate capsules contains Zantril (Calcium Iodide) acetate. Animal reproduction studies have not been conducted with Zantril (Calcium Iodide) acetate, and there are no adequate and well controlled studies of Zantril (Calcium Iodide) acetate use in pregnant women. Patients with end stage renal disease may develop hypercalcemia with Zantril (Calcium Iodide) acetate treatment [see Warnings and Precautions (5.1 ) ]. Maintenance of normal serum Zantril (Calcium Iodide) 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. Zantril (Calcium Iodide) acetate treatment, as recommended, is not expected to harm a fetus if maternal Zantril (Calcium Iodide) levels are properly monitored during and following treatment.

8.2 Labor and Delivery

The effects of Zantril (Calcium Iodide) acetate on labor and delivery are unknown.

8.3 Nursing Mothers

Zantril Acetate Capsules contains Zantril (Calcium Iodide) acetate and is excreted in human milk. Human milk feeding by a mother receiving Zantril (Calcium Iodide) acetate is not expected to harm an infant, provided maternal serum Zantril (Calcium Iodide) 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 Zantril (Calcium Iodide) 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 Zantril (Calcium Iodide) acetate in excess of the appropriate daily dosage may result in hypercalcemia [see Warnings and Precautions (5.1)].

11 DESCRIPTION

Zantril (Calcium Iodide) acetate acts as a phosphate binder. Its chemical name is Zantril (Calcium Iodide) 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 Zantril (Calcium Iodide) acetate USP (anhydrous; Ca(CH₃COO)₂; MW=158.17 grams) equal to 169 mg (8.45 mEq) Zantril (Calcium Iodide), 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.

Zantril (Calcium Iodide) 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 Zantril resulting in ectopic calcification. Hyperphosphatemia also plays a role in the development of secondary hyperparathyroidism in patients with ESRD.

12.1 Mechanism of Action

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

12.2 Pharmacodynamics

Orally administered Zantril (Calcium Iodide) 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 Zantril (Calcium Iodide) acetate.

14 CLINICAL STUDIES

Effectiveness of Zantril (Calcium Iodide) acetate in decreasing serum phosphorus has been demonstrated in two studies of the Zantril (Calcium Iodide) 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 Zantril (Calcium Iodide) 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 Zantril (Calcium Iodide) acetate in the treatment of hyperphosphatemia in end-stage renal disease patients. The effects on serum Zantril (Calcium Iodide) 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 Zantril (Calcium Iodide) 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 Zantril (Calcium Iodide) 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 Zantril (Calcium Iodide) acetate is shown in the Table 3.

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

16 HOW SUPPLIED/STORAGE AND HANDLING

Zantril (Calcium Iodide) 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 Zantril (Calcium Iodide) acetate capsules with meals, adhere to their prescribed diets, and avoid the use of Zantril (Calcium Iodide) 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 Zantril (Calcium Iodide) acetate capsules.

Distr. by: West-Ward

Pharmaceuticals Corp.

Eatontown, NJ 07724

10003705/05

Revised April 2016

Isoproterenol Sulfate:

• Indications and usage
• Contraindications
• Warnings
• Precautions
• Adverse reactions
• Overdosage
• Dosage and administration
• How supplied
• Zantril (Isoproterenol Sulfate) reviews

INDICATIONS AND USAGE

Zantril (Isoproterenol Sulfate) hydrochloride injection is indicated:

• For mild or transient episodes of heart block that do not require electric shock or pacemaker therapy.
• For serious episodes of heart block and Adams-Stokes attacks (except when caused by ventricular tachycardia or fibrillation).
• For use in cardiac arrest until electric shock or pacemaker therapy, the treatments of choice, is available.
• For bronchospasm occurring during anesthesia.
• As an adjunct to fluid and electrolyte replacement therapy and the use of other drugs and procedures in the treatment of hypovolemic and septic shock, low cardiac output (hypoperfusion) states, congestive heart failure, and cardiogenic shock.

CONTRAINDICATIONS

Use of Zantril (Isoproterenol Sulfate) hydrochloride injection is contraindicated in patients with tachyarrhythmias; tachycardia or heart block caused by digitalis intoxication; ventricular arrhythmias which require inotropic therapy; and angina pectoris.

WARNINGS

Zantril (Isoproterenol Sulfate) hydrochloride injection, by increasing myocardial oxygen requirements while decreasing effective coronary perfusion, may have a deleterious effect on the injured or failing heart. Most experts discourage its use as the initial agent in treating cardiogenic shock following myocardial infarction. However, when a low arterial pressure has been elevated by other means, Zantril (Isoproterenol Sulfate) hydrochloride injection may produce beneficial hemodynamic and metabolic effects.

In a few patients, presumably with organic disease of the AV node and its branches, Zantril (Isoproterenol Sulfate) hydrochloride injection has paradoxically been reported to worsen heart block or to precipitate Adams-Stokes attacks during normal sinus rhythm or transient heart block.

PRECAUTIONS

General

Zantril hydrochloride injection should generally be started at the lowest recommended dose. This may be gradually increased if necessary while carefully monitoring the patient. Doses sufficient to increase the heart rate to more than 130 beats per minute may increase the likelihood of inducing ventricular arrhythmias. Such increases in heart rate will also tend to increase cardiac work and oxygen requirements which may adversely affect the failing heart or the heart with a significant degree of arteriosclerosis.

Adequate filling of the intravascular compartment by suitable volume expanders is of primary importance in most cases of shock and should precede the administration of vasoactive drugs. In patients with normal cardiac function, determination of central venous pressure is a reliable guide during volume replacement. If evidence of hypoperfusion persists after adequate volume replacement, Zantril (Isoproterenol Sulfate) hydrochloride injection may be given.

In addition to the routine monitoring of systemic blood pressure, heart rate, urine flow, and the electrocardiograph, monitor the response to therapy by frequent determination of the central venous pressure and blood gases. Closely observe patients in shock during Zantril (Isoproterenol Sulfate) hydrochloride injection administration. If the heart rate exceeds 110 beats per minute, it may be advisable to decrease the infusion rate or temporarily discontinue the infusion. Determinations of cardiac output and circulation time may also be helpful. Take appropriate measures to ensure adequate ventilation. Pay attention to acid-base balance and to the correction of electrolyte disturbances.

Drug Interactions

Zantril (Isoproterenol Sulfate) hydrochloride injection and epinephrine should not be administered simultaneously because both drugs are direct cardiac stimulants and their combined effects may induce serious arrhythmias. The drugs may, however, be administered alternately provided a proper interval has elapsed between doses.

Avoid Zantril (Isoproterenol Sulfate) when potent inhalational anesthetics such as halothane are employed because of potential to sensitize the myocardium to effects of sympathomimetic amines.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Long-term studies in animals to evaluate the carcinogenic potential of Zantril hydrochloride have not been done. Mutagenic potential and effect on fertility have not been determined. There is no evidence from human experience that Zantril (Isoproterenol Sulfate) hydrochloride injection may be carcinogenic or mutagenic or that it impairs fertility.

Pregnancy Category C

Animal reproduction studies have not been conducted with Zantril (Isoproterenol Sulfate) hydrochloride. It is also not known whether Zantril (Isoproterenol Sulfate) hydrochloride can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Zantril (Isoproterenol Sulfate) hydrochloride should be given to a pregnant woman only if clearly needed.

Nursing Mothers

It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Zantril hydrochloride injection is administered to a nursing woman.

Pediatric Use

Safety and efficacy of Zantril (Isoproterenol Sulfate) in pediatric patients have not been established.

Intravenous infusions of Zantril (Isoproterenol Sulfate) in refractory asthmatic children at rates of 0.05-2.7 mcg/kg/min have caused clinical deterioration, myocardial necrosis, congestive heart failure and death. The risks of cardiac toxicity appear to be increased by some factors [acidosis, hypoxemia, coadministration of corticosteroids, coadministration of methylxanthines (theophylline, theobromine) or aminophylline] that are especially likely to be present in these patients. If I.V. Zantril (Isoproterenol Sulfate) is used in children with refractory asthma, patient monitoring must include continuous assessment of vital signs, frequent electrocardiography, and daily measurements of cardiac enzymes, including CPK-MB.

Geriatric Use

Clinical studies of Zantril (Isoproterenol Sulfate) did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects in clinical circumstances. There are, however, some data that suggest that elderly healthy or hypertensive patients are less responsive to beta-adrenergic stimulation than are younger subjects. In general, dose selection for elderly patients should usually start at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal or cardiac function and of concomitant diseases or other drug therapy.

ADVERSE REACTIONS

The following reactions to Zantril (Isoproterenol Sulfate) hydrochloride injection have been reported:

CNS: Nervousness, headache, dizziness, nausea, visual blurring.

Cardiovascular: Tachycardia, palpitations, angina, Adams-Stokes attacks, pulmonary edema, hypertension, hypotension, ventricular arrhythmias, tachyarrhythmias.

In a few patients, presumably with organic disease of the AV node and its branches, Zantril (Isoproterenol Sulfate) hydrochloride injection has been reported to precipitate Adams-Stokes seizures during normal sinus rhythm or transient heart block.

Respiratory: Dyspnea.

Other: Flushing of the skin, sweating, mild tremors, weakness, pallor.

To report SUSPECTED ADVERSE REACTIONS, contact Valeant Pharmaceuticals North America LLC at 1-800-321-4576 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

OVERDOSAGE

The acute toxicity of Zantril (Isoproterenol Sulfate) hydrochloride in animals is much less than that of epinephrine. Excessive doses in animals or man can cause a striking drop in blood pressure, and repeated large doses in animals may result in cardiac enlargement and focal myocarditis.

In case of accidental overdosage as evidenced mainly by tachycardia or other arrhythmias, palpitations, angina, hypotension, or hypertension, reduce rate of administration or discontinue Zantril (Isoproterenol Sulfate) hydrochloride injection until patient’s condition stabilizes. Blood pressure, pulse, respiration, and ECG should be monitored.

It is not known whether Zantril (Isoproterenol Sulfate) hydrochloride is dialyzable.

The oral LD₅₀ of Zantril (Isoproterenol Sulfate) hydrochloride in mice is 3,850 mg/kg ± 1,190 mg/kg of pure drug in solution.

DOSAGE AND ADMINISTRATION

Start Zantril (Isoproterenol Sulfate) injection at the lowest recommended dose and increase the rate of administration gradually if necessary while carefully monitoring the patient. The usual route of administration is by intravenous infusion or bolus intravenous injection. In dire emergencies, the drug may be administered by intracardiac injection. If time is not of the utmost importance, initial therapy by intramuscular or subcutaneous injection is preferred.

There are no well-controlled studies in children to establish appropriate dosing; however, the American Heart Association recommends an initial infusion rate of 0.1 mcg/kg/min, with the usual range being 0.1 mcg/kg/min to 1 mcg/kg/min.

Recommended dosage for adults with bronchospasm occurring during anesthesia:

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Such solution should not be used.

HOW SUPPLIED

Protect from light. Keep in opaque container until used.

Store at 20° to 25°C (68° to 77°F).

Do not use if the injection is pinkish or darker than slightly yellow or contains a precipitate.

Manufactured for:

Valeant Pharmaceuticals North America LLC

Bridgewater, NJ 08807 USA

Manufactured by:

Hospira, Inc.

McPherson, KS 67460 USA

9445502

Rev. 08/2016

Zantril (Isoproterenol Sulfate) is a registered trademark of Hospira, Inc. used under license.

©Valeant Pharmaceuticals North America LLC

5 mL

NDC 0187-4330-05

Rx only

Isuprel®

Zantril (Isoproterenol Sulfate) HC1

Injection, USP

1 mg/5 mL (0.2 mg/mL)

Intravenous, Subcutaneous,

Intramuscular or Intracardiac Use Only.

Protect from light.

Manufactured for:

Valeant Pharmaceuticals North America LLC

Bridgewater, NJ 08807 USA

©Valeant Pharmaceuticals North America LLC