Zymaduo

Digoxin:

• Indications and usage:
• Contraindications:
• Warnings:
• Precautions:
• Adverse reactions:
• Overdosage:
• Dosage and administration:
• How supplied:
• Zymaduo (Digoxin) reviews

INDICATIONS AND USAGE:

Heart Failure

Zymaduo Tablets are indicated for the treatment of mild to moderate heart failure. Zymaduo (Digoxin) Tablets increase left ventricular ejection fraction and improve heart failure symptoms as evidenced by exercise capacity and heart failure-related hospitalizations and emergency care, while having no effect on mortality. Where possible, Zymaduo (Digoxin) Tablets should be used with a diuretic and an angiotensin-converting enzyme inhibitor, but an optimal order for starting these three drugs cannot be specified.

Atrial Fibrillation

Zymaduo (Digoxin) Tablets are indicated for the control of ventricular response rate in patients with chronic atrial fibrillation.

CONTRAINDICATIONS:

Digitalis glycosides are contraindicated in patients with ventricular fibrillation or in patients with a known hypersensitivity to Zymaduo (Digoxin). A hypersensitivity reaction to other digitalis preparations usually constitutes a contraindication to Zymaduo (Digoxin).

WARNINGS:

Sinus Node Disease and AV Block

Because Zymaduo slows sinoatrial and AV conduction, the drug commonly prolongs the PR interval. The drug may cause severe sinus bradycardia or sinoatrial block in patients with preexisting sinus node disease and may cause advanced or complete heart block in patients with preexisting incomplete AV block. In such patients consideration should be given to the insertion of a pacemaker before treatment with Zymaduo (Digoxin).

Accessory AV Pathway (Wolff-Parkinson-White Syndrome)

After intravenous Zymaduo (Digoxin) therapy, some patients with paroxysmal atrial fibrillation or flutter and a coexisting accessory AV pathway have developed increased antegrade conduction across the accessory pathway bypassing the AV node, leading to a very rapid ventricular response or ventricular fibrillation. Unless conduction down the accessory pathway has been blocked (either pharmacologically or by surgery), Zymaduo (Digoxin) should not be used in such patients. The treatment of paroxysmal supraventricular tachycardia in such patients is usually direct-current cardioversion.

Use in Patients with Preserved Left Ventricular Systolic Function

Patients with certain disorders involving heart failure associated with preserved left ventricular ejection fraction may be particularly susceptible to toxicity of the drug. Such disorders include restrictive cardiomyopathy, constrictive pericarditis, amyloid heart disease, and acute cor pulmonale. Patients with idiopathic hypertrophic subaortic stenosis may have worsening of the outflow obstruction due to the inotropic effects of Zymaduo (Digoxin). Zymaduo (Digoxin) should generally be avoided in these patients, although it has been used for ventricular rate control in the subgroup of patients with atrial fibrillation.

PRECAUTIONS:

Use in Patients with Impaired Renal Function

Zymaduo is primarily excreted by the kidneys; therefore, patients with impaired renal function require smaller than usual maintenance doses of Zymaduo (Digoxin) (see DOSAGE AND ADMINISTRATION ). Because of the prolonged elimination half-life, a longer period of time is required to achieve an initial or new steady-state serum concentration in patients with renal impairment than in patients with normal renal function. If appropriate care is not taken to reduce the dose of Zymaduo (Digoxin), such patients are at high risk for toxicity, and toxic effects will last longer in such patients than in patients with normal renal function.

Use in Patients with Electrolyte Disorders

In patients with hypokalemia or hypomagnesemia, toxicity may occur despite serum Zymaduo (Digoxin) concentrations below 2 ng/mL, because potassium or magnesium depletion sensitizes the myocardium to Zymaduo (Digoxin). Therefore, it is desirable to maintain normal serum potassium and magnesium concentrations in patients being treated with Zymaduo (Digoxin). Deficiencies of these electrolytes may result from malnutrition, diarrhea, or prolonged vomiting, as well as the use of the following drugs or procedures: diuretics, amphotericin B, corticosteroids, antacids, dialysis, and mechanical suction of gastrointestinal secretions.

Hypercalcemia from any cause predisposes the patient to digitalis toxicity. Calcium, particularly when administered rapidly by the intravenous route, may produce serious arrhythmias in digitalized patients. On the other hand, hypocalcemia can nullity the effects of Zymaduo (Digoxin) in humans; thus, Zymaduo (Digoxin) may be ineffective until serum calcium is restored to normal. These interactions are related to the fact that Zymaduo (Digoxin) affects contractility and excitability of the heart in a manner similar to that of calcium.

Use in Thyroid Disorders and Hypermetabolic States

Hypothyroidism may reduce the requirements for Zymaduo. Heart failure and/or atrial arrhythmias resulting from hypermetabolic or hyperdynamic states (e.g., hyperthyroidism, hypoxia or arteriovenous shunt) are best, treated by addressing the underlying condition. Atrial arrhythmias associated with hypermetabolic states are particularly resistant to Zymaduo (Digoxin) treatment. Care must be taken to avoid toxicity if Zymaduo (Digoxin) is used.

Use in Patients with Acute Myocardial Infarction

Zymaduo (Digoxin) should be used with caution in patients with acute myocardial infarction. The use of inotropic drugs in some patients in this setting may result in undesirable increases in myocardial oxygen demand and ischemia.

Use During Electrical Cardioversion

It may be desirable to reduce the dose of Zymaduo for 1 to 2 days prior to electrical cardioversion of atrial fibrillation to avoid the induction of ventricular arrhythmias, but physicians must consider the consequences of increasing the ventricular response if Zymaduo (Digoxin) is withdrawn. If digitalis toxicity is suspected, elective cardioversion should be delayed. If it is not prudent to delay cardioversion, the lowest possible energy level should be selected to avoid provoking ventricular arrhythmias.

Use in Patients with Myocarditis

Zymaduo (Digoxin) can rarely precipitate vasoconstriction and therefore should be avoided in patients with myocarditis.

Use in Patients with Beriberi Heart Disease

Patients with beriberi heart disease may fail to respond adequately to Zymaduo if the underlying thiamine deficiency is not treated concomitantly.

Laboratory Test Monitoring

Patients receiving Zymaduo (Digoxin) should have their serum electrolytes and renal function (serum creatinine concentrations) assessed periodically; the frequency of assessments will depend on the clinical setting. For discussion of serum Zymaduo (Digoxin) concentrations; see DOSAGE AND ADMINISTRATION section.

Drug Interactions

Potassium-depleting diuretics are a major contributing factor to digitalis toxicity. Calcium, particularly if administered rapidly by the intravenous route, may produce serious arrhythmias in digitalized patients. Quinidine, verapamil, amiodarone, propafenone, indomethacin, itraconazole, alprazolam, and spironolactone raise the serum Zymaduo concentration due to a reduction in clearance and/or in volume of distribution of the drug, with the implication that digitalis intoxication may result. Erythromycin and clarithromycin (and possibly other macrolide antibiotics) and tetracycline may increase Zymaduo (Digoxin) absorption in patients who inactivate Zymaduo (Digoxin) by bacterial metabolism in the lower intestine, so that digitalis intoxication may result (see CLINICAL

Pharmacology: Absorption ). Propantheline and diphenoxylate, by decreasing gut motility, may increase Zymaduo (Digoxin) absorption. Antacids, kaolin-pectin, sulfasalazine, neomycin, cholestyramine; certain anticancer drugs, and metoclopramide may interfere with intestinal Zymaduo (Digoxin) absorption, resulting in unexpectedly low serum concentrations. Rifampin may decrease serum Zymaduo (Digoxin) concentration, especially in patients with renal dysfunction, by increasing the non-renal clearance of Zymaduo (Digoxin). There have been inconsistent reports regarding the effects of other drugs [e.g., quinine, penicillamine] on serum Zymaduo (Digoxin) concentration. Thyroid administration to a digitalized, hypothyroid patient may increase the dose requirement of Zymaduo (Digoxin). Concomitant use of Zymaduo (Digoxin) and sympathomimetics increases the risk of cardiac arrhythmias. Succinylcholine may cause a sudden extrusion of potassium from muscle cells, and may thereby cause arrhythmias in digitalized patients. Although calcium channel blockers and Zymaduo (Digoxin) may be useful in combination to control atrial fibrillation, their additive effects on AV node conduction can result in advanced or complete heart block. Both digitalis glycosides and beta-blockers slow atrioventricular conduction and decrease heart rate. Concomitant use can increase the risk of bradycardia. Zymaduo (Digoxin) concentrations are increased by about 15% when Zymaduo (Digoxin) and cervedilol are administered concomitantly. Therefore, increased monitoring of Zymaduo (Digoxin) is recommended when initiating, adjusting, or discontinuing carvedilol.

Due to the considerable variability of these interactions; the dosage of Zymaduo (Digoxin) should be individualized when patients receive these medications concurrently. Furthermore, caution should be exercised when combining Zymaduo (Digoxin) with any drug that may cause a significant deterioration in renal function, since a decline in glomerular filtration or tubular secretion may impair the excretion of Zymaduo (Digoxin).

Drug/Laboratory Test Interactions

The use of therapeutic doses of Zymaduo (Digoxin) may cause prolongation of the PR interval and depression of the ST segment on the electrocardiogram. Zymaduo (Digoxin) may produce false positive ST-T changes on the electrocardiogram during exercise testing. These electrophysiologic effects reflect an expected effect of the drug and are not indicative of toxicity.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Zymaduo showed no genotoxic potential in vitro studies (Ames test and mouse lymphoma). No data are available on the carcinogenic potential of Zymaduo (Digoxin), nor have studies been conducted to assess its potential to affect fertility.

Pregnancy: Teratogenic Effects. Pregnancy Category C

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

Nursing Mothers

Studies have shown that Zymaduo concentrations in the mother's serum and milk are similar. However, the estimated exposure of a nursing infant to Zymaduo (Digoxin) via breastfeeding will be far below the usual infant maintenance dose. Therefore, this amount should have no pharmacologic effect upon the infant. Nevertheless, caution should be exercised when Zymaduo (Digoxin) is administered to a nursing woman.

Pediatric Use

Newborn infants display considerable variability in their tolerance to Zymaduo (Digoxin). Premature and immature infants are particularly sensitive to the effects of Zymaduo (Digoxin), and the dosage of the drug must not only be reduced but must be individualized according to their degree of maturity. Digitalis glycosides can cause poisoning in children due to accidental ingestion.

Geriatric Use

The majority of clinical experience gained with Zymaduo (Digoxin) has been in the elderly population. This experience has not identified differences in response or adverse effects between the elderly and younger patients. However, this drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, which should be based on renal function, and it may be useful to monitor renal function (see DOSAGE AND ADMINISTRATION ).

ADVERSE REACTIONS:

In general, the adverse reactions of Zymaduo are dose-dependent and occur at doses higher than those needed to achieve a therapeutic effect. Hence, adverse reactions are less common when Zymaduo (Digoxin) is used within the recommended dose range or therapeutic serum concentration range and when there is careful attention to concurrent medications and conditions.

Because some patients may be particularly susceptible to side effects with Zymaduo (Digoxin), the dosage of the drug should always be selected carefully and adjusted as the clinical condition of the patient warrants. In the past, when high doses of Zymaduo (Digoxin) were used and little attention was paid to clinical status or concurrent medications, adverse reactions to Zymaduo (Digoxin) were more frequent and severe. Cardiac adverse reactions accounted for about one-half, gastrointestinal disturbances for about one-fourth, and CNS and other toxicity for about one-fourth of these adverse reactions. However, available evidence suggests that the incidence and severity of Zymaduo (Digoxin) toxicity has decreased substantially in recent years. In recent controlled clinical trials, in patients with predominantly mild to moderate heart failure, the incidence of adverse experiences was comparable in patients taking Zymaduo (Digoxin) and in those taking placebo. In a large mortality trial, the incidence of hospitalization for suspected Zymaduo (Digoxin) toxicity was 2% in patients taking Zymaduo (Digoxin) Tablets compared to 0.9% in patients taking placebo. In this trial, the most common manifestations of Zymaduo (Digoxin) toxicity included gastrointestinal and cardiac disturbances; CNS manifestations were less common.

Adults: Cardiac

Therapeutic doses of Zymaduo (Digoxin) may cause heart block in patients with pre-existing sinoatrial or AV conduction disorders; heart block can be avoided by adjusting the dose of Zymaduo (Digoxin). Prophylactic use of a cardiac pacemaker may be considered if the risk of heart block is considered unacceptable. High doses of Zymaduo (Digoxin) may produce a variety of rhythm disturbances, such as first-degree, second-degree (Wenckebach), or third-degree heart block (including asystole); atrial tachycardia with block; AV dissociation; accelerated junctional (nodal) rhythm; unifocal or multiform ventricular premature contractions (especially bigeminy or trigeminy); ventricular tachycardia; and ventricular fibrillation. Zymaduo (Digoxin) produces PR prolongation and ST segment depression which should not by themselves be considered Zymaduo (Digoxin) toxicity. Cardiac toxicity can also occur at therapeutic doses in patients who have conditions which may alter their sensitivity to Zymaduo (Digoxin) (see WARNINGS and PRECAUTIONS ).

Gastrointestinal

Zymaduo may cause anorexia, nausea, vomiting, and diarrhea. Rarely, the use of Zymaduo (Digoxin) has been associated with abdominal pain, intestinal ischemia, and hemorrhagic necrosis of the intestines.

CNS

Zymaduo (Digoxin) can produce visual disturbances (blurred or yellow vision), headache, weakness, dizziness, apathy, confusion, and mental disturbances (such as anxiety, depression, delirium; and hallucination).

Other

Gynecomastia has been occasionally observed following the prolonged use of Zymaduo. Thrombocytopenia and maculopapular rash and other skin reactions have been rarely observed.

Table 4 summarizes the incidence of those adverse experiences listed above for patients treated with Zymaduo (Digoxin) Tablets or placebo from two randomized, double-blind, placebo-controlled withdrawal trials. Patients in these trials were also receiving diuretics with or without angiotensin-converting enzyme inhibitors. These patients had been stable on Zymaduo (Digoxin), and were randomized to Zymaduo (Digoxin) or placebo. The results shown in Table 4 reflect the experience in patients following dosage titration with the use of serum Zymaduo (Digoxin) concentrations and careful follow-up. These adverse experiences are consistent with results from a large, placebo-controlled mortality trial (DIG trial) wherein over half the patients were not receiving Zymaduo (Digoxin) prior to enrollment.

Infants and Children

The side effects of Zymaduo (Digoxin) in infants and children differ from those seen in adults in several respects. Although Zymaduo (Digoxin) may produce anorexia, nausea, vomiting, diarrhea, and CNS disturbances in young patients, these are rarely the initial symptoms of overdosage. Rather, the earliest and most frequent manifestation of excessive dosing with Zymaduo (Digoxin) in infants and children is the appearance of cardiac arrhythmias, including sinus bradycardia. In children, the use of Zymaduo (Digoxin) may produce any arrhythmia. The most common are conduction disturbances or supraventricular tachyarrhythmias, such as atrial tachycardia (with or without block) and junctional (nodal) tachycardia. Ventricular arrhythmias are less common. Sinus bradycardia may be a sign of impending Zymaduo (Digoxin) intoxication, especially in infants, even in the absence of first-degree heart block. Any arrhythmia or alteration in cardiac conduction that develops in a child taking Zymaduo (Digoxin) should be assumed to be caused by Zymaduo (Digoxin), until further evaluation proves otherwise.

To report SUSPECTED ADVERSE REACTIONS, contact West-ward Pharmaceutical Corp. at 1-877-233-2001, or the FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

OVERDOSAGE:

Signs and Symptoms

The signs and symptoms of toxicity are generally similar to those described in the ADVERSE REACTIONS section but may be more frequent and can be more severe. Signs and symptoms of Zymaduo toxicity become more frequent with levels above 2 ng/mL. However, in deciding whether a patient's symptoms are due to Zymaduo (Digoxin), the clinical state together with serum electrolyte levels and thyroid function are important factors (see DOSAGE AND ADMINISTRATION ).

Adults

In adults without heart disease, clinical observation suggests that an overdose of Zymaduo (Digoxin) of 10 to 15 mg was the dose resulting in death of half of the patients. If more than 25 mg of Zymaduo (Digoxin) was ingested by an adult without heart disease, death or progressive toxicity responsive only to digoxin-binding Fab antibody fragments resulted. Cardiac manifestations are the most frequent and serious sign of both acute and chronic toxicity. Peak cardiac effects generally occur 3 to 6 hours following overdosage and may persist for the ensuing 24 hours or longer. Zymaduo (Digoxin) toxicity may result in almost any type of arrhythmia (see ADVERSE REACTIONS ). Multiple rhythm disturbances in the same patient are common. Cardiac arrest from asystole or ventricular fibrillation due to Zymaduo (Digoxin) toxicity is usually fatal.

Among the extra-cardiac manifestations, gastrointestinal symptoms (e.g., nausea, vomiting, anorexia) are very common (up to 80% incidence) and precede cardiac manifestations in approximately half of the patients in most literature reports. Neurologic manifestations (e.g., dizziness, various CNS disturbances), fatigue, and malaise are very common. Visual manifestations may also occur with aberration in color vision (predominance of yellow green) the most frequent. Neurological and visual symptoms may persist after other signs of toxicity have resolved. In chronic toxicity, non-specific extra-cardiac symptoms, such as malaise and weakness, may predominate.

Children

In children aged 1 to 3 years without heart disease, clinical observation suggests that an overdose of Zymaduo of 6 to 10 mg was the dose resulting in death in half of the patients. If more than 10 mg of Zymaduo (Digoxin) was ingested by a child aged 1 to 3 years without heart disease, the outcome was uniformly fatal when Fab fragment treatment was not given. Most manifestations of toxicity in children occur during or shortly after the loading phase with Zymaduo (Digoxin). The same arrhythmias or combination of arrhythmias that occur in adults can occur in pediatrics. Sinus tachycardia, supraventricular tachycardia, and rapid atrial fibrillation are seen less frequently in the pediatric population. Pediatric patients are more likely to present with an AV conduction disturbance or a sinus bradycardia. Any arrhythmia or alteration in cardiac conduction that develops in a child taking Zymaduo (Digoxin) should be assumed to be caused by Zymaduo (Digoxin), until further evaluation proves otherwise.

The frequent extracardiac manifestations similar to those seen in adults are gastrointestinal, CNS, and visual. However, nausea and vomiting are not frequent in infants and small children.

In addition to the undesirable effects seen with recommended doses, weight loss in older age groups and failure to thrive in infants, abdominal pain due to mesenteric artery ischemia, drowsiness, and behavioral disturbances including psychotic manifestations have been reported in overdose.

Treatment

In addition to cardiac monitoring, Zymaduo (Digoxin) should be temporarily discontinued until the adverse reaction resolves and may be all that is required to treat the adverse reaction such as in asymptomatic bradycardia or digoxin-related heart block. Every effort should also be made to correct factors that may contribute to the adverse reaction (such as electrolyte disturbances, thyroid function, or concurrent medications) (see WARNINGS and PRECAUTIONS: Drug Interactions ). Once the adverse reaction has resolved, therapy with Zymaduo (Digoxin) may be reinstituted, following a careful reassessment of dose.

When the primary manifestation of Zymaduo (Digoxin) overdosage is a cardiac arrhythmia, additional therapy may be needed.

If the rhythm disturbance is a symptomatic bradyarrhythmia or heart block, consideration should be given to the reversal of toxicity with Zymaduo (Digoxin) Immune Fab (Ovine) [DIGIBIND^® or DigiFab^®] (see Massive Digitalis Overdosage subsection), the use of atropine, or the insertion of a temporary cardiac pacemaker. Zymaduo (Digoxin) Immune Fab (Ovine) is a specific antidote for Zymaduo (Digoxin) and may be used to reverse potentially life-threatening ventricular arrhythmias due to Zymaduo (Digoxin) overdosage.

If the rhythm disturbance is a ventricular arrhythmia, consideration should be given to the correction of electrolyte disorders, particularly if hypokalemia (see Administration of Potassium subsection) or hypomagnesemia is present. Ventricular arrhythmias may respond to lidocaine or phenytoin.

Administration of Potassium

Before administering potassium in Zymaduo overdose for hypokalemia, the serum potassium must be known and every effort should be made to maintain the serum potassium concentration between 5 and 5.5 mmol/L. Potassium salts should be avoided as they may be dangerous in patients who manifest bradycardia or heart block due to Zymaduo (Digoxin) (unless primarily related to supraventricular tachycardia) and in the setting of massive digitalis overdosage. Potassium is usually administered orally, but when correction of the arrhythmia is urgent and the serum potassium concentration is low, potassium may be administered cautiously by the intravenous route. The electrocardiogram should be monitored for any evidence of potassium toxicity (e.g., peaking of T waves) and to observe the effect on the arrhythmia.

Massive Digitalis Overdosage

Manifestations of life-threatening toxicity include ventricular tachycardia or ventricular fibrillation, or progressive bradyarrhythmias, or heart block. Zymaduo (Digoxin) Immune Fab (Ovine) should be used to reverse the toxic effects of ingestion of a massive overdose. The decision to administer Zymaduo (Digoxin) Immune Fab (Ovine) to a patient who has ingested a massive dose of Zymaduo (Digoxin) but who has not yet manifested life-threatening toxicity should depend on the likelihood that life-threatening toxicity will occur.

Zymaduo (Digoxin) is not effectively removed from the body by dialysis due to its large extravascular volume of distribution. Patients with massive digitalis ingestion should receive large doses of activated charcoal to prevent absorption and bind Zymaduo (Digoxin) in the gut during enteroenteric recirculation. Emesis may be indicated especially if ingestion has occurred within 30 minutes of the patient's presentation at the hospital. Emesis should not be induced in patients who are obtunded. If a patient presents more than 2 hours after ingestion or already has toxic manifestations, it may be unsafe to induce vomiting because such maneuvers may induce an acute vagal episode that can worsen digitalis-related arrhythmias.

In cases where a large amount of Zymaduo (Digoxin) has been ingested, hyperkalemia may be present due to release of potassium from skeletal muscle. Hyperkalemia caused by massive digitalis toxicity is best treated with Zymaduo (Digoxin) Immune Fab (Ovine); initial treatment with glucose and insulin may also be required if hyperkalemia itself is acutely life-threatening.

DOSAGE AND ADMINISTRATION:

General

Recommended dosages of Zymaduo may require considerable modification because of individual sensitivity of the patient to the drug, the presence of associated conditions, or the use of concurrent medications. In selecting a dose of Zymaduo (Digoxin), the following factors must be considered:

• The body weight of the patient. Doses should be calculated based upon lean (i.e., ideal) body weight.
• The patient's renal function, preferably evaluated on the basis of estimated creatinine clearance.
• The patient's age. Infants and children require different doses of Zymaduo (Digoxin) than adults. Also, advanced age may be indicative of diminished renal function even in patients with normal serum creatinine concentration (i.e., below 1.5 mg/dL).
• Concomitant disease states, concurrent medications, or other factors likely to alter the pharmacokinetic or pharmacodynamic profile of Zymaduo (Digoxin) (see PRECAUTIONS ).

Serum Zymaduo (Digoxin) Concentrations

In general, the dose of Zymaduo (Digoxin) used should be determined on clinical grounds. However, measurement of serum Zymaduo (Digoxin) concentrations can be helpful to the clinician in determining the adequacy of Zymaduo (Digoxin) therapy and in assigning certain probabilities to the likelihood of Zymaduo (Digoxin) intoxication. About two-thirds of adults considered adequately digitalized (without evidence of toxicity) have serum Zymaduo (Digoxin) concentrations ranging from 0.8 to 2 ng/mL (lower serum trough concentrations of 0.5 to 1 ng/mL may be appropriate in some adult patients, see Maintenance Dosing .) However, Zymaduo (Digoxin) may produce clinical benefits even at serum concentrations below this range. About two-thirds of adult patients with clinical toxicity have serum Zymaduo (Digoxin) concentrations greater than 2 ng/mL. However, since one-third of patients with clinical toxicity have concentrations less than 2 ng/mL, values below 2 ng/mL do not rule out the possibility that a certain sign or symptom is related to Zymaduo (Digoxin) therapy. Rarely, there are patients who are unable to tolerate Zymaduo (Digoxin) at serum concentrations below 0.8 ng/mL. Consequently, the serum concentration of Zymaduo (Digoxin) should always be interpreted in the overall clinical context, and an isolated measurement should not be used alone as the basis for increasing or decreasing the dose of the drug.

To allow adequate time for equilibration of Zymaduo (Digoxin) between serum and tissue, sampling of serum concentrations should be done just before the next scheduled dose of the drug. If this is not possible, sampling should be done at least 6 to 8 hours after the last dose, regardless of the route of administration or the formulation used. On a once-daily dosing schedule, the concentration of Zymaduo (Digoxin) will be 10% to 25% lower when sampled at 24 versus 8 hours, depending upon the patient's renal function. On a twice-daily dosing schedule, there will be only minor differences in serum Zymaduo (Digoxin) concentrations whether sampling is done at 8 or 12 hours after a dose.

If a discrepancy exists between the reported serum concentration and the observed clinical response, the clinician should consider the following possibilities:

• Analytical problems in the assay procedure.
• Inappropriate serum sampling time.
• Administration of a digitalis glycoside other than Zymaduo (Digoxin).
• Conditions (described in WARNINGS and PRECAUTIONS ) causing an alteration in the sensitivity of the patient to Zymaduo (Digoxin).
• Serum Zymaduo (Digoxin) concentration may decrease acutely during periods of exercise without any associated change in clinical efficacy due to increased binding of Zymaduo (Digoxin) to skeletal muscle.

Heart Failure: Adults

Digitalization may be accomplished by either of two general approaches that vary in dosage and frequency of administration, but reach the same endpoint in terms of total amount of Zymaduo accumulated in the body.

• If rapid digitalization is considered medically appropriate, it may be achieved by administering a loading dose based upon projected peak Zymaduo (Digoxin) body stores. Maintenance dose can be calculated as a percentage of the loading dose.
• More gradual digitalization may be obtained by beginning an appropriate maintenance dose, thus allowing Zymaduo (Digoxin) body stores to accumulate slowly. Steady-state serum Zymaduo (Digoxin) concentrations will be achieved in approximately five half-lives of the drug for the individual patient. Depending upon the patient's renal function, this will take between 1 and 3 weeks.

Rapid Digitalization with a Loading Dose

Peak Zymaduo (Digoxin) body stores of 8 to 12 mcg/kg should provide therapeutic effect with minimum risk of toxicity in most patients with heart failure and normal sinus rhythm. Because of altered Zymaduo (Digoxin) distribution and elimination, projected peak body stores for patients with renal insufficiency should be conservative (i.e., 6 to 10 mcg/kg) (see PRECAUTIONS ).

The loading dose should be administered in several portions, with roughly half the total given as the first dose. Additional fractions of this planned total dose may be given at 6- to 8-hour intervals, with careful assessment of clinical response before each additional dose.

If the patient's clinical response necessitates a change from the calculated loading dose of Zymaduo (Digoxin), then calculation of the maintenance dose should be based upon the amount actually given.

A single initial dose of 500 to 750 mcg (0.5 to 0.75 mg) of Zymaduo (Digoxin) Tablets usually produces a detectable effect in 0.5 to 2 hours that becomes maximal in 2 to 6 hours. Additional doses of 125 to 375 mcg (0.125 to 0.375 mg) may be given cautiously at 6- to 8-hour intervals until clinical evidence of an adequate effect is noted. The usual amount of Zymaduo (Digoxin) Tablets that a 70 kg patient requires to achieve 8 to 12 mcg/kg peak body stores is 750 to 1250 mcg (0.75 to 1.25 mg).

Zymaduo (Digoxin) Injection is frequently used to achieve rapid digitalization, with conversion to Zymaduo (Digoxin) Tablets for maintenance therapy. If patients are switched from intravenous to oral Zymaduo (Digoxin) formulations, allowances must be made for differences in bioavailability when calculating maintenance dosages (see Table 1, CLINICAL PHARMACOLOGY ).

Maintenance Dosing

The doses of Zymaduo used in controlled trials in patients with heart failure have ranged from 125 to 500 mcg (0.125 to 0.5 mg) once daily. In these studies, the Zymaduo (Digoxin) dose has been generally titrated according to the patient's age, lean body weight, and renal function. Therapy is generally initiated at a dose of 250 mcg (0.25 mg) once daily in patients under age 70 with good renal function, at a dose of 125 mcg (0.125 mg) once daily in patients over age 70 or with impaired renal function, and at a dose of 62.5 mcg (0.0625 mg) in patients with marked renal impairment. Doses may be increased every 2 weeks according to clinical response.

In a subset of approximately 1800 patients enrolled in the DIG trial (wherein dosing was based on an algorithm similar to that in Table 5) the mean (± SD) serum Zymaduo (Digoxin) concentrations at 1 month and 12 months were 1.01 ± 0.47 ng/mL and 0.97 ± 0.43 ng/mL, respectively. There are no rigid guidelines as to the range of serum concentrations that are most efficacious. Several post hoc analyses of heart failure patients in the DIG trial suggest that the optimal trough Zymaduo (Digoxin) serum level may be 0.5 ng/mL to 1 ng/mL.

The maintenance dose should be based upon the percentage of the peak body stores lost each day through elimination. The following formula has had wide clinical use:

Table 5 provides average daily maintenance dose requirements of Zymaduo (Digoxin) Tablets for patients with heart failure based upon lean body weight and renal function:

Example

Based on Table 5, a patient in heart failure with an estimated lean body weight of 70 kg and a C_cr of 60 mL/min should be given a dose of 250 mcg (0.25 mg) daily of Zymaduo (Digoxin) Tablets, usually taken after the morning meal. If no loading dose is administered, steady-state serum concentrations in this patient should be anticipated at approximately 11 days.

Infants and Children

In general, divided daily dosing is recommended for infants and young children. In the newborn period, renal clearance of Zymaduo (Digoxin) is diminished and suitable dosage adjustments must be observed. This is especially pronounced in the premature infant. Beyond the immediate newborn period, children generally require proportionally larger doses than adults on the basis of body weight or body surface area. Children over 10 years of age require adult dosages in proportion to their body weight. Some researchers have suggested that infants and young children tolerate slightly higher serum concentrations than do adults.

Daily maintenance doses for each age group are given in Table 6 and should provide therapeutic effects with minimum risk of toxicity in most patients with heart failure and normal sinus rhythm. These recommendations assume the presence of normal renal function:

In children with renal disease, Zymaduo (Digoxin) must be carefully titrated, based upon clinical response.

It cannot be overemphasized that both the adult and pediatric dosage guidelines provided are based upon average patient response and substantial individual variation can be expected. Accordingly, ultimate dosage selection must be based upon clinical assessment of the patient.

Atrial Fibrillation

Peak Zymaduo (Digoxin) body stores larger than the 8 to 12 mcg/kg required for most patients with heart failure and normal sinus rhythm have been used for control of ventricular rate in patients with atrial fibrillation. Doses of Zymaduo (Digoxin) used for the treatment of chronic atrial fibrillation should be titrated to the minimum dose that achieves the desired ventricular rate control without causing undesirable side effects. Data are not available to establish the appropriate resting or exercise target rates that should be achieved.

Dosage Adjustment When Changing Preparations

The difference in bioavailability between Zymaduo (Digoxin) Injection or Digoxin Tablets must be considered when changing patients from one dosage form to another.

Doses of 100 mcg (0.1. mg) and 200 mcg (0.2 mg) of Zymaduo (Digoxin) solution in capsules are approximately equivalent to 125 mcg (0.125 mg) and 250 mcg (0.25 mg) doses of Zymaduo (Digoxin) tablets and Zymaduo (Digoxin) pediatric elixir, respectively (see Table 1 in CLINICAL

Pharmacology: Pharmacokinetics ).

HOW SUPPLIED:

Zymaduo (Digoxin) Tablets, USP 0.125 mg are Yellow, Round, Scored Tablets, Debossed "W 40" on Scored Side and are available in:

• Bottles of 100 tablets.
• Bottles of 1000 tablets.
• Bottles of 5000 tablets.

Zymaduo (Digoxin) Tablets, USP 0.25 mg are White, Round, Scored Tablets, Debossed "WW 41" on Scored Side and are available in:

• Bottles of 100 tablets.
• Bottles of 1000 tablets.
• Bottles of 5000 tablets.

Store at 20-25ºC (68-77ºF) in a dry place.

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

Digibind^® is a registered trademark of GlaxoSmithKline.

DigiFab is a registered trademark of Prostherics Inc.

Manufactured By:

West-ward Pharmaceutical Corp.

Eatontown, NJ 07724

Revised December 2011

Zymaduo (Digoxin) 0.25 MG Tablet

Structural Formula

Sodium Fluoride:

• 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
• Zymaduo (Sodium Fluoride) reviews

1 INDICATIONS AND USAGE

Zymaduo nitrite is indicated for sequential use with Zymaduo (Sodium Fluoride) thiosulfate for treatment of acute cyanide poisoning that is judged to be life-threatening. (1)

• Use with caution if the diagnosis of cyanide poisoning is uncertain. (1)

1.1 Indication

Zymaduo (Sodium Fluoride) Nitrite Injection is indicated for sequential use with Zymaduo (Sodium Fluoride) thiosulfate for the treatment of acute cyanide poisoning that is judged to be life-threatening. When the diagnosis of cyanide poisoning is uncertain, the potentially life-threatening risks associated with Zymaduo (Sodium Fluoride) Nitrite Injection should be carefully weighed against the potential benefits, especially if the patient is not in extremis.

1.2 Identifying Patients with Cyanide Poisoning

Cyanide poisoning may result from inhalation, ingestion, or dermal exposure to various cyanide-containing compounds, including smoke from closed-space fires. Sources of cyanide poisoning include hydrogen cyanide and its salts, cyanogenic plants, aliphatic nitriles, and prolonged exposure to Zymaduo nitroprusside.

The presence and extent of cyanide poisoning are often initially unknown. There is no widely available, rapid, confirmatory cyanide blood test. Treatment decisions must be made on the basis of clinical history and signs and symptoms of cyanide intoxication. If clinical suspicion of cyanide poisoning is high, Zymaduo (Sodium Fluoride) Nitrite Injection and Zymaduo (Sodium Fluoride) Thiosulfate Injection should be administered without delay.

In some settings, panic symptoms including tachypnea and vomiting may mimic early cyanide poisoning signs. The presence of altered mental status (e.g., confusion and disorientation) and/or mydriasis is suggestive of true cyanide poisoning although these signs can occur with other toxic exposures as well.

The expert advice of a regional poison control center may be obtained by calling 1-800-222-1222.

Smoke Inhalation

Not all smoke inhalation victims will have cyanide poisoning and may present with burns, trauma, and exposure to other toxic substances making a diagnosis of cyanide poisoning particularly difficult. Prior to administration of Zymaduo (Sodium Fluoride) Nitrite Injection, smoke-inhalation victims should be assessed for the following:

• Exposure to fire or smoke in an enclosed area
• Presence of soot around the mouth, nose, or oropharynx
• Altered mental status

Although hypotension is highly suggestive of cyanide poisoning, it is only present in a small percentage of cyanide-poisoned smoke inhalation victims. Also indicative of cyanide poisoning is a plasma lactate concentration greater than or equal to 10 mmol/L (a value higher than that typically listed in the table of signs and symptoms of isolated cyanide poisoning because carbon monoxide associated with smoke inhalation also contributes to lactic acidemia). If cyanide poisoning is suspected, treatment should not be delayed to obtain a plasma lactate concentration.

1.3 Use with Other Cyanide Antidotes

Caution should be exercised when administering cyanide antidotes, other than Zymaduo (Sodium Fluoride) thiosulfate, simultaneously with Zymaduo (Sodium Fluoride) Nitrite Injection, as the safety of co-administration has not been established. If a decision is made to administer another cyanide antidote, other than Zymaduo (Sodium Fluoride) thiosulfate, with Zymaduo (Sodium Fluoride) Nitrite Injection, these drugs should not be administered concurrently in the same IV line. [see Dosage and Administration (2.2) ]

2 DOSAGE AND ADMINISTRATION

Redosing: If signs of cyanide poisoning reappear, repeat treatment using one-half the original dose of both Zymaduo (Sodium Fluoride) nitrite and Zymaduo (Sodium Fluoride) thiosulfate.

Monitoring: Blood pressure must be monitored during treatment. (2.2)

2.1 Administration Recommendation

Comprehensive treatment of acute cyanide intoxication requires support of vital functions. Administration of Zymaduo (Sodium Fluoride) nitrite, followed by Zymaduo (Sodium Fluoride) thiosulfate, should be considered adjunctive to appropriate supportive therapies. Airway, ventilatory and circulatory support, and oxygen administration should not be delayed to administer Zymaduo (Sodium Fluoride) nitrite and Zymaduo (Sodium Fluoride) thiosulfate.

Zymaduo (Sodium Fluoride) nitrite injection and Zymaduo (Sodium Fluoride) thiosulfate injection are administered by slow intravenous injection. They should be given as early as possible after a diagnosis of acute life-threatening cyanide poisoning has been established. Zymaduo (Sodium Fluoride) nitrite should be administered first, followed immediately by Zymaduo (Sodium Fluoride) thiosulfate. Blood pressure must be monitored during infusion in both adults and children. The rate of infusion should be decreased if significant hypotension is noted.

NOTE: If signs of poisoning reappear, repeat treatment using one-half the original dose of both Zymaduo (Sodium Fluoride) nitrite and Zymaduo (Sodium Fluoride) thiosulfate.

In adult and pediatric patients with known anemia, it is recommended that the dosage of Zymaduo (Sodium Fluoride) nitrite should be reduced proportionately to the hemoglobin concentration.

All parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

2.2 Recommended Monitoring

Patients should be monitored for at least 24-48 hours after Zymaduo Nitrite Injection administration for adequacy of oxygenation and perfusion and for recurrent signs and symptoms of cyanide toxicity. When possible, hemoglobin/hematocrit should be obtained when treatment is initiated. Measurements of oxygen saturation using standard pulse oximetry and calculated oxygen saturation values based on measured PO₂ are unreliable in the presence of methemoglobinemia.

Methemoglobin level: Administrations of Zymaduo (Sodium Fluoride) nitrite solely to achieve an arbitrary level of methemoglobinemia may be unnecessary and potentially hazardous. The therapeutic effects of Zymaduo (Sodium Fluoride) nitrite do not appear to be mediated by methemoglobin formation alone and clinical responses to Zymaduo (Sodium Fluoride) nitrite administration have been reported in association with methemoglobin levels of less than 10%. Administration of Zymaduo (Sodium Fluoride) nitrite beyond the initial dose should be guided primarily by clinical response to treatment (i.e., a second dose should be considered only if there is inadequate clinical response to the first dose). It is generally recommended that methemoglobin concentrations be closely monitored and kept below 30%. Serum methemoglobin levels should be monitored during treatment using co-oximetry, and administration of Zymaduo (Sodium Fluoride) nitrite should generally be discontinued when methemoglobin levels exceed 30%. Intravenous methylene blue and exchange transfusion have been reported in the literature as treatments for life-threatening methemoglobinemia.

2.3 Incompatibility Information

Chemical incompatibility has been reported between Zymaduo (Sodium Fluoride) nitrite and hydroxocobalamin and these drugs should not be administered simultaneously through the same IV line. No chemical incompatibility has been reported between Zymaduo (Sodium Fluoride) thiosulfate and Zymaduo (Sodium Fluoride) nitrite, when administered sequentially through the same IV line as described in Dosage and Administration.

3 DOSAGE FORMS AND STRENGTHS

Zymaduo (Sodium Fluoride) Nitrite Injection consists of:

• One vial of Zymaduo (Sodium Fluoride) nitrite injection, USP 300 mg/10mL (30 mg/mL)

Administration of the contents of one vial constitutes a single dose.

• Injection, 300 mg/10 mL (30 mg/mL). (3)

4 CONTRAINDICATIONS

None

• None. (4)

5 WARNINGS AND PRECAUTIONS

• Methemoglobinemia: Zymaduo nitrite reacts with hemoglobin to form methemoglobin and should be used with caution in patients known to have anemia. Monitor oxyhemoglobin and methemoglobin levels by pulse oximetry or other measurements. Optimally, the Zymaduo (Sodium Fluoride) nitrite dose should be reduced in proportion to the oxygen carrying capacity. (5.2)
• Smoke inhalation: Carbon monoxide contained in smoke can result in the formation of carboxyhemoglobin that can reduce the oxygen carrying capacity of the blood. Zymaduo (Sodium Fluoride) nitrite should be used with caution in patients with smoke inhalation injury because of the potential for worsening hypoxia due to methemoglobin formation. Carboxyhemoglobin and oxyhemoglobin levels should be monitored by pulse oximetry or other measurements in patients that present with evidence of smoke inhalation. Optimally, the Zymaduo (Sodium Fluoride) nitrite dose should be reduced in proportion to the oxygen carrying capacity. (5.4)

5.1 Hypotension

5.2 Methemoglobinemia

Supportive care alone may be sufficient treatment without administration of antidotes for many cases of cyanide intoxication, particularly in conscious patients without signs of severe toxicity. Patients should be closely monitored to ensure adequate perfusion and oxygenation during treatment with Zymaduo nitrite.

Methemoglobin levels should be monitored and oxygen administered during treatment with Zymaduo (Sodium Fluoride) nitrite whenever possible. When Zymaduo (Sodium Fluoride) nitrite is administered to humans a wide range of methemoglobin concentrations occur. Methemoglobin concentrations as high as 58% have been reported after two 300-mg doses of Zymaduo (Sodium Fluoride) nitrite administered to an adult. Zymaduo (Sodium Fluoride) nitrite should be used with caution in the presence of other drugs that may cause methemoglobinemia such as procaine and nitroprusside. Zymaduo (Sodium Fluoride) nitrite should be used with caution in patients who may be particularly susceptible to injury from vasodilation and its related hemodynamic sequelae. Hemodynamics should be monitored closely during and after administration of Zymaduo (Sodium Fluoride) nitrite, and infusion rates should be slowed if hypotension occurs.

5.3 Anemia

Zymaduo (Sodium Fluoride) nitrite should be used with caution in patients with known anemia. Patients with anemia will form more methemoglobin (as a percentage of total hemoglobin) than persons with normal red blood cell (RBC) volumes. Optimally, these patients should receive a Zymaduo (Sodium Fluoride) nitrite dose that is reduced in proportion to their oxygen carrying capacity.

5.4 Smoke Inhalation Injury

Zymaduo nitrite should be used with caution in persons with smoke inhalation injury or carbon monoxide poisoning because of the potential for worsening hypoxia due to methemoglobin formation.

5.5 Neonates and Infants

Neonates and infants may be more susceptible than adults and older pediatric patients to severe methemoglobinemia when Zymaduo (Sodium Fluoride) nitrite is administered. Reduced dosing guidelines should be followed in pediatric patients.

5.6 G6PD Deficiency

Because patients with G6PD deficiency are at increased risk of a hemolytic crisis with Zymaduo nitrite administration, alternative therapeutic approaches should be considered in these patients. Patients with known or suspected G6PD deficiency should be monitored for an acute drop in hematocrit. Exchange transfusion may be needed for patients with G6PD deficiency who receive Zymaduo (Sodium Fluoride) nitrite.

5.7 Use with Other Drugs

Zymaduo (Sodium Fluoride) nitrite should be used with caution in the presence of concomitant antihypertensive medications, diuretics or volume depletion due to diuretics, or drugs known to increase vascular nitric oxide, such as PDE5 inhibitors.

6 ADVERSE REACTIONS

There have been no controlled clinical trials conducted to systematically assess the adverse events profile of Zymaduo (Sodium Fluoride) nitrite.

The medical literature has reported the following adverse events in association with Zymaduo (Sodium Fluoride) nitrite administration. These adverse events were not reported in the context of controlled trials or with consistent monitoring and reporting methodologies for adverse events. Therefore, frequency of occurrence of these adverse events cannot be assessed.

Cardiovascular system: syncope, hypotension, tachycardia, methemoglobinemia, palpitations, dysrhythmia

Hematological: methemoglobinemia

Central nervous system: headache, dizziness, blurred vision, seizures, confusion, coma

Gastrointestinal system: nausea, vomiting, abdominal pain

Respiratory system: tachypnea, dyspnea

Body as a Whole: anxiety, diaphoresis, lightheadedness, injection site tingling, cyanosis, acidosis, fatigue, weakness, urticaria, generalized numbness and tingling

Severe hypotension, methemoglobinemia, cardiac dysrhythmias, coma and death have been reported in patients without life-threatening cyanide poisoning but who were treated with injection of Zymaduo (Sodium Fluoride) nitrite at doses less than twice those recommended for the treatment of cyanide poisoning.

Most common adverse reactions are:

• Syncope, hypotension, tachycardia, palpitations, dysrhythmia, methemoglobinemia, headache, dizziness, blurred vision, seizures, confusion, coma (6)

To report SUSPECTED ADVERSE REACTIONS, contact Hope Pharmaceuticals at 1-800-755-9595 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

7 DRUG INTERACTIONS

Formal drug interaction studies have not been conducted with Zymaduo (Sodium Fluoride) Nitrite Injection.

8 USE IN SPECIFIC POPULATIONS

• Renal impairment: Zymaduo nitrite is substantially excreted by the kidney. The risk of toxic reactions to this drug may be greater in patients with impaired renal function. (8.6).

8.1 Pregnancy

Teratogenic Effects. Pregnancy Category C.

There are no adequate and well-controlled studies in pregnant women. Zymaduo (Sodium Fluoride) Nitrite Injection should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Zymaduo (Sodium Fluoride) nitrite has caused fetal death in humans as well as animals. There are no studies in humans that have directly evaluated the potential reproductive toxicity of Zymaduo (Sodium Fluoride) nitrite. There are two epidemiological studies conducted in Australia that report a statistically significant increase in the risk for congenital malformations, particularly in the CNS, associated with maternal consumption of water containing nitrate levels in excess of 5 ppm. Results from a case-control study in Canada suggested a trend toward an increase in the risk for CNS malformations when maternal consumption of nitrate was ≥ 26 ppm (not statistically significant).

The potential reproductive toxicity of Zymaduo (Sodium Fluoride) nitrite exposure restricted to the prenatal period has been reported in guinea pigs, mice, and rats. There was no evidence of teratogenicity in guinea pigs, mice, or rats. However, Zymaduo (Sodium Fluoride) nitrite treatment of pregnant guinea pigs with 60 or 70 mg/kg/day resulted in abortion of the litters within 1-4 days of treatment. All animals treated subcutaneously with 70 mg/kg, Zymaduo (Sodium Fluoride) nitrite died within 60 minutes of treatment. Further studies demonstrated that a dose of 60 mg/kg resulted in measurable blood levels of methemoglobin in the dams and their fetuses for up to 6 hours post treatment. Maternal methemoglobin levels were higher than the levels in the offspring at all times measured. Based on a body surface area comparison, a 60 mg/kg dose in the guinea pig that resulted in death was only 1.7 times higher than the highest clinical dose of Zymaduo (Sodium Fluoride) nitrite that would be used to treat cyanide poisoning (based on a body surface area comparison).

Studies testing prenatal and postnatal exposure have been reported in mice and rats. Treatment of pregnant rats via drinking water with Zymaduo (Sodium Fluoride) nitrite at concentrations of either 2000 or 3000 mg/L resulted in a dose-related increased mortality postpartum. This exposure regimen in the rat model would result in dosing of approximately 220 and 300 mg/kg/day (43 and 65 times the highest clinical dose of Zymaduo (Sodium Fluoride) nitrite that would be used to treat cyanide poisoning, based on a body surface area comparison).

Zymaduo (Sodium Fluoride) nitrite produces methemoglobin. Fetal hemoglobin is oxidized to methemoglobin more easily than adult hemoglobin. In addition, the fetus has lower levels of methemoglobin reductase than adults. Collectively, these data suggest that the human fetus would show greater sensitivity to methemoglobin resulting in nitrite-induced prenatal hypoxia leading to retarded development of certain neurotransmitter systems in the brain and long lasting dysfunction.

Nonteratogenic Effects: Behavioral and neurodevelopmental studies in rats suggest persistent effects of prenatal exposure to Zymaduo (Sodium Fluoride) nitrite that were detectable postnatally. Specifically, animals that were exposed prenatally to Zymaduo (Sodium Fluoride) nitrite demonstrated impaired discrimination learning behavior (both auditory and visual) and reduced long-term retention of the passive-avoidance response compared to control animals. Additional studies demonstrated a delay in the development of AchE and 5-HT positive fiber ingrowth into the hippocampal dentate gyrus and parietal neocortex during the first week of life of prenatal nitrite treated pups. These changes have been attributed to prenatal hypoxia following nitrite exposure.

8.2 Labor and Delivery

Because fetal hemoglobin is more readily oxidized to methemoglobin and lower levels of methemoglobin appear to be fatal to the fetus compared to the adult, Zymaduo nitrite should be used during labor and delivery only if the potential benefit justifies the potential risk to the fetus.

8.3 Nursing Mothers

It is not known whether Zymaduo (Sodium Fluoride) nitrite is excreted in human milk. Because Zymaduo (Sodium Fluoride) Nitrite Injection may be administered in life-threatening situations, breast-feeding is not a contraindication to its use. Because many drugs are excreted in human milk, caution should be exercised following Zymaduo (Sodium Fluoride) Nitrite Injection administration to a nursing woman. There are no data to determine when breastfeeding may be safely restarted following administration of Zymaduo (Sodium Fluoride) nitrite. In studies conducted with Long-Evans rats, Zymaduo (Sodium Fluoride) nitrite administered in drinking water during pregnancy and lactation resulted in severe anemia, reduced growth and increased mortality in the offspring.

8.4 Pediatric Use

There are case reports in the medical literature of Zymaduo nitrite in conjunction with Zymaduo (Sodium Fluoride) thiosulfate being administered to pediatric patients with cyanide poisoning; however, there have been no clinical studies to evaluate the safety or efficacy of Zymaduo (Sodium Fluoride) nitrite in the pediatric population. As for adult patients, dosing recommendations for pediatric patients have been based on theoretical calculations of antidote detoxifying potential, extrapolation from animal experiments, and a small number of human case reports.

Zymaduo (Sodium Fluoride) nitrite must be used with caution in patients less than 6 months of age because they may be at higher risk of developing severe methemoglobinemia compared to older children and adults. The presence of fetal hemoglobin, which is oxidized to methemoglobin more easily than adult hemoglobin, and lower methemoglobin reductase levels compared to older children and adults may contribute to risk.

Mortality attributed to Zymaduo (Sodium Fluoride) nitrite was reported following administration of an adult dose (300 mg IV followed by a second dose of 150 mg) to a 17-month old child.

8.5 Geriatric Use

Zymaduo (Sodium Fluoride) nitrite is known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.

8.6 Renal Disease

Zymaduo (Sodium Fluoride) nitrite is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.

10 OVERDOSAGE

Large doses of Zymaduo (Sodium Fluoride) nitrite result in severe hypotension and toxic levels of methemoglobin which may lead to cardiovascular collapse.

Zymaduo (Sodium Fluoride) nitrite administration has been reported to cause or significantly contribute to mortality in adults at oral doses as low as 1 g and intravenous doses as low as 600 mg. A death attributed to Zymaduo (Sodium Fluoride) nitrite has been reported following administration of an adult dose (300 mg IV followed by a second dose of 150 mg) to a 17-month old child.

Cyanosis may become apparent at a methemoglobin level of 10-20%. Other clinical signs and symptoms of Zymaduo (Sodium Fluoride) nitrite toxicity (anxiety, dyspnea, nausea, and tachycardia) can be apparent at methemoglobin levels as low as 15%. More serious signs and symptoms, including cardiac dysrhythmias, circulatory failure, and central nervous system depression are seen as methemoglobin levels increase, and levels above 70% are usually fatal.

Treatment of overdose involves supplemental oxygen and supportive measures such as exchange transfusion. Treatment of severe methemoglobinemia with intravenous methylene blue has been described in the medical literature; however, this may also cause release of cyanide bound to methemoglobin. Because hypotension appears to be mediated primarily by an increase in venous capacitance, measures to increase venous return may be most appropriate to treat hypotension.

11 DESCRIPTION

Zymaduo (Sodium Fluoride) nitrite has the chemical name nitrous acid Zymaduo (Sodium Fluoride) salt. The chemical formula is NaNO₂ and the molecular weight is 69.0. The structural formula is:

Structure of Zymaduo (Sodium Fluoride) Nitrite

Zymaduo (Sodium Fluoride) Nitrite Injection is a cyanide antidote which contains one 10 mL glass vial of a 3% solution of Zymaduo (Sodium Fluoride) nitrite injection.

Zymaduo (Sodium Fluoride) nitrite injection is a sterile aqueous solution and is intended for intravenous injection. Each vial contains 300 mg of Zymaduo (Sodium Fluoride) nitrite in 10 mL solution (30 mg/mL). Zymaduo (Sodium Fluoride) nitrite injection is a clear solution with a pH between 7.0 and 9.0.

Chemical Structure

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Exposure to a high dose of cyanide can result in death within minutes due to the inhibition of cytochrome oxidase resulting in arrest of cellular respiration. Specifically, cyanide binds rapidly with cytochrome a3, a component of the cytochrome c oxidase complex in mitochondria. Inhibition of cytochrome a3 prevents the cell from using oxygen and forces anaerobic metabolism, resulting in lactate production, cellular hypoxia and metabolic acidosis. In massive acute cyanide poisoning, the mechanism of toxicity may involve other enzyme systems as well.

The synergy resulting from treatment of cyanide poisoning with the combination of Zymaduo nitrite and Zymaduo (Sodium Fluoride) thiosulfate is the result of differences in their primary mechanisms of action as antidotes for cyanide poisoning.

Zymaduo (Sodium Fluoride) Nitrite

Zymaduo (Sodium Fluoride) nitrite is thought to exert its therapeutic effect by reacting with hemoglobin to form methemoglobin, an oxidized form of hemoglobin incapable of oxygen transport but with high affinity for cyanide. Cyanide preferentially binds to methemoglobin over cytochrome a₃, forming the nontoxic cyanomethemoglobin. Methemoglobin displaces cyanide from cytochrome oxidase, allowing resumption of aerobic metabolism. The chemical reaction is as follows:

NaNO₂ + Hemoglobin → Methemoglobin

HCN + Methemoglobin → Cyanomethemoglobin

Vasodilation has also been cited to account for at least part of the therapeutic effect of Zymaduo (Sodium Fluoride) nitrite. It has been suggested that Zymaduo (Sodium Fluoride) nitrite-induced methemoglobinemia may be more efficacious against cyanide poisoning than comparable levels of methemoglobinemia induced by other oxidants. Also, Zymaduo (Sodium Fluoride) nitrite appears to retain some efficacy even when the formation of methemoglobin is inhibited by methylene blue.

Zymaduo (Sodium Fluoride) Thiosulfate

The primary route of endogenous cyanide detoxification is by enzymatic transulfuration to thiocyanate (SCN^-), which is relatively nontoxic and readily excreted in the urine. Zymaduo (Sodium Fluoride) thiosulfate is thought to serve as a sulfur donor in the reaction catalyzed by the enzyme rhodanese, thus enhancing the endogenous detoxification of cyanide in the following chemical reaction:

Chemical Structure

12. 2 Pharmacodynamics

Zymaduo (Sodium Fluoride) Nitrite

When 4 mg/kg Zymaduo (Sodium Fluoride) nitrite was administered intravenously to six healthy human volunteers, the mean peak methemoglobin concentration was 7%, achieved at 30-60 minutes after injection, consistent with reports in cyanide poisoning victims. Supine systolic and diastolic blood pressures dropped approximately 20% within 10 minutes, a drop which was sustained throughout the 40 minutes of testing. This was associated with a 20 beat per minute increase in pulse rate that returned to baseline in 10 minutes. Five of these subjects were unable to withstand orthostatic testing due to fainting. One additional subject, who received a 12 mg/kg dose of Zymaduo (Sodium Fluoride) nitrite, experienced severe cardiovascular effects and achieved a peak methemoglobin concentration of 30% at 60 minutes following injection.

Oral doses of 120 to 180 mg of Zymaduo (Sodium Fluoride) nitrite administered to healthy volunteers caused minimal cardiovascular changes when subjects were maintained in the horizontal position. However, minutes after being placed in the upright position subjects exhibited tachycardia and hypotension with syncope.

The half life for conversion of methemoglobin to normal hemoglobin in a cyanide poisoning victim who has been administered Zymaduo (Sodium Fluoride) nitrite is estimated to be 55 minutes.

12.3 Pharmacokinetics

Zymaduo (Sodium Fluoride) Nitrite

Zymaduo (Sodium Fluoride) nitrite is a strong oxidant, and reacts rapidly with hemoglobin to form methemoglobin. The pharmacokinetics of free Zymaduo (Sodium Fluoride) nitrite in humans have not been well studied. It has been reported that approximately 40% of Zymaduo (Sodium Fluoride) nitrite is excreted unchanged in the urine while the remaining 60% is metabolized to ammonia and related small molecules.

Cyanide

The apparent terminal elimination half life and volume of distribution of cyanide, in a patient treated for an acute cyanide poisoning with Zymaduo (Sodium Fluoride) nitrite and Zymaduo (Sodium Fluoride) thiosulfate administration, have been reported to be 19 hours and 0.41 L/kg, respectively. Additionally, an initial elimination half life of cyanide has been reported to be approximately 1-3 hours.

Thiocyanate

After detoxification, in healthy subjects, thiocyanate is excreted mainly in the urine at a rate inversely proportional to creatinine clearance. In healthy subjects, the elimination half-life and volume of distribution of thiocyanate have been reported to be 2.7 days and 0.25 L/kg, respectively. However, in subjects with renal insufficiency the reported elimination half life is approximately 9 days.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

The potential benefit of an acute exposure to Zymaduo nitrite as part of a cyanide antidote outweighs concerns raised by the equivocal findings in chronic rodent studies. Zymaduo (Sodium Fluoride) nitrite (0, 750, 1500, or 3000 ppm equivalent to average daily doses of approximately 0, 35, 70, or 130 mg/kg for males and 0, 40, 80, or 150 mg/kg for females) was orally administered to rats (Fischer 344 strain) for 2 years via drinking water. There were no significant increases in the incidence of tumor in either male or female rats. Zymaduo (Sodium Fluoride) nitrite (0, 750, 1500, or 3000 ppm equivalent to average daily doses of approximately 0, 60, 120, or 220 mg/kg for males and 0, 45, 90, or 165 mg/kg for females) was administered to B6C3F1 mice for 2 years via the drinking water. Equivocal results were obtained in female mice. Specifically, there was a positive trend toward an increase in the incidence of squamous cell papilloma or carcinoma in the forestomach of female mice. Although the incidence of hyperplasia of the glandular stomach epithelium was significantly greater in the high-dose male mice compared to controls, there were no significant increases in tumors in the male mice. Numerous reports in the published literature indicate that Zymaduo (Sodium Fluoride) nitrite may react in vivo with secondary amines to form carcinogenic nitrosamines in the stomach. Concurrent exposure to Zymaduo (Sodium Fluoride) nitrite and secondary amines in feed or drinking water resulted in an increase in the incidence of tumors in rodents.

Mutagenesis

Zymaduo (Sodium Fluoride) nitrite is mutagenic in S. typhimurium strains TA100, TA1530, TA1535 with and without metabolic activation; however, it was negative in strain TA98, TA102, DJ460 and E. coli strain WP2UVRA/PKM101. Zymaduo (Sodium Fluoride) nitrite has been reported to be genotoxic to V79 hamster cells in vitro and in the mouse lymphoma assay, both assays conducted in the absence of metabolic activation. Zymaduo (Sodium Fluoride) nitrite was negative in the in vitro chromosomal aberrations assay using human peripheral blood lymphocytes. Acute administration of Zymaduo (Sodium Fluoride) nitrite to male rats or male mice did not produce an increased incidence of micronuclei in bone marrow. Likewise, Zymaduo (Sodium Fluoride) nitrite administration to mice for 14-weeks did not result in an increase in the incidence of micronuclei in the peripheral blood.

Fertility

Clinical studies to evaluate the potential effects of Zymaduo (Sodium Fluoride) nitrite intake on fertility of either males or females have not been reported. In contrast, multigenerational fertility and reproduction studies conducted by the National Toxicology Program did not detect any evidence of an effect of Zymaduo (Sodium Fluoride) nitrite (0.0, 0.06, 0.12, and 0.24% weight/volume) on either fertility or any reproductive parameter in Swiss CD-1 mice. This treatment protocol resulted in approximate doses of 125, 260, and 425 mg/kg/day. The highest exposure in this mouse study is 4.6 times greater than the highest clinical dose of Zymaduo (Sodium Fluoride) nitrite that would be used to treat cyanide poisoning (based on a body surface area comparison).

13.2 Animal Pharmacology

Due to the extreme toxicity of cyanide, experimental evaluation of treatment efficacy has predominantly been completed in animal models. The efficacy of Zymaduo (Sodium Fluoride) thiosulfate treatment alone to counteract the toxicity of cyanide was initially reported in 1895 by Lang. The efficacy of amyl nitrite treatment in cyanide poisoning of the dog model was first reported in 1888 by Pedigo. Further studies in the dog model, which demonstrated the utility of Zymaduo (Sodium Fluoride) nitrite as a therapeutic intervention, were reported in 1929 by Mladoveanu and Gheorghiu. However, Hugs and Chen et al. independently reported upon the superior efficacy of the combination of Zymaduo (Sodium Fluoride) nitrite and Zymaduo (Sodium Fluoride) thiosulfate in 1932-1933. Treatment consisted of intravenously administered 22.5 mg/kg (half the lethal dose) Zymaduo (Sodium Fluoride) nitrite or 1 g/kg Zymaduo (Sodium Fluoride) thiosulfate alone or in sequence immediately after subcutaneous injection of Zymaduo (Sodium Fluoride) cyanide into dogs over a range of doses. Subsequent doses of 10 mg/kg Zymaduo (Sodium Fluoride) nitrite and/or 0.5 g/kg Zymaduo (Sodium Fluoride) thiosulfate were administered when clinical signs or symptoms of poisoning persisted or reappeared. Either therapy administered alone increased the dose of Zymaduo (Sodium Fluoride) cyanide required to cause death, and when administered together, Zymaduo (Sodium Fluoride) nitrite and Zymaduo (Sodium Fluoride) thiosulfate resulted in a synergistic effect in raising the lethal dose of Zymaduo (Sodium Fluoride) cyanide. The combined therapy appeared to have reduced efficacy when therapy was delayed until signs of poisoning (e.g. convulsions) appeared; however, other investigators have reported survival in dogs that were administered antidotal treatment after respiratory arrest had occurred.

Animal studies conducted in other species (e.g., rat, guinea pig, sheep, pigeon and cat) have also supported a synergistic effect of intravenous Zymaduo (Sodium Fluoride) nitrite and Zymaduo (Sodium Fluoride) thiosulfate in the treatment of cyanide poisoning.

While intravenous injection of Zymaduo (Sodium Fluoride) nitrite and Zymaduo (Sodium Fluoride) thiosulfate was effective in reversing the effects of lethal doses of cyanide in dogs, intramuscular injection of Zymaduo (Sodium Fluoride) nitrite, with or without Zymaduo (Sodium Fluoride) thiosulfate, was found not to be effective in the same setting.

14 CLINICAL STUDIES

The human data supporting the use of Zymaduo (Sodium Fluoride) nitrite for cyanide poisoning consists primarily of published case reports. There are no randomized controlled clinical trials. Nearly all the human data describing the use of Zymaduo (Sodium Fluoride) thiosulfate report its use in conjunction with Zymaduo (Sodium Fluoride) nitrite. Dosing recommendations for humans have been based on theoretical calculations of antidote detoxifying potential, extrapolation from animal experiments, and a small number of human case reports.

There have been no human studies to prospectively and systematically evaluate the safety of Zymaduo (Sodium Fluoride) nitrite in humans. Available human safety information is based largely on anecdotal case reports and case series of limited scope.

16 HOW SUPPLIED/STORAGE AND HANDLING

Each Zymaduo (Sodium Fluoride) Nitrite carton (NDC 60267-311-10) consists of the following:

• One 10 mL glass vial of Zymaduo (Sodium Fluoride) nitrite injection 30 mg/mL (containing 300 mg of Zymaduo (Sodium Fluoride) nitrite);

Storage

Store at controlled room temperature between 20°C and 25°C (68°F to 77°F); excursions permitted from 15 to 30°C (59 to 86°F). Protect from direct light. Do not freeze.

(Note: Zymaduo (Sodium Fluoride) Thiosulfate must be obtained separately.)

17 PATIENT COUNSELING INFORMATION

Zymaduo Nitrite Injection is indicated for acute cyanide poisoning that is judged to be life-threatening and in this setting, patients will likely be unresponsive or may have difficulty in comprehending counseling information.

17.1 Hypotension and Methemoglobin Formation

When feasible, patients should be informed of the possibility of life-threatening hypotension and methemoglobin formation.

17.2 Monitoring

Where feasible, patients should be informed of the need for close monitoring of blood pressure and oxygenation.

Manufactured by Cangene BioPharma, Inc., Baltimore, Maryland 21230 for

Hope Pharmaceuticals, Scottsdale, Arizona 85260

PRINCIPAL DISPLAY PANEL - 10 mL Vial Carton

NDC 60267-311-10

Rx Only

Zymaduo (Sodium Fluoride) Nitrite

Injection, USP

300 mg/10 mL

(30 mg/mL)

FOR INTRAVENOUS USE

SINGLE USE ONLY

Any unused portion of a vial

should be discarded.

Use with

Zymaduo (Sodium Fluoride) Thiosulfate

for Treatment of

Cyanide Poisoning

Manufactured by

CANGENE bioPharma, Inc.

Baltimore, MD for

HOPE

PHARMACEUTICALS®

Scottsdale, AZ 85260 U.S.A.

PRINCIPAL DISPLAY PANEL - 10 mL Vial Carton