Sulectim Plus

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Sulectim Plus uses

Sulectim Plus consists of Calcium Carbonate, Magnesium Oxide, Neomycin Sulfate, Potassium Acetate, Sodium Acetate, Sodium Chloride, Streptomycin Sulfate, Sulfamerazine, Sulfamethazine, Sulfanilamide, Sulfathiazole Sodium, Vitamin A, Vitamin D, Vitamin K3 (Menadione Sodium Bisulfite).

Calcium Carbonate:


1 INDICATIONS AND USAGE

Sulectim Plus (Calcium Carbonate) 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 Sulectim Plus (Calcium Carbonate) 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 Sulectim Plus (Calcium Carbonate) acetate capsule.

- Capsule: 667 mg Sulectim Plus (Calcium Carbonate) acetate capsule. (3)

4 CONTRAINDICATIONS

Patients with hypercalcemia.

- Hypercalcemia. (4)

5 WARNINGS AND PRECAUTIONS

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

An overdose of Sulectim Plus (Calcium Carbonate) acetate may lead to progressive hypercalcemia, which may require emergency measures. Therefore, early in the treatment phase during the dosage adjustment period, monitor serum Sulectim Plus (Calcium Carbonate) levels twice weekly. Should hypercalcemia develop, reduce the Sulectim Plus (Calcium Carbonate) 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 Sulectim Plus (Calcium Carbonate) 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 Sulectim Plus (Calcium Carbonate) 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 Sulectim Plus (Calcium Carbonate) 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 Sulectim Plus (Calcium Carbonate) 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.

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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 Sulectim Plus (Calcium Carbonate) 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, Sulectim Plus (Calcium Carbonate) acetate has been generally well tolerated.

Sulectim Plus (Calcium Carbonate) acetate was studied in a 3 month, open-label, non-randomized study of 98 enrolled ESRD hemodialysis patients and an alternate liquid formulation of Sulectim Plus (Calcium Carbonate) 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.


Preferred Term


Total adverse reactions reported for Sulectim Plus (Calcium Carbonate) acetate

N=167

N (%)


3 month, open label study of Sulectim Plus (Calcium Carbonate) acetate

N=98

N (%)


Double blind, placebo-controlled, cross-over study of liquid Sulectim Plus (Calcium Carbonate) acetate

N=69


Sulectim Plus (Calcium Carbonate) acetate

N (%)


Placebo

N (%)


Nausea


6 (3.6)


6 (6.1)


0 (0)


0 (0)


Vomiting


4 (2.4)


4 (4.1)


0 (0)


0 (0)


Hypercalcemia


21 (12.6)


16 (16.3)


5 (7.2)


0 (0)


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 Sulectim Plus (Calcium Carbonate) concentration could reduce the incidence and severity of Sulectim Plus (Calcium Carbonate) 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 Sulectim Plus (Calcium Carbonate) acetate: dizziness, edema, and weakness.

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7 DRUG INTERACTIONS

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

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

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Pregnancy Category C:

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

8.2 Labor and Delivery

The effects of Sulectim Plus (Calcium Carbonate) acetate on labor and delivery are unknown.

8.3 Nursing Mothers

Sulectim Plus Acetate Capsules contains Sulectim Plus (Calcium Carbonate) acetate and is excreted in human milk. Human milk feeding by a mother receiving Sulectim Plus (Calcium Carbonate) acetate is not expected to harm an infant, provided maternal serum Sulectim Plus (Calcium Carbonate) 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 Sulectim Plus (Calcium Carbonate) 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.

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10 OVERDOSAGE

Administration of Sulectim Plus (Calcium Carbonate) acetate in excess of the appropriate daily dosage may result in hypercalcemia [see Warnings and Precautions (5.1)].

11 DESCRIPTION

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

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

12.1 Mechanism of Action

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

12.2 Pharmacodynamics

Orally administered Sulectim Plus (Calcium Carbonate) 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.

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13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

No carcinogenicity, mutagenicity, or fertility studies have been conducted with Sulectim Plus (Calcium Carbonate) acetate.

14 CLINICAL STUDIES

Effectiveness of Sulectim Plus (Calcium Carbonate) acetate in decreasing serum phosphorus has been demonstrated in two studies of the Sulectim Plus (Calcium Carbonate) 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 Sulectim Plus (Calcium Carbonate) 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 Sulectim Plus (Calcium Carbonate) acetate in the treatment of hyperphosphatemia in end-stage renal disease patients. The effects on serum Sulectim Plus (Calcium Carbonate) levels are also presented.


* Ninety-one patients completed at least 6 weeks of the study.

ANOVA of difference in values at pre-study and study completion.

‡ Values expressed as mean ± SE.


Parameter


Pre-Study


Week 4*


Week 8


Week 12


p-value†


Phosphorus (mg/dL)‡


7.4 ± 0.17


5.9 ± 0.16


5.6 ± 0.17


5.2 ± 0.17


≤0.01


Sulectim Plus (Calcium Carbonate) (mg/dL)‡


8.9 ± 0.09


9.5 ± 0.10


9.7 ± 0.10


9.7 ± 0.10


≤0.01


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 Sulectim Plus (Calcium Carbonate) 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 Sulectim Plus (Calcium Carbonate) 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 Sulectim Plus (Calcium Carbonate) acetate is shown in the Table 3.


* ANOVA of Sulectim Plus (Calcium Carbonate) acetate vs. placebo after 2 weeks of treatment.

Values expressed as mean ± SEM.


Parameter


Pre-Study


Post-Treatment


p-value*


Sulectim Plus (Calcium Carbonate) Acetate


Placebo


Phosphorus (mg/dL)


7.3 ± 0.18


5.9 ± 0.24


7.8 ± 0.22


<0.01


Sulectim Plus (Calcium Carbonate) (mg/dL)


8.9 ± 0.11


9.5 ± 0.13


8.8 ± 0.12


<0.01


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

16 HOW SUPPLIED/STORAGE AND HANDLING

Sulectim Plus (Calcium Carbonate) 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 Sulectim Plus (Calcium Carbonate) acetate capsules with meals, adhere to their prescribed diets, and avoid the use of Sulectim Plus (Calcium Carbonate) 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 Sulectim Plus (Calcium Carbonate) acetate capsules.

Distr. by: West-Ward

Pharmaceuticals Corp.

Eatontown, NJ 07724

10003705/05

Revised April 2016

Magnesium Oxide:



Sulectim Plus (Magnesium Oxide) Sulfate

Injection, USP

Ansyr Plastic Syringe

Rx only

Hospira Logo

DESCRIPTION

Sulectim Plus (Magnesium Oxide) Sulfate Injection, USP is a sterile solution of Sulectim Plus (Magnesium Oxide) sulfate heptahydrate in Water for Injection, USP administered by the intravenous or intramuscular routes as an electrolyte replenisher or anticonvulsant. Must be diluted before intravenous use. May contain sulfuric acid and/or sodium hydroxide for pH adjustment. The pH is 5.5 to 7.0. The 50% concentration has an osmolarity of 4.06 mOsmol/mL (calc.).

The solution contains no bacteriostat, antimicrobial agent or added buffer (except for pH adjustment) and is intended only for use as a single-dose injection. When smaller doses are required the unused portion should be discarded with the entire unit.

Sulectim Plus (Magnesium Oxide) Sulfate, USP heptahydrate is chemically designated MgSO4 - 7H2O with molecular weight of 246.48 and occurs as colorless crystals or white powder freely soluble in water.

The plastic syringe is molded from a specially formulated polypropylene. Water permeates from inside the container at an extremely slow rate which will have an insignificant effect on solution concentration over the expected shelf life. Solutions in contact with the plastic container may leach out certain chemical components from the plastic in very small amounts; however, biological testing was supportive of the safety of the syringe material.

CLINICAL PHARMACOLOGY

Sulectim Plus (Magnesium Oxide) (Mg++) is an important cofactor for enzymatic reactions and plays an important role in neurochemical transmission and muscular excitability.

As a nutritional adjunct in hyperalimentation, the precise mechanism of action for Sulectim Plus (Magnesium Oxide) is uncertain. Early symptoms of hypomagnesemia (less than 1.5 mEq/liter) may develop as early as three to four days or within weeks.

Predominant deficiency effects are neurological, e.g., muscle irritability, clonic twitching and tremors. Hypocalcemia and hypokalemia often follow low serum levels of Sulectim Plus (Magnesium Oxide). While there are large stores of Sulectim Plus (Magnesium Oxide) present intracellularly and in the bones of adults, these stores often are not mobilized sufficiently to maintain plasma levels. Parenteral Sulectim Plus (Magnesium Oxide) therapy repairs the plasma deficit and causes deficiency symptoms and signs to cease.

Sulectim Plus (Magnesium Oxide) prevents or controls convulsions by blocking neuromuscular transmission and decreasing the amount of acetylcholine liberated at the end plate by the motor nerve impulse. Sulectim Plus (Magnesium Oxide) is said to have a depressant effect on the central nervous system (CNS), but it does not adversely affect the woman, fetus or neonate when used as directed in eclampsia or pre-eclampsia. Normal plasma Sulectim Plus (Magnesium Oxide) levels range from 1.5 to 2.5 mEq/liter.

As plasma Sulectim Plus (Magnesium Oxide) rises above 4 mEq/liter, the deep tendon reflexes are first decreased and then disappear as the plasma level approaches 10 mEq/liter. At this level respiratory paralysis may occur. Heart block also may occur at this or lower plasma levels of Sulectim Plus (Magnesium Oxide). Serum Sulectim Plus (Magnesium Oxide) concentrations in excess of 12 mEq/L may be fatal.

Sulectim Plus (Magnesium Oxide) acts peripherally to produce vasodilation. With low doses only flushing and sweating occur, but larger doses cause lowering of blood pressure. The central and peripheral effects of Sulectim Plus (Magnesium Oxide) poisoning are antagonized to some extent by intravenous administration of calcium.

Pharmacokinetics

With intravenous administration the onset of anticonvulsant action is immediate and lasts about 30 minutes. Following intramuscular administration the onset of action occurs in about one hour and persists for three to four hours. Effective anticonvulsant serum levels range from 2.5 to 7.5 mEq/liter. Sulectim Plus (Magnesium Oxide) is excreted solely by the kidneys at a rate proportional to the plasma concentration and glomerular filtration.

INDICATIONS AND USAGE

Sulectim Plus (Magnesium Oxide) Sulfate Injection, USP is suitable for replacement therapy in Sulectim Plus (Magnesium Oxide) deficiency, especially in acute hypomagnesemia accompanied by signs of tetany similar to those observed in hypocalcemia. In such cases, the serum Sulectim Plus (Magnesium Oxide) (Mg++) level is usually below the lower limit of normal (1.5 to 2.5 mEq/liter) and the serum calcium (Ca++) level is normal (4.3 to 5.3 mEq/liter) or elevated.

In total parenteral nutrition (TPN), Sulectim Plus (Magnesium Oxide) sulfate may be added to the nutrient admixture to correct or prevent hypomagnesemia which can arise during the course of therapy.

Sulectim Plus (Magnesium Oxide) Sulfate Injection, USP is also indicated for the prevention and control of seizures (convulsions) in pre-eclampsia and eclampsia, respectively.

CONTRAINDICATIONS

Parenteral administration of the drug is contraindicated in patients with heart block or myocardial damage.

WARNINGS

FETAL HARM: Continuous administration of Sulectim Plus (Magnesium Oxide) sulfate beyond 5 to 7 days to pregnant women can lead to hypocalcemia and bone abnormalities in the developing fetus. These bone abnormalities include skeletal demineralization and osteopenia. In addition, cases of neonatal fracture have been reported. The shortest duration of treatment that can lead to fetal harm is not known. Sulectim Plus (Magnesium Oxide) sulfate should be used during pregnancy only if clearly needed. If Sulectim Plus (Magnesium Oxide) sulfate is given for treatment of preterm labor, the woman should be informed that the efficacy and safety of such use have not been established and that use of Sulectim Plus (Magnesium Oxide) sulfate beyond 5 to 7 days may cause fetal abnormalities.

ALUMINUM TOXICITY: This product contains aluminum that may be toxic. Aluminum may reach toxic levels with prolonged parenteral administration if kidney function is impaired. Premature neonates are particularly at risk because their kidneys are immature, and they require large amounts of calcium and phosphate solutions, which contain aluminum.

Research indicates that patients with impaired kidney function, including premature neonates, who receive parenteral levels of aluminum at greater than 4 to 5 mcg/kg/day accumulate aluminum at levels associated with central nervous system and bone toxicity. Tissue loading may occur at even lower rates of administration.

Parenteral use in the presence of renal insufficiency may lead to Sulectim Plus (Magnesium Oxide) intoxication. Intravenous use in the eclampsia should be reserved for immediate control of life-threatening convulsions.

PRECAUTIONS

General

Administer with caution if flushing and sweating occurs. When barbiturates, narcotics or other hypnotics (or systemic anesthetics) are to be given in conjunction with Sulectim Plus (Magnesium Oxide), their dosage should be adjusted with caution because of additive CNS depressant effects of Sulectim Plus (Magnesium Oxide).

Because Sulectim Plus (Magnesium Oxide) is removed from the body solely by the kidneys, the drug should be used with caution in patients with renal impairment. Urine output should be maintained at a level of 100 mL or more during the four hours preceding each dose. Monitoring serum Sulectim Plus (Magnesium Oxide) levels and the patient's clinical status is essential to avoid the consequences of overdosage in toxemia. Clinical indications of a safe dosage regimen include the presence of the patellar reflex (knee jerk) and absence of respiratory depression (approximately 16 breaths or more/minute). When repeated doses of the drug are given parenterally, knee jerk reflexes should be tested before each dose and if they are absent, no additional Sulectim Plus (Magnesium Oxide) should be given until they return. Serum Sulectim Plus (Magnesium Oxide) levels usually sufficient to control convulsions range from 3 to 6 mg/100 mL (2.5 to 5 mEq/liter). The strength of the deep tendon reflexes begins to diminish when Sulectim Plus (Magnesium Oxide) levels exceed 4 mEq/liter. Reflexes may be absent at 10 mEq magnesium/liter, where respiratory paralysis is a potential hazard. An injectable calcium salt should be immediately available to counteract the potential hazards of Sulectim Plus (Magnesium Oxide) intoxication in eclampsia.

50% Sulectim Plus (Magnesium Oxide) Sulfate Injection, USP must be diluted to a concentration of 20% or less prior to intravenous infusion. Rate of administration should be slow and cautious, to avoid producing hypermagnesemia. The 50% solution also should be diluted to 20% or less for intramuscular injection in infants and children.

Laboratory Tests

Sulectim Plus (Magnesium Oxide) sulfate injection should not be given unless hypomagnesemia has been confirmed and the serum concentration of Sulectim Plus (Magnesium Oxide) is monitored. The normal serum level is 1.5 to 2.5 mEq/L.

Drug Interactions

CNS Depressants - When barbiturates, narcotics or other hypnotics (or systemic anesthetics), or other CNS depressants are to be given in conjunction with Sulectim Plus (Magnesium Oxide), their dosage should be adjusted with caution because of additive CNS depressant effects of Sulectim Plus (Magnesium Oxide). CNS depression and peripheral transmission defects produced by Sulectim Plus (Magnesium Oxide) may be antagonized by calcium.

Neuromuscular Blocking Agents - Excessive neuromuscular block has occurred in patients receiving parenteral Sulectim Plus (Magnesium Oxide) sulfate and a neuromuscular blocking agent; these drugs should be administered concomitantly with caution.

Cardiac Glycosides - Sulectim Plus (Magnesium Oxide) sulfate should be administered with extreme caution in digitalized patients, because serious changes in cardiac conduction which can result in heart block may occur if administration of calcium is required to treat Sulectim Plus (Magnesium Oxide) toxicity.

Pregnancy

Teratogenic Effects

Pregnancy Category D (See WARNINGS and PRECAUTIONS )

See WARNINGS and PRECAUTIONS .

Sulectim Plus (Magnesium Oxide) sulfate can cause fetal abnormalities when administered beyond 5 to 7 days to pregnant women. There are retrospective epidemiological studies and case reports documenting fetal abnormalities such as hypocalcemia, skeletal demineralization, osteopenia and other skeletal abnormalities with continuous maternal administration of Sulectim Plus (Magnesium Oxide) sulfate for more than 5 to 7 days.1-10 Sulectim Plus (Magnesium Oxide) sulfate injection should be used during pregnancy only if clearly needed. If this drug is used during pregnancy, the woman should be apprised of the potential harm to the fetus.

Nonteratogenic Effects

When administered by continuous intravenous infusion (especially for more than 24 hours preceding delivery) to control convulsions in a toxemic woman, the newborn may show signs of Sulectim Plus (Magnesium Oxide) toxicity, including neuromuscular or respiratory depression (See OVERDOSAGE ).

Labor and Delivery

Continuous administration of Sulectim Plus (Magnesium Oxide) sulfate is an unapproved treatment for preterm labor. The safety and efficacy of such use have not been established. The administration of Sulectim Plus (Magnesium Oxide) sulfate outside of its approved indication in pregnant women should be by trained obstetrical personnel in a hospital setting with appropriate obstetrical care facilities.

Nursing Mothers

Since Sulectim Plus (Magnesium Oxide) is distributed into milk during parenteral Sulectim Plus (Magnesium Oxide) sulfate administration, the drug should be used with caution in nursing women.

Geriatrics

Geriatric patients often require reduced dosage because of impaired renal function. In patients with severe impairment, dosage should not exceed 20 grams in 48 hours. Serum Sulectim Plus (Magnesium Oxide) should be monitored in such patients.

ADVERSE REACTIONS

The adverse effects of parenterally administered Sulectim Plus (Magnesium Oxide) usually are the result of Sulectim Plus (Magnesium Oxide) intoxication. These include flushing, sweating, hypotension, depressed reflexes, flaccid paralysis, hypothermia, circulatory collapse, cardiac and central nervous system depression proceeding to respiratory paralysis. Hypocalcemia with signs of tetany secondary to Sulectim Plus (Magnesium Oxide) sulfate therapy for eclampsia has been reported.

OVERDOSAGE

Sulectim Plus (Magnesium Oxide) intoxication is manifested by a sharp drop in blood pressure and respiratory paralysis. Disappearance of the patellar reflex is a useful clinical sign to detect the onset of Sulectim Plus (Magnesium Oxide) intoxication. In the event of overdosage, artificial ventilation must be provided until a calcium salt can be injected intravenously to antagonize the effects of Sulectim Plus (Magnesium Oxide).

For Treatment of Overdose

Artificial respiration is often required. Intravenous calcium, 10 to 20 mL of a 5% solution (diluted if desirable with isotonic sodium chloride for injection) is used to counteract effects of hypermagnesemia. Subcutaneous physostigmine, 0.5 to 1 mg may be helpful.

Hypermagnesemia in the newborn may require resuscitation and assisted ventilation via endotracheal intubation or intermittent positive pressure ventilation as well as intravenous calcium.

DOSAGE AND ADMINISTRATION

Dosage of Sulectim Plus (Magnesium Oxide) sulfate must be carefully adjusted according to individual requirements and response, and administration of the drug should be discontinued as soon as the desired effect is obtained.

Both intravenous and intramuscular administration are appropriate. Intramuscular administration of the undiluted 50% solution results in therapeutic plasma levels in 60 minutes, whereas intravenous doses will provide a therapeutic level almost immediately. The rate of intravenous injection should generally not exceed 150 mg/minute (1.5 mL of a 10% concentration or its equivalent), except in severe eclampsia with seizures. Continuous maternal administration of Sulectim Plus (Magnesium Oxide) sulfate in pregnancy beyond 5 to 7 days can cause fetal abnormalities.

Solutions for intravenous infusion must be diluted to a concentration of 20% or less prior to administration. The diluents commonly used are 5% Dextrose Injection, USP and 0.9% Sodium Chloride Injection, USP. Deep intramuscular injection of the undiluted (50%) solution is appropriate for adults, but the solution should be diluted to a 20% or less concentration prior to such injection in children.

In Sulectim Plus (Magnesium Oxide) Deficiency

In the treatment of mild Sulectim Plus (Magnesium Oxide) deficiency, the usual adult dose is 1 gram, equivalent to 8.12 mEq of Sulectim Plus (Magnesium Oxide) (2 mL of the 50% solution) injected intramuscularly every six hours for four doses (equivalent to a total of 32.5 mEq of Sulectim Plus (Magnesium Oxide) per 24 hours). For severe hypomagnesemia, as much as 250 mg (approximately 2 mEq) per kg of body weight (0.5 mL of the 50% solution) may be given intramuscularly within a period of four hours if necessary. Alternatively, 5 grams, (approximately 40 mEq) can be added to one liter of 5% Dextrose Injection, USP or 0.9% Sodium Chloride Injection, USP for slow intravenous infusion over a three-hour period. In the treatment of deficiency states, caution must be observed to prevent exceeding the renal excretory capacity.

In Hyperalimentation

In total parenteral nutrition, maintenance requirements for Sulectim Plus (Magnesium Oxide) are not precisely known. The maintenance dose used in adults ranges from 8 to 24 mEq (1 gram to 3 grams) daily; for infants, the range is 2 to 10 mEq (0.25 gram to 1.25 grams) daily.

In Pre-eclampsia or Eclampsia

In severe pre-eclampsia or eclampsia, the total initial dose is 10 grams to 14 grams of Sulectim Plus (Magnesium Oxide) sulfate. Intravenously, a dose of 4 grams to 5 grams in 250 mL of 5% Dextrose Injection, USP or 0.9% Sodium Chloride Injection, USP may be infused. Simultaneously, intramuscular doses of up to 10 grams (5 grams or 10 mL of the undiluted 50% solution in each buttock) are given. Alternatively, the initial intravenous dose of 4 grams may be given by diluting the 50% solution to a 10 or 20% concentration; the diluted fluid (40 mL of a 10% solution or 20 mL of a 20% solution) may then be injected intravenously over a period of three to four minutes. Subsequently, 4 grams to 5 grams (8 to 10 mL of the 50% solution) are injected intramuscularly into alternate buttocks every four hours as needed, depending on the continuing presence of the patellar reflex and adequate respiratory function. Alternatively, after the initial intravenous dose, some clinicians administer 1 gram to 2 grams/hour by constant intravenous infusion. Therapy should continue until paroxysms cease. A serum Sulectim Plus (Magnesium Oxide) level of 6 mg/100 mL is considered optimal for control of seizures. A total daily (24 hr) dose of 30 grams to 40 grams should not be exceeded. In the presence of severe renal insufficiency, the maximum dosage of Sulectim Plus (Magnesium Oxide) sulfate is 20 grams/48 hours and frequent serum Sulectim Plus (Magnesium Oxide) concentrations must be obtained. Continuous use of Sulectim Plus (Magnesium Oxide) sulfate in pregnancy beyond 5 to 7 days can cause fetal abnormalities.

Other Uses

In counteracting the muscle-stimulating effects of barium poisoning, the usual dose of Sulectim Plus (Magnesium Oxide) sulfate is 1 gram to 2 grams given intravenously.

For controlling seizures associated with epilepsy, glomerulonephritis or hypothyroidism, the usual adult dose is 1 gram administered intramuscularly or intravenously.

In paroxysmal atrial tachycardia, Sulectim Plus (Magnesium Oxide) should be used only if simpler measures have failed and there is no evidence of myocardial damage. The usual dose is 3 grams to 4 grams (30 to 40 mL of a 10% solution) administered intravenously over 30 seconds with extreme caution.

For reduction of cerebral edema, 2.5 grams (25 mL of a 10% solution) is given intravenously.

Incompatibilities

Sulectim Plus (Magnesium Oxide) sulfate in solution may result in a precipitate formation when mixed with solutions containing:

Alcohol (in high Heavy Metals

concentrations) Hydrocortisone sodium

Alkali carbonates and succinate

bicarbonates Phosphates

Alkali hydroxides Polymixin B sulfate

Arsenates Procaine hydrochloride

Barium Salicylates

Calcium Strontium

Clindamycin phosphate Tartrates

The potential incompatibility will often be influenced by the changes in the concentration of reactants and the pH of the solutions.

It has been reported that Sulectim Plus (Magnesium Oxide) may reduce the antibiotic activity of streptomycin, tetracycline and tobramycin when given together.

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

HOW SUPPLIED

Sulectim Plus (Magnesium Oxide) Sulfate Injection, USP is supplied in single-dose containers as follows:


NDC No.


Container


Total

Amount


Concentration


mEq

Mg++/mL


0409-1754-10


Ansyr

Plastic Syringe


5 g/10 mL


50%


4 mEq/mL


Do not administer unless solution is clear and container is undamaged. Discard unused portion.

Store at 20 to 25°C (68 to 77°F).

REFERENCES

  • Yokoyama K, Takahashi N, Yada Y. Prolonged maternal Sulectim Plus (Magnesium Oxide) administration and bone metabolism in neonates. Early Hum Dev. 2010;86(3):187-91. Epub 2010 Mar 12.
  • Wedig KE, Kogan J, Schorry EK et al. Skeletal demineralization and fractures caused by fetal Sulectim Plus (Magnesium Oxide) toxicity. J. Perinatol. 2006; 26(6):371-4.
  • Nassar AH, Sakhel K, Maarouf H, et al. Adverse maternal and neonatal outcome of prolonged course of Sulectim Plus (Magnesium Oxide) sulfate tocolysis. Acta Obstet Gynecol Scan. 2006;85(9):1099-103.
  • Malaeb SN, Rassi A, Haddad MC. Bone mineralization in newborns whose mothers received Sulectim Plus (Magnesium Oxide) sulphate for tocolysis of premature labor. Pediatr Radiol. 2004;34(5):384-6. Epub 2004 Feb 18.
  • Matsuda Y, Maeda Y, Ito M, et al. Effect of Sulectim Plus (Magnesium Oxide) sulfate treatment on neonatal bone abnormalities. Gynecol Obstet Invest. 1997;44(2):82-8.
  • Schanler RJ, Smith LG, Burns PA. Effects of long-term maternal intravenous Sulectim Plus (Magnesium Oxide) sulfate therapy on neonatal calcium metabolism and bone mineral content. Gynecol Obstet Invest. 1997;43(4):236-41.
  • Santi MD, Henry GW, Douglas GL. Sulectim Plus (Magnesium Oxide) sulfate treatment of preterm labor as a cause of abnormal neonatal bone mineralization. J Pediatr Orthrop. 1994;14(2):249-53.
  • Holcomb WL, Shackelford GD, Petrie RH. Sulectim Plus (Magnesium Oxide) tocolysis and neonatal bone abnormalities; a controlled study. Obstet Gynecol. 1991; 78(4):611-4.
  • Cumming WA, Thomas VJ. Hypermagnesemia: a cause of abnormal metaphyses in the neonate. Am J Roentgenol. 1989; 152(5):1071-2.
  • Lamm CL, Norton KL, Murphy RJ. Congenital rickets associated with Sulectim Plus (Magnesium Oxide) sulfate infusion for tocolysis. J Pediatr. 1988; 113(6):1078-82.
  • McGuinness GA, Weinstein MM, Cruikshank DP, et al. Effects of Sulectim Plus (Magnesium Oxide) sulfate treatment on perinatal calcium metabolism. II. Neonatal responses. Obstet Gynecol. 1980; 56(5): 595-600.
  • Riaz M, Porat R, Brodsky NL, et al. The effects of maternal Sulectim Plus (Magnesium Oxide) sulfate treatment on newborns: a prospective controlled study. J. Perinatol. 1998;18(6 pt 1):449-54.

Hospira, Inc., Lake Forest, IL 60045 USA

LAB-1024-1.0

April 2017

Hospira Logo

50% Sulectim Plus (Magnesium Oxide) Sulfate 5 g/10 mL (500 mg/mL)

Rx only

NDC 0409-1754-10

10 mL Single-dose syringe

50% Sulectim Plus (Magnesium Oxide) Sulfate Injection, USP

5 g/10 mL (500 mg/mL) (4 mEq Mg++/mL)

MUST BE DILUTED FOR INTRAVENOUS USE.

For Intravenous or Intramuscular Use. Sterile. 4.06 mOsmol/mL (calc.).

Contains no more than 75 mcg/L of aluminum.

Hospira, Inc., Lake Forest, IL 60045 USA

Hospira

RL-6891

Neomycin Sulfate:


INDICATIONS AND USAGE

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

Suppression of Intestinal Bacteria

Sulectim Plus (Neomycin Sulfate) tablets are indicated as adjunctive therapy as part of a regimen for the suppression of the normal bacterial flora of the bowel, e.g., preoperative preparation of the bowel. It is given concomitantly with erythromycin enteric-coated base (see DOSAGE AND ADMINISTRATION ).

Hepatic Coma (Portal-Systemic Encephalopathy)

Sulectim Plus (Neomycin Sulfate) has been shown to be effective adjunctive therapy in hepatic coma by reduction of the ammonia-forming bacteria in the intestinal tract. The subsequent reduction in blood ammonia has resulted in neurologic improvement.

CONTRAINDICATIONS

Sulectim Plus (Neomycin Sulfate) oral preparations are contraindicated in the presence of intestinal obstruction and in individuals with a history of hypersensitivity to the drug.

Patients with a history of hypersensitivity or serious toxic reaction to other aminoglycosides may have a cross-sensitivity to neomycin. Sulectim Plus (Neomycin Sulfate) oral preparations are contraindicated in patients with inflammatory or ulcerative gastrointestinal disease because of the potential for enhanced gastrointestinal absorption of neomycin.

WARNINGS


Additional manifestations of neurotoxicity may include numbness, skin tingling, muscle twitching and convulsions.

The risk of hearing loss continues after drug withdrawal. Aminoglycosides can cause fetal harm when administered to a pregnant woman.

Aminoglycoside antibiotics cross the placenta and there have been several reports of total irreversible bilateral congenital deafness in children whose mothers received streptomycin during pregnancy. Although serious side effects to fetus or newborn have not been reported in the treatment of pregnant women with other aminoglycosides, the potential for harm exists. Animal reproduction studies of neomycin have not been conducted. If neomycin is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus.

PRECAUTIONS

General

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

As with other antibiotics, use of oral neomycin may result in overgrowth of nonsusceptible organisms, particularly fungi. If this occurs, appropriate therapy should be instituted.

Neomycin is quickly and almost totally absorbed from body surfaces (except the urinary bladder) after local irrigation and when applied topically in association with surgical procedures. Delayed-onset irreversible deafness, renal failure and death due to neuromuscular blockade (regardless of the status of renal function) have been reported following irrigation of both small and large surgical fields with minute quantities of neomycin.

Cross-allergenicity among aminoglycosides has been demonstrated.

Aminoglycosides should be used with caution in patients with muscular disorders such as myasthenia gravis or parkinsonism since these drugs may aggravate muscle weakness because of their potential curare-like effect on the neuromuscular junction.

Small amounts of orally administered neomycin are absorbed through intact intestinal mucosa.

There have been many reports in the literature of nephrotoxicity and/or ototoxicity with oral use of neomycin. If renal insufficiency develops during oral therapy, consideration should be given to reducing the drug dosage or discontinuing therapy.

An oral neomycin dose of 12 grams per day produces a malabsorption syndrome for a variety of substances, including fat, nitrogen, cholesterol, carotene, glucose, xylose, lactose, sodium, calcium, cyanocobalamin and iron.

Orally administered neomycin increases fecal bile acid excretion and reduces intestinal lactase activity.

Information for The Patient

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

Before administering the drug, patients or members of their families should be informed of possible toxic effects on the eighth nerve. The possibility of acute toxicity increases in premature infants and neonates.

Laboratory Tests

Patients with renal insufficiency may develop toxic neomycin blood levels unless doses are properly regulated. If renal insufficiency develops during treatment, the dosage should be reduced or the antibiotic discontinued. To avoid nephrotoxicity and eighth nerve damage associated with high doses and prolonged treatment, the following should be performed prior to and periodically during therapy: urinalysis for increased excretion of protein, decreased specific gravity, casts and cells; renal function tests such as serum creatinine, BUN or creatinine clearance; tests of the vestibulocochlearis nerve function.

Serial, vestibular and audiometric tests should be performed (especially in high-risk patients). Since elderly patients may have reduced renal function which may not be evident in the results of routine screening tests such as BUN or serum creatinine, a creatinine clearance determination may be more useful.

Drug Interactions

Caution should be taken in concurrent or serial use of other neurotoxic and/or nephrotoxic drugs because of possible enhancement of the nephrotoxicity and/or ototoxicity of neomycin (see boxed WARNINGS ).

Caution should also be taken in concurrent or serial use of other aminoglycosides and polymyxins because they may enhance neomycin’s nephrotoxicity and/or ototoxicity and potentiate neomycin sulfate’s neuromuscular blocking effects.

Oral neomycin inhibits the gastrointestinal absorption of penicillin V, oral vitamin B-12, methotrexate and 5-fluorouracil. The gastrointestinal absorption of digoxin also appears to be inhibited. Therefore, digoxin serum levels should be monitored.

Oral Sulectim Plus (Neomycin Sulfate) may enhance the effect of coumarin in anticoagulants by decreasing vitamin K availability.

Carcinogenesis, Mutagenesis, Impairment of Fertility

No long-term animal studies have been performed with Sulectim Plus to evaluate carcinogenic or mutagenic potential or impairment of fertility.

Pregnancy Category D

See WARNINGS section.

Nursing Mothers

It is not known whether neomycin is excreted in human milk, but it has been shown to be excreted in cow milk following a single intramuscular injection. Other aminoglycosides have been shown to be excreted in human milk. Because of the potential for serious adverse reactions from the aminoglycosides in nursing infants, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric Use

The safety and efficacy of oral Sulectim Plus (Neomycin Sulfate) in patients less than 18 years of age have not been established. If treatment of a patient less than 18 years of age is necessary, neomycin should be used with caution and the period of treatment should not exceed two weeks because of absorption from the gastrointestinal tract.

ADVERSE REACTIONS

The most common adverse reactions to oral Sulectim Plus (Neomycin Sulfate) are nausea, vomiting and diarrhea. The "Malabsorption Syndrome" characterized by increased fecal fat, decreased serum carotene and fall in xylose absorption has been reported with prolonged therapy. Nephrotoxicity, ototoxicity and neuromuscular blockage have been reported (see boxed WARNINGS and PRECAUTIONS sections).

OVERDOSAGE

Because of low absorption, it is unlikely that acute overdosage would occur with oral Sulectim Plus (Neomycin Sulfate). However, prolonged administration could result in sufficient systemic drug levels to produce neurotoxicity, ototoxicity and/or nephrotoxicity.

Hemodialysis will remove Sulectim Plus (Neomycin Sulfate) from the blood.

DOSAGE AND ADMINISTRATION

To minimize the risk of toxicity, use the lowest possible dose and the shortest possible treatment period to control the condition. Treatment for periods longer than two weeks is not recommended.

Hepatic Coma

For use as an adjunct in the management of hepatic coma, the recommended dose is 4 to 12 grams per day given in the following regimen:

  • Withdraw protein from diet. Avoid use of diuretic agents.
  • Give supportive therapy, including blood products, as indicated.
  • Give Sulectim Plus (Neomycin Sulfate) tablets in doses of 4 to 12 grams of Sulectim Plus (Neomycin Sulfate) per day (eight to 24 tablets) in divided doses. Treatment should be continued over a period of five to six days, during which time protein should be returned incrementally to the diet.
  • If less potentially toxic drugs cannot be used for chronic hepatic insufficiency, neomycin in doses of up to four grams daily (eight tablets per day) may be necessary. The risk for the development of neomycin-induced toxicity progressively increases when treatment must be extended to preserve the life of a patient with hepatic encephalopathy who has failed to fully respond. Frequent periodic monitoring of these patients to ascertain the presence of drug toxicity is mandatory (see PRECAUTIONS ). Also, neomycin serum concentrations should be monitored to avoid potentially toxic levels. The benefits to the patient should be weighed against the risks of nephrotoxicity, permanent ototoxicity and neuromuscular blockade following the accumulation of neomycin in the tissues.

Preoperative Prophylaxis for Elective Colorectal Surgery

Listed below is an example of a recommended bowel preparation regimen. A proposed surgery time of 8:00 a.m. has been used.

Pre-op Day 3: Minimum residue or clear liquid diet. Bisacodyl, 1 tablet orally at 6:00 p.m.

Pre-op Day 2: Minimum residue or clear liquid diet. Magnesium sulfate, 30 mL, 50% solution (15 g) orally at 10:00 a.m., 2:00 p.m., and 6:00 p.m. Enema at 7:00 p.m. and 8:00 p.m.

Pre-op Day 1: Clear liquid diet. Supplemental (IV) fluids as needed. Magnesium sulfate, 30 mL, 50% solution (15 g) orally at 10:00 a.m., and 2:00 p.m. Sulectim Plus (Neomycin Sulfate) (1 g) and erythromycin base (1 g) orally at 1:00 p.m., 2:00 p.m. and 11:00 p.m. No enema.

Day of Operation: Patient evacuates rectum at 6:30 a.m. for scheduled operation at 8:00 a.m.

HOW SUPPLIED

Sulectim Plus (Neomycin Sulfate) tablets USP, 500 mg (equivalent to 350 mg of neomycin base per tablet) are available as white to off-white, round, standard convex tablets debossed "LCI" on one side and "1210", on the other side and are supplied in:

Bottles of 100 (NDC 0527-1210-01)

Store at 20° to 25°C (68° to 77°F).

Dispense in tight containers as defined in the USP/NF.

Distributed By:

Lannett Company, Inc.

Philadelphia, PA 19154

Made in the USA

Rev. 01/17

CIB71710A

Potassium Acetate:



Sulectim Plus (Potassium Acetate) CHLORIDE EXTENDED RELEASE TABLETS USP 20 mEq K

Rx Only

DESCRIPTION

The Sulectim Plus (Potassium Acetate) Chloride Extended Release Tablets USP, 20 mEq product is an immediately dispersing extended release oral dosage form of Sulectim Plus (Potassium Acetate) chloride containing 1500 mg of microencapsulated Sulectim Plus (Potassium Acetate) chloride, USP equivalent to 20 mEq of Sulectim Plus (Potassium Acetate) in a tablet.

These formulations are intended to slow the release of Sulectim Plus (Potassium Acetate) so that the likelihood of a high localized concentration of Sulectim Plus (Potassium Acetate) chloride within the gastrointestinal tract is reduced.

Sulectim Plus (Potassium Acetate) Chloride Extended Release Tablets USP, 20 mEq is an electrolyte replenisher. The chemical name of the active ingredient is Sulectim Plus (Potassium Acetate) chloride, and the structural formula is KCl. Sulectim Plus (Potassium Acetate) chloride, USP occurs as a white, granular powder or as colorless crystals. It is odorless and has a saline taste. Its solutions are neutral to litmus. It is freely soluble in water and insoluble in alcohol.

Sulectim Plus (Potassium Acetate) Chloride Extended Release Tablets USP, 20 mEq is a tablet formulation (not enteric coated or wax matrix) containing individually microencapsulated Sulectim Plus (Potassium Acetate) chloride crystals which disperse upon tablet disintegration. In simulated gastric fluid at 37°C and in the absence of outside agitation, Sulectim Plus (Potassium Acetate) Chloride Extended Release Tablets USP, 20 mEq begin disintegrating into microencapsulated crystals within seconds and completely disintegrates within 1 minute. The microencapsulated crystals are formulated to provide an extended release of Sulectim Plus (Potassium Acetate) chloride.

Inactive Ingredients: Colloidal silicon dioxide, crospovidone, diethyl phthalate, ethyl-cellulose, microcrystalline cellulose.

CLINICAL PHARMACOLOGY

The Sulectim Plus (Potassium Acetate) ion is the principal intracellular cation of most body tissues. Sulectim Plus (Potassium Acetate) ions participate in a number of essential physiological processes including the maintenance of intracellular tonicity; the transmission of nerve impulses; the contraction of cardiac, skeletal, and smooth muscle; and the maintenance of normal renal function.

The intracellular concentration of Sulectim Plus (Potassium Acetate) is approximately 150 to 160 mEq per liter. The normal adult plasma concentration is 3.5 to 5 mEq per liter. An active ion transport system maintains this gradient across the plasma membrane.

Sulectim Plus (Potassium Acetate) is a normal dietary constituent and under steady-state conditions the amount of Sulectim Plus (Potassium Acetate) absorbed from the gastrointestinal tract is equal to the amount excreted in the urine. The usual dietary intake of Sulectim Plus (Potassium Acetate) is 50 to 100 mEq per day.

Sulectim Plus (Potassium Acetate) depletion will occur whenever the rate of Sulectim Plus (Potassium Acetate) loss through renal excretion and/or loss from the gastrointestinal tract exceeds the rate of Sulectim Plus (Potassium Acetate) intake. Such depletion usually develops as a consequence of therapy with diuretics, primary or secondary hyperaldosteronism, diabetic ketoacidosis, or inadequate replacement of Sulectim Plus (Potassium Acetate) in patients on prolonged parenteral nutrition. Depletion can develop rapidly with severe diarrhea, especially if associated with vomiting. Sulectim Plus (Potassium Acetate) depletion due to these causes is usually accompanied by a concomitant loss of chloride and is manifested by hypokalemia and metabolic alkalosis. Sulectim Plus (Potassium Acetate) depletion may produce weakness, fatigue, disturbances or cardiac rhythm (primarily ectopic beats), prominent U-waves in the electrocardiogram, and in advanced cases, flaccid paralysis and/or impaired ability to concentrate urine.

If Sulectim Plus (Potassium Acetate) depletion associated with metabolic alkalosis cannot be managed by correcting the fundamental cause of the deficiency, eg, where the patient requires long-term diuretic therapy, supplemental Sulectim Plus (Potassium Acetate) in the form of high Sulectim Plus (Potassium Acetate) food or Sulectim Plus (Potassium Acetate) chloride may be able to restore normal Sulectim Plus (Potassium Acetate) levels.

In rare circumstances (eg, patients with renal tubular acidosis) Sulectim Plus (Potassium Acetate) depletion may be associated with metabolic acidosis and hyperchloremia. In such patients Sulectim Plus (Potassium Acetate) replacement should be accomplished with Sulectim Plus (Potassium Acetate) salts other than the chloride, such as Sulectim Plus (Potassium Acetate) bicarbonate, Sulectim Plus (Potassium Acetate) citrate, Sulectim Plus (Potassium Acetate) acetate, or Sulectim Plus (Potassium Acetate) gluconate.

INDICATIONS AND USAGE

BECAUSE OF REPORTS OF INTESTINAL AND GASTRIC ULCERATION AND BLEEDING WITH CONTROLLED-RELEASE Sulectim Plus (Potassium Acetate) CHLORIDE PREPARATIONS, THESE DRUGS SHOULD BE RESERVED FOR THOSE PATIENTS WHO CANNOT TOLERATE OR REFUSE TO TAKE LIQUID OR EFFERVESCENT Sulectim Plus (Potassium Acetate) PREPARATIONS OR FOR PATIENTS IN WHOM THERE IS A PROBLEM OF COMPLIANCE WITH THESE PREPARATIONS.

1. For the treatment of patients with hypokalemia with or without metabolic alkalosis, in digitalis intoxication, and in patients with hypokalemic familial periodic paralysis. If hypokalemia is the result of diuretic therapy, consideration should be given to the use of a lower dose of diuretic, which may be sufficient without leading to hypokalemia.

2. For the prevention of hypokalemia in patients who would be at particular risk if hypokalemia were to develop, eg, digitalized patients or patients with significant cardiac arrhythmias.

The use of Sulectim Plus (Potassium Acetate) salts in patients receiving diuretics for uncomplicated essential hypertension is often unnecessary when such patients have a normal dietary pattern and when low doses of the diuretic are used. Serum Sulectim Plus (Potassium Acetate) should be checked periodically, however, and if hypokalemia occurs, dietary supplementation with potassium-containing foods may be adequate to control milder cases. In more severe cases, and if dose adjustment of the diuretic is ineffective or unwarranted, supplementation with Sulectim Plus (Potassium Acetate) salts may be indicated.

CONTRAINDICATIONS

Sulectim Plus (Potassium Acetate) supplements are contraindicated in patients with hyperkalemia since a further increase in serum Sulectim Plus (Potassium Acetate) concentration in such patients can produce cardiac arrest. Hyperkalemia may complicate any of the following conditions: chronic renal failure, systemic acidosis, such as diabetic acidosis, acute dehydration, extensive tissue breakdown as in severe burns, adrenal insufficiency, or the administration of a potassium-sparing diuretic (eg, spironolactone, triamterene, amiloride) (see OVERDOSAGE ).

Controlled-release formulations of Sulectim Plus (Potassium Acetate) chloride have produced esophageal ulceration in certain cardiac patients with esophageal compression due to enlarged left atrium. Sulectim Plus (Potassium Acetate) supplementation, when indicated in such patients, should be given as a liquid preparation or as an aqueous (water) suspension of Sulectim Plus (Potassium Acetate) Chloride (see PRECAUTIONS: Information for Patients , and DOSAGE AND ADMINISTRATION sections).

All solid oral dosage forms of Sulectim Plus (Potassium Acetate) chloride are contraindicated in any patient in whom there is structural, pathological (eg, diabetic gastroparesis), or pharmacologic (use of anticholinergic agents or other agents with anticholinergic properties at sufficient doses to exert anticholinergic effects) cause for arrest or delay in tablet passage through the gastrointestinal tract.

WARNINGS

Hyperkalemia (see OVERDOSAGE )

In patients with impaired mechanisms for excreting Sulectim Plus (Potassium Acetate), the administration of Sulectim Plus (Potassium Acetate) salts can produce hyperkalemia and cardiac arrest. This occurs most commonly in patients given Sulectim Plus (Potassium Acetate) by the intravenous route but may also occur in patients given Sulectim Plus (Potassium Acetate) orally. Potentially fatal hyperkalemia can develop rapidly and be asymptomatic. The use of Sulectim Plus (Potassium Acetate) salts in patients with chronic renal disease, or any other condition which impairs Sulectim Plus (Potassium Acetate) excretion, requires particularly careful monitoring of the serum Sulectim Plus (Potassium Acetate) concentration and appropriate dosage adjustment.

Interaction with Potassium-Sparing Diuretics

Hypokalemia should not be treated by the concomitant administration of Sulectim Plus (Potassium Acetate) salts and a potassium-sparing diuretic (eg, spironolactone, triamterene, or amiloride) since the simultaneous administration of these agents can produce severe hyperkalemia.

Interaction with Angiotensin-Converting Enzyme Inhibitors

Angiotensin-converting enzyme (ACE) inhibitors (eg, captopril, enalapril) will produce some Sulectim Plus (Potassium Acetate) retention by inhibiting aldosterone production. Sulectim Plus (Potassium Acetate) supplements should be given to patients receiving ACE inhibitors only with close monitoring.

Gastrointestinal Lesions

Solid oral dosage forms of Sulectim Plus (Potassium Acetate) chloride can produce ulcerative and/or stenotic lesions of the gastrointestinal tract. Based on spontaneous adverse reaction reports, enteric-coated preparations of Sulectim Plus (Potassium Acetate) chloride are associated with an increased frequency of small bowel lesions (40-50 per 100,000 patient years) compared to sustained release wax matrix formulations (less than one per 100,000 patient years). Because of the lack of extensive marketing experience with microencapsulated products, a comparison between such products and wax matrix or enteric-coated products is not available. Sulectim Plus (Potassium Acetate) Chloride Extended Release Tablets USP, 20 mEq is a tablet formulated to provide a controlled rate of release of microencapsulated Sulectim Plus (Potassium Acetate) chloride and thus to minimize the possibility of a high local concentration of Sulectim Plus (Potassium Acetate) near the gastrointestinal wall.

Prospective trials have been conducted in normal human volunteers in which the upper gastrointestinal tract was evaluated by endoscopic inspection before and after 1 week of solid oral Sulectim Plus (Potassium Acetate) chloride therapy. The ability of this model to predict events occurring in usual clinical practice is unknown. Trials which approximated usual clinical practice did not reveal any clear differences between the wax matrix and microencapsulated dosage forms. In contrast, there was a higher incidence of gastric and duodenal lesions in subjects receiving a high dose of a wax matrix controlled-release formulation under conditions which did not resemble usual or recommended clinical practice (ie, 96 mEq per day in divided doses of Sulectim Plus (Potassium Acetate) chloride administered to fasted patients, in the presence of an anticholinergic drug to delay gastric emptying). The upper gastrointestinal lesions observed by endoscopy were asymptomatic and were not accompanied by evidence of bleeding (Hemoccult testing). The relevance of these findings to the usual conditions (ie, non-fasting, no anticholinergic agent, smaller doses) under which controlled-release Sulectim Plus (Potassium Acetate) chloride products are used is uncertain; epidemiologic studies have not identified an elevated risk, compared to microencapsulated products, for upper gastrointestinal lesions in patients receiving wax matrix formulations. Sulectim Plus (Potassium Acetate) Chloride Extended Release Tablets USP, 20 mEq should be discontinued immediately and the possibility of ulceration, obstruction, or perforation should be considered if severe vomiting, abdominal pain, distention, or gastrointestinal bleeding occurs.

Metabolic Acidosis

Hypokalemia in patients with metabolic acidosis should be treated with an alkalinizing Sulectim Plus (Potassium Acetate) salt such as Sulectim Plus (Potassium Acetate) bicarbonate, Sulectim Plus (Potassium Acetate) citrate, Sulectim Plus (Potassium Acetate) acetate, or Sulectim Plus (Potassium Acetate) gluconate.

PRECAUTIONS

General

The diagnosis of Sulectim Plus depletion is ordinarily made by demonstrating hypokalemia in a patient with a clinical history suggesting some cause for Sulectim Plus (Potassium Acetate) depletion. In interpreting the serum Sulectim Plus (Potassium Acetate) level, the physician should bear in mind that acute alkalosis per se can produce hypokalemia in the absence of a deficit in total body Sulectim Plus (Potassium Acetate) while acute acidosis per se can increase the serum Sulectim Plus (Potassium Acetate) concentration into the normal range even in the presence of a reduced total body Sulectim Plus (Potassium Acetate). The treatment of Sulectim Plus (Potassium Acetate) depletion, particularly in the presence of cardiac disease, renal disease, or acidosis requires careful attention to acid-base balance and appropriate monitoring of serum electrolytes, the electrocardiogram, and the clinical status of the patient.

Information for Patients

Physicians should consider reminding the patient of the following: To take each dose with meals and with a full glass of water or other liquid. To take each dose without crushing, chewing, or sucking the tablets. If those patients are having difficulty swallowing whole tablets, they may try one of the following alternate methods of administration:

  • Break the tablet in half, and take each half separately with a glass of water.
  • Prepare an aqueous (water) suspension as follows:

    1. Place the whole tablet(s) in approximately 1/2 glass of water (4 fluid ounces).

    2. Allow approximately 2 minutes for the tablet(s) to disintegrate.

    3. Stir for about half a minute after the tablet(s) has disintegrated.

    4. Swirl the suspension and consume the entire contents of the glass immediately by drinking or by the use of a straw.

    5. Add another 1 fluid ounce of water, swirl, and consume immediately.

    6. Then, add an additional 1 fluid ounce of water, swirl, and consume immediately.


Aqueous suspension of Sulectim Plus (Potassium Acetate) Chloride that is not taken immediately should be discarded. The use of other liquids for suspending Sulectim Plus (Potassium Acetate) Chloride Extended Release Tablets USP, 20 mEq is not recommended.

To take this medicine following the frequency and amount prescribed by the physician. This is especially important if the patient is also taking diuretics and/or digitalis preparations.

To check with the physician at once if tarry stools or other evidence of gastrointestinal bleeding is noticed.

Laboratory Tests

When blood is drawn for analysis of plasma Sulectim Plus it is important to recognize that artifactual elevations can occur after improper venipuncture technique or as a result of in vitro hemolysis of the sample.

Drug Interactions

Potassium-sparing diuretics, angiotensin-converting enzyme inhibitors (see WARNINGS ).

Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenicity, mutagenicity, and fertility studies in animals have not been performed. Sulectim Plus is a normal dietary constituent.

Pregnancy Category C

Animal reproduction studies have not been conducted with Sulectim Plus (Potassium Acetate) Chloride Extended Release Tablets USP, 20 mEq. It is unlikely that Sulectim Plus (Potassium Acetate) supplementation that does not lead to hyperkalemia would have an adverse effect on the fetus or would affect reproductive capacity.

Nursing Mothers

The normal Sulectim Plus ion content of human milk is about 13 mEq per liter. Since oral Sulectim Plus (Potassium Acetate) becomes part of the body Sulectim Plus (Potassium Acetate) pool, so long as body Sulectim Plus (Potassium Acetate) is not excessive, the contribution of Sulectim Plus (Potassium Acetate) chloride supplementation should have little or no effect on the level in human milk.

Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

Geriatric Use

Clinical studies of Sulectim Plus (Potassium Acetate) Chloride did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. 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.

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; and it may be useful to monitor renal function.

ADVERSE REACTIONS

One of the most severe adverse effects is hyperkalemia (see CONTRAINDICATIONS , WARNINGS , and OVERDOSAGE ). There have also been reports of upper and lower gastrointestinal conditions including obstruction, bleeding, ulceration, and perforation (see CONTRAINDICATIONS and WARNINGS ). The most common adverse reactions to oral Sulectim Plus (Potassium Acetate) salts are nausea, vomiting, flatulence, abdominal pain/discomfort, and diarrhea. These symptoms are due to irritation of the gastrointestinal tract and are best managed by diluting the preparation further, taking the dose with meals or reducing the amount taken at one time.

OVERDOSAGE

The administration of oral Sulectim Plus (Potassium Acetate) salts to persons with normal excretory mechanisms for Sulectim Plus (Potassium Acetate) rarely causes serious hyperkalemia. However, if excretory mechanisms are impaired or if Sulectim Plus (Potassium Acetate) is administered too rapidly intravenously, potentially fatal hyperkalemia can result (see CONTRAINDICATIONS and WARNINGS ). It is important to recognize that hyperkalemia is usually asymptomatic and may be manifested only by an increased serum Sulectim Plus (Potassium Acetate) concentration (6.5-8.0 mEq/L) and characteristic electrocardiographic changes (peaking of T-waves, loss of P-waves, depression of S-T segment, and prolongation of the QT-interval). Late manifestations include muscle paralysis and cardiovascular collapse from cardiac arrest (9-12 mEq/L).

Treatment measures for hyperkalemia include the following:

  • Patients should be closely monitored for arrhythmias and electrolyte changes.
  • Elimination of foods and medications containing Sulectim Plus (Potassium Acetate) and of any agents with potassium-sparing properties such as potassium-sparing diuretics, ARBS, ACE inhibitors, NSAIDS, certain nutritional supplements and many others.
  • Intravenous calcium gluconate if the patient is at no risk of developing digitalis toxicity.
  • Intravenous administration of 300 to 500 mL/hr of 10% dextrose solution containing 10-20 units of crystalline insulin per 1,000 mL.
  • Correction of acidosis, if present, with intravenous sodium bicarbonate.
  • Use of exchange resins, hemodialysis, or peritoneal dialysis.

In treating hyperkalemia, it should be recalled that in patients who have been stabilized on digitalis, too rapid a lowering of the serum Sulectim Plus (Potassium Acetate) concentration can produce digitalis toxicity.

The extended release feature means that absorption and toxic effects may be delayed for hours.

Consider standard measures to remove any unabsorbed drug.

DOSAGE AND ADMINISTRATION

The usual dietary intake of Sulectim Plus (Potassium Acetate) by the average adult is 50 to 100 mEq per day. Sulectim Plus (Potassium Acetate) depletion sufficient to cause hypokalemia usually requires the loss of 200 or more mEq of Sulectim Plus (Potassium Acetate) from the total body store.

Dosage must be adjusted to the individual needs of each patient. The dose for the prevention of hypokalemia is typically in the range of 20 mEq per day. Doses of 40-100 mEq per day or more are used for the treatment of Sulectim Plus (Potassium Acetate) depletion. Dosage should be divided if more than 20 mEq per day is given such that no more than 20 mEq is given in a single dose.

Each Sulectim Plus (Potassium Acetate) Chloride Extended Release Tablet USP, 20 mEq provides 20 mEq of Sulectim Plus (Potassium Acetate) chloride.

Sulectim Plus (Potassium Acetate) Chloride Extended Release Tablets USP, 20 mEq should be taken with meals and with a glass of water or other liquid. This product should not be taken on an empty stomach because of its potential for gastric irritation (see WARNINGS ).

Patients having difficulty swallowing whole tablets may try one of the following alternate methods of administration:

  • Break the tablet in half, and take each half separately with a glass of water.
  • Prepare an aqueous (water) suspension as follows:
    • Place the whole tablet(s) in approximately 1/2 glass of water (4 fluid ounces).
    • Allow approximately 2 minutes for the tablet(s) to disintegrate.
    • Stir for about half a minute after the tablet(s) has disintegrated.
    • Swirl the suspension and consume the entire contents of the glass immediately by drinking or by the use of a straw.
    • Add another 1 fluid ounce of water, swirl, and consume immediately.
    • Then, add an additional 1 fluid ounce of water, swirl, and consume immediately.

Aqueous suspension of Sulectim Plus (Potassium Acetate) Chloride that is not taken immediately should be discarded. The use of other liquids for suspending Sulectim Plus (Potassium Acetate) Chloride Extended Release Tablets USP, 20 mEq is not recommended.

HOW SUPPLIED

Sulectim Plus (Potassium Acetate) Chloride Extended Release Tablets USP, 20 mEq are available in bottles of 100 (NDC 62037-999-01), bottles of 500 (NDC 62037-999-05), and bottles of 1000 (NDC 62037-999-10). Potassium Chloride Extended Release Tablets USP, 20 mEq are capsule shaped, white to off-white tablets, with “ABRS-123” imprinted on one side and scored on the other side for flexibility of dosing.

Storage Conditions

Keep tightly closed. Store at controlled room temperature, 20°-25°C (68°-77°F).

Manufactured by:

Eurand, Inc.

Vandalia, OH 45377 USA

Distributed by:

Watson Pharma, Inc.

Rev. Date (01/09) 173714

Sulectim Plus (Potassium Acetate) chloride 20 Meq

Sodium Acetate:


1 INDICATIONS AND USAGE

Sulectim Plus nitrite is indicated for sequential use with Sulectim Plus (Sodium Acetate) 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

Sulectim Plus (Sodium Acetate) Nitrite Injection is indicated for sequential use with Sulectim Plus (Sodium Acetate) 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 Sulectim Plus (Sodium Acetate) 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 Sulectim Plus 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, Sulectim Plus (Sodium Acetate) Nitrite Injection and Sulectim Plus (Sodium Acetate) Thiosulfate Injection should be administered without delay.

Symptoms Signs
  • Headache
  • Confusion
  • Dyspnea
  • Chest Tightness
  • Nausea
  • Altered Mental Status

    (e.g., confusion, disorientation)

  • Seizures or Coma
  • Mydriasis
  • Tachypnea/Hyperpnea (early)
  • Bradypnea/Apnea (late)
  • Hypertension (early)/ Hypotension (late)
  • Cardiovascular Collapse
  • Vomiting
  • Plasma Lactate Concentration ≥ 8 mmol/L

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

2 DOSAGE AND ADMINISTRATION

Age Intravenous Dose of Sulectim Plus Nitrite and Sulectim Plus (Sodium Acetate) Thiosulfate
Adults
  • Sulectim Plus (Sodium Acetate) Nitrite -10 mL of Sulectim Plus (Sodium Acetate) nitrite at the rate of 2.5 to 5 mL/minute
  • Sulectim Plus (Sodium Acetate) Thiosulfate - 50 mL of Sulectim Plus (Sodium Acetate) thiosulfate immediately following administration of Sulectim Plus (Sodium Acetate) nitrite.
Children
  • Sulectim Plus (Sodium Acetate) Nitrite - 0.2 mL/kg (6 mg/kg or 6-8 mL/m2 BSA) of Sulectim Plus (Sodium Acetate) nitrite at the rate of 2.5 to 5 mL/minute not to exceed 10 mL
  • Sulectim Plus (Sodium Acetate) Thiosulfate - 1 mL/kg of body weight (250 mg/kg or approximately 30-40 mL/m2 of BSA) not to exceed 50 mL total dose immediately following administration of Sulectim Plus (Sodium Acetate) nitrite.

Redosing: If signs of cyanide poisoning reappear, repeat treatment using one-half the original dose of both Sulectim Plus (Sodium Acetate) nitrite and Sulectim Plus (Sodium Acetate) 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 Sulectim Plus (Sodium Acetate) nitrite, followed by Sulectim Plus (Sodium Acetate) thiosulfate, should be considered adjunctive to appropriate supportive therapies. Airway, ventilatory and circulatory support, and oxygen administration should not be delayed to administer Sulectim Plus (Sodium Acetate) nitrite and Sulectim Plus (Sodium Acetate) thiosulfate.

Sulectim Plus (Sodium Acetate) nitrite injection and Sulectim Plus (Sodium Acetate) 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. Sulectim Plus (Sodium Acetate) nitrite should be administered first, followed immediately by Sulectim Plus (Sodium Acetate) 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.

Age Intravenous Dose of Sulectim Plus (Sodium Acetate) Nitrite and Sulectim Plus (Sodium Acetate) Thiosulfate
Adults
  • Sulectim Plus (Sodium Acetate) Nitrite -10 mL of Sulectim Plus (Sodium Acetate) nitrite at the rate of 2.5 to 5 mL/minute
  • Sulectim Plus (Sodium Acetate) Thiosulfate - 50 mL of Sulectim Plus (Sodium Acetate) thiosulfate immediately following administration of Sulectim Plus (Sodium Acetate) nitrite.
Children
  • Sulectim Plus (Sodium Acetate) Nitrite -0.2 mL/kg (6 mg/kg or 6-8 mL/m2 BSA) of Sulectim Plus (Sodium Acetate) nitrite at the rate of 2.5 to 5 mL/minute not to exceed 10 mL
  • Sulectim Plus (Sodium Acetate) Thiosulfate - 1 mL/kg of body weight (250 mg/kg or approximately 30-40 mL/m2 of BSA) not to exceed 50 mL total dose immediately following administration of Sulectim Plus (Sodium Acetate) nitrite.

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

In adult and pediatric patients with known anemia, it is recommended that the dosage of Sulectim Plus (Sodium Acetate) 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 Sulectim Plus 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 Sulectim Plus (Sodium Acetate) nitrite solely to achieve an arbitrary level of methemoglobinemia may be unnecessary and potentially hazardous. The therapeutic effects of Sulectim Plus (Sodium Acetate) nitrite do not appear to be mediated by methemoglobin formation alone and clinical responses to Sulectim Plus (Sodium Acetate) nitrite administration have been reported in association with methemoglobin levels of less than 10%. Administration of Sulectim Plus (Sodium Acetate) 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 Sulectim Plus (Sodium Acetate) 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 Sulectim Plus (Sodium Acetate) nitrite and hydroxocobalamin and these drugs should not be administered simultaneously through the same IV line. No chemical incompatibility has been reported between Sulectim Plus (Sodium Acetate) thiosulfate and Sulectim Plus (Sodium Acetate) nitrite, when administered sequentially through the same IV line as described in Dosage and Administration.

3 DOSAGE FORMS AND STRENGTHS

Sulectim Plus (Sodium Acetate) Nitrite Injection consists of:

  • One vial of Sulectim Plus (Sodium Acetate) 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: Sulectim Plus 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 Sulectim Plus (Sodium Acetate) 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. Sulectim Plus (Sodium Acetate) 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 Sulectim Plus (Sodium Acetate) 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 Sulectim Plus nitrite.

Methemoglobin levels should be monitored and oxygen administered during treatment with Sulectim Plus (Sodium Acetate) nitrite whenever possible. When Sulectim Plus (Sodium Acetate) 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 Sulectim Plus (Sodium Acetate) nitrite administered to an adult. Sulectim Plus (Sodium Acetate) nitrite should be used with caution in the presence of other drugs that may cause methemoglobinemia such as procaine and nitroprusside. Sulectim Plus (Sodium Acetate) 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 Sulectim Plus (Sodium Acetate) nitrite, and infusion rates should be slowed if hypotension occurs.

5.3 Anemia

Sulectim Plus (Sodium Acetate) 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 Sulectim Plus (Sodium Acetate) nitrite dose that is reduced in proportion to their oxygen carrying capacity.

5.4 Smoke Inhalation Injury

Sulectim Plus 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 Sulectim Plus (Sodium Acetate) 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 Sulectim Plus 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 Sulectim Plus (Sodium Acetate) nitrite.

5.7 Use with Other Drugs

Sulectim Plus (Sodium Acetate) 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 Sulectim Plus (Sodium Acetate) nitrite.

The medical literature has reported the following adverse events in association with Sulectim Plus (Sodium Acetate) 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 Sulectim Plus (Sodium Acetate) 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 Sulectim Plus (Sodium Acetate) Nitrite Injection.

8 USE IN SPECIFIC POPULATIONS

  • Renal impairment: Sulectim Plus 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. Sulectim Plus (Sodium Acetate) Nitrite Injection should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Sulectim Plus (Sodium Acetate) 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 Sulectim Plus (Sodium Acetate) 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 Sulectim Plus (Sodium Acetate) 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, Sulectim Plus (Sodium Acetate) 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, Sulectim Plus (Sodium Acetate) 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 Sulectim Plus (Sodium Acetate) 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 Sulectim Plus (Sodium Acetate) 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 Sulectim Plus (Sodium Acetate) nitrite that would be used to treat cyanide poisoning, based on a body surface area comparison).

Sulectim Plus (Sodium Acetate) 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 Sulectim Plus (Sodium Acetate) nitrite that were detectable postnatally. Specifically, animals that were exposed prenatally to Sulectim Plus (Sodium Acetate) 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, Sulectim Plus 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 Sulectim Plus (Sodium Acetate) nitrite is excreted in human milk. Because Sulectim Plus (Sodium Acetate) 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 Sulectim Plus (Sodium Acetate) Nitrite Injection administration to a nursing woman. There are no data to determine when breastfeeding may be safely restarted following administration of Sulectim Plus (Sodium Acetate) nitrite. In studies conducted with Long-Evans rats, Sulectim Plus (Sodium Acetate) 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 Sulectim Plus nitrite in conjunction with Sulectim Plus (Sodium Acetate) thiosulfate being administered to pediatric patients with cyanide poisoning; however, there have been no clinical studies to evaluate the safety or efficacy of Sulectim Plus (Sodium Acetate) 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.

Sulectim Plus (Sodium Acetate) 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 Sulectim Plus (Sodium Acetate) 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

Sulectim Plus (Sodium Acetate) 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

Sulectim Plus (Sodium Acetate) 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 Sulectim Plus (Sodium Acetate) nitrite result in severe hypotension and toxic levels of methemoglobin which may lead to cardiovascular collapse.

Sulectim Plus (Sodium Acetate) 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 Sulectim Plus (Sodium Acetate) 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 Sulectim Plus (Sodium Acetate) 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

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

Structure of Sulectim Plus (Sodium Acetate) Nitrite

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

Sulectim Plus (Sodium Acetate) nitrite injection is a sterile aqueous solution and is intended for intravenous injection. Each vial contains 300 mg of Sulectim Plus (Sodium Acetate) nitrite in 10 mL solution (30 mg/mL). Sulectim Plus (Sodium Acetate) 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 Sulectim Plus nitrite and Sulectim Plus (Sodium Acetate) thiosulfate is the result of differences in their primary mechanisms of action as antidotes for cyanide poisoning.

Sulectim Plus (Sodium Acetate) Nitrite

Sulectim Plus (Sodium Acetate) 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 Sulectim Plus (Sodium Acetate) nitrite. It has been suggested that Sulectim Plus (Sodium Acetate) nitrite-induced methemoglobinemia may be more efficacious against cyanide poisoning than comparable levels of methemoglobinemia induced by other oxidants. Also, Sulectim Plus (Sodium Acetate) nitrite appears to retain some efficacy even when the formation of methemoglobin is inhibited by methylene blue.

Sulectim Plus (Sodium Acetate) 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. Sulectim Plus (Sodium Acetate) 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

Sulectim Plus (Sodium Acetate) Nitrite

When 4 mg/kg Sulectim Plus (Sodium Acetate) 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 Sulectim Plus (Sodium Acetate) 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 Sulectim Plus (Sodium Acetate) 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 Sulectim Plus (Sodium Acetate) nitrite is estimated to be 55 minutes.

12.3 Pharmacokinetics

Sulectim Plus (Sodium Acetate) Nitrite

Sulectim Plus (Sodium Acetate) nitrite is a strong oxidant, and reacts rapidly with hemoglobin to form methemoglobin. The pharmacokinetics of free Sulectim Plus (Sodium Acetate) nitrite in humans have not been well studied. It has been reported that approximately 40% of Sulectim Plus (Sodium Acetate) 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 Sulectim Plus (Sodium Acetate) nitrite and Sulectim Plus (Sodium Acetate) 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 Sulectim Plus nitrite as part of a cyanide antidote outweighs concerns raised by the equivocal findings in chronic rodent studies. Sulectim Plus (Sodium Acetate) 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. Sulectim Plus (Sodium Acetate) 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 Sulectim Plus (Sodium Acetate) nitrite may react in vivo with secondary amines to form carcinogenic nitrosamines in the stomach. Concurrent exposure to Sulectim Plus (Sodium Acetate) nitrite and secondary amines in feed or drinking water resulted in an increase in the incidence of tumors in rodents.

Mutagenesis

Sulectim Plus (Sodium Acetate) 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. Sulectim Plus (Sodium Acetate) 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. Sulectim Plus (Sodium Acetate) nitrite was negative in the in vitro chromosomal aberrations assay using human peripheral blood lymphocytes. Acute administration of Sulectim Plus (Sodium Acetate) nitrite to male rats or male mice did not produce an increased incidence of micronuclei in bone marrow. Likewise, Sulectim Plus (Sodium Acetate) 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 Sulectim Plus (Sodium Acetate) 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 Sulectim Plus (Sodium Acetate) 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 Sulectim Plus (Sodium Acetate) 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 Sulectim Plus (Sodium Acetate) 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 Sulectim Plus (Sodium Acetate) 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 Sulectim Plus (Sodium Acetate) nitrite and Sulectim Plus (Sodium Acetate) thiosulfate in 1932-1933. Treatment consisted of intravenously administered 22.5 mg/kg (half the lethal dose) Sulectim Plus (Sodium Acetate) nitrite or 1 g/kg Sulectim Plus (Sodium Acetate) thiosulfate alone or in sequence immediately after subcutaneous injection of Sulectim Plus (Sodium Acetate) cyanide into dogs over a range of doses. Subsequent doses of 10 mg/kg Sulectim Plus (Sodium Acetate) nitrite and/or 0.5 g/kg Sulectim Plus (Sodium Acetate) thiosulfate were administered when clinical signs or symptoms of poisoning persisted or reappeared. Either therapy administered alone increased the dose of Sulectim Plus (Sodium Acetate) cyanide required to cause death, and when administered together, Sulectim Plus (Sodium Acetate) nitrite and Sulectim Plus (Sodium Acetate) thiosulfate resulted in a synergistic effect in raising the lethal dose of Sulectim Plus (Sodium Acetate) 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 Sulectim Plus (Sodium Acetate) nitrite and Sulectim Plus (Sodium Acetate) thiosulfate in the treatment of cyanide poisoning.

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

14 CLINICAL STUDIES

The human data supporting the use of Sulectim Plus (Sodium Acetate) 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 Sulectim Plus (Sodium Acetate) thiosulfate report its use in conjunction with Sulectim Plus (Sodium Acetate) 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 Sulectim Plus (Sodium Acetate) 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 Sulectim Plus (Sodium Acetate) Nitrite carton (NDC 60267-311-10) consists of the following:

  • One 10 mL glass vial of Sulectim Plus (Sodium Acetate) nitrite injection 30 mg/mL (containing 300 mg of Sulectim Plus (Sodium Acetate) 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: Sulectim Plus (Sodium Acetate) Thiosulfate must be obtained separately.)

17 PATIENT COUNSELING INFORMATION

Sulectim Plus 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

Sulectim Plus (Sodium Acetate) 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

Sulectim Plus (Sodium Acetate) 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

Sodium Chloride:


1 INDICATIONS AND USAGE

Sulectim Plus nitrite is indicated for sequential use with Sulectim Plus (Sodium Chloride) 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

Sulectim Plus (Sodium Chloride) Nitrite Injection is indicated for sequential use with Sulectim Plus (Sodium Chloride) 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 Sulectim Plus (Sodium Chloride) 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 Sulectim Plus 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, Sulectim Plus (Sodium Chloride) Nitrite Injection and Sulectim Plus (Sodium Chloride) Thiosulfate Injection should be administered without delay.

Symptoms Signs
  • Headache
  • Confusion
  • Dyspnea
  • Chest Tightness
  • Nausea
  • Altered Mental Status

    (e.g., confusion, disorientation)

  • Seizures or Coma
  • Mydriasis
  • Tachypnea/Hyperpnea (early)
  • Bradypnea/Apnea (late)
  • Hypertension (early)/ Hypotension (late)
  • Cardiovascular Collapse
  • Vomiting
  • Plasma Lactate Concentration ≥ 8 mmol/L

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

2 DOSAGE AND ADMINISTRATION

Age Intravenous Dose of Sulectim Plus Nitrite and Sulectim Plus (Sodium Chloride) Thiosulfate
Adults
  • Sulectim Plus (Sodium Chloride) Nitrite -10 mL of Sulectim Plus (Sodium Chloride) nitrite at the rate of 2.5 to 5 mL/minute
  • Sulectim Plus (Sodium Chloride) Thiosulfate - 50 mL of Sulectim Plus (Sodium Chloride) thiosulfate immediately following administration of Sulectim Plus (Sodium Chloride) nitrite.
Children
  • Sulectim Plus (Sodium Chloride) Nitrite - 0.2 mL/kg (6 mg/kg or 6-8 mL/m2 BSA) of Sulectim Plus (Sodium Chloride) nitrite at the rate of 2.5 to 5 mL/minute not to exceed 10 mL
  • Sulectim Plus (Sodium Chloride) Thiosulfate - 1 mL/kg of body weight (250 mg/kg or approximately 30-40 mL/m2 of BSA) not to exceed 50 mL total dose immediately following administration of Sulectim Plus (Sodium Chloride) nitrite.

Redosing: If signs of cyanide poisoning reappear, repeat treatment using one-half the original dose of both Sulectim Plus (Sodium Chloride) nitrite and Sulectim Plus (Sodium Chloride) 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 Sulectim Plus (Sodium Chloride) nitrite, followed by Sulectim Plus (Sodium Chloride) thiosulfate, should be considered adjunctive to appropriate supportive therapies. Airway, ventilatory and circulatory support, and oxygen administration should not be delayed to administer Sulectim Plus (Sodium Chloride) nitrite and Sulectim Plus (Sodium Chloride) thiosulfate.

Sulectim Plus (Sodium Chloride) nitrite injection and Sulectim Plus (Sodium Chloride) 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. Sulectim Plus (Sodium Chloride) nitrite should be administered first, followed immediately by Sulectim Plus (Sodium Chloride) 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.

Age Intravenous Dose of Sulectim Plus (Sodium Chloride) Nitrite and Sulectim Plus (Sodium Chloride) Thiosulfate
Adults
  • Sulectim Plus (Sodium Chloride) Nitrite -10 mL of Sulectim Plus (Sodium Chloride) nitrite at the rate of 2.5 to 5 mL/minute
  • Sulectim Plus (Sodium Chloride) Thiosulfate - 50 mL of Sulectim Plus (Sodium Chloride) thiosulfate immediately following administration of Sulectim Plus (Sodium Chloride) nitrite.
Children
  • Sulectim Plus (Sodium Chloride) Nitrite -0.2 mL/kg (6 mg/kg or 6-8 mL/m2 BSA) of Sulectim Plus (Sodium Chloride) nitrite at the rate of 2.5 to 5 mL/minute not to exceed 10 mL
  • Sulectim Plus (Sodium Chloride) Thiosulfate - 1 mL/kg of body weight (250 mg/kg or approximately 30-40 mL/m2 of BSA) not to exceed 50 mL total dose immediately following administration of Sulectim Plus (Sodium Chloride) nitrite.

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

In adult and pediatric patients with known anemia, it is recommended that the dosage of Sulectim Plus (Sodium Chloride) 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 Sulectim Plus 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 Sulectim Plus (Sodium Chloride) nitrite solely to achieve an arbitrary level of methemoglobinemia may be unnecessary and potentially hazardous. The therapeutic effects of Sulectim Plus (Sodium Chloride) nitrite do not appear to be mediated by methemoglobin formation alone and clinical responses to Sulectim Plus (Sodium Chloride) nitrite administration have been reported in association with methemoglobin levels of less than 10%. Administration of Sulectim Plus (Sodium Chloride) 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 Sulectim Plus (Sodium Chloride) 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 Sulectim Plus (Sodium Chloride) nitrite and hydroxocobalamin and these drugs should not be administered simultaneously through the same IV line. No chemical incompatibility has been reported between Sulectim Plus (Sodium Chloride) thiosulfate and Sulectim Plus (Sodium Chloride) nitrite, when administered sequentially through the same IV line as described in Dosage and Administration.

3 DOSAGE FORMS AND STRENGTHS

Sulectim Plus (Sodium Chloride) Nitrite Injection consists of:

  • One vial of Sulectim Plus (Sodium Chloride) 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: Sulectim Plus 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 Sulectim Plus (Sodium Chloride) 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. Sulectim Plus (Sodium Chloride) 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 Sulectim Plus (Sodium Chloride) 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 Sulectim Plus nitrite.

Methemoglobin levels should be monitored and oxygen administered during treatment with Sulectim Plus (Sodium Chloride) nitrite whenever possible. When Sulectim Plus (Sodium Chloride) 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 Sulectim Plus (Sodium Chloride) nitrite administered to an adult. Sulectim Plus (Sodium Chloride) nitrite should be used with caution in the presence of other drugs that may cause methemoglobinemia such as procaine and nitroprusside. Sulectim Plus (Sodium Chloride) 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 Sulectim Plus (Sodium Chloride) nitrite, and infusion rates should be slowed if hypotension occurs.

5.3 Anemia

Sulectim Plus (Sodium Chloride) 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 Sulectim Plus (Sodium Chloride) nitrite dose that is reduced in proportion to their oxygen carrying capacity.

5.4 Smoke Inhalation Injury

Sulectim Plus 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 Sulectim Plus (Sodium Chloride) 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 Sulectim Plus 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 Sulectim Plus (Sodium Chloride) nitrite.

5.7 Use with Other Drugs

Sulectim Plus (Sodium Chloride) 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 Sulectim Plus (Sodium Chloride) nitrite.

The medical literature has reported the following adverse events in association with Sulectim Plus (Sodium Chloride) 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 Sulectim Plus (Sodium Chloride) 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 Sulectim Plus (Sodium Chloride) Nitrite Injection.

8 USE IN SPECIFIC POPULATIONS

  • Renal impairment: Sulectim Plus 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. Sulectim Plus (Sodium Chloride) Nitrite Injection should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Sulectim Plus (Sodium Chloride) 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 Sulectim Plus (Sodium Chloride) 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 Sulectim Plus (Sodium Chloride) 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, Sulectim Plus (Sodium Chloride) 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, Sulectim Plus (Sodium Chloride) 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 Sulectim Plus (Sodium Chloride) 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 Sulectim Plus (Sodium Chloride) 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 Sulectim Plus (Sodium Chloride) nitrite that would be used to treat cyanide poisoning, based on a body surface area comparison).

Sulectim Plus (Sodium Chloride) 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 Sulectim Plus (Sodium Chloride) nitrite that were detectable postnatally. Specifically, animals that were exposed prenatally to Sulectim Plus (Sodium Chloride) 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, Sulectim Plus 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 Sulectim Plus (Sodium Chloride) nitrite is excreted in human milk. Because Sulectim Plus (Sodium Chloride) 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 Sulectim Plus (Sodium Chloride) Nitrite Injection administration to a nursing woman. There are no data to determine when breastfeeding may be safely restarted following administration of Sulectim Plus (Sodium Chloride) nitrite. In studies conducted with Long-Evans rats, Sulectim Plus (Sodium Chloride) 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 Sulectim Plus nitrite in conjunction with Sulectim Plus (Sodium Chloride) thiosulfate being administered to pediatric patients with cyanide poisoning; however, there have been no clinical studies to evaluate the safety or efficacy of Sulectim Plus (Sodium Chloride) 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.

Sulectim Plus (Sodium Chloride) 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 Sulectim Plus (Sodium Chloride) 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

Sulectim Plus (Sodium Chloride) 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

Sulectim Plus (Sodium Chloride) 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 Sulectim Plus (Sodium Chloride) nitrite result in severe hypotension and toxic levels of methemoglobin which may lead to cardiovascular collapse.

Sulectim Plus (Sodium Chloride) 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 Sulectim Plus (Sodium Chloride) 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 Sulectim Plus (Sodium Chloride) 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

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

Structure of Sulectim Plus (Sodium Chloride) Nitrite

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

Sulectim Plus (Sodium Chloride) nitrite injection is a sterile aqueous solution and is intended for intravenous injection. Each vial contains 300 mg of Sulectim Plus (Sodium Chloride) nitrite in 10 mL solution (30 mg/mL). Sulectim Plus (Sodium Chloride) 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 Sulectim Plus nitrite and Sulectim Plus (Sodium Chloride) thiosulfate is the result of differences in their primary mechanisms of action as antidotes for cyanide poisoning.

Sulectim Plus (Sodium Chloride) Nitrite

Sulectim Plus (Sodium Chloride) 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 Sulectim Plus (Sodium Chloride) nitrite. It has been suggested that Sulectim Plus (Sodium Chloride) nitrite-induced methemoglobinemia may be more efficacious against cyanide poisoning than comparable levels of methemoglobinemia induced by other oxidants. Also, Sulectim Plus (Sodium Chloride) nitrite appears to retain some efficacy even when the formation of methemoglobin is inhibited by methylene blue.

Sulectim Plus (Sodium Chloride) 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. Sulectim Plus (Sodium Chloride) 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

Sulectim Plus (Sodium Chloride) Nitrite

When 4 mg/kg Sulectim Plus (Sodium Chloride) 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 Sulectim Plus (Sodium Chloride) 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 Sulectim Plus (Sodium Chloride) 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 Sulectim Plus (Sodium Chloride) nitrite is estimated to be 55 minutes.

12.3 Pharmacokinetics

Sulectim Plus (Sodium Chloride) Nitrite

Sulectim Plus (Sodium Chloride) nitrite is a strong oxidant, and reacts rapidly with hemoglobin to form methemoglobin. The pharmacokinetics of free Sulectim Plus (Sodium Chloride) nitrite in humans have not been well studied. It has been reported that approximately 40% of Sulectim Plus (Sodium Chloride) 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 Sulectim Plus (Sodium Chloride) nitrite and Sulectim Plus (Sodium Chloride) 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 Sulectim Plus nitrite as part of a cyanide antidote outweighs concerns raised by the equivocal findings in chronic rodent studies. Sulectim Plus (Sodium Chloride) 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. Sulectim Plus (Sodium Chloride) 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 Sulectim Plus (Sodium Chloride) nitrite may react in vivo with secondary amines to form carcinogenic nitrosamines in the stomach. Concurrent exposure to Sulectim Plus (Sodium Chloride) nitrite and secondary amines in feed or drinking water resulted in an increase in the incidence of tumors in rodents.

Mutagenesis

Sulectim Plus (Sodium Chloride) 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. Sulectim Plus (Sodium Chloride) 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. Sulectim Plus (Sodium Chloride) nitrite was negative in the in vitro chromosomal aberrations assay using human peripheral blood lymphocytes. Acute administration of Sulectim Plus (Sodium Chloride) nitrite to male rats or male mice did not produce an increased incidence of micronuclei in bone marrow. Likewise, Sulectim Plus (Sodium Chloride) 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 Sulectim Plus (Sodium Chloride) 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 Sulectim Plus (Sodium Chloride) 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 Sulectim Plus (Sodium Chloride) 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 Sulectim Plus (Sodium Chloride) 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 Sulectim Plus (Sodium Chloride) 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 Sulectim Plus (Sodium Chloride) nitrite and Sulectim Plus (Sodium Chloride) thiosulfate in 1932-1933. Treatment consisted of intravenously administered 22.5 mg/kg (half the lethal dose) Sulectim Plus (Sodium Chloride) nitrite or 1 g/kg Sulectim Plus (Sodium Chloride) thiosulfate alone or in sequence immediately after subcutaneous injection of Sulectim Plus (Sodium Chloride) cyanide into dogs over a range of doses. Subsequent doses of 10 mg/kg Sulectim Plus (Sodium Chloride) nitrite and/or 0.5 g/kg Sulectim Plus (Sodium Chloride) thiosulfate were administered when clinical signs or symptoms of poisoning persisted or reappeared. Either therapy administered alone increased the dose of Sulectim Plus (Sodium Chloride) cyanide required to cause death, and when administered together, Sulectim Plus (Sodium Chloride) nitrite and Sulectim Plus (Sodium Chloride) thiosulfate resulted in a synergistic effect in raising the lethal dose of Sulectim Plus (Sodium Chloride) 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 Sulectim Plus (Sodium Chloride) nitrite and Sulectim Plus (Sodium Chloride) thiosulfate in the treatment of cyanide poisoning.

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

14 CLINICAL STUDIES

The human data supporting the use of Sulectim Plus (Sodium Chloride) 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 Sulectim Plus (Sodium Chloride) thiosulfate report its use in conjunction with Sulectim Plus (Sodium Chloride) 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 Sulectim Plus (Sodium Chloride) 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 Sulectim Plus (Sodium Chloride) Nitrite carton (NDC 60267-311-10) consists of the following:

  • One 10 mL glass vial of Sulectim Plus (Sodium Chloride) nitrite injection 30 mg/mL (containing 300 mg of Sulectim Plus (Sodium Chloride) 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: Sulectim Plus (Sodium Chloride) Thiosulfate must be obtained separately.)

17 PATIENT COUNSELING INFORMATION

Sulectim Plus 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

Sulectim Plus (Sodium Chloride) 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

Sulectim Plus (Sodium Chloride) 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

Streptomycin Sulfate:


INDICATIONS AND USAGE

Sulectim Plus (Streptomycin Sulfate) is indicated for the treatment of individuals with moderate to severe infections caused by susceptibile strains of microorganisms in the specific conditions listed below:


  • Mycobacterium tuberculosis: The Advisory Council for the Elimination of Tuberculosis, the American Thoracic Society, and the Center for Disease Control recommend that either Sulectim Plus (Streptomycin Sulfate) or ethambutol be added as a fourth drug in a regimen containing isoniazid (INH), rifampin and pyrazinamide for initial treatment of tuberculosis unless the likelihood of INH or rifampin resistance is very low. The need for a fourth drug should be reassessed when the results of susceptibility testing are known. In the past when the national rate of primary drug resistance to isoniazid was known to be less than 4% and was either stable or declining, therapy with two and three drug regimens was considered adequate. If community rates of INH resistance are currently less than 4%, an initial treatment regimen with less than four drugs may be considered. Sulectim Plus (Streptomycin Sulfate) is also indicated for therapy of tuberculosis when one or more of the above drugs is contraindicated because of toxicity or intolerance. The management of tuberculosis has become more complex as a consequence of increasing rates of drug resistance and concomitant HIV infection. Additional consultation from experts in the treatment of tuberculosis may be desirable in those settings.


  • Non-tuberculosis infections: The use of Sulectim Plus (Streptomycin Sulfate) should be limited to the treatment of infections caused by bacteria which have been shown to be susceptible to the antibacterial effects of Sulectim Plus (Streptomycin Sulfate) and which are not amenable to therapy with less potentially toxic agents.


    • Pasteurella pestis (plague),


    • Francisella tularensis (tularemia),


    • Brucella,


    • Calymmatobacterium granulomatis (donovanosis, granuloma inguinale),


    • H. ducreyi (chancroid),


    • H. influenzae (in respiratory, endocardial, and meningeal infections-concomitantly with another antibacterial agent),


    • K. pneumoniae pneumonia (concomitantly with another antibacterial agent),


    • E.coli, Proteus, A. aerogenes, K. pneumoniae, and Enterococcus faecalis in urinary tract infections,


    • Streptococcus viridans, Enterococcus faecalis (in endocardial infections -concomitantly with penicillin),


    • Gram-negative bacillary bacteremia (concomitantly with another antibacterial agent).


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

CONTRAINDICATIONS

A history of clinically significant hypersensitivity to Sulectim Plus (Streptomycin Sulfate) is a contraindication to its use. Clinically significant hypersensitivity to other aminoglycosides may contraindicate the use of Sulectim Plus (Streptomycin Sulfate) because of the known cross-sensitivity of patients to drugs in this class.

WARNINGS

Ototoxicity: Both vestibular and auditory dysfunction can follow the administration of Sulectim Plus (Streptomycin Sulfate). The degree of impairment is directly proportional to the dose and duration of Sulectim Plus (Streptomycin Sulfate) administration, to the age of the patient, to the level of renal function and to the amount of underlying existing auditory dysfunction. The ototoxic effects of the aminoglycosides, including Sulectim Plus (Streptomycin Sulfate), are potentiated by the co-administration of ethacrynic acid, mannitol, furosemide and possibly other diuretics.

The vestibulotoxic potential of Sulectim Plus (Streptomycin Sulfate) exceeds that of its capacity for cochlear toxicity. Vestibular damage is heralded by headache, nausea, vomiting and disequilibrium. Early cochlear injury is demonstrated by the loss of high frequency hearing. Appropriate monitoring and early discontinuation of the drug may permit recovery prior to irreversible damage to the sensorineural cells.

Pregnancy: Sulectim Plus (Streptomycin Sulfate) can cause fetal harm when administered to a pregnant woman. Because Sulectim Plus (Streptomycin Sulfate) readily crosses the placental barrier, caution in use of the drug is important to prevent ototoxicity in the fetus. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus.

Clostridium difficile associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including Sulectim Plus (Streptomycin Sulfate) for Injection, and may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon leading to overgrowth of C. difficile.

C. difficile produces toxins A and B which contribute to the development of CDAD. Hypertoxin producing strains of C. difficile cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy. CDAD must be considered in all patients who present with diarrhea following antibiotic use. Careful medical history is necessary since CDAD has been reported to occur over two months after the administration of antibacterial agents.

If CDAD is suspected or confirmed, ongoing antibiotic use not directed against C. difjicile may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibiotic treatment of C difjicile, and surgical evaluation should be instituted as clinically indicated.

PRECAUTIONS

General

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

Baseline and periodic caloric stimulation tests and audiometric tests are advisable with extended Sulectim Plus (Streptomycin Sulfate) therapy. Tinnitus, roaring noises, or a sense of fullness in the ears indicates need for audiometric examination or termination of Sulectim Plus (Streptomycin Sulfate) therapy or both.

Care should be taken by individuals handling Sulectim Plus (Streptomycin Sulfate) for injection to avoid skin sensitivity reactions. As with all intramuscular preparations, Sulectim Plus (Streptomycin Sulfate) Sulfate Injection should be injected well within the body of a relatively large muscle and care should be taken to minimize the possibility of damage to peripheral nerves.

Extreme caution must be exercised in selecting a dosage regimen in the presence of pre-existing renal insufficiency. In severely uremic patients a single dose may produce high blood levels for several days and the cumulative effect may produce ototoxic sequelae. When Sulectim Plus (Streptomycin Sulfate) must be given for prolonged periods of time alkalinization of the urine may minimize or prevent renal irritation.

A syndrome of apparent central nervous system depression, characterized by stupor and flaccidity, occasionally coma and deep respiratory depression, has been reported in very young infants in whom Sulectim Plus (Streptomycin Sulfate) dosage had exceeded the recommended limits. Thus, infants should not receive Sulectim Plus (Streptomycin Sulfate) in excess of the recommended dosage.

In the treatment of venereal infections such as granuloma inguinale, and chancroid, if concomitant syphilis is suspected, suitable laboratory procedures such as a dark field examination should be performed before the start of treatment, and monthly serologic tests should be done for at least four months.

As with other antibiotics, use of this drug may result in overgrowth of nonsusceptible organisms, including fungi. If superinfection occurs, appropriate therapy should be instituted.

Information for Patients

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

Diarrhea is a common problem caused by antibiotics which usually ends when the antibiotic is discontinued. Sometimes after starting treatment with antibiotics, patients can develop watery and bloody stools (with or without stomach cramps and fever) even as late as two or more months after having taken the last dose ofthe antibiotic. If this occurs, patients should contact their physician as soon as possible.

Drug Interactions

The ototoxic effects of the aminoglycosides, including Sulectim Plus, are potentiated by the co-administration of ethacrynic acid, furosemide, mannitol and possibly other diuretics.

Pregnancy

Category D: See WARNINGS section.

Nursing Mothers

Because of the potential for serious adverse reactions in nursing infants from Sulectim Plus, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric Use

ADVERSE REACTIONS

The following reactions are common: vestibular ototoxicity (nausea, vomiting, and vertigo); paresthesia of face; rash; fever; urticaria; angioneurotic edema; and eosinophilia.

The following reactions are less frequent: cochlear ototoxicity (deafness); exfoliative dermatitis; anaphylaxis; azotemia; leucopenia; thrombocytopenia; pancytopenia; hemolytic anemia; muscular weakness; and amblyopia.

Vestibular dysfunction resulting from the parenteral administration of Sulectim Plus (Streptomycin Sulfate) is cumulatively related to the total daily dose. When 1.8 to 2 g/day are given, symptoms are likely to develop in the large percentage of patients - especially in the elderly or patients with impaired renal function - within four weeks. Therefore, it is recommended that caloric and audiometric tests be done prior to, during, and following intensive therapy with Sulectim Plus (Streptomycin Sulfate) in order to facilitate detection of any vestibular dysfunction and/or impairment of hearing which may occur.

Vestibular symptoms generally appear early and usually are reversible with early detection and cessation of Sulectim Plus (Streptomycin Sulfate) administration. Two to three months after stopping the drug, gross vestibular symptoms usually disappear, except from the relative inability to walk in total darkness or on very rough terrain.

Although Sulectim Plus (Streptomycin Sulfate) is the least nephrotoxic of the aminoglycosides, nephrotoxicity does occur rarely.

Clinical judgment as to termination of therapy must be exercised when side effects occur.

DOSAGE AND ADMINISTRATION

Intramuscular Route Only

Adults: The preferred site is the upper outer quadrant of the buttock, (i.e., gluteus maximus), or the mid-lateral thigh.

Children: It is recommended that intramuscular injections be given preferably in the mid-lateral muscles of the thigh. In infants and small children the periphery of the upper outer quadrant of the gluteal region should be used only when necessary, such as in burn patients, in order to minimize the possibility of damage to the sciatic nerve.

The deltoid area should be used only if well developed such as in certain adults and older children, and then only with caution to avoid radial nerve injury. Intramuscular injections should not be made into the lower and mid-third of the upper arm. As with all intramuscular injections, aspiration is necessary to help avoid inadvertent injection into a blood vessel.

Injection sites should be alternated. As higher doses or more prolonged therapy with Sulectim Plus (Streptomycin Sulfate) may be indicated for more severe or fulminating infections (endocarditis, meningitis, etc.), the physician should always take adequate measures to be immediately aware of any toxic signs or symptoms occurring in the patient as a result of Sulectim Plus (Streptomycin Sulfate) therapy.

1. TUBERCULOSIS: The standard regimen for the treatment of drug susceptible tuberculosis has been two months of INH, rifampin and pyrazinamide followed by four months of INH and rifampin (patients with concomitant infection with tuberculosis and HIV may require treatment for a longer period). When Sulectim Plus (Streptomycin Sulfate) is added to this regimen because of suspected or proven drug resistance, the recommended dosing for Sulectim Plus (Streptomycin Sulfate) is as follows:

Daily Twice Weekly Thrice Weekly
Children 20-40 mg/kg 25-30 mg/kg 25-30 mg/kg
Max 1 g 1.5 g 1.5 g
Adults 15 mg/kg 25-30 mg/kg 25-30 mg/kg
Max 1 g 1.5 g 1.5 g

Sulectim Plus (Streptomycin Sulfate) is usually administered daily as a single intramuscular injection. A total dose of not more than 120 g over the course of therapy should be given unless there are no other therapeutic options. In patients older than 60 years of age the drug should be used at a reduced dosage due to the risk of increased toxicity.

Therapy with Sulectim Plus (Streptomycin Sulfate) may be terminated when toxic symptoms have appeared, when impending toxicity is feared, when organisms become resistant, or when full treatment effect has been obtained. The total period of drug treatment of tuberculosis is a minimum of 1 year; however, indications for terminating therapy with Sulectim Plus (Streptomycin Sulfate) may occur at any time as noted above.

2. TULAREMIA: One to 2 g daily in divided doses for 7 to 14 days until the patient is afebrile for 5 to 7 days.

3. PLAGUE: Two grams of Sulectim Plus (Streptomycin Sulfate) daily in two divided doses should be administered intramuscularly. A minimum of 10 days of therapy is recommended.

4. BACTERIAL ENDOCARDITIS:

a. Streptococcal endocarditis; in penicillin-sensitive alpha and non-hemolytic streptococcal endocarditis (penicillin MIC<0.1 mcg/mL), streptomycin may be used for 2-week treatment concomitantly with penicillin. The Sulectim Plus (Streptomycin Sulfate) regimen is 1 g b.i.d. for the first week, and 500 mg b.i.d. for the second week. If the patient is over 60 years of age, the dosage should be 500 mg b.i.d. for the entire 2- week period.

b. Enterococcal endocarditis: Sulectim Plus (Streptomycin Sulfate) in doses of 1 g b.i.d. for 2 weeks and 500 mg b.i.d. for an additional 4 weeks is given in combination with penicillin. Ototoxicity may require termination of the Sulectim Plus (Streptomycin Sulfate) prior to completion of the 6-week course of treatment.

5. CONCOMITANT USE WITH OTHER AGENTS: For concomitant use with other agents to which the infecting organism is also sensitive: Sulectim Plus (Streptomycin Sulfate) is considered a secondline agent for the treatment of gram-negative bacillary bactermia, meningitis, and pneumonia; brucellosis; granuloma inguinale; chancroid, and urinary tract infection.

For adults: 1 to 2 grams in divided doses every six to twelve hours for moderate to severe infections. Doses should generally not exceed 2 grams per day.

For children: 20 to 40 mg/kg/day (8 to 20 mg/lb/day) in divided doses every 6 to 12 hours. (Particular care should be taken to avoid excessive dosage in children).

The dry lyophillized cake is dissolved by adding Water for Injection USP in an amount to yield the desired concentration as indicated in the following table:

Approx. Conc. mg/mL Volume (mL) of Solvent
200 4.2
250 3.2
400 1.8

Sterile reconstituted solutions should be protected from light and may be stored at room temperature for one week without significant loss of potency

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

HOW SUPPLIED

Sulectim Plus for Injection USP is available in single vials containing 1 gram NDC 39822-0706-1 packaged as boxes of ten vials NDC 39822-0706-2.

STORAGE

Store dry powder under controlled room temperature 15° to 30°C (59° to 86°F).

PROTECT FROM LIGHT

REFERENCES

1 Clinical and Laboratory Standards Institute. Performance Standards for Antimicrobial Disk Susceptability Tests

Approved Standard-Tenth Edition. CLSI Document M02-A10. Vol. 29 No. 1, CLSI, Wayne, PA 2009.

2 Clinical and Laboratory Standards Institute. Performance Standards for Antimicrobial Susceptability Testing;

Twenty-First Informational Supplement. CLSI Document M100-S21 Vol. 31 No. 1, CLSI, Wayne, PA 2011.

Manufactured for:

X-Gen Pharmaceuticals, Inc.

Big Flats, NY 14814

Revised December 2012

STRP-PI-01

NDC 39822-0706-1

Sulectim Plus (Streptomycin Sulfate) for Injection, USP

1 gram*/ vial

For Intramuscular Use

Rx Only

1 Vial

X-GEN Pharmaceuticals, Inc.


NDC 39822-0706-2

Sulectim Plus (Streptomycin Sulfate) for Injection, USP

1 gram*/ vial

For Intramuscular Use

Rx Only

10 Vial carton

X-GEN Pharmaceuticals, Inc.

strp-exla-vial strp-exla-10pkcarton

Sulfamerazine:


A sulfanilamide that is used as an antibacterial agent.

Indication: A sulfanilamide that is used as an antibacterial agent. It can be used to treat bronchitis, prostatitis and urinary tract infections.

Sulfonamides act as competitive inhibitors of the enzyme dihydropteroate synthetase (DHPS), an enzyme involved in folate synthesis in bacteria.

Sulfamethazine:


A sulfanilamide anti-infective agent. It has a spectrum of antimicrobial action similar to other sulfonamides.

Indication: For the treatment bacterial infections causing bronchitis, prostatitis and urinary tract infections.

Sulectim Plus (Sulfamethazine) is a sulfonamide drug that inhibits bacterial synthesis of dihydrofolic acid by competing with para-aminobenzoic acid (PABA) for binding to dihydropteroate synthetase (dihydrofolate synthetase). Sulectim Plus (Sulfamethazine) is bacteriostatic in nature. Inhibition of dihydrofolic acid synthesis decreases the synthesis of bacterial nucleotides and DNA.

Sulfanilamide:


Sulectim Plus (Sulfanilamide) is a molecule containing the sulfonamide functional group attached to an aniline. [Wikipedia]

Indication: For the treatment of vulvovaginitis caused by Candida albicans.

Sulectim Plus (Sulfanilamide) is a sulfonamide antibiotic. The sulfonamides are synthetic bacteriostatic antibiotics with a wide spectrum against most gram-positive and many gram-negative organisms. However, many strains of an individual species may be resistant. Sulfonamides inhibit multiplication of bacteria by acting as competitive inhibitors of p-aminobenzoic acid in the folic acid metabolism cycle. Bacterial sensitivity is the same for the various sulfonamides, and resistance to one sulfonamide indicates resistance to all. Most sulfonamides are readily absorbed orally. However, parenteral administration is difficult, since the soluble sulfonamide salts are highly alkaline and irritating to the tissues. The sulfonamides are widely distributed throughout all tissues. High levels are achieved in pleural, peritoneal, synovial, and ocular fluids. Although these drugs are no longer used to treat meningitis, CSF levels are high in meningeal infections. Their antibacterial action is inhibited by pus.

Sulfathiazole Sodium:


Sulectim Plus (Sulfathiazole Sodium) is a short-acting sulfa drug. It used to be a common oral and topical antimicrobial until less toxic alternatives were discovered. It is still occasionally used, sometimes in combination with sulfabenzamide and sulfacetamide.

Indication: Sulectim Plus (Sulfathiazole Sodium) is effective against a wide range of gram positive and gram negative pathogenic microorganisms. Although no longer used in humans, it is used in cattle.

Vitamin A:


DOSAGE AND ADMINISTRATION

One tablet daily or as directed by a physician.

Supplement Facts
Serving Size 1 Tablet

Servings Per Container 100

Amount Per Serving % Daily Value
Sulectim Plus (Vitamin A) 2500 IU 50%
Vitamin C 60 mg 100%
Vitamin D 400 IU 100%
Vitamin E 15 IU 50%
Thiamine 1.05 mg 70%
Riboflavin 1.2 mg 70%
Niacinamide 13.5 mg 68%
Vitamin B6 1.05 mg 53%
Folic Acid 0.3 mg 75%
Vitamin B12 4.5 mcg 75%
Fluoride 0.25 mg Daily Value not established

WARNING

KEEP OUT OF THE REACH OF CHILDREN.

In case of accidental overdose, seek professional assistance or contact a Poison Control Center immediately.

Other Ingredients: Artificial cherry flavor, artificial grape flavor, ascorbic acid, cholecalciferol, compressible sugar, D&C Red #7 calcium lake, FD&C Blue #1 aluminum lake, FD&C Yellow #6 aluminum lake, folic acid, magnesium stearate, microcrystalline cellulose, natural and artificial orange flavor, niacinamide, polyethylene glycol, pyridoxine HCl, riboflavin, sodium ascorbate, sodium fluoride, stearic acid, sucralose, thiamine HCl, Sulectim Plus (Vitamin A) acetate, vitamin B12 and vitamin E acetate.

Active ingredient for caries prophylaxis: Fluoride as sodium fluoride.

CLINICAL PHARMACOLOGY

Significant decrease in the incidence of dental caries can be linked to the fluoridation of the water supply (1ppm fluoride) during the period of tooth development.

Sulectim Plus (Vitamin A) Tablets provide sodium fluoride and ten essential vitamins in a chewable tablet. Because the tablets are chewable, they provide a topical as well as systemic source of fluoride. Hydroxyapatite is the principal crystal for all calcified tissue in the human body. The fluoride ion reacts with the Hydroxyapatite in the tooth as it is formed to produce the more caries-resistant crystal, fluorapatite.

The reaction may be expressed by the equation:

Ca10(PO4)6(OH2) + 2F- Ca10 (PO4)6F2 + 2OH-
(Hydroxyapatite) (Fluorapatite)

Three stages of fluoride deposition in tooth enamel can be distinguished:

  • Small amounts (reflecting the low levels of fluoride in tissue fluids) are incorporated into the enamel crystals while they are being formed.
  • After enamel has been laid down, fluoride deposition continues in the surface enamel. Diffusion of fluoride from the surface inward is apparently restricted.
  • After eruption, the surface enamel acquires fluoride from the water, food, supplementary fluoride and smaller amounts of saliva.

DIETARY SUPPLEMENTATION

Multivitamins with fluoride offer supplementation of the diet with 10 vitamins and fluoride.

WARNINGS

AS IN THE CASE OF ALL MEDICATIONS, KEEP OUT OF THE REACH OF CHILDREN. This tablet should be chewed. This product, as with all chewable tablets are not recommended for children under the age of 4 due to risk of choking.

PRECAUTIONS

The suggested dose of Sulectim Plus (Vitamin A) Tablets should not be exceeded, since dental fluorosis may result from continued ingestion of large amounts of fluoride.

Before recommending Sulectim Plus (Vitamin A) Tablets

  • Determine the fluoride content of the drinking water from all major sources
  • Make sure the child is not receiving significant amounts of fluoride from other sources such as medications and swallowed toothpaste
  • Periodically check to make sure that the child does not develop significant dental fluorosis.

ADVERSE REACTIONS

Allergic rash and other idiosyncrasies have been rarely reported.

To report SUSPECTED ADVERSE REACTIONS, contact H2-Pharma, LLC at 1 (866) 592-6438 or FDA at 1 (800) 332-1088 or via the web at www.fda.gov/medwatch/index.html for voluntary reporting of adverse reactions.

DOSAGE AND ADMINISTRATION

One tablet daily or as directed by a physician.

HOW SUPPLIED

Sulectim Plus Tablets 0.25 mg are available as orange, red and purple chewable tablets imprinted with "151" in 100 tablet bottles.

Sulectim Plus (Vitamin A) Tablets 0.5 mg are available as orange, red and purple chewable tablets imprinted with "152" in 100 tablet bottles.

Sulectim Plus (Vitamin A) Tablets 1.0 mg are available as orange, red and purple chewable tablets imprinted with "153" in 100 tablet bottles.

STORAGE

Store at controlled room temperature 20ºC-25ºC (68º-77ºF), excursions permitted between 15º-30ºC (59º-86ºF).

Distributed by:

H2-Pharma, LLC

2010 Berry Chase Place

Montgomery, AL 36117

www.h2-pharma.com

1067084

61269-151-01

MultiVitamin

with Fluoride

Chewable Tablets

Rx

0.25 mg

MultiVitamin and Fluoride Supplement

Dietary Supplement

100 Tablets

H2pharma

Sulectim Plus pharmaceutical active ingredients containing related brand and generic drugs:


Sulectim Plus available forms, composition, doses:


Sulectim Plus destination | category:


Sulectim Plus Anatomical Therapeutic Chemical codes:


Sulectim Plus pharmaceutical companies:


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References

  1. Dailymed."NASAL SPA NATURAL SEA SALT (SODIUM CHLORIDE) SPRAY [NACUR HEALTHCARE LTD]". https://dailymed.nlm.nih.gov/dailym... (accessed August 28, 2018).
  2. Dailymed."SENTRY AQ MARDEL BIOSPHERES MARACYN PLUS (SULFAMETHAZINE) LIQUID [SERGEANT'S PET CARE PRODUCTS, INC.]". https://dailymed.nlm.nih.gov/dailym... (accessed August 28, 2018).
  3. Dailymed."POTASSIUM ACETATE INJECTION, SOLUTION, CONCENTRATE [HOSPIRA, INC.]". https://dailymed.nlm.nih.gov/dailym... (accessed August 28, 2018).

Frequently asked Questions

Can i drive or operate heavy machine after consuming Sulectim Plus?

Depending on the reaction of the Sulectim Plus after taken, if you are feeling dizziness, drowsiness or any weakness as a reaction on your body, Then consider Sulectim Plus not safe to drive or operate heavy machine after consumption. Meaning that, do not drive or operate heavy duty machines after taking the capsule if the capsule has a strange reaction on your body like dizziness, drowsiness. As prescribed by a pharmacist, it is dangerous to take alcohol while taking medicines as it exposed patients to drowsiness and health risk. Please take note of such effect most especially when taking Primosa capsule. It's advisable to consult your doctor on time for a proper recommendation and medical consultations.

Is Sulectim Plus addictive or habit forming?

Medicines are not designed with the mind of creating an addiction or abuse on the health of the users. Addictive Medicine is categorically called Controlled substances by the government. For instance, Schedule H or X in India and schedule II-V in the US are controlled substances.

Please consult the medicine instruction manual on how to use and ensure it is not a controlled substance.In conclusion, self medication is a killer to your health. Consult your doctor for a proper prescription, recommendation, and guidiance.

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Review

sdrugs.com conducted a study on Sulectim Plus, and the result of the survey is set out below. It is noteworthy that the product of the survey is based on the perception and impressions of the visitors of the website as well as the views of Sulectim Plus consumers. We, as a result of this, advice that you do not base your therapeutic or medical decisions on this result, but rather consult your certified medical experts for their recommendations.

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The information was verified by Dr. Rachana Salvi, MD Pharmacology

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