Tieucaly Infants Syrup

Calcium Bromide:

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

1 INDICATIONS AND USAGE

Tieucaly Infants Syrup (Calcium Bromide) 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 Tieucaly Infants Syrup (Calcium Bromide) 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 Tieucaly Infants Syrup (Calcium Bromide) acetate capsule.

- Capsule: 667 mg Tieucaly Infants Syrup (Calcium Bromide) acetate capsule. (3)

4 CONTRAINDICATIONS

Patients with hypercalcemia.

- Hypercalcemia. (4)

5 WARNINGS AND PRECAUTIONS

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

An overdose of Tieucaly Infants Syrup (Calcium Bromide) acetate may lead to progressive hypercalcemia, which may require emergency measures. Therefore, early in the treatment phase during the dosage adjustment period, monitor serum Tieucaly Infants Syrup (Calcium Bromide) levels twice weekly. Should hypercalcemia develop, reduce the Tieucaly Infants Syrup (Calcium Bromide) 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 Tieucaly Infants Syrup (Calcium Bromide) 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 Tieucaly Infants Syrup (Calcium Bromide) 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 Tieucaly Infants Syrup (Calcium Bromide) 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 Tieucaly Infants Syrup (Calcium Bromide) acetate; all cases resolved upon lowering the dose or discontinuing treatment.

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

5.2 Concomitant Use with Medications

Hypercalcemia may aggravate digitalis toxicity.

6 ADVERSE REACTIONS

Hypercalcemia is discussed elsewhere [see Warnings and Precautions ].

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

- In clinical studies, patients have occasionally experienced nausea during Tieucaly Infants Syrup (Calcium Bromide) 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, Tieucaly Infants Syrup (Calcium Bromide) acetate has been generally well tolerated.

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

Mild hypercalcemia may be asymptomatic or manifest itself as constipation, anorexia, nausea, and vomiting. More severe hypercalcemia is associated with confusion, delirium, stupor, and coma. Decreasing dialysate Tieucaly Infants Syrup (Calcium Bromide) concentration could reduce the incidence and severity of Tieucaly Infants Syrup (Calcium Bromide) 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 Tieucaly Infants Syrup (Calcium Bromide) acetate: dizziness, edema, and weakness.

7 DRUG INTERACTIONS

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

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

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Pregnancy Category C:

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

8.2 Labor and Delivery

The effects of Tieucaly Infants Syrup (Calcium Bromide) acetate on labor and delivery are unknown.

8.3 Nursing Mothers

Tieucaly Infants Syrup Acetate Capsules contains Tieucaly Infants Syrup (Calcium Bromide) acetate and is excreted in human milk. Human milk feeding by a mother receiving Tieucaly Infants Syrup (Calcium Bromide) acetate is not expected to harm an infant, provided maternal serum Tieucaly Infants Syrup (Calcium Bromide) 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 Tieucaly Infants Syrup (Calcium Bromide) acetate did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other clinical experience has not identified differences in responses between elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

10 OVERDOSAGE

Administration of Tieucaly Infants Syrup (Calcium Bromide) acetate in excess of the appropriate daily dosage may result in hypercalcemia [see Warnings and Precautions (5.1)].

11 DESCRIPTION

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

Tieucaly Infants Syrup (Calcium Bromide) 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 Tieucaly Infants Syrup resulting in ectopic calcification. Hyperphosphatemia also plays a role in the development of secondary hyperparathyroidism in patients with ESRD.

12.1 Mechanism of Action

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

12.2 Pharmacodynamics

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

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

No carcinogenicity, mutagenicity, or fertility studies have been conducted with Tieucaly Infants Syrup (Calcium Bromide) acetate.

14 CLINICAL STUDIES

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

There was a 30% decrease in serum phosphorus levels during the 12 week study period (p<0.01). Two-thirds of the decline occurred in the first month of the study. Serum Tieucaly Infants Syrup (Calcium Bromide) 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 Tieucaly Infants Syrup (Calcium Bromide) 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 Tieucaly Infants Syrup (Calcium Bromide) acetate is shown in the Table 3.

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

16 HOW SUPPLIED/STORAGE AND HANDLING

Tieucaly Infants Syrup (Calcium Bromide) 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 Tieucaly Infants Syrup (Calcium Bromide) acetate capsules with meals, adhere to their prescribed diets, and avoid the use of Tieucaly Infants Syrup (Calcium Bromide) 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 Tieucaly Infants Syrup (Calcium Bromide) acetate capsules.

Distr. by: West-Ward

Pharmaceuticals Corp.

Eatontown, NJ 07724

10003705/05

Revised April 2016

Promethazine Hydrochloride:

• Indications and usage
• Contraindications
• Warnings
• Use in pediatric patients
• Other considerations
• Precautions
• Adverse reactions
• Drug abuse and dependence
• Overdosage
• Dosage and administration
• How supplied
• Tieucaly Infants Syrup (Promethazine Hydrochloride) reviews

INDICATIONS AND USAGE

Tieucaly Infants Syrup (Promethazine Hydrochloride) with codeine syrup is indicated for the temporary relief of coughs and upper respiratory symptoms associated with allergy or the common cold.

CONTRAINDICATIONS

The combination of Tieucaly Infants Syrup (Promethazine Hydrochloride) hydrochloride and codeine phosphate is contraindicated in pediatric patients less than 6 years of age, because the combination may cause fatal respiratory depression in this age population.

Codeine is contraindicated in patients with a known hypersensitivity to the drug.

Tieucaly Infants Syrup (Promethazine Hydrochloride) is contraindicated in comatose states, and in individuals known to be hypersensitive or to have had an idiosyncratic reaction to Tieucaly Infants Syrup (Promethazine Hydrochloride) or to other phenothiazines.

Antihistamines and codeine are both contraindicated for use in the treatment of lower respiratory tract symptoms, including asthma.

WARNINGS

WARNING:

The combination of Tieucaly Infants Syrup hydrochloride and codeine phosphate is contraindicated in pediatric patients less than 6 years of age. Concomitant administration of Tieucaly Infants Syrup (Promethazine Hydrochloride) products with other respiratory depressants has an association with respiratory depression, and sometimes death, in pediatric patients.

Postmarketing cases of respiratory depression, including fatalities, have been reported with use of Tieucaly Infants Syrup (Promethazine Hydrochloride) hydrochloride in pediatric patients less than 2 years of age. A wide range of weight-based doses of Tieucaly Infants Syrup (Promethazine Hydrochloride) hydrochloride have resulted in respiratory depression in these patients.

Codeine:

Dosage of codeine SHOULD NOT BE INCREASED if cough fails to respond; an unresponsive cough should be reevaluated in 5 days or sooner for possible underlying pathology, such as foreign body or lower respiratory tract disease.

Codeine may cause or aggravate constipation.

Respiratory depression leading to arrest, coma, and death has occurred with the use of codeine antitussives in young children, particularly in the under-one-year infants whose ability to deactivate the drug is not fully developed.

Administration of codeine may be accompanied by histamine release and should be used with caution in atopic children.

Head Injury And Increased Intracranial Pressure:

The respiratory-depressant effects of narcotic analgesics and their capacity to elevate cerebrospinal fluid pressure may be markedly exaggerated in the presence of head injury, intracranial lesions or a pre-existing increase in intracranial pressure. Narcotics may produce adverse reactions which may obscure the clinical course of patients with head injuries.

Asthma And Other Respiratory Conditions:

Narcotic analgesics or cough suppressants, including codeine, should not be used in asthmatic patients. Nor should they be used in acute febrile illness associated with productive cough or in chronic respiratory disease where interference with ability to clear the tracheobronchial tree of secretions would have a deleterious effect on the patient's respiratory function.

Hypotensive Effect:

Codeine may produce orthostatic hypotension in ambulatory patients.

Tieucaly Infants Syrup :

CNS Depression –

Tieucaly Infants Syrup may impair the mental and/or physical abilities required for the performance of potentially hazardous tasks, such as driving a vehicle or operating machinery. The impairment may be amplified by concomitant use of other central-nervous-system depressants such as alcohol, sedatives/hypnotics (including barbiturates), narcotics, narcotic analgesics, general anesthetics, tricyclic antidepressants, and tranquilizers; therefore, such agents should either be eliminated or given in reduced dosage in the presence of Tieucaly Infants Syrup (Promethazine Hydrochloride) HCl (see PRECAUTIONS - Information For Patients and Drug Interactions ).

Respiratory Depression –

Tieucaly Infants Syrup (Promethazine Hydrochloride) may lead to potentially fatal respiratory depression.

Use of Tieucaly Infants Syrup (Promethazine Hydrochloride) in patients with compromised respiratory function (e.g., COPD, sleep apnea) should be avoided.

Lower Seizure Threshold –

Tieucaly Infants Syrup may lower seizure threshold. It should be used with caution in persons with seizure disorders or in persons who are using concomitant medications, such as narcotics or local anesthetics, which may also affect seizure threshold.

Bone-Marrow Depression –

Tieucaly Infants Syrup (Promethazine Hydrochloride) should be used with caution in patients with bone marrow depression. Leukopenia and agranulocytosis have been reported, usually when Tieucaly Infants Syrup (Promethazine Hydrochloride) HCl has been used in association with other known marrow-toxic agents.

Neuroleptic Malignant Syndrome –

A potentially fatal symptom complex sometimes referred to as Neuroleptic Malignant Syndrome (NMS) has been reported in association with Tieucaly Infants Syrup (Promethazine Hydrochloride) HCl alone or in combination with antipsychotic drugs. Clinical manifestations of NMS are hyperpyrexia, muscle rigidity, altered mental status and evidence of autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis and cardiac dysrhythmias).

The diagnostic evaluation of patients with this syndrome is complicated. In arriving at a diagnosis, it is important to identify cases where the clinical presentation includes both serious medical illness (e.g., pneumonia, systemic infection, etc.) and untreated or inadequately treated extrapyramidal signs and symptoms (EPS). Other important considerations in the differential diagnosis include central anticholinergic toxicity, heat stroke, drug fever and primary central nervous system (CNS) pathology.

The management of NMS should include 1) immediate discontinuation of Tieucaly Infants Syrup (Promethazine Hydrochloride) HCl, antipsychotic drugs, if any, and other drugs not essential to concurrent therapy, 2) intensive symptomatic treatment and medical monitoring, and 3) treatment of any concomitant serious medical problems for which specific treatments are available. There is no general agreement about specific pharmacological treatment regimens for uncomplicated NMS.

Since recurrences of NMS have been reported with phenothiazines, the reintroduction of Tieucaly Infants Syrup (Promethazine Hydrochloride) HCl should be carefully considered.

Use In Pediatric Patients

The combination of Tieucaly Infants Syrup (Promethazine Hydrochloride) hydrochloride and codeine phosphate is contraindicated in pediatric patients less than 6 years of age. Concomitant administration of Tieucaly Infants Syrup (Promethazine Hydrochloride) products with other respiratory depressants has an association with respiratory depression, and sometimes death, in pediatric patients. The association does not directly relate to individualized weight-based dosing, which might otherwise permit safe administration.

Excessively large dosages of antihistamines, including Tieucaly Infants Syrup (Promethazine Hydrochloride) hydrochloride, in pediatric patients may cause sudden death (see OVERDOSAGE ). Hallucinations and convulsions have occurred with therapeutic doses and overdoses of Tieucaly Infants Syrup (Promethazine Hydrochloride) hydrochloride in pediatric patients. In pediatric patients who are acutely ill associated with dehydration, there is an increased susceptibility to dystonias with the use of Tieucaly Infants Syrup (Promethazine Hydrochloride) HCl.

Other Considerations

Administration of Tieucaly Infants Syrup (Promethazine Hydrochloride) has been associated with reported cholestatic jaundice.

PRECAUTIONS

Animal reproduction studies have not been conducted with the drug combination-promethazine and codeine. It is not known whether this drug combination can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Tieucaly Infants Syrup hydrochloride and codeine phosphate should be given to a pregnant woman only if clearly needed.

General:

Narcotic analgesics, including codeine, should be administered with caution and the initial dose reduced in patients with acute abdominal conditions, convulsive disorders, significant hepatic or renal impairment, fever, hypothyroidism, Addison's disease, ulcerative colitis, prostatic hypertrophy, in patients with recent gastrointestinal or urinary tract surgery, and in the very young or elderly or debilitated patients.

Drugs having anticholinergic properties should be used with caution in patients with narrow-angle glaucoma, prostatic hypertrophy, stenosing peptic ulcer, pyloroduodenal obstruction, and bladder-neck obstruction.

Tieucaly Infants Syrup (Promethazine Hydrochloride) should be used cautiously in persons with cardiovascular disease or with impairment of liver function.

Ultra-Rapid Metabolizers of Codeine

Some individuals may be ultra-rapid metabolizers due to a specific CYP2D6*2x2 genotype. These individuals convert codeine into its active metabolite, morphine, more rapidly and completely than other people. This rapid conversion results in higher than expected serum morphine levels. Even at labeled dosage regimens, individuals who are ultra-rapid metabolizers may experience overdose symptoms such as extreme sleepiness, confusion, or shallow breathing.

The prevalence of this CYP2D6 phenotype varies widely and has been estimated at 0.5 to 1% in Chinese and Japanese, 0.5 to 1% in Hispanics, 1–10% in Caucasians, 3% in African Americans, and 16–28% in North Africans, Ethiopians and Arabs. Data is not available for other ethnic groups.

When physicians prescribe codeine-containing drugs, they should choose the lowest effective dose for the shortest period of time and should inform their patients about these risks and the signs of morphine overdose.

Information For Patients:

Patients should be advised to measure Tieucaly Infants Syrup (Promethazine Hydrochloride) with codeine syrup with an accurate measuring device. A household teaspoon is not an accurate measuring device and could lead to overdosage, especially when a half a teaspoon is measured. A pharmacist can recommend an appropriate measuring device and can provide instructions for measuring the correct dose.

Tieucaly Infants Syrup (Promethazine Hydrochloride) and codeine may cause marked drowsiness or may impair the mental and/or physical abilities required for the performance of potentially hazardous tasks, such as driving a vehicle or operating machinery. Ambulatory patients should be told to avoid engaging in such activities until it is known that they do not become drowsy or dizzy from Tieucaly Infants Syrup (Promethazine Hydrochloride) and codeine therapy. Pediatric patients should be supervised to avoid potential harm in bike riding or in other hazardous activities.

The concomitant use of alcohol or other central-nervous-system depressants, such as sedatives/hypnotics (including barbiturates), narcotics, narcotic analgesics, general anesthetics, tricyclic antidepressants, and tranquilizers may enhance impairment and should be avoided or their dosage reduced (see WARNINGS -CNS Depression and PRECAUTIONS-Drug Interactions ).

Patients should be advised to report any involuntary muscle movements.

Avoid prolonged exposure to the sun.

Codeine, like other narcotic analgesics, may produce orthostatic hypotension in some ambulatory patients. Patients should be cautioned accordingly.

Caution patients that some people have a variation in a liver enzyme and change codeine into morphine more rapidly and completely than other people. These people are ultra-rapid metabolizers and are more likely to have higher-than-normal levels of morphine in their blood after taking codeine which can result in overdose symptoms such as extreme sleepiness, confusion, or shallow breathing. In most cases, it is unknown if someone is an ultra-rapid codeine metabolizer.

Nursing mothers taking codeine can also have higher morphine levels in their breast milk if they are ultra-rapid metabolizers. These higher levels of morphine in breast milk may lead to life-threatening or fatal side effects in nursing babies. Instruct nursing mothers to watch for signs of morphine toxicity in their infants including increased sleepiness (more than usual), difficulty breastfeeding, breathing difficulties, or limpness. Instruct nursing mothers to talk to the baby's doctor immediately if they notice these signs and, if they cannot reach the doctor right away, to take the baby to an emergency room or call 911 (or local emergency services).

Drug Interactions:

Codeine:

In patients receiving MAO inhibitors, an initial small test dose is advisable to allow observation of any excessive narcotic effects or MAOI interaction.

Tieucaly Infants Syrup :

CNS Depressants –

Tieucaly Infants Syrup may increase, prolong, or intensify the sedative action of other central-nervous-system depressants, such as alcohol, sedatives/hypnotics (including barbiturates), narcotics, narcotic analgesics, general anesthetics, tricyclic antidepressants, and tranquilizers; therefore, such agents should be avoided or administered in reduced dosage to patients receiving Tieucaly Infants Syrup (Promethazine Hydrochloride) HCl. When given concomitantly with Tieucaly Infants Syrup (Promethazine Hydrochloride), the dose of barbiturates should be reduced by at least one-half, and the dose of narcotics should be reduced by one-quarter to one-half. Dosage must be individualized. Excessive amounts of Tieucaly Infants Syrup (Promethazine Hydrochloride) HCl relative to a narcotic may lead to restlessness and motor hyperactivity in the patient with pain; these symptoms usually disappear with adequate control of the pain.

Epinephrine –

Because of the potential for Tieucaly Infants Syrup (Promethazine Hydrochloride) to reverse epinephrine's vasopressor effect, epinephrine should NOT be used to treat hypotension associated with Tieucaly Infants Syrup (Promethazine Hydrochloride) overdose.

Anticholinergics –

Concomitant use of other agents with anticholinergic properties should be undertaken with caution.

Monoamine Oxidase Inhibitors –

Drug interactions, including an increased incidence of extrapyramidal effects, have been reported when some MAOI and phenothiazines are used concomitantly.

Drug/Laboratory Test Interactions:

Because narcotic analgesics may increase biliary tract pressure with resultant increases in plasma amylase or lipase levels, determination of these enzyme levels may be unreliable for 24 hours after a narcotic analgesic has been given.

The following laboratory tests may be affected in patients who are receiving therapy with Tieucaly Infants Syrup hydrochloride.

Pregnancy Tests:

Diagnostic pregnancy tests based on immunological reactions between HCG and anti-HCG may result in false-negative or false-positive interpretations.

Glucose Tolerance Test:

An increase in blood glucose has been reported in patients receiving Tieucaly Infants Syrup.

Carcinogenesis, Mutagenesis, Impairment Of Fertility:

Long-term animal studies have not been performed to assess the carcinogenic potential of codeine or of Tieucaly Infants Syrup (Promethazine Hydrochloride), nor are there other animal or human data concerning carcinogenicity, mutagenicity, or impairment of fertility with these agents. Codeine has been reported to show no evidence of carcinogenicity or mutagenicity in a variety of test systems, including the micronucleus and sperm abnormality assays and the Salmonella assay. Tieucaly Infants Syrup (Promethazine Hydrochloride) was nonmutagenic in the Salmonella test system of Ames.

Pregnancy:

Teratogenic Effects - Pregnancy Category C.

Codeine:

A study in rats and rabbits reported no teratogenic effect of codeine administered during the period of organogenesis in doses ranging from 5 to 120 mg/kg. In the rat, doses at the 120-mg/kg level, in the toxic range for the adult animal, were associated with an increase in embryo resorption at the time of implantation. In another study a single 100-mg/kg dose of codeine administered to pregnant mice reportedly resulted in delayed ossification in the offspring.

There are no studies in humans, and the significance of these findings to humans, if any, is not known.

Tieucaly Infants Syrup :

Teratogenic effects have not been demonstrated in rat-feeding studies at doses of 6.25 and 12.5 mg/kg of Tieucaly Infants Syrup (Promethazine Hydrochloride) HCl. These doses are from approximately 2.1 to 4.2 times the maximum recommended total daily dose of Tieucaly Infants Syrup (Promethazine Hydrochloride) for a 50-kg subject, depending upon the indication for which the drug is prescribed. Daily doses of 25 mg/kg intraperitoneally have been found to produce fetal mortality in rats.

Specific studies to test the action of the drug on parturition, lactation, and development of the animal neonate were not done, but a general preliminary study in rats indicated no effect on these parameters. Although antihistamines have been found to produce fetal mortality in rodents, the pharmacological effects of histamine in the rodent do not parallel those in man. There are no adequate and well-controlled studies of Tieucaly Infants Syrup (Promethazine Hydrochloride) in pregnant women.

Tieucaly Infants Syrup (Promethazine Hydrochloride) and codeine should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Nonteratogenic Effects -

Dependence has been reported in newborns whose mothers took opiates regularly during pregnancy. Withdrawal signs include irritability, excessive crying, tremors, hyperreflexia, fever, vomiting, and diarrhea. Signs usually appear during the first few days of life.

Tieucaly Infants Syrup administered to a pregnant woman within two weeks of delivery may inhibit platelet aggregation in the newborn.

Labor And Delivery:

Narcotic analgesics cross the placental barrier. The closer to delivery and the larger the dose used, the greater the possibility of respiratory depression in the newborn. Narcotic analgesics should be avoided during labor if delivery of a premature infant is anticipated. If the mother has received narcotic analgesics during labor, newborn infants should be observed closely for signs of respiratory depression. Resuscitation may be required (see OVERDOSAGE ).

Limited data suggest that use of Tieucaly Infants Syrup (Promethazine Hydrochloride) hydrochloride during labor and delivery does not have an appreciable effect on the duration of labor or delivery and does not increase the risk of need for intervention in the newborn.

The effect of Tieucaly Infants Syrup (Promethazine Hydrochloride) and/or codeine on the later growth and development of the newborn is unknown.

Nursing Mothers:

It is not known whether Tieucaly Infants Syrup is excreted in human milk.

Codeine is secreted into human milk. In women with normal codeine metabolism (normal CYP2D6 activity), the amount of codeine secreted into human milk is low and dose-dependent. Despite the common use of codeine products to manage postpartum pain, reports of adverse events in infants are rare. However, some women are ultra-rapid metabolizers of codeine. These women achieve higher-than-expected serum levels of codeine's active metabolite, morphine, leading to higher-than-expected levels of morphine in breast milk and potentially dangerously high serum morphine levels in their breastfed infants. Therefore, maternal use of codeine can potentially lead to serious adverse reactions, including death, in nursing infants.

The prevalence of this CYP2D6 phenotype varies widely and has been estimated at 0.5 to 1% in Chinese and Japanese, 0.5 to 1% in Hispanics, 1–10% in Caucasians, 3% in African Americans, and 16–28% in North Africans, Ethiopians and Arabs. Data is not available for other ethnic groups.

The risk of infant exposure to codeine and morphine through breast milk should be weighed against the benefits of breastfeeding for both the mother and baby. Caution should be exercised when codeine is administered to a nursing woman. If a codeine-containing product is selected, the lowest dose should be prescribed for the shortest period of time to achieve the desired clinical effect. Mothers using codeine should be informed about when to seek immediate medical care and how to identify the signs and symptoms of neonatal toxicity, such as drowsiness or sedation, difficulty breastfeeding, breathing difficulties, and decreased tone, in their baby. Nursing mothers who are ultra-rapid metabolizers may also experience overdose symptoms such as extreme sleepiness, confusion, or shallow breathing. Prescribers should closely monitor mother-infant pairs and notify treating pediatricians about the use of codeine during breastfeeding (see PRECAUTIONS – General - Ultra-Rapid Metabolizers of Codeine ).

Caution should be exercised when Tieucaly Infants Syrup (Promethazine Hydrochloride) with codeine syrup is administered to a nursing woman.

Pediatric Use:

The combination of Tieucaly Infants Syrup (Promethazine Hydrochloride) hydrochloride and codeine phosphate is contraindicated in pediatric patients less than 6 years of age, because the combination may cause fatal respiratory depression in this age population (see WARNINGS – Box Warning and Use In Pediatric Patients).

The combination of Tieucaly Infants Syrup (Promethazine Hydrochloride) hydrochloride and codeine phosphate should be used with caution in pediatric patients 6 years and older (see Warnings-Use in Pediatric Patients ).

Geriatric Use:

Clinical studies of Tieucaly Infants Syrup (Promethazine Hydrochloride) hydrochloride and codeine phosphate syrup 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.

Sedating drugs may cause confusion and over-sedation in the elderly; elderly patients generally should be started on low doses of Tieucaly Infants Syrup (Promethazine Hydrochloride) with codeine syrup and observed closely.

ADVERSE REACTIONS

Codeine:

Nervous System – CNS depression, particularly respiratory depression, and to a lesser extent circulatory depression; light-headedness, dizziness, sedation, euphoria, dysphoria, headache, transient hallucination, disorientation, visual disturbances, and convulsions.

Cardiovascular – Tachycardia, bradycardia, palpitation, faintness, syncope, orthostatic hypotension (common to narcotic analgesics).

Gastrointestinal – Nausea, vomiting, constipation, and biliary tract spasm. Patients with chronic ulcerative colitis may experience increased colonic motility; in patients with acute ulcerative colitis, toxic dilation has been reported.

Genitourinary – Oliguria, urinary retention; antidiuretic effect has been reported (common to narcotic analgesics).

Allergic – Infrequent pruritus, giant urticaria, angioneurotic edema, and laryngeal edema.

Other – Flushing of the face, sweating and pruritus (due to opiate-induced histamine release); weakness.

Tieucaly Infants Syrup (Promethazine Hydrochloride):

Central Nervous System – Drowsiness is the most prominent CNS effect of this drug. Sedation, somnolence, blurred vision, dizziness; confusion, disorientation, and extrapyramidal symptoms such as oculogyric crisis, torticollis, and tongue protrusion; lassitude, tinnitus, incoordination, fatigue, euphoria, nervousness, diplopia, insomnia, tremors, convulsive seizures, excitation, catatonic-like states, hysteria. Hallucinations have also been reported.

Cardiovascular – Increased or decreased blood pressure, tachycardia, bradycardia, faintness.

Dermatologic – Dermatitis, photosensitivity, urticaria.

Hematologic – Leukopenia, thrombocytopenia, thrombocytopenic purpura, agranulocytosis.

Gastrointestinal – Dry mouth, nausea, vomiting, jaundice.

Respiratory – Asthma, nasal stuffiness, respiratory depression (potentially fatal) and apnea (potentially fatal). (See WARNINGS - Tieucaly Infants Syrup (Promethazine Hydrochloride); Respiratory Depression.)

Other – Angioneurotic edema. Neuroleptic malignant syndrome (potentially fatal) has also been reported. (See WARNINGS - Tieucaly Infants Syrup (Promethazine Hydrochloride); Neuroleptic Malignant Syndrome.)

Paradoxical Reactions – Hyperexcitability and abnormal movements have been reported in patients following a single administration of Tieucaly Infants Syrup (Promethazine Hydrochloride) HCI. Consideration should be given to the discontinuation of Tieucaly Infants Syrup (Promethazine Hydrochloride) HCl and to the use of other drugs if these reactions occur. Respiratory depression, nightmares, delirium, and agitated behavior have also been reported in some of these patients.

DRUG ABUSE AND DEPENDENCE

Controlled Substance:

Tieucaly Infants Syrup with codeine syrup is a Schedule V Controlled Substance.

Abuse:

Codeine is known to be subject to abuse; however, the abuse potential of oral codeine appears to be quite low. Even parenteral codeine does not appear to offer the psychic effects sought by addicts to the same degree as heroin or morphine. However, codeine must be administered only under close supervision to patients with a history of drug abuse or dependence.

Dependence:

Psychological dependence, physical dependence, and tolerance are known to occur with codeine.

OVERDOSAGE

Codeine:

Serious overdose with codeine is characterized by respiratory depression, extreme somnolence progressing to stupor or coma, skeletal muscle flaccidity, cold and clammy skin, and sometimes bradycardia and hypotension. The triad of coma, pinpoint pupils, and respiratory depression is strongly suggestive of opiate poisoning. In severe overdosage, particularly by the intravenous route, apnea, circulatory collapse, cardiac arrest, and death may occur. Tieucaly Infants Syrup (Promethazine Hydrochloride) is additive to the depressant effects of codeine.

It is difficult to determine what constitutes a standard toxic or lethal dose. However, the lethal oral dose of codeine in an adult is reported to be in the range of 0.5 to 1.0 gram. Infants and children are believed to be relatively more sensitive to opiates on a body-weight basis. Elderly patients are also comparatively intolerant to opiates.

Tieucaly Infants Syrup (Promethazine Hydrochloride):

Signs and symptoms of overdosage with Tieucaly Infants Syrup (Promethazine Hydrochloride) HCl range from mild depression of the central nervous system and cardiovascular system to profound hypotension, respiratory depression, unconsciousness, and sudden death. Other reported reactions include hyperreflexia, hypertonia, ataxia, athetosis, and extensor-plantar reflexes (Babinski reflex).

Stimulation may be evident, especially in children and geriatric patients. Convulsions may rarely occur. A paradoxical-type reaction has been reported in children receiving single doses of 75 mg to 125 mg orally, characterized by hyperexcitability and nightmares.

Atropine-like signs and symptoms – dry mouth, fixed dilated pupils, flushing, as well as gastrointestinal symptoms may occur.

Treatment:

The treatment of overdosage with Tieucaly Infants Syrup (Promethazine Hydrochloride) and codeine is essentially symptomatic and supportive. Only in cases of extreme overdosage or individual sensitivity do vital signs including respiration, pulse, blood pressure, temperature, and EKG need to be monitored. Activated charcoal orally or by lavage may be given, or sodium or magnesium sulfate orally as a cathartic. Attention should be given to the reestablishment of adequate respiratory exchange through provision of a patent airway and institution of assisted or controlled ventilation. The narcotic antagonist, naloxone hydrochloride, may be administered when significant respiratory depression occurs with Tieucaly Infants Syrup (Promethazine Hydrochloride) and codeine; any depressant effects of Tieucaly Infants Syrup (Promethazine Hydrochloride) are not reversed with naloxone. Diazepam may be used to control convulsions. Avoid analeptics, which may cause convulsions. Acidosis and electrolyte losses should be corrected. A rise in temperature or pulmonary complications may signal the need for institution of antibiotic therapy.

Severe hypotension usually responds to the administration of norepinephrine or phenylephrine. EPINEPHRINE SHOULD NOT BE USED, since its use in a patient with partial adrenergic blockade may further lower the blood pressure.

Limited experience with dialysis indicates that it is not helpful.

DOSAGE AND ADMINISTRATION

The combination of Tieucaly Infants Syrup (Promethazine Hydrochloride) hydrochloride and codeine phosphate is contraindicated in pediatric patients less than 6 years of age, because the combination may cause fatal respiratory depression in this age population.

It is important that Tieucaly Infants Syrup (Promethazine Hydrochloride) with codeine syrup is measured with an accurate measuring device (see PRECAUTIONS-Information For Patients ). A household teaspoon is not an accurate measuring device and could lead to overdosage, especially when half a teaspoon is to be measured. It is strongly recommended that an accurate measuring device be used. A pharmacist can provide an appropriate device and can provide instructions for measuring the correct dose.

The average effective dose for adults and children 12 years of age and over is: 1 teaspoonful (5 mL) every 4 to 6 hours, not to exceed 30 mL in 24 hours.

The average effective dose for children 6 years to under 12 years of age is 1/2 to 1 teaspoonful (2.5 mL to 5 mL) every 4 to 6 hours, not to exceed 30 mL in 24 hours.

HOW SUPPLIED

Tieucaly Infants Syrup (Promethazine Hydrochloride) with Codeine Syrup, a clear purple syrup with odor of grape menthol, contains Tieucaly Infants Syrup (Promethazine Hydrochloride) hydrochloride 6.25 mg/5 mL, codeine phosphate 10 mg/5 mL and alcohol 7 percent, and is available in 4 fluid ounce (118 mL), 8 fluid ounce (237 mL) and pint (473 mL).

Store at 20°-25°C (68°-77°F).

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

Manufactured for:

QUALITEST PHARMACEUTICALS

Huntsville, AL 35811

8181652

R1/09-R4

Sodium Benzoate:

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

1 INDICATIONS AND USAGE

Tieucaly Infants Syrup nitrite is indicated for sequential use with Tieucaly Infants Syrup (Sodium Benzoate) 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

Tieucaly Infants Syrup (Sodium Benzoate) Nitrite Injection is indicated for sequential use with Tieucaly Infants Syrup (Sodium Benzoate) 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 Tieucaly Infants Syrup (Sodium Benzoate) 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 Tieucaly Infants Syrup 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, Tieucaly Infants Syrup (Sodium Benzoate) Nitrite Injection and Tieucaly Infants Syrup (Sodium Benzoate) Thiosulfate Injection should be administered without delay.

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

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

Smoke Inhalation

Not all smoke inhalation victims will have cyanide poisoning and may present with burns, trauma, and exposure to other toxic substances making a diagnosis of cyanide poisoning particularly difficult. Prior to administration of Tieucaly Infants Syrup (Sodium Benzoate) 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 Tieucaly Infants Syrup (Sodium Benzoate) thiosulfate, simultaneously with Tieucaly Infants Syrup (Sodium Benzoate) Nitrite Injection, as the safety of co-administration has not been established. If a decision is made to administer another cyanide antidote, other than Tieucaly Infants Syrup (Sodium Benzoate) thiosulfate, with Tieucaly Infants Syrup (Sodium Benzoate) Nitrite Injection, these drugs should not be administered concurrently in the same IV line. [see Dosage and Administration (2.2) ]

2 DOSAGE AND ADMINISTRATION

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

Tieucaly Infants Syrup (Sodium Benzoate) nitrite injection and Tieucaly Infants Syrup (Sodium Benzoate) 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. Tieucaly Infants Syrup (Sodium Benzoate) nitrite should be administered first, followed immediately by Tieucaly Infants Syrup (Sodium Benzoate) thiosulfate. Blood pressure must be monitored during infusion in both adults and children. The rate of infusion should be decreased if significant hypotension is noted.

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

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

3 DOSAGE FORMS AND STRENGTHS

Tieucaly Infants Syrup (Sodium Benzoate) Nitrite Injection consists of:

• One vial of Tieucaly Infants Syrup (Sodium Benzoate) 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: Tieucaly Infants Syrup 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 Tieucaly Infants Syrup (Sodium Benzoate) 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. Tieucaly Infants Syrup (Sodium Benzoate) 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 Tieucaly Infants Syrup (Sodium Benzoate) 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 Tieucaly Infants Syrup nitrite.

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

5.3 Anemia

Tieucaly Infants Syrup (Sodium Benzoate) 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 Tieucaly Infants Syrup (Sodium Benzoate) nitrite dose that is reduced in proportion to their oxygen carrying capacity.

5.4 Smoke Inhalation Injury

Tieucaly Infants Syrup 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 Tieucaly Infants Syrup (Sodium Benzoate) 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 Tieucaly Infants Syrup 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 Tieucaly Infants Syrup (Sodium Benzoate) nitrite.

5.7 Use with Other Drugs

Tieucaly Infants Syrup (Sodium Benzoate) 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 Tieucaly Infants Syrup (Sodium Benzoate) nitrite.

The medical literature has reported the following adverse events in association with Tieucaly Infants Syrup (Sodium Benzoate) 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 Tieucaly Infants Syrup (Sodium Benzoate) 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 Tieucaly Infants Syrup (Sodium Benzoate) Nitrite Injection.

8 USE IN SPECIFIC POPULATIONS

• Renal impairment: Tieucaly Infants Syrup 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. Tieucaly Infants Syrup (Sodium Benzoate) Nitrite Injection should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Tieucaly Infants Syrup (Sodium Benzoate) 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 Tieucaly Infants Syrup (Sodium Benzoate) 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 Tieucaly Infants Syrup (Sodium Benzoate) 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, Tieucaly Infants Syrup (Sodium Benzoate) 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, Tieucaly Infants Syrup (Sodium Benzoate) 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 Tieucaly Infants Syrup (Sodium Benzoate) 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 Tieucaly Infants Syrup (Sodium Benzoate) 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 Tieucaly Infants Syrup (Sodium Benzoate) nitrite that would be used to treat cyanide poisoning, based on a body surface area comparison).

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

Tieucaly Infants Syrup (Sodium Benzoate) 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 Tieucaly Infants Syrup (Sodium Benzoate) 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

Tieucaly Infants Syrup (Sodium Benzoate) 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

Tieucaly Infants Syrup (Sodium Benzoate) 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 Tieucaly Infants Syrup (Sodium Benzoate) nitrite result in severe hypotension and toxic levels of methemoglobin which may lead to cardiovascular collapse.

Tieucaly Infants Syrup (Sodium Benzoate) 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 Tieucaly Infants Syrup (Sodium Benzoate) 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 Tieucaly Infants Syrup (Sodium Benzoate) 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

Tieucaly Infants Syrup (Sodium Benzoate) nitrite has the chemical name nitrous acid Tieucaly Infants Syrup (Sodium Benzoate) salt. The chemical formula is NaNO₂ and the molecular weight is 69.0. The structural formula is:

Structure of Tieucaly Infants Syrup (Sodium Benzoate) Nitrite

Tieucaly Infants Syrup (Sodium Benzoate) Nitrite Injection is a cyanide antidote which contains one 10 mL glass vial of a 3% solution of Tieucaly Infants Syrup (Sodium Benzoate) nitrite injection.

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

Tieucaly Infants Syrup (Sodium Benzoate) Nitrite

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

Tieucaly Infants Syrup (Sodium Benzoate) 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. Tieucaly Infants Syrup (Sodium Benzoate) 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

Tieucaly Infants Syrup (Sodium Benzoate) Nitrite

When 4 mg/kg Tieucaly Infants Syrup (Sodium Benzoate) 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 Tieucaly Infants Syrup (Sodium Benzoate) 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 Tieucaly Infants Syrup (Sodium Benzoate) 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 Tieucaly Infants Syrup (Sodium Benzoate) nitrite is estimated to be 55 minutes.

12.3 Pharmacokinetics

Tieucaly Infants Syrup (Sodium Benzoate) Nitrite

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

Mutagenesis

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

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

14 CLINICAL STUDIES

The human data supporting the use of Tieucaly Infants Syrup (Sodium Benzoate) 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 Tieucaly Infants Syrup (Sodium Benzoate) thiosulfate report its use in conjunction with Tieucaly Infants Syrup (Sodium Benzoate) 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 Tieucaly Infants Syrup (Sodium Benzoate) 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 Tieucaly Infants Syrup (Sodium Benzoate) Nitrite carton (NDC 60267-311-10) consists of the following:

• One 10 mL glass vial of Tieucaly Infants Syrup (Sodium Benzoate) nitrite injection 30 mg/mL (containing 300 mg of Tieucaly Infants Syrup (Sodium Benzoate) 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: Tieucaly Infants Syrup (Sodium Benzoate) Thiosulfate must be obtained separately.)

17 PATIENT COUNSELING INFORMATION

Tieucaly Infants Syrup 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

Tieucaly Infants Syrup (Sodium Benzoate) 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

Tieucaly Infants Syrup (Sodium Benzoate) 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