Sinarest Syrup

Acetaminophen:

• Pharmacological action
• Why is Sinarest Syrup (Acetaminophen) prescribed?
• Sinarest Syrup dosage and administration
• Sinarest Syrup side effects, adverse reactions
• Contraindications
• Using during pregnancy and breastfeeding
• Special Instructions
• Sinarest Syrup (Acetaminophen) Drug Interactions
• Sinarest Syrup in case of emergency / overdose
• Sinarest Syrup (Acetaminophen) reviews

Pharmacological action

Sinarest Syrup is an analgesic-antipyretic. It has analgesic, antipyretic and weak anti-inflammatory action. The mechanism of action is associated with inhibition of prostaglandin synthesis, the predominant influence on the thermoregulation center in the hypothalamus, enhances heat transfer.

Why is Sinarest Syrup (Acetaminophen) prescribed?

Pain weak and moderate intensity of different genesis (including headache, migraine, toothache, neuralgia, myalgia, algomenorrhea; pain in trauma, burns). Fever in infectious and inflammatory diseases.

Sinarest Syrup dosage and administration

Oral or rectally adults and adolescents with a body weight over 60 kg is used in a single dose of 500 mg, the multiplicity of admission - up to 4 times / Maximum duration of treatment - 5-7 days.

Maximum dose: single - 1 g, daily - 4 g.

Single dose for oral administration for children aged 6-12 years - 250-500 mg, 1-5 years - 120-250 mg, from 3 months to 1 year - 60-120 mg, up to 3 months - 10 mg / kg. Single dose rectal in children aged 6-12 years - 250-500 mg, 1-5 years - 125-250 mg.

Multiplicity - 4 at intervals of not less than 4 h. The maximum duration of treatment - 3 days.

Maximum dose: 4 single dose per day.

Sinarest Syrup side effects, adverse reactions

Digestive system: rarely - dyspepsia; long-term use at high doses - hepatotoxic effects, methemoglobinemia, renal dysfunction and liver, hypochromic anemia. Hemopoietic system: rarely - thrombocytopenia, leukopenia, pancytopenia, neutropenia, agranulocytosis. Allergic reactions: rarely - skin rash, itching, hives.

Contraindications

Chronic active alcoholism, increased sensitivity to Sinarest Syrup, marked disturbances of liver function and / or kidney disease, anemia, pregnancy (I term).

Using during pregnancy and breastfeeding

Sinarest Syrup (Acetaminophen) crosses the placental barrier. So far, no observed adverse effects of Sinarest Syrup (Acetaminophen) on the fetus in humans.

Sinarest Syrup (Acetaminophen) is excreted in breast milk: the content in milk was 0.04-0.23% of the dose adopted mother.

If necessary, use of Sinarest Syrup (Acetaminophen) during pregnancy and lactation (breastfeeding) should carefully weigh the potential benefits of therapy for the mother and the potential risk to the fetus or child.

In experimental studies found no embryotoxic, teratogenic and mutagenic action of Sinarest Syrup (Acetaminophen).

Special Instructions

Sinarest Syrup is used with caution in patients with disorders of the liver and kidneys, with benign hyperbilirubinemia, as well as in elderly patients.

With prolonged use of Sinarest Syrup (Acetaminophen) is necessary to monitor patterns of peripheral blood and functional state of the liver.

Used for treatment of premenstrual tension syndrome in combination with pamabrom (diuretic, a derivative of xanthine) and mepyramine (Histamine H1-receptors blocker).

Sinarest Syrup (Acetaminophen) Drug Interactions

With the simultaneous use with inducers of microsomal liver enzymes, means having hepatotoxic effect, increasing the risk of hepatotoxic action of Sinarest Syrup (Acetaminophen).

With the simultaneous use of anticoagulants may be slight to moderate increase in prothrombin time.

With the simultaneous use of anticholinergics may decrease absorption of Sinarest Syrup (Acetaminophen).

With the simultaneous use of oral contraceptives accelerated excretion of Sinarest Syrup (Acetaminophen) from the body and may reduce its analgesic action.

With the simultaneous use with urological means reduced their effectiveness.

With the simultaneous use of activated charcoal reduced bioavailability of Sinarest Syrup (Acetaminophen).

When Sinarest Syrup (Acetaminophen) applied simultaneously with diazepam may decrease excretion of diazepam.

There have been reports about the possibility of enhancing mielodepression effect of zidovudine while applying with Sinarest Syrup (Acetaminophen). A case of severe toxic liver injury.

Described cases of toxic effects of Sinarest Syrup (Acetaminophen), while the use of isoniazid.

When applied simultaneously with carbamazepine, phenytoin, phenobarbital, primidonom decreases the effectiveness of Sinarest Syrup (Acetaminophen), which is caused by an increase in its metabolism and excretion from the body. Cases of hepatotoxicity, while the use of Sinarest Syrup (Acetaminophen) and phenobarbital.

In applying cholestyramine a period of less than 1 h after administration of Sinarest Syrup (Acetaminophen) may decrease of its absorption.

At simultaneous application with lamotrigine moderately increased excretion of lamotrigine from the body.

With the simultaneous use of metoclopramide may increase absorption of Sinarest Syrup (Acetaminophen) and its increased concentration in blood plasma.

When applied simultaneously with probenecid may decrease clearance of Sinarest Syrup (Acetaminophen), with rifampicin, sulfinpyrazone - may increase clearance of Sinarest Syrup (Acetaminophen) due to increasing its metabolism in the liver.

At simultaneous application of Sinarest Syrup (Acetaminophen) with ethinylestradiol increases absorption of Sinarest Syrup (Acetaminophen) from the gut.

Enhances the effect of indirect anticoagulants (coumarin derivatives and indandione). Antipyretic and analgesic activity of caffeine increases, reduce - rifampicin, phenobarbital and alcohol (accelerated biotransformation, inducing microsomal liver enzymes).

Sinarest Syrup in case of emergency / overdose

At a reception in toxic doses (10-15 g in adults) may develop liver necrosis.

Symptoms of overdose may include: nausea, vomiting, loss of appetite, sweating, extreme tiredness, unusual bleeding or bruising, pain in the upper right part of the stomach, yellowing of the skin or eyes, flu-like symptoms

Chlorpheniramine Maleate:

• Uses
• Warnings
• Directions
• Other information
• Inactive ingredients
• Questions? comments?
• Sinarest Syrup (Chlorpheniramine Maleate) reviews

Drug Facts

Uses

temporarily relieves these symptoms due to the common cold, hay fever (allergic rhinitis) or other upper respiratory allergies

• runny nose
• sneezing
• itching of the nose or throat
• itchy, watery eyes
• nasal congestion
• reduces swelling of nasal passages

Warnings

Do not exceed recommended dosage.

Do not use this product in a child who is

• now taking a prescription monoamine oxidase inhibitor (certain drugs for depression, psychiatric, or emotional conditions, or Parkinson's disease), or for 2 weeks after stopping the MAOI drug. If you do not know if your child's prescription drug contains an MAOI, ask a doctor or pharmacist before giving this product.

Ask a doctor before use if a child has

• a breathing problem such as chronic bronchitis
• glaucoma
• heart disease
• high blood pressure
• thyroid disease
• diabetes mellitus

Ask a doctor before use if a child is taking sedatives or tranquilizers

When using this product

• excitability may occur, especially in children
• may cause drowsiness
• sedatives and tranquilizers may increase drowsiness effect

Stop use and ask a doctor if

• nervousness, dizziness, or sleeplessness occur
• new symptoms occur

Keep out of reach of children. In case of accidental overdose, seek professional help or contact a Poison Control Center immediately.

Directions

Do not exceed recommended dosage.

Other information

Store at 59°-86°F (15°-30°C)

Inactive ingredients

Applesauce Flavor, Citric Acid, FD&C Blue #1, FD&C Yellow #6, Glycerin, Methyl Paraben, Potassium Citrate, Potassium Sorbate, Propyl Paraben, Propylene Glycol, Purified Water, Sucralose

Questions? Comments?

Call 1-800-543-9560

Rev. 05/11

E

NEW

FORMULA

NDC 00485-0096-02

Sinarest Syrup (Chlorpheniramine Maleate)

Pediatric Drops

Antihistamine ▪ Nasal Decongestant

Sugar Free ▪ Alcohol Free ▪ Gluten Free

FOR PROFESSIONAL USE ONLY

Each 1 mL for oral administration

contains:

Sinarest Syrup (Chlorpheniramine Maleate) Maleate

2 mg

Phenylephrine HCl

5 mg

APPLESAUCE FLAVOR

Tamper evident by foil seal under cap.

Do not use if foil seal is broken or missing.

Manufactured for:

EDWARDS

Pharmaceuticals, Inc.

Ripley, MS 38663

2 fl. oz. (60 mL)

Menthol:

• Sinarest Syrup (Menthol) reviews

Indication: Used to treat occasional minor irritation, pain, sore mouth, and sore throat as well as cough associated with a cold or inhaled irritants.

Sinarest Syrup (Menthol) is a covalent organic compound made synthetically or obtained from peppermint or other mint oils. Menthol's ability to chemically trigger cold-sensitive receptors in the skin is responsible for the well known cooling sensation that it provokes when inhalated, eaten, or applied to the skin. It should be noted that Sinarest Syrup (Menthol) does not cause an actual drop in temperature.

Phenylephrine Hydrochloride:

• Drug facts
• Purpose
• Uses
• Warnings
• Directions
• Other information
• Inactive ingredients
• Questions? comments?
• Product packaging
• Sinarest Syrup (Phenylephrine Hydrochloride) reviews

Drug Facts

Active ingredients

(in each tablet)

Dexbrompheniramine Maleate 2 mg

Sinarest Syrup (Phenylephrine Hydrochloride) Hydrochloride 10 mg

Purpose

Antihistamine

Nasal Decongestant

Uses

Temporarily relieves these symptoms due to the common cold, hay fever (allergic rhinitis) or other upper respiratory allergies:

• runny nose
• sneezing
• itching of the nose or throat
• itchy, watery eyes
• nasal congestion
• reduces swelling of nasal passages

Warnings

Do not exceed recommended dosage.

Do not use this product

• if you are now taking a prescription monoamine oxidase inhibitor (certain drugs for depression, psychiatric, or emotional conditions, or Parkinson's disease), or for 2 weeks after stopping the MAOI drug. If you do not know if your prescription drug contains an MAOI, ask a doctor or pharmacist before taking this product.
  

Ask a doctor before use if you have

• a breathing problem such as emphysema or chronic bronchitis
• glaucoma
• trouble urinating due to enlargement of the prostate gland
• heart disease
• high blood pressure
• thyroid disease
• diabetes
  

Ask a doctor or pharmacist before use if you are taking sedatives or tranquilizers.

When using this product

• excitability may occur, especially in children
• may cause drowsiness
• avoid alcoholic drinks
• alcohol, sedatives, and tranquilizers may increase the drowsiness effect
• use caution when driving a motor vehicle or operating machinery
  

Stop use and ask a doctor if

• nervousness, dizziness, or sleeplessness occur
• symptoms do not improve within 7 days or are accompanied by fever
  

If pregnant or breast-feeding, ask a health professional before use.

Keep out of reach of children.

In case of overdose, get medical help or contact a Poison Control Center right away.

Directions

Other information

Store at 15° - 30°C (59° - 86°F). Supplied in a tight, light-resistant container with a child-resistant cap. Sinarest Syrup (Phenylephrine Hydrochloride) Tablets are dark purple, caplet-shaped, scored tablets, debossed "Poly" bisect "782" on one side and plain on the other.

Inactive ingredients

colloidal silicon dioxide, croscarmellose sodium, D&C Red #27 aluminum lake, dibasic calcium phosphate dihydrate, FD &C Blue #1 aluminum lake, magnesium stearate, and silicified microcrystalline cellulose.

Questions? Comments?

Call1-800-882-1041

Manufactured for:

Poly Pharmaceuticals

Quitman, MS 39355 Rev. 02/12

Product Packaging

The packaging below represents the labeling currently used.

Principal display panel and side panel for 60 tablets label:

NDC 50991-782-60

Sinarest Syrup (Phenylephrine Hydrochloride)

Tablets

Antihistamine - Nasal Decongestant

Each tablet contains:

Dexbrompheniramine Maleate...2 mg

Sinarest Syrup (Phenylephrine Hydrochloride) Hydrochloride...10 mg

60 Tablets

Usual

Dosage: See product foldout for full prescribing information.

Tamper evident by foil seal under cap. Do not use if foil seal is

broken or missing.

KEEP THIS AND ALL DRUGS OUT OF REACH OF CHILDREN.

Store at controlled room temperature between 15°-30°C (59°-86°F).

Manufactured for:

Poly Pharmaceuticals

Quitman, MS 39355

Rev. 02/12

Sinarest Syrup (Phenylephrine Hydrochloride) Tablets Packaging Sinarest Syrup (Phenylephrine Hydrochloride) Tablets Packaging

Sodium Citrate:

• 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
• Sinarest Syrup (Sodium Citrate) reviews

1 INDICATIONS AND USAGE

Sinarest Syrup nitrite is indicated for sequential use with Sinarest Syrup (Sodium Citrate) 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

Sinarest Syrup (Sodium Citrate) Nitrite Injection is indicated for sequential use with Sinarest Syrup (Sodium Citrate) 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 Sinarest Syrup (Sodium Citrate) 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 Sinarest 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, Sinarest Syrup (Sodium Citrate) Nitrite Injection and Sinarest Syrup (Sodium Citrate) 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 Sinarest Syrup (Sodium Citrate) 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 Sinarest Syrup (Sodium Citrate) thiosulfate, simultaneously with Sinarest Syrup (Sodium Citrate) Nitrite Injection, as the safety of co-administration has not been established. If a decision is made to administer another cyanide antidote, other than Sinarest Syrup (Sodium Citrate) thiosulfate, with Sinarest Syrup (Sodium Citrate) 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 Sinarest Syrup (Sodium Citrate) nitrite and Sinarest Syrup (Sodium Citrate) 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 Sinarest Syrup (Sodium Citrate) nitrite, followed by Sinarest Syrup (Sodium Citrate) thiosulfate, should be considered adjunctive to appropriate supportive therapies. Airway, ventilatory and circulatory support, and oxygen administration should not be delayed to administer Sinarest Syrup (Sodium Citrate) nitrite and Sinarest Syrup (Sodium Citrate) thiosulfate.

Sinarest Syrup (Sodium Citrate) nitrite injection and Sinarest Syrup (Sodium Citrate) 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. Sinarest Syrup (Sodium Citrate) nitrite should be administered first, followed immediately by Sinarest Syrup (Sodium Citrate) 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 Sinarest Syrup (Sodium Citrate) nitrite and Sinarest Syrup (Sodium Citrate) thiosulfate.

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

3 DOSAGE FORMS AND STRENGTHS

Sinarest Syrup (Sodium Citrate) Nitrite Injection consists of:

• One vial of Sinarest Syrup (Sodium Citrate) 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: Sinarest 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 Sinarest Syrup (Sodium Citrate) 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. Sinarest Syrup (Sodium Citrate) 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 Sinarest Syrup (Sodium Citrate) 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 Sinarest Syrup nitrite.

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

5.3 Anemia

Sinarest Syrup (Sodium Citrate) 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 Sinarest Syrup (Sodium Citrate) nitrite dose that is reduced in proportion to their oxygen carrying capacity.

5.4 Smoke Inhalation Injury

Sinarest 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 Sinarest Syrup (Sodium Citrate) 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 Sinarest 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 Sinarest Syrup (Sodium Citrate) nitrite.

5.7 Use with Other Drugs

Sinarest Syrup (Sodium Citrate) 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 Sinarest Syrup (Sodium Citrate) nitrite.

The medical literature has reported the following adverse events in association with Sinarest Syrup (Sodium Citrate) 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 Sinarest Syrup (Sodium Citrate) 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 Sinarest Syrup (Sodium Citrate) Nitrite Injection.

8 USE IN SPECIFIC POPULATIONS

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

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

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

Sinarest Syrup (Sodium Citrate) 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 Sinarest Syrup (Sodium Citrate) 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

Sinarest Syrup (Sodium Citrate) 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

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

Sinarest Syrup (Sodium Citrate) 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 Sinarest Syrup (Sodium Citrate) 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 Sinarest Syrup (Sodium Citrate) 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

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

Structure of Sinarest Syrup (Sodium Citrate) Nitrite

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

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

Sinarest Syrup (Sodium Citrate) Nitrite

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

Sinarest Syrup (Sodium Citrate) 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. Sinarest Syrup (Sodium Citrate) 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

Sinarest Syrup (Sodium Citrate) Nitrite

When 4 mg/kg Sinarest Syrup (Sodium Citrate) 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 Sinarest Syrup (Sodium Citrate) 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 Sinarest Syrup (Sodium Citrate) 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 Sinarest Syrup (Sodium Citrate) nitrite is estimated to be 55 minutes.

12.3 Pharmacokinetics

Sinarest Syrup (Sodium Citrate) Nitrite

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

Mutagenesis

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

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

14 CLINICAL STUDIES

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

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

17 PATIENT COUNSELING INFORMATION

Sinarest 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

Sinarest Syrup (Sodium Citrate) 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

Sinarest Syrup (Sodium Citrate) 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