Sodium Nitrite Solution for Injection 30mg/1mL in Prefilled Syringe Taj Pharma

Sodium Nitrite Solution for Injection 30mg/1mL in Prefilled Syringe Taj Pharma

1. Name of the medicinal product

Sodium Nitrite Solution for Injection 30mg/1mL in Prefilled Syringe Taj Pharma

2. Qualitative and quantitative composition

Each Prefilled Syringe contains
300 mg of sodium nitrite (30 mg/mL).

For the full list of excipients, see section 6.1.

3. Pharmaceutical form

Solutions for Injection

The solution for injection is a clear and colourless sterile solution.

4. Clinical particulars

4.1 Therapeutic indications

Sodium nitrite is indicated for sequential use with sodium 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 sodium nitrite should be carefully weighed against the potential benefits, especially if the patient is not in extremis.

4.2 Posology and method of administration

Posology

For intravenous use. For single use only.

Adults

10 mL of sodium nitrite (rate of 2.5 to 5 mL/minute) should be administered intravenously, immediately followed by 50 mL of sodium thiosulfate (rate of 5 mL/minute).

Special populations

Older people

No specific dose adjustment is required in elderly patients (aged ≥ 65 years).

Paediatric population

0.2 mL/kg (6 mg/kg or 6-8 mL/m² BSA) of sodium nitrite (rate of 2.5 to 5 mL/minute) not to exceed 10 mL should be administered intravenously, immediately followed by 1 mL/kg of body weight (250 mg/kg or approximately 30-40 mL/m² of BSA) (rate of 5 mL/minute) not to exceed 50 mL total dose of sodium thiosulfate.

NOTE: If signs of poisoning reappear, repeat treatment using one-half the original dose of both sodium nitrite and sodium thiosulfate.

In adult and paediatric patients with known anaemia, it is recommended that the dosage of sodium nitrite should be reduced proportionately to the hemoglobin concentration (see section 4.4).

Method of administration

Comprehensive treatment of acute cyanide intoxication requires support of vital functions. 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. Administration of sodium nitrite, followed by sodium thiosulfate, should be considered adjunctive to appropriate supportive therapies such as airway, ventilatory, and circulatory support. Supportive therapies, including oxygen administration, should not be delayed to administer sodium nitrite and sodium thiosulfate.

Sodium nitrite injection and sodium 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. Sodium nitrite should be administered first, followed immediately by sodium 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.

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

4.3 Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

4.4 Special warnings and precautions for use

Sodium nitrite has been associated with severe hypotension, methemoglobinemia, and death at doses less than twice recommended therapeutic doses. When the diagnosis of cyanide poisoning is uncertain and/or the patient is not in extremis, special consideration should be given to administration of sodium nitrite if the patient is known or suspected to have diminished oxygen or cardiovascular reserve (e.g., smoke inhalation victims, pre-existing anaemia, substantial blood loss, cardiac or respiratory compromise) or to be at higher risk of developing methemoglobinemia (e.g., congenital methemoglobin reductase deficiency).

4.4.1 Hypotension

Hemodynamics should be monitored closely during and after administration of sodium nitrite, and infusion rates should be slowed if hypotension occurs. Sodium nitrite should be used with caution in the presence of other drugs that can reduce blood pressure.

4.4.2 Methemoglobinemia

Methemoglobin levels should be monitored and oxygen administered during treatment with sodium nitrite whenever possible. When sodium 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 sodium nitrite administered to an adult. Sodium nitrite should be used with caution in the presence of other drugs that may cause methemoglobinemia such as procaine and nitroprusside.

4.4.3 Anaemia

Sodium nitrite should be used with caution in patients with known anaemia. Patients with anaemia 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 sodium nitrite dose that is reduced in proportion to their oxygen carrying capacity.

4.4.4 Smoke Inhalation Injury

Sodium 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.

4.4.5 Neonates and Infants

Neonates and infants may be more susceptible than adults and older paediatric patients to severe methemoglobinemia when sodium nitrite is administered. Reduced dosing guidelines should be followed in paediatric patients.

4.4.6 G6PD Deficiency

Because patients with G6PD deficiency are at increased risk of a hemolytic crisis with sodium 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 sodium nitrite.

4.5 Interaction with other medicinal products and other forms of interaction

No interaction studies have been performed. Possible interaction may occur with hydroxocobalamin.

Sodium nitrite should be used with caution in the presence of other drugs that may cause methemoglobinemia such as procaine and nitroprusside. It should also be used with caution in the presence of other drugs that can reduce blood pressure.

4.6 Fertility, pregnancy and lactation

Pregnancy Based on human experience sodium nitrite is suspected to cause congenital malformations when administered during pregnancy. Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity (see section 5.3).

Sodium nitrite should not be used during pregnancy unless the clinical condition of the woman requires treatment with sodium nitrite.

Breastfeeding

It is unknown whether sodium nitrite is excreted in human milk. A risk to the suckling child cannot be excluded.

Breast-feeding should be discontinued during treatment with sodium nitrite.

Fertility

There are no fertility data from the use of sodium nitrite in animals.

4.7 Effects on ability to drive and use machines

Not relevant.

4.8 Undesirable effects

There have been no controlled clinical trials conducted to systematically assess the adverse events profile of sodium nitrite.

The medical literature has reported the following adverse events in association with sodium 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.

*Description of selected adverse reactions

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 sodium nitrite at doses less than twice those recommended for the treatment of cyanide poisoning.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system.

4.9 Overdose

Large doses of sodium nitrite result in severe hypotension and toxic levels of methemoglobin which may lead to cardiovascular collapse.

Sodium 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 sodium 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 sodium 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.

5. Pharmacological properties

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: antidotes.

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 sodium nitrite and sodium thiosulfate is the result of differences in their primary mechanisms of action as antidotes for cyanide poisoning.

Pharmacodynamic effects

Sodium Nitrite

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

Sodium 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. Sodium 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:

Clinical efficacy and safety

There have been no controlled clinical trials conducted to systematically assess the clinical efficacy and safety of sodium nitrite.

5.2 Pharmacokinetic properties

Absorption

Intravenous administration of sodium nitrite is 100% bioavailable.

Distribution

After a 30 minutes intravenous infusion of 290-370 mg sodium nitrite, the reported half-life was approximately 40 minutes

Biotransformation and elimination

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

5.3 Preclinical safety data

Effects in non-clinical studies were observed only at exposures considered sufficiently in excess of the maximum human exposure indicating little relevance to clinical use and development.

6. Pharmaceutical particulars

6.1 List of excipients

Water for Injections

6.2 Incompatibilities

Chemical incompatibility has been reported between sodium nitrite and hydroxocobalamin and these drugs should not be administered simultaneously through the same IV line. No chemical incompatibility has been reported between sodium thiosulfate and sodium nitrite, when administered sequentially through the same IV line.

6.3 Shelf life

5 years

6.4 Special precautions for storage

Do not store above 25°C.

Store in the original package in order to protect from light.

6.5 Nature and contents of container

Each carton of Sodium Nitrite Solution for Injection contains one 10 mL glass Prefilled Syringe of sodium nitrite 30 mg/mL solution for injection (containing 300 mg of sodium nitrite).

6.6 Special precautions for disposal and other handling

No special requirements for disposal.

7. Manufactured in India by:
   TAJ PHARMACEUTICALS LTD.
   Mumbai, India
   Unit No. 214.Old Bake House,
   Maharashtra chambers of  Commerce Lane,
   Fort, Mumbai – 400001
   at:Gujarat, INDIA.
   Customer Service and Product Inquiries:
   1-800-TRY-FIRST (1-800-222-434 & 1-800-222-825)
   Monday through Saturday 9:00 a.m. to 7:00 p.m. EST
   E-mail: tajgroup@tajpharma.com

Sodium Nitrite Solution for Injection 30mg/1mL in Prefilled Syringe Taj Pharma

Read all of this leaflet carefully

• This leaflet contains information about Sodium Nitrite, which will have already been given to you by injection into one of your veins.

• Although you will not be taking this medicine yourself, this leaflet contains important information to help you understand how Sodium Nitrite is used.

• Keep this leaflet. You may need to read it again.
• If you have any further questions, ask your doctor or nurse.

• If you get any side effects talk to your doctor or nurse.

This includes any possible side effects not listed in this leaflet. See section 4.

In this leaflet:

1. What Sodium Nitrite is and what it is used for

2. Before you are given Sodium Nitrite
3. How Sodium Nitrite is given
4. Possible side effects
5. How to store Sodium Nitrite
6. Further information

1. What Sodium Nitrite is and what it is used for

Sodium Nitrite 30 mg/mL Solution for Injection is used as an antidote for cyanide poisoning. Cyanide poisoning is a condition that develops when you inhale, touch, or swallow cyanide. Cyanide is a poisonous chemical that prevents your body from absorbing oxygen. The lack of oxygen can damage your organs and be life-threatening.

2. Before you are given Sodium Nitrite

Take special care with Sodium Nitrite if you:

• are pregnant or breast-feeding (See Pregnancy and breast-feeding);

• have low blood pressure;
• have a condition called anaemia (This is a reduction in number of red blood cells in the bloodstream. Anaemia can make the skin appear pale and can cause weakness or breathlessness);

• suffer from Glucose-6-Phosphate Dehydrogenase (G6PD) deficiency

(This may result in anaemia.);

• have a history of elevated levels of methemoglobin (This is a modified form of hemoglobin that reduces the amount of oxygen in the bloodstream and can cause weakness or breathlessness.);

• have inhaled smoke from a fire.

You will be monitored during use with

Sodium Nitrite, and the dose of the medication will be adjusted if necessary.

Using other medicines

Tell your doctor or pharmacist if you are taking or have recently taken any other medicines, including medicines obtained without a prescription.

The following medicines have side effects that are similar to the side effects that may occur with Sodium Nitrite.

• Medicines used to treat high blood pressure such as beta blockers, diuretics, and nitrates;

• Medicines that can increase methemoglobin levels such as procaine (used as a local anesthetic) and nitroprusside (used to reduce blood pressure).

It may be necessary for your doctor to adjust the dose of Sodium Nitrite or one of your other medications.

Do not take sodium nitrite concurrently with hydroxocobalamin.

Pregnancy and breast-feeding

Sodium Nitrite should not be used during pregnancy or while breast-feeding. Tell your doctor right away if you are pregnant or breast feeding.

3. How Sodium Nitrite will be Given

Sodium Nitrite will be given by injection into a vein by a doctor or nurse. Your doctor will choose the dose that is right for you.

If signs of cyanide poisoning reappear, your doctor will decide if you should receive more sodium nitrite.

If you have any further questions on the use of Sodium Nitrite, ask your doctor or nurse.

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody gets them.

The side effects of sodium nitrite include:

• Cardiovascular: reduced blood pressure,

rapid heart rate, irregular pulse, transient

loss of consciousness, palpitations

• Hematological: blood disorder resulting in oxygen deprivation in tissues(methemoglobinemia)

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

• Psychiatric: anxiety
• Gastrointestinal: nausea, vomiting, abdominal pain• Respiratory: rapid breathing, shortness of breath

• Skin: urticaria (skin rash notable for pale, red, raised, itchy bumps)

• Body as a whole: sweating, light headedness, injection site tingling, fatigue, weakness, generalized numbness and tingling, blue or purple coloured skin

The frequencies at which the above reactions occur are not known yet.

Death was reported after administration of a dose of sodium nitrite that was higher than the recommended therapeutic dose, but less than twice the recommended therapeutic dose.

Reporting of side effects:

If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet. You can help make sure that medicines remain as safe as possible by reporting any unwanted side effects directly.

5. How to store Sodium Nitrite

Keep this medicine out of the sight and reach of children.

Do not use Sodium Nitrite Solution for

Injection after the expiry date which is stated on the Prefilled Syringe label and carton.

The expiry date refers to the last day of that month.

Store below 25°C.

Sodium Nitrite 30 mg/mL Solution for

Injection must be clear and colorless.

If particulate matter or discoloration is present, the solution must not be used and should be discarded.

For single use only. Use immediately after opening. Discard any unused portions.

Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to dispose of medicines no longer required. These measures will help protect the environment.

6. Further information

What Sodium Nitrite contains

Each 10 mL Prefilled Syringe of Sodium Nitrite 30 mg/mL Solution for Injection contains 300 mg of the active ingredient sodium nitrite (30mg/mL). The other ingredient is water for injections.

What Sodium Nitrite looks like and

contents of the pack

Each carton of Sodium Nitrite 30 mg/mL

Solution for Injection contains one 10 mL glass Prefilled Syringe.

7. Manufactured in India by:
   TAJ PHARMACEUTICALS LTD.
   Mumbai, India
   Unit No. 214.Old Bake House,
   Maharashtra chambers of  Commerce Lane,
   Fort, Mumbai – 400001
   at:Gujarat, INDIA.
   Customer Service and Product Inquiries:
   1-800-TRY-FIRST (1-800-222-434 & 1-800-222-825)
   Monday through Saturday 9:00 a.m. to 7:00 p.m. EST
   E-mail: tajgroup@tajpharma.com