Metamizole Sodium for injection 1g Taj Pharma

Metamizole Sodium for injection 1g Taj Pharma

1. NAME OF THE MEDICINAL PRODUCTS

Metamizole Sodium 1g solution for injection

2. QUALITIVE AND QUANTITATIVE COMPOSITION

Metamizole Sodium 1g solution for injection

1 ml solution for injection contains 500 mg metamizole sodium

Each vial with 2 ml solution for injection contains 1g metamizole sodium

For a full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Solution for injection

4. CLINICAL PARTICULARS
   • Therapeutic indications

• Acute severe pain after injury or surgery -Colic,
• Tumour pain,

– Other acute or chronic severe pain, where other therapeutic measures are not indicated,

– High fever not responding to other measures.

Parenteral use is indicated only where enteric administration cannot be considered.

Not used as routine analgesic

4.2 Posology and method of administration

Posology

The dose depends on the severity of the pain or fever and the sensitivity of the individual’s reaction to Metamizole Sodium.

Essentially the lowest dose effective in controlling the pain and fever should be selected.

In fever, a dose of 10 mg metamizole per kilogram body weight is generally adequate in children.

A clear effect can be expected 30 to 60 minutes after oral use and approx. 30 minutes after parenteral administration.

For children and adolescents up to 14 years of age, the single dose is 8 to 16 mg metamizole sodium per kilogram body weight. Adults and young people aged 15 and over (> 53 kg) can take up to 1000 mg per single dose. In the event of inadequate efficacy the single dose may be given up to 4 times a day, depending on the maximum daily dose.

The recommended single doses and maximum daily doses are shown in the dosage table below.

The single dose usually given by parenteral administration is 6 mg to 16 mg metamizole per kilogram body weight. Infants from 3 months of age to 1 year are given Metamizole Sodium solution for injection by the intramuscular route only.

As hypotensive reactions to the injection may possibly be dose-related, single parenteral doses of more than 1g Metamizole Sodium must not be given unless strictly indicated.

Elderly patients

In elderly patients the dose should be reduced, as elimination of the products of metabolism of Metamizole Sodium may be delayed.

In impaired general health and reduced creatinine clearance

In patients with impaired general health and reduced creatinine clearance, the dose should be reduced as elimination of the products of metabolism of Metamizole Sodium may be delayed.

Impaired renal or hepatic function

Since the rate of elimination is reduced in patients with an impaired renal or hepatic function, repeated high doses should be avoided. Only in short-term use is no dose reduction necessary. No experience is available in respect of long-term administration.

Method of administration

The method of administration depends on the therapeutic effect

desired and the condition of the patient. In many cases oral administration is adequate to achieve a satisfactory effect. If rapid onset of the effect is necessary or if oral or rectal administration is not indicated, intravenous or intramuscular injection of Metamizole Sodium is recommended. When selecting the method of administration it must be borne in mind that parenteral administration of the drug is associated with an increased risk of anaphylactic or anaphylactoid reactions.

Metamizole Sodium is injected by the intravenous or intramuscular route but in infants (3 – 11 months) by the intramuscular route only. The intramuscular injection should always be given in a solution at body heat.

In view of the possibility of incompatibility, Metamizole Sodium solution for injection should not be injected or infused together with other medications.

Duration of administration

The duration of administration depends on the nature and severity of the disease. During longer-term treatment with Metamizole Sodium, regular blood counts should be performed, including a differential blood count.

Safety precautions for injection

A single dose of more than 2 ml Metamizole Sodium (equivalent to 1,000 mg metamizole sodium ) requires particularly careful verification of the indication, as it is suspected that non-allergic critical falls in blood pressure are dose-related.

For parenteral administration of Metamizole Sodium, the patient must be lying down and closely monitored by medical stau.

To minimise the risk of a hypotensive reaction and to ensure that the injection can be discontinued at the first signs of an anaphylactic or ana¬phylactoid reaction, the intravenous injection should be given very slowly, i.e. at a rate of not more than 1 ml (equivalent to 500 mg metamizole sodium) per minute.

4.3 Contraindications

-Hypersensitivity to the active substance or other pyrazolones or pyrazolidines (this also includes patients who have reacted, for example, with agranulocytosis after using these substances) or to any of the excipients listed in section 6.1,

• Patients with known analgesic asthma syndrome or with known analgesic intolerance of the urticaria-angioedema type, i.e. patients who react with bronchospasm or other forms of anaphylactoid reaction (e.g. urticaria, rhinitis, angioedema) to salicylates, paracetamol or other non-narcotic analgesics such as diclofenac, ibuprofen, indometacin or naproxen,
• Disorders of bone marrow function (e.g. following cytostatic treatment) or diseases of the haematopoietic system,
• Congenital glucose-6-phosphate dehydrogenase deficiency (risk of haemolysis),
• Acute intermittent hepatic porphyria (risk of triggering a porphyria attack),
• Last trimester of pregnancy (see section 4.6),
• Lactation (see section 4.6),
• Neonates and children less than 3 months of age or under 5 kg body weight, as no scientific information is available concerning this use,
• Infants (3-11 months) as an intravenous injection,
• Patients with existing hypotension and unstable circulatory situation.

4.4 Special warnings and precautions for use

Metamizole Sodium contains the pyrazolone derivative metamizole and carries the rare but life-threatening risk of shock and agranulocytosis (see section 4.8).

Patients who show anaphylactoid reactions to Metamizole Sodium are also particularly at risk of reacting in the same way to other non-narcotic analgesics.

Patients who show an anaphylactic or other immunologically mediated reaction to Metamizole Sodium (e.g. agranulocytosis), are also particularly at risk of reacting in the same way to other pyrazolones and pyrazolidines.

Agranulocytosis:  If signs of agranulocytosis or thrombocytopenia (see section 4.8) are observed, the use of Metamizole Sodium must be discontinued immediately and the blood count monitored (including differential blood count). The treatment should be discontinued without waiting for the results of the laboratory tests.

Pancytopenia:  In case of pancytopenia, treatment must be immediately discontinued and the complete blood count should be monitored until it normalizes (see section 4.8). All patients should be advised to seek immediate medical attention if they develop signs and symptoms during treatment which are suggestive of blood dyscrasias (e.g. general malaise, infection, persistent fever, bruising, bleeding, pallor).

Anaphylactic/anaphylactoid reactions:  In selecting the method of administration it should be borne in mind that the parenteral administration of Metamizole Sodium is associated with a higher risk of anaphylactic and anaphylactoid reactions (see section 4.2 “Safety precautions for injection”).

The risk of possibly serious anaphylactoid reactions to Metamizole Sodium is clearly elevated for patients with:

–           Analgesic asthma syndrome or analgesic intolerance of the urticaria- angioedema type (see section 4.3),

–           Asthma, in particular with concomitant rhinosinusitis and nasal polyps,

–           Chronic urticaria,

–           Intolerance to colouring agents (e.g. tartrazine) or preservatives (e.g. benzoates),

–           Alcohol intolerance. These patients react even to small quantities of alcoholic beverages with symptoms such as sneezing, watering eyes and severe reddening of the face. Alcohol intolerance of this kind may be a sign of undiagnosed analgesic asthma syndrome (see section 4.3).

An anaphylactic shock may predominantly occur in sensitive patients. Therefore, the administration in asthmatic or atopic patients is subject to particular caution.

Severe cutaneous reactions: The life-threatening cutaneous reactions of the Stevens-Johnson syndrome (SJS) and Toxic Epidermal Necrolysis (TEN) have been reported with the use of metamizole. If symptoms or sings of SJS or TEN (such as progressive skin rash often with blisters of mucosal lesions) develop, the treatment with Metamizole Sodium must be discontinued immediately, and must not be

re-initiated at any time.

Patients should be advised of the signs and symptoms and monitored closely for skin reactions, particularly within the first weeks of treatment

Isolated hypotensive reactions: Metamizole Sodium can trigger hypotensive reactions (see also section 4.8). These reactions may be dose-related and should be expected more often in parenteral than in enteral administration. The risk of such reactions is also increased in the case of:

– Too rapid intravenous injection (see section 4.2),

• Patients with, for example, preexisting hypotension, volume deficiency or dehydration, unstable circulation or incipient circulatory failure (such as patients with myocardial infarction or multiple injuries),
• Patients with a high fever.

Careful examination of the indication (see also section 4.3) and close monitoring is therefore necessary in these patients. Preventive measures (e.g. stabilisation of the circulation) may be necessary to reduce the risk of hypotensive reactions.

The use of Metamizole Sodium must be accompanied by careful monitoring of the haemodynamic parameters in patients in whom a decrease in blood pressure must be avoided at all costs, e.g. in severe coronary heart disease or significant stenosis of the blood vessels supplying the brain.

Metamizole Sodium should only be used after strict benefit-to-risk analysis and with appropriate precautionary measures in patients with impaired renal or hepatic functions (see section 4.2).

Before giving Metamizole Sodium, the patient must be questioned appropriately. In patients with a high risk of anaphylactoid reactions Metamizole Sodium should only be used after careful consideration of the possible risks, weighed against the expected benefits. If Metamizole Sodium is given in these cases, the patient should be subject to close medical monitoring and facilities for emergency treatment should be kept immediately to hand.

On external packaging:  Warning:  contains metamizole.

1 ml contains 1.42 mmol (32.7 mg) sodium. To be taken into consideration by patients on a controlled sodium diet.

4.5 Interaction with other medicinal products and other forms of interaction

Metamizole may lead to a reduction in serum cyclosporin levels. These must therefore be monitored if Metamizole Sodium is used concomitantly.

During concomitant use of Metamizole Sodium and chlorpromazine, severe hypothermia may occur.

Adding metamizole to methotrexate may increase the hematotoxicity of methotrexate particularly in elderly patients. Therefore, this combination should be avoided.

Metamizole may reduce the effect of acetylsalicylic acid (aspirin) on platelet aggregation, when taken concomitantly. Therefore, this combination should be used with caution in patients taking low dose aspirin for cardioprotection.

Metamizole may cause a reduction in bupropion blood concentrations. Therefore, caution is advised when metamizole and bupropion are administered concurrently.

For the pyrazolones, it is known that interactions can occur with oral anticoagulants, captopril, lithium, and triamterene and the eficacy of antihypertensive drugs and diuretics may be modified. The extent to which metamizole also leads to these interactions is unknown.

Interference with laboratory tests:  Interference with laboratory tests which use Trinder/Trinder-like reactions (e.g. tests to measure serum levels of creatinine, triglycerides, HDL cholesterol, and uric acid) has been reported in patients using metamizole.

• Fertility, pregnancy and lactation

Pregnancy:  No adequate data is available on the use of Metamizole Sodium in pregnant women. Metamizole crosses the placental barrier. In animal experimental studies metamizole showed no teratogenic effects (see section 5.3). Since no adequate information is available in humans, Metamizole Sodium should not be used during the first trimester of pregnancy and should be used only after strict medical analysis of the benefit-to-risk ratio in the second trimester.

Although metamizole is only a weak inhibitor of prostaglandin synthesis, the possibility of premature closure of the ductus arteriosus (duct of Botallo) and perinatal complications due to a reduction in foetal and maternal platelet aggregation cannot be ruled out. Metamizole Sodium is therefore contraindicated during the last trimester of pregnancy (see section 4.3).

Lactation: The metabolites of metamizole are eliminated in breast milk, so that breast feeding should be discontinued when using metamizole and for at least 48 hours after taking the last dose of Metamizole Sodium (see section 4.3).

• Effects on ability to drive and use machines

No impairment of concentration and the ability to react is known in the normal dose range. As a precautionary measure, however, at least at higher doses, the possibility of impairment should be considered and the use of machines, driving vehicles and other hazardous activities should be avoided. This is particularly the case in combination with alcohol.

• Undesirable effects

The incidences of undesirable effects are based on the following categories:

very common ( >1/10)                                      common (> 1/100 to <1/10)
uncommon ( > 1/1,000 to <1/100)         rare ( >1/10,000 to <1/1,000) very rare ( <1/10,000)

not known (cannot be estimated from the available data)

Rare:    Leucopenia

Very rare:  Agranulocytosis, including fatal outcome, thrombocytopenia. Not known:  Aplastic anaemia, pancytopenia, including fatal outcome.

These reactions may also occur when metamizole has previously been given without complications.

There are occasional indications that the risk of agranulocytosis may be increased when Metamizole Sodium is used for more than one week.

This reaction is not dose dependent and may occur at any time during treatment. The signs are a high fever, chills, sore throat, swallowing difficulties and inflammation in the mouth, nose, throat and genital or anal area. In patients receiving antibiotics these signs may, however, be minimal. Swelling of lymph nodes or the spleen is slight or entirely absent. The erythrocyte sedimentation rate is greatly accelerated, granulocytes are considerably reduced or entirely absent. In general, but not invariably, values for haemoglobin, red cells and platelets are normal (see section 4.4).

Immediate discontinuation is crucial for recovery. It is therefore strictly recommended that Metamizole Sodium should be discontinued immediately without waiting for the results of diagnostic laboratory investigations, if the patient’s general condition unexpectedly deteriorates, fever does not abate or recurs, or if painful changes to the mucous membranes are observed, particularly in the mouth, nose and throat.

In case of pancytopenia, treatment must be immediately discontinued and the complete blood count should be monitored until it normalizes (see section 4.4). Immune system disorders

Rare:    Anaphylactic/anaphylactoid reactions*.

Very rare:  Analgesic induced asthma syndrome. In patients with an analgesic asthma syndrome, intolerance reactions typically appear in the form of asthma attacks.

Not known:  Anaphylactic shock*.

*These reactions may occur in particular after parenteral administration, may be severe and life-threatening, sometimes fatal. They may occur even after metamizole has previously been used on many occasions without complications. These reactions may develop during the injection or immediately after administration but may also appear some hours later. However, they develop primarily during the first hour after administration. Milder reactions are typically seen in the skin and mucous membranes (such as itching, burning, reddening, urticaria, swelling), dyspnoea and – more rarely – gastrointestinal disorders. These milder reactions may progress to more severe forms with generalised urticaria, severe angioedema (also affecting the larynx), severe bronchospasm, disorders of cardiac rhythm, hypotension (sometimes also with a preceding increase in blood pressure), circulatory shock.

Therefore, if skin reactions develop, Metamizole Sodium must be discontinued immediately.

Cardiac disorders:                Not known:  Kounis syndrome

Vascular disorders:

Uncommon:  Hypotensive reactions during or after use, which may have a pharmacological cause and are not accompanied by other signs of anaphylactoid or anaphylactic reaction. A reaction of this kind can lead to a fall in blood pressure that may be serious. Rapid intravenous injection increases the risk of a hypotensive reaction.

In the event of a high fever, there may also be a critical fall in blood pressure related to dose, with no further sings of a hypersensitivity reaction, Gastrointestinal disorders

Not known:  Cases of gastrointestinal bleeding have been reported. Skin and subcutaneous tissue disorders

Uncommon:  Fixed drug eruptions.

Rare:    Rash (e.g. maculo-papular exanthema).

Very rare:  Sevens-Johnson syndrome or Toxic Epidermal Necrolysis (discontinue treatment, see section 4.4).

Renal and urinary disorders

Very rare:   acute deterioration in renal function, very rarely involving development of proteinuria, oliguria or anuria, and/or acute renal failure; acute interstitial nephritis.

General disorders and administration site conditions

With injections, pain can occur at the injection site and there may be local reactions, very rarely even phlebitis.

A red coloration of the urine has been sometimes observed, which may be due to a harmless metamizole metabolite present at low concentration:  rubazonic acid. 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.

4.9 Overdose

Symptoms of an overdose

In the event of acute overdose, nausea, vomiting, abdominal pain, impaired renal function/acute renal failure (e.g. in the form of interstitial nephritis) and – more rarely – central nervous symptoms (dizziness, somnolence, coma, seizures) and hypotension or even shock and tachycardia have been reported.

After very high doses the elimination of rubazonic acid can cause red discolouration of the urine.

Therapeutic measures in case of an overdose

No specific antidote is known for metamizole. If the metamizole has been taken recently, an attempt may be made to limit uptake in the body by primary detoxification (e. g. gastric lavage) or by means of measures to reduce absorption (e.g. activated carbon). The main metabolite (4 N-methyl¬-amino–antipyrine) can be eliminated by dialysis, haemofiltration, haemoperfusion or plasma filtration.

The treatment of poisoning and the prevention of serious complications may require general and specific intensive medical monitoring and treatment.

Immediate measures in the event of serious hypersensitivity reactions (shock)

At the first sings (e.g. cutaneous reactions such as urticaria and Hushing, restlessness, headache, sweating, nausea), discontinue the injection. Leave the cannula in the vein or create a venous access. In addition to the usual emergency measures involving lowering the head and upper body, maintaining the airway and administration of oxygen, the administration of sympathomimetics, volume replacement or glucocorticoids may be necessary.

5. PHARMACOLOGICAL PROPERTIES
   • Pharmacodynamic properties

Pharmacotherapeutic group:  analgesics, other analgesics and antipyretics, pyrazolones.

Metamizole is a pyrazolone derivative and has analgesic, antipyretic and spasmolytic properties. The mechanism of action is not fully understood. The results of some investigations have shown that metamizole and the main metabolite (4 N methyl-amino-antipyrine) presumably have both a central and also a peripheral mechanism of action.

• Pharmacokinetic properties

Metamizole is completely hydrolysed after oral administration to the pharmacologically active 4 N methyl-amino-antipyrine (MAA). The bioavailability of MAA is approx. 90% and is slightly higher after oral administration than after parenteral administration. Ingestion with meals has no significant effect on the kinetics of metamizole.

Its clinical eficacy relies mainly on MAA, to a certain extent also on the metabolite 4 amino-antipyrine (AA). The AUC values for AA represent approx. 25% of the AUC values for MAA. The metabolites 4 N acetyl-amino-antipyrine (AAA) and 4 N formyl-amino-antipyrine (FAA) appear to be pharmacologically inactive. It should be noted that all metabolites have a non-linear pharmacokinetic action. The clinical significance of this phenomenon is unknown. During short-term treatment, the accumulation of the metabolites is of little significance.

Metamizole crosses the placental barrier. The metabolites of metamizole are excreted in breast milk.

Plasma protein binding for MAA is 58%, for AA 48%, for FAA 18% and for AAA 14%. After intravenous administration the plasma half-life for metamizole is approx. 14 minutes. After intravenous administration approx. 96% of a radioactively labelled dose is recovered in the urine and approx. 6% in the faeces. After a single oral dose 85% of metabolites eliminated in the urine were identified. Of these, 3±1% were MAA, 6±3% AA, 26±8% AAA and 23±4% FAA. Renal clearance of a single oral dose of 1g metamizole was 5±2 for MAA, 38±1 for AA, 61±8 for AAA and 49±5 ml/min for FAA.

The associated plasma half-lives were 2.7±0.5 hours for MAA, 3.7±1.3 hours for AA, 9.5±1.5 hours for AAA and 11.2±1.5 hours for FAA.

Elderly:  During the treatment of elderly patients the AUC increases 2 to 3-fold. After oral administration of a single dose in patients with hepatic cirrhosis, the half-lives of MAA and FAA rises approximately 3-fold while the half-lives of AA and AAA do not rise to the same degree. High doses should be avoided in these patients.

5.3 Preclinical safety data

Subchronic and chronic toxicity investigations have been performed in various animal species. Rats were given 100 to 900 mg metamizole per kg BW orally for 6 months. At the highest dose (900 mg per kg BW) an increase in reticulocytes and Heinz’ bodies were observed after 13 weeks.

Dogs were given metamizole at doses of 30 to 600 mg per kg BW for 6 months.

Dose-related haemolytic anaemia and functional renal and hepatic changes were observed from 300 mg per kg BW.

In-vitro and in-vivo investigations have shown contradictory findings for metamizole in the same test systems.

In long-term investigations in rats no indications of carcinogenic potential were seen. In two out of three long-term investigations in mice, increased liver cell adenomas were reported at high doses.

Embryotoxicity studies in rats and rabbits showed no evidence of teratogenic effects.

Lethal effects on embryos were reported in rabbits from a non-maternotoxic daily dose of 100 mg per kg BW. In rats, fatal embryotoxic effects occurred at doses in the maternotoxic range. Daily doses of more than 100 mg per kg BW in rats led to a prolonged gestation time and impairment of the birth process

with increased mortality of dams and young.

Fertility tests showed a slightly reduced gravidity rate in the parent generation at a dose of more than 250 mg per kg BW a day. The fertility of the F1generation was not impaired.

The metabolites of metamizole pass into breast milk. There is no information regarding the effects on the nursing young.

6. PHARMACEUTICAL PARTICULARS

6.1 List of excipients:  Water for injection

6.2 Incompatibilities

In view of the possibility of incompatibility, it is recommended that the solution for injection should not be mixed with other therapeutic agents for injection or infusion (with respect to miscibility with solutions for infusion, see also section 4.2).

6.3 Shelf life: 3 years.

6.4 Special precautions for storage:  Refer to outer pack

6.5 Nature and contents of container
Metamizole Sodium 1g solution for injection:

Glass vials supplied in packs of 5 x 2 ml and 10 x2 ml and hospital packs of 96 x 2 ml and 100 x 2 ml

Not all pack sizes may be marketed.

6.6 Special precautions for disposal No special requirements.

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