Metamalgin (Solution) Instructions for Use

Marketing Authorization Holder

Danson-BG (Bulgaria)

Manufactured By

Vetprom, AD (Bulgaria)

Contact Information

DOMINANTA-SERVIS AO (Russia)

ATC Code

N02BB02 (Metamizole sodium)

Active Substance

Metamizole sodium (Rec.INN registered by WHO)

Dosage Form

Metamalgin

Solution for intravenous and intramuscular administration 500 mg/1 ml: amp. 2 ml or 5 ml 5 or 10 pcs.

Dosage Form, Packaging, and Composition

Solution for intravenous and intramuscular administration in the form of a transparent, colorless or slightly yellowish liquid.

Excipients: water for injections – up to 1 ml.

2 ml – dark glass ampoules (5) – contour cell packs (1) – cardboard boxes.
2 ml – dark glass ampoules (10) – contour cell packs (1) – cardboard boxes.
5 ml – dark glass ampoules (5) – contour cell packs (1) – cardboard boxes.
5 ml – dark glass ampoules (10) – contour cell packs (1) – cardboard boxes.

Clinical-Pharmacological Group

Analgesic-antipyretic

Pharmacotherapeutic Group

Non-narcotic analgesic agent

Pharmacological Action

Metamalgin is a non-narcotic analgesic agent of the pyrazolone group, possessing analgesic, antipyretic, and spasmolytic action.

Its mechanism of action has not been definitively established.

Available data suggest that metamizole and its main metabolite (4N-methylaminoantipyrine [4-MAA]) have central and peripheral mechanisms of action.

In doses exceeding therapeutic doses, an anti-inflammatory effect may be achieved, possibly due to the suppression of prostaglandin synthesis.

Pharmacokinetics

Absorption

After intravenous administration of the drug, the bioavailability of the main metabolite of metamizole (4-MAA) is 87%. The mean time to reach C_max after intramuscular administration is 1.7 hours.

Distribution

The binding of 4-MAA to plasma proteins is 58%. Other metabolites of metamizole bind to plasma proteins to the following extent: 4-aminoantipyrine – 48%, 4-formylaminoantipyrine – 18%, and 4-acetylaminoantipyrine – 14%. Metamizole crosses the placental barrier. Metamizole metabolites pass into the breast milk of nursing mothers.

Metabolism

The main metabolite of metamizole, 4-MAA, undergoes further metabolism in the liver through oxidation, demethylation, and subsequent acetylation. Other main metabolites of metamizole are 4-aminoantipyrine (4-AA), 4-formylaminoantipyrine (4-FAA), and 4-acetylaminoantipyrine (4-AcAA). A study of the properties of the four main metabolites of metamizole showed that the antipyretic, analgesic, and anti-inflammatory effects of the drug may be due to the metabolites 4-MAA and 4-AA.

Excretion

In healthy men, more than 90% of the drug dose administered intravenously is excreted in the urine within 7 days. The T_1/2 of radioisotope-labeled metamizole is about 10 hours. For 4-MAA, the terminal T_1/2 values for different routes of administration range from 2.5±0.06 to 3.2±0.8 hours, while for other metabolites, T_1/2 ranges from 3.7 to 11.2 hours.

Linearity/non-linearity

All metabolites of metamizole are characterized by non-linear pharmacokinetics. The clinical significance of this fact has not been established. With a short course of treatment, the accumulation of metabolites is minimal.

Pharmacokinetics in special patient groups

Elderly patients. In healthy elderly volunteers, the T_1/2 of 4-MAA was significantly longer, and the clearance of 4-MAA was significantly lower than in young individuals.

Pediatric patients. The excretion of metabolites in children occurs significantly faster than in adults.

Hepatic impairment. In patients with impaired liver function, the T_1/2 of 4-MAA and 4-FAA increases approximately 3-fold. Therefore, patients with impaired liver function should avoid the use of the drug in high doses.

Renal impairment. In cases of impaired renal function, the excretion rate of some metabolites (4-AcAA, 4-FAA) is reduced. Therefore, patients with impaired renal function should avoid the use of the drug in high doses.

Indications

• Severe acute or chronic pain syndrome in trauma and in the postoperative period, in colic, oncological diseases, and other conditions when other therapeutic measures are contraindicated;
• Fever resistant to other treatments.

ICD codes

Dosage Regimen

Intravenous, intramuscular deep into the muscle.

Parenteral administration of the drug is indicated only when oral administration is not possible.

Before administration, it is recommended to warm the drug to body temperature.

Adults and adolescents over 15 years of age are recommended a single dose of 1-2 ml (500-1000 mg) of metamizole solution (IM or IV). The maximum single dose is 1000 mg (2 ml). The maximum daily dose is 4 ml (2000 mg), divided into 2-3 administrations.

Children aged 3-11 months (body weight from over 5 kg to 9 kg) the drug is administered only intramuscularly at a dose of 50-100 mg per 10 kg of body weight (0.1-0.2 ml of 500 mg/ml solution). The single dose can be divided into 2-3 administrations.

The following table contains the recommended doses of the drug

Intravenous administration should be performed very slowly (injection rate not exceeding 1 ml/min) with the patient in a lying position, under blood pressure control. At the first signs of anaphylactic/anaphylactoid reactions, administration of the drug must be stopped.

Since hypotensive reactions are dose-dependent, parenteral administration of a 1000 mg dose of metamizole should be performed with particular caution.

If the drug is administered too quickly, a critical decrease in blood pressure and shock may be observed.

Special patient groups

Elderly patients should use the drug in lower doses due to the possible reduction in the excretion of metamizole metabolites from the body.

Patients in severe condition and with impaired renal function should use the drug in lower doses due to the possible reduction in the excretion of metamizole metabolites from the body.

In patients with impaired liver and kidney function, the excretion rate of the drug is slowed, so repeated use of the drug should be avoided. There is no experience with long-term use. For short-term therapy, dose adjustment is not required.

Duration of treatment

When used as an analgesic, the duration of treatment is 1-5 days. When used as an antipyretic – 1-3 days.

Adverse Reactions

Adverse reactions are classified by frequency and by system-organ class. Frequency according to MedDRA is defined as follows: very common (≥1/10), common (≥1/100, <1/10), uncommon (≥1/1000, <1/100), rare (≥1/10000, <1/1000), very rare (<1/10000) and frequency not known (cannot be estimated from the available data).

Cardiac disorders frequency not known – Kounis syndrome (allergic angina or allergic myocardial infarction).

Vascular disorders uncommon – during or after drug administration, isolated transient hypotensive reactions may develop (possibly pharmacologically determined and not accompanied by other manifestations of anaphylactic/anaphylactoid reactions); in rare cases – a sharp decrease in blood pressure. Rapid intravenous administration of the drug increases the risk of such hypotensive reactions.

Immune system disorders rare – anaphylactic or anaphylactoid reactions, which can be severe and life-threatening; in some cases, anaphylactic reactions can be fatal. In case of development of anaphylactic/anaphylactoid reactions, it is necessary to immediately stop the administration of the drug, provide emergency medical care to the patient, and perform a complete blood count. These reactions can occur even if the drug has been used repeatedly before without any complications. Such drug reactions can develop during the injection of sodium metamizole or several hours after its administration, but they are usually observed within one hour after drug administration.

Usually, milder anaphylactic and anaphylactoid reactions manifest as skin and mucous membrane symptoms (itching, burning, redness, urticaria, swelling), shortness of breath, or gastrointestinal complaints. Milder reactions can progress to severe forms with the development of generalized urticaria, severe angioedema (especially involving the larynx), severe bronchospasm, cardiac arrhythmias, a sharp decrease in blood pressure (sometimes preceded by an increase in blood pressure) and the development of hemodynamic shock.

Very rare – in patients with a complete or incomplete combination of bronchial asthma, recurrent nasal and sinus polyposis and intolerance to acetylsalicylic acid or other NSAIDs (including in the anamnesis) intolerance reactions usually manifest as asthma attacks. Frequency not known – anaphylactic shock.

Skin and subcutaneous tissue disorders uncommon – in addition to the manifestations of anaphylactic/anaphylactoid reactions on the skin and mucous membranes listed above, fixed drug eruption may occur infrequently; rare – skin rash; very rare – Stevens-Johnson syndrome or Lyell’s syndrome (toxic epidermal necrolysis).

Blood and lymphatic system disorders rare – leukopenia; very rare – agranulocytosis (including fatal cases), thrombocytopenia; frequency not known – aplastic anemia, pancytopenia (including fatal cases). These reactions are immunological in nature. They can occur even if the drug has been taken repeatedly before without any complications.

Typical symptoms of agranulocytosis are lesions of the mucous membranes (oral cavity and pharynx, anorectal area and genitals), sore throat, fever (including persistent fever of unknown origin or recurrent fever). It should be considered that if the patient is receiving antibiotic therapy, the typical manifestations of agranulocytosis may be minimal. The erythrocyte sedimentation rate increases significantly, while the enlargement of lymph nodes is mild or absent.

Typical symptoms of thrombocytopenia are increased bleeding tendency and the appearance of petechiae on the skin and mucous membranes.

In case of development of the above blood and lymphatic system disorders, it is necessary to stop the use of the drug and perform a complete blood count (see “Special Precautions”).

General disorders and administration site conditions uncommon – pain and local reactions (redness) may occur at the injection site; very rare – phlebitis.

Renal and urinary disorders uncommon – red discoloration of urine is possible due to the presence of the metabolite – rubazonic acid in the urine; very rare – acute deterioration of renal function (acute renal failure) is possible, especially in patients with kidney disease, in some cases with oliguria, anuria or proteinuria; in isolated cases, acute interstitial nephritis may develop.

Gastrointestinal disorders cases of gastrointestinal bleeding have been reported.

Contraindications

• Hypersensitivity to sodium metamizole and other excipients, as well as to other pyrazolones (phenazone, propyphenazone, isopropylaminophenazone) or to pyrazolidines (phenylbutazone, oxyphenbutazone) including, for example, a history of agranulocytosis development when using one of these drugs;
• Impaired bone marrow hematopoiesis (e.g., after treatment with cytotoxic drugs) or diseases of the hematopoietic system;
• History of bronchospasm or other anaphylactic reactions (e.g., urticaria, rhinitis, angioedema) when using analgesic drugs such as salicylates, paracetamol, diclofenac, ibuprofen, indomethacin, naproxen;
• Acute intermittent hepatic porphyria (risk of porphyria exacerbations);
• Arterial hypotension, hemodynamic instability;
• Congenital glucose-6-phosphate dehydrogenase deficiency (risk of hemolysis);
• I and III trimesters of pregnancy;
• Breastfeeding period;
• Children under 3 months of age or with body weight less than 5 kg (insufficient scientific data on the use of the drug in this group of children);
• Children aged 3 to 12 months (only for intravenous administration).

With caution

• In cases of reduced circulating blood volume, incipient heart failure, high fever (increased risk of a sharp decrease in blood pressure);
• In diseases where a significant decrease in blood pressure may pose an increased danger (patients with severe coronary artery disease and significant stenosis of cerebral arteries);
• In alcoholism;
• In cases of increased risk of developing severe anaphylactic/anaphylactoid reactions in patients with:
  • Bronchial asthma, especially in combination with concomitant polypous rhinosinusitis;
  • Chronic urticaria and other types of atopy (allergic diseases in the development of which a hereditary predisposition to sensitization plays a significant role – hay fever, allergic rhinitis, etc.) (increased risk of developing anaphylactic/anaphylactoid reactions);
  • Alcohol intolerance (reaction even to small amounts of certain alcoholic beverages with symptoms such as itching, lacrimation and pronounced facial redness);
  • Intolerance to dyes (e.g., tartrazine) or preservatives (e.g., benzoate).
• In severe impairment of liver and kidney function (low doses are recommended due to the possibility of slowed excretion of sodium metamizole);
• In the II trimester of pregnancy.

Use in Pregnancy and Lactation

Pregnancy

There are no data on the negative effect of metamizole on the fetus: in rats and rabbits, metamizole did not have a teratogenic effect, and a toxic effect on the fetus was observed only at high doses toxic to the mother’s body. However, clinical data on the use of Metamalgin during pregnancy are insufficient.

Metamizole crosses the placental barrier.

In the first trimester of pregnancy, the use of Metamalgin is contraindicated. In the second trimester of pregnancy, treatment with the drug should be carried out for strict medical reasons, if the expected benefit to the mother outweighs the potential risk to the fetus. The use of the drug in the third trimester of pregnancy is also contraindicated. This is due to the fact that although metamizole is a weak inhibitor of prostaglandin synthesis, it is impossible to completely exclude the possibility of premature closure of the arterial (Botallo’s) duct and complications in the perinatal period associated with impaired platelet aggregation in the mother and newborn.

Breastfeeding period

Metamizole metabolites pass into breast milk. Breastfeeding is not allowed during treatment with Metamalgin and for 48 hours after the last administration of the drug.

Use in Hepatic Impairment

The drug should be prescribed with caution in cases of severe liver dysfunction.

Use in Renal Impairment

The drug should be prescribed with caution in cases of severe kidney dysfunction.

Pediatric Use

The use of the drug is contraindicated in children under 3 months of age or with a body weight of less than 5 kg.

Intravenous administration is contraindicated in children aged 3 to 12 months.

Geriatric Use

Elderly patients should use the drug in lower doses due to the possible reduction in the excretion of metamizole metabolites from the body.

Special Precautions

When treating patients receiving cytotoxic agents and children under 5 years of age, treatment with sodium metamizole should be carried out only under medical supervision.

Anaphylactic/anaphylactoid reactions

When choosing the route of administration of the drug, it should be taken into account that parenteral administration is associated with a higher risk of anaphylactic/anaphylactoid reactions.

The following conditions increase the risk of developing anaphylactic/anaphylactoid reactions to Metamizole sodium

• analgesic-induced bronchial asthma;
• analgesic intolerance manifested as urticaria or angioedema;
• Complete or incomplete combination of bronchial asthma, recurrent nasal and sinus polyposis, and intolerance to acetylsalicylic acid or other NSAIDs (including in the medical history);
• chronic urticaria;
• alcohol intolerance (hypersensitivity to alcohol), where even small amounts of certain alcoholic beverages cause patients to experience sneezing, tearing, and pronounced facial redness. Alcohol intolerance may indicate a previously undiagnosed syndrome of analgesic-associated bronchial asthma (aspirin asthma);
• intolerance or hypersensitivity to dyes (e.g., tartrazine) or to preservatives (e.g., benzoates);
• History of anaphylactic or other immunological reactions to other pyrazolones, pyrazolidines, and other non-narcotic analgesics (see the “Contraindications” section).

Before using Metamalgin, a thorough patient interview must be conducted. If it is determined that the patient belongs to a special risk group for developing anaphylactoid reactions, the drug should be prescribed only after careful weighing of potential risks and expected benefits. If a decision is made to use Metamalgin in such patients, strict medical monitoring of their condition is required, and means for providing emergency care in case of anaphylactic/anaphylactoid reactions must be available.

Anaphylactic shock may occur in predisposed patients; therefore, Metamizole sodium should be prescribed with caution to patients with asthma or atopy.

Severe skin reactions

Life-threatening skin reactions such as Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) have been reported with the use of sodium metamizole. If symptoms of SJS or TEN appear (such as a progressive skin rash, often with blisters or mucosal lesions), treatment with sodium metamizole should be discontinued immediately. Re-treatment with the drug is strictly prohibited.

Patients should be informed about the subjective and objective symptoms of these conditions. Skin reactions should be carefully monitored, especially during the first weeks of treatment.

Agranulocytosis

Agranulocytosis developing during treatment with metamizole is of immunoallergic origin and lasts for at least one week. Such a reaction is very rare, can be severe, life-threatening, and even fatal. This reaction is not dose-dependent and can occur at any time during treatment.

All patients must be instructed to discontinue the drug and immediately consult their physician if the following subjective and objective symptoms, possibly associated with neutropenia, appear: fever, chills, sore throat, mouth ulcers. If neutropenia develops (neutrophil count <1500 per mm³), treatment must be stopped immediately, a complete blood count must be urgently performed, and blood composition monitoring must continue until the blood cell counts return to normal.

Pancytopenia

If pancytopenia develops, treatment should be stopped immediately, and complete blood count parameters must be monitored until they normalize.

All patients must be instructed to seek immediate medical attention if subjective or objective symptoms suggesting blood disorders (e.g., general malaise, infections, persistent fever, bruising, bleeding, pallor) appear during treatment with metamizole.

Isolated hypotensive reactions

Administration of sodium metamizole can cause isolated hypotensive reactions. These reactions may be dose-dependent and occur more frequently after parenteral administration. To avoid the development of severe hypotensive reactions, the following recommendations must be observed:

• Intravenous administration of the drug should be performed slowly;
• Patients with existing hypotension, reduced blood volume, dehydration, hemodynamic instability, or the initial stage of circulatory failure require prior hemodynamic stabilization;
• Caution should be exercised when treating patients with high body temperature.

In such patients, the indications for using metamizole should be evaluated with particular care, and if Metamalgin is administered under such circumstances, careful medical supervision must be ensured. Preventive measures (hemodynamic stabilization) may be required to reduce the risk of hypotensive reactions.

In patients who must avoid a decrease in blood pressure, such as those with severe coronary artery disease or stenoses of cerebral blood vessels, the use of Metamalgin is permitted only with careful monitoring of hemodynamic parameters.

Acute abdominal pain

The drug must not be used to relieve acute abdominal pain (until its cause is determined).

Impaired liver and kidney function

In patients with impaired liver or kidney function, Metamalgin should be used only after consulting a doctor, as these patients have a reduced rate of drug elimination.

Effect on laboratory test results

Changes in the results of laboratory tests using the Trinder reaction and similar reactions (e.g., analysis of serum creatinine, triglycerides, HDL cholesterol, and uric acid concentrations) have been recorded in patients treated with metamizole.

Effect on the ability to drive vehicles and machinery

There is no evidence that the drug, when used in recommended doses, has an undesirable effect on concentration and reaction speed. However, during therapy with high doses of the drug, the possibility of impaired concentration and reduced reaction speed should be taken into account, which may pose a risk in situations where these abilities are particularly important (e.g., driving a car or operating machinery), especially when combined with alcohol consumption.

Overdose

Symptoms

Overdose may cause the following symptoms: nausea, vomiting, abdominal pain, decreased kidney function/acute renal failure with oliguria (e.g., due to interstitial nephritis), less frequent CNS symptoms (dizziness, somnolence, coma, seizures), and a sharp decrease in blood pressure (sometimes progressing to shock), as well as cardiac arrhythmia (tachycardia). After administration of very high doses, the renal excretion of the non-toxic metabolite (rubazonic acid) may cause red discoloration of urine.

Treatment

There is no specific antidote for sodium metamizole. The main metabolite of metamizole (4-N-methylaminoantipyrine) is removed by hemodialysis, hemofiltration, hemoperfusion, or plasma filtration. If a seizure syndrome develops – intravenous administration of diazepam and fast-acting barbiturates.

Drug Interactions

With cyclosporine

Metamizole sodium may reduce serum cyclosporine concentrations; therefore, cyclosporine concentrations should be monitored when used concomitantly.

With other non-narcotic analgesics

Concomitant use of sodium metamizole with other non-narcotic analgesics may lead to mutual enhancement of toxic effects.

With tricyclic antidepressants, oral contraceptives, allopurinol

Tricyclic antidepressants, oral contraceptives, and allopurinol impair the hepatic metabolism of sodium metamizole and increase its toxicity.

With barbiturates, phenylbutazone, and other inducers of hepatic microsomal enzymes

Barbiturates, phenylbutazone, and other inducers of hepatic microsomal enzymes weaken the effect of sodium metamizole.

With sedatives and tranquilizers

Sedatives and tranquilizers enhance the analgesic effect of sodium metamizole. Concomitant use of sodium metamizole and chlorpromazine may lead to severe hypothermia.

With drugs that have a high degree of plasma protein binding (oral hypoglycemic agents, indirect anticoagulants, glucocorticoids, and indomethacin)

Metamizole sodium, by displacing oral hypoglycemic drugs, indirect anticoagulants, glucocorticoids, and indomethacin from plasma protein binding sites, enhances their effects.

With myelotoxic drugs

Myelotoxic drugs enhance the hematotoxicity of sodium metamizole.

With methotrexate

Adding sodium metamizole to methotrexate treatment may enhance the hematotoxic effect of methotrexate, especially in elderly patients. Therefore, concomitant use of these drugs should be avoided.

With thiamazole and sarcolysin

Thiamazole and sarcolysin increase the risk of leukopenia.

With codeine, histamine H₂-receptor blockers, and propranolol

Codeine, histamine H₂-receptor blockers, and propranolol enhance the effects of sodium metamizole.

With radiocontrast agents, colloidal blood substitutes, and penicillin

Radiocontrast agents, colloidal blood substitutes, and penicillin should not be used during treatment with sodium metamizole (increased risk of anaphylactic/anaphylactoid reactions).

With acetylsalicylic acid

When used concomitantly, Metamizole sodium may reduce the effect of acetylsalicylic acid on platelet aggregation. Therefore, this combination should be used with caution in patients taking low doses of acetylsalicylic acid for cardioprotection (thrombosis prevention).

With CYP2B6 substrates

Metamizole is a weak inducer of CYP2B6. Concomitant use of metamizole with CYP2B6 substrates, such as bupropion and efavirenz, may lead to a decrease in the blood concentrations of these drugs, which should be taken into account.

Storage Conditions

The drug should be stored out of the reach of children at a temperature not exceeding 25°C (77°F).

Shelf Life

Shelf life is 3 years. Do not use after the expiration date.

Dispensing Status

The drug is dispensed by prescription.

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.