Spasmalgone®

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT SPASMALGON® (SPASMALGON®)

Composition:

Active substances: metamizole sodium monohydrate, pitophenone hydrochloride, fenpiverine bromide;

1 ml of injection solution contains: metamizole sodium monohydrate 500 mg; pitophenone hydrochloride 2 mg; fenpiverine bromide 0.02 mg;

Excipients: water for injections.

Pharmaceutical form. Injection solution.

Main physicochemical characteristics: clear liquid, almost free from particles.

Pharmacotherapeutic group.

Spasmolytics in combination with analgesics.

ATC code A03D A02.

Pharmacological Properties

Pharmacodynamics

Spasmalgone® is a combined medicinal product with pronounced spasmolytic and analgesic activity.

Metamizole has pronounced analgesic and antipyretic effects, combined with weaker anti-inflammatory and spasmolytic activity. Its effects result from inhibition of prostaglandin and endogenous algogen synthesis, elevation of excitation threshold in the thalamus, influence on the hypothalamus, and suppression of endogenous pyrogen formation.

Phenpiverine has moderately expressed ganglion-blocking and anticholinergic (cholinolytic) effects. It reduces the tone and motility of smooth musculature of the stomach, intestines, bile ducts, and urinary tract.

Pitofenone hydrochloride has a papaverine-like effect with pronounced spasmolytic activity on smooth muscle.

Pharmacokinetics

Absorption: After intramuscular administration, it is rapidly absorbed. Metamizole has a systemic bioavailability of approximately 85%.

Distribution: Metamizole is 50–60% bound to plasma proteins. It penetrates the blood-brain barrier and placental barrier. The volume of distribution is approximately 0.7 L/kg.

Metabolism: Metamizole undergoes intensive biotransformation in the liver. Its main metabolite, 4-methyl-amino-antipyrine (MAA), is further metabolized in the liver into other metabolites, including 4-amino-antipyrine (AA), which is pharmacologically active. Maximum plasma concentrations (for all metabolites) are reached approximately within 30–90 minutes.

Elimination: It is excreted by the kidneys in the form of metabolites, with only 3% of the administered metamizole excreted unchanged. The elimination half-life is approximately 10 hours.

Patients with hepatic impairment: The elimination half-life of the active metabolite MAA is prolonged by approximately threefold in patients with impaired liver function. These patients should be treated with lower doses of metamizole.

Patients with renal impairment: In patients with impaired renal function, reduced excretion of certain metabolites is observed. These patients should be treated with lower doses of metamizole.

Clinical characteristics.

Indications.

For short-term symptomatic treatment of pain syndrome due to smooth muscle spasms of internal organs:

• Gastric and intestinal colic;
• Renal colic in urolithiasis;
• Spastic biliary dyskinesia;
• Dysmenorrhea.

Contraindications.

Hypersensitivity to active substances, to pyrazolone derivatives, or to other nonsteroidal anti-inflammatory drugs (NSAIDs).

Agranulocytosis in history induced by metamizole, other pyrazolones or pyrazolidines.

Severe impairment of liver and kidney function.

Acute hepatic porphyria.

Glucose-6-phosphate dehydrogenase deficiency.

Gastrointestinal obstruction and megacolon.

Bone marrow dysfunction (e.g., after cytostatic therapy) or hematopoietic system disorders (leukopenia, anemia of any etiology, including aplastic anemia, infectious neutropenia).

Prostate adenoma grade II and III.

Atony of gallbladder and urinary bladder.

Suspicion of surgical pathology.

Hypotensive conditions and hemodynamic instability.

Collapse-like states.

Tachyarrhythmia.

Closed-angle glaucoma.

Bronchial asthma.

Interaction with other medicinal products and other types of interactions.

Combining Spazmalgon® with other medicinal products requires special caution due to the presence of metamizole, which is a hepatic enzyme inducer.

Alcohol intake should be avoided during treatment, as mutual potentiation of effects is possible.

Coumarin anticoagulants. When used concomitantly, metamizole may reduce the activity of coumarin anticoagulants due to induction of hepatic enzymes.

Chlorpromazine and other phenothiazine derivatives. When used concomitantly with metamizole, there is a risk of developing severe hypothermia.

Cyclosporine. Metamizole decreases plasma levels of cyclosporine when used concomitantly.

Chloramphenicol and other myelotoxic agents. When used concomitantly with metamizole, there is an increased risk of bone marrow suppression.

Enzyme inducers (barbiturates, glutethimide, phenylbutazone) may weaken the effect of metamizole.

Metamizole significantly increases maximum plasma concentrations of chloroquine.

CNS depressants, when combined with metamizole, enhance its analgesic effect.

Tricyclic antidepressants (psychophorin, amitriptyline), oral contraceptives, analgesics, allopurinol, and alcohol slow down the metabolism of metamizole, potentiate its effect when used concomitantly, and increase its toxicity.

Concomitant use with other analgesics and NSAIDs increases the risk of hypersensitivity reactions and other adverse effects.

Sedatives and tranquilizers enhance the analgesic effect of the drug.

Concomitant use of Spazmalgon® with quinine preparations may enhance the anticholinergic effect.

Spazmalgon® can be combined with hyoscine butylbromide, furosemide, glyburide.

For pyrazolone derivatives, it is known that they may interact with captopril, lithium, methotrexate, and triamterene, as well as alter the effectiveness of antihypertensive drugs and diuretics. To what extent metamizole causes these interactions is unknown.

Since metamizole may reduce the effect of certain drugs, Spazmalgon® should be used with caution when administered concomitantly with the following medicinal products:

• Bupropion – used for treatment of depression or as an aid for smoking cessation;
• Efavirenz – used for treatment of HIV/AIDS;
• Methadone – used for treatment of addiction to controlled substances (so-called opioids);
• Valproate – used for treatment of epilepsy or bipolar disorder;
• Tacrolimus – used to prevent organ rejection in transplant patients;
• Sertraline – used for treatment of depression.

Special precautions for use.

There is a risk of developing anaphylactic reactions during treatment with Spazmalgon®. If the first signs of hypersensitivity occur, administration of the drug should be immediately discontinued and emergency measures should be taken to control the condition (adrenaline, glucocorticoids, antihistamine drugs).

The risk of hypersensitivity reactions (anaphylactoid reactions) with metamizole use is significantly increased in patients with:

• food or drug hypersensitivity or atopic diseases (e.g., hay fever);
• analgesic asthma syndrome or analgesic idiosyncrasy presenting as urticaria, angioedema, especially in the presence of concomitant rhinosinusitis and nasal polyps;
• chronic urticaria;
• idiosyncrasy to dyes (e.g., tartrazine) or preservatives (e.g., benzoates);
• alcohol intolerance. Such patients react to even minimal amounts of alcoholic beverages with symptoms such as sneezing, lacrimation, and severe visual disturbances. This type of alcohol intolerance may indicate undiagnosed analgesic asthma syndrome.

Severe skin reactions, including Stevens-Johnson syndrome, toxic epidermal necrolysis, and drug-induced eosinophilia with systemic symptoms (DRESS syndrome), which may be life-threatening or fatal, have been reported during treatment with metamizole. Patients should be informed about the signs and symptoms of skin reactions and closely monitored. If signs or symptoms suggestive of these reactions occur, treatment with metamizole should be discontinued and must never be restarted (see section "Contraindications").

Spazmalgon® contains the active substance metamizole, which carries a small but life-threatening risk of shock during treatment.

The drug should be used with caution in patients with chronic alcoholism and in elderly patients, as this may lead to an increased frequency of adverse reactions, particularly those affecting the gastrointestinal system.

The drug should be used cautiously in patients receiving concomitant cytostatic agents (only under physician supervision).

Do not use for relief of acute abdominal pain.

When treating patients with hematological disorders or a history of such conditions with Spazmalgon®, a risk-benefit assessment must be performed and hematological status should be monitored during treatment.

The drug should be used with caution in patients with impaired renal function or a history of kidney diseases (e.g., pyelonephritis, glomerulonephritis).

In patients with kidney or liver diseases, the dosage regimen should be individually adjusted due to possible adverse effects of metamizole on the kidneys and prolonged elimination half-life of metamizole metabolites in case of impaired hepatocyte function.

The drug should be used with caution in patients with obstructive gastrointestinal disorders (e.g., achalasia, pyloroduodenal stenosis). Repeated administration of Spazmalgon® in such cases may lead to delayed gastrointestinal content evacuation and intoxication.

Use of Spazmalgon® in patients with gastroesophageal reflux disease, intestinal atony, inflammatory bowel diseases including ulcerative colitis and Crohn’s disease, glaucoma, myasthenia gravis, or cardiac diseases (arrhythmias, ischemic heart disease, congestive heart failure) requires special caution and physician supervision.

The drug should be used with caution in patients with myocardial infarction, marked arterial hypotension, and in patients with systolic blood pressure below 100 mm Hg.

Metamizole, included in the composition of Spazmalgon®, may cause hypotensive reactions. These reactions are dose-dependent and occur more frequently with parenteral administration. The risk of such reactions is increased in the following cases:

• in patients with pre-existing arterial hypotension, reduced fluid and electrolyte volume, or dehydration, unstable hemodynamics, or circulatory insufficiency (e.g., patients with myocardial infarction or polytrauma);
• in patients with elevated body temperature.

In such patients, careful evaluation of the need for drug use and strict monitoring are required. Preventive measures (e.g., circulatory stabilization) may be necessary to reduce the risk of arterial hypotension.

Spazmalgon® should be administered only with careful monitoring of hemodynamic parameters in patients in whom a drop in blood pressure must be avoided, such as those with severe ischemic heart disease or significant cerebral vessel stenosis.

Hepatitis has been observed in patients treated with metamizole, with symptoms appearing from several days to several months after the start of treatment.

If a patient develops symptoms suggestive of liver injury, such as nausea or vomiting, fever, fatigue, loss of appetite, dark urine, pale stools, jaundice of the skin or sclera, pruritus, rash, or upper abdominal pain, treatment with Spazmalgon® should be discontinued immediately and the patient should consult a physician. The physician should evaluate the patient’s liver function.

Spazmalgon® should not be used if the patient previously experienced liver injury during treatment with metamizole.

Spazmalgon® should be used only after strict assessment of benefit-risk ratio and appropriate precautionary measures in patients with impaired renal or liver function.

Do not exceed the recommended doses of the drug.

Use during pregnancy or breastfeeding.

Pregnancy. The use of the drug during pregnancy is contraindicated due to lack of clinical data.

Breastfeeding. Since metabolites of metamizole are excreted in breast milk, the drug should not be administered during breastfeeding. If use of the drug cannot be avoided, breastfeeding should be discontinued for 48 hours from the time of drug administration.

Ability to influence reaction rate while driving or operating machinery.

The active ingredient phenylpiperine bromide has anticholinergic effects and may cause dizziness and accommodation disturbances. Metamizole may adversely affect attention and impair reaction speed. Patients who drive vehicles or operate machinery should be warned about possible adverse effects of the drug. Activities requiring high attention should be suspended until adverse effects subside.

Dosage and Administration

Spazmalgon®, injection solution, must be used only intramuscularly! Use only for short-term treatment!

The injection solution should be administered under strict medical supervision due to the risk of anaphylactic shock in patients with hypersensitivity to metamizole or pyrazolone derivatives.

Adults and children aged 15 years and older

For adults and children aged 15 years and older (with body weight above 53 kg), administer 2 to 5 mL of injection solution intramuscularly. The dose may be repeated, if necessary, after 6–8 hours. The maximum daily dose must not exceed 6 mL of injection solution (equivalent to 3 g of sodium metamizole). Treatment duration: 2–3 days. After achieving therapeutic effect, treatment may be switched to oral analgesics and spasmolytics. If no therapeutic effect is observed, discontinue treatment with the drug.

Patients aged 65 years and older

Dosage reduction is usually not required. However, in patients with age-related hepatic or renal impairment, dosage should be reduced, as the elimination half-life of metamizole metabolites may be prolonged.

Patients with renal impairment

Metamizole is excreted in urine in the form of metabolites. In patients with mild to moderate renal impairment, it is recommended to use ½ of the adult dose.

Patients with hepatic impairment

In these patients, the elimination half-life of active metabolites of metamizole is prolonged. High doses should be avoided in patients with hepatic impairment. No dosage adjustment is required for short-term use.

There is insufficient experience with prolonged use in patients with renal or hepatic impairment.

Children

The drug must not be used for treatment of children under 15 years of age.

Overdose

Symptoms: Predominantly symptoms of metamizole intoxication in combination with anticholinergic manifestations. Most commonly observed are toxic-allergic syndrome, hematotoxicity, gastrointestinal disturbances, and central nervous system manifestations, including hypothermia, marked decrease in arterial blood pressure, palpitations, dyspnea, tinnitus, nausea, vomiting, gastralgia, weakness, oliguria, anuria, drowsiness, delirium, disturbances of consciousness, tachycardia, convulsive syndrome; acute agranulocytosis, hemorrhagic syndrome, acute renal and hepatic failure, and respiratory muscle paralysis may develop.

Treatment: Discontinue the drug and take measures to promote rapid elimination from the body (forced diuresis, infusion of saline solutions, hemodialysis if necessary). Apply symptomatic therapy. There is no specific antidote.

Side effects.

The adverse reactions listed below are mainly caused by metamizole, which is a component of the medicinal product.

Blood and lymphatic system disorders: leucopenia, agranulocytosis, thrombocytopenia, anaemia (haemolytic anaemia, aplastic anaemia).

Immune system disorders: anaphylactic shock, anaphylactic or anaphylactoid reactions, especially after parenteral administration. Such reactions may occur during administration or immediately after discontinuation of the drug, but may also appear several hours later. Usually they occur within the first hour after injection. Milder reactions manifest as typical skin and mucous membrane reactions (such as itching, burning, erythema, urticaria, oedema – local or general), dyspnoea, and rarely gastrointestinal complaints. Mild reactions may progress to more severe forms with generalized urticaria, severe angioedema (including laryngeal), severe bronchospasm, cardiac rhythm disturbances, and decreased blood pressure (sometimes preceded by increased blood pressure).

For this reason, if any hypersensitivity skin reaction, symptoms of impaired renal function, or haematotoxic reactions occur, the drug must be discontinued immediately.

Asthmatic attack (in patients with analgesic-induced asthma), circulatory shock. Shock may be accompanied by cold sweat, dizziness, drowsiness, altered consciousness, pallor, chest tightness, shallow or rapid breathing (tachypnoea), tachycardia, cold extremities, and a sharp drop in blood pressure. If the first signs of shock appear, treatment must be discontinued immediately and appropriate emergency measures taken.

Skin and subcutaneous tissue disorders: fixed drug eruption, maculopapular and other types of rashes, Lyell’s syndrome, angioneurotic oedema, decreased sweating. Severe skin reactions have been reported, including Stevens-Johnson syndrome, toxic epidermal necrolysis, and (with unknown frequency) drug-induced eosinophilia with systemic symptoms (DRESS), associated with the use of metamizole (see section "Special precautions").

If any skin reaction occurs, the use of metamizole must be discontinued immediately.

Nervous system disorders: dizziness, headache.

Sensory organ disorders (vision): visual disturbances, accommodation disorders.

Cardiovascular system disorders: palpitations, tachycardia, cardiac rhythm disturbances, cyanosis, arterial hypotension, hyperaemia. Hypotensive reactions may rarely occur during or after administration. They may or may not be accompanied by other symptoms of anaphylactoid or anaphylactic reactions. Rarely, such reactions may result from a sudden drop in blood pressure. Rapid intravenous administration increases the risk of hypotensive reactions.

Critical drop in blood pressure without other signs of hypersensitivity is dose-dependent and may occur in cases of hyperpyrexia.

Gastrointestinal disorders: dry mouth, nausea, vomiting, abdominal pain and discomfort, constipation, exacerbation of gastritis and peptic ulcer disease, rarely vomiting with blood and intestinal bleeding, ulcerations, burning sensation in the epigastric area.

Hepatobiliary disorders: drug-induced liver injury, including acute hepatitis, jaundice, elevated liver enzyme levels.

Renal and urinary system disorders: proteinuria, oliguria, anuria, polyuria, interstitial nephritis, red discoloration of urine, urinary retention, difficult urination, impaired kidney function.

Respiratory system disorders: bronchospasm.

General disorders and administration site conditions: following parenteral administration – asthenia, pain at injection site, and local reactions.

Shelf life. 3 years.

Storage conditions.

Keep out of reach and sight of children.

Store in the original packaging at a temperature not exceeding 25 °C. Do not freeze.

Incompatibilities.

The drug must not be mixed with other medicinal products in the same syringe.

Packaging.

2 ml or 5 ml of solution for injection in an ampoule. 5 or 10 ampoules in a blister. 1 blister pack in a cardboard box.

Prescription category. Prescription only.

Manufacturer.

JSC "Sofarma".

Manufacturer's name and address.

16 Iliensko Shose Str., Sofia, 1220, Bulgaria.