Pyralgin

Package leaflet: Information for the patient

Pyralgin, 500 mg/ml, solution for injection
Metamizolum natricum monohydricum
Pyralgin may cause abnormally low levels of white blood cells (agranulocytosis), which
can lead to severe and life-threatening infections (see section 4).
Treatment should be discontinued and immediate medical advice sought if any of the following
symptoms occur: fever, chills, sore throat, painful ulcers in the nose, mouth or throat, or in the genital or anal area.
If agranulocytosis has ever occurred in the patient during treatment with metamizole or similar
medicines, this medicine must never be used again in the future (see section 2).
Please read carefully all the information in this leaflet before using this medicine, as it contains
important information for the patient.

• Keep this leaflet, so that you can read it again if necessary.
• If you have any further questions, please consult your doctor, pharmacist or nurse.
• This medicine has been prescribed for a specific individual. Do not pass it on to others. It may harm other people, even if their symptoms are similar.
• If the patient experiences any adverse reactions, including any not listed in this leaflet, inform your doctor, pharmacist or nurse. See section 4.

Leaflet contents

1. What Pyralgin is and what it is used for
2. Important information before using Pyralgin
3. How to use Pyralgin
4. Possible side effects
5. How to store Pyralgin
6. Contents of the pack and other information

1. What Pyralgin is and what it is used for

Pyralgin contains metamizole sodium monohydrate, a pyrazolone derivative with analgesic, antipyretic and spasmolytic properties.
Indications:
Severe pain of various origins.
Fever when other treatment methods are ineffective.
Pyralgin solution for injection should only be used when oral administration is not appropriate.

2. Important information before using Pyralgin

When not to use Pyralgin:

• if the patient has previously experienced a significant decrease in the number of white blood cells called granulocytes caused by metamizole or other similar drugs known as pyrazolones or pyrazolidines;
• if the patient has impaired bone marrow function or a condition affecting the production or function of blood cells;
• if the patient is allergic to metamizole, other pyrazolone or pyrazolidine derivatives (e.g. propyphenazone, phenazone or phenylbutazone), or to any of the other ingredients of this medicine (listed in section 6);
• if the patient has analgesic-induced asthma syndrome or known intolerance to painkillers manifesting as urticaria, angioedema (swelling of the tongue, face, lips and/or throat), i.e. patients who react with bronchospasm or other anaphylactoid reactions to salicylates, paracetamol, or other non-opioid analgesics, including non-steroidal anti-inflammatory drugs (NSAIDs), such as: diclofenac, ibuprofen, indomethacin or naproxen;
• if the patient has acute renal or hepatic failure, or acute hepatic porphyria;
• if the patient has congenital glucose-6-phosphate dehydrogenase deficiency (a rare hereditary disease);
• if the patient is taking a medicine from the group of pyrazolone and pyrazolidine derivatives (e.g. phenylbutazone, propyphenazone);
• if the patient has low blood pressure and circulatory disorders;
• if the patient is in the last three months of pregnancy.

Warnings and precautions
Before starting treatment with Pyralgin, discuss this with your doctor or pharmacist:

• if the patient has systolic blood pressure below 100 mm Hg or has heart disease and circulatory disorders (e.g. myocardial infarction, coronary artery disease or multi-organ trauma), cerebral vessel constriction, reduced circulating blood volume, or is dehydrated, as the medicine may cause a drop in blood pressure;
• if the patient has high fever;
• if the patient has renal and/or hepatic impairment;
• if the patient has peptic ulcer disease of the stomach and/or duodenum;
• if the patient has bronchial asthma, particularly if associated with nasal and sinus mucosal polyps;
• if the patient has allergic diseases, including atopic conditions, chronic urticaria;
• if the patient has intolerance to certain dyes (e.g. tartrazine) or preservatives (e.g. benzoates);
• in patients with alcohol intolerance presenting with sneezing, lacrimation and intense facial flushing even after small amounts of alcohol; this may indicate previously unrecognized analgesic-induced asthma.

Due to the risk of life-threatening reactions, the medicine must be discontinued immediately and medical help sought if symptoms of an allergic (anaphylactic) reaction occur, such as:

• swelling of the face, lips, tongue and/or throat, which may cause difficulty in swallowing or breathing;
• severe bronchospasm;
• skin and mucous membrane changes such as itching, burning sensation, redness, urticaria;
• shock (decreased blood pressure, weakness, fainting). Patients who have shown an allergic or other immunological reaction to metamizole are also at risk of similar reactions to other pyrazolones and pyrazolidines, as well as other non-opioid analgesics. Anaphylactic shock may occur in patients with hypersensitivity. Therefore, particular caution is advised when using the medicine in patients with asthma or atopy (e.g. atopic dermatitis or mucosal inflammation, hay fever, allergic asthma). Patients at increased risk of reactions similar to severe hypersensitivity reactions to metamizole should only receive the medicine after careful benefit-risk assessment. If necessary, it should be administered under strict medical supervision with immediate access to emergency care.

Too rapid administration of metamizole, particularly by intravenous route, may cause anaphylactic shock.
The medicine must be discontinued immediately and medical advice sought if any of the following symptoms occur:

• thrombocytopenia, e.g.: skin and mucosal petechiae, bruising, recurrent bleeding from gums, nose, gastrointestinal tract;
• pancytopenia (marked reduction in all blood cells: red and white blood cells and platelets), e.g.: general malaise, fever, signs of infection, bruising, bleeding, pallor.

Low white blood cell count (agranulocytosis)
Pyralgin may cause agranulocytosis, i.e. a very low number of a type of white blood cells called granulocytes, which play an important role in fighting infections (see section 4).
Metamizole treatment must be stopped and medical advice sought immediately if any of the following symptoms occur, as they may indicate possible agranulocytosis: chills, fever, sore throat, and painful mucosal ulcers, especially in the mouth, nose, throat, or in the genital or anal areas.
The doctor will order laboratory tests to check the patient's blood cell count.
If metamizole is used for fever, some symptoms of developing agranulocytosis may remain unnoticed. Similarly, symptoms may also be masked if the patient is receiving antibiotics.
Agranulocytosis may develop at any time during treatment with Pyralgin, and even shortly after stopping metamizole.
Agranulocytosis may occur even if metamizole was previously administered without complications.

Severe skin reactions
Severe skin reactions have been reported during treatment with metamizole, including Stevens-Johnson syndrome: blisters and erosions on the skin, in the mouth, eyes and genital organs, fever and joint pain; toxic epidermal necrolysis (Lyell's syndrome): rupturing of large blisters, extensive skin erosions, peeling of large sheets of epidermis, and fever; drug reaction with eosinophilia and systemic symptoms (DRESS syndrome). If any of these symptoms related to severe skin reactions listed in section 4 occur, metamizole must be discontinued immediately and medical help sought.
If severe skin reactions occurred during previous treatment with metamizole, Pyralgin or any other medicine containing metamizole must never be taken again (see section 4).

Liver-related disorders
Cases of hepatitis have been reported in patients taking metamizole, with symptoms appearing from several days to several months after starting treatment.
Treatment with Pyralgin must be discontinued and medical advice sought if the patient develops liver-related symptoms such as: malaise (nausea or vomiting), fever, fatigue, loss of appetite, dark urine, pale stools, jaundice (yellowing of the skin or whites of the eyes), itching, rash, or upper abdominal pain. The doctor will check the patient's liver function.
The patient should not take Pyralgin if they have previously taken any medicine containing metamizole and experienced liver-related adverse effects.

Pyralgin and other medicines
Inform your doctor about all medicines currently used, recently used, or planned for use.
Concomitant use of Pyralgin is contraindicated:

• with medicines from the group of pyrazolone and pyrazolidine derivatives (phenylbutazone, propyphenazone).

Inform your doctor if the patient is taking:

• anticoagulants of the coumarin derivatives;
• oral antidiabetic medicines;
• phenytoin (antiepileptic medicine);
• sulfonamides (antibacterial agents);
• cyclosporine, tacrolimus (immunosuppressive medicines used, among others, to prevent transplant rejection);
• barbiturates (e.g. phenobarbital – used, among others, in epilepsy);
• monoamine oxidase inhibitors (e.g. selegiline, moclobemide – used, among others, in depression);
• chlorpromazine (used, among others, in schizophrenia treatment);
• lithium, sertraline (antidepressants);
• bupropion (used in depression treatment or as an aid in smoking cessation);
• antihypertensive medicines (e.g. captopril);
• diuretics (e.g. triamterene);
• methotrexate (used in cancer treatment);
• efavirenz (used in HIV (AIDS) infection treatment);
• methadone (used in treatment of addiction to illicit narcotic drugs (opioids));
• valproate (used in epilepsy or bipolar affective disorder treatment).

Metamizole may reduce the effect of acetylsalicylic acid on platelets.
Caution is advised when administering acetylsalicylic acid concomitantly for cardiovascular prevention.

Pyralgin and alcohol
Do not drink alcohol while taking this medicine.

Pregnancy, breastfeeding and fertility

If the patient is pregnant or breastfeeding, suspects she may be pregnant, or is planning to have a child, she should consult a doctor or pharmacist before using this medicine.

Pregnancy
Available data on the use of metamizole during the first three months of pregnancy are limited but do not indicate harmful effects on the embryo. In selected cases, if no other treatment options are available, after consultation with a doctor or pharmacist, single doses of metamizole may be taken during the first and second trimesters, provided that the benefit-risk balance is carefully considered. In principle, metamizole administration during the first and second trimesters is not recommended.
Pyralgin must not be taken during the last three months of pregnancy due to increased risk of complications for mother and child (bleeding, premature closure of a vital fetal blood vessel, the so-called ductus arteriosus Botalli, which normally closes only after birth).

Breastfeeding
Metamizole metabolites pass into breast milk in significant amounts, and risk to the breastfed infant cannot be excluded. Therefore, repeated use of metamizole during breastfeeding should be particularly avoided.
After a single dose of metamizole, mothers should be advised to collect and discard breast milk for 48 hours after administration of the medicine.

Fertility
No data are available on the effect of metamizole on fertility.

Driving and operating machinery
At the recommended dosage, this medicine does not affect the ability to drive or operate machinery.
However, when higher than recommended doses are used, especially in combination with alcohol, driving and operating machinery should be avoided, as reaction time and concentration may be impaired.

Pyralgin contains sodium
This medicine contains 34.5 mg of sodium per 1 ml. This corresponds to 1.7% of the maximum recommended daily sodium intake in the adult diet.
The medicine can be mixed with the following solutions: 5% glucose solution, 0.9% sodium chloride solution, Ringer's solution. The sodium content from the diluent should be taken into account when calculating the total sodium content in the prepared diluted solution. For precise information on the sodium content in the diluent used, refer to the package leaflet of the diluent.

3. How to use Pyralgin

This medicine should always be used according to the doctor's instructions. If in doubt, consult
your doctor.
Detailed dosage instructions, method of administration, and preparation of the medicine for use
are provided at the end of this leaflet under the section “Information intended exclusively for
healthcare professionals”.
Use of a higher than recommended dose of Pyralgin
If the patient suspects having received an excessive dose of Pyralgin, inform the doctor
immediately.
In case of overdose, symptoms such as dizziness, tinnitus, hearing disturbances, psychomotor
excitation, disturbances of consciousness, coma, tonic-clonic seizures, or decreased arterial
pressure may occur. Heart rhythm disorders (tachycardia) may also develop. Overdose of
metamizole may additionally cause abdominal pain, vomiting, erosions of the gastric and
duodenal mucosa, bleeding, perforations, liver cell damage, interstitial nephritis, and allergic
bronchospasm. Cases of skin rash, urticaria, edema, exfoliative dermatitis, and toxic epidermal
necrolysis (Lyell's syndrome) have been reported.
After ingestion of very high doses, excretion of rubazonic acid may cause red discoloration of
urine.
There is no specific antidote for metamizole.
In case of overdose, seek immediate medical advice. Symptomatic and supportive treatment
may be necessary.

4. Possible adverse reactions

Like all medicines, this medicine can cause adverse reactions, although not everyone will experience them.
Due to the risk of life-threatening reactions, the medicine must be discontinued immediately and medical help must be sought if the patient experiences any of the following severe adverse reactions:

• Severe allergic (anaphylactic) reactions:
  • rare swelling of the face, lips, tongue, and (or) throat, which may cause difficulty swallowing or breathing;
  • very rare severe bronchospasm;
  • skin and mucous membrane changes such as itching, burning, redness, urticaria;
  • anaphylactic shock (life-threatening drop in blood pressure, weakness, fainting) – frequency unknown;
• Severe skin reactions:
  • red, flat lesions on the trunk in the shape of target-like rings or circular rashes, often with blisters in the center, skin peeling, ulceration in the mouth, throat, nose, genital organs, and eyes. Such serious skin rashes may be preceded by fever and flu-like symptoms (Stevens-Johnson syndrome, toxic epidermal necrolysis);
  • widespread rash, high body temperature, and enlarged lymph nodes (DRESS syndrome or drug hypersensitivity syndrome).

The medicine must be discontinued immediately and a doctor must be consulted if any of the following severe adverse reactions occur:

• pancytopenia (marked decrease in all blood cells: red and white blood cells and platelets), manifesting as general malaise, fever, signs of infection, bruising, bleeding, and pale skin;
• agranulocytosis (complete or near-complete absence of granulocytes in the blood), including fatal cases, manifesting as:
  • fever, chills;
  • sore throat, difficulty swallowing, and inflammatory conditions of the mucous membranes of the mouth, nose, throat, genital organs, and rectum;
  • elevated ESR (erythrocyte sedimentation rate);
  • not always abnormal hemoglobin, erythrocyte, and platelet values, although they are usually within normal range;
  • slightly enlarged lymph nodes and spleen, although often unchanged (see also section 2 "Warnings and precautions");
• general malaise (nausea or vomiting), fever, feeling of fatigue, loss of appetite, dark-colored urine, pale stools, yellowing of the skin or whites of the eyes, itching, rash, or pain in the upper abdomen. These may be symptoms of liver damage. See also section 2 "Warnings and precautions".

Other adverse reactions:
Consult a doctor if any of the following adverse reactions occur:
Not common (occurring in less than 1 in 100 patients):

• drug rash (transient rash of various types: nodular, macular, pustular, erythematous);
• excessive decrease in blood pressure (rapid intravenous administration increases the risk of hypotension).

Rare (occurring in less than 1 in 1,000 patients):

• maculopapular skin changes;
• leukopenia (reduced number of white blood cells in the blood).

Very rare (occurring in less than 1 in 10,000 patients):

• analgesic-induced asthma (see section 2 "When not to use Pyralgin");
• asthma attacks;
• agranulocytosis (complete or near-complete absence of granulocytes in the blood), including fatal cases (see above "The medicine must be discontinued immediately and a doctor must be consulted if any of the following severe adverse reactions occur");
• thrombocytopenia (bruising, bleeding);
• sudden worsening of kidney function with proteinuria, oliguria, or anuria;
• acute kidney failure;
• interstitial nephritis.

Frequency unknown (frequency cannot be determined from available data):

• nausea, vomiting, abdominal pain, gastric irritation, diarrhea, dry mouth;
• liver damage;
• hepatitis, jaundice (yellowing of the skin and whites of the eyes), increased liver enzyme activity in blood;
• headache, dizziness;
• hemolytic anemia, aplastic anemia, bone marrow damage, sometimes leading to death. In patients with glucose-6-phosphate dehydrogenase deficiency, the medicine causes hemolysis of red blood cells;
• red discoloration of urine (after administration of very high doses of metamizole);
• after injection of metamizole, pain at the injection site and local reactions may occur, and in very rare cases, phlebitis.

Reporting of adverse reactions
If any adverse symptoms occur, including any adverse symptoms not listed in this leaflet, inform your doctor, pharmacist, or nurse. Adverse reactions can be reported directly to the Department of Monitoring Adverse Drug Reactions of the Office for Registration of Medicinal Products, Medical Devices and Biocidal Products
Al. Jerozolimskie 181C
02-222 Warsaw
Tel.: +48 22 49 21 301
Fax: +48 22 49 21 309
Website: https://smz.ezdrowie.gov.pl
Adverse reactions can also be reported to the marketing authorization holder.
Reporting adverse reactions helps to provide more information on the safety of the medicine.

5. How to store Pyralgin

Keep this medicine out of sight and reach of children.
Store below 25°C. Keep in the original packaging.
Do not use this medicine after the expiry date stated on the container.
The expiry date refers to the last day of the stated month.
The label on the packaging shows "EXP" followed by the expiry date and "Lot" followed by the batch number.
Medicines must not be disposed of via wastewater or household waste. Ask your pharmacist how to dispose of medicines no longer required. These measures help protect the environment.

6. Contents of the pack and other information

What Pyralgin contains

• The active substance is metamizole sodium monohydrate. Each ml of injection solution contains 500 mg of metamizole sodium monohydrate. Each 2 ml ampoule contains 1000 mg of metamizole sodium monohydrate. Each 5 ml ampoule contains 2500 mg of metamizole sodium monohydrate.
• The other ingredient is water for injections.

What Pyralgin looks like and contents of the pack
The immediate packaging of Pyralgin injection solution consists of colourless glass ampoules
with a capacity of 2 ml and 5 ml, containing a clear, colourless to slightly yellow solution.
The medicine is packed with 5 ampoules per cardboard box, together with the leaflet.
Marketing Authorisation Holder and Manufacturer
Zakłady Farmaceutyczne POLPHARMA S.A.
ul. Pelplińska 19, 83-200 Starogard Gdański
tel. + 48 22 364 61 01

Information intended exclusively for healthcare professionals:

The dose is determined by the intensity of pain or fever and the individual response to Pyralgin.
It is essential to select the lowest dose that provides adequate control of pain and (or) fever.
In children and adolescents up to 14 years of age, metamizole may be administered as a single dose of
8–16 mg per kg of body weight. In children with fever, a dose of metamizole of 10 mg per kilogram of body weight is usually sufficient.
Adults and adolescents aged 15 years and older (>53 kg) may receive a maximum single dose of 1000 mg.
Depending on the maximum daily dose, the single dose may be administered no more frequently than
4 times daily, at intervals of 6–8 hours.
Pronounced effects can be expected within 30 minutes after parenteral administration.
To minimize the risk of hypotensive reactions, intravenous injections must be administered very slowly.
The table below provides recommended single doses and maximum daily doses based on body weight or age:

*If necessary, the single dose may be increased to 5 ml (corresponding to 2500 mg of metamizole),
and the daily dose to 10 ml (corresponding to 5000 mg of metamizole).
Elderly persons, debilitated patients, and patients with reduced creatinine clearance
In elderly individuals, debilitated patients, and patients with reduced creatinine clearance, the dose should be reduced due to the possibility of prolonged elimination of metamizole metabolites from the body.
Hepatic and renal function disorders
In case of impaired renal or hepatic function, elimination rate is reduced; therefore, repeated administration of high doses should be avoided. There is no need to reduce the dose when the drug is used for a short period. Previous experience with long-term use of metamizole in patients with severe hepatic and renal impairment is insufficient.
Method of administration and precautions
To reduce the risk of anaphylactic shock and hypotensive reactions during intravenous administration, the following precautions should be observed:

• warm the solution to body temperature before administration;
• intravenous injection must be performed very slowly (500 mg/1 min).

The necessity of administering a dose higher than recommended above should be carefully considered, as the risk of dangerous drop in arterial blood pressure probably increases with increasing dose.
Having the patient in a lying position and continuous monitoring of blood pressure, heart rate, and respiratory rate facilitates early detection of anaphylactic, anaphylactoid, and hypotensive reactions.
Before intravenous administration, the drug may be diluted 1:10 (2 ml of drug in 20 ml, 5 ml of drug in 50 ml).
The drug may be diluted with:

• 5% glucose solution,
• 0.9% sodium chloride solution,
• Ringer's solution.

Since the stability of such mixtures is limited, they should be administered immediately after preparation. After dilution, a change and/or intensification of color towards yellow may occur, without altering the drug's properties. Metamizole should not be mixed with other drugs except for injection solutions containing tramadol 50 mg/ml.

Mixing with tramadol
It has been demonstrated that Pyralgin 500 mg/ml injection solution can be mixed with injection solutions containing tramadol 50 mg/ml (composition: tramadol hydrochloride, sodium acetate trihydrate, water for injections).
The tramadol and metamizole mixture should be prepared in a 1:10 mass ratio and diluted in the diluents mentioned above; for example, 2 ml of tramadol-containing solution (100 mg tramadol hydrochloride) and 2 ml of Pyralgin (1000 mg sodium metamizole monohydrate) diluted in 20 ml of 0.9% sodium chloride solution, Ringer's solution, or 5% glucose solution. The ready-to-use mixture of metamizole and tramadol may appear slightly yellowish after dilution.
From a microbiological standpoint, the resulting mixture should be used immediately. If the mixture is not used immediately, the responsibility for storage conditions and duration prior to use lies with the user.
Shelf life after first opening
Pyralgin should be used immediately after opening.
Shelf life after dilution
Pyralgin should be used immediately after dilution.
Duration of treatment
The duration of treatment depends on the type and severity of the disease.