Pyreoxing

Package leaflet: Information for the user

Pyreoxing, 500 mg/ml, solution for injection
Metamizolum natricum
Please read all of this leaflet carefully before use, as it contains important information for the patient.

• Keep this leaflet for future reference.
• If you have any further questions, please consult your doctor or pharmacist.
• This medicine has been prescribed for a specific individual. Do not give it to others. This medicine may harm someone else, even if their symptoms are the same.
• If you experience any adverse reactions, including any not listed in this leaflet, inform your doctor or pharmacist. See section 4.

Pyreoxing may cause a low white blood cell count (agranulocytosis), which can lead to severe and
life-threatening infections (see section 4).
Treatment must be discontinued and medical advice should be sought immediately if any of the
following symptoms occur: fever, chills, sore throat, painful ulcers in the nose, mouth, throat, genital
area, or around the anus.
If the patient has ever experienced agranulocytosis while taking metamizole or similar medicines,
this medicine must never be used again in the future (see section 2).

Contents of the leaflet

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

1. What Pyreoxing is and what it is used for

Pyreoxing is a non-addictive analgesic (pain-relieving), antipyretic (fever-reducing), and spasmolytic (smooth muscle relaxant) medicine.
It is used to relieve severe acute pain and fever when other treatment methods are ineffective. The injectable solution formulation should only be used when oral administration is not appropriate.
Intravenous administration enables a very strong analgesic effect under various conditions, allowing control of pain that would otherwise only respond to opioid-containing products. Unlike opioids, Pyreoxing does not cause dependence or respiratory depression, even at high doses. Pyreoxing does not interfere with intestinal peristalsis or uterine contractions during childbirth.
It is indicated for the treatment of severe, sudden, or persistent pain and fever unresponsive to other treatments.
The active substance of Pyreoxing is metamizole.

2. Important information before using Pyreoxing

When not to use Pyreoxing

• If the patient is allergic to metamizole or any of the other ingredients of this medicine (listed in section 6), or to other similar active substances (e.g. phenazone, propyphenazone, phenylbutazone, oxyphenbutazone).
• If the patient has bone marrow dysfunction or a disease affecting the production or function of blood cells.
• If the patient has previously experienced a significant decrease in white blood cells called granulocytes, caused by metamizole or other similar medicines known as pyrazolones or pyrazolidines.
• If the patient currently has or has ever had asthma or allergic reactions to painkillers (salicylates, paracetamol, or other painkillers such as diclofenac, ibuprofen, indomethacin, naproxen), such as urticaria or so-called angioedema (facial swelling and swelling of the respiratory or gastrointestinal mucous membranes).
• If the patient has severe liver disease, i.e. porphyria (risk of porphyria attack).
• If the patient has congenital glucose-6-phosphate dehydrogenase deficiency (risk of hemolysis).
• During the last three months of pregnancy.
• If the patient has low blood pressure or circulatory problems.

Warnings and precautions
Before starting treatment with Pyreoxing, discuss the following with your doctor or pharmacist:

• If fever, chills, sore throat, or oral ulcers occur, treatment must be stopped immediately and medical advice sought. These symptoms may indicate neutropenia (extremely low levels of white blood cells called neutrophil granulocytes). This reaction is very rare, may be severe, and can be life-threatening. It is not dose-dependent and may occur at any time during treatment. If neutropenia occurs (neutrophil granulocyte count of 1,500 per microlitre of blood or less), treatment must be stopped immediately.

• If any symptoms suggesting blood disorders occur (e.g. general weakness, infection, persistent fever, bruising, bleeding, pallor), seek medical attention immediately. These symptoms may be due to pancytopenia (reduction in all types of blood cells).

• If the patient has bronchial asthma or atopy (a type of allergy), there is an increased risk of anaphylactic shock (a life-threatening allergic reaction) after administration of metamizole, especially when given by injection.

• If the patient has any of the following conditions, due to an increased risk of severe anaphylactoid reactions after metamizole administration:

  • Bronchial asthma and coexisting mucosal inflammation;
  • Chronic and/or persistent urticaria;
  • Alcohol intolerance, manifesting as sneezing, lacrimation, and marked facial flushing after even small amounts of alcoholic beverages;
  • Hypersensitivity to dyes (e.g. tartrazine) or preservatives (e.g. benzoates).

• If the patient has low blood pressure or is dehydrated, has unstable body fluid volume, early-stage circulatory failure, or high fever. In such cases, there is an increased risk of severe hypotensive reactions (reactions related to a drop in blood pressure). Therefore, administration of metamizole should be carefully considered, and if used, strict medical supervision is required. Preventive measures must be taken to reduce the risk of hypotensive reactions. Metamizole administration may cause hypotensive reactions unrelated to the above conditions. These reactions appear to be dose-dependent and are more likely after intravenous or intramuscular injection.

• If the patient has severe coronary artery disease or significant narrowing of blood vessels supplying the brain. In such cases, lowering blood pressure must be strictly avoided; therefore, metamizole should only be administered after careful monitoring of circulatory function.

• If the patient has kidney or liver disease. In such cases, high doses of metamizole should not be administered, as its elimination is reduced.

• If the patient has previously taken any medicine containing metamizole and experienced liver problems.

Liver problems
Cases of hepatitis have been observed in patients taking metamizole, with symptoms appearing from several days to several months after starting treatment. Treatment with Pyreoxing should be discontinued and medical advice sought if symptoms of liver dysfunction occur, such as 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 assess liver function.
Pyreoxing should not be used if the patient previously took any medicine containing metamizole and experienced liver-related adverse effects.

Severe skin reactions
Severe skin reactions have been reported with metamizole treatment, including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and drug reaction with eosinophilia and systemic symptoms (DRESS). If any of these symptoms associated with severe skin reactions (described in section 4) occur, metamizole must be discontinued immediately and urgent medical attention sought.
Pyreoxing must not be restarted under any circumstances if the patient has ever experienced severe skin reactions (see section 4).

Abnormally low white blood cell count (agranulocytosis)
Pyreoxing 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 should be discontinued and medical advice sought immediately if the following symptoms occur, as they may indicate possible agranulocytosis: chills, fever, sore throat, and painful mucosal ulcers, especially in the mouth, nose, throat, genital area, or anus. The doctor will order laboratory tests to check blood cell counts.
If metamizole is used for fever, some symptoms of developing agranulocytosis may go unnoticed. Similarly, symptoms may also be masked if the patient is receiving antibiotics.
Agranulocytosis may develop at any time during treatment with Pyreoxing, and even shortly after discontinuation of metamizole.
Agranulocytosis may occur even if metamizole was previously administered without complications.

Pyreoxing with other medicines
Inform your doctor or pharmacist about all medicines currently used, recently used, or planned for use.
Metamizole may reduce the effectiveness of certain medicines:

• Bupropion, used to treat depression or as an aid in smoking cessation;
• Efavirenz, used to treat HIV/AIDS infection;
• Methadone, used to treat addiction to illegal opioids;
• Valproate, used to treat epilepsy or bipolar affective disorder;
• Tacrolimus, used to prevent organ transplant rejection;
• Sertraline, used to treat depression;
• Cyclosporine, an immunosuppressant.

The doctor should carefully monitor whether the patient is taking metamizole concurrently with any of the above medicines.
Adding metamizole to methotrexate (an immunosuppressive drug) may enhance methotrexate’s toxic effects on the blood-forming system, particularly in elderly patients. Concurrent use of these drugs should be avoided.
Caution is advised when using Pyreoxing together with aspirin taken to prevent cardiovascular events.

Pregnancy and breastfeeding
If the patient is pregnant or breastfeeding, suspects she may be pregnant, or is planning a pregnancy, she should consult her doctor or pharmacist before using this medicine.

Pregnancy
Available data on metamizole use during the first three months of pregnancy are limited but do not indicate harmful effects on the fetus. In selected cases, when no other treatment options are available, after consultation with a doctor or pharmacist, single doses of metamizole may be used during the first and second trimesters of pregnancy, provided that the benefits and risks are carefully weighed. However, metamizole is generally not recommended during the first and second trimesters of pregnancy.
Pyreoxing must not be used during the last three months of pregnancy due to increased risk of complications for both mother and child (bleeding, premature closure of the fetal arterial duct, i.e. the so-called Botall’s duct, which normally closes 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 are advised to express and discard breast milk for 48 hours after taking the medicine.

Driving and operating machinery
At the recommended dosage, this medicine does not affect the ability to drive or operate machinery.
However, using Pyreoxing at doses higher than recommended and consuming alcohol simultaneously may impair reaction time and concentration. In such cases, driving or operating machinery should be avoided.

Pyreoxing contains sodium
This medicine contains 32.7 mg of sodium (the main component of table salt) per millilitre of injection solution, equivalent to 1.63% of the maximum recommended daily dietary sodium intake for adults.

3. How to use Pyreoxing

This medicine should always be used as directed by a physician or pharmacist. If in doubt, consult a
physician or pharmacist.
The dose depends on the severity of pain or fever and on the individual patient's sensitivity to
Pyreoxing. Pyreoxing will be administered as an intravenous or intramuscular injection. Onset of
effect occurs about 30 minutes after administration, and the duration of action is usually approximately 4 hours.
If the analgesic effect after a single dose is insufficient, or if the effect wears off after some time, the
physician may administer another dose, without exceeding the maximum daily dose listed in the table below.
Adults and adolescents aged 15 years and above
For adults and adolescents aged 15 years and above (with body weight exceeding 53 kg), the medicine may
be administered intravenously or intramuscularly as a single dose of 1–2 ml; if necessary, the single
dose may be increased up to 5 ml (corresponding to 2500 mg of Pyreoxing). The maximum daily dose
is 8 ml; if necessary, the daily dose may be increased to 10 ml (corresponding to 5000 mg of
Pyreoxing).
Infants and children
The following scheme should be followed for administration of single intravenous or
intramuscular doses:

Elderly patients and patients in poor general condition and (or) with impaired renal function
In elderly, debilitated patients and those with impaired renal function, the dose should be reduced due to the possibility of prolonged elimination of metamizole metabolites.
Patients with impaired renal or hepatic function
Since elimination rate is reduced in patients with impaired renal or hepatic function, repeated administration of high doses should be avoided, as drug elimination is slowed in these patients. Dose reduction is not required for short-term use. There are no available data regarding long-term use of the medicinal product.
It is important that the patient remains under physician supervision during injection and is closely monitored after administration of the drug.
Use of a higher than recommended dose of Pyreoxing
The drug is administered by a physician; therefore, overdose is unlikely.
Symptoms of acute overdose include nausea, vomiting, abdominal pain, impaired renal function and (or) renal failure, disturbances of the nervous system (dizziness, drowsiness, coma, convulsions), hypotension and cardiac arrhythmias. Very high doses may cause harmless discoloration of urine to red color.
Missed dose of Pyreoxing
A double dose should not be administered to make up for a missed dose.
If you have any further questions concerning use of this medicinal product, consult your physician or pharmacist.

4. Possible adverse effects

Like all medicines, this medicinal product can cause adverse effects, although not everyone experiences them.
Adverse effects are listed below by frequency according to the following convention: 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); frequency not known (frequency cannot be estimated from the available data).

Discontinue use of Pyreoxing and contact your doctor immediately if any of the following symptoms occur:
nausea or vomiting, fever, feeling of fatigue, loss of appetite, dark urine, pale stools, yellowing of the skin or whites of the eyes, itching, rash, or pain in the upper abdomen. These symptoms may indicate liver damage. See also section 2 "Warnings and precautions".

Discontinue metamizole and immediately consult a doctor if any of the following adverse effects occur (frequency not known):

• Reddish, flat, disc-shaped or circular skin lesions on the trunk, often with blisters in the center, skin peeling, and mucosal ulcers in the mouth, throat, nose, genital organs, or eyes. These severe skin reactions may be preceded by fever and influenza-like symptoms (Stevens-Johnson syndrome; toxic epidermal necrolysis);
• Widespread rash, high body temperature, and swollen lymph nodes (DRESS syndrome or drug hypersensitivity syndrome).

Blood and lymphatic system disorders
Rare: disorders of the haematopoietic system may occur, including reduced number of red blood cells due to bone marrow suppression (aplastic anaemia), reduction or absence of one type of white blood cells (agranulocytosis), and reduced number of red blood cells, white blood cells, and platelets (pancytopenia), including cases leading to death. Also includes reduced number of white blood cells (leukopenia) and thrombocytopenia (reduced number of platelets).
Very rare: typical symptoms of thrombocytopenia (reduced number of platelets) include increased tendency to bleeding and appearance of small reddish to brownish spots (petechiae) on the skin and mucous membranes. Symptoms of agranulocytosis (reduction or complete absence of one type of white blood cells in the blood) include inflammatory changes of mucous membranes, mainly in the oral cavity, nose, and throat, as well as inflammatory changes of the rectum and genital organs, sore throat, and fever (which unexpectedly does not subside or recurs). However, in patients treated with antibiotics, these symptoms may be mild. There is a significant increase in ESR (erythrocyte sedimentation rate), while lymph node enlargement is moderate or absent.

Immune system disorders
Rare: metamizole may cause allergic reactions (anaphylactic shock, anaphylactic and/or anaphylactoid reactions), which may be severe, even life-threatening, and sometimes lead to death. Such reactions may occur even if metamizole has previously been administered multiple times without complications. These reactions usually develop within the first hour after taking Pyreoxing, but may occur immediately or several hours later.
Moderate anaphylactic and/or anaphylactoid reactions may present with skin and mucous membrane symptoms (such as itching, burning, redness, urticaria, and swelling), respiratory problems, or rarely gastrointestinal complaints. However, these symptoms may progress to severe generalized urticaria, with severe cases characterized by swelling of the face, tongue, throat, or larynx (angioedema), severe dyspnoea, cardiac arrhythmias, low blood pressure (sometimes preceded by elevated blood pressure), and shock. In patients with bronchial asthma, these reactions may manifest as asthma attacks.
Frequency not known: Kounis syndrome (heart disease caused by an allergic reaction).

Vascular disorders
Frequency not known: transient, rarely critical, isolated drop in blood pressure without further symptoms of hypersensitivity.

Skin and subcutaneous tissue disorders
Rare: rash.
Frequency not known: severe skin reactions.

Renal and urinary disorders
Very rare: transient disturbances in kidney function with reduced urine output (oliguria) or complete cessation of urine (anuria), or acute kidney failure associated with proteinuria (excretion of protein in the urine).
Frequency not known: kidney inflammation (interstitial nephritis).

General disorders and administration site conditions
Frequency not known: pain at the injection site, phlebitis.
The medicine may affect the results of certain blood tests (e.g. creatinine, triglycerides, HDL cholesterol, and uric acid levels).

Hepatobiliary and biliary tract disorders
Frequency not known:
hepatitis, yellowing of the skin and whites of the eyes (jaundice), increased liver enzyme activity in blood.

Reporting of adverse effects
If any adverse effects occur, including any not listed in this leaflet, inform your doctor or pharmacist. Adverse effects can be reported directly to the Department of Monitoring Adverse Drug Reactions, 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 effects can also be reported to the marketing authorisation holder.
Reporting adverse effects helps provide more information on the safety of this medicine.

5. How to store the medicine Pyreoxing

Do not store above 25°C. Keep in the original packaging to protect from light.
Keep the medicine out of sight and reach of children.
Do not use this medicine after the expiry date (EXP) stated on the carton and label. The expiry date refers to the last day of the stated month.
Medicines must not be disposed of via wastewater or household waste. Ask your pharmacist how to dispose of medicines no longer in use. This will help protect the environment.

6. Contents of the pack and other information

What Pyreoxing contains

• The active substance is metamizole sodium. Each millilitre of solution contains 500 mg of metamizole sodium.
• The other ingredient is water for injections.

What Pyreoxing looks like and contents of the pack
A clear, colourless to slightly brownish-yellow solution, practically free from solid particles.
Amber glass ampoules containing the solution, packed in PVC blisters within a cardboard box.
Pack sizes: 10 ampoules of 2 ml, 10 ampoules of 5 ml, 5 ampoules of 2 ml, 5 ampoules of 5 ml.
Not all pack sizes may be marketed.

Marketing Authorisation Holder and Manufacturer
Marketing Authorisation Holder:
Bausch Health Ireland Limited
3013 Lake Drive
Citywest Business Campus
Dublin 24, D24PPT3
Ireland
Tel: +48 17 865 51 00

Manufacturer:
Przedsiębiorstwo Farmaceutyczne Jelfa S.A.
ul. Wincentego Pola 21
58-500 Jelenia Góra
Poland

This medicinal product is authorised in the European Economic Area countries under the following names:
Bulgaria: Амизолмет 500 mg/ml инжекционен разтвор
Poland: Pyreoxing
Lithuania: Metamizole sodium Bausch Health 500 mg/ml injekcinis tirpalas

Information intended exclusively for healthcare professionals:

Parenteral administration carries a high risk of anaphylactic and/or anaphylactoid reactions.
If injection is considered in children aged 3 to 11 months, it should be noted that
metamizole in these children should be administered only intramuscularly.
It is crucial to ensure that administration of the medicinal product is discontinued
immediately upon the first signs of an anaphylactic and/or anaphylactoid reaction, and
to minimize the risk of isolated hypotension.
During parenteral administration, it is essential to ensure that the patient is in a supine position and under close medical supervision. Furthermore, to prevent hypotensive reactions, intravenous injection must be performed very slowly, i.e., no more than 1 ml (500 mg of metamizole) per minute.
The injection solution may be diluted with 5% glucose solution, 0.9% sodium chloride solution, or Ringer's solution; however, these diluted solutions must be used immediately, as their stability is limited.
Due to possible incompatibilities, the metamizole solution should not be administered simultaneously with other medicinal products in the same injection.