PIXALZINA

Package leaflet: Information for the user

Pixalzina, 500 mg/ml, solution for injection
Metamizolum natricum monohydricum
Pixalzina may cause abnormally low numbers of white blood cells (agranulocytosis), which may
lead to severe and life-threatening infections (see section 4).
The medicine should be discontinued and medical advice sought immediately if any of the
following symptoms occur: fever, chills, sore throat, painful ulcers of the nose, mouth and throat, or in the genital or anal area.
If a patient has ever experienced agranulocytosis 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 the medicine, as it contains
important information for the patient.

• Keep this leaflet, as you may need to read it again.
• If you have any questions, please consult your doctor or pharmacist.
• 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 the same.
• If any side effects occur in the patient, including any not listed in this leaflet, inform your doctor, pharmacist or nurse. See section 4.

Leaflet contents

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

1. What Pixalzina is and what it is used for

Pixalzina contains the active substance metamizole sodium monohydrate, which belongs to the pyrazolone group.
Pixalzina is a medicine with analgesic, antipyretic and spasmolytic properties.
It is used in the treatment of severe acute or persistent pain and high fever unresponsive to other treatments.

2. Important information before using Pixalzina

When not to use Pixalzina

• if the patient is allergic to metamizole or to other pyrazolones (e.g. phenazone, propyphenazone) or pyrazolidines (e.g. phenylbutazone, oxyphenbutazone), including patients who have ever experienced, for example, a severe skin reaction (see section 4) after administration of any of these substances, or any of the other ingredients (listed in point 6).
• if the patient has previously experienced a significant decrease in the number of white blood cells called granulocytes, caused by metamizole or other similar medicines known as pyrazolones or pyrazolidines.
• if the patient has bone marrow dysfunction or a disease affecting the production or function of blood cells.
• if the patient has disorders of blood cell production (haematopoietic disorders).
• if the patient has analgesic intolerance (analgesic asthma syndrome or analgesic intolerance manifested by urticaria and/or angioedema). This applies to patients who react with bronchospasm (sudden narrowing of the lower airways) or other allergic reactions (hypersensitivity), such as itching, rhinitis, and swelling (urticaria, rhinitis, angioedema) after taking analgesics such as salicylates, paracetamol, diclofenac, ibuprofen, indometacin, or naproxen.
• if the patient has congenital glucose-6-phosphate dehydrogenase deficiency (risk of haemolysis).
• if the patient has severe liver disease – porphyria (a hereditary disorder characterized by impaired haemoglobin synthesis).
• if the patient is in the third trimester of pregnancy (last 3 months of pregnancy).
• if the patient has low blood pressure or circulatory disorders.

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

• if any symptoms indicating blood disorders occur (e.g. general weakness, infection, persistent fever, bruising, bleeding, pallor), seek medical advice immediately. These symptoms may be due to pancytopenia (reduction in all types of blood cells).
• if the patient suffers from any of the following conditions, due to an increased risk of severe anaphylactoid reactions to metamizole:
• bronchial asthma with concurrent rhinitis.
• chronic and/or persistent urticaria.
• intolerance or hypersensitivity to dyes (e.g. tartrazine) or preservatives (e.g. benzoates).
• alcohol intolerance, i.e. patients who react even to minimal amounts of alcohol with sneezing, lacrimation, and pronounced facial flushing.
• if the patient has hypotension, fluid loss, unstable fluid volume, signs of early circulatory disturbances, 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 considered with particular caution, and if used under these circumstances, close medical supervision is required. Appropriate measures must be taken to minimize the risk of severe arterial hypotension. Administration of metamizole may cause these reactions even in the absence of the above-mentioned disorders. These reactions appear to be dose-dependent.
• if the patient has severe coronary artery disease or significant narrowing of blood vessels supplying blood to the brain. In these cases, arterial hypotension must be strictly avoided, and therefore metamizole may only be administered under strict monitoring of circulatory parameters.
• if the patient has kidney or liver disease. In such cases, high doses of metamizole should not be used due to reduced elimination of the drug.
• if the doctor is planning to perform any laboratory tests, because metamizole may affect the results of certain tests (e.g. blood creatinine levels, lipids, HDL cholesterol, or uric acid).

Low white blood cell count (agranulocytosis)
Pixalzina may cause agranulocytosis, i.e. a very low number of a certain 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 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, genital area, or anus. 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 Pixalzina, and even shortly after discontinuation of metamizole.
Agranulocytosis may occur even if metamizole was previously administered without complications.

Liver-related disorders
Cases of liver inflammation have been reported in patients taking metamizole, with symptoms appearing from several days to several months after starting treatment.
Pixalzina should be discontinued and medical advice sought if the patient experiences 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 assess liver function in the patient.
The patient should not take Pixalzina if they have previously taken any medicine containing metamizole and experienced liver-related adverse effects.

Severe skin reactions
Severe skin reactions have been reported in association with metamizole treatment, including Stevens-Johnson syndrome, toxic epidermal necrolysis (TEN), and drug reaction with eosinophilia and systemic symptoms (DRESS syndrome). If the patient develops any of these symptoms related to severe skin reactions listed in section 4, metamizole should be discontinued immediately and medical help sought without delay.
If the patient has ever experienced severe skin reactions, treatment with Pixalzina should never be repeated in the future (see section 4).

Pixalzina and other medicines
Inform your doctor or pharmacist about all medicines currently or recently taken, as well as any medicines planned for future use, especially the following:

• methotrexate (a medicine used in the treatment of cancer or certain rheumatic diseases). Concurrent use may increase the potential risk of blood cell damage by methotrexate, particularly in elderly patients. Concomitant use of these medicines should be avoided.
• acetylsalicylic acid (aspirin). Metamizole may reduce its effect on platelets. Pixalzina should be used cautiously when administered together with low-dose acetylsalicylic acid for cardioprotection. Metamizole may weaken the effect of medicines such as:
• cyclosporine (an immunosuppressive medicine).
• efavirenz (a medicine used in the treatment of HIV/AIDS infection).
• methadone (a medicine used in the treatment of addiction to illegal narcotics (so-called opioids)).
• valproic acid (a medicine used in the treatment of epilepsy or bipolar affective disorder).
• tacrolimus (a medicine used to prevent organ rejection in transplant patients).
• sertraline (a medicine used in the treatment of depression).
• bupropion (a medicine used in the treatment of depression or as an aid in smoking cessation). The doctor will closely monitor the patient's condition if metamizole is administered concurrently with any of the above medicines.

Use of Pixalzina with alcohol
Do not consume alcohol while using Pixalzina.

Pregnancy and breastfeeding
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
Metamizole is not recommended during the first 6 months of pregnancy. Available data on the use of metamizole during the first 3 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, the patient may take single doses of metamizole during the first and second trimesters of pregnancy, provided that the benefits and risks of taking the medicine are carefully considered.

Pixalzina must not be taken during the last three months of pregnancy due to increased risk of complications for both mother and child (bleeding, premature closure of an important blood vessel in the foetus, the so-called ductus arteriosus Botalli, which normally closes only after birth).

Breastfeeding
Breastfeeding is not recommended during repeated use of this medicine. Metamizole metabolites pass into breast milk in significant amounts, and risk to the breastfed infant cannot be excluded. After a single dose of metamizole, mothers should be advised to express and discard breast milk for 48 hours after administration of the drug.

Driving and operating machinery
At the recommended dosage range, no adverse effects affecting reaction ability or concentration have been observed.
However, as a precaution, especially when higher doses are used, the possibility of impaired abilities should be considered, and patients should refrain from operating machinery, driving vehicles, or performing tasks involving risk. This is particularly relevant when used in combination with alcohol.

Pixalzina contains sodium
This medicine contains 32.7 mg of sodium (the main component of table salt) in 1 ml of injection/infusion solution, corresponding to 1.6% of the maximum recommended daily dietary sodium intake for adults.

3. How to use Pixalzina

This medicine should always be used according to the instructions given by your doctor or pharmacist. If in
doubt, consult your doctor or pharmacist.
The dose depends on the severity of pain or fever and on the individual's sensitivity to Pixalzina. Pixalzina
will be administered intravenously or intramuscularly (into a vein or muscle).
Onset of effect can be expected approximately 30 minutes after administration; the duration of action usually lasts
about 4 hours.
If the analgesic effect after a single dose is insufficient, or if the effect wears off after some time, your doctor may
administer another dose, without exceeding the maximum daily dose as described below.
During administration (injection), the patient should remain lying down and under medical supervision to ensure
appropriate monitoring of the patient's health status.
Recommended doses
Use in adults and adolescents over 15 years of age
Adults and adolescents over 15 years of age (with body weight exceeding 53 kg) may receive a single dose of 1–2 ml administered intravenously (into a vein) or intramuscularly (into a muscle); if necessary, the single dose may be increased up to a maximum of 5 ml (corresponding to 2500 mg of metamizole). The maximum daily dose is 8 ml; if necessary, the daily dose may be increased up to a maximum of 10 ml (corresponding to 5000 mg of metamizole).
Use in children
The following dosing schedule should be followed for single intravenous or intramuscular doses:

Elderly individuals and patients in poor general health or with impaired kidney function
In elderly individuals, debilitated patients, and patients with impaired kidney function, the dose should be reduced due to the potential for prolonged elimination of metamizole metabolites.

Patients with impaired kidney or liver function
Due to reduced elimination rate in patients with impaired kidney or liver function, repeated administration of high doses should be avoided. For short-term use, dose adjustment is not required. There is no experience regarding long-term use.

Use of a higher than recommended dose of Pixalzina
In case of overdose, immediate contact with a physician is necessary to initiate appropriate measures.
Symptoms of overdose include nausea, vomiting, abdominal pain, kidney problems, and less frequently, neurological disturbances (dizziness, drowsiness, loss of consciousness, seizures). Severe overdose may also lead to low blood pressure (sometimes progressing to shock) and rapid heartbeat.
At very high doses, a harmless metabolite may be excreted, causing red discoloration of urine, which resolves upon discontinuation of treatment.

Missed dose of Pixalzina
A double dose should not be administered to make up for a missed dose.
If there are any further doubts regarding the use of this medicinal product, consult a physician or pharmacist.

4. Possible adverse reactions

Like any medicine, this medicine can cause adverse reactions, although not everyone will experience them.
The following adverse reactions may have serious consequences. Stop using Pixalzina immediately and contact your doctor without delay:
If any of these adverse reactions occur suddenly or worsen, inform your doctor immediately, as some reactions (e.g. severe hypersensitivity reactions, severe skin reactions such as Stevens-Johnson syndrome or toxic epidermal necrolysis, agranulocytosis, pancytopenia) may, in certain situations, be life-threatening. In such cases, Pixalzina must never be used again without medical supervision. Immediate discontinuation of treatment is crucial for recovery.

• Hypersensitivity reactions (anaphylactoid or anaphylactic reactions) – rare adverse reactions. Typical symptoms of mild reactions include: burning eyes, cough, nasal symptoms, nasal mucosal hyperaemia, sneezing, chest pain, skin redness (especially in the face and head area), urticaria and facial swelling, and less frequently: nausea and stomach cramps. Warning signs particularly include burning, itching, and a sensation of warmth on and under the tongue, and especially in the palms and soles. Such mild reactions may progress to more severe forms with acute urticaria, severe angioedema (including in the larynx), severe bronchospasm (spastic narrowing of lower airways), increased heart rate (sometimes decreased heart rate), cardiac arrhythmias, drop in blood pressure (sometimes preceded by a rise), loss of consciousness, and circulatory failure. These reactions may occur despite previous uneventful use of the medicine and may be life-threatening, and in some cases lead to death. In patients with analgesic-induced asthma syndrome, hypersensitivity reactions usually manifest as asthma attacks (see section 2 "When not to use Pixalzina").

• Reddish, flat, target-shaped or circular rashes on the trunk, often with blisters in the centre, skin peeling, mucosal ulcers in the mouth, throat, nose, genital organs, and around the eyes. Such severe skin rashes may be preceded by fever and flu-like symptoms (Stevens-Johnson syndrome, toxic epidermal necrolysis) – frequency unknown.

• Widespread rash, high fever, and swollen lymph nodes (DRESS syndrome or drug hypersensitivity syndrome).

• General malaise (nausea or vomiting), fever, 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 may be symptoms of liver damage. See also section 2 "Warnings and precautions".

• Significant decrease in granulocyte count – specific white blood cells (agranulocytosis), including fatal cases, or reduced platelet count (thrombocytopenia) – rare adverse reactions. These reactions are likely immune-mediated. They may also occur even if metamizole was previously administered without complications. If symptoms of agranulocytosis, pancytopenia, or thrombocytopenia occur (see below and section 2 "Warnings and precautions"), treatment with Pixalzina must be stopped immediately, without waiting for laboratory test results. Blood count (including differential blood count) must be monitored by a physician.
  Pixalzina should not be used if any of the following symptoms occur, which may indicate possible agranulocytosis:

• Unexpected deterioration in general condition (e.g. fever, chills, sore throat, difficulty swallowing).

• If fever does not subside or recurs.

• If painful mucosal lesions occur, especially in the oral cavity, nose, throat, genital area, or around the anus. Typical symptoms of reduced platelet count include increased tendency to bleeding and petechiae (pinpoint bleeding) on the skin and mucous membranes. Reduced blood volume with accompanying bone marrow dysfunction (aplastic anaemia), decreased numbers of white and red blood cells and platelets (pancytopenia), including fatal cases. Symptoms of pancytopenia and aplastic anaemia include general malaise (weakness), infections, persistent fever, bruising, bleeding, and pallor.

Other possible adverse reactions
Uncommon adverse reactions (may occur in up to 1 in 100 people)

• Drop in blood pressure (isolated hypotensive reaction), probably due to the direct effect of the medicine and not accompanied by other hypersensitivity symptoms. Such a reaction causes a serious drop in blood pressure only rarely. This risk may also be increased in patients with very high fever. Typical symptoms of significant hypotension include: increased heart rate, pallor, trembling, dizziness, nausea, and loss of consciousness.

Rare adverse reactions (may occur in up to 1 in 1,000 people)

• Decreased white blood cell count (leukopenia) or red blood cell count (aplastic anaemia).
• Skin rash.

Very rare adverse reactions (may occur in up to 1 in 10,000 people)

• Impaired kidney function, in some cases with absence or very low volume of urine output (oligo- or anuria), proteinuria (protein in urine), or acute kidney failure.
  Frequency unknown (frequency cannot be estimated from available data)
• Myocardial infarction occurring during an allergic reaction (Kounis syndrome),
• Gastrointestinal bleeding.
• Hepatitis, jaundice (yellowing of skin and whites of the eyes), increased liver enzyme activity in blood.
• Purple to dark red skin rash, sometimes with blisters (fixed drug eruption).
• Kidney failure (acute interstitial nephritis).
• Pain and local reactions at the injection site, phlebitis (vein inflammation).
  Reporting of adverse reactions
  If any adverse reactions occur, including any possible adverse reactions not listed in this leaflet, inform your doctor or pharmacist. Adverse reactions can be reported directly to:

Department of Monitoring Adverse Reactions of Medicinal Products
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 authorisation holder.
Reporting adverse reactions helps to provide more information on the safety of the medicine.

5. How to store Pixalzina

Keep this medicine out of sight and reach of children.
Store below 25 °C. Keep in the original packaging to protect from light.
Do not use this medicine after the expiry date stated on the packaging after the word EXP. 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 required. Such measures help protect the environment.

6. Contents of the packaging and other information

What Pixalzina contains

• The active substance is metamizole sodium monohydrate. 1 ml of injection solution contains 500 mg of metamizole sodium monohydrate. One 2 ml ampoule of injection solution contains 1000 mg of metamizole sodium monohydrate. One 5 ml ampoule of injection solution contains 2500 mg of metamizole sodium monohydrate.
• Other ingredients: sulfuric acid 10%, water for injections.

What Pixalzina looks like and contents of the pack

Pixalzina is a clear, colourless to slightly yellow solution. It does not contain visible particles.
A brown 2 ml ampoule made of borosilicate glass with neutral hydrolytic resistance of type I, marked with a grey breaking point and two green identification rings, contains 2 ml of Pixalzina.
A brown 5 ml ampoule made of borosilicate glass with neutral hydrolytic resistance of type I, marked with a grey breaking point and two green identification rings, contains 5 ml of Pixalzina.
Pixalzina 2 ml ampoules are available in packs of 5, 10, and 100 ampoules.
Pixalzina 5 ml ampoules are available in packs of 5 and 10 ampoules.
Not all pack sizes may be marketed.

Marketing Authorisation Holder
Zentiva, k.s.
U kabelovny 130
Dolní Měcholupy
102 37 Prague 10
Czech Republic

Manufacturer
Zentiva S.A.
B-dul Theodor Pallady nr. 50, sector 3
032266 Bucharest
Romania

For further information about this medicine, please contact the local representative of the Marketing Authorisation Holder:
Zentiva Polska Sp. z o.o.
ul. Bonifraterska 17
00-203 Warsaw
tel.: +48 22 375 92 00

This medicinal product is authorised in the Member States of the European Economic Area under the following names:
Czech Republic: Afexil
Austria: Metamizol Zentiva
Poland: Pixalzina
Slovakia: Nofebran

Information intended exclusively for healthcare professionals:
Parenteral administration of this medicinal product is associated with a high risk of anaphylactic or anaphylactoid reactions.
The injection must be stopped immediately at the first signs of an anaphylactic or anaphylactoid reaction, and the risk of isolated hypotensive reactions should be minimized. During parenteral administration, the patient must be in a lying position and under close medical supervision. Additionally, to prevent hypotensive reactions, intravenous administration must be performed very slowly, i.e. no more than 1 ml (500 mg of metamizole) per minute.
The injection solution may be diluted using 5% glucose solution (50 mg/ml), 0.9% sodium chloride solution (9 mg/ml), or Ringer's solution. The mixture should be administered immediately after preparation due to its limited stability. Due to possible pharmaceutical incompatibilities, metamizole solution must not be administered together with other injectable medicines.