METAMIZOL KRKA

Package leaflet: Information for the user

Metamizol Krka, 500 mg/ml, solution for injection / infusion
Metamizolum natricum monohydricum
Please read all of this leaflet carefully before using this medicine, because it contains
important information for the patient.

• Keep this leaflet, as you may need to read it again.
• If you have any further questions, please consult your doctor or pharmacist.
• If you experience any adverse reactions, including any not listed in this leaflet, inform your doctor, pharmacist or nurse. See section 4.

Contents of the leaflet

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

1. What Metamizol Krka is and what it is used for

Metamizol Krka contains the active substance – sodium metamizole monohydrate. It is an analgesic and antipyretic medicine belonging to the pyrazolone group.
Metamizol Krka is used in the treatment of:

• acute severe pain following trauma or surgery,
• colicky abdominal pain (colic),
• cancer pain,
• other acute or chronic severe pain when alternative treatments are not feasible,
• high fever unresponsive to other medications.

The solution for injection / infusion should only be used when other pharmaceutical forms (tablets, oral solution, suppositories) are not appropriate.

2. Important information before using Metamizol Krka

When not to use Metamizol Krka

• if the patient is allergic to metamizole or any of the other ingredients of this medicine (listed in section 6),
• if the patient is allergic to other pyrazolones (e.g. phenazone, propyphenazone) or pyrazolidines (e.g. phenylbutazone, oxyphenbutazone). This also applies to patients who have experienced a significant decrease in the number of certain white blood cells (agranulocytosis) after using these substances,
• if the patient has intolerance to painkillers (analgesic asthma syndrome or painkiller intolerance manifested by urticaria and (or) angioedema). This applies to patients who, after taking painkillers such as salicylates, paracetamol, diclofenac, ibuprofen, indomethacin or naproxen, experience sudden (spastic) narrowing of the lower airways or other symptoms of hypersensitivity reactions, such as urticaria with itching and blisters, rhinitis, and angioedema,
• if the patient has bone marrow dysfunction, e.g. after treatment with certain anticancer drugs,
• if the patient has blood formation disorders,
• if the patient has a hereditary condition associated with the risk of red blood cell breakdown (glucose-6-phosphate dehydrogenase deficiency),
• if the patient has a congenital disorder associated with impaired synthesis of haemoglobin (acute intermittent porphyria),
• if the patient has low blood pressure or circulatory disorders,
• if the patient is in the third trimester of pregnancy (last 3 months of pregnancy).

Warnings and precautions
Before starting treatment with Metamizol Krka, discuss this with your doctor, pharmacist, or nurse.
Metamizole may cause rare but life-threatening risks of:

• sudden circulatory collapse,
• agranulocytosis (acute disorder caused by a significant decrease in granulocytes, a type of white blood cells).

If any of the following symptoms occur, which may indicate the possibility of agranulocytosis, discontinue the use of Metamizol Krka and contact your doctor immediately:

• unexpected worsening of the patient's general condition (symptoms such as fever, chills, sore throat, difficulty swallowing),
• persistent or recurring fever,
• painful changes in mucous membranes, especially in the oral cavity, nose, throat, genital area, or anus. See section 4 "Possible side effects".

If the patient develops symptoms indicating a decrease in all blood cells (pancytopenia) (such as general malaise, infections or persistent fever, bruising, bleeding, and pallor) or platelets (thrombocytopenia) (such as increased tendency to bleeding and petechiae (pinpoint bleeding) on the skin and mucous membranes), immediately discontinue the use of Metamizol Krka and contact your doctor (see section 4 "Possible side effects").
The doctor may regularly monitor blood cell counts and discontinue treatment if certain changes in blood morphology occur.
Patients who have experienced an allergic reaction or another immunologically mediated reaction to Metamizol Krka (e.g. agranulocytosis) are also particularly at risk of similar reactions to other pyrazolones and pyrazolidines or other painkillers (such as phenazone, propyphenazone, phenylbutazone, oxyphenbutazone).
Patients who have experienced an allergic reaction or another immunologically mediated reaction to other pyrazolones, pyrazolidines, or other painkillers have an increased risk of a similar reaction to Metamizol Krka.
When deciding on the route of administration (intramuscular or intravenous), consider the increased risk of hypersensitivity reactions after parenteral administration.
Severe hypersensitivity reactions
When using Metamizol Krka, the risk of severe allergic reactions is higher compared to other metamizole-containing medicines taken orally or as suppositories.
If the patient has any of the following conditions, the risk of severe hypersensitivity reactions to Metamizol Krka may be significantly increased:

• intolerance to painkillers or anti-rheumatic drugs manifested by itching, blisters, or swelling; In case of such symptoms, do not use Metamizol Krka. For further information, see section 2 "When not to use Metamizol Krka".
• breathing difficulties, e.g. in asthma, especially if accompanied by nasal polyps or rhinosinusitis,
• chronic urticaria,
• hypersensitivity to dyes (e.g. tartrazine) or preservatives (e.g. benzoates),
• alcohol intolerance; sneezing, tearing, and intense facial flushing even after small amounts of alcohol. This may indicate previously unrecognized painkiller intolerance (see section 2 "When not to use Metamizol Krka").

Metamizol Krka may be administered to patients at increased risk of hypersensitivity reactions only after careful consideration of the benefit-risk ratio (see also section 2 "When not to use Metamizol Krka"). If Metamizol Krka is administered in such cases, the patient must be under strict medical supervision with immediate access to emergency equipment.
Anaphylactic shock may occur in patients with hypersensitivity (see section 4 of the leaflet). Therefore, patients with asthma or a tendency to hypersensitivity should exercise particular caution.
Severe skin reactions
Severe skin reactions, including Stevens-Johnson syndrome, toxic epidermal necrolysis, and drug reaction with eosinophilia and systemic symptoms (DRESS syndrome), have been reported with metamizole treatment. If the patient develops any of these symptoms related to severe skin reactions listed in section 4, discontinue metamizole and seek immediate medical help.
Metamizol Krka should never be re-administered in the future if the patient has ever experienced severe skin reactions (see section 4).
Reduction in blood pressure
During treatment with Metamizol Krka, a decrease in blood pressure may occur (see also section 4). This reaction occurs more frequently when the medicine is administered by injection than in tablet form. The risk of such reactions increases:

• if the medicine is administered too rapidly intravenously (see section 3),
• if the patient has low blood pressure, severe dehydration, poor circulation, or early stages of circulatory failure (e.g. in case of heart attack or severe trauma),
• if the patient has high fever.

Therefore, to reduce the risk of any drop in blood pressure, the doctor will carefully consider the need for administration, closely monitor the patient's condition during treatment, and if necessary, take preventive measures (e.g. correction of circulatory disturbances) (see section 2 "When not to use Metamizol Krka").
Metamizol Krka may be used only under strict circulatory monitoring in patients in whom a drop in blood pressure must absolutely be avoided, such as:

• severe ischemic heart disease,
• narrowing of blood vessels supplying the brain (cerebral vascular insufficiency).

Renal or hepatic impairment
Metamizol Krka should be used in patients with renal or hepatic impairment only after careful consideration of benefits and risks and with appropriate precautions.
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.
Discontinue Metamizol Krka and contact your doctor 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 assess liver function.
The patient should not take Metamizol Krka if they have previously used any medicinal products containing metamizole and experienced liver-related disorders.
Effect on laboratory test results
Inform your doctor before any laboratory tests that you are using Metamizol Krka injection/infusion solution, as the active substance, metamizole, may affect the results of certain tests, e.g. creatinine, lipid, HDL cholesterol, or serum uric acid levels.
Metamizol Krka and other medicines
Tell your doctor or pharmacist about all medicines you are currently taking or have recently taken, as well as any medicines you plan to take.
In particular, inform your doctor about taking the following medicines, which may affect the action of Metamizol Krka or whose action may be affected by Metamizol Krka:

• cyclosporine, an immunosuppressive medicine. The doctor will monitor cyclosporine blood levels during concomitant use.
• methotrexate, a medicine used in cancer or rheumatic disease treatment. Concomitant use may increase the potential risk of methotrexate-induced blood cell damage, especially in elderly patients. Concomitant use of these medicines should be avoided.
• acetylsalicylic acid, used in low doses for cardioprotection. Concomitant use may reduce the antiplatelet effect of acetylsalicylic acid.
• bupropion, a medicine used to treat depression or as an aid in smoking cessation. Concomitant use may reduce bupropion blood levels.
• efavirenz, a medicine used in the treatment of HIV infection (AIDS).
• methadone, a medicine used in the treatment of addiction to illegal narcotics (opioids).
• valproate, 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.
• chlorpromazine, a medicine used in the treatment of psychiatric disorders. Concomitant use may lead to excessive lowering of body temperature.

Pyrazolones – the group of medicines to which metamizole belongs – may interact with certain medicines:

• oral anticoagulants,
• captopril, a medicine used to treat high blood pressure and certain heart conditions,
• lithium, a medicine used in the treatment of psychiatric disorders,
• diuretics used to increase urine output, such as triamterene,
• antihypertensive medicines. The potential effect of Metamizol Krka on these interactions is not known.

Use of Metamizol Krka with alcohol
Do not consume alcohol while using Metamizol Krka.
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
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. Generally, administration of metamizole during the first and second trimesters is not recommended.
Metamizol Krka must not be taken during the last three months of pregnancy due to the increased risk of complications in mother and child (bleeding, premature closure of an important blood vessel in the fetus, the so-called ductus arteriosus Botalli, which normally closes only after birth).
Breastfeeding
Metamizole metabolites pass into the breast milk of nursing mothers in significant amounts, and a risk to the breastfed infant cannot be excluded. Therefore, repeated use of metamizole should be particularly avoided during breastfeeding.
After a single dose of metamizole, mothers should be advised to express and discard breast milk for 48 hours after administration of the medicine.
Driving and operating machinery
At the recommended dosage range, no adverse effects affecting reaction ability and concentration have been observed.
However, as a precaution, especially when higher doses are used, the possibility of impaired ability should be considered, and operation of machinery, driving vehicles, or performing tasks involving risk should be avoided. This particularly applies to use in combination with alcohol.
Metamizol Krka contains sodium
This medicine contains 32.7 mg of sodium (the main component of table salt) per 1 ml of injection/infusion solution, equivalent to 1.635% of the maximum recommended daily dietary sodium intake for adults.

3. How to use Metamizol Krka

The dose depends on the severity of pain or fever and on the individual's sensitivity to Metamizol Krka. Metamizol Krka will be administered into a vein or muscle (intravenous or intramuscular administration).
If the analgesic effect after a single dose is insufficient, or if the effect wears off after some time, the doctor may administer another dose, without exceeding the maximum daily dose as described below.

Duration of treatment
The duration of treatment depends on the type and severity of the disease and is determined by the physician. Do not use analgesic medications for longer than 3–5 days unless otherwise advised by a doctor or dentist.

Use of a higher than recommended dose of Metamizol Krka
Symptoms of overdose include:

• nausea,
• vomiting,
• abdominal pain,
• impaired kidney function, and even acute kidney failure (with symptoms of interstitial nephritis),
• dizziness,
• drowsiness,
• loss of consciousness,
• seizures,
• reduced blood pressure up to circulatory failure (shock),
• cardiac arrhythmias (tachycardia).

In case of overdose, seek immediate medical advice.
Note: After ingestion of very high doses, excretion of a harmless metabolite (rubazonic acid) may cause red discoloration of urine.

If you have any further questions regarding the use of this medicine, consult your doctor, pharmacist, or nurse.

4. Possible adverse reactions

Like all medicines, this medicine can cause adverse reactions, although not everyone will experience them.

The following adverse reactions may have serious consequences. You must stop taking Metamizol Krka immediately if any of the following adverse reactions occur. If any of these adverse reactions occur suddenly or worsen, you must immediately inform your doctor, because some reactions to the medicine (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, Metamizol Krka must never be taken again without medical supervision. Immediate discontinuation of treatment is crucial for recovery.

You must stop taking metamizole and seek immediate medical help if the patient experiences any of the following severe adverse reactions:

• Reddish, flat spots on the trunk in the shape of a target or circular, often with blisters in the centre, peeling of the skin, ulcers in the mouth, throat, nose, genital organs and inside the eyes. The occurrence of such serious skin rashes may be preceded by fever and flu-like symptoms (Stevens-Johnson syndrome, toxic epidermal necrolysis);
• Extensive rash, high body temperature and enlarged lymph nodes (DRESS syndrome or drug hypersensitivity syndrome).

If symptoms of agranulocytosis, pancytopenia or thrombocytopenia occur (see below and section 2 "Warnings and precautions"), you must immediately stop taking Metamizol Krka and your doctor will recommend a blood count test, including blood smear examination. You should not wait to discontinue treatment until laboratory results are obtained.

You must stop taking Metamizol Krka and immediately seek medical help if any of the following symptoms occur: General malaise (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 part of the abdomen. These may be symptoms of liver damage. See also section 2 "Warnings and precautions".

Other possible adverse reactions

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

• Purple to dark red skin rash, sometimes with vesicles (drug eruption),
• Decrease in blood pressure, probably caused by the direct effect of the drug and not accompanied by other hypersensitivity symptoms. Such a reaction causes a severe drop in blood pressure only in rare cases. The risk of decreased blood pressure increases with rapid intravenous injection of the medicine. This risk may also be increased in patients with very high fever. Typical symptoms of severe reduction in blood pressure 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)

• Hypersensitivity reactions (pseudo-anaphylactic or anaphylactic reactions). Symptoms of mild reactions include:

• burning eyes,

• cough, runny nose, sneezing,

• chest tightness,

• skin redness, especially in the face and head area,

• urticaria and facial swelling,

• less frequently: nausea and stomach cramps. Particularly important warning signs are burning, itching and a feeling of warmth on and under the tongue, and especially on the palms and soles. Such mild reactions may progress to more severe forms, with:

• severe urticaria,

• severe angioedema (including in the larynx),

• severe bronchospasm,

• increased heart rate, sometimes decreased heart rate, cardiac arrhythmias,

• drop in blood pressure, sometimes preceded by an increase,

• loss of consciousness and circulatory failure. These reactions may occur especially after intravenous administration of the medicine and may be life-threatening, and in some cases lead to death. They may also occur even after previous use of the medicine without complications. In patients with analgesic-induced asthma syndrome, hypersensitivity reactions usually manifest as asthma attacks (see section 2 "When not to use Metamizol Krka").

• Decreased number of white blood cells (leukopenia),

• Skin rash (e.g. maculopapular rash).

Very rare adverse reactions (may occur in not more than 1 in 10,000 people)

• Marked decrease in granulocytes – specific white blood cells (agranulocytosis), including cases with fatal outcome, or decreased number of platelets (thrombocytopenia). These reactions are probably immune system-dependent. They may also occur when metamizole was previously administered without complications. Isolated reports suggest that the risk of agranulocytosis may increase when Metamizol Krka is administered as an injection/infusion solution for longer than one week. Symptoms of agranulocytosis include high fever, chills, sore throat, difficulty swallowing, and inflammatory conditions of the mouth, nose, throat, genital area or anus. However, in patients taking antibiotics (medicines used for bacterial infections), these symptoms may be less pronounced. Erythrocyte sedimentation rate (red blood cells) is markedly increased, while lymph nodes are usually only slightly or not enlarged at all. Typical symptoms of decreased platelet count include, for example, increased tendency to bleeding and petechiae (pinpoint bleeding) on the skin and mucous membranes.
• Asthma attacks,
• Development of extensive blisters and skin lesions (Stevens-Johnson syndrome or toxic epidermal necrolysis),
• Acute worsening of kidney function, in some cases with absence or very low volume of urine output, excretion of blood proteins in urine, acute kidney failure; inflammation of the kidneys (acute interstitial nephritis).

Frequency unknown (frequency cannot be estimated from available data)

• Sudden circulatory failure resulting from a severe allergic reaction (anaphylactic shock),
• Myocardial infarction during an allergic reaction (Kounis syndrome),
• Anaemia with accompanying bone marrow dysfunction (aplastic anaemia), decreased number of white and red blood cells and platelets (pancytopenia), including cases with fatal outcome. Symptoms of pancytopenia and aplastic anaemia include: general malaise, infections, persistent fever, bruising, bleeding and pallor of the skin.
• Gastrointestinal bleeding.
• Hepatitis, yellowing of the skin and whites of the eyes, increased liver enzyme activity in blood.
• Severe skin reactions.

Excretion of a harmless metabolite of metamizole may cause red discoloration of urine.

Reactions at the site of administration Pain at the site of administration and local reactions may occur, and in very rare cases phlebitis.

Reporting of adverse reactions

If any adverse reactions occur, including any possible adverse reactions not listed in this leaflet, you should inform your doctor or pharmacist.

Adverse reactions can be reported directly to the Department of Monitoring of 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 reactions can also be reported to the marketing authorisation holder.

By reporting adverse reactions, more information on the safety of the medicine can be collected.

5. How to store Metamizol Krka

Keep the medicine out of the sight and reach of children.
Do not use this medicine after the expiry date stated on the packaging after the EXP abbreviation. The expiry date refers to the last day of the stated month.
There are no special requirements regarding the storage temperature of the medicine.
Store in the original packaging to protect from light.
After first opening and (or) after dilution, the medicine should be used immediately.
Medicines must not be disposed of via wastewater or household waste. Ask your pharmacist how to dispose of medicines no longer required. This helps protect the environment.

6. Contents of the pack and other information

What Metamizol Krka contains

• The active substance is metamizole sodium monohydrate. 1 ml of solution for injection / infusion contains 500 mg of metamizole sodium monohydrate. One 2 ml ampoule of solution for injection / infusion contains 1000 mg of metamizole sodium monohydrate. One 5 ml ampoule of solution for injection / infusion contains 2500 mg of metamizole sodium monohydrate.
• The other ingredient is: water for injections. See section 2 "Metamizol Krka contains sodium".

What Metamizol Krka looks like and contents of the pack
The solution for injection / infusion is a clear, colourless to slightly yellow solution.
Cartons are available containing 5 ampoules (packed in blisters) of 2 ml solution for injection / infusion. The ampoules are marked with a white dot with a yellow and red ring.
Cartons are available containing 5 ampoules (packed in blisters) of 5 ml solution for injection / infusion. The ampoules are marked with a white dot with a yellow ring.
Not all pack sizes may be marketed.

Marketing Authorisation Holder
KRKA, d.d., Novo mesto, Šmarješka cesta 6, 8501 Novo mesto, Slovenia

Manufacturer
KRKA, d.d., Novo mesto, Šmarješka cesta 6, 8501 Novo mesto, Slovenia
TAD Pharma GmbH, Heinz-Lohmann-Strasse 5, 27472 Cuxhaven, Germany

For further information regarding this medicinal product, please contact the local representative of the Marketing Authorisation Holder:
Krka - Polska Sp. z o.o.
Równoległa 5 Street
02-235 Warsaw, Poland
Telephone: +48 22 573 75 00

Information intended exclusively for medical professionals:

Metamizol Krka, 500 mg/ml, solution for injection / for infusion
Metamizolum natricum monohydricum
Dosage and administration
The dose of the drug depends on the severity of pain or fever and on the individual patient's sensitivity to Metamizol Krka. The key principle is to select the lowest dose that provides effective control of pain and fever.

In children and adolescents up to 14 years of age, metamizole may be administered at a single dose of 8–16 mg per kilogram of body weight. In children with fever, a dose of 10 mg per kilogram of body weight is usually sufficient. For adults and adolescents aged 15 years and older (with body weight >53 kg), the maximum single dose of metamizole is 1000 mg.

Depending on the maximum daily dose, single doses may be administered no more frequently than four times daily, with intervals of 6–8 hours.

A clear therapeutic effect can be expected within 30 minutes after parenteral administration.

To minimize the risk of hypotensive reactions, intravenous injection 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).
The use of Metamizol Krka solution for injection/infusion is not recommended in infants under 3 months of age.
Other pharmaceutical forms of the drug suitable for use in children under 3 months of age are available.
Duration of treatment
The duration of treatment depends on the type and severity of the disease. During long-term treatment with
Metamizol Krka, regular blood tests should be performed, including complete blood count with blood smear.
Special patient groups
Elderly patients, debilitated patients, and patients with reduced creatinine clearance
In elderly patients, debilitated patients, and patients with reduced creatinine clearance, the dose should be reduced due to the possible prolonged elimination of metamizole metabolites from the body.
Hepatic and renal function disorders
In case of impaired renal or hepatic function, elimination is slowed down; 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. Current experience with long-term use of metamizole in patients with severe hepatic or renal impairment is insufficient.
Method of administration
Metamizol Krka is administered intravenously or intramuscularly. For intramuscular injection, the solution should always be warmed to body temperature.
Precautions to be taken during administration of the medicinal product
Since there is a suspicion that a critical drop in blood pressure following administration of the drug (not related to allergic reaction) is dose-dependent, the indication for use should be carefully considered and particular caution should be exercised when administering a single dose of Metamizol Krka exceeding 2 ml (corresponding to 1000 mg of sodium metamizole monohydrate).
During parenteral administration of Metamizol Krka, the patient should remain in a lying position and under strict medical supervision.
To minimize the risk of hypotensive reactions and to allow for interruption of drug administration upon the first signs of anaphylactic or anaphylactoid reaction, intravenous injection should be performed very slowly, i.e., no faster than 1 ml (500 mg of sodium metamizole monohydrate) per minute.
Warnings and precautions
Metamizol Krka contains a pyrazolone derivative – metamizole, and its use is associated with a rare but life-threatening risk of shock and agranulocytosis (see section 4.8).
Patients who have experienced an anaphylactoid reaction after administration of Metamizol Krka are at particularly high risk of a similar reaction upon administration of other non-opioid analgesics.
Patients who have experienced an anaphylactic reaction or another immunologically mediated reaction (e.g., agranulocytosis) to Metamizol Krka are particularly susceptible to the risk of a similar reaction upon administration of other pyrazolones and pyrazolidines.
Patients who have experienced an anaphylactic reaction or another immunologically mediated reaction to other pyrazolones, pyrazolidines, or other non-opioid analgesics are at high risk of similar reactions also after administration of Metamizol Krka.