Pyralgina plus

Package leaflet: Information for the patient

PYRALGINA PLUS, 400 mg + 60 mg + 40 mg, coated tablets
Metamizolum natricum + Coffeinum + Drotaverini hydrochloridum
Pyralgina Plus may cause a very low number of white blood cells (agranulocytosis), which may lead to severe and life-threatening infections (see section 4).
Treatment with this medicine 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, 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 taken again in the future (see section 2).
Please read the entire leaflet carefully before taking this medicine, as it contains important information for the patient.
This medicine should always be taken exactly as described in this patient leaflet or as directed by a doctor or pharmacist.

• Keep this leaflet so that you can read it again if necessary.
• If you need advice or further information, please consult your doctor or pharmacist.
• If you experience any adverse reactions, including any possible adverse reactions not listed in this leaflet, inform your doctor or pharmacist. See section 4.
• If there is no improvement or if you feel worse, contact your doctor.

Table of contents

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

1. What Pyralgina Plus is and what it is used for

Pyralgina Plus is intended for use in adults for symptomatic treatment of:

• severe pain of various origins
• pain associated with spastic conditions of smooth muscles:
  • urinary and genital system (renal colic, painful menstruation),
  • gastrointestinal tract (intestinal colic, irritable bowel syndrome),
  • biliary tract (cholecystitis, cholangitis), when the use of other medicines is contraindicated or ineffective.

Pyralgina Plus contains three active substances. Sodium metamizole has analgesic properties, and drotaverine hydrochloride exerts a spasmolytic effect on smooth muscles. Caffeine is an additive commonly used in many analgesic medicines.

2. Important information before taking Pyralgina Plus

When not to take Pyralgina Plus:

• 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 disorders of bone marrow function or a condition affecting the production or function of blood cells;
• if the patient is allergic to metamizole, caffeine, drotaverine, pyrazolone derivatives (e.g. phenazone, propyphenazone) or pyrazolidine derivatives (e.g. phenylbutazone, oxyphenbutazone), or any of the other ingredients of this medicine (listed in section 6);
• if the patient has asthma or intolerance associated with taking certain pain-relieving medicines such as salicylates, paracetamol, diclofenac, ibuprofen, indomethacin or naproxen, manifesting as bronchospasm, urticaria, rhinitis, or angioedema;
• if the patient has severe renal or hepatic impairment;
• if the patient has severe heart failure;
• if the patient has second- or third-degree atrioventricular block;
• if the patient has certain metabolic disorders (porphyria, glucose-6-phosphate dehydrogenase deficiency);
• if the patient has anaemia;
• if the patient is under 18 years of age;
• if the patient is pregnant or breastfeeding;
• if the patient has hypersensitivity to soy or peanuts (the medicine contains soy lecithin).

Warnings and precautions
Before starting to take Pyralgina Plus, discuss with your doctor or pharmacist:

• if the patient has asthma or intolerance to certain pain-relieving medicines (see section When not to take Pyralgina Plus) manifesting as urticaria, angioedema, particularly if associated with nasal polyposis and sinusitis;
• if the patient has bronchial asthma, especially when associated with sinusitis and nasal polyps;
• if the patient has allergies or atopy, as anaphylactic shock may occur. Therefore, particular caution is advised when using metamizole in patients with asthma or atopy (see also section When not to take Pyralgina Plus);
• if the patient has chronic urticaria;
• if the patient has intolerance to certain dyes (e.g. tartrazine) or preservatives (e.g. benzoates);
• if the patient has alcohol intolerance, manifesting as sneezing, lacrimation and marked facial flushing even after small amounts of alcohol; this may indicate previously undiagnosed asthma related to certain pain-relieving medicines (see section When not to take Pyralgina Plus);
• if the patient has low blood pressure, circulatory problems, or has experienced fluid loss or dehydration;
• if the patient has hypertension;
• if the patient has high fever;
• if the patient has kidney or liver problems;
• if the patient is over 65 years of age, in poor general health, or has renal impairment;
• if the patient has hypersensitivity to other substances. If in doubt whether any of the above conditions apply, consult the treating physician before starting Pyralgina Plus.

Low white blood cell count (agranulocytosis)
Pyralgina Plus 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). Discontinue metamizole and contact a doctor 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 taken 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 Pyralgina Plus, and even shortly after stopping metamizole.
Agranulocytosis may occur even if metamizole was previously administered without complications.

Abnormal platelet and other blood cell counts
Metamizole may cause thrombocytopenia, manifesting as increased tendency to bleeding, petechiae or bleeding on the skin and mucous membranes. If symptoms of thrombocytopenia occur, the patient should immediately discontinue the medicine and contact a doctor.
During treatment, a serious decrease in the number of red and white blood cells, as well as platelets, known as pancytopenia, may also occur. Patients should immediately consult a doctor if, during treatment with Pyralgina Plus, symptoms such as malaise, infection, persistent fever, bruising, bleeding, or pallor occur. If blood tests reveal abnormalities in blood cell or platelet counts, treatment must be immediately discontinued and blood cell and platelet counts monitored until they return to normal.

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 Pyralgina Plus and contact a doctor 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 eyes), itching, rash, or upper abdominal pain. The doctor will assess liver function.
The patient should not take Pyralgina Plus if they previously used any medicinal products containing metamizole and experienced liver-related problems.

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 any of these symptoms related to severe skin reactions (listed in section 4) occur, discontinue metamizole and seek immediate medical attention.
If the patient has ever experienced severe skin reactions, Pyralgina Plus should never be used again in the future (see section 4).

Severe allergic reaction
A severe allergic reaction, known as anaphylactic reaction, may suddenly manifest as facial or throat swelling, generalized urticaria, or bronchospasm, and may be life-threatening. Therefore, Pyralgina Plus should not be used in patients hypersensitive to its ingredients or in patients with a history of allergic reactions to other pain-relieving medicines (a detailed list of contraindications is provided above in When not to take Pyralgina Plus). Patients who have had an anaphylactic or other immunological reaction to metamizole are also at risk of similar reactions to other pyrazolones and pyrazolidines.

Reduction in blood pressure
Pyralgina Plus may cause a reduction in blood pressure (hypotension), which is likely dose-dependent. The risk of severe hypotension is increased in patients with pre-existing low blood pressure, circulatory problems, or those who have experienced fluid loss or dehydration (see above). In such patients, Pyralgina Plus should be used with caution and only after consultation with a doctor.

Elderly patients
See section 3.

Patients with kidney or liver problems
See section 3.

Due to the caffeine content of the medicine, excessive intake of caffeine (e.g. coffee, tea, and certain other beverages) should be avoided during treatment.
The medicine should not be taken immediately before going to sleep.

Children and adolescents
Pyralgina Plus should not be used in individuals under 18 years of age (see When not to take Pyralgina Plus in section 2).

Pyralgina Plus and other medicines
Inform your doctor or pharmacist about all medicines currently or recently taken, as well as any medicines planned for future use.
When using Pyralgina Plus with other medicines, consider the following interactions:

• Cyclosporine (used in transplant patients) – serum cyclosporine levels should be monitored, as they may decrease due to interaction with metamizole;
• Methotrexate (used in treating certain cancers) – metamizole may increase methotrexate toxicity to the bone marrow (where new blood cells are produced), especially in elderly patients. Therefore, concurrent use of methotrexate and Pyralgina Plus should be avoided;
• Acetylsalicylic acid – metamizole may reduce the antiplatelet effect of low-dose acetylsalicylic acid. Patients taking low-dose acetylsalicylic acid for cardiovascular prevention should use Pyralgina Plus with caution;
• Bupropion (an antidepressant and smoking cessation aid) – metamizole may reduce bupropion blood levels. Therefore, caution is advised when using Pyralgina Plus and bupropion together;
• Efavirenz (used in treating HIV infection (AIDS)) – metamizole may reduce plasma levels of this drug and reduce its clinical efficacy;
• Methadone (used in treating addiction to illegal opioids) – metamizole may reduce plasma levels of this drug and reduce its clinical efficacy;
• Valproate (used in treating epilepsy or bipolar disorder) – metamizole may reduce plasma levels of this drug and reduce its clinical efficacy;
• Tacrolimus (used to prevent organ rejection in transplant patients) – metamizole may reduce plasma levels of this drug and reduce its clinical efficacy;
• Sertraline (used in treating depression) – metamizole may reduce plasma levels of this drug and reduce its clinical efficacy;
• Medicines metabolized by the liver (e.g. clarithromycin, ethinylestradiol, sertraline) – caffeine may increase their blood concentration;
• Salicylates – caffeine may enhance their absorption;
• Cimetidine (a medicine reducing gastric acid), oral contraceptives, ciprofloxacin and enoxacin (used in treating infections), mexiletine (used in treating cardiac arrhythmias) – these medicines may increase caffeine blood levels;
• Muscle relaxants – some muscle relaxants inhibit caffeine metabolism; therefore, concomitant use of Pyralgina Plus with these medicines is not recommended;
• Nicotine – increases caffeine excretion;
• Disulfiram (used in treating alcoholism), ethinylestradiol (used in treating menstrual disorders and as contraception) – may increase the effects of caffeine;
• Levodopa (used in symptomatic treatment of Parkinson's disease) – the effect of levodopa may be reduced; therefore, tremors and rigidity may worsen in patients with Parkinson's disease when Pyralgina Plus is used concomitantly.

Pyralgina Plus and alcohol
Concurrent alcohol consumption may affect concentration and reaction time (see Driving and operating machinery).

Pregnancy and breastfeeding
If the patient is pregnant or breastfeeding, suspects she may be pregnant, or is planning to become pregnant, she should consult a doctor or pharmacist before using this medicine.
Do not take Pyralgina Plus during pregnancy or breastfeeding.

Driving and operating machinery
At the recommended dosage, Pyralgina Plus has not been shown to affect concentration or reaction time. However, at higher doses of metamizole or after alcohol consumption, concentration and reaction time may be impaired. Drotaverine may cause dizziness, while caffeine may cause psychomotor hyperactivity, nervousness, or exhaustion, posing a risk in situations where alertness is critical (e.g. driving or operating machinery).

Pyralgina Plus contains lactose monohydrate, sodium, and soy lecithin

Pyralgina Plus contains lactose monohydrate
If the patient has previously been diagnosed with intolerance to certain sugars, they should consult a doctor before taking this medicine.

Pyralgina Plus contains sodium
Each coated tablet contains 27.6 mg of sodium (the main component of table salt), equivalent to 1.4% of the WHO-recommended maximum daily intake of 2 g of sodium for adults.

Pyralgina Plus contains soy lecithin
Do not use this medicine if hypersensitivity to peanuts or soy has been diagnosed.

3. How to take Pyralgina Plus

This medicine should always be taken exactly as described in this patient information leaflet, or as directed by a doctor or pharmacist. If in doubt, consult a doctor or pharmacist.
The dose depends on the severity of pain and the individual's response to Pyralgina Plus.
Always use the lowest effective dose necessary to control pain.

Adults
The recommended dose for adults, when necessary, is 1 or 2 tablets (400 or 800 mg of metamizole sodium, 60 or 120 mg of caffeine, and 40 or 80 mg of drotaverine hydrochloride) two or three times daily, no more frequently than every 6–8 hours. The maximum daily dose is 6 tablets (2,400 mg of metamizole sodium, 360 mg of caffeine, and 240 mg of drotaverine hydrochloride).
If symptoms do not improve within 3–5 days of using Pyralgina Plus, or if symptoms worsen despite taking the medicine, the patient should seek medical advice without delay.

Children and adolescents
Pyralgina Plus must not be used in individuals under 18 years of age (see When not to take Pyralgina Plus in section 2).

Elderly patients and patients in poor general health or with renal impairment (see also When not to take Pyralgina Plus and Warnings and precautions in section 2)
In elderly patients, weakened patients, and patients with impaired renal function, the dose of metamizole should be reduced due to the potential for prolonged elimination of metamizole metabolites.
In elderly patients with poor general health and reduced creatinine clearance, a lower dose of drotaverine is recommended due to slower metabolism of this active substance.

Patients with impaired renal or hepatic function (see also When not to take Pyralgina Plus and Warnings and precautions in section 2)
Due to reduced elimination of metamizole in patients with impaired renal or hepatic function, repeated administration of high doses of metamizole should be avoided. For short-term use, dose reduction of metamizole is not required. There is no experience with long-term use of metamizole.

Method of administration
For oral use. Tablets should be taken with sufficient fluid (e.g. a glass of water).

Taking more Pyralgina Plus than recommended
After ingestion of very high doses, excretion of a harmless metabolite may cause red discoloration of urine.
Acute overdose may cause nausea, vomiting, abdominal pain, impaired renal function or acute renal failure, and less commonly, central nervous system symptoms (dizziness, drowsiness, coma, seizures), as well as hypotension. Patients may also experience chest discomfort, nervousness, irritability, tremor, muscle cramps, headache, insomnia, anxiety, euphoria, confusion, disorientation, or agitation. Palpitations, cardiac arrhythmias, and cardiac dysfunction may also occur, potentially leading to syncope or cardiac arrest. Caffeine overdose may cause the following symptoms: epigastric pain, vomiting, diuresis, tachycardia or cardiac arrhythmias, and central nervous system stimulation (insomnia, restlessness, excitation, psychomotor agitation, nervousness, tremors, and seizures).
There are no known cases of drotaverine overdose.
In case of accidental overdose with Pyralgina Plus, inform a doctor or pharmacist immediately, or contact the nearest hospital emergency department for further advice.

Missing a dose of Pyralgina Plus
If a dose is missed, it should be taken as soon as remembered, unless it is almost time for the next dose. Do not take a double dose to make up for a missed dose.
If there are any further doubts about the use of this medicine, consult a doctor or pharmacist.

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 severe allergic (anaphylactic) reactions occur:
Uncommon adverse reactions (occurring in fewer than 1 in 1,000 patients):

• swelling of the face, lips, tongue, and (or) throat, which may cause difficulty in swallowing or breathing;
• skin and mucous membrane changes such as itching, burning sensation, redness, rash, urticaria;

Very rare adverse reactions (occurring in fewer than 1 in 10,000 patients):

• severe bronchospasm;

Adverse reactions with unknown frequency (frequency cannot be estimated from available data):

• anaphylactic shock (life-threatening drop in blood pressure, weakness, fainting) (see Warnings and precautions in section 2).

The medicine must be discontinued and immediate medical help sought if any of the following serious adverse reactions occur:
Very rare adverse reactions (occurring in fewer than 1 in 10,000 patients):

• agranulocytosis (complete or near-complete absence of granulocytes in the blood), including fatal cases, manifested by:
• fever, chills;
• sore throat, difficulty swallowing, and inflammatory changes of the mucous membranes of the oral cavity, nose, throat, genital organs, and rectum;
• elevated ESR;
• hemoglobin, red blood cells, and platelets not always abnormal, although usually within normal limits;
• slightly enlarged lymph nodes and spleen, although often unchanged (see also Warnings and precautions in section 2);
• pancytopenia (marked reduction in all blood cells: red and white blood cells and platelets), presenting as general malaise, fever, signs of infection, bruising, bleeding, and pale skin (see Warnings and precautions in section 2);
• hemolytic anemia, aplastic anemia, bone marrow damage, sometimes resulting in death. In patients with glucose-6-phosphate dehydrogenase deficiency, the medicine may cause hemolysis of red blood cells;
• reduced platelet count (thrombocytopenia, usually presenting as increased tendency to bleed, petechiae on the skin and mucous membranes).

Adverse reactions with unknown frequency (frequency cannot be estimated from available data):

• severe skin reactions – red, flat spots on the trunk in the shape of target-like lesions or circular lesions, often with blisters in the center, skin peeling, ulcers in the mouth, throat, nose, genital organs, and eyes. Such serious skin eruptions may be preceded by fever and flu-like symptoms (Stevens-Johnson syndrome, toxic epidermal necrolysis); widespread rash, high fever, and enlarged lymph nodes (DRESS syndrome or drug hypersensitivity syndrome);
• acute generalized exanthematous pustulosis;
• skin blisters (bullous eruptions);
• acute kidney failure, which may present with low urine output (oliguria), cessation of urine output (anuria), or excess protein in urine (proteinuria), acute interstitial nephritis, red discoloration of urine;
• Kounis syndrome (acute coronary syndrome);
• liver damage;
• excessive drop in blood pressure (frequency for metamizole – unknown, for drotaverine – rare; see Warnings and precautions in section 2);
• analgesic-induced asthma (see When not to use Pyralgina Plus in section 2), asthma attacks.

Discontinue taking Pyralgina Plus and seek immediate medical help if any of the following symptoms occur:
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 abdomen. These may be symptoms of liver damage.
See also section 2 Warnings and precautions.
Other adverse reactions:
Not very common (occurring in fewer than 1 in 100 patients):

• drug rash (transient rash of various types: papular, macular, pustular, erythematous);

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

• papular-macular skin changes;
• leukopenia (reduced number of white blood cells in blood);
• insomnia (related to drotaverine);
• tremor;
• palpitations.

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

• gastrointestinal disorders, peptic ulcers and bleeding, vomiting, heartburn, bloating, nausea, abdominal pain, constipation, gastric irritation, diarrhea, dry mouth;
• hepatitis, jaundice (yellowing of skin and whites of eyes), increased liver enzyme activity in blood;
• headache and dizziness;
• red discoloration of urine (after very high doses of metamizole);
• changes in blood glucose levels (high and low glucose levels);
• irritability, insomnia (related to caffeine), nervousness, restlessness;
• psychomotor hyperactivity;
• increased myocardial contractility, irregular heart rhythm (arrhythmia), rapid heartbeat (tachycardia);
• flushing of the face, neck, and décolleté;
• various types of skin rashes/eruptions, exudative lesions, excessive sweating;
• muscle cramps;
• exhaustion;
• low blood pressure;
• drug withdrawal syndrome (the most common symptom of caffeine withdrawal is headache), nervousness;
• rapid heartbeat, increased urine flow, increased creatinine clearance, increased excretion of sodium and calcium.

Reporting of adverse reactions
If any adverse reactions occur, including any not listed in this leaflet, inform your doctor or pharmacist. 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.: 22 49-21-301, fax: 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 provide more information on the safety of the medicine.

5. How to store Pyralgina Plus

Do not store at temperatures above 30°C. Keep in the original packaging to protect from light and moisture.
The medicine should be stored out of sight and reach of children.
Do not use this medicine after the expiry date stated on the carton and blister after: 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. This will help protect the environment.

6. Contents of the pack and other information

What Pyralgina Plus contains

• The active substances are: metamizole sodium in the form of monohydrate metamizole sodium, caffeine, drotaverine hydrochloride.
• Other components (excipients) are: microcrystalline cellulose type 112, monohydrate lactose, crospovidone, talc, magnesium stearate, coating ingredients: polyvinyl alcohol, titanium dioxide (E 171), talc, soy lecithin, xanthan gum.

What Pyralgina Plus looks like and contents of the pack
Film-coated tablets, white or almost white, oval-shaped, engraved with the number "40" on one side.
Blister packs made of OPA/Aluminium/PVC/Aluminium foil containing 6 or 12 film-coated tablets in a cardboard box.

Marketing Authorisation Holder and Manufacturer
Marketing Authorisation Holder
Zakłady Farmaceutyczne POLPHARMA S.A.
Pelplińska Street 19, 83-200 Starogard Gdański
Phone: +48 22 364 61 01

Manufacturer
Adamed Pharma S.A.
Józefa Piłsudskiego Marszałka Street 5
95-200 Pabianice