COMBOVAL 10 mg/mL + 3 mg/mL Solution for Infusion

Introduction

Package Leaflet: Information for the Patient

Comboval 10 mg/ml + 3 mg/ml Solution for Infusion

paracetamol/ibuprofen

Read all of this leaflet carefully before you start taking this medicine because it contains important information for you.

• Keep this leaflet, you may need to read it again.
• If you have any further questions, ask your doctor or pharmacist.
• This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, even if their signs of illness are the same as yours.
• If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet. See section 4.
• Do not use this medicine for more than 2 days.

Contents of the Package Leaflet

1. What is Comboval and what is it used for
2. What you need to know before you are given Comboval
3. How Comboval is given
4. Possible side effects
5. Storage of Comboval
6. Contents of the pack and other information

1. What is Comboval and what is it used for

This medicine contains the active substances paracetamol and ibuprofen. Ibuprofen belongs to a group of medicines called non-steroidal anti-inflammatory drugs (or NSAIDs). Paracetamol works differently from ibuprofen, but both substances act together to relieve pain.

This medicine is used in adults for the short-term symptomatic treatment of moderate pain, when intravenous administration is necessary and/or when other routes of administration are not possible.

2. What you need to know before you are given Comboval

Comboval must not be given to you:

• if you are allergic to the active substances, other NSAIDs or any of the other ingredients of this medicine (listed in section 6);
• if you have severe heart failure, severe liver failure or severe kidney failure;
• if you habitually consume large amounts of alcohol;
• if you have asthma, urticaria or allergic reactions after taking acetylsalicylic acid or another NSAID;
• if you have a history of gastrointestinal bleeding or perforation related to previous NSAID therapy;
• if you have an active or recurrent peptic ulcer (e.g. stomach or duodenal ulcer), or bleeding (two or more episodes of ulceration or bleeding confirmed differently) active or recurrent.
• if you have cerebral hemorrhage (cerebrovascular hemorrhage) or other active bleeding;
• if you have coagulation disorders or a greater tendency to bleeding;
• if you have severe dehydration (caused by vomiting, diarrhea or insufficient fluid intake);
• during the last three months of pregnancy;
• if you are under 18 years old.

Warnings and Precautions

To avoid the risk of overdose,

• check that other medicines do not contain paracetamol,
• do not exceed the maximum recommended dose (see section 3).

Adverse effects can be minimized by using the minimum effective dose for the shortest duration necessary to control symptoms. Do not use this medicine for more than 2 days.

Consult your doctor or nurse before you are given Comboval if:

• you are taking other medicines that contain paracetamol, ibuprofen or any other analgesic anti-inflammatory (NSAID) (to avoid the risk of overdose);
• you have heart problems, even heart failure, angina pectoris (chest pain), or if you have had a heart attack, surgical revascularization, peripheral arteriopathy (poor circulation in the legs and feet due to narrow or blocked arteries), or any type of stroke (including 'mini-stroke' or transient ischemic attack 'TIA).

• you have high blood pressure, diabetes, high cholesterol, have a family history of heart disease or stroke, or if you smoke;
• you have liver disease, hepatitis, kidney disease or difficulty urinating
• you currently have an infection; this medicine may hide the symptoms and signs of an infection (fever, pain and swelling);
• you have or have had in the past stomach acid, indigestion, stomach ulcers or any other stomach problems;
• you have recently had or are scheduled to have surgery;
• you have an infection (see the heading 'Infections' below);
• you have asthma;
• you are dehydrated or have diarrhea;
• you have intestinal problems such as ulcerative colitis or Crohn's disease;
• you have a hereditary or acquired genetic disorder of certain enzymes that manifests as neurological complications or skin problems or occasionally both; i.e. porphyria;
• you have an autoimmune disease such as systemic lupus erythematosus or other collagen diseases, as there may be a greater risk of aseptic meningitis (inflammation of the protective membrane that covers the brain);
• you have allergic rhinitis, nasal polyps or chronic obstructive respiratory disorders due to a greater risk of allergic reactions;
• you are pregnant or plan to become pregnant (see section Pregnancy, breastfeeding and fertility).

During treatment with Comboval, inform your doctor immediately if: If you have severe diseases, such as severe kidney failure or sepsis (when bacteria and their toxins circulate in the blood, causing damage to organs), or if you have malnutrition, chronic alcoholism or if you are also taking flucloxacillin (an antibiotic). A serious disease called metabolic acidosis (an anomaly in the blood and fluids) has been reported in patients in these situations when paracetamol is used at regular doses for a prolonged period or when paracetamol is taken with flucloxacillin. The symptoms of metabolic acidosis may include: severe breathing difficulties with deep and rapid breathing, drowsiness, feeling unwell (nausea) and vomiting.

Cardiovascular Risk

Anti-inflammatory/analgesic medicines like ibuprofen may be associated with a slight increase in the risk of heart attack or stroke, especially when used at high doses. Do not exceed the recommended dose or treatment duration.

Gastrointestinal Symptoms

Severe gastrointestinal adverse effects (affecting the stomach and intestines) have been reported with the use of NSAIDs, including ibuprofen. The effects can occur with or without warning symptoms. The risk of these adverse effects is greater in patients with a history of stomach or intestinal ulcers, especially in the presence of bleeding or perforation. Elderly patients have a greater risk of gastrointestinal adverse effects. You should inform your doctor about any history of gastrointestinal problems and be alert to any unusual abdominal symptoms, including nausea, vomiting, diarrhea, constipation, indigestion, abdominal pain, black stools or vomiting blood.

Elderly patients should first consult treatment with a doctor. Elderly patients have a greater risk of adverse effects, particularly bleeding and perforation of the digestive tract.

Skin Reactions:

Severe skin reactions have been reported in association with ibuprofen treatment. You should inform your doctor or nurse immediately if you present any skin rash, lesions on the mucous membranes, blisters or other signs of allergy, as these may be the first signs of a very severe skin reaction. See section 4.

Infections

Comboval may hide signs of infections such as fever and pain. Consequently, this medicine may delay appropriate treatment of the infection, which can increase the risk of complications. This has been observed in pneumonia caused by bacteria and in bacterial skin infections related to chickenpox. If you are given this medicine while you have an infection and the symptoms of the infection persist or worsen, consult a doctor without delay.

Prolonged Use of Analgesics

Long-term use of analgesics can cause headaches, which should not be treated with more analgesics. If you think this applies to your case, consult your doctor or pharmacist.

Visual Disorders

If you notice any problems with your vision after using this medicine, stop using this treatment and consult a doctor.

Urinalysis and Blood Tests

If you need to provide a blood or urine sample for analysis, you should inform the doctor that you are taking this medicine, as it may interfere with the test results.

Children and Adolescents

This medicine must not be used in children and adolescents under 18 years old.

Other Medicines and Comboval

Inform your doctor or nurse if you are taking, have recently taken or might take any other medicine.

Always inform your doctor if you are taking other medicines that contain paracetamol, ibuprofen or other analgesic NSAIDs, even those that can be purchased without a prescription. This avoids the risk of overdose.

Comboval may affect or be affected by other medicines. For example:

• acetylsalicylic acid, salicylates or other NSAID medicines (including COX-2 inhibitors such as celecoxib or etoricoxib);
• medicines for treating heart diseases (e.g. digoxin or beta-blockers);
• corticosteroids, such as prednisone, cortisone;
• anticoagulant medicines (i.e. to dilute blood/prevent coagulation, e.g. acetylsalicylic acid, warfarin, ticlopidine);
• medicines that lower high blood pressure (ACE inhibitors such as captopril, beta-blockers such as atenolol, angiotensin-II receptor antagonists such as losartan);
• medicines for treating epilepsy or convulsions (e.g. phenytoin, phenobarbital, carbamazepine);
• medicines used to treat mania (e.g. lithium);
• medicines used to treat depression (e.g. SSRIs (selective serotonin reuptake inhibitors));
• probenecid, a medicine used to treat gout;
• diuretics, medicines used to increase urine production;
• methotrexate, a medicine used to treat arthritis and certain types of cancer;
• tacrolimus or cyclosporin, immunosuppressive medicines used after organ transplantation;
• zidovudine, a medicine used to treat HIV (the virus that causes AIDS);
• sulfonylureas, a medicine used to treat diabetes;
• a type of antibiotics known as quinolones (e.g. ciprofloxacin);
• a type of antibiotics known as aminoglycosides (e.g. gentamicin, streptomycin);
• chloramphenicol, an antibiotic used to treat ear and eye infections;
• antifungal medicines such as voriconazole or fluconazole;
• medicines for treating tuberculosis such as isoniazid and rifampicin;
• mifepristone, a medicine for medical termination of pregnancy;
• certain plant-based medicines, such as ginkgo biloba (sometimes used for dementia), or St. John's Wort (Hypericum, sometimes used for mild depression).
• flucloxacillin (antibiotic), due to a serious risk of blood and fluid anomaly (called metabolic acidosis) that requires urgent treatment (see section 2).

Other medicines may also affect or be affected by treatment with Comboval. Therefore, you should always consult your doctor, nurse or pharmacist before using other medicines.

Using Comboval with Alcohol

Do not consume alcoholic beverages when being treated with this medicine. Combining alcohol with this medicine can cause liver damage.

Pregnancy, Breastfeeding and Fertility

If you are pregnant or breastfeeding, think you may be pregnant or are planning to have a baby, ask your doctor or nurse for advice before you are given this medicine.

Pregnancy

This medicine must not be given during the last 3 months of pregnancy, as it may harm the unborn child or cause problems during delivery. It may cause kidney and heart problems in the unborn baby. It may affect your tendency to bleed and that of your baby and make delivery delayed or longer than expected.

Treatment during the first six months of pregnancy should only be given if it is clearly necessary and under the guidance of a doctor. If you need treatment during this period or while trying to become pregnant, the lowest dose should be used for the shortest possible time. If taken for more than a few days from 20 weeks of gestation onwards, this medicine may cause kidney problems in your unborn baby that can lead to low levels of amniotic fluid surrounding the baby (oligohydramnios) or narrowing of a blood vessel (ductus arteriosus) in the baby's heart. If you need treatment for more than a few days, your doctor may recommend additional monitoring.

Breastfeeding

Only small amounts of paracetamol and ibuprofen pass into breast milk. This medicine can be given during breastfeeding, if used at the recommended dose and for the shortest possible time.

Fertility

This product may impair fertility and is not recommended in women who are trying to become pregnant. This effect is reversible upon discontinuation of this medicine.

Driving and Using Machines

Adverse effects such as dizziness, drowsiness, fatigue and visual disturbances are possible after taking NSAIDs. You should not drive or use machines if you are affected.

Comboval Contains Sodium

This medicine contains 35 mg of sodium (main component of cooking/table salt) in each 100 ml (1.52 mmol per 100 ml). This is equivalent to 1.75% of the maximum recommended daily intake of sodium for an adult.

3. How to Use Comboval

This medicine will be given to you by a healthcare professional through infusion into one of your veins. The infusion should be given over 15 minutes.

This medicine is only for short-term use, a maximum of 2 days.

The recommended dose is:

For adults weighing more than 50 kg: 1 vial every 6 hours, as needed.

The maximum daily dose is four vials, which is equivalent to 4000 mg (400 ml) of paracetamol and 1200 mg (400 ml) of ibuprofen.

If you weigh 50 kg or less, are an elderly patient or have liver and kidney problems:Your doctor may decide to reduce your dose or increase the time between doses due to the greater risk of adverse effects.

A dose higher than recommended does not increase pain relief, but may create serious risks (see the section "If you are given more Comboval than you should"). The effective dose should be given for the shortest time necessary to relieve symptoms. If you have an infection, consult a doctor without delay if the symptoms (such as fever and pain) persist or worsen (see section 2).

If You Are Given More Comboval Than You Should

Contact a doctor or nurse immediatelyif you think you have been accidentally given too much of this medicine. You should do this even if you feel well. An overdose of paracetamol can cause serious delayed liver damage, which can be fatal. You may need urgent medical attention, even if there are no signs of discomfort or poisoning: Toxicology Information Service, phone: 91 562 04 20.

It is essential to obtain medical treatment as soon as possible to avoid liver damage. The shorter the interval between ingestion and the start of treatment with the antidote (the fewer hours possible), the greater the probability of preventing liver injury.

Additional symptoms of overdose may include nausea, stomach pain, vomiting (which may be blood-stained), headache, ringing in the ears, confusion and unsteady eye movements. At high doses, somnolence, chest pain, palpitations, loss of consciousness, convulsions (mainly in children), weakness and dizziness, blood in the urine, low potassium levels in the blood, feeling cold and breathing problems have been reported.

4. Possible Adverse Effects

Like all medicines, this medicine can cause adverse effects, although not all people suffer from them.

Stop usingComboval and inform your doctor immediatelyor go to the emergency room of the nearest hospital if you notice any of the following adverse effects:

Uncommon:

• vomiting with blood or substances similar to coffee grounds;
• rectal bleeding, black sticky stools (feces) or bloody diarrhea;
• swelling of the face, lips or tongue that could cause difficulty swallowing or breathing.

Very rare:

• asthma, wheezing, shortness of breath;
• sudden or severe itching, skin rash, hives;
• severe rash with blisters and bleeding of the lips, eyes, mouth, nose, and genitals (Stevens-Johnson syndrome). Very rare cases of severe skin reactions have been reported;
• worsening of severe skin infections (you may notice a rash, blistering, and changes in skin color, fever, drowsiness, diarrhea, and a feeling of discomfort), or worsening of other infections, including chickenpox or shingles, or a severe infection with destruction (necrosis) of subcutaneous and muscle tissue, blistering, and peeling of the skin;
• fever, feeling of general discomfort, nausea, stomach pain, headache, and stiffness of the neck (symptoms of aseptic meningitis, an inflammation of the protective membrane that covers the brain).

Unknown (frequency cannot be estimated from available data):

• a severe skin reaction known as DRESS syndrome may occur. The symptoms of DRESS syndrome include: skin rash, fever, swelling of the lymph nodes, and elevated eosinophils (a type of white blood cell).
• generalized scaly red rash, with bumps under the skin and blisters mainly on the skin folds, trunk, and upper limbs, accompanied by fever at the start of treatment (acute generalized exanthematous pustulosis). See section 2.
• A severe disease that can make the blood more acidic (called metabolic acidosis) in patients with severe disease using paracetamol (see section 2).

Other adverse effects that may occur:

Frequent (may affect up to 1 in 10 people):

• nausea or vomiting;
• loss of appetite;
• heartburn or pain in the upper part of the stomach;
• stomach spasms, flatulence, constipation, or diarrhea, mild gastrointestinal bleeding;
• skin rashes, itching of the skin;
• headache;
• dizziness;
• feeling of nervousness;
• ringing or buzzing in the ears;
• unusual weight gain, swelling, and fluid retention, swelling of the ankles or legs (edema).

Uncommon (may affect up to 1 in 100 people):

• decrease in red blood cells, nosebleeds, and heavy menstrual bleeding (menstrual bleeding);
• allergic reactions - skin rash, fatigue, joint pain (e.g., serum sickness, lupus erythematosus, Henoch-Schönlein vasculitis, angioedema);
• increase in breast tissue in men; low blood sugar levels;
• insomnia;
• mood changes, such as depression, confusion, nervousness;
• eye problems such as blurred vision (reversible), irritated red eyes, itching;
• thickness of mucus;
• severe stomach pain or sensitivity; peptic ulcer/gastrointestinal ulcer;
• inflammation of the intestine and worsening of inflammation of the colon (colitis) and the digestive tract (Crohn's disease) and complications of diverticulitis of the large intestine (perforation or fistula);
• inability to empty the bladder completely (urinary retention);
• abnormal laboratory test results (abnormal liver and kidney enzyme test results).

Rare (may affect up to 1 in 1,000 people):

• tingling in the hands and feet;
• abnormal dreams, seeing things (hallucinations);
• kidney tissue damage (especially with long-term use);
• high levels of uric acid in the blood (hyperuricemia).

Very rare (may affect up to 1 in 10,000 people):

• low potassium levels - weakness, fatigue, muscle cramps (hypokalemia);
• signs of anemia, such as fatigue, headaches, feeling short of breath, and being pale;
• appearance of bleeding or bruising more easily than normal, reddish or purplish spots under the skin;
• severe or persistent headache;
• feeling of dizziness (vertigo);
• rapid or irregular heartbeat, also called palpitations;
• increase in blood pressure and possible heart problems;
• inflammation of the esophagus;
• yellowing of the skin and/or eyes, also called jaundice;
• liver damage (especially with long-term use);
• hair loss;
• increased sweating;
• signs of frequent or disturbing infections such as fever, chills, sore throat, or mouth ulcers;
• various forms of nephrotoxicity, including interstitial nephritis, nephrotic syndrome, and acute and chronic renal failure.

Reporting of Adverse Effects

If you experience any type of adverse effect, consult your doctor or pharmacist, even if it is a possible adverse effect that is not listed in this prospectus. You can also report them directly through the national reporting system included in the Spanish Pharmacovigilance System for Human Use Medicines: www.notificaRAM.es. By reporting adverse effects, you can contribute to providing more information on the safety of this medicine.

5. Storage of Comboval

Keep this medicine out of sight and reach of children.

Store below 25°C. Do not refrigerate or freeze. Keep in the original packaging to protect it from light.

Do not use this medicine after the expiration date that appears on the box and vial after CAD. The expiration date is the last day of the month indicated.

Do not use this medicine if you notice that the packaging is broken or shows signs of tampering. Do not use this medicine if you notice visible particles or discoloration.

This medicine is for single use. The product must be used immediately after opening. Any unused solution must be discarded.

Medicines should not be thrown down the drain or into the trash. Ask your pharmacist how to dispose of the packaging and medicines that are no longer needed. This will help protect the environment.

6. Package Contents and Additional Information

Composition of Comboval

The active ingredients are 10 mg/ml of paracetamol and 3 mg/ml of ibuprofen (as sodium dihydrate).

The other components are monohydrate hydrochloride of cysteine, dihydrate sodium hydrogen phosphate, mannitol, hydrochloric acid (for pH adjustment), sodium hydroxide (for pH adjustment), and water for injectable preparations.

Appearance of the Product and Package Contents

Clear, colorless, and particle-free solution for infusion. It is presented in transparent glass vials of 100 ml, closed with gray bromobutyl rubber stoppers and a flip-off aluminum cap. It is presented in packages of 10 vials.

Marketing Authorization Holder:

Laboratoire AGUETTANT

1, rue Alexander Fleming

69007 Lyon

France

Manufacturer:

S.M. Farmaceutici S.r.l.

Zona Industriale Tito Scalo Snc

85050 Tito (PZ)

Italy

Local Representative:

AGUETTANT Ibérica SL

Baldiri Reixac, 4-8, Torre I, 4º

08028 Barcelona

Date of the Last Revision of this Prospectus

23/01/2025

Other Sources of Information:

Detailed information about this medicine is available on the website of the Spanish Agency for Medicines: http://www.aemps.gob.es/

This information is intended only for healthcare professionals:

Comboval 10 mg/ml + 3 mg/ml solution for infusion

Before administration, the solution should be visually inspected to verify the absence of particles and discoloration, when the solution and packaging permit. The solution should not be used if opaque particles, discoloration, or other foreign particles are observed.

In the absence of compatibility studies, this medicine should not be mixed with diluents. If less than a full vial is required for a single dose, the appropriate amount should be infused and the remaining solution discarded.

This medicine is for single-patient use only. It does not contain any antimicrobial preservative. Any unused solution should be discarded.

Method of administration

This medicine should be administered as a 15-minute intravenous infusion.

Use a 0.8 mm needle (21 gauge needle) to extract the solution vertically and pierce the stopper at the point expressly indicated.

In patients who weigh less than 50 kg for whom a full vial (100 ml) is not needed, the correct amount should be infused and the remaining solution discarded.

As with all solutions for infusion presented in glass vials, it should be remembered that close supervision is required, especially at the end of the infusion, regardless of the route of administration. This supervision at the end of the infusion applies particularly to central venous infusion, to avoid a gas embolism.