Package leaflet: Information for the patient

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

paracetamol/ibuprofen
Please read all of this leaflet carefully before taking this medicine because it contains important information for you.

Keep this leaflet. You may need to read it again.
If you have any questions, ask your doctor or pharmacist.
This medicine has been prescribed for you only. Do not give it to other people, even if their symptoms are the same as yours, as it may be harmful.
If you experience any side effect, including those not listed in this leaflet, talk to your doctor or pharmacist. See section 4.
Do not use this medicine for more than 2 days.

Contents of this leaflet

What Combogesic is and what it is used for
What you need to know before taking Combogesic
How to take Combogesic
Possible side effects
How to store Combogesic
Contents of the pack and other information

1. What Combogesic is and what it is used for

Combogesic contains the active substances paracetamol and ibuprofene. Ibuprofene belongs to a group of medicines called non-steroidal anti-inflammatory drugs (NSAIDs). Paracetamol works differently from ibuprofene, but both substances work together to reduce pain.
Combogesic is used in adults for the short-term symptomatic treatment of moderate acute pain, when intravenous administration is required and/or when other routes of administration are not possible.

2. What you need to know before taking Combogesic

Do not take Combogesic:

if you are allergic to the active substances, to other NSAIDs, or to any of the other ingredients of this medicine (listed in section 6);
if you have severe heart, liver, or kidney failure;
if you regularly drink large amounts of alcohol;
if you have asthma, urticaria, or allergic-type reactions after taking acetylsalicylic acid or other NSAIDs;
if you have a history of gastrointestinal bleeding or perforation related to previous NSAID therapy;
if you have active or recurrent peptic ulcer (i.e. gastric or duodenal ulcer), or active bleeding (two or more distinct episodes of ulceration or bleeding confirmed);
if you have cerebral hemorrhage (cerebrovascular hemorrhage) or other active bleeding;
if you have a blood coagulation disorder or increased tendency to bleed;
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 of age.

Warnings and precautions
To avoid the risk of overdose:

check that other medicines do not contain paracetamol;
do not exceed the recommended maximum doses (see section 3).

Undesirable effects can be minimized by using the lowest effective dose for the shortest duration necessary to control symptoms. Do not use Combogesic for more than 2 days.
Consult your doctor or nurse before taking Combogesic if:

you are taking other medicines containing paracetamol, ibuprofen, or other anti-inflammatory painkillers (NSAIDs) (to avoid the risk of overdose);
you have heart problems, including heart failure, angina pectoris (chest pain), or if you have had a heart attack, coronary bypass surgery, peripheral arterial disease (poor circulation in the legs or feet due to narrowed or blocked arteries), or any type of stroke (including "mini-stroke" or transient ischemic attack "TIA");
you have high blood pressure, diabetes, high cholesterol levels, a family history of heart disease or stroke, or if you are a smoker;
you have liver disease, hepatitis, kidney disease, or difficulty urinating;
you currently have an infection; Combogesic may mask symptoms or signs of infection (fever, pain, and swelling);
you have previously experienced heartburn, indigestion, gastric ulcer, or any other stomach problem;
you have recently undergone or are scheduled for surgery;
you have an infection (see section "Infections" below);
you have asthma;
you are dehydrated or have diarrhea;
you have intestinal disorders such as ulcerative colitis or Crohn's disease;
you have an inherited or acquired genetic defect in certain enzymes, manifesting with neurological complications, skin problems, or occasionally both, for example porphyria;
you have an autoimmune disease such as systemic lupus erythematosus or other connective tissue disorders, as there may be an increased risk of aseptic meningitis (inflammation of the protective membrane surrounding the brain);
you suffer from hay fever, nasal polyps, or chronic obstructive respiratory disorders, as there may be an increased risk of allergic reactions;
you are pregnant or planning to become pregnant (see section "Pregnancy, breastfeeding and fertility").

Cardiovascular risk
Anti-inflammatory/pain-relieving medicines such as ibuprofen may be associated with a small increased risk of heart attack or stroke, particularly when used at high doses. Do not exceed the recommended dose or duration of treatment.
Gastrointestinal symptoms
Serious gastrointestinal adverse effects (affecting the stomach and intestines) have been reported with the use of NSAIDs, including ibuprofen. These may occur with or without warning symptoms. The risk of such adverse effects is higher in patients with a history of stomach or intestinal ulcers, especially if bleeding or perforation has occurred. Elderly patients are at greater risk of gastrointestinal adverse effects. Inform your doctor of any gastrointestinal problems, and be alert to any unusual abdominal symptoms, including nausea, vomiting, diarrhea, constipation, indigestion, abdominal pain, tarry stools, or vomiting blood.
Elderly patients should first consult a doctor before starting treatment. Elderly patients are at higher risk of gastrointestinal adverse effects, especially bleeding and perforation in the digestive tract.
Skin reactions
Severe skin reactions have been reported in association with ibuprofen treatment. Inform your doctor or nurse immediately if you develop any skin rash, mucosal lesions, blisters, or other signs of allergy, as these may be the first signs of a very serious skin reaction. See section 4.
Infections
Combogesic may mask signs of infection such as fever and pain. Therefore, Combogesic may delay appropriate treatment of the infection, potentially increasing the risk of complications. This has been observed in bacterial pneumonia and bacterial skin infections associated with chickenpox. If you are given this medicine while having an infection and infection symptoms persist or worsen, consult a doctor immediately.
Prolonged use of painkillers
If you use painkillers for a long time, this may cause headaches, which should not be treated with additional painkillers. If you think this applies to you, discuss it with your doctor or pharmacist.
Vision problems
If you notice any vision problems after using Combogesic, stop taking the medicine and consult a doctor.
Children and adolescents
Combogesic must not be used in children and adolescents under 18 years of age.
Other medicines and Combogesic
Inform your doctor or nurse if you are taking, have recently taken, or might take any other medicines.
Always inform your doctor if you are taking other medicines containing paracetamol, ibuprofen, or other NSAID painkillers, including those available without prescription, to avoid the risk of overdose.
Combogesic may affect or be affected by other medicines. For example:

acetylsalicylic acid, salicylates, or other NSAID drugs (including COX-2 inhibitors such as celecoxib or etoricoxib);
medicines used to treat heart conditions (e.g. digoxin or beta-blockers);
corticosteroids, such as prednisone and cortisone;
medicines that are anticoagulants (thin the blood/prevent clotting, 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 used to treat epilepsy or seizures (e.g. phenytoin, phenobarbital, carbamazepine);
medicines used to treat mania (e.g. lithium);
medicines used to treat depression, for example 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 cyclosporine, immunosuppressive drugs used after organ transplantation;
zidovudine, a medicine used to treat HIV (the virus that causes AIDS);
sulfonylureas, medicines used to treat diabetes;
a type of antibiotics known as quinolone antibiotics (e.g. ciprofloxacin);
a type of antibiotics known as aminoglycosides (e.g. gentamicin, streptomycin);
chloramphenicol, an antibiotic used to treat eye and ear infections;
antifungal medicines such as voriconazole or fluconazole;
medicines used to treat tuberculosis such as isoniazid and rifampicin;
mifepristone, a medicine used for medical termination of pregnancy;
certain herbal remedies, such as ginkgo biloba (sometimes used for dementia), or St. John's wort (Hypericum, sometimes used for mild depression).

Other medicines may also affect or be affected by treatment with Combogesic. Therefore, always consult your doctor, nurse, or pharmacist before taking any other medicine.
If you are required to provide a blood or urine sample for testing, inform your doctor that you are taking this medicine, as it may interfere with test results.
Combogesic and alcohol
Do not drink alcoholic beverages during treatment with this medicine. Combining alcohol with Combogesic may cause liver damage.
Pregnancy, breastfeeding and fertility
If you are pregnant, think you may be pregnant, are planning to become pregnant, or are breastfeeding, consult your doctor or pharmacist before taking this medicine.
Pregnancy
This medicine must not be taken during the last three months of pregnancy. Use during the first six months of pregnancy should only occur when strictly necessary and under direct medical supervision.
Breastfeeding
Only small amounts of paracetamol and ibuprofen are excreted in breast milk. This medicine may be used during breastfeeding if taken at the recommended dose and for the shortest possible duration.
Fertility
It may impair female fertility and is not recommended for women attempting to conceive. This effect is reversible upon discontinuation of the medicine.
Driving and using machines
Adverse effects such as dizziness, drowsiness, fatigue, and visual disturbances are possible after taking NSAIDs. If such effects occur, patients must not drive or operate machinery.
Combogesic contains sodium
This medicine contains 35 mg of sodium (a main component of table salt) per 100 ml. This corresponds to 1.75% of the maximum daily dietary intake recommended for an adult.

3. How to use Combogesic

Combogesic will be administered to you by a healthcare professional through an intravenous infusion into one of your veins.
The infusion must be given over 15 minutes.
This medicine is for short-term use only, maximum 2 days.
The recommended dose is:
For adults weighing more than 50 kg: 1 vial every 6 hours, if necessary.
The maximum daily dose is four vials, equivalent to 4000 mg (4 g) of paracetamol and 1200 mg of ibuprofen.
If you weigh 50 kg or less, if you are elderly, or if you have liver or kidney problems: your doctor may decide to reduce the dose or increase the time between doses due to an increased risk of adverse effects.
A higher than recommended dose does not increase pain relief but may lead to serious risks (see also section "If you have been given more Combogesic than you should"). The lowest effective dose should be given for the shortest duration necessary to relieve symptoms. If you have an infection, consult a doctor immediately if symptoms (such as fever and pain) persist or worsen (see section 2).
If you have been given more Combogesic than you should
Contact a doctor or nurse immediately if you think you have accidentally received an excessive amount of this medicine. Do this even if you feel well. This is because an excessive amount of paracetamol can cause delayed, severe liver damage, which may be fatal. Even if there are no signs of illness or poisoning, you may still need urgent medical treatment.
To prevent liver damage, it is essential to receive medical treatment as soon as possible. The shorter the interval between ingestion and the start of treatment with the antidote (the fewer hours possible), the greater the likelihood that liver damage can be avoided.
Other symptoms may include nausea, stomach ache, vomiting (which may be blood-streaked), headache, ringing in the ears, confusion, and flickering eye movements. At high doses, drowsiness, chest pain, palpitations, loss of consciousness, seizures (especially in children), weakness, dizziness, blood in the urine, feeling cold, and breathing difficulties have been reported.

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everyone experiences them.
Stop using Combogesic and inform your doctor immediately or go to the nearest hospital emergency department if you experience any of the following side effects:

Uncommon:

vomiting blood or material resembling coffee grounds;
bleeding from the rectum, black and sticky bowel movements (faeces), bloody diarrhoea;
swelling of the face, lips or tongue which may cause difficulty in swallowing and breathing.

Very rare:

asthma, shortness of breath, difficulty breathing;
sudden or severe itching, skin reactions, urticaria;
severe skin rash with blisters and bleeding in the lips, eyes, mouth, nose and genitals (Stevens-Johnson syndrome). Very rare cases of serious skin reactions have been reported;
worsening of severe pre-existing skin infections (you may notice a skin rash, blisters and skin discolouration, fever, drowsiness, diarrhoea and malaise), or worsening of other infections including chickenpox, herpes or serious infections with destruction (necrosis) of subcutaneous and muscular tissue, blisters and peeling of the skin;
fever, general malaise, nausea, stomach pain, headache and neck stiffness (symptoms of aseptic meningitis, inflammation of the protective membrane surrounding the brain).

Not known (frequency cannot be estimated from the available data):

a serious skin reaction known as DRESS syndrome may occur. Symptoms of DRESS include: skin rash, fever, swollen lymph nodes and increased eosinophils (a type of white blood cells).
widespread, red, scaly rash with bumps under the skin and blisters mainly located in skin folds, trunk and upper extremities, accompanied by fever at the beginning of treatment (generalised pustular eruption). See also section 2.

Additional side effects:
Common (may affect up to 1 in 10 people):

nausea or vomiting;
loss of appetite;
heartburn or pain in the upper stomach;
stomach cramps, flatulence, constipation or diarrhoea, mild gastrointestinal bleeding;
skin rashes, skin itching;
headache;
dizziness;
feeling nervous;
noises or ringing in the ears;
unusual weight gain, swelling and fluid retention, swelling of the ankles and legs (oedema).

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

decrease in red blood cells, nosebleeds and heavier menstrual periods (menstrual bleeding);
allergic reactions – skin rash, fatigue, joint pain (e.g. serum sickness, lupus-like syndrome, Henoch-Schönlein vasculitis, angioedema);
breast enlargement in men; low blood sugar levels;
insomnia;
mood changes, such as depression, confusion, nervousness;
eye problems such as blurred vision (reversible), painful red eyes, itching;
thickened mucus;
severe pain or tightness in the stomach; peptic/gastrointestinal ulcer;
intestinal inflammation and worsening of colon inflammation (colitis) and digestive tract inflammation (Crohn’s disease), and complications of diverticula of the large intestine (perforation or fistula);
inability to completely empty the bladder (urinary retention);
abnormal laboratory test results (blood test results, liver and kidney enzymes).

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

tingling in hands and feet;
unusual dreams, hallucinations;
kidney tissue damage (particularly with long-term use);
high levels of uric acid in the blood (hyperuricaemia).

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

low potassium levels – weakness, fatigue, muscle cramps (hypokalaemia);
signs of anaemia such as tiredness, headache, shortness of breath and pale appearance;
bleeding or bruising more easily than normal, reddish or purplish spots under the skin;
severe and persistent headache;
sensation of spinning (dizziness);
fast or irregular heartbeat, also known as palpitations;
increased blood pressure and possible heart problems;
inflammation of the oesophagus;
yellowing of the skin and/or eyes, also known as jaundice;
liver damage (particularly with long-term use);
hair loss;
increased sweating;
signs of frequent and concerning infections such as fever, severe chills, sore throat or mouth ulcers;
nephrotoxicity in various forms, including interstitial nephritis, nephrotic syndrome and acute and chronic renal failure.

Reporting of side effects
If you experience any side effect, including those not listed in this leaflet, talk to your doctor or pharmacist. You can also report side effects directly via the national reporting system at https://www.aifa.gov.it/content/segnalazioni-reazioni-avverse.
By reporting side effects, you can help provide more information on the safety of this medicine.

5. How to store Combogesic

Keep this medicine out of the sight and reach of children and adolescents.
Store below 25°C. Do not refrigerate or freeze. Keep in the original packaging to protect the medicine from light.
Do not use this medicine after the expiry date stated on the packaging and vial after Exp. The expiry date refers to the last day of that month.
Do not use this medicine if the packaging is torn or shows signs of tampering. Do not use this medicine if you notice any visible particles or discoloration.
This product is for single use only. The product must be used immediately after opening.
Any unused solution must be discarded.
Dispose of in accordance with local requirements.

6. Package contents and other information

What Combogesic contains
The active substances are 10 mg/ml of paracetamol and 3 mg/ml of ibuprofen.
The other components are cysteine hydrochloride monohydrate, disodium phosphate dihydrate, mannitol, hydrochloric acid (for pH adjustment), sodium hydroxide (for pH adjustment), and water for injections.

Description of the appearance of Combogesic and contents of the pack
Combogesic is a clear, colourless infusion solution free from visible particles. It is supplied in 100 ml transparent glass vials closed with a grey bromobutyl rubber stopper and an aluminium flip-off cap. It is available in packs of 10 vials.

Marketing Authorisation Holder and Manufacturer
Marketing Authorisation Holder:
EVER Valinject GmbH
Oberburgau 3
4866 Unterach am Attersee
Austria

Manufacturer:
S.M. Farmaceutici SRL
Zona Industriale
85050 Tito (PZ)
Italy

This medicinal product is authorised in the European Economic Area Member States under the following names:
Sweden Paraibucomb
Germany Comboval 10 mg/ml + 3 mg/ml Infusionslösung
Austria Comboval 10 mg/ml + 3 mg/ml Infusionslösung
France Cetafen 10 mg/ml + 3 mg/ml par mL, solution pour perfusion

The following information is intended exclusively for healthcare professionals:

Combogesic
Visually inspect Combogesic for the presence of particulate matter and discoloration prior to administration, whenever solution and container permit. If opaque particles, discoloration, or other foreign particles are observed, the solution must not be used.

In the absence of compatibility studies, this medicinal product must not be mixed with diluents. If less than an entire vial (100 ml) is required for a single dose, the appropriate amount should be infused and the remaining solution discarded.

Combogesic is intended for use in a single patient on a single occasion only. It does not contain antimicrobial preservatives. Unused solution must be discarded.

Method of administration
Combogesic must be administered as a 15-minute intravenous infusion.

To withdraw the solution, use a 0.8 mm needle (21 gauge) and puncture the stopper vertically at the specifically marked point.

In patients weighing less than 50 kg for whom a full vial (100 ml) is not required, the appropriate volume should be infused and the remaining solution discarded.

As with all infusion solutions presented in glass vials, close monitoring is required, particularly at the end of the infusion, regardless of the route of administration. This end-of-infusion monitoring is particularly important when administering via central lines, in order to prevent air embolism.

Combgesic