Isofenal

Package leaflet: Information for the patient

Isofenal 100 mg/2 ml injectable solution for intramuscular use

ketoprofen
Generic medicine
Please read this leaflet carefully before using 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 others, even if their symptoms are the same as yours, as it could be harmful.
• If you experience any side effect, including those not listed in this leaflet, contact your doctor or pharmacist. See section 4.

Contents of this leaflet:

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

1. What Isofenal is and what it is used for

Isofenal contains the active substance ketoprofen.
Ketoprofen belongs to a group of medicines called non-steroidal anti-inflammatory and anti-rheumatic drugs, used for the short-term symptomatic treatment of inflammatory conditions associated with pain affecting the joints, muscles, tendons and ligaments (musculoskeletal system).

2. What you need to know before using Isofenal

Do not use Isofenal

• if you are allergic (hypersensitive) to ketoprofen, to medicines similar to it (NSAIDs), or to any of the other ingredients of this medicine (listed in section 6);
• if you have previously experienced an allergic reaction after taking acetylsalicylic acid (aspirin) or other non-steroidal anti-inflammatory drugs. There is a possibility that if you are allergic to these substances, you may also be allergic to ketoprofen, and thus may experience breathing difficulties (bronchospasm, asthma attacks), rhinitis, urticaria, or other allergic-type reactions. Severe, sudden-onset allergic reactions (anaphylactic), rarely fatal, have been reported in such patients;
• if you are in the third trimester of pregnancy (see section “Pregnancy and breastfeeding”);
• if the person taking this medicine is a child or adolescent under 18 years of age;
• if you are undergoing intensive therapy with drugs that stimulate diuresis (diuretics);
• if you have had or currently have bleeding (hemostatic disorders), lesions (ulcers), or perforation in the stomach or intestines, even as a result of previous treatment with non-steroidal anti-inflammatory drugs;
• if you have severe kidney problems;
• if you suffer from a reduced number of white blood cells (leucopenia) or a reduced number of platelets (thrombocytopenia);
• if you have active bleeding or a predisposition to bleeding (hemorrhagic diathesis);
• if you have difficulty stopping bleeding (hemorrhages) or are being treated with drugs that inhibit clot formation;
• if you have severe heart problems;
• if you suffer from gastritis or chronic digestive disorders (dyspepsia);
• if you have severe liver problems;
• if you experience bleeding in the brain or any other type of bleeding;
• if you are taking other non-steroidal anti-inflammatory drugs, including those that selectively inhibit an enzyme called cyclooxygenase-2 (see “Warnings and precautions” and “Other medicines and Isofenal”).

Warnings and precautions
Talk to your doctor or pharmacist before taking Isofenal.

• If you suffer from asthma or have chronic rhinitis, chronic sinusitis, and/or nasal polyps. These conditions may increase your risk of developing allergic reactions to anti-inflammatory drugs and aspirin (acetylsalicylic acid) (see “Other medicines and Isofenal”).
• If you have severe kidney, heart, or liver disorders, if you are being treated with diuretic medicines, or if you are elderly. In all these cases, the use of ketoprofen may reduce blood flow to the kidneys and lead to renal failure. Only your doctor can decide whether you may use Isofenal and, if so, will monitor your kidney function closely.
• If you are hypertensive (prone to high blood pressure) or suffer from mild to moderate heart failure. You may develop fluid retention and swelling (edema).
• If you have heart problems (uncontrolled hypertension, congestive heart failure, established ischemic heart disease, peripheral arterial disease, and/or cerebrovascular disease) or conditions that predispose you to cardiovascular diseases (e.g., hypertension, hyperlipidemia, diabetes mellitus, smoking). The use of Isofenal should be evaluated by your doctor, who will determine whether the benefits outweigh the potential risks.
• If you are an elderly patient. Your age increases the risk of adverse effects from anti-inflammatory drugs, especially gastrointestinal bleeding and perforation of the stomach or intestine, sometimes even fatal. The risk increases with higher doses. Your doctor may advise starting treatment with the lowest available dose and taking gastroprotective agents.
• If you are taking other medicines that increase the risk of ulceration or bleeding, such as oral corticosteroids, anticoagulants like warfarin, antidepressants (selective serotonin reuptake inhibitors), or antiplatelet agents such as aspirin or nicorandil (see section “Other medicines and Isofenal”).
• If you suffer from stomach or intestinal diseases (ulcerative colitis, Crohn’s disease). The use of NSAIDs may worsen your condition (see section 4).
• If you have low body weight. This condition increases the risk of bleeding.
• If you suffer from heart failure, cirrhosis (chronic liver disease), or nephrotic syndrome, in patients on diuretic therapy, and in patients with chronic renal failure, especially in the elderly.
• If you have an infection (see section “Infections” below).

While using Isofenal, keep in mind that:

• Using this medicine at the lowest doses and for short periods reduces the occurrence of adverse effects (see below and section 3).
• This drug cannot be considered a simple painkiller and must be used under strict medical supervision.
• After the acute painful episode has passed, it is advisable to switch to non-parenteral formulations, which, although causing qualitatively similar adverse effects, are less likely to induce severe reactions. Prolonged use of injectable intramuscular Isofenal is permitted only in hospitals and care facilities. Injections must be administered strictly following hygienic guidelines.
• Concomitant use of Isofenal with other anti-inflammatory drugs should be avoided, including selective cyclooxygenase-2 inhibitors (see “Other medicines and Isofenal”).
• The use of anti-inflammatory drugs, especially at high doses and for long periods, may increase the risk of developing heart attack or stroke.
• Ketoprofen may cause serious heart and circulatory problems (arterial thrombotic events, heart attack, or stroke), particularly at high doses, during prolonged treatment, or when used to treat pain before or after coronary artery bypass surgery (see section “Possible side effects”);
• During treatment with all non-steroidal anti-inflammatory drugs (NSAIDs), gastrointestinal bleeding, ulceration, and perforation of the stomach and intestine—potentially fatal—have been reported at any time, with or without warning symptoms or previous history of serious gastrointestinal reactions. The risk of such reactions appears to be higher with ketoprofen than with other NSAIDs, especially at high doses (see also “Do not take Isofenal” and section 4).
• If you are a patient with a history of ulcers complicated by bleeding and perforation, especially if elderly, report any abdominal symptoms (particularly gastrointestinal bleeding) immediately, especially during the initial stages of treatment.
• If you experience gastrointestinal bleeding or ulceration, stop treatment immediately and contact your doctor or go to the nearest hospital.
• During long-term treatments, blood cell count tests (hematological monitoring) and liver function tests (especially if you have liver problems) and kidney function tests should be performed regularly.
• Concomitant use of NSAIDs and other drugs that cause high blood potassium levels may lead to an increase in this condition (see “Other medicines and Isofenal”).
• As with other NSAIDs, in case of infections, it should be noted that the anti-inflammatory, analgesic, and antipyretic properties of ketoprofen may mask characteristic symptoms of infection progression, such as fever.
• The use of NSAIDs may rarely cause severe skin reactions, some of which are fatal, including widespread and peeling skin irritation (exfoliative dermatitis), severe skin reaction with skin peeling and swelling, blisters on skin, mouth, eyes, genitals (Stevens-Johnson Syndrome), often accompanied by malaise, chills, myalgia, and fever (toxic epidermal necrolysis) (see section 4). These reactions usually occur within the first month of treatment. Immediately discontinue treatment with Isofenal at the first sign of skin rash, mucosal lesions, or any other sign of allergy (hypersensitivity).

Elderly patients
Elderly patients have a higher frequency of developing adverse reactions to NSAIDs, especially gastrointestinal bleeding and perforation, which may be fatal (see section 3).
Children
The safety and efficacy of ketoprofen have not been studied in children. The medicine is contraindicated in children and adolescents under 18 years of age.
Other medicines and Isofenal
Inform your doctor or pharmacist if you are taking, have recently taken, or might take any other medicine.
Some medicines may alter the effect of Isofenal, or the effect of these medicines may be altered by Isofenal. This type of interaction may reduce the effect of one or both medicines. Alternatively, it may increase the risk or severity of adverse effects.
Do not take Isofenal with:

• Lithium (a drug used for depression): risk of increased lithium levels in the blood,
• Other non-steroidal anti-inflammatory drugs (NSAIDs) and high doses of salicylates: increased risk of gastrointestinal ulceration and bleeding.
• Methotrexate at doses exceeding 15 mg/week: increased risk of blood toxicity caused by methotrexate. A 12-hour interval must be maintained between stopping or starting ketoprofen treatment and methotrexate administration.
• Anticoagulants (heparin, warfarin, dabigatran, apixaban, rivaroxaban, edoxaban): NSAIDs may enhance the effects of anticoagulants such as warfarin and heparin.
• Antiplatelet agents such as ticlopidine, clopidogrel, or substances like tirofiban, eptifibatide, abciximab, and iloprost: increased risk of gastrointestinal bleeding (see “Warnings and precautions”). If co-administration is unavoidable, inform your doctor, who will monitor you closely.

Exercise particular caution when using Isofenal if you are taking the following medicines:

• corticosteroids (used for allergies and inflammation): concomitant use may increase the risk of gastrointestinal ulceration or bleeding (see “Warnings and precautions”);
• drugs that may cause increased blood potassium concentration;
• pentoxifylline (used to inhibit blood clot formation in vessels): these drugs increase the risk of bleeding when taken together with ketoprofen. Your doctor will perform more frequent clinical checks and monitor bleeding time;
• diuretics: NSAIDs may reduce the effect of diuretics and other drugs used to lower blood pressure (antihypertensives). In patients, especially dehydrated patients taking diuretics, there is a high risk of developing renal dysfunction. These patients should be adequately rehydrated before starting co-administration with NSAIDs, and their renal function should be monitored when treatment begins (see “Warnings and precautions”).
• drugs that lower blood pressure (ACE inhibitors and angiotensin II antagonists): in patients with impaired renal function (e.g., dehydrated patients or elderly patients), co-administration of a blood pressure-lowering drug such as an ACE inhibitor or angiotensin II antagonist with an NSAID may lead to further worsening of renal function.
• methotrexate (used in the treatment of neoplasms and autoimmune diseases) at doses below 15 mg/week;
• nicorandil, a medicine used to prevent or relieve chest pain due to heart problems;
• cardioactive glycosides, medicines used to treat the heart’s inability to adequately supply blood to the body;
• sulfonylureas (used in the treatment of Type 2 Diabetes), and other oral medications that reduce blood sugar levels;
• Drugs used in the treatment of HIV infection (Tenofovir).

Inform your doctor if you are taking the following medicines. Only the doctor can determine whether you may take Isofenal together with the following medicines:

• Phenytoin (used to treat epilepsy) and sulfonamides (antibacterials): dosage reduction of phenytoin or sulfonamides may be necessary if administered concurrently.
• Antihypertensives (beta-blockers, angiotensin-converting enzyme inhibitors, diuretics). Administration together with NSAIDs may reduce antihypertensive efficacy.
• Thrombolytics (used to induce clot breakdown): increase the risk of bleeding.
• Antiplatelet drugs: tirofiban, eptifibatide, abciximab, and iloprost. The use of multiple antiplatelet agents increases the risk of bleeding.
• Antidepressants (Selective Serotonin Reuptake Inhibitors (SSRIs)): there is an increased risk of gastrointestinal bleeding.
• Probenecid (used in the treatment of hyperuricemia and gout): concomitant administration of probenecid may significantly reduce the plasma clearance of ketoprofen.
• Gemeprost (used in obstetric-gynecological treatments): concurrent use with ketoprofen may reduce the effectiveness of gemeprost.
• Intrauterine contraceptive devices (IUDs): concurrent use may reduce the effectiveness of the device, leading to pregnancy.
• Mifepristone: a medicine used for termination of pregnancy.
• Cyclosporine, tacrolimus (immunosuppressive drugs): when used with ketoprofen, they increase the risk of kidney toxicity, especially in the elderly.
• Quinolone antibiotics. Patients taking NSAIDs and quinolones may have an increased risk of developing seizures.

Hyperkalemia
Some medicines or therapeutic classes may promote increased potassium concentrations in the blood (hyperkalemia), such as potassium salts, potassium-sparing diuretics, angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, NSAIDs, heparins (low molecular weight or unfractionated), cyclosporine, tacrolimus, and trimethoprim.
The occurrence of hyperkalemia may depend on the presence of various factors, and this risk increases when the above-mentioned substances are administered simultaneously.
Infections
Isofenal may mask symptoms of infections such as fever and pain. Therefore, Isofenal may delay appropriate treatment of the infection, potentially increasing the risk of complications. This has been observed in bacterial pneumonia and bacterial skin infections related to varicella. If you take this medicine while having an infection and infection symptoms persist or worsen, consult your doctor immediately.
Fertility, pregnancy, and breastfeeding
If you are pregnant, suspect you may be pregnant, are planning a pregnancy, or are breastfeeding, consult your doctor or pharmacist before taking this medicine.
Use of the drug near delivery may delay labor itself; furthermore, if administered during this period, it may cause serious respiratory consequences for the newborn.
Fertility
The use of NSAIDs may impair female fertility and is not recommended in women attempting to conceive. In women with fertility problems or undergoing fertility investigations, discontinuation of NSAID treatment should be considered.
Pregnancy
The use of Isofenal is not recommended in women planning to become pregnant.
During the first and second trimesters of pregnancy, ketoprofen should not be administered unless strictly necessary. If ketoprofen is used by a woman trying to conceive, or during the first and second trimesters of pregnancy, the dose should be the lowest possible and the duration of treatment as short as possible.
During the third trimester of pregnancy, all prostaglandin synthesis inhibitors may expose

• the fetus to:
• cardiopulmonary toxicity (with premature closure of the ductus arteriosus and pulmonary hypertension);
• renal dysfunction, which may progress to renal failure with oligo-hydramnios;
• the mother and the newborn, at the end of pregnancy, to:
• possible prolongation of bleeding time, and antiplatelet effect, which may occur even at very low doses;
• inhibition of uterine contractions, resulting in delayed or prolonged labor. Consequently, ketoprofen is contraindicated during the third trimester of pregnancy.

Breastfeeding
No data are available on the excretion of ketoprofen in breast milk. Ketoprofen is contraindicated in women who are breastfeeding.
Driving and use of machines
Isofenal may cause dizziness, drowsiness, vertigo, lightheadedness, seizures, or visual disturbances.
If these symptoms occur, do not drive or operate machinery and avoid activities requiring special alertness.
Isofenal contains benzyl alcohol
This medicine contains 40 mg of benzyl alcohol per vial, equivalent to 40 mg/2 ml.
Benzyl alcohol has been associated with the risk of serious adverse effects, including respiratory problems (gasping syndrome), in young children.
Consult your doctor or pharmacist if you are pregnant or breastfeeding. This is because large amounts of benzyl alcohol may accumulate in the body and cause adverse effects (such as metabolic acidosis).
Consult your doctor or pharmacist if you have liver or kidney disease. This is because large amounts of benzyl alcohol may accumulate in the body and cause adverse effects (such as metabolic acidosis).

3. How to take Isofenal

Take this medicine exactly as directed by your doctor or pharmacist. If you have
any doubts, consult your doctor or pharmacist.
The recommended daily dose of Isofenal is 50–100 mg, administered 1–2 times daily.
The maximum daily dose of ketoprofen (excluding over-the-counter OTC medicines, which have lower authorized maximum doses of less than 200 mg) is 200 mg. The risk-benefit ratio must be carefully considered before initiating treatment with the 200 mg daily dose, and higher doses are not recommended (see also “Warnings and precautions”).
The lowest effective dose for the shortest necessary duration to relieve symptoms should be used. If you have an infection, contact your doctor immediately if symptoms (e.g., fever and pain) persist or worsen (see section 2).
Taking the medicine with food (during meals or with milk) reduces the frequency and severity of possible adverse effects.
Injectable solutions must not be mixed with acidic solvents, such as solutions containing lidocaine.
Open the ampoules along the designated break line.
Inject immediately after drawing the solution into the syringe. Any unused solution must be discarded.

Use in patients with renal impairment and elderly patients
If you are elderly or have kidney problems, your doctor will advise reducing the initial dose and continuing treatment with the lowest effective dose. Only your doctor can determine whether a dose adjustment is necessary.

Use in patients with hepatic impairment
If you have mild to moderate liver function problems, your doctor will advise using the lowest effective daily dose (see “Warnings and precautions”).

If you take more Isofenal than you should
If you are given an excessive amount of ketoprofen, stop taking the medicine immediately and inform your doctor or go to the nearest hospital.
In adults, symptoms of high-dose ketoprofen intake include headache, dizziness, drowsiness, nausea, vomiting, diarrhoea, and abdominal pain. In cases of severe overdose, low blood pressure, respiratory depression, and gastrointestinal bleeding have also been observed.
If you experience any of the symptoms listed above, your doctor or the hospital doctor will provide the most appropriate therapeutic treatment based on your symptoms. There are no specific antidotes.

If you forget to take Isofenal
Do not take a double dose to make up for a missed dose. Inform your doctor, who will advise you on how to continue the treatment.

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

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everyone gets them.
If you experience any of the following serious side effects, stop taking
Isofenal immediately and contact your doctor right away or go to the nearest hospital.

• Severe skin reactions, some of which have been fatal, such as severe skin reaction with peeling and swelling of the skin, skin blisters, mouth, eyes, genitals (Stevens-Johnson Syndrome), often accompanied by malaise, chills, myalgia, and fever (toxic epidermal necrolysis);
• Severe allergic reaction with sudden onset, including sudden and severe swelling of the skin or mucous membranes, for example swelling around the eyes, face, lips, mouth, or throat (angioedema);
• Severe kidney damage and kidney diseases, with impairment of kidney function;
• Severe inflammation of the liver;
• Severe allergic reaction with sudden onset (shock);
• Gastrointestinal perforation or bleeding, sometimes fatal, particularly in the elderly.

Other side effects that may occur with Isofenal
Common: affects up to 1 in 10 people

• Indigestion (dyspepsia)
• Nausea
• Vomiting
• Stomach pain, abdominal pain

Uncommon: affects up to 1 in 100 people

• Headache
• Dizziness
• Vertigo
• Drowsiness
• Constipation
• Flatulence
• Diarrhea
• Gastritis
• Skin rash
• Itching (pruritus)
• Swelling due to fluid retention (edema)

Rare: affects up to 1 in 1,000 people

• Decrease in red blood cells due to bleeding (haemorrhagic anaemia)
• Decrease in white blood cells (leucopenia)
• Blurred vision
• Ringing in the ears (tinnitus)
• Asthma
• Ulcerative stomatitis
• Peptic ulcers
• Colitis
• Increased liver enzymes, increased serum bilirubin due to liver disease, yellowing of the skin and whites of the eyes (jaundice)
• Weight gain
• Altered sensation in limbs (paraesthesia)

Not known: frequency cannot be estimated from the available data

• Changes in blood cell counts (thrombocytopenia, agranulocytosis)
• Low haemoglobin concentration (a protein in red blood cells) in the blood
• Bone marrow disorder (bone marrow failure)
• Depression
• Hallucinations
• Confusion
• Mood changes
• Seizures
• Taste disturbances
• Heart failure
• Heightened awareness of heartbeat (palpitations)
• Changes in heart rhythm and rate (atrial fibrillation and tachycardia)
• Increased blood pressure (hypertension)
• Inflammation of blood vessels (vasculitis, including leukocytoclastic vasculitis)
• Breathing difficulty (dyspnoea)
• Nasal congestion
• Altered breathing
• Bleeding from rectum and stomach
• Urticaria, worsening of chronic urticaria
• Erythema
• Light sensitivity reactions (photosensitivity)
• Skin rash
• Localised or widespread hair loss (alopecia)
• Difficulty urinating
• Fluid or sodium retention, possibly leading to oedema
• Increased potassium levels in the blood
• Reduced sodium levels in the blood
• Pain and burning sensation at the injection site
• Kidney damage
• Presence of protein in the urine
• Reduced kidney function
• Inflammation of the membranes covering the brain, not caused by bacteria (aseptic meningitis)
• Anaphylactic reactions
• Bullous reactions
• Stevens-Johnson Syndrome
• Toxic epidermal necrolysis and generalised exanthematous pustulosis
• Pancreatitis
• Stomach and intestinal problems (gastrointestinal perforation or bleeding, worsening of colitis, and chronic intestinal inflammation (Crohn's disease))
• Anaphylactic reactions (including shock).

Please note that
Clinical studies and epidemiological data suggest that the use of medicines such as Isofenal (especially at high doses and for long-term treatment) may be associated with a small increased risk of arterial thrombotic events (e.g., myocardial infarction or stroke).
Reporting of side effects
If you experience any side effect, including those not listed in this leaflet, please inform your doctor or pharmacist. You may also report side effects directly via the national reporting system at www.aifa.gov.it/content/segnalazioni-reazioni-avverse. Reporting side effects can help provide more information on the safety of this medicine.

5. How to store Isofenal

Keep this medicine out of the sight and reach of children.
Do not use this medicine after the expiry date stated on the label after "Exp.". The expiry date refers to the last day of that month and applies to the product in its original sealed packaging, correctly stored.
Do not store above 25°C. Keep in the original packaging to protect the medicine from light.
Do not dispose of any medicine via wastewater or household waste. Ask your pharmacist how to dispose of medicines you no longer use. This will help protect the environment.

6. Package contents and other information

What Isofenal contains
The active substance is ketoprofen.
One vial of Isofenal solution contains 100 mg of ketoprofen.
The other components are: arginine, benzyl alcohol, monohydrate citric acid, water for injectable preparations.

Description of the appearance of Isofenal and package contents
Isofenal is an injectable solution for intramuscular use.
It is available in a carton containing 6 glass vials of 2 ml each.

Marketing Authorization Holder and Manufacturer
MARKETING AUTHORIZATION HOLDER
So.Se.PHARM S.r.l.
Via dei Castelli Romani, 22
00071 Pomezia (RM)
Italy

MANUFACTURER
ESSETI Farmaceutici
Via Campobello, 15
00071 Pomezia (RM)
Italy