KELIS - PACKAGE LEAFLET - LEAFLETS

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Kelis - Package Leaflet

Indications Contraindications Precautions for use Interactions Warnings Dosage and method of use Overdose Unwanted Effects Shelf Life

Active ingredients: Ketoprofen

KELIS "80 mg powder for oral solution"

Indications Why is Kelis used? What is it for?

PHARMACOTHERAPEUTIC CATEGORY

Anti-inflammatory, antirheumatic, non-steroidal drugs. Derivatives of propionic acid

THERAPEUTIC INDICATIONS

Adults: symptomatic treatment of inflammatory states associated with pain, including: rheumatoid arthritis, ankylosing spondylitis, painful arthrosis, extra-articular rheumatism, post-traumatic inflammation, painful inflammatory diseases in dentistry, otolaryngology, urology and pneumology

In pediatrics: symptomatic and short-term treatment of inflammatory states associated with pain, also accompanied by pyrexia, such as those affecting the osteoarticular system, post-operative pain and ear infections.

Contraindications When Kelis should not be used

Ketoprofen lysine salt is contraindicated in patients with a history of hypersensitivity reactions, such as bronchospasm, asthma attacks, rhinitis, nasal polyps, urticaria, angioneurotic edema or other allergic type reactions, ketoprofen lysine salt, acetylsalicylic acid ( ASA) or other non-steroidal anti-inflammatory drugs (NSAIDs).

Serious, rarely fatal, anaphylactic reactions have been reported in these patients (see section "Undesirable Effects").

Ketoprofen lysine salt is contraindicated in patients with hypersensitivity to any of the excipients of the drug.

Ketoprofen lysine salt is also contraindicated in the following cases:

Active peptic ulcer, or a history of gastrointestinal bleeding, ulceration or perforation;
Gastrointestinal bleeding or other active bleeding or bleeding disorders;
Crohn's disease or ulcerative colitis;
Previous bronchial asthma;
Severe heart failure;
Severe hepatic insufficiency;
Severe renal insufficiency;
Hemorrhagic diathesis and other coagulation disorders, or patients subject to anticoagulant therapy
Pregnancy and breastfeeding
Children under the age of 6.

Precautions for use What you need to know before taking Kelis

Administer with caution in patients with allergic manifestations or previous allergy. Treatment with ketoprofen lysine salt should be discontinued at the first appearance of skin rash, mucosal lesions or any other signs of hypersensitivity.

Undesirable effects can be minimized by using the lowest effective dose for the shortest possible duration of treatment needed to control symptoms (see section "Dose, Method and Time of Administration" and the paragraphs below).

The concomitant use of ketoprofen lysine salt with other NSAIDs, including selective cyclooxygenase-2 inhibitors, should be avoided.

Elderly: Elderly patients have an increased frequency of adverse reactions to NSAIDs, especially gastrointestinal bleeding and perforation, which can be fatal (see section "Dose, Method and Time of Administration").

As with other non-steroidal anti-inflammatory drugs, in the presence of infection, the anti-inflammatory, analgesic and antipyretic effects of the ketoprofen salt of lysine may mask the symptoms of progression of the infection such as fever.

Cardiovascular and cerebrovascular effects

Adequate monitoring and instruction are required in patients with a history of mild to moderate hypertension and / or congestive heart failure as fluid retention and edema have been reported in association with NSAID treatment.

Clinical studies and epidemiological data suggest that the use of some NSAIDs (especially at high doses and for long-term treatment) may be associated with a modest increased risk of arterial thrombotic events (eg myocardial infarction or stroke). there are sufficient data to exclude a similar risk for ketoprofen lysine salt.

Patients with uncontrolled hypertension, congestive heart failure, established ischemic heart disease, peripheral arterial disease and / or cerebrovascular disease should only be treated with ketoprofen lysine salt after careful consideration. Similar considerations should be made before initiating long-term treatment in patients with risk factors for cardiovascular disease (eg hypertension, hyperlipidaemia, diabetes mellitus, smoking).

Gastrointestinal effects

Gastrointestinal bleeding, ulceration or perforation: Gastrointestinal bleeding, ulceration and perforation, which can be fatal, have been reported during treatment with all NSAIDs, at any time, with or without warning symptoms or a previous history of serious gastrointestinal events.

Some epidemiological evidence suggests that ketoprofen lysine salt may be associated with a higher risk of severe gastrointestinal toxicity, compared to other NSAIDs, especially at high doses (see also section "Dose, Method and Time of Administration" and "Contraindications").

In the elderly and in patients with a history of ulcer, particularly if complicated with haemorrhage or perforation (see section "Contraindications"), the risk of gastrointestinal bleeding, ulceration or perforation is higher with increased doses of NSAIDs. These patients should start treatment with the lowest available dose. Concomitant use of protective agents (misoprostol or proton pump inhibitors) should be considered for these patients and also for patients taking low doses of aspirin or other drugs that may increase the risk of gastrointestinal events (see below and section "Interactions" ).

Patients with a history of gastrointestinal toxicity, particularly the elderly, should report any unusual gastrointestinal symptoms (especially gastrointestinal bleeding) particularly in the initial stages of treatment.

Caution should be exercised in patients taking concomitant medications that may increase the risk of ulceration or bleeding, such as oral corticosteroids, anticoagulants such as warfarin, selective serotonin reuptake inhibitors or antiplatelet agents such as aspirin (see section "Interactions").

When gastrointestinal bleeding or ulceration occurs in patients taking ketoprofen lysine salt the treatment should be discontinued. NSAIDs should be administered with caution to patients with a history of gastrointestinal disease (ulcerative colitis, Crohn's disease) as these conditions may be exacerbated (see section "Undesirable Effects").

In some pediatric patients treated with ketoprofen lysine salt, gastrointestinal haemorrhages, occasionally severe, and ulcer have been reported (see section "Undesirable effects"); therefore the product must be administered under strict supervision of the physician who will have to evaluate the necessary dosage schedule each time.

Effects on the skin

Serious skin reactions, some of them fatal, including exfoliative dermatitis, Stevens-Johnson syndrome and toxic epidermal necrolysis, have been reported very rarely in association with the use of NSAIDs (see section "Undesirable Effects"). In the early stages of therapy i patients appear to be at higher risk: the onset of the reaction occurs in most cases within the first month of treatment. Ketoprofen lysine salt should be discontinued at the first appearance of skin rash, mucosal lesions or any other signs of hypersensitivity.

Renal and hepatic effects

As with all NSAIDs, the drug can increase plasma urea nitrogen and creatinine.

As with other prostaglandin synthesis inhibitors, the drug may be associated with adverse events on the renal system which can lead to glomerular nephritis, renal papillary necrosis, nephrotic syndrome and acute renal failure.

Renal function should be carefully monitored at the initiation of treatment in patients with heart failure, with cirrhosis and nephrosis, in patients on diuretic therapy, with chronic renal failure particularly if elderly. In such patients the administration of ketoprofen lysine salt may cause a reduced renal blood flow, caused by the inhibition of prostaglandins and lead to renal alterations.

As with other NSAIDs, the drug may cause transient small increases in some liver parameters and also significant increases in SGOT and SGPT (see section "Undesirable Effects"). In the event of a significant increase in these parameters, therapy must be discontinued.

In patients with impaired hepatic function or with previous liver disease, transaminases should be evaluated regularly, particularly during long-term therapy. Cases of jaundice and hepatitis have been reported with ketoprofen lysine salt.

Ketoprofen lysine salt should be administered with caution in patients with haematopoietic disorders, systemic lupus erythematosus or mixed connective tissue disorders.

Treatment should be discontinued if visual disturbances such as blurred vision occur.

Asthmatic subjects with chronic rhinitis, chronic sinusitis and / or nasal polyposis have a higher risk of allergy to aspirin and / or NSAIDs than the rest of the population. Administration of this medicine can cause asthma attacks or bronchospasm, especially in subjects allergic to aspirin or NSAIDs (see section "Contraindications").

Interactions Which drugs or foods can modify the Kelis effect

Tell your doctor or pharmacist if you have recently taken any other medicines, even those without a prescription.

The following interactions relate to NSAIDs in general:

Associations not recommended:

Other NSAIDs (including cyclooxygenase-2 inhibitors), including high doses of salicylates (≥ 3 g / day): increased risk of gastrointestinal ulcers and bleeding.
Anticoagulants (e.g. heparin and warfarin): NSAIDs can amplify the effects of anticoagulants
Antiplatelet agents (eg ticlopidine and clopidogrel): increased risk of gastrointestinal bleeding (see section "Precautions for use"). If concomitant administration cannot be avoided, patients should be followed closely
Lithium: risk of increased plasma lithium levels, which can sometimes reach toxic levels due to reduced renal excretion of lithium. Where necessary, plasma lithium levels should be monitored with possible dosage adjustment during and after NSAID therapy.
Methotrexate, at doses above 15 mg / week: increased risk of haematological toxicity from methotrexate, particularly when administered at high doses (> 15 mg / week); possibly due to protein binding shift of methotrexate and reduced renal clearance.
Hydantoins and sulphonamides: the toxic effects of these substances can be increased.

Associations requiring precaution:

Corticosteroids: increased risk of gastrointestinal ulceration or bleeding (see section "Precautions for Use").
Diuretics: Patients, and particularly those taking diuretics and dehydrated, are at high risk of developing secondary renal failure due to decreased renal blood flow. Patients should be adequately hydrated and monitoring of renal function should be considered after initiation of concomitant therapy (see "Precautions for Use" section).
ACE inhibitors and angiotensin II antagonists: In some patients with impaired renal function (e.g. dehydrated patients or elderly patients with impaired renal function) co-administration of an ACE inhibitor or angiotensin II antagonist and agents that inhibiting the cyclooxygenase system can lead to further deterioration of renal function, which includes possible acute renal failure.
Methotrexate, used at doses below 15 mg / week: A complete blood count should be performed every week during the first few weeks of combination therapy. In the presence of impaired renal function or in elderly patients, monitoring should be more frequent.
Pentoxifylline: it determines an increased risk of bleeding. Closer clinical monitoring and bleeding time monitoring is required.

Associations that need to be considered:

Antihypertensives (beta-blockers, angiotensin converting enzyme inhibitors, diuretics): risk of decreasing their antihypertensive effect by inhibiting prostaglandin synthesis by NSAIDs.
Thrombolytics: increased risk of bleeding.
Probenecid: Concomitant administration of probenecid can significantly reduce the plasma clearance of the ketoprofen lysine salt.
Selective serotonin reuptake inhibitors (SSRIs): increased risk of gastrointestinal bleeding (see section "Precautions for use").
Ciclosporin, tacrolimus: risk of additive nephrotoxic effects, particularly in the elderly.
Zidovudine: risk of increased toxicity on the red cell line by action on reticulocytes, with severe anemia occurring one week after starting treatment with the NSAID.Check the complete blood count and reticulocyte count one to two weeks after starting treatment with the NSAID.
Sulfonylureas: NSAIDs can increase the hypoglycemic effect of sulfonylureas by displacing them from plasma protein binding sites.

Warnings It is important to know that:

Use in pregnancy

Ask your doctor or pharmacist for advice before taking any medicine

Inhibition of prostaglandin synthesis may adversely affect pregnancy and / or embryo / fetal development; therefore ketoprofen lysine salt should not be administered during pregnancy. Results from epidemiological studies suggest an increased risk of miscarriage and cardiac malformation and gastroschisis after the use of a prostaglandin synthesis inhibitor in the early stages of pregnancy. The absolute risk of cardiac malformations increased from less than 1% to approximately 1.5%. The risk was considered to increase with dose and duration of therapy. In animals, administration of prostaglandin synthesis inhibitors has been shown to cause increased pre- and post-implantation loss and embryo-fetal mortality.

In addition, an increased incidence of various malformations, including cardiovascular, has been reported in animals given prostaglandin synthesis inhibitors during the organogenetic period.

During the third trimester of pregnancy, all prostaglandin synthesis inhibitors can expose the fetus to:

cardiopulmonary toxicity (with premature closure of the arterial duct and pulmonary hypertension);
renal dysfunction, which can progress to renal failure with oligo-hydroamnios;

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

Use while breastfeeding

Since no data are available on the secretion of ketoprofen lysine salt in breast milk, Ketoprofen should not be administered during lactation.

Fertility

The use of ketoprofen lysine salt, as well as any drug that inhibits prostaglandin synthesis and cyclooxygenase, is not recommended in women who intend to become pregnant.

Administration of ketoprofen lysine salt should be discontinued in women who have fertility problems or who are undergoing fertility investigations.

Driving and using machines

Patients should be informed of the potential for somnolence, dizziness or seizures and should avoid driving or engaging in activities that require special vigilance if such symptoms occur.

Important information about some of the ingredients of Kelis

Kelis contains Sorbitol: Contact your doctor before taking this medicine if the patient has been diagnosed with intolerance to some sugars.

The sorbitol content of one sachet is approximately 1.7 g; the caloric value of sorbitol is 2.6 Kcal / g: consider for administration to diabetic patients or those who follow a low-calorie diet.

Dosage and method of use How to use Kelis: Dosage

Adults: one 80 mg sachet (full dose) three times a day with meals.

Children aged between 6 and 14: half a 40 mg sachet (half dose) three times a day with meals

Senior citizens: the posology must be carefully established by the doctor who will have to evaluate a "possible reduction of the dosages indicated above (see" Precautions for use ").

Patients with hepatic insufficiency: it is recommended to start therapy at the minimum daily dosage (see "Precautions for use").

Patients with mild or moderate renal insufficiency: monitoring of urine output and renal function is recommended (see "Precautions for use").

Instructions on the use of the sachet: opening the sachet along the line indicated "half dose" gives a dose of 40 mg. Opening the sachet along the line marked "full dose" gives a dose of 80 mg. Pour the contents of a sachet or half a sachet into half a glass of water and mix

Overdose What to do if you have taken too much Kelis

Cases of overdose have been reported with doses up to 2.5 g of ketoprofen lysine salt. In most cases, the symptoms observed were benign in nature and limited to lethargy, somnolence, nausea, vomiting and epigastric pain.

There are no specific antidotes for an overdose of ketoprofen lysine salt. In case of suspicion of a severe overdose, gastric lavage and the institution of supportive care and acidosis if present is recommended.

In case of renal insufficiency, hemodialysis may be useful to remove the drug from the circulation.

In case of accidental ingestion / intake of an overdose of Kelis, notify your doctor immediately or go to the nearest hospital

If in doubt about the use of Kelis, ask your doctor or pharmacist

Side Effects What are the side effects of Kelis

Like all medicines, Kelis can cause side effects, although not everybody gets them

The following adverse reactions have been observed following the administration of ketoprofen lysine salt in adults.

The frequency of adverse events is classified as follows: very common (≥1 / 10); common (≥1 / 100 to <1/10); uncommon (≥1 / 1000 to <1/100); rare (≥1 / 10,000, <1/1000); very rare (<1 / 10,000), not known (cannot be estimated from the available data).

Disorders of the blood and lymphatic system:

Rare: anemia due to bleeding.

Very rare: leukocytosis, lymphangitis, purpura, purpura thrombocytopenia, leukocytopenia Not known: agranulocytosis, thrombocytopenia, bone marrow aplasia.

Immune system disorders:

Not known: anaphylactic responses (including shock).

Psychiatric disorders:

Very rare: A single case of anxiety, visual hallucinations, hyperexcitability and altered behavior was reported in a pediatric patient who received twice the dose recommended in the SmPC. Symptoms disappeared spontaneously within 1-2 days.

Not known: mood alteration.

Nervous system disorders:

Uncommon: headache, dizziness, somnolence.

Rare: paraesthesia.

Very rare: insomnia, chills, transient dyskinesia, asthenia, dizziness. A single case of tremor and hyperkinesis has been reported in an elderly patient treated concomitantly with a quinolone antibiotic.

Not known: convulsions, dysgeusia.

Visual disturbances:

Rare: blurred vision.

Ear and labyrinth disorders:

Rare: tinnitus

Cardiac disorders:

Very rare: palpitations, tachycardia.

Not known: heart failure.

Vascular disorders:

Very rare: hypotension, edema, vasculitis

Not known: hypertension, vasodilation.

Respiratory, thoracic and mediastinal disorders:

Rare: asthma.

Very rare: dyspnoea, laryngeal edema, laryngospasm. A single case of acute respiratory failure with fatal outcome has been reported in an aspirin-sensitive asthmatic patient.

Not known: bronchospasm (particularly in patients with known hypersensitivity to acetyl salicylic acid and other NSAIDs), rhinitis.

Gastrointestinal disorders: The most commonly observed adverse events are gastrointestinal in nature. Peptic ulcers, perforation or gastrointestinal bleeding, sometimes fatal, may occur, particularly in the elderly (see section "Precautions for use").

Nausea, vomiting, diarrhea, flatulence, constipation, dyspepsia, abdominal pain, melaena, haematemesis, ulcerative stomatitis, exacerbation of colitis and Crohn's disease have been reported following administration of ketoprofen lysine salt (see section "Precautions for use" ) Gastritis has been observed less frequently.

Metabolic disorders:

Very rare: periorbital edema.

Hepatobiliary disorders:

Rare: hepatitis, increased transaminase levels, elevated serum bilirubin levels due to liver disorders.

Skin and subcutaneous tissue disorders:

Uncommon: rash, pruritus.

Very rare: erythema, rash, maculo-papular rash, dermatitis, skin redness, photosensitivity reactions, Lyell's syndrome.

Not known: photosensitization, alopecia, urticaria, angioedema, rash, including Stevens-Johnson syndrome and toxic epidermal necrolysis

Renal and urinary disorders:

Very rare: face edema and haematuria. A single case of oliguria has been reported.

Not known: acute renal failure, tubulointerstitial nephritis, nephrotic syndrome, renal function test abnormality.

General disorders and administration site conditions:

Uncommon: edema.

Not known: fatigue.

General conditions:

Very rare: edema of the mouth. Single cases of peripheral edema and syncope have been reported, respectively

Investigations:

Rare: weight gain

If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please tell your doctor or pharmacist.

Expiry and Retention

See the expiration date indicated on the package

The expiry date refers to the product in intact packaging, correctly stored.

Warning: do not use the medicine after the expiry date shown on the package.

KEEP OUT OF THE REACH AND SIGHT OF CHILDREN

Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. This will help protect the environment.

COMPOSITION

A bipartite sachet contains:

active ingredient: ketoprofen 80 mg lysine salt (equivalent to 50 mg of ketoprofen)

Excipients: Sorbitol (Neosorb P60), Sorbitol (Neosorb P30 / P60), Povidone, Silica, colloidal anhydrous, Sodium chloride, Sodium saccharin, Ammonium Glycyrised, Mint flavor.

PHARMACEUTICAL FORM AND CONTENT

Powder for oral solution. Lithographed cardboard box containing 30 bipartite sachets of 80 mg of ketoprofen lysine salt.

Source Package Leaflet: AIFA (Italian Medicines Agency). Content published in January 2016. The information present may not be up-to-date.
To have access to the most up-to-date version, it is advisable to access the AIFA (Italian Medicines Agency) website. Disclaimer and useful information.

Further information on Kelis can be found in the "Summary of Characteristics" tab. 01.0 NAME OF THE MEDICINAL PRODUCT 02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION 03.0 PHARMACEUTICAL FORM 04.0 CLINICAL PARTICULARS 04.1 Therapeutic indications 04.2 Posology and method of administration 04.3 Contraindications 04.4 Special warnings and appropriate precautions for use 04.5 Interactions with other medicinal products and other forms of interaction04.6 Pregnancy and lactation04.7 Effects on ability to drive and use machines04.8 Undesirable effects04.9 Overdose05.0 PHARMACOLOGICAL PROPERTIES05.1 Pharmacodynamic properties05.2 Pharmacokinetic properties05.3 Preclinical safety data06.0 INFORMATION PHARMACEUTICALS 06.1 Excipients 06.2 Incompatibilities 06.3 Shelf life 06.4 Special precautions for storage 06.5 Nature of the immediate packaging and contents of the package 06.6 Instructions for use and handling 07.0 MARKETING AUTHORIZATION HOLDER08 .0 MARKETING AUTHORIZATION NUMBER 09.0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION 10.0 DATE OF REVISION OF THE TEXT 11.0 FOR RADIOPharmaceuticals, FULL DATA ON INTERNAL RADIATION DOSIMETRY 12.0 FOR RADIO DRUGS, FURTHER DETAILED INSTRUCTIONS ON ESTEMPORANEA PREPARATION AND CONTROL

01.0 NAME OF THE MEDICINAL PRODUCT

KELIS 80 MG POWDER FOR ORAL SOLUTION

02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION

A bipartite sachet contains:

Active principle: ketoprofen lysine salt 80 mg corresponding to 50 mg of ketoprofen.

Excipient with known effects: sorbitol

For the full list of excipients, see section 6.1.

03.0 PHARMACEUTICAL FORM

Powder for oral solution

04.0 CLINICAL INFORMATION

04.1 Therapeutic indications

04.2 Posology and method of administration

Dosage

Adults: one 80 mg sachet (full dose) three times a day with meals.

Children aged between 6 and 14: half a 40 mg sachet (half dose) three times a day with meals.

Senior citizens: the posology must be carefully established by the physician who will have to evaluate a "possible reduction of the dosages indicated above (see section 4.4).

Patients with hepatic insufficiency: it is recommended to initiate therapy at the minimum daily dosage (see section 4.4).

Patients with mild or moderate renal insufficiency: monitoring of urine output and renal function is advised (see section 4.4).

KELIS must not be used in patients with severe hepatic and renal dysfunction (see section 4.3).

Undesirable effects can be minimized with the use of the shortest possible duration of treatment that is needed to control symptoms (see section 4.4).

Method of administration

Instructions on the use of the sachet: opening the sachet along the line marked "half dose" gives a dose of 40 mg. Opening the sachet along the line marked "full dose" gives a dose of 80 mg. Pour the contents of a sachet or half a sachet into half a glass of water and mix.

04.3 Contraindications

KELIS should not be given in the following cases:

• Hypersensitivity to the active substance, to other non-steroidal anti-inflammatory drugs (NSAIDs) or to any of the excipients listed in section 6.1.

• In patients with a history of hypersensitivity reactions, such as bronchospasm, asthma attacks, acute rhinitis, nasal polyps, urticaria, angioneurotic edema or other allergic-type reactions to ketoprofen or substances with a similar mechanism of action (for example acetylsalicylic acid , ASA, or other non-steroidal anti-inflammatory drugs, NSAIDs). Serious, rarely fatal, anaphylactic reactions have been reported in these patients (see section 4.8).

• Active peptic ulcer / bleeding, or a history of gastrointestinal bleeding, ulceration or perforation (two or more distinct, proven episodes of bleeding or ulceration) or chronic dyspepsia.

• Gastrointestinal bleeding or gastrointestinal perforation following previous NSAID therapy or other active bleeding or bleeding disorders.

• Crohn's disease or ulcerative colitis.

• Previous bronchial asthma.

• Severe heart failure.

• Severe hepatic insufficiency.

• Severe renal insufficiency.

• Bleeding diathesis and other coagulation disorders, or patients subject to anticoagulant therapy.

• Third trimester of pregnancy and lactation (see section 4.6).

• Children under the age of 6.

04.4 Special warnings and appropriate precautions for use

Undesirable effects can be minimized with the use of the lowest effective dose for the shortest possible duration of treatment needed to control symptoms (see section 4.2 and the paragraphs below on gastrointestinal and cardiovascular risks).

The concomitant use of ketoprofen lysine salt with other NSAIDs, including selective cyclooxygenase-2 inhibitors, should be avoided.

Elderly: Elderly patients have an increased frequency of adverse reactions to NSAIDs, especially gastrointestinal bleeding and perforation, which can be fatal (see section 4.2).

Cardiovascular and cerebrovascular effects

Patients with uncontrolled hypertension, congestive heart failure, established ischemic heart disease, peripheral arterial disease and / or cerebrovascular disease should only be treated with ketoprofen lysine salt, as well as with all NSAIDs, after careful consideration. Similar considerations should be made before initiating long-term treatment in patients with risk factors for cardiovascular disease (eg hypertension, hyperlipidaemia, diabetes mellitus, smoking).

Gastrointestinal effects

Gastrointestinal bleeding, ulceration and perforation, which can be fatal, have been reported during treatment with all NSAIDs at any time, with or without warning symptoms or a previous history of serious gastrointestinal events.

In the elderly and in patients with a history of ulcer, particularly if complicated with haemorrhage or perforation (see section 4.3), the risk of gastrointestinal bleeding, ulceration or perforation is higher with increasing doses of NSAIDs. These patients should start treatment with the lowest available dose. Concomitant use of protective agents (misoprostol or proton pump inhibitors) should be considered for these patients and also for patients taking low dose aspirin or other drugs that may increase the risk of gastrointestinal events (see below and section 4.5).

When gastrointestinal bleeding or ulceration occurs in patients taking ketoprofen lysine salt the treatment should be discontinued.

NSAIDs should be administered with caution to patients with a history of gastrointestinal disease (ulcerative colitis, Crohn's disease) as these conditions may be exacerbated (see section 4.8).

Gastrointestinal haemorrhages, occasionally severe, and ulcer have been reported in some pediatric patients treated with ketoprofen lysine salt (see section 4.8); therefore the product must be administered under strict supervision of the physician who will have to evaluate the necessary dosage schedule each time.

Effects on the skin

Serious skin reactions, some of them fatal, including exfoliative dermatitis, Stevens-Johnson syndrome and toxic epidermal necrolysis, have been reported very rarely in association with the use of NSAIDs (see section 4.8). In the early stages of therapy patients appear to be at higher risk: the onset of the reaction occurs in most cases within the first month of treatment. Ketoprofen lysine salt should be discontinued at the first appearance of skin rash, mucosal lesions or any other signs of hypersensitivity.

Renal and hepatic effects

As with all NSAIDs, the drug can increase plasma urea nitrogen and creatinine.

As with other NSAIDs, the drug may cause transient small increases in some liver parameters and also significant increases in SGOT and SGPT (see section 4.8). In the event of a significant increase in these parameters, therapy must be discontinued.

Ketoprofen lysine salt should be administered with caution in patients with haematopoietic disorders, systemic lupus erythematosus or mixed connective tissue disorders.

The use of NSAIDs can impair fertility and is not recommended in women planning to become pregnant.

The administration of ketoprofen should be discontinued in women who have difficulty conceiving or who are undergoing investigation of fertility.

Treatment should be discontinued if visual disturbances such as blurred vision occur.

Asthmatics with chronic rhinitis, chronic sinusitis and / or nasal polyposis have a higher risk of allergy to aspirin and / or NSAIDs than the rest of the population. Administration of this medicine can cause asthma attacks or bronchospasm, especially in subjects allergic to aspirin or NSAIDs (see section 4.3).

To avoid any phenomena of hypersensitivity or photosensitization, it is advisable not to expose yourself to the sun during use.

Important information about some of the ingredients

Kelis contains sorbitol: patients with rare hereditary problems of fructose intolerance should not take this medicine.

04.5 Interactions with other medicinal products and other forms of interaction

Associations not recommended:

• Other NSAIDs (including selective cyclooxygenase-2 inhibitors), including high doses of salicylates (≥ 3 g / day): co-administration of several NSAIDs may increase the risk of gastrointestinal ulcers and bleeding, due to a synergistic effect.

• Anticoagulants (eg heparin and warfarin): NSAIDs may amplify the effects of anticoagulants by increasing the risk of bleeding due to inhibition of platelet function and damage to the gastrointestinal mucosa (see section 4.4). If concomitant administration cannot be avoided, patients should be carefully monitored.

• Antiplatelet agents (eg ticlopidine and clopidogrel): increased risk of gastrointestinal bleeding due to inhibition of platelet function and damage to the gastrointestinal mucosa (see section 4.4). If concomitant administration cannot be avoided, patients should be followed closely.

• Lithium: risk of increased plasma lithium levels, which can sometimes reach toxic levels due to reduced renal excretion of lithium. Where necessary, plasma lithium levels should be monitored with possible dosage adjustment during and after NSAID therapy.

• Methotrexate, used at high doses of 15 mg / week or more: increased risk of methotrexate blood toxicity, particularly when given in high doses (> 15 mg / week), possibly due to displacement of methotrexate from protein binding and reduction its renal clearance.

• Hydantoins and sulphonamides: the toxic effects of these substances can be increased.

Associations requiring precaution:

• Corticosteroids: increased risk of gastrointestinal ulceration or bleeding (see section 4.4).

• Diuretics: Patients and in particular, those taking diuretics and dehydrated, are at high risk of developing secondary renal failure due to decreased renal blood flow. Patients should be adequately hydrated and monitoring of renal function should be considered after initiation of concomitant therapy (see section 4.4). NSAIDs may reduce the effect of diuretics.

• ACE inhibitors and angiotensin II antagonists: in some patients with impaired renal function (eg dehydrated patients or elderly patients with impaired renal function) the co-administration of an ACE inhibitor or angiotensin II antagonist and agents which inhibit the cyclooxygenase system may lead to further deterioration of renal function, including possible acute renal failure. Therefore, the combination should be administered with caution, especially in elderly patients.

Patients should be adequately hydrated and monitoring of renal function should be considered after initiation of concomitant therapy.

• Methotrexate, used in low doses, less than 15 mg / week: a complete blood count should be performed every week during the first weeks of combination therapy. In the presence of impaired renal function or in elderly patients, monitoring should be more frequent.

• Pentoxifylline: increased risk of bleeding. Clinical monitoring should be increased and bleeding time monitored more frequently.

• Zidovudine: risk of increased toxicity on the red cell line by action on reticulocytes, with severe anemia occurring one week after starting treatment with the NSAID. Check the complete blood count and reticulocyte count one or two weeks after starting treatment with the NSAID.

• Sulfonylureas: NSAIDs can increase the hypoglycemic effect of sulfonylureas by displacing them from plasma protein binding sites.

Associations that need to be considered:

• Antihypertensives (beta-blockers, angiotensin converting enzyme inhibitors, diuretics): NSAIDs can reduce the effect of antihypertensive drugs by inhibiting prostaglandin synthesis.

• Thrombolytics: increased risk of bleeding.

• Probenecid: concomitant administration of probenecid can significantly reduce the plasma clearance of ketoprofen and consequently the plasma concentrations of ketoprofen may be increased; this interaction may be due to an inhibitory mechanism at the site of renal tubular secretion and glucuronide conjugation and requires an adjustment of the ketoprofen dose.

• Anti-aggregating agents and selective serotonin reuptake inhibitors (SSRIs): increased risk of gastrointestinal bleeding (see section 4.4).

• Ciclosporin, tacrolimus: risk of additive nephrotoxic effects, particularly in the elderly. Renal function should be measured during associated therapy.

04.6 Pregnancy and lactation

Use in pregnancy

In addition, an increased incidence of various malformations, including cardiovascular, has been reported in animals given prostaglandin synthesis inhibitors during the organogenetic period.

Therefore ketoprofen lysine salt should not be administered during the first and second trimester of pregnancy unless strictly necessary. If ketoprofen lysine salt is used in women who wish to become pregnant or during the first and second trimester of pregnancy, the dose and duration of treatment should be kept as low as possible.

During the third trimester of pregnancy, all prostaglandin synthesis inhibitors can expose

the fetus to:

• cardiopulmonary toxicity (with premature closure of the arterial duct and pulmonary hypertension);

• renal dysfunction, which can progress to renal failure with oligo-hydroamnios;

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.

KELIS is therefore contraindicated during the third trimester of pregnancy.

Feeding time

Since no data are available on the secretion of ketoprofen lysine salt in breast milk, Ketoprofen should not be administered during lactation.

Fertility

The use of ketoprofen lysine salt, as well as any drug that inhibits prostaglandin synthesis and cyclooxygenase, is not recommended in women who intend to become pregnant.

Administration of ketoprofen lysine salt should be discontinued in women who have fertility problems or who are undergoing fertility investigations.

04.7 Effects on ability to drive and use machines

Patients should be informed of the potential for somnolence, dizziness or seizures and should avoid driving or engaging in activities requiring special alertness if such symptoms occur (see section 4.8).

04.8 Undesirable effects

The experience derived from the marketing of oral formulations of ketoprofen salt of lysine shows that the occurrence of undesirable effects is a very rare event. Based on the estimate of exposed patients, derived from the number of packs sold, and considering the number of spontaneous reports, less one out of every 100,000 patients experienced adverse reactions, in most cases the symptoms were transient and resolved upon discontinuation of therapy and, in some cases, with specific pharmacological treatment.

The following adverse reactions have been observed following the administration of ketoprofen lysine salt in adults.

The frequency of adverse events is classified as follows: very common (≥1 / 10); common (≥1 / 100,

Disorders of the blood and lymphatic system:

Rare: anemia due to bleeding.

Not known: agranulocytosis, thrombocytopenia, bone marrow aplasia.

Single cases of leukocytosis, lymphangitis, purpura, thrombocytopenic purpura, and leukocytopenia have been reported, respectively.

Immune system disorders:

Not known: anaphylactic reactions (including shock).

Psychiatric disorders:

Not known: mood alteration, excitability, insomnia.

A single case of anxiety, visual hallucinations, hyperexcitability and altered behavior was reported in a pediatric patient who received twice the dose recommended in the CPR. Symptoms disappeared spontaneously within 1-2 days.

Nervous system disorders:

Uncommon: headache, dizziness, somnolence.

Rare: paraesthesia.

Not known: convulsions, dysgeusia.

Chills, transient dyskinesia, asthenia, dizziness were observed only occasionally. A single case of tremor and hyperkinesis has been reported in an elderly patient treated concomitantly with a quinolone antibiotic.

Eye disorders:

Rare: blurred vision (see section 4.4).

Not known: periorbital edema

Ear and labyrinth disorders:

Rare: tinnitus

Cardiac disorders:

Not known: heart failure, palpitations, tachycardia.

Vascular disorders:

Not known: hypertension, vasodilation, hypotension.

Cases of vasculitis and skin redness have been exceptionally reported.

Respiratory, thoracic and mediastinal disorders:

Rare: asthma.

Not known: bronchospasm (mainly in patients with known hypersensitivity to acetylsalicylic acid and other NSAIDs), rhinitis, dyspnoea, laryngeal edema, laryngospasm.

A single case of acute respiratory failure with fatal outcome has been reported in an aspirin-sensitive asthmatic patient. Most reactions in allergic / asthmatic patients and / or known hypersensitivity to NSAIDs were severe in nature.

Gastrointestinal disorders:

the most commonly observed adverse events are gastrointestinal in nature. Peptic ulcers, gastrointestinal perforation or haemorrhage, sometimes fatal, may occur, particularly in the elderly (see section 4.4).

Common: nausea, vomiting, dyspepsia, abdominal pain.

Uncommon: constipation, diarrhea, flatulence, gastritis.

Rare: ulcerative stomatitis, peptic ulcer.

Not known: exacerbation of colitis and Crohn's disease, gastrointestinal haemorrhage and perforation (see section 4.4).

Gastric and duodenal ulcer and erosive gastritis have been reported. In two single cases, haematemesis or melaena occurred respectively. Two single cases of ulcerative stomatitis and tongue edema have been reported, respectively.

Hepatobiliary disorders:

Rare: hepatitis, increased transaminase levels, elevated serum bilirubin levels due to liver disorders.

Skin and subcutaneous tissue disorders:

Uncommon: rash, pruritus.

Not known: photosensitization, alopecia, urticaria, angioedema, bullous eruptions including Stevens-Johnson syndrome and toxic epidermal necrolysis, erythema, rash, maculo-papular rash, dermatitis, rash, contact eczema.

Some NSAIDs, including ketoprofen, can cause, but are extremely rare, severe mucocutaneous reactions (such as Stevens-Johnson syndrome, Lyell syndrome).

Renal and urinary disorders:

Not known: acute renal failure, tubulointerstitial nephritis, nephritic syndrome, renal function test abnormality, dysuria.

Face edema and haematuria have also been reported. A single case of oliguria has been reported.

General disorders and administration site conditions:

Uncommon: edema, fatigue.

Not known: allergic and anaphylactoid reactions, anaphylactic shock, mouth edema.

Single cases of peripheral edema and syncope have been reported, respectively.

Diagnostic tests:

Rare: weight gain

Reporting of suspected adverse reactions

Reporting of suspected adverse reactions occurring after authorization of the medicinal product is important as it allows continuous monitoring of the benefit / risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system. "address http://www.agenziafarmaco.gov.it/it/responsabili.

04.9 Overdose

Cases of overdose have been reported with doses exceeding 2.5 g of ketoprofen lysine salt. In most cases, the symptoms observed were benign in nature and limited to lethargy, somnolence, nausea, vomiting and epigastric pain. Symptoms of overdose may also include: central nervous system disorders, such as headache, dizziness, confusion and loss of consciousness, as well as pain, nausea and vomiting. Hypotension, respiratory depression, and cyanosis can also occur.

There are no specific antidotes for an overdose of ketoprofen lysine salt. If severe overdose is suspected, gastric lavage and the institution of supportive and symptomatic therapies are recommended to compensate for dehydration, to monitor renal function and to correct acidosis if present.

In case of renal insufficiency, hemodialysis may be useful to remove the drug from the circulation.

05.0 PHARMACOLOGICAL PROPERTIES

05.1 Pharmacodynamic properties

Pharmacotherapeutic group: Anti-inflammatory, antirheumatic, non-steroidal drugs. Derivatives of propionic acid. ATC: M01AE03

Ketoprofen lysine salt is the lysine salt of 2- (3-benzoylphenyl) propionic acid, an analgesic, anti-inflammatory and antipyretic drug belonging to the class of NSAIDs (M01AE).

Ketoprofen lysine salt is more soluble than acid ketoprofen.

The mechanism of action of NSAIDs is related to the reduction of prostaglandin synthesis by inhibiting the cyclooxygenase enzyme.

Specifically, there is an inhibition of the transformation of arachidonic acid into cyclic endoperoxides, PGG 2 and PGH 2, precursors of prostaglandins PGE 1, PGE 2, PGF 2a and PGD 2 and also of prostacyclin PGI 2 and thromboxanes (TxA 2 and TxB 2). Furthermore, the inhibition of prostaglandin synthesis can interfere with other mediators such as kinins, causing an indirect action that would add to the direct action.

Ketoprofen lysine salt possesses a marked analgesic effect, correlated both with its anti-inflammatory effect and with a central effect.

Ketoprofen lysine salt exerts an antipyretic activity without interfering with the normal thermoregulation processes.

Painful inflammatory manifestations are eliminated or attenuated by promoting joint mobility.

05.2 Pharmacokinetic properties

The ketoprofen lysine salt possesses higher solubility than acid ketoprofen.

The form for oral use allows the assumption of the active principle already in aqueous solution and therefore leads to a rapid increase in plasma levels and an early reaching of the peak value. This is manifested, clinically, with a more rapid onset and a greater intensity of the analgesic and anti-inflammatory effect.

The kinetic profile in the child does not differ from that of the adult.

Repeated administration does not change the kinetics of the drug or produce accumulation.

Ketoprofen is 95-99% bound to plasma proteins. Significant levels of ketoprofen were found in tonsillar tissue and synovial fluid after systemic administration.

Elimination is rapid and essentially via the kidney: 50% of the product administered systemically is excreted in the urine in 6 hours. Ketoprofen is extensively metabolised: about 60-80% of the product administered systemically is in the form of metabolites in the urine.

05.3 Preclinical safety data

The LD 50 of ketoprofen lysine salt in rats and mice orally resulted respectively of 102 and 444 mg / kg, equal to 30-120 times the active dose as anti-inflammatory and analgesic in the animal. Intraperitoneally the LD 50 of ketoprofen lysine salt was found to be 104 and 610 mg / kg in rat and mouse, respectively.

Prolonged treatment in rats, dogs and monkeys with oral ketoprofen lysine salt at doses equal to or higher than the prescribed therapeutic dosages did not cause the appearance of any toxic phenomenon. At high doses, gastrointestinal and renal alterations were found due to the known side effects caused in animals by non-steroidal anti-inflammatory drugs. In a prolonged toxicity study conducted in rabbits by the oral or rectal route, ketoprofen was shown to be better tolerated when administered orally. rectal versus oral In an intramuscular tolerability study in rabbits, ketoprofen lysine salt was well tolerated.

Ketoprofen lysine salt was found to be non-mutagenic in genotoxicity tests carried out "in vitro" and in "vivo". Carcinogenicity studies with ketoprofen in mice and rats showed the absence of carcinogenic effects.

As regards embryo-fetal toxicity and teratogenesis of NSAIDs in animals, please refer to section 4.6.

06.0 PHARMACEUTICAL INFORMATION

06.1 Excipients

Sorbitol (Neosorb P60), Sorbitol (Neosorb P30 / P60), Povidone, Silica, colloidal anhydrous, Sodium chloride, Saccharin sodium, Ammonium Glycyrized, Mint flavor.