Akis - Package Leaflet

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

Active ingredients: Diclofenac (Diclofenac sodium)

AKIS 25, 50.75 mg / ml solution for injection

Why is Akis used? What is it for?

AKIS contains the active substance diclofenac sodium. AKIS belongs to the class of non-steroidal anti-inflammatory drugs (NSAIDs). Other NSAIDs include aspirin and ibuprofen.

These drugs reduce pain and inflammation.

AKIS is used for the symptomatic treatment of conditions such as:

  • Joint inflammation or back pain
  • Gout attacks
  • Pain caused by kidney stones
  • Pain caused by wounds, fractures or trauma
  • It is also used to treat pain following operations

Contraindications When Akis should not be used

Do not use Akis:

  • If you are allergic to diclofenac, aspirin, ibuprofen or other NSAIDs
  • If you are allergic to any of the other ingredients of this medicine (listed in section 6)
  • If you have a history of gastrointestinal bleeding after taking non-steroidal anti-inflammatory drugs (NSAIDs)
  • If you have had two or more distinct episodes of gastric (stomach) or peptic (duodenum) ulcer or digestive tract haemorrhage (including blood in vomiting or bowel movements, or black tarry stools)
  • If you have or have suffered from severe liver failure
  • If you have or have suffered from severe heart failure
  • If you have overt heart disease and / or cerebral vascular disease, eg have had a heart attack, stroke, mini-stroke (TIA) or "blockage of blood vessels to the heart or brain or surgery to eliminate or avoid such obstructions
  • If you have or have suffered from blood circulation problems (peripheral arterial disease)
  • If you have or have suffered from severe kidney failure
  • If you have asthma, hives or acute rhinitis (allergy) caused by the use of NSAIDs or aspirin
  • If you have blood clotting problems or are using blood thinners (such as warfarin)
  • If you are past the sixth month of pregnancy
  • If you are under the age of 18.

Precautions for use What you need to know before taking Akis

Take care with Akis

Make sure your doctor knows before taking diclofenac

  • If you smoke
  • If you have diabetes
  • If you have angina, blood clots, high blood pressure, raised cholesterol or raised triglycerides.

Undesirable effects can be minimized by using the lowest effective dose for the shortest duration necessary.

Talk to your doctor before using Akis:

  • If you have ever had oesophageal, gastric or duodenal ulcers, or gastrointestinal bleeding, symptoms of which may include blood on vomit or during bowel movement, or black tarry stools
  • If you have bowel disease, including ulcerative colitis and Crohn's disease
  • If you have or have had kidney or liver problems
  • If you have suffered or are suffering from blood disorders or bleeding
  • If you have or have suffered from asthma, chronic obstructive pulmonary disease (COPD), nasal polyps or allergic rhinitis
  • If you suffer from lupus (systemic lupus erythematosus or SLE) or similar diseases
  • If you are planning to become pregnant, as Akis may interfere with conception.

Interactions Which drugs or foods can change the effect of Akis

Tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines, including non-prescription medicines (such as over-the-counter or recreational drugs). Some medicines may interfere with your treatment.

Tell your doctor if you are taking any of the following medicines:

  • Other NSAIDs or cyclo-oxygenase-2 inhibitors, such as aspirin or ibuprofen (pain relievers)
  • Antidiabetic
  • Anticoagulants (blood thinners such as warfarin or heparin)
  • Antiaggregants (to prevent blood clots)
  • Diuretics (medicines that increase urinary flow)
  • Lithium (a medicine to treat some types of depression)
  • Phenytoin (a medicine to treat epilepsy)
  • Cardiac glycosides (e.g. digoxin; medicine for heart problems)
  • Methotrexate (medicine for some types of inflammation and cancer)
  • Ciclosporin and tacrolimus (for some types of inflammation and immunosuppressants after organ transplants)
  • Quinolone antibiotics (medicines used to treat some infections)
  • Steroids (medicines for inflammation and to treat immune system problems)
  • Colestipol (a medicine used for lowering cholesterol)
  • Cholestyramine (a medicine used to treat liver problems and Crohn's disease)
  • Sulfinpyrazone (a medicine used to treat gout)
  • Voriconazole (a medicine used to treat fungal infections)
  • Pemetrexed (chemotherapy drug for some forms of cancer)
  • Deferasirox (drug used in patients subject to frequent blood transfusions)
  • Mifepristone a medicine used for induction of drug abortion)
  • Medicines for heart failure or high blood pressure, such as beta blockers or ACE inhibitors
  • Anxiolytics or antidepressants known as selective serotonin reuptake inhibitors (SSRIs)
  • Zidovudine (for the treatment of human immunodeficiency virus (HIV) infection.

Warnings It is important to know that:

  • Medicines such as AKIS may be associated with a small increased risk of heart attack (myocardial infarction) or stroke. The risk increases with high dosages and prolonged treatments. Do not exceed the recommended dose or the established treatment duration.
  • AKIS is an anti-inflammatory drug, so it may reduce the symptoms of an infection, such as headache or fever. If you feel unwell and need to be examined, remember to tell your doctor that you are using AKIS.
  • Elderly patients are more prone to side effects associated with AKIS: warn your doctor if you have any unusual symptoms.

Pregnancy and breastfeeding

Ask your doctor or pharmacist for advice before taking any medicine.

  • AKIS may make conception difficult. Tell your doctor if you have difficulty conceiving.
  • If you are pregnant, think you may be pregnant or are planning to have a baby, ask your doctor for advice, who will decide whether to use AKIS.
  • AKIS should not be used after the sixth month of pregnancy as it may damage the circulation or kidneys of the fetus and delay or prolong labor
  • If you are breast-feeding, ask your doctor for advice, who will decide whether to use AKIS.

Driving and using machines

AKIS may make you feel dizzy, sleepy or have blurred vision. Refrain from driving or using machines if you experience these complaints.

Dose, Method and Time of Administration How to use Akis: Posology

Your doctor will decide when and how you should use the treatment with AKIS solution for injection.You will be given an 'intramuscular injection (into a muscle, usually in the buttocks) or a' subcutaneous injection (under the skin, usually in the buttock or thigh). AKIS should not be administered intravenously (i.v.).

Adults: the recommended starting dose ranges from 25 to 75 mg, depending on the severity of the pain. If severe pain persists, your doctor may decide to give you a second injection after 6 hours. The maximum daily dosage is 150 mg. AKIS can be administered for one or two days.

Elderly patients: your doctor may set a lower dose than is recommended for an adult if you are elderly.

Children: Do not use in children (under 18 years of age).

A doctor, nurse or pharmacist will prepare the injection. A nurse or doctor will give you the injection. The injection should not be given two consecutive times at the same site.

Overdose What to do if you have taken too much Akis

If you take more AKIS than you should, you may experience the following symptoms: nausea, vomiting, stomach pain, gastrointestinal bleeding, rarely diarrhea, dizziness, tinnitus (buzzing, wheezing, ringing, ringing or other persistent ringing in the ears) and occasionally seizures (seizure or seizure). In severe cases, kidney or liver damage (symptoms include difficulty urinating or increased urination, muscle cramps, tiredness, swelling of the hands, feet and face, nausea or vomiting, yellowing of the skin (jaundice). Tell your doctor right away. or a nurse if you think you have been given more AKIS than you should.

Side Effects What are the side effects of Akis

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

Tell your doctor immediately if you experience the following symptoms:

  • Severe allergic reactions, which include: swelling of the face, throat or tongue, difficulty breathing, wheezing, rhinitis and skin rash
  • Heartburn or pain, digestive problems, wind, nausea or vomiting
  • Any symptoms of gastrointestinal bleeding, such as presence of blood during bowel movement, black discoloration of stool, blood in vomit
  • Severe rash, itching, hives, bruising, pain in red areas, blistering or peeling skin, giant wheals (swollen skin accompanied by itching and burning). These conditions can also affect the lips, eyes, nose, and genitals
  • Yellowing of the skin (jaundice) or the sclera of the eyes
  • Persistent pharyngitis or fever
  • Unusual changes in the amount of urine produced and / or its appearance
  • Unusual predisposition to bruising or frequent pharyngitis and infections.

Very common side effects (likely to affect up to 1 in 10 patients)

  • Pain, redness or hardness at the injection site

Common side effects (likely to affect between 1 in 100 and 1 in 10 patients)

  • Nausea

Uncommon side effects (reported by 1 in 1000 and 1 in 100 patients)

  • Dizziness and headache
  • Diarrhea, vomiting and constipation
  • Inflammation of the gastric mucosa with pain, vomiting and loss of appetite
  • Liver problems
  • Skin rash, itching

Other side effects

Patients treated with NSAIDs have reported the following list of undesirable effects.

Cardiac, thoracic and blood and lymphatic disorders

  • Medicines such as AKIS may be associated with a moderate increased risk of heart attack (myocardial infarction) or stroke
  • Hypertension, heart attack, palpitations, chest pain and swelling of the torso, hands and feet
  • Asthma, dyspnoea
  • Blood disorders such as anemia (reduced number of red blood cells). Symptoms include tiredness, headache, dizziness and paleness.

Gastrointestinal disorders

  • Peptic stomach ulcers, mouth ulcers, tongue infections, colon disorders (including intestinal inflammation and worsening of Crohn's disease)
  • Inflammation of the pancreas and gastric mucosa (symptoms including severe stomach pain which may extend to the back or shoulder).

Nervous system disorders

  • Tingling or numbness, tingling in the hands, feet or limbs, tremors, blurred vision or diplopia, hearing loss or problems, tinnitus (ringing in the ears), sleepiness, tiredness
  • Hallucinations (seeing or hearing things that are not there), depression, disorientation, sleep disturbances, irritability, anxiety, memory impairment and seizures (seizure or seizure)
  • Inflammation of the meninges. Symptoms include neck stiffness, headache, nausea, vomiting, fever or disorientation, and extreme sensitivity to light. Liver and kidney disorders
  • Hepatic insufficiency. Symptoms may include nausea, loss of appetite, general malaise, occasional jaundice
  • Kidney failure or problems. Symptoms include hematuria, foamy urine, swelling of the hands, feet, and torso.

Skin and subcutaneous tissue disorders

  • Severe skin rashes such as Stevens-Johnson syndrome and other skin conditions that may worsen with sun exposure
  • Hair loss

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.

You can also report side effects directly via the national reporting system at "www.agenziafarmaco.gov.it/it/responsabili". By reporting side effects you can help provide more information on the safety of this medicine

Expiry and Retention

  • Keep this medicine out of the sight and reach of children
  • Do not use this medicine after the expiry date which is stated on the vial after {expiry} (The expiry date refers to the last day of that month)
  • Store below 25 ° C. Do not refrigerate or freeze. Store in the original package to protect the medicine from light
  • The medicinal product should be used immediately after opening: any remaining solution should be discarded
  • Do not use this medicine if you notice cloudiness or particles.

After the correct dose has been given, your doctor or nurse will throw away any remaining solution along with the syringe, needles and containers.

Do not throw any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. This will help protect the environment.

Deadline "> Other information

What AKIS contains

The active ingredient is: diclofenac sodium.

Each 1ml vial contains:

  • 25 mg of diclofenac sodium or
  • 50 mg of diclofenac sodium or
  • 75 mg of diclofenac sodium

The other ingredients are: hydroxypropylbetacyclodextrin, polysorbate 20, water for injections.

Description of AKIS appearance and contents of the package

This medicine is a clear or slightly amber solution for injection in a clear glass container (ampoule).

This medicine is supplied with a sterile administration kit containing:

  • 2 ml syringe
  • needle for subcutaneous injection (27 gauge) of gray color
  • green colored intramuscular injection needle (21 gauge)

Packs of 1 ampoule with 1 administration kit, 3 ampoules with 3 administration kits and 5 ampoules with 5 administration kits.

This medicine is also available in a pre-filled syringe.

Not all pack sizes may be marketed.

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 Akis 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 interaction - 04.6 Pregnancy and lactation - 04.7 Effects on the ability to drive and use machines - 04.8 Undesirable effects - 04.9 Overdose - 05.0 PHARMACOLOGICAL PROPERTIES - 05.1 "Pharmacodynamic properties - 05.2 Pharmacokinetic properties" - 05.3 Preclinical safety data - 06.0 PHARMACEUTICAL PARTICULARS - 06.1 Excipients - 06.2 Incompatibility "- 06.3 Shelf life" - 06.4 Special precautions for storage - 06.5 Nature of the primary packaging and contents of the package - 06.6 Instructions for use and handling - 07.0 AUTHORIZATION HOLDER ALL "PLACING ON THE MARKET - 08.0 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 RADIO DRUGS, COMPLETE DATA ON INTERNAL RADIATION DOSIMETRY - 12.0 INSTRUCTIONS FOR RADIOPHONES ON EXTEMPORARY PREPARATION AND QUALITY CONTROL -

01.0 NAME OF THE MEDICINAL PRODUCT -

AKIS SOLUTION FOR INJECTION

02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION -

The active ingredient is: diclofenac sodium

Each 1ml vial contains:

25 mg of diclofenac sodium

50 mg of diclofenac sodium

75 mg of diclofenac sodium

For the full list of excipients, see section 6.1.

03.0 PHARMACEUTICAL FORM -

Injectable solution

Transparent solution of light or slightly amber color

04.0 CLINICAL INFORMATION -

04.1 Therapeutic indications -

AKIS solution for injection is indicated in acute painful episodes such as renal colic, exacerbations of osteoarthritis and rheumatoid arthritis, acute back pain, acute attacks of gout, acute trauma and fractures, post-operative pain (see sections 4.3 and 4.4).

AKIS is indicated in adults. Use in children is not recommended.

04.2 Posology and method of administration -

Undesirable effects can be minimized by administering the lowest effective dose for the shortest duration necessary to control symptoms (see section 4.4 Special warnings and precautions for use).

Dosage

Adults

AKIS solution for injection can be administered intramuscularly or subcutaneously. AKIS is indicated for short treatments only and should not be used for more than two days.

In case of mild or moderate pain, the use of the lowest dosage is sufficient. A dose of 75 mg may be necessary in case of severe pain, such as renal colic. Exceptionally and in severe cases, a second dose of 75 mg may be given. mg after six hours The maximum daily dose (24 h) should not exceed 150 mg.

If more than one injection is required (up to a daily maximum of 150 mg), it is advisable to change the administration site for subsequent injections.

If necessary, an AKIS injection can be used with other diclofenac formulations, up to a maximum daily dosage of 150 mg.

Special populations

Senior citizens

The elderly are at an increased risk of undesirable effects (see sections 4.4 and 5.2). If NSAID treatment is required, the use of the lowest effective dose for the shortest possible duration of treatment is recommended. The patient should be monitored regularly for gastrointestinal bleeding during NSAID use. The maximum recommended daily dose for AKIS solution for injection is 150 mg.

Patients with kidney problems

Hydroxypropylbetacyclodextrin (HPβCD), an excipient of AKIS solution for injection is eliminated mainly by glomerular filtration. Therefore, patients with severe kidney problems (with a creatinine clearance below 30 ml / min) should not be treated with AKIS solution for injection ( see sections 4.4 and 5.2) Patients with non-severe renal problems should be treated with the lowest effective dose.

Pediatric population

The safety and efficacy of AKIS solution for injection in children aged 0 to 18 years have not yet been established.

Method of administration

AKIS solution for injection should only be administered by medical personnel. It can be administered intramuscularly or subcutaneously in clean, healthy tissue.

A single injection should be used instead of two to achieve a fixed dose. For example, a single 75 mg injection rather than a 25 mg and a 50 mg injection or a 50 mg injection rather than two 25 mg should be used. .

Intramuscular

Observe the following instructions for intramuscular administration to avoid damaging a nerve or other tissue at the injection site. The injection should be given deep into the upper-outer quadrant of the buttock. If two injections per day are required, it is recommended to switch administration sides for the second injection. The product should be injected slowly to minimize local tissue damage.

Subcutaneous

The injection should be made in the subcutaneous tissue, preferably in the upper part of the buttocks or in the upper part of the thigh. If two injections are required per day, it is advisable to alternate the injection area between the buttocks and the thigh. The needle should be inserted entirely into the thickness of the skin fold that forms between the thumb and forefinger. Make sure it does not penetrate a blood vessel. The product should be administered slowly and at a constant rate. injection.

AKIS should not be injected intravenously (i.v.).

For instructions on use and handling, see section 6.6.

04.3 Contraindications -

• Known hypersensitivity to the active substance or to any of the excipients.

• Active stomach or intestinal ulcer, bleeding or perforation

• History of gastrointestinal bleeding or perforation after taking non-steroidal anti-inflammatory drugs (NSAIDs)

• Active or past recurrent peptic ulcer / haemorrhage (two or more distinct episodes of proven ulceration or bleeding)

• Last trimester of pregnancy (see section 4.6).

• Severe hepatic insufficiency, severe renal insufficiency or severe heart failure (see section 4.4)

• Like other non-steroidal anti-inflammatory drugs (NSAIDs), diclofenac is also contraindicated in patients who have experienced asthma attacks, urticaria or acute rhinitis after taking acetylsalicylic acid or other NSAIDs

• Problems with haemostasis or anticoagulant treatments in progress (for intramuscular administration only)

• Overt congestive heart failure (NYHA class II-IV), ischemic heart disease, peripheral arterial disease and / or cerebral vascular disease.

04.4 Special warnings and appropriate precautions for use -

General

Undesirable effects can be minimized by administering the lowest effective dose for the shortest duration necessary to control symptoms (see section 4.2 and the paragraphs below on gastrointestinal and cardiovascular risks).

The concomitant use of diclofenac with other systemic NSAIDs, including selective cyclo-oxygenase-2 inhibitors, should be avoided due to the lack of any evidence showing synergistic benefits and based on potential additive side effects.

From a general medical point of view, caution is required in the elderly. In particular, in frail elderly patients or in those with a low body weight, the use of the lowest effective dose is recommended.

As with other NSAIDs, allergic reactions, including anaphylactic / anaphylactoid reactions, may also occur in rare cases without prior exposure to diclofenac.

Like other NSAIDs, diclofenac can mask the signs and symptoms of infections due to its pharmacodynamic properties.

The instructions for intramuscular injection should be strictly followed to avoid injection site adverse events which may cause muscle weakness, muscle paralysis, hypoesthesia and injection site necrosis.

Gastrointestinal effects

During treatment with all NSAIDs, including diclofenac, they have been reported and may appear at any time, with or without warning symptoms or a previous history of serious gastrointestinal events, gastrointestinal bleeding, ulceration or perforation, which can be fatal.

They generally have more serious consequences in the elderly. If gastrointestinal bleeding or ulceration occurs in patients receiving diclofenac, the medicinal product should be discontinued.

As with all NSAIDs, including diclofenac, close medical surveillance is mandatory and particular caution should be used when prescribing diclofenac to patients with symptoms indicative of gastrointestinal (GI) disorders or with a history indicative of gastric or intestinal ulceration, bleeding or perforation ( see section 4.8). The risk of gastrointestinal bleeding is higher with increased doses of NSAIDs and in patients with a history of ulcer, especially if complicated with haemorrhage or perforation. The elderly have a higher frequency of adverse reactions, especially gastrointestinal bleeding and perforation which can be fatal.

To reduce the risk of GI toxicity in patients with a history of ulcer, particularly if complicated with haemorrhage or perforation, and in the elderly, treatment should be initiated and maintained at the lowest effective dose.

The concomitant use of protective agents (proton pump inhibitors or misoprostol) should be considered for these patients and also for patients requiring concomitant use of medicinal products containing low doses of acetylsalicylic acid (ASA / aspirin) or other medicinal products which are likely to increase gastrointestinal risk.

Patients with a history of gastrointestinal toxicity, particularly the elderly, should report any unusual gastrointestinal symptoms (especially gastrointestinal bleeding). Caution is advised in patients taking concomitant medications that may increase the risk of ulceration or bleeding, such as systemic corticosteroids, anticoagulants, antiplatelet agents or selective serotonin reuptake inhibitors (see section 4.5). Close medical surveillance and caution should also be exercised in patients with ulcerative colitis or Crohn's disease as these conditions may be exacerbated (see section 4.8).

Hepatic effects

Close medical surveillance is required when prescribing Diclofenac to patients with hepatic insufficiency as their condition may be exacerbated.

Like other NSAIDs, diclofenac can increase the values ​​of one or more liver enzymes. During prolonged treatment with diclofenac, regular checks of liver function are indicated as a precautionary measure. If liver function parameters are persistently altered or worsened, if clinical signs or consistent symptoms of liver disease develop, or if other manifestations (e.g. eosinophilia, rash) occur, diclofenac treatment should be discontinued. A "hepatitis with the use of diclofenac" can occur without prodromal symptoms.

Particular caution should be exercised in the use of diclofenac in patients with hepatic porphyria, as it could trigger an attack.

Kidney effects

Since fluid retention and edema have been reported in association with NSAID therapy, including diclofenac, special caution is required in case of heart or renal failure, history of hypertension, in the elderly, in patients receiving concomitant diuretics or medicinal products that may significantly affect renal function and in those patients with substantial extracellular volume depletion due to any cause (e.g. before or after major surgery) (see section 4.3). In such cases, monitoring of renal function is recommended as a precaution when administering Diclofenac. Discontinuation of therapy is usually followed by a return to pre-treatment conditions.

The HPβCD component is eliminated primarily in the kidneys by glomerular filtration.

Therefore, patients with severe kidney problems (with a creatinine clearance below 30 ml / min) should not be treated with AKIS solution for injection. Patients with non-severe kidney problems should be treated with the lowest effective dose.

Skin effects

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. AKIS should be discontinued at the first appearance of skin rash, mucosal lesions or any other signs of hypersensitivity.

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 diclofenac (especially at high doses, 150 mg / day and in long-term treatments) may be associated with a modest increased risk of arterial thrombotic events (eg myocardial infarction). or stroke).

Patients with significant risk factors for cardiovascular events (e.g. hypertension, hyperlipidaemia, diabetes mellitus, smoking) should only be treated with diclofenac after careful consideration.

Since the cardiovascular risks of diclofenac may increase with dose and duration of exposure, the shortest possible duration and the lowest effective daily dose should be used. The response to therapy and the need for symptom improvement should be reassessed periodically.

Hematological effects

During prolonged treatment with diclofenac, as with other NSAIDs, blood count checks are recommended.

Like other NSAIDs, diclofenac may temporarily inhibit platelet aggregation. Patients with haemostatic defects should be carefully monitored.

As a result of water retention or effects on erythropoiesis, anemia may arise.

Consequently, hemoglobin and hematocrit levels should be monitored for symptoms of anemia.

Hyperkalaemia may occur in diabetic patients or in addition to potassium-sparing drugs (see section 4.5).

Pre-existing asthma

In patients with asthma, seasonal allergic rhinitis, swelling of the nasal mucosa (eg, nasal polyps), chronic obstructive pulmonary disease or chronic respiratory tract infections (especially when linked to symptoms similar to allergic rhinitis), are more common than in others patients reactions to NSAIDs such as asthma exacerbations (so-called analgesic intolerance / analgesic asthma), Quincke's edema or urticaria. Special precaution is therefore recommended in such patients (preparing for emergency).

This also applies to patients allergic to other substances, eg. with skin reactions, itching or hives.

SLE and mixed connective tissue diseases

In patients with systemic lupus erythematosus (SLE) and mixed connective tissue diseases, there may be an increased risk of aseptic meningitis (see section 4.8).

Administration

Injections must be performed according to strict rules of asepsis and antisepsis.

Duration of treatment

AKIS should not be administered for more than 2 days. After 2 days of therapy, the need to switch to other NSAIDs should be considered and, if long-term treatment with such medicinal products is required, patients should be monitored for renal and hepatic dysfunction or blood cell abnormalities. they are particularly important in the elderly.

04.5 Interactions with other medicinal products and other forms of interaction -

The following interactions include those observed with diclofenac gastro-resistant tablets and / or with other pharmaceutical forms of diclofenac.

Lithium: NSAIDs may elevate plasma lithium concentrations due to reduced renal lithium excretion. If concomitant use is necessary, monitoring of serum lithium levels is recommended at the beginning, during adjustment and at the end of diclofenac treatment.

Digoxin: when administered concomitantly, diclofenac may elevate plasma concentrations of digoxin. Monitoring of serum digoxin levels is recommended.

Diuretics, ACE inhibitors and angiotensin-II antagonists : NSAIDs may reduce the antihypertensive effect of diuretics and other antihypertensive drugs, (such as beta blockers or angiotensin converting enzyme (ACE) inhibitors). In some patients with impaired renal function (dehydrated patients or elderly patients with renal impairment), the concomitance of an ACE inhibitor or angiotensin-II antagonist and agents that inhibit cyclo-oxygenase may cause further impairment of renal function, including acute renal failure, which is usually reversible. Hence, the combination should be taken with caution, especially in the elderly. Patients should be adequately hydrated and monitoring of renal function should be considered after initiation of concomitant therapy and periodically thereafter (see section 4.4). Concomitant treatment with potassium-sparing drugs may be associated with increased levels serum potassium, which should therefore be monitored frequently (see section 4.4)

Other NSAIDs, corticosteroids and acetylsalicylic acid : concomitant use of diclofenac and other systemic non-steroidal anti-inflammatory drugs, corticosteroids or acetylsalicylic acid it is not recommended as it may increase the incidence of gastrointestinal side effects (see section 4.4).

Anticoagulants and heparin (given to the elderly or at therapeutic doses): Caution is recommended as co-administration may increase the risk of bleeding by inhibition of platelet aggregation or damage to the gastrointestinal mucosa (see section 4.4). NSAIDs may increase the effects of anticoagulants such as warfarin and heparin. The use of heparin. it is not recommended for administration to the elderly or therapeutic doses. If concomitant use cannot be avoided, careful monitoring by international normalized ratio (INR) is required.

Although there is no indication from clinical trial data of an "influence of diclofenac on the effect of anticoagulants", there have been reports of an increased risk of haemorrhage in patients receiving diclofenac concomitantly with anticoagulants. Careful monitoring is therefore recommended for these patients.

Thrombolytics and antiplatelet agents: Caution is recommended as co-administration with NSAIDs may increase the risk of bleeding due to inhibition of platelet function and damage to the gastroduodonal mucosa.

Selective Serotonin Reuptake Inhibitors (SSRIs): co-administration of systemic NSAIDs, including diclofenac, and SSRIs may increase the risk of gastrointestinal bleeding (see section 4.4).

Antidiabetics: clinical studies have shown that diclofenac can be administered together with oral antidiabetic agents without affecting their clinical effect. However, isolated cases of both hypo- and hyperglycemic effects have been reported, with the need to modify the dosage of the antidiabetic agents administered during treatment with diclofenac For this reason, monitoring of blood glucose levels is recommended as a precautionary measure in case of concomitant therapy.

Methotrexate: diclofenac may inhibit renal tubular release of methotrexate by increasing its levels. Caution is advised when NSAIDs, including diclofenac, are administered less than 24 hours before or after methotrexate treatment as blood concentrations of methotrexate and consequently the toxicity of this substance may increase. Weekly monitoring of blood count during the first few weeks of concomitant treatment is recommended. Monitoring should be prolonged in patients with impaired renal function and in the elderly.

Pemetrexed in patients with normal renal function CLcr> 80 mL / min: increased risk of toxicity of pemetrexed due to its reduced elimination. Biological monitoring of renal function is recommended.

Calcineurin inhibitors (cyclosporine, tacrolimus): due to their effects on renal prostaglandins, NSAIDs may increase the nephrotoxicity of calcineurin inhibitors. Monitoring of renal function is recommended during concomitant treatment, especially in the elderly.

Deferasirox: concomitant use of NSAIDs and deferasirox may increase the risk of gastrointestinal toxicity. The combination of these medicinal products requires careful clinical monitoring.

Quinolone antibacterials: There have been isolated reports of seizures, probably due to the concomitant use of quinolones and NSAIDs.

Phenytoin: When phenytoin is used together with diclofenac, monitoring of phenytoin plasma concentrations is recommended due to increased exposure to this substance.

Colestipol and cholestyramine: these agents may induce a delay or decrease in the absorption of diclofenac. Therefore, it is recommended that diclofenac be administered at least one hour before or 4-6 hours after colestipol / cholestyramine administration.

Potent CYP2C9 inhibitors: Caution is advised when prescribing diclofenac in combination with potent inhibitors of CYP2C9 (such as sulfinpyrazone and voriconazole), which could result in a significant increase in peak plasma concentration and exposure to diclofenac due to an "inhibition of its metabolism".

Mifepristone: NSAIDs should not be given for 8-12 days after mifespristone administration, as they may reduce the effects of mifepristone.

Zidovudine: increased risk of haematological toxicity in concomitant treatment with NSAIDs. There is evidence of an increased risk of hemarthrosis and hematomas in seropositive haemophiliacs receiving concomitant treatment of zidovudine and ibuprofen.

Although largely bound to proteins, AKIS does not interfere with the protein binding of: salicylates, tolbutamide, prednisolone.

04.6 Pregnancy and breastfeeding -

Pregnancy

Inhibition of prostaglandin synthesis can adversely affect pregnancy and / or embryo / fetal development. Results from epidemiological studies suggest an increased risk of spontaneous abortion and cardiac malformation and gastroschisis after 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 first and second trimester of pregnancy, diclofenac should not be administered except in strictly necessary cases. If diclofenac is used by a woman attempting to conceive, or during the first and second trimester of pregnancy, the dose should be kept as low as possible and the duration of treatment as short 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.

Consequently, diclofenac is contraindicated during the third trimester of pregnancy

Feeding time

Like other NSAIDs, diclofenac passes into breast milk in small amounts. Therefore, diclofenac should not be administered during breastfeeding to avoid undesirable effects in the infant.

Fertility

As with other NSAIDs, the use of diclofenac may impair female fertility and is not recommended in women wishing to conceive. Discontinuation of diclofenac in women who have difficulty conceiving or are undergoing investigation of infertility should be considered.

04.7 Effects on ability to drive and use machines -

Patients who have experienced visual disturbances, dizziness, vertigo, somnolence or other central nervous system disorders with the use of diclofenac should refrain from driving vehicles or operating machinery that requires integrity of alertness.

04.8 Undesirable effects -

Clinical Studies

The most common undesirable effects observed during clinical trials with AKIS are gastrointestinal in nature or reactions at the injection site which are generally mild and transient.

Clinical trial results suggest that the use of diclofenac solution for injection is associated with injection site reactions, such as pain and hematoma. The frequency of injection site adverse reactions was significantly lower with doses of 25 and 50 mg compared to 75 mg Nausea, vomiting, diarrhea and constipation have also been reported after administration of diclofenac.

The adverse reactions listed below are according to the MedDRA classification by system organ class (SOC) and by frequency of observation, according to the following convention: very common (> 1/10); common (≥ 1/100,

System organ class Frequency Undesirable effect Infections and infestations Not known Necrosis at the injection site Nervous system disorders Uncommon Dizziness, Headache Gastrointestinal disorders common Nausea Uncommon Diarrhea, Vomiting, Constipation, Gastritis Not known Ischemic colitis Hepatobiliary disorders Uncommon Increased liver enzymes Skin and subcutaneous tissue disorders Uncommon Itching General disorders and administration site conditions Very common Injection site reactions

The most appropriate MedDRA term has been used to describe a specific reaction. However, synonyms and related conditions not listed should be considered as expected.

Class effects

Adverse reactions (Table 1) are listed by frequency, most frequent first, using the following convention: very common (> 1/10); common (≥ 1/100,

The following side effects include those reported with short or long term use.

Table 1

Disorders of the blood and lymphatic system Very rare Thrombocytopenia, leukopenia, anemia (including haemolytic and aplastic anemia), agranulocytosis Disorders of the immune system Rare Hypersensitivity, anaphylactic and anaphylactoid reactions (including hypotension and shock) Very rare Angioneurotic edema (including face edema) Psychiatric disorders Very rare Disorientation, depression, insomnia, nightmares, irritability, psychotic reactions Nervous system disorders common Headache, dizziness Rare Drowsiness Very rare Paraesthesia, memory impairment, seizures, anxiety, tremors, aseptic meningitis, taste disturbances, cerebrovascular accidents Eye disorders Very rare Disturbed vision, blurred vision, diplopia Ear and labyrinth disorders common Dizziness Very rare Tinnitus, hearing impairment Cardiac pathologies Very rare Palpitations, chest pain, heart failure, myocardial infarction Vascular pathologies Very rare Hypertension, vasculitis Respiratory, thoracic and mediastinal disorders Rare Asthma (including dyspnoea) Very rare Pneumonia Gastrointestinal disorders common Nausea, vomiting, diarrhea, dyspepsia, abdominal pain, flatulence, anorexia Rare Gastritis, gastrointestinal haemorrhage, haematemesis, haemorrhagic diarrhea, melaena, gastrointestinal ulcer (with or without bleeding or perforation) Very rare Colitis (including haemorrhagic colitis and exacerbation of ulcerative colitis or Crohn's disease), constipation, stomatitis (including ulcerative stomatitis), glossitis, oesophageal disorders, diaphragm-like intestinal stricture, pancreatitis Hepatobiliary disorders common Increased transaminases Rare Hepatitis, jaundice, liver disorders Very rare Fulminant hepatitis, hepatic necrosis, hepatic failure Skin and subcutaneous tissue disorders common Rash Rare Urticaria Very rare Bullous rashes, eczema, erythema, erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis (Lyell's syndrome), exfoliative dermatitis, hair loss, photosensitivity reaction, purpura, allergic purpura, pruritus Renal and urinary disorders Very rare Acute renal failure, haematuria, proteinuria, nephrotic syndrome, interstitial nephritis, renal papillary necrosis General disorders and administration site conditions common Injection site reactions, injection site pain, injection site induration Rare Injection site necrosis Edema Infections and infestations Very rare Abscess at the injection site

Clinical trials and epidemiological data consistently indicate an increased risk of arterial thrombotic events (for example, myocardial infarction or stroke) associated with the use of diclofenac, especially at high doses (150 mg / day) and with long-term treatment ( see sections 4.3 and 4.4 for Contraindications and Special Warnings and Precautions for Use).

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" www.agenziafarmaco.gov.it/it/responsabili ".

04.9 Overdose -

Symptoms

There is no typical clinical picture resulting from diclofenac overdose. Overdose can cause symptoms such as vomiting, gastrointestinal bleeding, diarrhea, dizziness, tinnitus or convulsions. In the case of significant poisoning, acute renal failure and liver damage are possible.

Therapeutic measures

Treatment of acute NSAID poisoning, including diclofenac, essentially consists of supportive measures and symptomatic treatment. In case of complications such as hypotension, renal failure, seizures, gastrointestinal disturbances and respiratory depression, supportive measures and symptomatic treatment should be adopted.

Specific therapies, such as forced diuresis, dialysis or haemoperfusion, are unlikely to help eliminate NSAIDs, including diclofenac, due to their high plasma protein binding and extensive metabolism.

05.0 PHARMACOLOGICAL PROPERTIES -

05.1 "Pharmacodynamic properties -

Pharmacotherapeutic group: anti-inflammatory, non-steroidal drugs (NSAIDs).

ATC code: M01AB05.

Therapeutic subgroup: musculoskeletal system / anti-inflammatory drugs and non-steroidal antirheumatic drugs / derivatives of acetic acid and related substances.

Mechanism of action:

AKIS solution for injection is a non-steroidal agent with marked analgesic and anti-inflammatory properties. It is an inhibitor of prostaglandin synthesis (cyclo-oxygenase). Diclofenac sodium in vitro it does not suppress the biosynthesis of proteoglycans in cartilage at concentrations equivalent to those achieved in humans. When used concomitantly with opioids for the treatment of post-operative pain, diclofenac often reduces the need for them.

Clinical efficacy:

The analgesic efficacy of AKIS 25, 50 and 75 mg solution for injection was evaluated in two pivotal dental pain studies. Patients with moderate to severe dental pain following tooth extraction were included in these studies.

In one study, the analgesic efficacy of AKIS 25, 50 and 75 mg / ml, administered subcutaneously, was compared with placebo. All doses of AKIS produced a statistically higher and statistically significant reduction in pain (measured according to visual analog scale VAS) compared to placebo (p

In the second dental pain study, the analgesic efficacy of AKIS 75 mg / ml administered subcutaneously was compared with that of Voltarol 75 mg / 3 ml administered intramuscularly. No significant difference was observed between the two treatments. in the 8 hours following administration. At 1.5 hours after dosing (primary measure of efficacy of the study) the 95% confidence interval, relative to the difference between the two treatments, was entirely above the established margin of non-inferiority (-15 mm). AKIS was therefore therapeutically equivalent to Voltarol. The mean differences between the two treatments and the 95% confidence intervals at each control over the 8 hours following drug administration are shown in the table following.

Weather Difference in means (95% CI) p Check Difference in means (95% CI) Pain value 15 minutes 0.7 (-4.02; 5.41) 0.7708 30 minutes 1.6 (-4.26; 7.55) 0.5826 45 minutes 1.3 (-4.93; 7.48) 0.6857 1 hour -2.1 (-8.63; 4.44) 0.5272 1.5 hours -1.8 (-8.26; 4.61) 0.5764 2 hours -2.9 (-8.81; 3.11) 0.3457 3 hours -3.7 (-10.12; 2.72) 0.2559 4 hours -5.6 (-12.48; 1.21) 0.1061 5 hours -5.7 (-12.84; 1.50) 0.1205 6 hours -5.5 (-13.73; 2.70) 0.1864 7 hours -6.7 (-15.47; 1.98) 0.1284 8 hours -5.4 (-14.08; 3.25) 0.2183

05.2 "Pharmacokinetic properties -

Absorption

Intramuscular injection

After administration of AKIS 75mg / ml solution for injection by the IM route, absorption is rapid and the peak plasma concentration of 2.603 ± 0.959 mcg / ml (2.5 ug / ml corresponds to approximately 8 mcmol / L) is reached after 34 minutes. .

The area under the concentration curve (AUC) is equal to AUC0-t 250.07 ± 46.89 mcg / ml.min. In comparative clinical studies the main peak plasma concentration for intramuscular Voltarol (75mg / 3ml) is 2.242 ± 0.566 mcg / ml and is reached after 27 minutes while the AUC0-t value is 246.70 ± 39.74 mcg / ml.min. The AUC after intramuscular administration is approximately double that of an oral or rectal administration, since this route avoids the "hepatic first pass effect.

Subcutaneous injection

After administration of AKIS 75mg / ml solution for sc injection, absorption is rapid and the peak plasma concentration of 2,138 ± 0.646 mcg / ml (2.5 mcg / ml corresponds to approximately 8 mcmol / l) is reached in 40 minutes. .

The AUC0-t is 261.94 ± 53.29 mcg / ml.min. In comparative clinical studies the peak plasma concentration for intramuscular Voltarol is 2.242 ± 0.566 mcg / ml at 27 minutes while the AUC0-t value is 246.70 ± 39.74 mcg /ml.min.

AKIS 75 mg administered subcutaneously was bioequivalent to Voltarol 75 mg / 3 ml administered intramuscularly in terms of both AUC and Cmax. The AUC after subcutaneous administration is approximately double that of an oral or rectal administration, since this route avoids the hepatic first pass effect.

Dose linearity in terms of AUC was demonstrated following subcutaneous administration of diclofenac. Cmax was found not to be dose proportional, with mean Cmax values ​​of 1090 ng / ml, 1648.9 ng / ml and 1851.1 ng / ml after administration of 25 mg, 50 mg and 75 mg of AKIS, respectively.

Distribution

Diclofenac is 99.7% bound to plasma proteins, mainly with albumin (99.4%). Diclofenac penetrates into the synovial fluid, where maximum concentrations are detected 2-4 hours after reaching plasma peaks. The apparent half-life elimination from synovial fluids is 3-6 hours. Two hours after reaching plasma peaks, concentrations of active substance are higher in synovial fluid than in plasma and remain so for up to 12 hours.

Biotransformation

The biotransformation of diclofenac occurs in part via glucuronidation of the molecule as such, but mainly there is a single or multiple hydroxylation and methoxylation resulting in numerous phenolic metabolites, many of which are converted to glucuronic conjugates. Two phenolic metabolites are biologically active, but in measure much lower than that of diclofenac.

Elimination

Total systemic clearance of diclofenac in plasma is 263 ± 56 mL / min (mean value ± SD). The terminal half-life in plasma is 1-2 hours. Four of the metabolites, including the two active ones, also have a short half-life of 1-3 hours.

About 60% of the administered dose is excreted in the urine in the form of glucuronic conjugate of the molecule as such and as metabolites, many of which are converted into glucuronic conjugates; less than 1% is excreted as unchanged substance. The remainder of the administered dose is excreted in the bile and faeces.

Characteristics in patients

Senior citizens: No relevant differences in age-dependent drug absorption, metabolism or excretion were observed.

Patients with kidney problems: in patients with renal insufficiency, if the normal dosage regimen is observed, no accumulation of the active substance is observed in kinetic studies after single dose administration. With creatinine clearance values, steady-state plasma levels of the hydroxylated metabolites are approximately 4 times higher than in normal subjects. However, the metabolites are eliminated via the bile.

Patients with liver disease: in patients with chronic hepatitis or decompensated cirrhosis, the kinetics and metabolism of diclofenac remain the same as in patients without hepatic disorders.

05.3 Preclinical safety data -

No new preclinical studies have been conducted on diclofenac sodium. The safety profile of the product is well known.

The local tolerance study demonstrated that the formulation does not give rise to significant or unexpected local toxicity either after intramuscular or subcutaneous administration.

06.0 PHARMACEUTICAL INFORMATION -

06.1 Excipients -

Hydroxypropylbetacyclodextrin,

Polysorbate 20,

Water for injections

06.2 Incompatibility "-

In the absence of incompatibility studies, this medicinal product must not be mixed with other products.

06.3 Period of validity "-

2 years

The medicinal product should be used immediately after opening: any remaining solution should be discarded.

06.4 Special precautions for storage -

Store below 25 ° C. Do not refrigerate or freeze.

Store in the original package to protect the medicine from light.

06.5 Nature of the immediate packaging and contents of the package -

Type I clear glass vial.

Packs of 1, 3 and 5 ampoules.

Not all pack sizes may be marketed.

06.6 Instructions for use and handling -

There is an overdose in each vial, to ensure the extraction of 1 ml of solution.

Vials: No special instructions.

The product should not be used if crystals or precipitates are observed.

Unused medicine and waste derived from this medicine must be disposed of in accordance with local regulations

07.0 HOLDER OF THE "MARKETING AUTHORIZATION" -

IBSA Farmaceutici Italia Srl, via Martiri di Cefalonia, 2, 26900 Lodi

08.0 MARKETING AUTHORIZATION NUMBER -

AKIS "75 mg / ml solution for injection" 1 Ampoule - AIC: 040528073;

AKIS "75 mg / ml solution for injection" 3 Ampoules - AIC: 040528085;

AKIS "75 mg / ml solution for injection" 5 Ampoules - AIC: 040528097;

AKIS "50 mg / ml solution for injection" 1 Ampoule - AIC: 040528061;

AKIS "50 mg / ml solution for injection" 3 Ampoules - AIC: 040528059;

AKIS "50 mg / ml solution for injection" 5 Ampoules - AIC: 040528046;

AKIS "25 mg / ml solution for injection" 1 Ampoule - AIC: 040528010;

AKIS "25 mg / ml solution for injection" 3 Ampoules - AIC: 040528022;

AKIS "25 mg / ml solution for injection" 5 Ampoules - AIC: 040528034;

09.0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION -

Date of first authorization: 22 November 2013

10.0 DATE OF REVISION OF THE TEXT -

09/2016

11.0 FOR RADIO DRUGS, COMPLETE DATA ON THE INTERNAL RADIATION DOSIMETRY -

12.0 FOR RADIO DRUGS, FURTHER DETAILED INSTRUCTIONS ON EXEMPORARY PREPARATION AND QUALITY CONTROL -

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