Special Warning : אזהרת שימוש

Warnings
Gastrointestinal bleeding ulceration or perforation, which can be fatal, have been reported with all NSAIDs and may occur at any time during treatment, with or without warning symptoms or a previous history of serious gastrointestinal events. They generally have more serious consequences in the elderly. If gastrointestinal bleeding or ulceration occurs in patients receiving Abitren, the medicinal product should be withdrawn.
ABITREN INJECTION July 2014,       28 7. 2014, RH                   Page 2 of 13 
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, including diclofenac (see Undesirable effects).
Patients appear to be at highest risk of these reactions early in the course of therapy, the onset of the reaction occurring in the majority of cases within the first month of treatment. Abitren should be discontinued at the first appearance of skin rash, mucosal lesions or any other sign of hypersensitivity.

As with other NSAIDs, allergic reactions, including anaphylactic/anaphylactoid reactions, can also occur in rare cases without earlier exposure to diclofenac. The sodium metabisulfite in the solution for injection can also lead to isolated severe hypersensitivity reactions and bronchospasm.

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

Special populations)
(see also Precautions)
Elderly
Although the pharmacokinetics of Abitren is not impaired to any clinically relevant extent in elderly patients, nonsteroidal anti-inflammatory drugs should be used with particular caution in such patients who generally are more prone to adverse reactions.
In particular it is recommended that the lowest effective dosage be used in frail elderly patients or those with a low body weight and the patient should be monitored for GI bleeding during NSAID therapy.

Renal impairment
Diclofenac is contraindicated in patients with severe renal impairment (see Contraindications). No specific studies have been carried out in patients with renal impairment, therefore, no specific dose adjustment recommendations can be made.
Caution is advised when administering diclofenac to patients with mild to moderate renal impairment.

Hepatic impairment
Diclofenac is contraindicated in patients with severe hepatic impairment (see Contraindications). No specific studies have been carried out in patients with hepatic impairment; therefore, no specific dose adjustment recommendations can be made.
Caution is advised when administering diclofenac to patients with mild to moderate hepatic impairment.

Children and adolescents
(see Posology and method of administration.

Precautions
General
Undesirable effects may be minimised by using the lowest effective dose for the shortest duration necessary to control symptoms.
The      concomitant    use    of    diclofenac   with systemic NSAIDs including cyclooxygenase-2 selective inhibitors, should be avoided due to the absence of any evidence demonstrating synergistic benefits and the potential for additive undesirable effects.
Caution is indicated in the elderly on basic medical grounds. In particular it is recommended that the lowest effective dose be used in frail elderly patients or those with a low body weight.

ABITREN INJECTION July 2014,       28 7. 2014, RH                    Page 3 of 13 Arterial thrombotic events)
Clinical trial and epidemiological data consistently point towards an increased risk of arterial thrombotic events (for example myocardial infarction or stroke) associated with the use of diclofenac, particularly at high dose (150 mg daily) and in long-term treatment.
Patients with cardiovascular disease or with significant risk for cardiovascular events (e.g. hypertension, hyperlipidaemia, diabetes mellitus, smoking) may also be at greater risk and should only be treated with diclofenac after careful consideration. To minimise the potential risk of an adverse cardiovascular event in patients taking an NSAID, especially in those with cardiovascular risk factors, the lowest effective dose should be used for the shortest possible duration The patient's need for symptomatic relief and response to therapy should be re-evaluated periodically.

There is no consistent evidence that the concurrent use of aspirin mitigates the possible increased risk of serious cardiovascular thrombotic events associated with NSAID use.

Hypertension)
NSAIDs may lead to the onset of new hypertension or worsening of pre-existing hypertension and patients taking anti-hypertensives with NSAIDs may have an impaired anti-hypertensive response. Caution is advised when prescribing NSAIDs to patients with hypertension. Blood pressure should be monitored closely during initiation of NSAID treatment and at regular intervals thereafter.

Heart failure)
Fluid retention and oedema have been observed in some patients taking NSAIDs, therefore caution is advised in patients with fluid retention or heart failure.

Pre-existing asthma
In patients with asthma, seasonal allergic rhinitis, swelling of the nasal mucosa (i.e.
nasal polyps), chronic obstructive pulmonary diseases or chronic infections of the respiratory tract (especially if linked to allergic rhinitis-like symptoms), reactions on NSAIDs like asthma exacerbations (so-called intolerance to analgesics/analgesic- asthma), Quincke’s edema or urticaria are more frequent than in other patients.

Therefore special precaution is recommended in such patients (readiness for emergency). This is applicable as well for patients who are allergic to other substances, e.g. with skin reactions, pruritus or urticaria.

Special caution is recommended when Abitren injection is used parenterally in patients with bronchial asthma because symptoms may be exacerbated.

Gastrointestinal effects
Gastrointestinal bleeding (haematemesis, melaena), ulceration or perforation which can be fatal has been reported with all NSAIDs including diclofenac and may occur at any time during treatment, with or without warning symptoms or a previous history of serious GI events. They generally have more serious consequences in the elderly. If gastrointestinal bleeding or ulceration occurs in patients receiving diclofenac, the drug should be withdrawn .

As with all NSAIDs, close medical surveillance is imperative and particular caution should be exercised when prescribing Abitren in patients with symptoms indicative of gastrointestinal (GI) disorders or with a history suggestive of gastric or intestinal ulceration, bleeding or perforation, (see Undesirable effects). The risk of GI bleeding is higher with increasing NSAID doses and in patients with a history of ulcer, particularly if complicated with hemorrhage or perforation and in the elderly.

ABITREN INJECTION July 2014,       28 7. 2014, RH                    Page 4 of 13 
The elderly have increased frequency of adverse reactions to NSAIDs especially gastro intestinal bleeding and perforation which may be fatal (see Posology and method of administration).

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, the treatment should be initiated and maintained at the lowest effective dose.

Combination therapy with protective agents (e.g. proton pump inhibitors or misoprostol) should be considered for these patients, and also for patients requiring concomitant use of medicinal products containing low-dose acetylsalicylic acid (ASA)/aspirin, or other medicinal products likely to increase gastrointestinal risk .
Patients with a history of GI toxicity, particularly the elderly, should report any unusual abdominal symptoms (especially GI bleeding). Caution is recommended in patients receiving concomitant medications which could increase the risk of ulceration or bleeding, such as systemic corticosteroids, anticoagulants, anti-platelet agents or selective serotonin-reuptake inhibitors (see Interaction with other medicinal products and other forms of interaction).
Close medical surveillance and caution should also be exercised in patients with ulcerative colitis or Crohn’s disease, as their condition may be exacerbated (see Undesirable effects)

Hepatic effects
Close medical surveillance is required when prescribing diclofenac to patients with impairment of hepatic function as their condition may be exacerbated.

Elevations of one or more liver tests may occur during therapy with diclofenac sodium. These laboratory abnormalities may progress, may remain unchanged, or may be transient with continued therapy. Borderline elevations (i.e. less than 3 times the ULN [ULN = the upper limit of normal range]) or greater elevations of transaminases occurred in about 15% of diclofenac-treated patients. Of the markers of hepatic function, ALT (SGPT) is recommended for the monitoring of liver injury.

In clinical trials, meaningful elevations (i.e., more than 3 times the ULN) of AST (GOT) (ALT was not measured in all studies) occurred in about 2% of approximately 5,700 patients at some time during diclofenac treatment. In a large, open-label, controlled trial of 3,700 patients treated for 2-6 months, patients were monitored first at 8 weeks and 1,200 patients were monitored again at 24 weeks. Meaningful elevations of ALT and/or AST occurred in about 4% of patients and included marked elevations (i.e., more than 8 times the ULN) in about 1% of the 3,700 patients.

In that open-label study, a higher incidence of borderline (less than 3 times the ULN), moderate (3-8 times the ULN), and marked (> 8 times the ULN) elevations of ALT or AST was observed in patients receiving diclofenac when compared to other NSAIDs.
Elevations in transaminases were seen more frequently in patients with osteoarthritis than in those with rheumatoid arthritis.

Almost all meaningful elevations in transaminases were detected before patients became symptomatic. Abnormal tests occurred during the first 2 months of therapy with diclofenac in 42 of the 51 patients in all trials who developed marked transaminase elevations.


ABITREN INJECTION July 2014,        28 7. 2014, RH                    Page 5 of 13 In postmarketing reports, cases of drug-induced hepatotoxicity have been reported in the first month, and in some cases, the first 2 months of therapy, but can occur at any time during treatment with diclofenac. Postmarketing surveillance has reported cases of severe hepatic reactions, including liver necrosis, jaundice, fulfillment hepatitis with and without jaundice, and liver failure. Some of these reported cases resulted in fatalities or liver transplantation.

Physicians should measure transaminases periodically in patients receiving long-term therapy with diclofenac, because severe hepatotoxicity may develop without a prodrome of distinguishing symptoms. The optimum times for making the first and subsequent transaminase measurements are not known. Based on clinical trial data and postmarketing experiences, transaminases should be monitored within 4 to 8 weeks after initiating treatment with diclofenac. However, severe hepatic reactions can occur at any time during treatment with diclofenac.

If abnormal liver tests persist or worsen, if clinical signs and/or symptoms consistent with liver disease develop, or if systemic manifestations occur (e.g., eosinophilia, rash, abdominal pain, diarrhea, dark urine, etc.), diclofenac sodium should be discontinued immediately. To minimize the possibility that hepatic injury will become severe between transaminase measurements, physicians should inform patients of the warning signs and symptoms of hepatotoxicity (e.g., nausea, fatigue, lethargy, diarrhea, pruritus, jaundice, right upper quadrant tenderness, and “flu-like” symptoms), and the appropriate action patients should take if these signs and symptoms appear.

To minimize the potential risk for an adverse liver related event in patients treated with diclofenac sodium, the lowest effective dose should be used for the shortest duration possible. Caution should be exercised in prescribing diclofenac sodium with concomitant drugs that are known to be potentially hepatotoxic (e.g., antibiotics, anti- epileptics).
Hepatitis may occur with diclofenac without prodromal symptoms.
Caution is called for when using diclofenac in patients with hepatic porphyria, since it may trigger an attack.
Renal effects
As fluid retention and edema have been reported in association with NSAID therapy, particular caution is called for in patients with impaired cardiac or renal function, history of hypertension, the elderly, patients receiving concomitant treatment with diuretics or medicinal products that can significantly impact renal function, and in those patients with substantial extracellular volume depletion of any cause, e.g.
before or after major surgery (see Contraindications). Monitoring of renal function is recommended as a precautionary measure when using Abitren in such cases.
Discontinuation of therapy is normally followed by recovery to the pre-treatment state.
Hematological effects
During prolonged treatment with diclofenac, as with other NSAIDs, monitoring of the blood count is recommended.
Like other NSAIDs, diclofenac may temporarily inhibit platelet aggregation. Patients with defects of hemostasis, bleeding diasthesis or hematological abnormalities should be carefully monitored.
Severe skin reactions
Serious skin reactions, some of them fatal, including exfoliative dermatitis, Stevens- Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), have been reported very rarely in association with the use of NSAIDs, including diclofenac. These serious adverse events are idiosyncratic and are independent of dose or duration of use.
ABITREN INJECTION July 2014,        28 7. 2014, RH                    Page 6 of 13 Patients appear to be at highest risk of these reactions early in the course of therapy, the onset of the reaction occurring in the majority of cases within the first month of treatment. Patients should be advised of the signs and symptoms of serious skin reactions and to consult their doctor at the first appearance of skin rash, mucosal lesions or any other sign of hypersensitivity, and Abitren should be discontinued.

Systemic lupus erythematosus and mixed connective tissue disease
In patients with systemic lupus erythematosus and mixed connective tissue disorders there may be an increased risk of aseptic meningitis.

Effects on Driving