Special Warning : אזהרת שימוש

4.4   Special warnings and precautions for use

Epidemiological evidence suggests that ketorolac may be associated with a high risk of serious gastrointestinal toxicity, relative to some other NSAIDs, especially when used outside the licensed indications and/or for prolonged periods of time (see also sections 4.1, 4.2 and 4.3).

Physicians should be aware that in some patients pain relief may not occur until upwards of 30 minutes after intravenous or intramuscular administration.

The use of ketorolac with concomitant NSAIDs including cyclooxygenase-2 selective inhibitors should be avoided.

Undesirable effects may be minimised by using the minimum effective dose for the shortest duration necessary to control symptoms.

The elderly patients have an increased frequency of adverse reactions to NSAIDs, especially gastrointestinal bleedings or perforations which may be fatal (see section 4.2 and the cardiovascular and the gastrointestinal risks listed below). Debilitated patients seem to tolerate ulceration or bleeding less well than others. Most of the fatal gastrointestinal events associated with non-steroidal anti- inflammatory drugs occurred in the elderly and/or debilitated patients.

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

The risk of gastrointestinal bleeding, ulceration or perforation is higher with increasing NSAID doses, including ketorolac administered intravenously, in patients with a history of ulcer, particularly if complicated with haemorrhage or perforation (see section 4.3), and in the elderly patients. These patients should commence on the lowest dose available. Combination therapy with protective agents (e.g. misoprostol or proton pump inhibitors) should be considered for these patients, and also for patients requiring concomitant low dose aspirin, or other drugs likely to increase gastrointestinal risk (see section 4.5).

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

Caution should be advised in patients receiving concomitant medications which could increase the risk of ulceration or bleeding, such as oral corticosteroids, anticoagulants such as warfarin, selective serotonin-reuptake inhibitors or anti-platelet agents such as acetylsalicylic acid (see section 4.5).

The concomitant use of anticoagulants, such as warfarin, is contraindicated (see section 4.3).

NSAIDs should be given with caution in patients with a history of gastrointestinal diseases (ulcerative colitis, Crohn's disease) as these may be exacerbated (see section 4.8). When gastrointestinal bleeding or ulcerations occur in patients receiving ketorolac trometamol intravenously, the treatment should be withdrawn.

As with other NSAIDs, the incidence and severity of the gastrointestinal complications may increase with increasing dose and duration of treatment with ketorolac trometamol administered intravenously.
The risk of clinically serious gastrointestinal bleeding is dose-dependent. This is particularly true in elderly patients who receive an average daily dose of ketorolac trometamol administered intravenously greater than 60 mg/day. A history of peptic ulcer disease increases the possibility of developing serious gastrointestinal complications during treatment with ketorolac trometamol.

Haematological effects:

The use of ketorolac trometamol in patients who have coagulation disorders should be undertaken very cautiously, and those patients should be carefully monitored. Although studies do not indicate a significant interaction between ketorolac trometamol and warfarin or heparin, the concurrent use of ketorolac trometamol and therapy that affects haemostasis, including therapeutic doses of anticoagulation therapy, i.e., warfarin, prophylactic low-dose heparin (2500-5000 units 12-hourly) and dextran, may be associated with an increased risk of bleeding. The administration of ketorolac trometamol to such patients should be done extremely cautiously, and these patients should be closely monitored.
In post-marketing experience, postoperative haematomas and other signs of wound bleeding have been reported in association with the peri-operative use of ketorolac trometamol, solution for injection.
Physician should be aware of the potential risk of bleeding when haemostasis is critical in cases such as, but not limited to, resection of the prostate, tonsillectomy, cosmetic surgery.

Skin reactions:
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). Patients appear to be at highest risk of these reactions at the beginning of therapy. Treatment with ketorolac should be discontinued at the first appearance of skin rash, mucosal lesions, or any other sign of hypersensitivity.

Sodium/fluid retention in cardiovascular diseases and peripheral oedema: Caution is recommended in patients with a history of hypertension and/or heart failure as fluid retention and oedema have been reported in association with NSAID therapy.

Fluid retention, hypertension and peripheral oedema has been observed in some patients taking NSAIDs including ketorolac and it should therefore be used with caution in patients with cardiac decompensation, hypertension or similar conditions.

Cardiovascular and cerebrovascular effects:
Appropriate monitoring and advice are required for patients with a history of hypertension and/or mild to moderate congestive heart failure as fluid retention and oedema have been reported in association with NSAID therapy.

Clinical trial and epidemiological data suggest that use of coxibs and some NSAIDs (particularly at high doses and long term treatment) may be associated with a small increased risk of arterial thrombotic events (for example: myocardial infarction or stroke). Although ketorolac has not shown to increase thrombotic events such as myocardial infarction, there are insufficient data to exclude such a risk for ketorolac.

Patients with uncontrolled hypertension, congestive heart failure, established ischaemic heart disease, peripheral arterial disease, and/or cerebrovascular disease should only be treated with ketorolac after careful consideration. Similar consideration should be made before initiating treatment of patients with risk factors for cardiovascular disease (e.g., hypertension, hyperlipidaemia, diabetes mellitus, and smoking).

Renal effects:
As with other NSAIDs, ketorolac should be used with caution in patients with impaired renal function or a history of kidney disease, because it is a potent inhibitor of prostaglandin synthesis. Caution should be observed as renal toxicity has been seen with ketorolac and other NSAIDs in patients with conditions leading to a reduction in blood volume and/or renal blood flow where renal prostaglandins have a supportive role in the maintenance of renal perfusion. In these patients administration of ketorolac or other NSAIDs may cause a dose-dependent reduction in renal prostaglandin formation and may precipitate overt renal decompensation or failure. Patients at greatest risk of this reaction are those with impaired renal function, hypovolaemia, heart failure, liver dysfunction, those taking 

diuretics and the elderly. Discontinuation of ketorolac or other non-steroidal anti-inflammatory therapy is usually followed by recovery to the pre-treatment state.

Anaphylactic (anaphylactoid) reactions:
Anaphylactic (anaphylactoid) reactions (including, but not limited to, anaphylaxis, bronchospasm, vasomotor reactions, skin rashes, hypotension, laryngeal oedema and angioedema) may occur in patients with or without a history of hypersensitivity to aspirin, other NSAIDs or ketorolac. These may also occur in individuals with a history of angioedema, bronchospastic reactivity (e.g. asthma) and nasal polyps. Anaphylactoid reactions, like anaphylaxis, may have a fatal outcome. Therefore, ketorolac should be used with caution in patients with a history of asthma and in patients with the complete or partial syndrome of nasal polyps, angioedema and bronchospasm.

Precautions related to fertility:
The use of intravenous ketorolac, as with any drug known to inhibit cyclooxygenase/prostaglandin synthesis, may impair fertility and is not recommended in women attempting to conceive. In women who have difficulty conceiving or are undergoing investigation of infertility, withdrawal of ketorolac should be considered.

Fluid retention and oedema:
Fluid retention, hypertension and oedema have been reported with the use of ketorolac and it should therefore be used with caution in patients with cardiac decompensation, hypertension or similar conditions.
Caution is advised when probenecid is administered concurrently since alterations in the pharmacokinetics of ketorolac have been reported with this combination.
Caution is advised when methotrexate is administered concurrently since some prostaglandin synthesis-inhibiting drugs have been reported to reduce the clearance of methotrexate, and thus possibly enhance its toxicity.

Pediatric use:
Ketorolac Trometamol Rompharm 30 mg/ml solution for injection is contraindicated in children and adolescents under 16 years of age (see section 4.3).

Drug abuse and dependence:
Ketorolac is devoid of addictive potential. No withdrawal symptoms have been observed following abrupt discontinuation of ketorolac.

Excipients:
This medicinal product contains less than 1 mmol sodium (23 mg) per dose, i.e., that is to say essentially “sodium-free”.

This medicinal product contains alcohol (ethanol) 100 mg in each ml. The amount in one ml of this medicine is equivalent to less than 2.5 ml beer or 1 ml wine. The small amount of alcohol in this medicine will not have any noticeable effects.

Effects on Driving

4.7   Effects on ability to drive and use machines

Some patients may experience dizziness, vertigo, insomnia or depression with the use of ketorolac trometamol. If patients experience these adverse effects or other similar ones, they should exercise caution in carrying out activities that require cortical alertness.