COMPOSITION Each 1 mL ampoule contains 30 mg of ketorolac tromethamine.
PHARMACOLOGICAL CLASSIFICATION A. 2.7 Anti-pyretic or anti-pyretic and anti-inflammatory analgesics.
PHARMACOLOGICAL ACTION Ketorolac tromethamine is an analgesic agent of the non-steroidal anti-inflammatory class (NSAID), with analgesic, anti-inflammatory and antipyretic properties. Minimal anti-inflammatory effect is demonstrated at its analgesic dose. Ketorolac inhibits the cyclo-oxygenase enzyme system and hence prostaglandin synthesis.
Ketorolac has no known effects on opiate receptors and is considered a peripherally acting analgesic.
Absorption: IMAdministration: Ketorolac is completely absorbed following IM administration with a mean peak plasma concentration of 2,2 - 3,0 micrograms/mL occurring on an average of 50 minutes after a single 30 mg dose. Bolus Administration:IV administration of a single 10 mg dose of ketorolac results in a mean peak plasma concentration of 2,4 micrograms/mL occurring an average of 5,4 minutes after dosing. IVinfusion: In young, healthy adult volunteers, mean peak plasma concentrations occur about 5 minutes after an initial loading dose of 30 mg IV has been completed. Continuous infusion at 5 mg/hour thereafter, maintains plasma concentrations in the same range as those achieved following IM administration of a single 30 mg dose every 6 hours. Distribution: The pharmacokinetics of ketorolac in humans, following single or multiple IM or IV doses, are linear. Steady-state plasma levels are approached after the fourth dose when ketorolac is administered as an IV bolus every 6 hours, for one day. Ketorolac is over 99% bound to plasma protein, with a mean volume of distribution of 0,15 L/kg following IV and IM administration of single 10 mg doses to young, healthy adult volunteers. Nearly all the drug-related material circulating in plasma is ketorolac or the pharmacologically inactive p-hydroxyketorolac. Approximately 10% of ketorolac crosses the placenta. Low concentrations of ketorolac has been detected in breast milk. Metabolism: Ketorolac is largely metabolised in the liver. The major metabolic pathway is glucuronic acid conjugation. P-hydroxylation is an additional major pathway. Elimination: The principal route of elimination of ketorolac and its metabolites, is renal. About 92% of a given dose is found in the urine; approximately 40% as metabolites and 60% as unchanged ketorolac. Approximately 6% of a dose is excreted in the faeces. The terminal plasma half-life averages 5,3 hours, ranging from 2,4 - 9,2 hours, and the total plasma clearance averages 0,023 L/h/kg, in young healthy subjects.
Pharmacokinetics in special populations:
The elderly: In the elderly, the terminal plasma half-life of ketorolac is prolonged, compared to young, healthy volunteers, to an average of 7 hours, ranging from 4,3 - 8,6 hours. The total plasma clearance may be reduced, on average to 0,019 L/h/kg. Renal impairment: Elimination of ketorolac is significantly decreased in patients with renal impairment as reflected by a prolonged plasma half-life and reduced plasma clearance, when compared to young healthy subjects. The rate of elimination is reduced, roughly proportional to the degree of renal impairment, except for patients who are severely renally impaired, in whom there is a higher plasma clearance of ketorolac than estimated from the degree of renal impairment alone. Hepatic impairment: Patients with impaired hepatic function have significant prolongation of Tmaxand terminal plasma half-life compared to young healthy volunteers.
BEDORAL 30 is used in the short-term management of moderate post-operative pain.
CONTRA-INDICATIONS Hypersensitivity to ketorolac tromethamine or other NSAIDs and those patients in whom aspirin or other prostaglandin synthesis inhibitors induce allergic reactions (severe anaphylactic-like reactions have been observed in such patients).
In patients with recent gastrointestinal bleeding or perforation, in patients with active peptic ulcer disease and in patients with a history of peptic ulcer disease or gastrointestinal bleeding. Haemorrhagic diatheses, including coagulation disorders. Patients on anti-coagulation therapy including prophylactic low-dose heparin or low molecular weight heparins or heparinoids. BEDORAL 30 inhibits platelet function and is therefore contra-indicated in patients with suspected or confirmed cerebrovascular bleeding, patients who have had operations with a high risk of haemorrhage or incomplete haemostasis and those at high risk of bleeding.
In patients with moderate or severe renal impairment (serum creatinine >442 micromol/L) or in patients at risk of renal failure due to volume depletion or dehydration. BEDORAL 30 is contra-indicated during pregnancy and lactation. (see: Pregnancy and Lactation).
Safety and efficacy in children under 16 years of age have not been established. As prophylactic analgesics before surgery, due to inhibition of platelet aggregation, and also intra-operatively, because of increased risk of bleeding. BEDORAL 30 is contra-indicated for neuraxial (epidural or intrathecal) administration. The combination of BEDORAL 30 and oxpentifylline is contra-indicated.
Gastrointestinal ulceration, bleeding and perforation: Gastrointestinal mucosal injury may occur. Serious gastrointestinal toxicity, including gastrointestinal irritation, bleeding, ulceration or perforation, can occur at anytime with, or without, previous symptoms. Studies to date have not identified any subset of patients not at risk of developing peptic ulceration and bleeding. There may be a greater risk of gastrointestinal ulceration, bleeding and perforation in debilitated patients and in the elderly. Most spontaneous reports of fatal GI events are in this population.
The severity and incidence of gastrointestinal complications increases with increasing dose and duration of treatment with BEDORAL 30. The risk of clinically serious gastrointestinal bleeding is dose-dependent. This is particularly true in elderly patients who receive an average daily dose greater than 60 mg/day of BEDORAL 30.
Use in Patients with impaired renal function:
BEDORAL 30 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.
In patients on renal dialysis, BEDORAL 30 clearance was reduced to approximately half the normal rate and terminal half-life increased approximately three-fold. Caution should be observed as renal toxicity has been seen with BEDORAL 30 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 BEDORAL 30 or other NSAIDs may cause a dose-dependent reduction in renal prostaglandin formation and may precipitate overt renal decomposition or renal failure. Patients at greater risk of this reaction are those with impaired renal function, hypovolemia, heart failure, liver dysfunction, those taking diuretics and the elderly. Discontinuation of BEDORAL 30 or other NSAID therapy is usually followed by recovery to the pre-treatment state. Anaphylactic reactions: Anaphylactic reactions, including, but not limited to, anaphylaxis, bronchospasm, flushing, rash. Hypotension, laryngeal oedema and angioedema may occur in patients, with or without a history of hypersensitivity to aspirin, other NSAIDs or BEDORAL 30. These may also occur in individuals with a history of angioedema, bronchospastic reactivity (e.g. asthma), and nasal polyps. Anaphylactoid reactions, like anaphylaxis, may havea fatal outcome.
Therefore, BEDORAL 30 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. BEDORAL 30 should not be used for chronic painful conditions.
INTERACTIONS Because of the potential for additive side-effects, BEDORAL 30 should not be used with other NSAIDs.
There is an increased tendency to bleeding when oxpentifylline is administered concurrently and this combination should be avoided. Caution is advised when methotrexate is administered concurrently, since some prostaglandin-synthesis-inhibiting medicines have been reported to reduce the clearance of methotrexate, and thus possibly enhance its toxicity. Inhibition of renal lithium clearance, leading to an increase in plasma lithium concentration, has been reported with some prostaglandin synthesis-inhibiting drugs.
Cases of increased lithium plasma concentrations during BEDORAL 30 therapy have been reported.
There is an increased risk of renal impairment when BEDORAL 30 is administered concurrently with ACE inhibitors particularly in volume depleted patients. BEDORAL 30 does not alter digoxin protein binding.
Salicylate, at therapeutic concentrations of 300 microgram/mL and above, reduces the protein binding of BEDORAL 30 approximately 99,2 - 97,5%, representing a two-fold increase in unbound BEDORAL 30 plasma concentrations. Therapeutic concentrations of warfarin, naproxen, ibuprofen, piroxicam, acetaminophen, phenytoin and tolbutamide does not alter BEDORAL 30 protein binding. BEDORAL 30 should not be given to patients already receiving anticoagulants or to those who will require prophylactic anticoagulant therapy, including low dose heparin. BEDORAL 30 injection reduces the diuretic response to furosemide in normovolaemic healthy subjects by approximately 20%, so particular care should be exercised in patients with cardiac decompensation.
ABUSE AND DEPENDENCE:
BEDORAL 30 is devoid of addictive potential. Following abrupt discontinuation of BEDORAL 30, no withdrawal symptoms have been observed.
PREGNANCY AND LACTATION
BEDORAL 30 is contraindicated during pregnancy and lactation.
During pregnancy, labour, delivery or lactation, because of its prostaglandin synthesis inhibiting effect, it may adversely affect foetal circulation and inhibit uterine contractions, thus increasing the risk of uterine haemorrhage.
DOSAGE AND DIRECTIONS FOR USE
Children: BEDORAL 30 injection is not recommended for use in children under 16 years of age. Adults:BEDORAL 30 injection may be used as a single or multiple dose IM or bolus IV injection, or IV infusion. BEDORAL 30 injection may be used for short-term IV or IM use, not exceeding two days.
The maximum duration for use of the IV infusion, is not to exceed 24 hours. The lowest effective dose should be given. If further pain relief is required, opiate analgesics (e.g. morphine, pethidine) may be used concomitantly.
When used in association with BEDORAL 30, the daily dose of morphine required is less than that normally required following major surgery. However, opioid side-effects should still be considered, especially in day-case surgery. Hypovolemia should be corrected prior to the administration of BEDORAL 30. BEDORAL 30 infusion should be used only in patients with adequate fluid and electrolyte balance. Bolus doses should be given over no less than 15 seconds. The IM administration should be given slowly and deeply into the muscle. The analgesic effect begins in approximately 30 minutes with maximum effect within 1 - 2 hours after dosing.
The median duration of analgesia is generally 4 - 6 hours. 1) Single dose treatment IM Dosing: Patients < 65 years of age: One dose of 10 - 60 mg according to the severity of the pain. Patients > 65 years of age, or mildly renally impaired patients: One dose of 10 - 30 mg. IV Dosing: Patients < 65 years of age: One dose of 10 - 30 mg. Patients >65 years of age, or mildly renally impaired patients: One dose of 10 - 15 mg.
2) Multiple-dose treatment (IV or IM) Dosage should be adjusted according to the severity of the pain and the patient response. Note that the maximum combined duration of use of multiple bolus IM or IV doses of BEDORAL 30 injection is not to exceed 2 days. Patients < 65 years of age: The maximum daily dose should not exceed 90 mg. IM Dosing: The recommended usual initial dose of BEDORAL 30 is 10 - 30 mg, followed by 10 - 30 mg every 4 - 6 hours as required, up to a maximum daily dose of 90 mg. IV Dosing: IV Bolus:10 - 30 mg initial dose, followed by 10 - 30 mg every 6 hours as required up to a maximum daily dose of 90 mg. Continuous IV infusion: 30 mg initial dose, followed by continuous infusion at a rate of up to 5 mg/h for up to 24 hours, up to a maximum daily dose of 90 mg. Patients > 65 years of age, or renally impaired patients: The maximum daily dose should not exceed 60 mg. IM Dosing: The recommended dose is 10 - 15 mg every 4 - 6 hours as required up to a maximum daily dose of 60 mg. IV Dosing: IV Bolus: 10 - 15 mg every 6 hours as required, up to a maximum daily dose of 60 mg. Continuous IV infusionis not recommended in this population as experience is limited.
Transition from BEDORAL 30 injection to ketorolac tablets: On the day of transition to the oral formulation, a total combined daily dose of all forms of BEDORAL 30 should not exceed 90 mg for patients < 65 years of age and 60 mg for patients > 65 years of age, renally impaired patients and patients weighing less than 50 kg. The total oral dose should not exceed 40 mg on the day the change of formulation is made. Elderly patients (> 65 years of age):
BEDORAL 30 may be cleared more slowly by the elderly who are also more sensitive to the adverse effects of NSAIDs, therefore extra caution and reduced dosages must be used when treating the elderly (see: Side-effects and special precautions). Patients with renal impairment :
BEDORAL 30 and its metabolites are eliminated primarily via the kidneys, which, in patients with reduced creatinine clearance, will result in diminished plasma clearance of the drug. BEDORAL 30 is contra-indicated in moderate or severe renal impairment (serum creatinine > 442 micromol/L). BEDORAL 30 should be used with caution in patients with lesser renal impairment (serum creatinine 170 442 micromol/L). Such patients should receive a reduced dose of BEDORAL 30 and their renal status should be closely monitored. It is recommended that the daily dose be reduced by half; a total daily dose of 60 mg should not be exceeded. Dialysis does not significantly clear BEDORAL 30 from the blood stream.
BEDORAL 30 injection is compatible with 0,9% sodium chloride solution, 5% dextrose, Ringers lactate, plasmalyte solutions. BEDORAL 30 should not be mixed in small volume (e.g. in a syringe) with morphine sulphate, pethidine hydrochloride, promethazine hydrochloride or hydroxyzine hydrochloride, as precipitation of BEDORAL 30 will occur. When mixed together in IV solutions contained in standard bottles or bag administration sets, it is compatible with aminophylline, lidocaine hydrochloride, morphine sulphate, meperidine hydrochloride, dopamine hydrochloride, regular human insulin and heparin sodium. DO NOT USE if particulate matter is present.
SIDE-EFFECTS AND SPECIAL PRECAUTIONS
Gastrointestinal: Very common (> 10%): Nausea, dyspepsia, gastrointestinal pain. Common (>1% < 10%): Abdominal discomfort, diarrhoea, constipation, flatulence, fullness, stomatitis, vomiting. Uncommon or rare (< 1%): Melaena, peptic ulcer, rectal bleeding, haemorrhage, perforation, pancreatitis. The following side-effects have been reported but the frequencies are not known: Gastritis, eructation, esophagitis. Central nervous/Musculoskeletal systems: Very common (> 10%): Headache. Common (>1% < 10%): Drowsiness, dizziness, sweating. Uncommon or rare (< 1%): Depression, convulsions, excessive thirst, hallucinations, hyperkinesia, aseptic meningitis, psychotic reactions. The following side-effects have been reported but the frequencies are not known: Dry mouth, nervousness, abnormal thinking, euphoria, inability to concentrate, paraesthesia, insomnia, vertigo, myalgia, abnormal dreams, anxiety. Urinary tract and kidneys: Uncommon or rare (< 1%): Increased urinary frequency, oliguria, acute renal failure, haemolytic uraemic syndrome, flank pain (with or without haematuria), interstitial nephritis. Signs of renal impairment, such as, but not limited to, elevations of creatinine and potassium, can occur after one dose of BEDORAL 30. The following side-effects have been reported but the frequencies are not known: Hyponatraemia, hyperkalaemia, raised serum urea and creatinine, urinary retention, nephrotic syndrome. Cardiovascular: Common (>1% < 10%): Hypertension. Uncommon or rare (< 1%): Hypotension. The following side-effects have been reported but the frequencies are not known: Flushing, bradycardia, pallor, palpitations, chest pain. Hepatobiliary: Uncommon or rare (< 1%): Hepatitis, cholestatic jaundice. The following side-effects have been reported but the frequencies are not known: Abnormal liver function tests, liver failure. Respiratory: Uncommon or rare (< 1%): Dyspnoea, asthma, pulmonary oedema. Dermatological: Uncommon or rare (< 1%):Pruritus, urticaria, Lyells syndrome, Stevens-Johnson syndrome, exfoliative dermatitis, maculopapular rash. Hematological: Common (>1% < 10%): Purpura. Uncommon or rare (< 1%): Thrombocytopaenia, post-operative wound haemorrhage, epistaxis. The following side-effects have been reported but the frequencies are not known: Haematoma, increased bleeding time. Special senses: Uncommon or rare (< 1%): Abnormal vision, tinnitus, hearing loss. The following side-effects have been reported but the frequencies are not known: Abnormal taste. Other: Common (>1% < 10%): Oedema, weight gain, injection site reactions. Uncommon or rare (< 1%): Fever. The following side-effects have been reported but the frequencies are not known: Asthenia.
Paediatric Use : Safety and efficacy in children (less than 16 years of age) have not been established. Therefore the use of BEDORAL 30 in children is not recommended. Elderly patients: Elderly patients may be at a greater risk of experiencing undesirable effects than younger patients. In elderly patients the terminal plasma half-life of BEDORAL 30 is prolonged and plasma clearance may be reduced. The lower end of the dosage range is recommended. Hematological effects:
BEDORAL 30 inhibits platelet aggregation, reduces thromboxane concentrations and prolongs bleeding time. Platelet function returns to normal within 24 to 48 hours after BEDORAL 30 is discontinued. The use of BEDORAL 30 in patients who have coagulation disorders should be undertaken very cautiously, and those patients should be carefully monitored. The concurrent use of BEDORAL 30 and therapy that affects haemostasis, including therapeutic doses of anticoagulation therapy (warfarin), prophylactic lowdose heparin (2500-5000 units 12-hourly) and dextrans, may be associated with an increased risk of bleeding (see Contra-indications). Increased post-operative wound haemorrhage has been reported in association with the immediate peri-operative use of BEDORAL 30 injection. Therefore, BEDORAL 30 should not be used in patients who have had operations with a high risk of haemorrhage or incomplete haemostasis. Caution should be used where strict haemostasis is critical, e.g. in cosmetic or day-case surgery. Haematoma and other signs of wound haemorrhage and epistaxis have been reported with the use of BEDORAL 30. Physicians should be aware of the pharmacological similarity of BEDORAL 30 to other non-steroidal anti-inflammatory agents, drugs that inhibit cyclo-oxygenase and the risk of bleeding, particularly in the elderly. Fluid retention and oedema: Fluid retention, hypertension and oedema have been reported with the use of BEDORAL 30 and it should therefore be used with caution in patients with cardiac decompensation, hypertension or similar conditions. Driving and operating machinery: Patients may experience drowsiness, dizziness, vertigo, insomnia or depression with the use of BEDORAL 30. If patients experience these, or other similar undesirable effects, caution should be exercised in carrying out activities that require alertness. Hepatic effects: Elevations of one or more liver tests may occur. These abnormalities may be transient, may remain unchanged, or may progress with continued therapy. BEDORAL 30 should be discontinued if clinical signs and symptoms consistent with liver disease develop, or if systemic manifestations occur.
KNOWN SYMPTOMS OF OVERDOSAGE AND PARTICULARS OF ITS TREATMENT Doses of 360 mg given intramuscularly over an 8-hour interval for five consecutive days have caused abdominal pain, nausea, vomiting, hyperventilation, erosive gastritis, renal dysfunction and peptic ulcers which have healed after discontinuation of dosing. BEDORAL 30 is not appreciably cleared by dialysis.
IDENTIFICATION A clear, colourless solution, free from visible particles and fibres.
PRESENTATION 1 mL Clear, flint USP type 1 glass ampoules each containing 1 mL solution.
Ampoules are supplied in cartons of 10 ampoules.
STORAGE INSTRUCTIONS Store below 25°C. Protect from light.
STORE BEDORAL 30 OUT OF REACH OF CHILDREN.
REGISTRATION NUMBER A40/2.7/0147
NAME AND BUSINESS ADDRESS OF THE HOLDER OF THE CERTIFICATE OF REGISTRATION BE-TABS PHARMACEUTICALS (PTY) LTD.
14 LAUTRE ROAD
DATE OF PUBLICATION OF THIS PACKAGE INSERT 7 July 2006
IBEDO30 New addition to this site: January 2008
Source: Pharmaceutical Industry