30 mg/ml, 60 mg/2 ml
For the use of a Registered Medical Practitioner or a Hospital or a Institution only.
KETLAC* is a non-narcotic, non-steroidal agent with pronounced analgesic activity. It is used as tromethamine salt for the short term management of moderate to severe painful conditions. Chemically, it is a pyrrolo-pyrrole derivative. The chemical name is (±)-5-benzoyl-2, 3-dihydro-1H-pyrrolizine-1-carboxylic acid, compound with 2-amino-2-(hydroxymethyl)-1, 3-propanediol (1:1)
Each ml contains :
Ketorolac Tromethamine USP 30 mg
Sodium Chloride USP 4.35 mg
Absolute Alcohol USP 11.7 % v/v
Water for Injection USP q.s.
KETLAC* is a new alpha substituted arylacetic acid, a highly potent member of a new class of analgesic compounds. KETLAC is both an analgesic and an anti-inflammatory agent. However, it possesses greater systemic analgesic than anti-inflammatory activity. In standard animal models of analgesic activity, KETLAC* has exhibited upto 800 times the potency of aspirin (weight for weight). In all assays, KETLAC* has shown more potent analgesic activity than indomethacin, naproxen and phenylbutazone. Animal models of systemic anti-inflammatory activity have shown variable activity equal or superior to indomethacin, greater than naproxen and phenylbutazone, KETLAC* has been demonstrated to provide antipyretic activity in rats greater than aspirin and phenylbutazone and equal to that of indomethacin and naproxen. Like other NSAIDs KETLAC* appears to inhibits platelet aggregation induced by arachidonic acid and collagen but not that induced by ADP. KETLAC* prolongs mean bleeding time. KETLAC* has indicated a favourable therapeutic ratio in respect to gastrointestinal erosion. Intramuscular administration of KETLAC* 10 to 30 mg. 4 times daily resulted in significantly less mucosal injury than did oral aspirin 650 mg. 4 times daily. KETLAC*, unlike narcotic analgesics did not depress respiratory centre, there was no significant increase in end-tidal PCO2 as compared to morphine. KETLAC*, unlike morphine did not affect vital cardiac functions or changed significantly haemodynamic effects. KETLAC* has no effect on psychomotor performance which in contrast is significantly impared by centrally acting analgesics such as morphine, pethidine and buprenorphine. In human clinical trials KETLAC* in single intramuscular doses of 30 to 90 mg, has shown analgesic activity superior to that of opioid analgesics : morphine 6-12 mg. pethidine 50 and 100 mg. and pentazocine 30mg. Multiple dose studies showed KETLAC* 30 mg to be equivalent to morphine 12 mg when administered upto 5 days. The efficacy of KETLAC* given intramusculary has been demonstrated in various pain states such as post-operative pain, acute musculoskeletal pain dental pain, sciatica and cancer pain etc.
The pharmacokinetic properties of KETLAC* have been studied after intramuscular doses in healthy subjects, in renal and hepatic impairment and in the elderly. The tromethamine salt enhances the solubility and rate of absorption of ketorolac. After injection, ketorolac tromethamine dissociates into the anion-form of ketorolac at physiological pH. KETLAC* is rapidly and completely absorbed after administration in humans. Peak plasma concentrations are achieved at 45-50 minutes after administration. It does not appear to undergo a significant degree of presystemic metabolism. Mean peak plasma concentration of approximately 3 mg/l after 30 mg dose have been reported in healthy volunteers. The pharmacokinetics are linear within therapeutically effective dose ranges. There is no accumulation in the dose range of 10 to 90 mg. As with other NSAIDs KETLAC* is extensively bound to plasma proteins to an extent more than 99 %. The apparent volume of distribution is low. KETLAC* achieves high concentration in aqueous humour. The major metabolic pathway of KETLAC* is alucwornic acid conjugation. More that 90 % of the dose is excreted in urine with 60 % as unchanged KETLAC*. The rest is excreted in faeces.The mean terminal phase elimination half-life of KETLAC* is about 4-6 hours after administration. The kinetics of KETLAC* are altered in the elderly, and in patients with renal dysfunction. The rate of elimination is reduced in elderly with a mean half-life of 6.21 hours after administration. The Tmax is prolonged and mean AUC increased in the elderly. The clinical significance is however not known. In patients with renal impairment the total clearance is reduced and the elimination half life is increased (9.62 to 9.91 hours) which warrants dosage reductions. The influence of hepatic disease is less clear, but any pharmacokinetic alteration is of minor clinical significance. KETLAC* is transferred from maternal to foetal circulation (ratio 0.116). It is also excreted in breast milk (ratio 0.015 to 0.037) Caution must be observed when administered to pregnant or lactating women.
Mechanism of Action :
KETLAC* is a non-narcotic, non-steroidal agent with pronounce analgesic effects. It acts at the cyclooxygenase pathway of arachidonic acid metabolism to inhibit prostaglandin biosynthesis.
Indications and usage :
KETLAC* is indicated for the short term management of moderate to severe pain. Therapy should always be initiated with KETLAC* Intravenous / Intramuscular, and oral dose is to be used only as continuation treatment, if necessary. Combined use of KETLAC* Intravenous / Intramuscular and oral dose is not to exceed 5 days of use. Patients should be switched to alternative analgesics as soon as possible, but KETLAC* therapy is not to exceed 5 days.
Patients with hypersensitivity to KETLAC* or other NSAIDs, and those in whom aspirin or other inhibitors induce allergic reactions (severe anaphylactic - like reactions have been observed in such patients) and patients with the complete or partial syndrome of nasal polyps, angioedema, or bronchospasm, and in patients with asthma dehydration and hypovolaemia from any cause. History of peptic ulcer or coagulation disorders, patients with suspected or confirmed gastrointestinal bleedings and/or cerebrovascular bleedings. Moderate to severe renal impairment. During pregnancy, labour, delivery or lactation. Children under 16 years, patients with haemorrhagic diathesis, patients who underwent operations having haemorrhagic high risk or incomplete haemostasis, patients on full anticoagulation therapy, or the concomitant use of the prophylactic low-dose heparin (2,500-5000 u 12 hourly) KETLAC*, as NSAIDs should not be used with other NSAIDs pentoxifylline, probenecid and lithium salts.
KETLAC* injection is not indicated for long term use. KETLAC* is not recommended for use as an obstetrical pre-operative medication or for obstetrical analgesia because of lack of adequate studies as well as known effects of NSAIDs on uterine contractility and foetal circulation.
Impaired renal or hepatic functions : As with other NSAIDs KETLAC* should be used with caution with impaired renal or hepatic function, or a history of kidney or liver disease. As with other NSAIDs, long term administration to animal resulted in renal papillary necrosis and other abnormal renal pathology. In conditions leading to a reduction in blood volume and/or renal blood flow an NSAID may precipitate renal failure. Patients with the greatest risk are those with impaired renal function, heart failure, liver dysfunction, taking diuretics and the elderly. Discontinuation of the NSAID is typically followed by recovery. KETLAC* should be used with caution in patients with mild impairment of renal clearance of the drug. Such patients should be followed closely. It is contraindicated in moderate to severe renal impairment.
Drug Interaction :
KETLAC* is highly bound to plasma proteins (>99 %) independent of concentration. In vitro binding of warfarin to plasma protein is slightly reduced by KETLAC*. KETLAC* does not alter digoxin protein binding. At therapeutic concentrations of salicylate in vitro, binding of KETLAC* was reduced from 99.2 % to 97.5 % a potential 2-fold increase in unbound KETLAC* plasma levels. Hence use KETLAC*with caution (or at reduced dosage) in patients being treated with high dose salicylate regimens. Therapeutic concentrations of digoxin, warfarin, ibuprofen, naproxen, acetaminophen, phenytoin, tolbutamide and piroxicam did not alter KETLAC* protein binding. There is no evidence that KETLAC* induces or inhibits the hepatic enzymes which metabolize it or other drugs. Some NSAIDs inhibit renal lithium excretion, leading to increased plasma concentrations, This has not been studied with KETLAC*. KETLAC* has been administered concurrently with morphine in clinical trials without adverse interactions. KETLAC* & Narcotic should not be given in same syringe.
Fluid retention and oedema :
These have been reported with NSAIDs. KETLAC* should be used with caution in patients with cardiac decompensation, hypertension or similar conditions.
Carcinogenesis, mutagenesis and impairment of fertility :
Studies in mice and rats at oral doses equal to 2.5 times the parenteral (maximum recommended human dose) showed no evidence of tumorigenicity. KETLAC* was not mutagenic in standard bacterial tests and did not cause chromosome breakage in the in vivo mouse micronucleus assay. Impairment of fertility did not occur in male or female at 8 times the parenteral maximum recommended human dose.
Haematological effects :
KETLAC* inhibits platelet aggregation and may prolong bleeding time but does not affect platelet count, prothrombin time (PT) or partial thromboplastin time (PTT) Carefully observe patients with coagulation disorders or who are receiving drug therapy that interferes with haemostasis. Inhibition of platelet function by KETLAC* disappears within 24-48 hours after the drug is discontinued. In clinical studies the incidence of clinically significant post-operative bleeding was infrequent. (0.4 %).
Pregnancy : Category B :
Reproduction studies in rabbits and rats with daily 5 times the parenteral maximum recommended dose, did not reveal evidence to harm to the foetus. KETLAC* caused delayed parturition and dystocia in rats at oral higher than the parenteral MRHD like other NSAIDs. There are no adequate and well controlled studies in pregnant women and KETLAC* is not recommended during pregnancy.
Labour and Delivery :
KETLAC* is not recommended for use during labour and delivery as it may prolong the course of labour, similar to other NSAIDs.
Lactation and Nursing :
After a single oral dose of KETLAC* 10 mg to humans, maximum milk concentration was 7.3 ng/ml and maximum milk to plasma ratio was 0.037. KETLAC* is not recommended during lactation.
Paediatric Use :
KETLAC* is not recommended for use in children under 16 years of age.
Use in Elederly :
KETLAC* is cleared more slowly by elderly, hence, extra caution and reduced dosages should be used when treating the elderly.
Adverse Reactions :
KETLAC* is usually well tolerated after intramuscular administration. It is devoid of narcotic side effects like sedation, amnesia and vomiting. The usual side effects after single dose or short term use of KETLAC* are 1/2 to 1/10 the rates associated with its chronic usage. The usual precautions observed during NSAIDs treatment also apply to KETLAC* therapy. After administration of up to 20 doses of KETLAC* 30 mg over 5 days post-operatively, adverse events probably causally related to treatment in 509 patients included : somnolence (7 %), injection site pain (2 %), increased sweating (1 %), nausea (1 %), headache, dizziness, vomiting, pruritus, vasodilation or dysgeusia (<1 %) each event). KETLAC* administered long term was at least as well tolerated as aspirin and no differences between the 2 groups were observed with regard to laboratory values, audiograms, ECG or ophthalmic test results. There was a higher incidence of adverse effects with the highest dose of morphine (12 mg) than with the highest dose of KETLAC* (90 mg).
Drug abuse and physical dependence :
KETLAC* is not a narcotic agonist or antagonist, subjects did not show any symptoms of withdrawal upon abrupt discontinuation. KETLAC* does not have central opiate like activity.
Acute overdosage experience in humans is not available. At single oral dosage > 100 mg/kg in animals, symptoms such as decreased activity, diarrhoea, pallor, laboured breathing rates and vomiting were observed.
Dosage and Administration :
KETLAC* injection may be used on a regular schedule or as and when required, although current recommendations for pain management are to use analgesics on a regular schedules rather than on demand based upon return of pain. Hypovolemia should be corrected prior to the administration of KETLAC*. When administration KETLAC* Intravenous, the intravenous bolus must be given over no less than 15 seconds. The Intramuscular administration should be given slowly and deeply into the muscle.
Single-Dose Treatment :
The following regimen should be limited to single administration use only.
Store at controlled room temperature 15-30OC (59-86OF),
protected from light. Do not refrigerate.
30 mg/1ml vial for I.M. / I.V. use only.
60 mg/2ml vial for I.M. use only.
Disclaimer : For the use of a Registered Medical Practitioner or a Hospital or a Institution only. Also it is not intended to be used by healthcare professionals or patients for the purpose of prescribing or administering these products. Questions regarding the complete and current content of product labeling / specification / presentation should be directed to SGPharma.