Geriatrics: Patients older than 65 years and frail or debilitated patients are more susceptible to a variety of adverse reactions from NSAIDs. There may be a greater risk of GI ulcerations, bleeding and perforation in elderly patients and most spontaneous reports of fatal GI events are in this population.

Pediatrics (<18 years of age):Safety and efficacy have not been established in pediatric population.

THERAPEUTIC INDICATIONS:Monak is indicated for the short-term management of moderate to severe acute pain, including pain following major abdominal, orthopaedic and gynecological operative procedures.

DOSAGE AND ADMINISTRATION:Use of Monak should be limited to the lowest effective dose for the shortest possible duration of treatment. The total duration of combined IM and oral treatment should not exceed 5 days. In no case is the duration of Monak treatment to exceed 7 days.

Recommended Dose and Dosage AdjustmentAdults (>18 years of age):The recommended usual initial dose of Monak in adults (>18 years of age) is 10-30mg, according to pain severity. Subsequent dosing may be 10mg to 30mg every 4-6 hours as needed to control pain. The administra-tion of Monak IM/IV should be limited to short term therapy (not over two days). The total daily dose should not exceed 120mg because of the risk of toxicity appears to increase with longer use at recommended doses.

Elderly, Frail or Debilitated Patients:These patients are at increased risk of the serious consequences of adverse reactions. The lower end of the dosage range is recommended. The initial dose should be 10mg. The total daily dose of Monak in the elderly should not exceed 60mg.

ADVERSE REACTIONS:The most common adverse reactions encountered with NSAIDs are gastrointestinal, of which peptic ulcer with or without bleeding is the most severe. Fatalities have occurred, particularly in the elderly. Other adverse reactions are somnolence, headache, sweating, dizziness, nausea, vomiting, injection site pain and vasodilation.

CONTRAINDICATIONS: A history of peptic ulcer or gastrointestinal bleeding.Suspected or confirmed cerebrovascular bleeding.Haemorrhagic diathesis, including coagulation disorders.Patients with hypersensitivity to ketorolac trometamol or other NSAIDs and patients in whom aspirin or other prostaglandin synthesis inhibitors induced allergic reactions (severe anaphylactic reactions have been observed in such patients).Patients with complete or partial syndrome of nasal polyps, angioedema or bronchospasm.Concurrent use with other NSAIDs and concomitant use with oxpentifylline and probenecid.Hypovolemia from any cause, or dehydration.Moderate to severe renal impairment (serum creatinine > 442 µmol/L and/or creatinine clearance < 30mL/min or 0.5mL/sec) or deteriorating renal disease.Immediately before any major surgery and intraoperatively when hemostasis is critical because of the increased risk of bleeding.Patients on anticoagulants including low dose heparin (2500 to 5000 units 12 hourly).During pregnancy, labour, delivery or lactation.Children under 18 years of age.

PRECAUTIONS: To minimize the potential risk of an adverse event, the lowest effective dose should be used for the shortest possible duration.

Risk of GI adverse events:Monak is associated with an increased incidence of gastrointestinal adverse events (such as peptic/duodenal ulceration, perforation, obstruction and GI bleeding).

Haematologic: NSAIDs inhibiting prostaglandin biosynthesis interfere with platelet function to varying degrees; patients who may be adversely affected by such an action, such as those on anticoagulants or suffering from haemophilia or platelet disorders should be carefully observed when Monak is administered.

DESCRIPTION:Monak (Ketorolac Trometamol) is a non-selective COX inhibitor with anti-inflammatory, analgesicand antipyretic activity. Chemically, ketorolac trometamol belongs to the family of heterocyclicacetic acid derivatives compounded with 2-amino-2-(hydroxymethyl)propane-1,3-diol;5-benzoyl-2,3-dihy-dro-1~{H}-pyrrolizine-1-carboxylic acid having molecular formula of C19H24N2O6. The structural formula of ketorolac trometamol is:

COMPOSITION:Monak (Ketorolac Trometamol) 30mg:Each 1ml ampoule contains:Ketorolac Trometamol USP……... 30mgProduct Specs.: USP

CLINICAL PHARMACOLOGY:Mechanism of action:The analgesic activity of ketorolac trometamol is produced via a peripheral action in which blockade of pain impulse generation results from decreased prostaglandin activity. The anti-inflammatory activity is due to inhibition of both cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2) which leads to the inhibition of prostaglandin synthesis leading to decreased formation of precursors of prostaglandins and thromboxanes from arachidonic acid.

Pharmacokinetics: The pharmacokinetics is linear following single and multiple dosing. Steady state plasma levels are attained after one day of Q.I.D. dosing. The parenteral administration of ketorolac trometamol has not been demonstrated to affect the haemodynamics of anesthetized patients. Absorption: Ketorolac trometamol was rapidly (Tmax ranged from 0.25 to 1.5 hours) and completely absorbed after oral and IM doses (>99%).Distribution: The volume of distribution of ketorolac trometamol was estimated following intravenous dosing and it averaged 0.15L/kg. Ketorolac was highly protein bound (99.2%). Binding was concentration independent. Metabolism: Ketorolac is largely metabolized in the liver. The major metabolic path of ketorolac in humans is glucuronic acid conjugation. P-hydroxylation is an additional minor pathway. The metabolism and excretion patterns of ketorolac and its metabolites were similar following PO, IV and IM dosing in the species studied. Ketorolac and its metabolites were excreted predominantly in the urine averaged 92% in humans. Elimination: The primary route of excretion of ketorolac trometamol and its metabolites (conjugates and the p-hydroxy metabolite) is in the urine (91.4%) with the remainder (6.1%) being excreted in the faeces.

SPECIAL POPULATIONS:Pregnant Women: Ketorolac trometamol is contraindicated for use during the third trimester of pregnancy because of risk of premature closure of ductus arteriosus and the potential to prolong parturition.Caution should be exercised in prescribing ketorolac trometamol during the first and second trimesters of pregnancy.Ketorolac trometamol is not recommended in labour and delivery because, through their prostaglandin synthesis inhibitory effect, they may adversely affect fetal circulation and inhibit uterine contractions, thus increasing the risk of uterine haemorrhage.

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Anticoagulants: Concomitant use of NSAIDs and anticoagulants increases the risk of bleeding. Concurrent therapy of Monak with warfarin requires close monitoring of INR. Prothrombin time should be carefully monitored in all patients receiving oral anticoagulant therapy concomitantly with Monak.

Anti-platelet effects: Concomitant administration of Monak with low dose ASA increases the risk of GI ulceration and associated complications.

Blood dyscrasias: Blood dyscrasias (such as neutropenia, leukopenia, thrombocytopenia, aplastic anemia and agranulocyto-sis) associated with the use of NSAIDs are rare, but could occur with severe consequences. Anemia is sometimes seen in patients receiving Monak.

Hepatic/Biliary/Pancreatic: As with other NSAIDs, borderline elevations of one or more liver enzyme tests (AST, ALT, alkaline phospha-tase) may occur in upto 15% of patients. Severe hepatic reactions including jaundice and cases of fatal hepatitis, liver necrosis and hepatic failure, some of them with fatal outcomes, have been reported with NSAIDs.

Potential effects on driving and using machinery: Some patients may experience drowsiness, dizziness, vertigo, insomnia or depression with the use of Monak. Therefore, patients should exercise caution in carrying out potentially hazardous activities that require alertness.

Renal effects: Drugs that inhibit prostaglandin biosynthesis (including NSAIDs) have been reported to cause nephrotoxici-ty, including but not limited to glomerular nephritis, interstitial nephritis, renal papillary necrosis, nephritic syndrome and acute renal failure. In patients with renal, cardiac or hepatic impairment, caution is required since the use of NSAIDs may result in deterioration of renal function.

Respiratory effect: Bronchospasm may be precipitated in patients with history of asthma.

Fluid retention and edema: Have been reported with the use of Monak and it should therefore be used with caution in patients with cardiac decompensation, hypertension or similar conditions.

DRUG INTERACTIONS:Acetylsalicylic acid (ASA) or other NSAIDs:The use of ketorolac trometamol for analgesic and/or anti-inflammatory effects is usually contraindicated because of the absence of any evidence demonstrating any synergistic benefits and the potential for additive adverse reactions.

Anti-hypertensives: Combination of ACE inhibitors, angiotensin II antagonists or diuretics with NSAIDs might have an increased risk of acute renal failure and hyperkalemia.

Anti-platelet agents (including ASA): There is an increased risk of bleeding via inhibition of platelet function, when anti-platelet agents are combined with ketorolac trometamol.

Digoxin: Concomitant administration of an NSAID with digoxin can result in an increase in digoxin concentrations which may result in digitalis toxicity.

Diuretics: Ketorolac trometamol reduces the diuretic response of furosemide by approximately 20% in normovolemic subjects, so particular care should be taken in patients with cardiac decompensation.

Glucocorticoids: Some studies have shown that the concomitant use of NSAIDs and oral glucocorticoids increase the risk of GI ulceration and bleeding.

Lithium: Cases of increased lithium plasma concentrations during therapy with ketorolac trometamol have been reported.

Methotrexate: It has been reported that NSAIDs reduce the clearance of MTX, thus enhancing its toxicity.

Oxpentifylline: The concomitant use of ketorolac trometamol and oxpentifylline is contraindicated due to increased tendency of bleeding.

Probenecid: Concomitant administration of ketorolac trometamol and probenecid results in the decreased clearance and volume of distribution of ketorolac and a significant increase in ketorolac plasma levels.

Selective Serotonin Reuptake Inhibitors (SSRIs): Concomitant use of NSAIDs and SSRIs may increase the risk of GI ulceration and bleeding.

OVERDOSAGE:Dose of 360mg given intramuscularly over an 8 hour interval for 5 consecutive days have caused abdominal pain, peptic ulcer/erosive gastritis, nausea, vomiting, hyperventilation, GI bleeding and renal dysfunction which have generally resolved after discontinuation of dosing.Treatment: Patients should be managed by symptomatic and supportive care following overdose. There are no specific antidotes. Dialysis does not significantly clear ketorolac from the bloodstream. INSTRUCTIONS:Store below 30°C.Protect from light and moisture.Keep all medicines out of the reach of children.

HOW SUPPLIED:Monak (Ketorolac Trometamol) 30mg is available in a pack of 1ml x 5 ampoules.

To be sold on prescription of a registered medical practitioner only.

Marketed by:

Plot No. 224, Sector 23, Korangi IndustrialArea, Karachi, Pakistan.

Mfg. Lic. No. 000339

Manufactured by:

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