Novo-Ketorolac - Tab 10mg Product Monograph

ACTION AND CLINICAL PHARMACOLOGY

NOVO-KETOROLAC (ketorolac tromethamine) is a non-steroidal anti-inflammatory drug

(NSAID) that has analgesic activity. It is considered to be a peripherally acting analgesic. It is thought to inhibit the cyclo-oxygenase enzyme system, thereby inhibiting the synthesis of prostaglandins. At analgesic doses it has minimal anti-inflammatory and antipyretic activity.

The peak analgesic effect occurs at 2 to 3 hours post-dosing with no evidence of a statistically significant difference over the recommended dosage range. The greatest difference between large and small doses of administered ketorolac is in the duration of analgesia.

Following oral administration, ketorolac tromethamine is rapidly and completely absorbed, and pharmacokinetics are linear following single and multiple dosing. Steady state plasma levels are achieved after one day of q.i.d. dosing.

Peak plasma concentrations of 0.7 to 1.1 µg/mL occurred at 44 minutes following a single oral dose of 10 mg. The terminal plasma elimination half-life ranged between 2.4 and 9 hours in healthy adults, while in the elderly subjects (mean age: 72 years) it ranged between 4.3 and 7.6 hours. A high fat meal decreased the rate but not the extent of absorption of oral ketorolac tromethamine, while antacid had no effect.

In renally impaired patients there is a reduction in clearance and an increase in the terminal half-life of ketorolac tromethamine (See Table 1).

Table 1 - The Influence of Age, Liver and Kidney Function on the Clearance and Terminal Half-

Life of Oral¹ Ketorolac Tromethamine

1 - Estimated from 10 mg single oral doses of ketorolac tromethamine 2 - Litres/hour/kilogram

The primary route of elimination of ketorolac tromethamine and its metabolites (conjugates and the p-hydroxy metabolite) is in the urine (91.4%) and the remainder (6.1%) is excreted in the feces.

More than 99% of the ketorolac in plasma is protein bound over a wide concentration range.

A comparative, two-way single dose bioavailability study was performed on two ketorolac tromethamine 10 mg tablet formulations, Novo-Ketorolac and Toradol^®. The pharmacokinetic data calculated for ketorolac tromethamine in the Novo-Ketorolac and Toradol^® tablet formulations is tabulated below:

Pharmacokinetic Indices for Ketorolac Tromethamine:

*For the Tmax and T_1/2 parameters these are the arithmetic means (standard deviation). ** Toradol^® 10 mg Tablets (Syntex Inc., Canada)

INDICATIONS AND CLINICAL USE

NOVO–KETOROLAC (ketorolac tromethamine) is indicated for the short-term management of mild to moderately severe pain, including post-surgical pain (such as general, orthopedic and dental surgery), acute musculoskeletal trauma pain and post-partum uterine cramping pain.

CONTRAINDICATIONS

Hypersensitivity

Like other non-steroidal anti-inflammatory drugs, NOVO-KETOROLAC (ketorolac tromethamine) has been associated with hypersensitivity reactions. NOVO-KETOROLAC should not be used when there is a known or suspected hypersensitivity to the drug and should be discontinued in patients who develop symptoms of hypersensitivity during therapy. Because of the possibility of cross-sensitivity, NOVO-KETOROLAC should not be used in patients with the complete or partial syndrome of nasal polyps, angioedema, bronchospastic reactivity (e.g.

asthma) or other allergic manifestations to acetylsalicylic acid (ASA) or other nonsteroidal anti-inflammatory drugs. Severe and fatal anaphylactoid reactions have occurred in such individuals.

Gastrointestinal:

NOVO-KETOROLAC should not be used in patients with suspected or confirmed peptic ulcer disease, gastrointestinal bleeding or perforation, or active inflammatory disease of the gastrointestinal system or in patients who have a history of these disorders.

Severe and fatal reactions have occurred in such individuals.

Renal Impairment:

NOVO-KETOROLAC is contraindicated in patients with moderate to severe renal impairment or in patients at risk for renal failure due to volume depletion.

Hemorrhagic Risk:

NOVO-KETOROLAC is contraindicated immediately before any major surgery, and is contraindicated intraoperatively when hemostasis is critical because of the increased risk of bleeding. NOVO-KETOROLAC is also contraindicated in patients with coagulation disorders, postoperative patients with high hemorrhagic risk or incomplete hemostasis, and in patients with suspected or confirmed cerebrovascular bleeding.

Obstetrics:

NOVO-KETOROLAC is contraindicated in labor and delivery because, through its prostaglandin synthesis inhibitory effect, it may adversely affect fetal circulation and inhibit uterine musculature, thus increasing the risk of uterine hemorrhage.

Concomitant Medications:

NOVO-KETOROLAC is contraindicated in patients currently receiving ASA or NSAIDs because of the cumulative risks of inducing serious NSAID-related adverse events. The concomitant use of NOVO-KETOROLAC and probenecid is also contraindicated.

WARNINGS

The long-term administration of NOVO-KETOROLAC (ketorolac tromethamine) is not recommended as the incidence of side-effects increases with the duration of treatment (see

INDICATIONS and DOSAGE AND ADMINISTRATION).

The most serious risks associated with NSAIDs including NOVO-KETOROLAC are:

Gastrointestinal Ulcerations, Bleeding and Perforation

Serious gastrointestinal toxicity, such as bleeding, ulceration, and perforation, can occur at any time, with or without warning symptoms, during therapy with non-steroidal anti-inflammatory drugs. The incidence of gastrointestinal complications increases with dosage and duration of treatment. Elderly and debilitated patients are more susceptible to these complications.

To date, studies with NSAIDs have not identified any subset of patients not at risk for developing peptic ulceration and bleeding.

Post-marketing experience with ketorolac tromethamine suggests that there may be a greater risk of gastrointestinal ulcerations, bleeding, and perforation in the elderly, and most spontaneous reports of fatal gastrointestinal events are in the aged population.

THE LONG-TERM USE OF NOVO-KETOROLAC IS NOT RECOMMENDED. Renal Toxicity

The following renal abnormalities have been associated with ketorolac tromethamine and other drugs that inhibit renal prostaglandin biosynthesis: acute renal failure, nephrotic syndrome, interstitial nephritis, renal papillary necrosis. Elevations of blood urea nitrogen (BUN) and creatinine have been reported in clinical trials with ketorolac tromethamine. NOVO-

KETOROLAC is contraindicated in patients with moderate to severe renal impairment.

Hypovolemia should be corrected before treatment with NOVO-KETOROLAC is initiated.

Patients who are volume depleted may be dependent on renal prostaglandin production to maintain renal perfusion and, therefore, glomerular filtration rate. In such patients, the use of drugs which inhibit prostaglandin synthesis has been associated with further decreases in renal blood flow and may precipitate acute renal failure. Predisposing factors include dehydration

(e.g. as a result of extreme exercise, vomiting or diarrhea associated with the loss of at least 5 to

10% of total body weight, unreplenished blood loss of approximately 500 mL), sepsis, impaired renal function, heart failure, liver dysfunction, diuretic therapy, and advanced age. Caution is advised if ketorolac tromethamine is used in such circumstances. Close monitoring of urine output, serum urea and serum creatinine is recommended until renal function recovers.

Fluid Retention and Edema

Fluid retention, edema, NaCl retention, oliguria, elevations of serum urea nitrogen and creatinine have been observed in patients treated ketorolac tromethamine. Therefore, the possibility of precipitating congestive heart failure in elderly patients or those with compromised cardiac function should be considered. NOVO-KETOROLAC should be used with caution in patients with cardiac decompensation, hypertension or other conditions which cause a predisposition to fluid retention.

Hemorrhage

NOVO-KETOROLAC is contraindicated in patients who have coagulation disorders. If NOVO-

KETOROLAC is to be administered to patients who are receiving drug therapy that interferes with hemostasis, careful observation is advised.

Use of NOVO-KETOROLAC in patients who are receiving therapy that affects hemostasis should be undertaken with caution, including close monitoring. The concurrent use of NOVO-

KETOROLAC and prophylactic, low dose heparin (2500-5000 units q12h), warfarin and dextrans may also be associated with an increased risk of bleeding (see DRUG

INTERACTIONS).

Hypersensitivity Reactions

The possibility of severe or fatal hypersensitivity reactions should be considered, even for patients with no known history of previous exposure or hypersensitivity to ketorolac or other

NSAIDs. As with other NSAIDs, patients should be questioned for history of allergy to NSAIDs or ASA or for the syndrome consisting of nasal polyps, ASA allergy and asthma before prescribed NOVO-KETOROLAC. Asthmatic patients with triad asthma (the syndrome of nasal polyps, asthma and hypersensitivity to ASA or other NSAIDs) may be at particular risk for severe hypersensitivity reactions.

Use in Pregnancy and Lactation

The administration of ketorolac tromethamine is not recommended during pregnancy or lactation. After 1 day at 10 mg q.i.d. oral dosing, ketorolac has been detected in the milk of lactating women at a maximum concentration of 7.9 ng/mL.

Use in Children

Safety and efficacy in children have not been established. Therefore, NOVO-KETOROLAC is not recommended for use in children under age 16.

Use in the Elderly

Because ketorolac is cleared somewhat more slowly by the elderly (see

PHARMACOKINETICS) who are also more sensitive to the gastrointestinal and renal effects of

NSAIDs, (see WARNINGS and PRECAUTIONS) extra caution and the lowest effective dose

(see DOSAGE AND ADMINISTRATION) should be used.

PRECAUTIONS

Physicians should be alert to the pharmacologic similarity of NOVO-KETOROLAC (ketorolac tromethamine) to other non-steroidal anti-inflammatory drugs that inhibit cyclo-oxygenase.

Gastrointestinal Effects

Close medical supervision is recommended in patients prone to gastrointestinal tract irritation.

In these cases, the physician must weigh the benefits of treatment against the possible hazards.

Patients taking any NSAID including ketorolac tromethamine should be instructed to contact a physician immediately if they experience symptoms or signs suggestive of peptic ulceration or gastrointestinal bleeding. These reactions can occur at any time during the treatment. If peptic ulceration is suspected or confirmed, or if gastrointestinal bleeding occurs, ketorolac tromethamine should be discontinued and appropriate treatment instituted with close patient monitoring.

Hepatic Effects

Caution should be observed if NOVO-KETOROLAC is to be used in patients with impaired hepatic function, or a history of liver disease. Treatment with NOVO-KETOROLAC may cause elevations of liver enzymes, and in patients with pre-existing liver dysfunction, it may lead to the development of a more severe hepatic reaction. Meaningful elevations (greater than 3 times normal) of serum transaminases (glutamate pyruvate [SGPT or ALT] and glutamic oxaloacetic

[SGOT or AST]), occurred in controlled clinical trials in less than 1% of patients. If clinical signs and symptoms consistent with liver disease develop, or if systemic manifestations occur

(e.g., eosinophilia, rash, etc.), ketorolac tromethamine should be discontinued. Patients with impaired hepatic function from cirrhosis do not have any clinically important changes in ketorolac tromethamine clearance. Studies in patients with active hepatitis or cholestasis have not been performed.

Hematologic Effects

Ketorolac tromethamine inhibits platelet function and may prolong bleeding time. It does not affect platelet count, prothrombin time (PT) or partial thromboplastin time (PTT). Unlike the prolonged effects from ASA the inhibition of platelet function by ketorolac tromethamine is normalized within 24 to 48 hours after the drug is discontinued.

Blood dyscrasias associated with the use of NSAIDs are rare, but could occur with severe consequences.

Infection

In common with other non-steroidal anti-inflammatory drugs, ketorolac tromethamine may mask the usual signs of infection.

DRUG INTERACTIONS

Protein Binding

NOVO-KETOROLAC (ketorolac tromethamine) is highly bound to human plasma protein

(mean 99.2%) and binding is independent of concentration. As ketorolac tromethamine is a highly potent drug and present in low concentrations in plasma, it would not be expected to displace other protein-bound drugs significantly. Therapeutic concentrations of digoxin, warfarin, acetaminophen, phenytoin, and tolbutamide did not alter ketorolac tromethamine protein binding.

Anticoagulant Therapy

Prothrombin time should be carefully monitored in all patients receiving oral anticoagulant therapy concomitantly with ketorolac tromethamine.

The in vitro binding of warfarin to plasma proteins is only slightly reduced by ketorolac tromethamine (99.5% control vs. 99.3%) at plasma concentrations of 5 to10 :g/mL. Digoxin

Ketorolac tromethamine does not alter digoxin protein binding.

Salicylates

In vitro studies indicated that, at therapeutic concentrations of salicylates (300 :g/mL), the binding of ketorolac tromethamine was reduced from approximately 99.2% to 97.5% representing a potential two-fold increase in unbound ketorolac plasma levels.

Enzyme Induction

There is no evidence, in animal or human studies, that ketorolac tromethamine induces or inhibits the hepatic enzymes capable of metabolizing itself or other drugs. Hence, it would not be expected to alter the pharmacokinetics of other drugs due to enzyme induction or inhibition mechanisms.

Probenecid

Concomitant administration of ketorolac tromethamine and probenecid results in the decreased clearance of ketorolac and a significant increase in ketorolac plasma levels (approximately three-fold increase) and terminal half-life (approximately two-fold increase). The concomitant use of

NOVO-KETOROLAC and probenecid is, therefore, contraindicated.

Furosemide

Ketorolac tromethamine reduces the diuretic response to furosemide by approximately 20% in normovolemic subjects.

Lithium

Some NSAIDs have been reported to inhibit renal lithium clearance, leading to an increase in plasma lithium concentrations and potential lithium toxicity. The effect of ketorolac tromethamine on lithium plasma levels has not been studied.

Methotrexate

The concomitant administration of methotrexate and some NSAIDs has been reported to reduce the clearance of methotrexate, thus enhancing its toxicity. The effect of ketorolac tromethamine on methotrexate clearance has not been studied.

ACE Inhibitors

Concomitant use of ACE inhibitors and other NSAIDs may increase the risk of renal impairment, particularly in volume depleted patients.

ADVERSE EVENTS

KETOROLAC TROMETHAMINE TABLETS:

Short-Term Patient Studies: The incidence of adverse reactions in 371 patients receiving multiple 10 mg doses of ketorolac tromethamine for pain resulting from surgery or dental extraction during the post operative period (less than 2 weeks) is listed below. These reactions may or may not be drug related.

Incidence Between 4 and 9%:

Nervous System: Somnolence, insomnia

Digestive System: Nausea

Incidence Between 2 and 3%:

Nervous System: Nervousness, headache, dizziness

Digestive System: Diarrhea, dyspepsia, gastrointestinal pain, constipation.

Body As A Whole: Fever

Incidence 1% or Less:

Nervous System: Abnormal dreams, anxiety, dry mouth, hyperkinesia, paresthesia, increased sweating, euphoria, hallucinations.

Digestive System: Anorexia, flatulence, vomiting, stomatitis, gastritis, gastrointestinal disorder, sore throat

Body As A Whole: Asthenia, pain, back pain

Cardiovascular System: Vasodilatation, palpitation, migraine, hypertension.

Respiratory System: Cough increased, rhinitis, dry nose.

Musculo-skeletal System: Myalgia, arthralgia

Skin & Appendages: Rash, urticaria

Special Senses: Blurred vision, ear pain

Urogenital System: Dysuria

Long-Term Patient Study

The adverse reactions listed below were reported to be probably related to study drug in 553 patients receiving long-term oral therapy (approximately 1 year) with ketorolac tromethamine. Incidence Between 10 and 12%:

Digestive System: Dyspepsia, gastrointestinal pain

Incidence Between 4 and 9%:

Digestive System: Nausea, constipation

Nervous System: Headache

Incidence Between 2 and 3%:

Digestive System: Diarrhea, flatulence, gastrointestinal fullness, peptic ulcers

Nervous System: Dizziness, somnolence

Metabolic and Nutritional Disorder: Edema

Incidence 1% or Less:

Digestive System: Eructation, stomatitis, vomiting, anorexia, duodenal ulcer, gastritis, gastrointestinal hemorrhage, increased appetite, melena, mouth ulceration, rectal bleeding, sore mouth

Nervous System: Abnormal dreams, anxiety, depression, dry mouth, insomnia, nervousness, paresthesia

Special Senses: Tinnitus, taste perversion, abnormal vision, blurred vision, deafness, lacrimation disorder

Metabolic and Nutritional Disorder: Weight gain, alkaline phosphatase increase, BUN increased, excessive thirst, generalized edema, hyperuricemia

Skin & Appendages: Pruritus, rash, burning sensation skin

Body as a Whole: Asthenia, pain, back pain, face edema, hernia

Musculo-skeletal System: Arthralgia, myalgia, joint disorder

Cardiovascular System: Chest pain, chest pain substernal, migraine

Respiratory System: Dyspnea, asthma, epistaxis

Urogenital System: Hematuria, increased urinary frequency, oliguria, polyuria

Hemic & Lymphatic: Anemia, purpura

Postmarketing Experience

The following postmarketing adverse experiences have been reported for patients who have received ketorolac tromethamine:

Renal Events: acute renal failure, flank pain with or without hematuria and/or azotemia, nephritis, hyponatremia, hyperkalemia, hemolytic uremic syndrome, urinary retention.

Hypersensitivity reactions: bronchospasm, laryngeal edema, asthma, hypotension, flushing, rash, anaphylaxis, and anaphylactoid reactions. Such reactions have occurred in patients with no prior history of hypersensitivity.

Gastrointestinal Events: gastrointestinal hemorrhage, peptic ulceration, gastrointestinal perforation, pancreatitis, melena.

Hematologic Events: postoperative wound hemorrhage, rarely requiring blood transfusion (see

PRECAUTIONS), thrombocytopenia, epistaxis, leukopenia

Central Nervous System: Convulsions, abnormal dreams, hallucinations, hyperkinesia, hearing loss, aseptic meningitis, extrapyramidal symptoms.

Hepatic Events: hepatitis, liver failure, cholestatic jaundice

Cardiovascular: pulmonary edema, hypotension, flushing

Dermatology: Lyell's syndrome, Stevens-Johnson syndrome, exfoliative dermatitis, maculopapular rash, urticaria

Body as Whole: infection

SYMPTOMS AND TREATMENT OF OVERDOSAGE

In a gastroscopic study of healthy subjects, daily doses of 360 mg given over an 8-hour interval for each of five consecutive days (3 times the highest recommended dose) caused pain and peptic ulcers which resolved after discontinuation of dosing.

Metabolic acidosis has been reported following intentional overdosage. Single oral doses of 200 mg have been administered to patients with no apparent serious side effects. Dialysis does not appreciably clear ketorolac from the blood stream.

DOSAGE AND ADMINISTRATION

Adults: Dosage should be adjusted according to the severity of the pain and the response of the patient.

Oral: The usual oral dose of NOVO-KETOROLAC (ketorolac tromethamine) is 10 mg every 4 to 6 hours for pain as required. Doses exceeding 40 mg per day are not recommended. The maximum duration of treatment with the oral formulation is 5 days for post-surgical patients and

7 days for patients with musculoskeletal pain.

Patients Under 50 kg, Over Age 65 years, or With Less Severe Pain at Baseline:

Oral: The lowest effective dose is recommended.

Impaired Renal Function: NOVO-KETOROLAC is not recommended for patients with moderate to severe renal impairment.

Conversion from Parenteral to Oral Therapy:

NOVO-KETOROLAC tablets may be used either as monotherapy or as follow-on therapy to parenteral ketorolac.

When NOVO-KETOROLAC tablets are used as a follow-on therapy to parenteral ketorolac, the total combined daily dose of ketorolac (oral + parenteral) should not exceed 120 mg in younger adult patients or 60 mg in elderly patients on the day the change of formulation is made. On subsequent days, oral dosing should not exceed the recommended daily maximum of 40 mg

The total duration of combined intramuscular and oral treatment should not exceed 5 days.

PHARMACEUTICAL INFORMATION

DRUG SUBSTANCE:

Proper Name: ketorolac tromethamine

Chemical Name: (±)-5-benzoyl-2,3-dihydro-1H-pyrrolizine-1-carboxylic acid, 2-amino-2-

(hydroxymethyl)-1,3-propanediol.

Structural Formula:

N CO2

O

H₃NC(CH₂OH)₃ - +

Molecular Formula: C19H24N2O6 Molecular Weight: 376.41

Description: Ketorolac tromethamine (pKa = 3.46) is an off-white to white crystalline powder that melts at about 162°C with decomposition. It is freely soluble in water and methanol, slightly soluble in tetrahydrofuran, 190 proof and 200 proof ethanol and practically insoluble or insoluble in acetone, dichlormethane, toluene, ethylacetate, dioxane, hexane, butanol and acetonitrile. The pH of a 1% (w/v) solution in distilled water is 5.7 - 6.7. Stability and Storage Recommendations:

Store between 15–30°C and protect from light. Unit dose strips should be stored between 15-

25°C and protected from high humidity and light.

AVAILABILITY OF DOSAGE FORMS

NOVO–KETOROLAC (ketorolac tromethamine) is available as:

10 mg – White, round, biconvex, film coated tablet, embossed N on one side and 10 on the other side.

Supplied: Bottles of 100, 500, and 1000 and in boxes of 100 as unit dose strips.