Toradol - Package Leaflet

Indications Contraindications Precautions for use Interactions Warnings Dosage and method of use Overdose Undesirable Effects Shelf Life and Storage

Active ingredients: ketorolac trometamine

TORA-DOL 10 mg film-coated tablets TORA-DOL 20 mg / ml oral drops, solution

Toradol package inserts are available for pack sizes:
  • TORA-DOL 10 mg film-coated tablets TORA-DOL 20 mg / ml oral drops, solution
  • TORA-DOL 10 mg / ml solution for injection TORA-DOL 30 mg / ml solution for injection

Indications Why is Toradol used? What is it for?

TORA-DOL is part of the non-steroidal anti-inflammatory / antirheumatic drugs.

TORA-DOL is only indicated for the short-term (maximum 5 days) treatment of moderate postoperative pain.

Contraindications When Toradol should not be used

Warning: the drug is not indicated in mild or chronic pain.

  • Hypersensitivity to the active substance or to any of the excipients.
  • Patients with already demonstrated hypersensitivity to ketorolac or other NSAIDs and patients in whom aspirin or other inhibitors of prostaglandin synthesis induce allergic reactions (severe anaphylactic-type reactions have been observed in these patients).
  • Complete or partial syndrome of nasal polyposis, angioedema, bronchospasm.
  • Asthma.
  • Active peptic ulcer, or a history of gastrointestinal bleeding, ulceration or perforation.
  • As with other NSAIDs, ketorolac is contraindicated in patients with severe heart failure.
  • Previous, current or suspected cerebrovascular bleeding.
  • Hypovolemia or dehydration.
  • Patients with moderate or severe renal insufficiency (serum creatinine> 442µmol / l) or patients at risk of renal insufficiency due to hypovolaemia or dehydration.
  • Cirrhosis of the liver or severe hepatitis.
  • Hemorrhagic diathesis.
  • Disorders of coagulation.
  • Patients on anticoagulant therapy.
  • Concomitant treatment with ASA or other NSAIDs and with lithium salts, probenecid or pentoxifylline (see Interactions). - Patients in intensive diuretic therapy.
  • In analgesic prophylaxis before surgery and during surgery because it increases the risk of bleeding, due to the inhibition of platelet aggregation and the prolongation of bleeding time.
  • Ketorolac inhibits platelet function and is therefore contraindicated in patients with suspected or confirmed cerebrovascular haemorrhages.
  • Patients who have undergone surgery with a high risk of haemorrhage or incomplete haemostasis and in those at high risk of bleeding.
  • In children and adolescents under the age of 16.
  • The use of TORA-DOL is contraindicated during the third trimester of pregnancy, labor, delivery and during lactation (see Special warnings).

Precautions for use What you need to know before taking Toradol

Warning: TORA-DOL cannot be considered a simple pain reliever and requires to be used under the strict supervision of the doctor.

It should not be used in the treatment of mild or chronic pain.

Epidemiological evidence suggests that ketorolac may be associated with a higher risk of severe gastrointestinal toxicity, compared to other NSAIDs, especially when used outside the authorized indications and / or for prolonged periods (see also Therapeutic indications, Dose, method and time of administration. and Contraindications).

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

Undesirable effects can be minimized by using the lowest effective dose for the shortest possible duration of treatment needed to control symptoms.

Before initiating therapy with TORA-DOL it should be ensured that the patient has not previously had hypersensitivity reactions to ketorolac, acetylsalicylic acid and / or other non-steroidal anti-inflammatory drugs.

Fertility related precautions

The use of TORA-DOL, like any drug that inhibits cyclooxygenase / prostaglandin synthesis, may reduce fertility and is not recommended in women trying to become pregnant. In women who have difficulty conceiving or who are undergoing tests for infertility, discontinuation of ketorolac should be considered.

Senior citizens

Particular caution should be exercised in elderly or debilitated patients, as the incidence of some of the undesirable effects may be higher than in younger patients. Elderly patients have an increased frequency of adverse reactions to NSAIDs, especially gastrointestinal bleeding and perforation, which may be fatal (see Dose, method and time of administration).

In elderly subjects, there may also be an increase in the elimination half-life of the drug and a concomitant reduction in clearance. Therefore, in addition to a reduction in the overall dose, a longer interval between doses may be appropriate.

Gastrointestinal effects

TORA-DOL can cause gastrointestinal irritation, ulcer and bleeding in patients with or without a previous history of gastrointestinal disease. Patients with current or previous inflammatory diseases of the gastrointestinal tract should only undergo the treatment under strict medical supervision. The incidence of these effects increases with dose and duration of treatment.

Do not use TORA-DOL and other non-steroidal anti-inflammatory drugs at the same time.

Gastrointestinal ulcer, bleeding and perforation

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

Elderly patients have an increased frequency of adverse reactions to NSAIDs, especially gastrointestinal bleeding and perforation, which can be fatal. Debilitated patients appear to tolerate less ulceration or bleeding than others. Most fatal gastrointestinal events associated with nonsteroidal anti-inflammatory drugs have occurred in elderly and / or debilitated patients. The risk of gastrointestinal bleeding, ulceration or perforation is higher with high doses of NSAIDs, including ketorolac, in patients with a history of ulcer, particularly if complicated with haemorrhage or perforation and in elderly patients. The clinically severe risk of gastrointestinal bleeding is dose-dependent. These patients should start treatment with the lowest available dose. Concomitant use of protective agents (misoprostol or proton pump inhibitors) should be considered for these patients and also for patients taking low doses of aspirin or other drugs that may increase the risk of gastrointestinal events (see Interactions).

NSAIDs should be administered with caution to patients with a history of gastrointestinal disease (ulcerative colitis, Crohn's disease) as their condition may be exacerbated (see Undesirable effects). Patients with a history of gastrointestinal toxicity, particularly the elderly, should report any unusual gastrointestinal symptoms (especially gastrointestinal bleeding) particularly in the initial stages of treatment. When gastrointestinal bleeding or ulceration occurs in patients treated with ketorolac the treatment should be discontinued.

Caution should be exercised in patients taking concomitant medications that could increase the risk of ulceration or bleeding, such as oral corticosteroids, anticoagulants such as warfarin, selective serotonin reuptake inhibitors or antiplatelet agents such as aspirin (see Interactions).

As with other NSAIDs, the incidence and severity of gastrointestinal complications may increase with increasing dose and duration of ketorolac treatment. The risk of clinically severe gastrointestinal bleeding is dose-dependent, especially in elderly patients who receive a mean daily dose greater than 60 mg / day of injectable ketorolac. A history of peptic ulcer increases the chance of developing serious gastrointestinal complications during ketorolac therapy.

Respiratory effects

Due to the interaction with the metabolism of arachidonic acid, the drug can cause, in asthmatics and predisposed subjects, crises of bronchospasm and possibly other pseudo-allergic phenomena or shock.

Anaphylactic (anaphylactoid) reactions

Anaphylactic (anaphylactoid) reactions (including, but not limited to, anaphylaxis, bronchospasm, flushing, rash, hypotension, laryngeal edema and angioedema) may occur in patients with or without a history of hypersensitivity to other NSAIDs or aspirin or ketorolac. These can also occur in people with a history of angioedema, bronchospastic reactivity (eg asthma) and nasal polyps. Anaphylactoid reactions, such as anaphylaxis, can be fatal. Therefore, ketorolac should be used with caution in patients with a history of asthma and in patients with complete or partial syndrome of nasal polyposis, angioedema and bronchospasm.

Cardiovascular and cerebrovascular effects

Since fluid retention and edema have been reported in association with the use of NSAIDs, patients with a history of hypertension and / or mild to moderate congestive heart failure should be appropriately monitored and alerted.

Clinical studies and epidemiological data suggest that the use of selective cyclooxygenase-2 inhibitors and some NSAIDs (particularly at high doses) may be associated with a slightly increased risk of arterial thrombotic events (eg myocardial infarction or stroke). Although ketorolac has not been shown to increase thrombotic events such as myocardial infarction, insufficient data are available to exclude this risk with ketorolac.

Patients with uncontrolled hypertension, congestive heart failure, chronic ischemic heart disease, peripheral arterial disease and / or cerebral vascular disease should only be treated with ketorolac after careful consideration. A similar assessment should be made before starting treatment of patients with risk factors for cardiovascular disease (e.g. hypertension, hyperlipidaemia, diabetes mellitus and smoking).

Kidney effects

As with other NSAIDs, ketorolac should be used with caution in patients with impaired renal function or with a history of renal disease, as it is a potent inhibitor of prostaglandin synthesis, can cause nephrotoxicity, including glomerulonephritis, interstitial nephritis, papillary necrosis, nephrotic syndrome and acute renal failure. Caution should be observed as renal toxicity has been reported with ketorolac and other NSAIDs in patients whose conditions lead to decreased renal volume and / or blood flow, where renal prostaglandins play a supporting role in maintaining renal perfusion. In these patients, administration of ketorolac or other NSAIDs can cause a dose-dependent reduction in the production of renal prostaglandins and can lead to overt renal failure or failure.

Patients at greatest risk of this reaction are those with reduced kidney function, kidney hypoperfusion states, kidney disease, hypovolaemia, heart failure, liver dysfunction, liver cirrhosis or severe hepatitis, those taking diuretics, and the elderly. Discontinuation of ketorolac or other non-steroidal anti-inflammatory drugs is usually followed by recovery from the pretreatment state.

Patients with impaired renal function

Since TORA-DOL and its metabolites are mainly excreted by the kidney, caution should be exercised in patients with impaired renal function during treatment with TORA-DOL. In particular, the use of TORA-DOL in patients with serum creatinine values ​​greater than 442µmol / l is contraindicated.

The drug is contraindicated in intensive diuretic therapy.

Sodium / fluid retention in patients with cardiovascular disease and peripheral edema

Caution is warranted in patients with a history of hypertension and / or heart failure as fluid retention and edema have been reported in association with NSAID therapy. Fluid retention, hypertension and peripheral edema have been observed in some patients taking NSAIDs including ketorolac and therefore should be used with caution in patients with heart failure, hypertension or similar conditions.

Patients with impaired liver function

Mild changes in liver function tests have rarely been noted during treatment with TORA-DOL, however of no clinical relevance. However, it is advisable to monitor liver function in patients in whom this was previously impaired, and to discontinue treatment with TORADOL if there is evidence of severe hepatic impairment.

Hematological effects

TORA-DOL inhibits platelet function and may prolong bleeding time. TORA-DOL should not be given to patients who have coagulation disorders. Although studies do not indicate a significant interaction between ketorolac and warfarin or heparin, concomitant use of ketorolac with drugs that interfere with haemostasis, including therapeutic doses of anticoagulant therapy, including warfarin, low-dose heparin prophylaxis (2500- 5000 units every 12 hours) and dextrans, may be associated with an increased risk of bleeding (see Contraindications).

In post-marketing experience, post-operative haematomas and other signs of wound bleeding have been reported in association with the peri-operative use of ketorolac solution for injection. Physicians should consider the potential risk of bleeding when haemostasis is critical, for example in cases of prostate resection, tonsillectomy or cosmetic surgery (see Contraindications).

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 Undesirable Effects). Patients appear to be at higher risk of such reactions at the beginning of therapy.

Ketorolac should be discontinued at the first appearance of skin rash, mucosal lesions or any other signs of hypersensitivity. Ketorolac should not be administered concomitantly with probenecid, as alterations in the pharmacokinetics of ketorolac have been reported with this combination.

Caution is advised when methotrexate is administered concomitantly, as some drugs that inhibit prostaglandin synthesis have been observed to reduce the clearance of methotrexate, and therefore, may increase its toxicity.

Abuse and addiction

Ketorolac is not addictive. No withdrawal symptoms were observed following an abrupt discontinuation of Ketorolac.

Interactions Which drugs or foods can modify the effect of Toradol

Tell your doctor or pharmacist if you are taking or have recently taken any other medicines, even those without a prescription.

The concomitant use of TORA-DOL and other non-steroidal anti-inflammatory drugs should be avoided. ASA and other NSAIDs: The risk of inducing serious NSAID-related side effects may be increased in patients currently treated with ASA or other NSAIDs.

Corticosteroids: increased risk of gastrointestinal ulceration or bleeding (see Precautions for use).

Anticoagulants: NSAIDs can increase the effects of anticoagulants, such as warfarin. Although studies do not indicate a significant interaction between ketorolac and warfarin or heparin, concomitant use of ketorolac with drugs that interfere with haemostasis, including therapeutic doses of anticoagulant therapy (warfarin), low-dose heparin prophylaxis (2500- 5000 units every 12 hours) and dextrans may be associated with an increased risk of bleeding.

Antiplatelet agents and selective serotonin reuptake inhibitors: there is an increased risk of gastrointestinal bleeding when anti-platelet aggregating agents and selective serotonin reuptake inhibitors (SSRIs) are combined with NSAIDs (see Precautions for use) Ketorolac inhibits platelet aggregation, reduces thromboxane concentrations and prolongs bleeding time. Unlike the prolonged effects of aspirin, platelet function returns to normal within 24 to 48 hours after stopping ketorolac.

Pentoxifylline: When ketorolac is administered concomitantly with pentoxifylline, there is an increased tendency to bleed.

Probenecid: Decreased plasma clearance and volume of distribution of ketorolac, increased plasma concentration of ketorolac and increased half-life of ketorolac have been reported when ketorolac is co-administered with probenecid.

Methotrexate: Some drugs that inhibit prostaglandin synthesis have been reported to reduce the clearance of methotrexate, and therefore, may increase its toxicity.

Lithium: Some drugs that inhibit prostaglandin synthesis have been reported to inhibit the renal clearance of lithium, leading to an increase in plasma lithium concentration. There have been reports of increased plasma lithium concentrations during ketorolac therapy.

Ketorolac tromethamine does not modify the protein binding of digoxin. In vitro studies indicate that, at therapeutic concentrations of salicylate (300 µg / ml), the binding of ketorolac was reduced by approximately 99.2- 97.5%, corresponding to a potential twofold increase in the plasma concentration of unbound ketorolac. . Therapeutic concentrations of digoxin, warfarin, ibuprofen, naproxen, piroxicam, acetaminophen, phenytoin and tolbutamide did not alter the protein binding of ketorolac tromethamine.

Diuretics, ACE inhibitors and angiotensin II antagonists: NSAIDs may reduce the effect of diuretics and antihypertensives.The risk of acute renal failure, which is generally reversible, may increase in some patients with impaired renal function (eg dehydrated patients or elderly patients) when ACE inhibitors and / or angiotensin II receptor antagonists are combined with NSAIDs. Therefore, the combination should be administered with caution, especially in the elderly. Patients should be adequately titrated and hydrated and monitoring of renal function should be considered at the initiation of concomitant therapy and periodically thereafter.

Ketorolac solution for injection reduced the diuretic response to furosemide in healthy normovolaemic subjects by approximately 20%, therefore caution should be exercised in patients with heart failure.

Ketorolac has been shown to reduce the need for concomitant opioid analgesic therapy when used for postoperative pain relief.

Oral administration of ketorolac tablets after a high-fat meal resulted in a delay and reduction in peak ketorolac concentration of approximately 1 hour. Antacids did not affect the extent of absorption.

Warnings It is important to know that:

The film-coated tablets contain lactose. If you have been told by your doctor that you have an intolerance to some sugars, contact your doctor before taking this medicinal product.

The oral drops, solution contain methyl parahydroxybenzoate and propyl parahydroxybenzoate which can cause allergic reactions (even delayed).

Warning: TORA-DOL cannot be considered a simple pain reliever and requires to be used under the strict supervision of the doctor.

Fertility, pregnancy and breastfeeding

Ask your doctor or pharmacist for advice before taking any medicine.

Pregnancy:

The use of TORA-DOL is contraindicated during the third trimester of pregnancy, labor, delivery and during lactation (see Contraindications).

Inhibition of prostaglandin synthesis can adversely affect pregnancy and / or embryo / fetal development.

Results of epidemiological studies suggest an increased risk of miscarriage and cardiac malformation and gastroschisis after use of a prostaglandin synthesis inhibitor in early pregnancy. The absolute risk of cardiac malformations increased from less than 1% to approximately 1.5%. The risk has been considered to increase with dose and duration of therapy. In animals, administration of prostaglandin synthesis inhibitors has been shown to cause increased loss of pre- and post-implantation and of embryo-fetal mortality.

In addition, an increased incidence of various malformations, including cardiovascular, has been reported in animals given prostaglandin synthesis inhibitors during the organogenetic period.

During the first and second trimester of pregnancy, ketorolac should not be administered except in strictly necessary cases.

If ketorolac is used by a woman conceiving, or during the first and second trimester of pregnancy, the dose and duration of treatment should be kept as low as possible.

During the third trimester of pregnancy, all prostaglandin synthesis inhibitors can expose the fetus to:

  • cardiopulmonary toxicity (with premature closure of the arterial duct and pulmonary hypertension);
  • renal dysfunction, which can progress to renal failure with oligo-hydroamnios;

the mother and the newborn, at the end of pregnancy, to:

  • possible prolongation of bleeding time, and antiplatelet effect which may occur even at very low doses;
  • inhibition of uterine contractions resulting in delayed or prolonged labor.

Consequently, ketorolac is contraindicated during the third trimester of pregnancy. Ketorolac should only be given as needed during the first two trimesters of pregnancy.

Ketorolac crosses the placenta to the extent of about 10%.

In women of childbearing age, any pregnancy must always be excluded before the start of treatment and effective contraceptive coverage must be ensured during treatment.

Labor and Childbirth:

Ketorolac is contraindicated during labor and delivery since, through its inhibitory effect on prostaglandin synthesis, it can negatively affect fetal circulation with serious consequences for the unborn baby's breathing and inhibit uterine contractions with possible delay in delivery, thus increasing the risk of uterine bleeding

Feeding time:

Ketorolac and its metabolites have been identified in fetus and animal milk.

The drug is excreted in breast milk in small quantities therefore its use is contraindicated during lactation.

Fertility:

The use of TORA-DOL, like any drug that inhibits cyclooxygenase / prostaglandin synthesis, can reduce fertility and is not recommended in women trying to become pregnant. In women who have difficulty conceiving or who are undergoing tests for infertility, discontinuation of ketorolac should be considered.

Effects on ability to drive and use machines

TORA-DOL, although it has no narcotic effect or effects on the Central Nervous System, can cause drowsiness.

Some patients may experience somnolence, dizziness, vertigo, insomnia or depression with the use of ketorolac. If patients experience these or other similar side effects, they should exercise caution in performing activities that require attention.

It is therefore advisable to exercise caution when driving and using machines.

Dosage and method of use How to use Toradol: Dosage

Warning: The treatment duration should not exceed 5 days.

ADULTS

The dose administered should be the lowest effective dose in relation to pain severity and patient response.

The recommended dose in adults is 10 mg (equivalent to 1 film-coated tablet or 10 drops of solution), as needed, every 4-6 hours up to a maximum of 40 mg / day.

On the day of transition from parenteral to oral therapy, the total daily dose of 90 mg should not be exceeded, remembering that the maximum oral dose should not exceed 40 mg. The dose should be adequately reduced in subjects weighing less than 50 kg.

ELDERLY (≥ 65 years)

In the elderly patient, the dosage must be carefully established by the doctor, who will have to evaluate a possible reduction of the dosages indicated above.

CHILDREN

The safety and efficacy in children has not been established. The use of the drug is therefore contraindicated below 16 years (see Contraindications).

The oral drops formulation is particularly suitable for patients with swallowing difficulties.

If you have any further questions on the use of this medicine, ask your doctor or pharmacist.

Overdose What to do if you have taken too much Toradol

Symptoms and signs

Single overdoses of ketorolac have been associated in different circumstances with abdominal pain, nausea, vomiting, hyperventilation, peptic ulcer and / or erosive gastritis and renal dysfunction, which resolved after discontinuation of treatment. Gastrointestinal bleeding may occur. Rarely, hypertension, acute renal failure, respiratory depression and coma may occur after ingestion of NSAIDs.

Anaphylactoid reactions have been reported with therapeutic use of NSAIDs; this may occur following overdose.

Treatment

Following NSAID overdose, patients should be managed with symptomatic and supportive therapies with the addition of normal safety measures (induction of vomiting, gastric lavage, administration of activated charcoal). There are no specific antidotes. Dialysis does not significantly eliminate ketorolac from the bloodstream.

If you have taken too much TORA-DOL, notify your doctor immediately or go to the nearest hospital.

Side Effects What are the side effects of Toradol

Like all medicines, this can cause side effects, although not everybody gets them.

Post Marketing

The following side effects may occur in patients treated with ketorolac; the frequencies of the reported events are not known, because they were reported voluntarily by a non-quantifiable number of people.

Infections and infestations: aseptic meningitis.

Disorders of the blood and lymphatic system: thrombocytopenia, purpura, epistaxis.

Immune system disorders: anaphylaxis, anaphylactoid reactions such as anaphylaxis, may be fatal, hypersensitivity reactions such as bronchospasm, vasodilation, flushing, rash, hypotension, laryngeal edema.

Metabolism and nutrition disorders: anorexia, hyperkalaemia, hyponatremia.

Psychiatric disorders: abnormal thinking, depression, insomnia, anxiety, irritability, nervousness, psychotic reactions, abnormal dreams, hallucinations, euphoria, impaired concentration, lethargy, confusion.

Nervous system disorders: headache, dizziness, convulsions, paraesthesia, hyperkinesia, altered taste.

Eye disorders: vision disturbances, abnormal vision.

Ear and labyrinth disorders: tinnitus, hearing loss, dizziness.

Cardiac disorders: palpitations, bradycardia, heart failure. Edema, hypertension and heart failure have been reported in association with NSAID treatment.

Vascular disorders: hypertension, vasodilation, hypotension, hematomas, redness, pallor, post-operative wound haemorrhage. Clinical studies and epidemiological data suggest that the use of coxibs and some NSAIDs (especially at high doses and for long-term treatments) may be associated with a modest increased risk of arterial thrombotic events (for example myocardial infarction or stroke). (see Precautions for use). Although ketorolac has not been shown to increase thrombotic events such as myocardial infarction, there are insufficient data to exclude a similar risk with ketorolac.

Respiratory, thoracic and mediastinal disorders: pulmonary edema, dyspnoea, asthma.

Gastrointestinal disorders: the most commonly observed adverse events are gastrointestinal in nature. Peptic ulcer, ulcer, perforation or gastrointestinal bleeding, sometimes fatal, may occur, particularly in the elderly (see Precautions for use). Nausea, vomiting, diarrhea, flatulence, constipation, dyspepsia have been reported after administration of TORA-DOL. , abdominal pain / discomfort, sense of fullness, melaena, rectal bleeding, haematemesis, stomatitis, ulcerative stomatitis, esophagitis, belching, gastrointestinal ulcer, pancreatitis, dry mouth, exacerbation of colitis and Crohn's disease (see Precautions for use) . Gastritis was observed less frequently.

Hepatobiliary disorders: hepatitis, cholestatic jaundice, hepatic failure.

Skin and subcutaneous tissue disorders: angioedema, exfoliative dermatitis, sweating, maculo-papular rash, urticaria, pruritus, purpura, bullous reactions including Stevens-Johnson syndrome and toxic epidermal necrolysis (very rare).

Musculoskeletal and connective tissue disorders: myalgia

Renal and urinary disorders: polyuria, increased urinary frequency, oliguria, acute renal failure, uremic-haemolytic syndrome, interstitial nephritis, urinary retention, nephrotic syndrome, flank pain (with or without haematuria + - azotaemia). As with other drugs that inhibit prostaglandin synthesis, signs of renal failure, such as increases in creatinine and potassium, may occur after a dose of ketorolac.

Reproductive system and breast disorders: female infertility.

General disorders and administration site conditions: asthenia, fever, injection site reactions, edema, chest pain, excessive thirst.

Investigations: increased bleeding time, increased serum urea, increased creatinine, abnormal liver function tests. Compliance with the instructions contained in the package leaflet reduces the risk of undesirable effects.

Reporting of side effects.

If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet. Side effects can also be reported directly via the national reporting system at https://www.aifa.gov.it/content/segnalazioni-reazioni-avverse. By reporting side effects you can help provide more information on safety of this medicine

Expiry and Retention

Expiry: see the expiry date printed on the package.

The expiry date indicated refers to the product in intact packaging, correctly stored.

Warning: do not use the medicine after the expiry date shown on the package.

Oral drops: Store in the original package to protect the medicine from light.

Tablets: Do not store above 30 ° C. Keep this medicine out of the sight and reach of children.

Medicines should not be disposed of via wastewater or household waste.

Ask your pharmacist how to throw away medicines you no longer use. This will help protect the environment.

Source Package Leaflet: AIFA (Italian Medicines Agency). Content published in January 2016. The information present may not be up-to-date.
To have access to the most up-to-date version, it is advisable to access the AIFA (Italian Medicines Agency) website. Disclaimer and useful information.

Further information on Toradol can be found in the "Summary of Characteristics" tab. 01.0 NAME OF THE MEDICINAL PRODUCT 02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION 03.0 PHARMACEUTICAL FORM 04.0 CLINICAL PARTICULARS 04.1 Therapeutic indications 04.2 Posology and method of administration 04.3 Contraindications 04.4 Special warnings and appropriate precautions for use 04.5 Interactions with other medicinal products and other forms of interaction04.6 Pregnancy and lactation04.7 Effects on ability to drive and use machines04.8 Undesirable effects04.9 Overdose05.0 PHARMACOLOGICAL PROPERTIES05.1 Pharmacodynamic properties05.2 Pharmacokinetic properties05.3 Preclinical safety data06.0 INFORMATION PHARMACEUTICALS 06.1 Excipients 06.2 Incompatibilities 06.3 Shelf life 06.4 Special precautions for storage 06.5 Nature of the immediate packaging and contents of the package 06.6 Instructions for use and handling 07.0 MARKETING AUTHORIZATION HOLDER08 .0 MARKETING AUTHORIZATION NUMBER 09.0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION 10.0 DATE OF REVISION OF THE TEXT 11.0 FOR RADIOPharmaceuticals, FULL DATA ON INTERNAL RADIATION DOSIMETRY 12.0 FOR RADIO DRUGS, ADDITIONAL DETAILED INSTRUCTIONS ON ESTEMPORANEA PREPARATION AND CONTROL

01.0 NAME OF THE MEDICINAL PRODUCT

TORA-DOL

02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION

TORA-DOL 10 mg film-coated tablets

Each film-coated tablet contains:

Active ingredient: ketorolac trometamine 10 mg.

TORA-DOL 10 mg / ml solution for injection

Each vial contains:

Active ingredient: ketorolac trometamine 10 mg.

TORA-DOL 30 mg / ml solution for injection

Each vial contains:

Active ingredient: ketorolac trometamine 30 mg.

TORA-DOL 20 mg / ml oral drops, solution

100 ml of solution for oral drops contains:

Active ingredient: ketorolac trometamine 2 g.

For the full list of excipients, see section 6.1.

03.0 PHARMACEUTICAL FORM

TORA-DOL is available as film-coated tablets, solution for oral drops, solution for injection for i.m. use. or i.v.

04.0 CLINICAL INFORMATION

04.1 Therapeutic indications

TORA-DOL film-coated tablets and oral drops

TORA-DOL is only indicated for the short-term (maximum 5 days) treatment of moderate postoperative pain.

TORA-DOL solution for injection

TORA-DOL administered intramuscularly or intravenously is indicated for treatment short term (maximum two days) of moderate to severe acute postoperative pain.

In cases of major surgery or very severe pain, intravenous TORA-DOL can be used as a complement to an opioid analgesic.

TORA-DOL 30 mg solution for injection is also indicated in the treatment of pain due to renal colic.

04.2 Posology and method of administration

TORA-DOL film-coated tablets and oral drops

Warning: the treatment duration should not exceed 5 days.

ADULTS

The dose administered should be the lowest effective dose in relation to pain severity and patient response.

The recommended dose in adults is 10 mg (equivalent to 1 film-coated tablet or 10 drops of solution), as needed, every 4-6 hours up to a maximum of 40 mg / day.

On the day of transition from parenteral to oral therapy, the total daily dose of 90 mg should not be exceeded, remembering that the maximum oral dose should not exceed 40 mg.

The dose should be adequately reduced in subjects weighing less than 50 kg.

ELDERLY (≥ 65 years old)

In the elderly patient, the dosage must be carefully established by the doctor, who will have to evaluate a possible reduction of the dosages indicated above.

The oral drops formulation is particularly suitable for patients with swallowing difficulties.

CHILDREN

The safety and efficacy in children has not been established. The use of the drug is therefore contraindicated under 16 years (see section 4.3-Contraindications).

TORA-DOL solution for injection

Warning: The solution for injection contains ethanol therefore it must not be used epidurally or intrathecally.

Parenterally, the duration of therapy should not exceed 2 days in case of bolus administration and 1 day in case of continuous infusion.

The dose administered should be the lowest effective dose in relation to pain severity and patient response.

Intramuscular administration

ADULTS

Adults are advised to start with a dose of 10 mg, followed by doses of 10-30 mg to be repeated every 4-6 hours, as needed, up to a maximum of 90 mg / day, using the lowest effective dose.

The duration of therapy should not exceed 2 days.

On the day of transition from parenteral to oral therapy, the total daily dose of 90 mg should not be exceeded, remembering that the maximum oral dose should not exceed 40 mg.

The dose should be adequately reduced in subjects weighing less than 50 kg.

ELDERLY (≥ 65 years old)

In the elderly patient, the dosage must be carefully established by the doctor, who will have to evaluate a possible reduction of the dosages indicated above.

In elderly patients, however, the maximum daily dose should not exceed 60 mg / day.

CHILDREN

The safety and efficacy in children has not been established. The use of the drug is therefore contraindicated below 16 years.

Intravenous administration

INTRAVENOUS USE OF THE PREPARATION IS RESERVED TO HOSPITALS AND CARE HOMES.

ADULTS

In situations characterized by severe acute pain (such as in post-operative pain attack therapy) an initial dose of 10 mg is recommended, followed by doses of 10-30 mg which can be repeated, if necessary, after 4-6 hours, using the lowest effective dose If necessary, treatment can be continued at longer intervals, however the daily dose of 90 mg should not be exceeded.

ELDERLY (≥ 65 years old)

In elderly patients, however, the maximum daily dose should not exceed 60 mg / day.

CHILDREN

The safety and efficacy in children has not been established. The use of the drug is therefore contraindicated below 16 years.

Renal colic

The recommended posology is a 30 mg vial for intramuscular or intravenous administration.

04.3 Contraindications

Warning: The drug is not indicated in mild or chronic pain

- Hypersensitivity to the active substance or to any of the excipients.

- Due to the possibility of cross-sensitivity TORA-DOL is also contraindicated in patients in whom acetylsalicylic acid and / or other non-steroidal anti-inflammatory drugs have induced allergic manifestations, due to the risk of onset of severe anaphylactic reactions.

- Complete or partial syndrome of nasal polyposis, angioedema, bronchospasm.

- Asthma.

- Active peptic ulcer, or a history of gastrointestinal bleeding, ulceration or perforation.

- Severe heart failure.

- Previous, current or suspected cerebrovascular bleeding.

- Hypovolemia or dehydration.

- Moderate or severe renal insufficiency (serum creatinine> 1.8 mg / dl).

- Cirrhosis of the liver or severe hepatitis.

- Hemorrhagic diathesis.

- Coagulation disorders.

- Patients who have undergone surgery with a high risk of bleeding or incomplete haemostasis.

- Patients on anticoagulant therapy.

- Concomitant treatment with other non-steroidal anti-inflammatory drugs and with salts of lithium, probenecid or pentoxifylline (see section 4.5).

- Patients in intensive diuretic therapy.

- TORA-DOL inhibits platelet function and prolongs bleeding time, therefore it is contraindicated for use in surgical analgesic prophylaxis and during surgery because it increases the risk of bleeding.

- In children and adolescents under the age of 16.

- The use of TORA-DOL is contraindicated during pregnancy, near and during childbirth and during breastfeeding.

Warning: The solution for injection contains ethanol therefore use via epidural or intrathecal route is contraindicated.

04.4 Special warnings and appropriate precautions for use

Warning: TORA-DOL cannot be considered a simple pain reliever and requires to be used under the strict supervision of the doctor.

It should not be used in the treatment of mild or chronic pain.

The concomitant use of TORA-DOL with other NSAIDs should be avoided, including selective cyclooxygenase-2 inhibitors.

Undesirable effects can be minimized by using the lowest effective dose for the shortest possible duration of treatment needed to control symptoms.

Before initiating therapy with TORA-DOL it should be ensured that the patient has not previously had hypersensitivity reactions to ketorolac, acetylsalicylic acid and / or other non-steroidal anti-inflammatory drugs.

The use of TORA-DOL, like any drug that inhibits prostaglandin synthesis and cyclooxygenase, is not recommended in women who intend to become pregnant.

The administration of TORA-DOL should be discontinued in women who have fertility problems or who are undergoing fertility investigations.

Elderly: Particular caution should be exercised in elderly or debilitated patients, as the incidence of some of the undesirable effects may be higher than in younger patients. Elderly patients have an increased frequency of adverse reactions to NSAIDs, especially gastrointestinal bleeding and perforation, which can be fatal (see section 4.2).

In elderly subjects, there may also be an increase in the elimination half-life of the drug and a concomitant reduction in clearance. Therefore, in addition to a reduction in the overall dose, a longer interval between doses may be appropriate.

Gastrointestinal Effects TORA-DOL can cause gastrointestinal irritation, ulcer and bleeding in patients with or without a history of gastrointestinal disease. Patients with current or previous inflammatory diseases of the gastrointestinal tract should only undergo the treatment under strict medical supervision. The incidence of these effects increases with dose and duration of treatment.

Do not use TORA-DOL and other non-steroidal anti-inflammatory drugs at the same time.

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

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

In the elderly and in patients with a history of ulcer, particularly if complicated with haemorrhage or perforation (see section 4.3), the risk of gastrointestinal bleeding, ulceration or perforation is higher with increasing doses of NSAIDs. These patients should start treatment with the lowest available dose. Concomitant use of protective agents (misoprostol or proton pump inhibitors) should be considered for these patients and also for patients taking low dose aspirin or other drugs that may increase the risk of gastrointestinal events (see below and section 4.5).

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

Caution should be exercised in patients taking concomitant medications that may increase the risk of ulceration or bleeding, such as oral corticosteroids, anticoagulants such as warfarin, selective serotonin reuptake inhibitors or antiplatelet agents such as aspirin (see section 4.5).

When gastrointestinal bleeding or ulceration occurs in patients taking TORA-DOL the treatment should be discontinued.

NSAIDs should be administered with caution to patients with a history of gastrointestinal disease (ulcerative colitis, Crohn's disease) as these conditions may be exacerbated (see section 4.8).

Respiratory effects For the interaction with the metabolism of arachidonic acid, the drug can cause, in asthmatics and predisposed subjects, crises of bronchospasm and possibly other pseudo-allergic phenomena or shock.

Cardiovascular and cerebrovascular effects Since fluid retention and edema have been reported in association with the use of NSAIDs, it is necessary to appropriately monitor and alert patients with a history of hypertension and / or mild to moderate congestive heart failure.

Clinical studies and epidemiological data suggest that the use of selective cyclooxygenase-2 inhibitors and some NSAIDs (particularly at high doses) may be associated with a slightly increased risk of arterial thrombotic events (eg myocardial infarction or stroke) .

Although ketorolac has not been shown to increase thrombotic events such as myocardial infarction, insufficient data are available to exclude this risk with ketorolac.

Patients with uncontrolled hypertension, congestive heart failure, chronic ischemic heart disease, peripheral arterial disease and / or cerebral vascular disease should only be treated with TORA-DOL after careful consideration. A similar assessment should be made before starting treatment of patients with risk factors for cardiovascular disease (e.g. hypertension, hyperlipidaemia, diabetes mellitus, smoking).

Renal Effects TORA-DOL, like other non-steroidal anti-inflammatory drugs (NSAIDs), inhibits prostaglandin synthesis, which can cause nephrotoxicity, including glomerulonephritis, interstitial nephritis, papillary necrosis, nephrotic syndrome and acute renal failure.

Therefore, TORA-DOL requires special precautions or requires its exclusion from use when the following conditions are present in the patient: states of kidney hypoperfusion, kidney disease, liver cirrhosis or severe hepatitis.

Patients with impaired renal function Since TORA-DOL and its metabolites are primarily excreted by the kidney, caution should be exercised in patients with impaired renal function during treatment with TORA-DOL. In particular, the use of TORA-DOL in patients with serum creatinine values ​​greater than 1.8 mg / dl is contraindicated.

The drug is contraindicated in intensive diuretic therapy.

Water retention and edema Due to the potential water retention effect, TORA-DOL should be administered with caution in patients with heart failure, hypertension and similar conditions.

Caution should be exercised in patients with a history of hypertension and / or heart failure as fluid retention and edema have been reported in association with NSAID therapy.

Patients with impaired hepatic function Mild changes in liver function tests have rarely been noted during treatment with TORA-DOL, however of no clinical relevance. However, it is advisable to monitor liver function in patients in whom this was previously impaired, and to discontinue treatment with TORA-DOL if there is evidence of severe hepatic impairment.

Haematological Effects TORA-DOL inhibits platelet function and may prolong bleeding time.

TORA-DOL must not be administered to patients with coagulation disorders or to patients being treated with drugs that interfere with haemostasis, including low-dose heparin (2500-5000 IU) given for prophylactic purposes (see section 4.3).

In post-marketing experience, post-operative haematomas and other signs of wound bleeding have been reported in association with the peri-operative use of TORA-DOL solution for injection. Physicians should consider the potential risk of bleeding when haemostasis is critical, for example in cases of prostate resection, tonsillectomy or cosmetic surgery (see section 4.3).

Skin effects 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 in the early stages of therapy they appear to be at higher risk: the onset of the reaction occurs in most cases within the first month of treatment.

TORA-DOL should be discontinued at the first appearance of skin rash, mucosal lesions or any other signs of hypersensitivity.

The injections must be performed according to strict standards of sterilization, asepsis and antisepsis.

The film-coated tablets contain lactose are therefore not suitable for individuals with lactase deficiency, galactosemia or glucose / galactose malabsorption syndrome.

04.5 Interactions with other medicinal products and other forms of interaction

The concomitant use of TORA-DOL and other non-steroidal anti-inflammatory drugs should be avoided.

Corticosteroids: increased risk of gastrointestinal ulceration or bleeding (see section 4.4).

Antiplatelet agents and selective serotonin reuptake inhibitors (SSRIs): increased risk of gastrointestinal bleeding (see section 4.4).

Anticoagulants: NSAIDs may amplify the effects of anticoagulants, such as warfarin (see section 4.4).

TORA-DOL inhibits platelet aggregation, reduces thromboxane concentrations and prolongs bleeding time. Unlike aspirin, whose effects are prolonged, platelet function returns to normal within 24-48 hours after stopping treatment. with TORA-DOL.

In vitro TORA-DOL causes a negligible reduction in the binding of warfarin to plasma proteins.

As with other drugs that inhibit prostaglandin synthesis, the concomitant administration of TORA-DOL with methotrexate or lithium should be implemented with caution, as a decrease in the clearance of the latter may occur, with a consequent increase in their toxicity.

TORA-DOL can interact with furosemide, decreasing its diuretic action.

Diuretics, ACE inhibitors and angiotensin II antagonists: NSAIDs may reduce the effect of diuretics and other antihypertensive drugs. In some patients with impaired renal function (e.g. dehydrated patients or elderly patients with impaired renal function) the co-administration of an ACE inhibitor or angiotensin II antagonist and agents that inhibit the cyclo-oxygenase system may lead to further deterioration of renal function, including possible acute renal failure, usually reversible. These interactions should be considered in patients taking TORA-DOL concomitantly with ACE inhibitors or angiotensin II antagonists. Therefore, the combination should be administered with caution, especially in elderly patients.

Patients should be adequately hydrated and monitoring of renal function should be considered after initiation of concomitant therapy.

Simultaneous use of pentoxifylline may increase the risk of bleeding.

The concomitant administration of probenecid and TORA-DOL leads to a reduction in the clearance of the latter and, consequently, to higher and prolonged plasma concentrations.

For incompatibilities see section 6.2.

04.6 Pregnancy and breastfeeding

The use of TORA-DOL is contraindicated in pregnancy, near or during delivery and during lactation (see section 4.4).

Inhibition of prostaglandin synthesis can adversely affect pregnancy and / or embryo / fetal development.

Results of epidemiological studies suggest an increased risk of miscarriage and cardiac malformation and gastroschisis after use of a prostaglandin synthesis inhibitor in early pregnancy. The absolute risk of cardiac malformations increased from less than 1% to approximately 1.5%. The risk has been considered to increase with dose and duration of therapy. In animals, administration of prostaglandin synthesis inhibitors has been shown to cause increased loss of pre- and post-implantation and of embryo-fetal mortality.

In addition, an increased incidence of various malformations, including cardiovascular, has been reported in animals given prostaglandin synthesis inhibitors during the organogenetic period.

During the third trimester of pregnancy, all prostaglandin synthesis inhibitors can expose

the fetus to:

- cardiopulmonary toxicity (with premature closure of the arterial duct and pulmonary hypertension);

- renal dysfunction, which can progress to renal failure with oligo-hydroamnios;

the mother and the newborn, at the end of pregnancy, to:

- possible prolongation of bleeding time, and antiplatelet effect which may occur even at very low doses;

- inhibition of uterine contractions resulting in delayed or prolonged labor.

The use of the drug close to the birth can cause the delay of the birth itself; moreover the drug can cause, if administered in this period, alterations of the haemodynamics of the small circulation of the unborn child, with serious consequences for the breathing.

In women of childbearing age, any pregnancy must always be excluded before the start of treatment and effective contraceptive coverage must be ensured during treatment.

The drug is excreted in breast milk in small quantities therefore its use is contraindicated during lactation.

Fertility:

The use of TORA-DOL, like any drug that inhibits prostaglandin synthesis and cyclooxygenase, is not recommended in women who intend to become pregnant.

The administration of TORA-DOL should be discontinued in women who have fertility problems or who are undergoing fertility investigations.

04.7 Effects on ability to drive and use machines

TORA-DOL, although it has no narcotic effect or effects on the Central Nervous System, can cause drowsiness.

It is therefore advisable to exercise caution when driving cars and using machines.

04.8 Undesirable effects

Infections and infestations: aseptic meningitis.

Disorders of the blood and lymphatic system: thrombocytopenia, purpura, epistaxis.

Disorders of the immune system: anaphylaxis; anaphylactoid reactions, such as anaphylaxis, can have a fatal outcome; hypersensitivity reactions (bronchospasm, vasodilation, rash, hypotension, laryngeal edema).

Metabolism and nutrition disorders: anorexia, hyperkalaemia, hyponatremia.

Psychiatric disorders: depression, insomnia, anxiety, irritability, psychotic reactions, abnormal dream activity, hallucinations, euphoria, difficulty concentrating, lethargy, confusion.

Nervous system disorders: headache, dizziness, convulsions, paraesthesia, hyperkinesia, altered taste.

Eye disorders: vision disturbances.

Ear and labyrinth disorders: tinnitus, hearing loss, dizziness.

Cardiac pathologies: palpitations, bradycardia, heart failure.

Edema, hypertension and heart failure have been reported in association with NSAID treatment.

Vascular pathologies: hypertension, vasodilation, hypotension, hematoma, flushing, pallor, post-operative wound bleeding.

Clinical studies and epidemiological data suggest that the use of some NSAIDs (especially at high doses and for long-term treatment) may be associated with a modest increased risk of arterial thrombotic events (eg myocardial infarction or stroke) (see section 4.4).

Respiratory, thoracic and mediastinal disorders: pulmonary edema, dyspnoea, asthma.

Gastrointestinal system: the most commonly observed adverse events are gastrointestinal in nature. Peptic ulcers, gastrointestinal perforation or haemorrhage, sometimes fatal, may occur, particularly in the elderly (see section 4.4).

Nausea, vomiting, diarrhea, flatulence, constipation, dyspepsia, abdominal pain / discomfort, fullness, melaena, rectal bleeding, haematemesis, ulcerative stomatitis, oesophagitis, belching, gastrointestinal ulceration, pancreatitis, have been reported following administration of TORA-DOL. dry mouth, exacerbation of colitis and Crohn's disease (see section 4.4).

Gastritis has been observed less frequently.

Hepatobiliary disorders: hepatitis, cholestatic jaundice, liver failure.

Skin and subcutaneous tissue disorders: angioedema, exfoliative dermatitis, increased sweating, maculo-papular rash, urticaria, pruritus, purpura, bullous reactions including Steven-Johnson syndrome and toxic epidermal necrolysis (very rarely).

Musculoskeletal and connective tissue disorders: myalgia.

Renal and urinary disorders: polyuria, pollakiuria, oliguria, acute renal failure, uremic-haemolytic syndrome, interstitial nephritis, urinary retention, nephrotic syndrome, flank pain.

Diseases of the reproductive system and breast: female infertility.

General disorders and administration site conditions: asthenia, fever, injection site reactions, edema, chest pain, excessive thirst.

Diagnostic tests: increased bleeding time, increased serum urea, increased creatinine, abnormal liver function tests.

04.9 Overdose

Dosages of 360 mg / day i.m. were administered to healthy volunteers for 5 days. Were found: erosive gastritis, peptic ulcer and abdominal pain, which disappeared with the suspension of treatment. Gastrointestinal bleeding may occur. Rarely, hypertension, acute renal failure, respiratory depression and coma may occur after ingestion of NSAIDs.

Anaphylactoid reactions have been reported with therapeutic use of NSAIDs; this may occur following overdose.

There are no specific antidotes. Supportive therapy should be adopted and normal safety measures should be added to this (induction of vomiting, gastric lavage, administration of activated charcoal).

Dialysis does not eliminate ketorolac significantly from the bloodstream.

05.0 PHARMACOLOGICAL PROPERTIES

05.1 Pharmacodynamic properties

Pharmacotherapeutic group: non-steroidal anti-inflammatory / antirheumatic,

ATC code: M01AB15.

The active ingredient of TORA-DOL is Ketorolac trometamine, a drug belonging to the class of non-steroidal anti-inflammatory drugs (NSAIDs). Its activity is mainly carried out by inhibiting the synthesis of prostaglandins, in particular PGE2 and PGF2 alpha.

In preclinical pharmacological studies it showed 350 times more potent analgesic activity than aspirin in mice in the phenylquinone induced pain inhibition test and 800 times more potent than rat aspirin in inhibiting flexion pain response. tarsus-tibialis of rat paw with induced arthritis.

TORA-DOL also showed anti-inflammatory (superior to phenylbutazone) and antipyretic (superior to aspirin) activity.

TORA-DOL was 37 times more active than aspirin in inhibiting collagen-induced aggregation of human platelets.

TORA-DOL has no effect on the Central Nervous System; the effects on the cardiovascular and respiratory systems are minimal.

From clinical studies it emerged that the analgesic activity of TORA-DOL at a dose of 10 mg was equal to or greater than aspirin 650 mg, paracetamol 600 and 1000 mg, the combination of paracetamol 600 mg and 1000 mg + codeine 60 mg; 400 mg glafenine, 400 mg ibuprofen, 50 mg diclofenac.

TORA-DOL administered i.m. at the dose of 30 mg it was found in numerous clinical studies comparable to morphine 12 mg and meperidine 100 mg and superior to morphine 6 mg and meperidine 50 mg.

TORA-DOL i.m. 30 mg showed a longer duration of action than morphine and meperidine.

The analgesic effect occurs within 1 hour after oral administration, 30 minutes after i.m. administration and the maximum analgesic effect appears within 2-3 hours and 1-2 hours, respectively.

For both formulations the average duration of the analgesic effect is 4-6 hours.

TORA-DOL is devoid of morphine-like effects, does not cause respiratory depression and, compared to morphine, the incidence of undesirable effects affecting the central nervous system (somnolence) is significantly lower.

05.2 Pharmacokinetic properties

Absorption

TORA-DOL is rapidly and completely absorbed orally with a peak plasma concentration of 0.87 mcg / ml within 35 minutes of administration of 10 mg tablets and a peak of 1.11 mcg / ml within 26 minutes of administration of 10 mg in solution.

Tablets and 2% solution were found to be bioequivalent in terms of AUC and half-life.

Likewise, after intramuscular administration of 30 mg, TORA-DOL is rapidly and completely absorbed with a mean peak plasma concentration of 2.2 mcg / ml.

After intravenous administration of 30 mg, the peak plasma concentration is 5 mcg / ml.

The pharmacokinetics of TORA-DOL in humans, both after single and repeated administration, are linear; plasma steady state is achieved after one day for every 6 hour administration.

The half-life was 5.4 hours after oral administration and 5.3 hours after i.m. administration and 5.1 hours after i.v.

In the elderly, these values ​​are slightly higher: for example 6.2 and 7.

The intake of antacids does not affect the absorption of TORA-DOL.

Distribution

The plasma protein binding of ketorolac is 99%.

Therapeutic concentrations of digoxin, warfarin, ibuprofen, naproxen, piroxicam, acetaminophen, phenytoin and tolbutamide do not modify the protein binding of TORA-DOL.

Volume of distribution is 0.11 L / kg.

Metabolism

Ketorolac is metabolised in the liver; the main metabolites are para-hydroxylated (12%) and glucuronate (75%) derivatives, all inactive.

Elimination

The major route of elimination of TORA-DOL and its metabolites is via urine and the remainder is eliminated in the faeces. Renal clearance of ketorolac is 0.35-0.55 mL / min / kg.

05.3 Preclinical safety data

Acute toxicity

LD 50 orally in mice 529 mg / kg (M and F); in rats from 100 to 400 mg / kg (M and F) and in monkeys above 200 mg / kg (M and F); via i.p. in mice 473 mg / kg (M and F), in rats from 100 to 400 mg / kg (M and F).

Repeated dose toxicity

Daily high dose oral administration in mice (30 mg / kg for 6 months) and monkeys (9 mg / kg for 12 months) showed gastroenteropathy (in mice) and mild nephrotoxicity. I.m. administrations in rabbits (15 mg / kg for 1 month) and monkeys (13.5 mg / kg for 3 months) showed a mild inflammatory reaction at the injection site.

IV administrations in rabbits and monkeys (2.5 mg / kg for 2 weeks) they were well tolerated.

Fetal toxicity

There is no further information on preclinical data other than that already reported elsewhere in this Summary of Product Characteristics (see section 4.6).

Mutagenesis, carcinogenesis, tolerability

The compound was found to be non-mutagenic, non-carcinogenic, did not induce sensitization in the guinea pig and lacked immunogenic activity.

06.0 PHARMACEUTICAL INFORMATION

06.1 Excipients

TORA-DOL 10 mg film-coated tablets

microcrystalline cellulose, lactose, magnesium stearate, hypromellose, titanium dioxide, macrogol 8000.

TORA-DOL 10 mg / ml solution for injection

alcohol, sodium chloride, water for injections.

TORA-DOL 30 mg / ml solution for injection

alcohol, sodium chloride, water for injections.

TORA-DOL 20 mg / ml oral drops, solution

citric acid, monobasic sodium phosphate, methyl parahydroxybenzoate, propyl parahydroxybenzoate, sodium hydroxide at pH 6.5 ± 0.5, purified water.

06.2 Incompatibility

TORA-DOL is compatible with aminophylline, xylocaine, morphine, meperidine, dopamine, insulin and heparin mixed together in solution contained in an intravenous drip bag, but cannot be mixed with morphine, meperidine, promethazine or hydroxyzine in a syringe.

06.3 Period of validity

Film-coated tablets: 3 years.

Solution for injection 30 mg / ml: 3 years.

Solution for injection 10 mg / ml: 2 years.

Oral drops: 2 years.

06.4 Special precautions for storage

Oral drops: keep away from light.

Tablets: Do not store above 30 ° C

06.5 Nature of the immediate packaging and contents of the package

type I glass ampoules, yellow color

TORA-DOL 10 mg / ml solution for injection - 6 vials of 1 ml

TORA-DOL 30 mg / ml solution for injection - 3 ampoules of 1 ml PVC and aluminum blister

TORA-DOL 10 mg film-coated tablets - 10 amber type III glass bottle tablets

TORA-DOL 20 mg / ml oral drops, solution - bottle 10 ml

06.6 Instructions for use and handling

No special instructions.

07.0 MARKETING AUTHORIZATION HOLDER

RECORDATI Chemical and Pharmaceutical Industries S.p.A. - Via M. Civitali, 1 - 20148 Milan

08.0 MARKETING AUTHORIZATION NUMBER

10 mg film-coated tablets - 10 A.I.C. n. 027253032

10 mg / ml solution for injection - 6 ampoules of 1 ml A.I.C. n. 027253018

30 mg / ml solution for injection - 3 ampoules of 1 ml A.I.C. n. 027253020

20 mg / ml oral drops solution - 10 ml bottle A.I.C. n. 027253069

09.0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION

Renewal: June 2010

10.0 DATE OF REVISION OF THE TEXT

May 2012

11.0 FOR RADIO DRUGS, COMPLETE DATA ON THE INTERNAL RADIATION DOSIMETRY

12.0 FOR RADIO DRUGS, FURTHER DETAILED INSTRUCTIONS ON EXEMPORARY PREPARATION AND QUALITY CONTROL

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