Active ingredients: Ketorolac
KEVINDOL 20 mg / ml oral drops, solution
Kevindol package inserts are available for pack sizes:- KEVINDOL 20 mg / ml oral drops, solution
- KEVINDOL 30 mg / ml solution for injection
Why is Kevindol used? What is it for?
PHARMACOTHERAPEUTIC CATEGORY: non-steroidal anti-inflammatory / antirheumatic drugs
THERAPEUTIC INDICATIONS KEVINDOL: administered intramuscularly or intravenously, it is indicated for the short-term treatment (maximum two days) of moderate to severe acute postoperative pain. In cases of major surgery or very severe pain KEVINDOL administered intravenously can be used as a complement to an opioid analgesic.
KEVINDOL solution for injection is also indicated in the treatment of pain due to renal colic.
Contraindications When Kevindol should not be used
Warning: the drug is not indicated in mild or chronic pain Kevindol is contraindicated in the following cases
- Hypersensitivity to the active substance or to any of the excipients.
- In patients with already demonstrated hypersensitivity to KEVINDOL or other NSAIDs and in patients in whom aspirin or other inhibitors of prostaglandin synthesis have induced allergic manifestations (severe anaphylactic-type reactions have been observed in these patients).
- Complete or partial syndrome of nasal polyposis, angioedema, bronchospasm.
- Asthmatic attacks, rhinitis, urticaria.
- Active peptic ulcer, or a history of gastrointestinal bleeding, ulceration or perforation.
- Like other non-steroidal anti-inflammatory drugs, KEVINDOL is contraindicated in patients with severe heart failure.
- KEVINDOL inhibits platelet function, and is therefore contraindicated in patients with previous, current or suspected cerebrovascular bleeding, in patients who have undergone high bleeding risk surgery or incomplete haemostasis and in those patients at high risk of bleeding.
- Moderate or severe renal insufficiency (serum creatinine> 442 µmol / L), or in patients at risk of renal insufficiency due to hypovolaemia or dehydration.
- Cirrhosis of the liver or severe liver failure.
- Hemorrhagic diathesis.
- Disorders of coagulation.
- Patients who have undergone high-risk bleeding surgery or incomplete haemostasis
- Patients on anticoagulant therapy.
- Concomitant treatment with ASA or other non-steroidal anti-inflammatory drugs and with lithium salts, probenecid or pentoxifylline (see section Interactions).
- Intensive diuretic therapy patients.
- KEVINDOL 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 KEVINDOL is contraindicated in the third trimester of pregnancy, near and during childbirth and during breastfeeding.
Warning: The solution for injection contains ethanol therefore use via epidural or intrathecal route is contraindicated.
Precautions for use What you need to know before taking Kevindol
Warning: KEVINDOL 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.
Some epidemiological evidence suggests that KEVINDOL 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 Therapeutic indications, Dose, method and time of administration and Contraindications).
The concomitant use of KEVINDOL 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 starting therapy with KEVINDOL, it should be ensured that the patient has not previously had hypersensitivity reactions. towards KEVINDOL, acetylsalicylic acid and / or other non-steroidal anti-inflammatory drugs.
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.
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 section Dose, method and time of administration).
Debilitated patients are at increased risk of ulceration and bleeding. Most fatal gastrointestinal events associated with NSAID use occur in elderly and / or debilitated patients.
In elderly subjects, an increase in the elimination half-life of the drug and a concomitant reduction in clearance may also occur. Therefore, in addition to a reduction in the overall dose, a longer interval between doses may be appropriate (see section Dose, method and time of administration).
Gastrointestinal effects
KEVINDOL 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 KEVINDOL and other non-steroidal anti-inflammatory drugs at the same time.
In the elderly and in patients with a history of ulcer, particularly if complicated with haemorrhage or perforation (see section Contraindications), the risk of gastrointestinal bleeding, ulceration or perforation is higher with increased doses of NSAIDs, including KEVINDOL solution for injection. The risk of severe gastrointestinal bleeding is dose dependent. These patients should start treatment with the lowest available dose. Concomitant therapy with protective agents (e.g. 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 Interactions section).
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 Undesirable effects).
When gastrointestinal bleeding or ulceration occurs in patients taking KEVINDOL the treatment should be discontinued.
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 Interactions section).
As with other NSAIDs, also with KEVINDOL, the incidence and severity of gastrointestinal complications may increase with increasing dose and duration of treatment. The risk of severe gastrointestinal bleeding is dose dependent. This is especially true in elderly patients who receive an average daily dose of more than 60mg / day of KEVINDOL. A history of peptic ulcer increases the chance of developing serious gastrointestinal complications during therapy with KEVINDOL.
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.
Hematological effects
KEVINDOL inhibits platelet function and may prolong bleeding time. KEVINDOL should be administered with great caution to patients with coagulation disorders and these should be carefully monitored.Although studies do not indicate a significant interaction between KEVINDOL and warfarin or heparin, concomitant use of KEVINDOL and drugs that interfere with haemostasis, including therapeutic doses of anticoagulants, such as warfarin, low dose heparin (2500-5000 IU each 12 hours) given prophylactically and dextrans, may be associated with an increased risk of bleeding. KEVINDOL should be administered with great caution in these patients, who should be carefully monitored (see section 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 KEVINDOL 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 section Undesirable effects). at higher risk: the onset of the reaction occurs in most cases within the first month of treatment. KEVINDOL should be discontinued at the first appearance of rash, mucosal lesions or any other signs of hypersensitivity. Sodium / fluid retention in patients with cardiovascular disease, and peripheral edema
Caution should be exercised in patients with a history of mild to moderate hypertension and / or congestive 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 KEVINDOL, and therefore should be used with caution in patients with heart failure, hypertension or similar conditions.
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 and for a long time) may be associated with an increased risk of arterial thrombotic events (eg myocardial infarction or stroke) Although KEVINDOL has not been shown to increase thrombotic events such as myocardial infarction, insufficient data are available to exclude this risk with KEVINDOL.
Patients with uncontrolled hypertension, congestive heart failure, chronic ischemic heart disease, peripheral arterial disease and / or cerebral vascular disease should only be treated with KEVINDOL 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).
Kidney effects
KEVINDOL, like other non-steroidal anti-inflammatory drugs (NSAIDs), inhibits the synthesis of prostaglandins, which can cause nephrotoxicity, including glomerulonephritis, interstitial nephritis, papillary necrosis, nephrotic syndrome and acute renal failure.
Therefore KEVINDOL 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
KEVINDOL, like other non-steroidal anti-inflammatory drugs (NSAIDs), should be used with caution in patients with renal impairment or with a history of renal disease, as it inhibits prostaglandin synthesis. In such patients the administration of KEVINDOL and other NSAIDs may cause a reduction in blood volume and / or renal blood flow, in which prostaglandins play a supporting role in maintaining renal perfusion. In such patients, administration of KEVINDOL or other NSAIDs may result in a dose-dependent reduction in renal prostaglandin production and may precipitate evident renal impairment or failure. Patients at greatest risk for this reaction are those with chronic renal impairment, heart failure, hepatic insufficiency, patients on diuretic therapy and the elderly. Symptoms usually resolve with discontinuation of KEVINDOL or other non-steroidal anti-inflammatory drugs (NSAIDs).
Since KEVINDOL and its metabolites are mainly excreted by the kidney, caution should be exercised in patients with impaired renal function during treatment with KEVINDOL. In particular, the use of KEVINDOL in patients with serum creatinine values greater than 442 µg / L is contraindicated.
The drug is contraindicated in intensive diuretic therapy.
Patients with impaired liver function
Mild changes in liver function tests have rarely been noted during treatment with KEVINDOL, 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 KEVINDOL if there is evidence of severe hepatic impairment.
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 aspirin, other NSAIDs or KEVINDOL. These can also occur in people with a "history of angioedema, bronchospastic reactivity (eg asthma), hypersensitivity, and nasal polyposis." Anaphylactoid reactions, such as anaphylaxis, can be fatal. Therefore, KEVINDOL 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.
Fertility related precautions
The use of KEVINDOL solution for injection, as with any prostaglandin synthesis and cyclooxygenase inhibitor drug, may impair fertility and is not recommended in women intending to become pregnant.
KEVINDOL administration should be discontinued in women who have fertility problems or who are undergoing fertility investigations.
Sodium / fluid retention in patients with cardiovascular disease and peripheral edema
Fluid retention, hypertension and edema have been reported with the use of KEVINDOL and should therefore be used with caution in patients with heart failure, hypertension or similar conditions.
Drug abuse and addiction
KEVINDOL was found to be free of potential addiction. No withdrawal symptoms have been observed following abrupt discontinuation of KEVINDOL solution for injection.
Interactions Which drugs or foods can modify the effect of Kevindol
The concomitant use of KEVINDOL and other non-steroidal anti-inflammatory drugs should be avoided.
Corticosteroids: increased risk of gastrointestinal ulceration or bleeding (see section Precautions for use).
Antiplatelet agents and selective serotonin reuptake inhibitors (SSRIs): increased risk of gastrointestinal bleeding (see section Precautions for use).
In patients treated concomitantly with ASA or other NSAIDs, the risk of NSAID-related serious adverse events appears to be increased. KEVINDOL 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 KEVINDOL. .
Anticoagulants: NSAIDs may amplify the effects of anticoagulants, such as warfarin (see section Precautions for use). In vitro KEVINDOL causes a negligible reduction in the binding of warfarin to plasma proteins.
Pentoxifylline: The concomitant use of pentoxifylline may increase the risk of bleeding. Probenecid: The concomitant administration of probenecid and KEVINDOL leads to a reduction of the latter clearance and to an increase in the volume of distribution, increased plasma concentrations and increased blood pressure. "half-life of KEVINDOL. Methotrexate: It has been reported that some drugs that inhibit prostaglandin synthesis, reduce the synthesis of methotrexate, and therefore may increase its toxicity. Some drugs that inhibit prostaglandin synthesis have been reported to inhibit renal clearance. of lithium, leading to an increase in the plasma concentration of the latter. There have been reports of increased plasma lithium concentrations during therapy with KEVINDOL.
KEVINDOL 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 KEVINDOL was reduced from approximately 99.2 to 97.5%, which represents a potential two-fold increase in the plasma concentration of KEVINDOL not tied up. Therapeutic concentrations of digoxin, warfarin, ibuprofen, naproxen, piroxicam, acetaminophen, phenytoin and tolbutamide do not alter the protein binding of KEVINDOL tromethamine.
Furosemide: KEVINDOL solution for injection can interact with furosemide, decreasing its diuretic action, in healthy normovolemic subjects, by about 20%, therefore special attention should be paid in patients with heart failure.
Diuretics, ACE inhibitors and angiotensin II antagonists: NSAIDs may reduce the effect of diuretics and other antihypertensive drugs. The risk of acute renal failure, which is usually reversible, may be increased 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. These interactions should be considered in patients taking KEVINDOL 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 and periodically thereafter.
KEVINDOL has been shown to reduce the need for concomitant opioid analgesics for the relief of postoperative pain. Antacids do not affect the degree of absorption.
Warnings It is important to know that:
SPECIAL WARNINGS
Important information about some of the ingredients of KEVINDOL solution for injection Warning: The solution for injection contains ethanol therefore must not be used neuraxially (epidural or intrathecal).
This medicine contains 12.7 vol% ethanol (alcohol), eg. up to 100 mg per serving, equivalent to approximately 2.5 ml of beer and 1.1 ml of wine per serving.
It can be harmful to alcoholics.
To be taken into consideration in pregnant or lactating women, children and high-risk groups such as people with liver disease or epilepsy.
For those who carry out sporting activities, the use of medicines containing ethyl alcohol can determine positive doping tests in relation to the alcohol concentration limits indicated by some sports federations.
Pregnancy and breastfeeding
Pregnancy
KEVINDOL is contraindicated in the third trimester of pregnancy, during labor, delivery and breastfeeding (see Contraindications).
KEVINDOL should only be used during pregnancy if the potential benefit to the mother justifies the potential risk to the fetus.
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% up to approximately 1.5%. The risk has been believed to increase with dose and duration of therapy. In animals, administration of prostaglandin synthesis inhibitors has been shown to cause increased pre- and post-implantation loss and 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, KEVINDOL should only be given if strictly necessary.
If KEVINDOL is used in women attempting to conceive, or during the first and second trimester of pregnancy, the dose should be kept low and the duration of treatment as short 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, KEVINDOL is contraindicated during the third trimester of pregnancy.
KEVINDOL should only be administered during the first two trimesters of pregnancy if strictly necessary. KEVINDOL crosses the placenta, to the extent of about 10%.
Fertility
The use of KEVINDOL, as with any prostaglandin synthesis and cyclooxygenase inhibitor drug, is not recommended in women intending to become pregnant. The administration of KEVINDOL should be discontinued in women who have fertility problems or are undergoing fertility investigations .
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
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. KEVINDOL is contraindicated during labor and delivery because, through its effect of inhibition of prostaglandin synthesis, it can have negative effects on the circulation of the fetus and inhibit uterine contractions, thus increasing the risk of uterine bleeding.
Feeding time
KEVINDOL and its metabolites have been detected in the fetus and in the milk of animals. KEVINDOL is excreted in breast milk in small quantities, therefore it is contraindicated in nursing mothers.
Ask your doctor or pharmacist for advice before taking any medicine.
Effects on ability to drive and use machines
With the use of KEVINDOL solution for injection, some patients may experience somnolence, dizziness, vertigo, insomnia or depression. If patients experience these, or other similar side effects, they should exercise caution in performing activities that require attention. use caution when driving and using machines.
Dosage and method of use How to use Kevindol: Dosage
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.
The solution is clear and slightly yellowish, this color does not affect the efficacy and safety of the medicine.
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 elderly patients, the posology must be carefully established by the doctor, who will have to evaluate a possible reduction in the dosages indicated above. In elderly patients, the maximum daily dose must 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 NURSING 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 continue 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.
Overdose What to do if you have taken an overdose of Kevindol
Symptoms and signs
Following an overdose of KEVINDOL, the following were found: erosive gastritis, peptic ulcer, abdominal pain, nausea, vomiting, hyperventilation and renal dysfunction, which disappeared upon discontinuation of the drug.
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 intake of NSAIDs; this can happen as a result of overdose.
Treatment: There are no specific antidotes.
In the event of an overdose of NSAIDs, symptomatic and supportive therapy should be used. In case of accidental ingestion, normal safety measures must be added to this (induction of vomiting, gastric lavage, administration of activated charcoal).
Dialysis does not significantly eliminate KEVINDOL from the bloodstream.
In case of accidental ingestion / intake of an excessive dose of KEVINDOL, notify your doctor immediately or go to the nearest hospital. If you have any questions about the use of KEVINDOL, ask your doctor or pharmacist.
Side Effects What are the side effects of Kevindol
Like all medicines, this can cause side effects, although not everybody gets them.
Post-marketing experience
The following side effects may occur in patients treated with Ketorolac; the frequency of reported events is not known, as these events were reported voluntarily by a non-quantifiable number of people.
Gastrointestinal disorders: the most commonly observed adverse events are gastrointestinal in nature. Gastrointestinal ulcers, peptic ulcers, perforation or bleeding, sometimes fatal, may occur, particularly in the elderly (see section Precautions for use). Nausea, vomiting, diarrhea, flatulence, constipation, dyspepsia have been reported after administration of KEVINDOL. abdominal pain / discomfort, sense of fullness, melaena, rectal bleeding, haematemesis, ulcerative stomatitis, oesophagitis, belching, gastrointestinal ulceration, pancreatitis, dry mouth, exacerbation of colitis and Crohn's disease (see Precautions for use).
Gastritis has been observed less frequently.
Infections and infestations: aseptic meningitis
Disorders of the blood and lymphatic system: thrombocytopenia, purpura, epistaxis.
Immune system disorders: anaphylaxis; anaphylactoid reactions such as anaphylaxis can have a fatal outcome; hypersensitivity reactions such as bronchospasm, vasodilation, rash, hypotension, laryngeal edema.
Metabolism and nutrition disorders: anorexia, hyperkalaemia, hyponatremia
Psychiatric disorders: abnormal ideation of thought, depression, insomnia, anxiety, irritability, psychotic reactions, abnormal dream activity, hallucinations, euphoria, difficulty concentrating, drowsiness, lethargy, confusion. Nervous system disorders: headache, dizziness, convulsions, paraesthesia, hyperkinesia, altered taste.
Eye disorders: visual disturbances.
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, postoperative bleeding from wounds. 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 (eg myocardial infarction or stroke ) (see section Precautions for use). Although KEVINDOL has not been shown to increase thrombotic events such as myocardial infarction, there are insufficient data to exclude a similar risk for KEVINDOL.
Reproductive system and breast disorders: female infertility.
Respiratory thoracic and mediastinal disorders: pulmonary edema, dyspnoea, asthma.
Hepatobiliary disorders: hepatitis, cholestatic jaundice, hepatic failure.
Skin and subcutaneous tissue disorders: angioedema, exfoliative dermatitis, increased sweating, maculo-papular rash, urticaria, pruritus, purpura, bullous reactions, including Stevens-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 (with or without hematuria, +/- azotaemia). As with other drugs which inhibit the synthesis of renal prostaglandins, signs of renal impairment may occur after administration of KEVINDOL, for example, but not limited to, increased levels of creatinine and potassium.
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 www.agenziafarmaco.it/it/responsabili. By reporting side effects you can help provide more information on the 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. Store in the original packaging to protect the product from light.
Shelf life after reconstitution of the solution for injection:
In accordance with the rules of good pharmaceutical practice, the intravenous solutions must be prepared at the time of infusion. The reconstituted solution must be used immediately and any residues discarded.
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.
KEEP THE MEDICINAL PRODUCT OUT OF THE REACH AND SIGHT OF CHILDREN
Other Information
COMPOSITION
Each vial contains
Active ingredient: ketorolac trometamol 30 mg
Excipients: ethyl alcohol, sodium chloride, water for injections.
PHARMACEUTICAL FORM AND CONTENT
Solution for injection. Box of 3 ampoules of 1 ml.
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.
01.0 NAME OF THE MEDICINAL PRODUCT
KEVINDOL
02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION
KEVINDOL 30 mg / ml solution for injection
Each vial contains:
Active ingredient: ketorolac trometamol 30 mg
KEVINDOL 20 mg / ml oral drops, solution
1 ml of solution contains:
Active ingredient: ketorolac trometamol 20 mg
For the list of excipients, see section 6.1.
03.0 PHARMACEUTICAL FORM
Injectable solution.
Oral drops, solution
04.0 CLINICAL INFORMATION
04.1 Therapeutic indications
KEVINDOL oral drops, solution
KEVINDOL is only indicated for the short-term (maximum 5 days) treatment of moderate postoperative pain.
KEVINDOL solution for injection
KEVINDOL administered intramuscularly or intravenously is indicated for the short-term (maximum two days) treatment of moderate to severe acute postoperative pain.
In cases of major surgery or very severe pain KEVINDOL administered intravenously can be used as a complement to an opioid analgesic.
KEVINDOL solution for injection is also indicated in the treatment of pain due to renal colic.
04.2 Posology and method of administration
KEVINDOL oral drops, solution
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 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 below 16 years (see section 4.3).
KEVINDOL 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.
The solution is clear and slightly yellowish, this color does not affect the efficacy and safety of the medicine.
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 NURSING 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.
KIDNEY 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.
Kevindol is contraindicated in the following cases
• Hypersensitivity to the active substance or to any of the excipients.
• In patients with already demonstrated hypersensitivity to KEVINDOL or other NSAIDs and in patients in whom aspirin or other prostaglandin synthesis inhibitors have induced allergic reactions (severe anaphylactic-type reactions have been observed in these patients).
• Complete or partial syndrome of nasal polyposis, angioedema, bronchospasm.
• Asthmatic attacks, rhinitis, urticaria.
• Active peptic ulcer, or a history of gastrointestinal bleeding, ulceration or perforation.
• Like other non-steroidal anti-inflammatory drugs, KEVINDOL is contraindicated in patients with severe heart failure.
• KEVINDOL inhibits platelet function, and is therefore contraindicated in patients with previous, current or suspected cerebrovascular bleeding, in patients who have undergone high-risk bleeding surgery or incomplete haemostasis and, in those patients at high risk of bleeding.
• Moderate or severe renal insufficiency (serum creatinine> 442 μmol / L), or in patients at risk of renal insufficiency due to hypovolaemia or dehydration.
• Cirrhosis of the liver or severe liver failure.
• 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 ASA or other non-steroidal anti-inflammatory drugs and with salts of lithium, probenecid or pentoxifylline (see section 4.5).
• Patients in intensive diuretic therapy.
• KEVINDOL 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 KEVINDOL is contraindicated in the third trimester of 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: KEVINDOL cannot be considered a simple pain reliever and requires to be used under the strict supervision of the doctor.
KEVINDOL should not be used in the treatment of mild or chronic pain.
Some epidemiological evidence suggests that KEVINDOL 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).
The concomitant use of KEVINDOL 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 KEVINDOL, it must be ensured that the patient has not previously had hypersensitivity reactions to KEVINDOL, acetylsalicylic acid and / or other non-steroidal anti-inflammatory drugs.
Gastrointestinal bleeding, ulceration and perforation
Gastrointestinal bleeding, ulceration and perforation, which can be fatal, have been reported at any time during treatment with all NSAIDs, including KEVINDOL, with or without warning symptoms or a previous history of serious gastrointestinal events.
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 section 4.2).
Debilitated patients are at increased risk of ulceration and bleeding. Most fatal gastrointestinal events associated with NSAID use occur in elderly and / or debilitated patients.
In elderly subjects, an increase in the elimination half-life of the drug and a concomitant reduction in clearance may also occur. Therefore, in addition to a reduction in the overall dose, a longer interval between doses may be appropriate (see section 4.2).
Gastrointestinal effects
KEVINDOL 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 KEVINDOL and other non-steroidal anti-inflammatory drugs at the same time.
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 increased doses of NSAIDs, including KEVINDOL solution for injection. The risk of severe gastrointestinal bleeding is dose dependent. These patients should start treatment with the lowest available dose. Concomitant therapy with protective agents (e.g. 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 section 4.5).
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).
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.
When gastrointestinal bleeding or ulceration occurs in patients taking KEVINDOL solution for injection the treatment should be discontinued.
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 re-uptake inhibitors or antiplatelet agents such as aspirin (see section 4.5).
As with other NSAIDs, also with KEVINDOL, the incidence and severity of gastrointestinal complications may increase with increasing dose and duration of treatment. The risk of severe gastrointestinal bleeding is dose dependent. This is especially true in elderly patients who receive an average daily dose of more than 60mg / day of KEVINDOL. A history of peptic ulcer increases the chance of developing serious gastrointestinal complications during therapy with KEVINDOL.
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.
Hematological effects
KEVINDOL inhibits platelet function and may prolong bleeding time.
KEVINDOL should be administered with great caution to patients with coagulation disorders and these should be carefully monitored. Although studies do not indicate a significant interaction between KEVINDOL and warfarin or heparin, concomitant use of KEVINDOL and drugs that interfere with haemostasis, including therapeutic doses of anticoagulants, such as warfarin, low dose heparin (2500-5000 IU each 12 hours) given prophylactically and dextrans, may be associated with an increased risk of bleeding. KEVINDOL should be administered with caution in these patients, who should be carefully monitored (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 KEVINDOL 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 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 section 4.8). In the early stages of therapy, patients appear to be at higher risk: the onset of the reaction occurs in most cases within the first month of treatment.
KEVINDOL should be discontinued at the first appearance of rash, mucosal lesions or any other signs of hypersensitivity.
Sodium / fluid retention in patients with cardiovascular disease, and peripheral edema
Caution should be exercised in patients with a history of mild to moderate hypertension and / or congestive 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 KEVINDOL, and therefore should be used with caution in patients with heart failure, hypertension or similar conditions.
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 and for a long time) may be associated with an increased risk of arterial thrombotic events (eg myocardial infarction or stroke) Although KEVINDOL has not been shown to increase thrombotic events such as myocardial infarction, insufficient data are available to exclude this risk with KEVINDOL.
Patients with uncontrolled hypertension, congestive heart failure, chronic ischemic heart disease, peripheral arterial disease and / or cerebral vascular disease should only be treated with KEVINDOL 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).
Kidney effects
KEVINDOL, 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 KEVINDOL 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
KEVINDOL, like other non-steroidal anti-inflammatory drugs (NSAIDs), should be used with caution in patients with renal impairment or with a history of renal disease, as it inhibits prostaglandin synthesis. In such patients the administration of KEVINDOL and other NSAIDs may cause a reduction in blood volume and / or renal blood flow, in which prostaglandins play a supporting role in maintaining renal perfusion. In such patients, administration of KEVINDOL or other NSAIDs may result in a dose-dependent reduction in renal prostaglandin production and may precipitate evident renal impairment or failure. Patients at greater risk of this reaction are those with chronic renal impairment, heart failure, hepatic insufficiency, patients on diuretic therapy and the elderly. Symptoms usually resolve with discontinuation of KEVINDOL or other non-steroidal anti-inflammatory drugs (NSAIDs).
Since KEVINDOL and its metabolics are mainly excreted by the kidney, caution should be exercised in patients with impaired renal function during treatment with KEVINDOL. In particular, the use of KEVINDOL in patients with serum creatinine values greater than 442 μmol / L is contraindicated.
The drug is contraindicated in intensive diuretic therapy.
Patients with impaired liver function
Mild changes in liver function tests have rarely been noted during treatment with KEVINDOL, 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 KEVINDOL if there is evidence of severe hepatic impairment.
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 aspirin, other NSAIDs or KEVINDOL These may also occur in individuals with a "history of angioedema, bronchospastic reactivity (eg asthma), hypersensitivity, and nasal polyposis." Anaphylactoid reactions, such as anaphylaxis, can be fatal. Therefore, KEVINDOL 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.
Fertility related precautions
The use of KEVINDOL solution for injection, as with any prostaglandin synthesis and cyclooxygenase inhibitor drug, may impair fertility and is not recommended in women intending to become pregnant.
KEVINDOL administration should be discontinued in women who have fertility problems or who are undergoing fertility investigations.
Sodium / fluid retention in patients with cardiovascular disease and peripheral edema
Fluid retention, hypertension and edema have been reported with the use of KEVINDOL and should therefore be used with caution in patients with heart failure, hypertension or similar conditions.
Drug abuse and addiction
KEVINDOL was found to be free of potential addiction. No withdrawal symptoms have been observed following abrupt discontinuation of KEVINDOL
KEVINDOL oral drops, solution contains parahydroxybenzoates which may cause allergic reactions (including delayed).
KEVINDOL solution for injection contains 100 mg of ethyl alcohol for each vial, corresponding to 10%; therefore, the product may be harmful to alcoholics and should be administered with caution in groups of patients at risk such as subjects suffering from liver disease and epilepsy.
The injections must be performed according to strict standards of sterilization, asepsis and antisepsis.
04.5 Interactions with other medicinal products and other forms of interaction
The concomitant use of KEVINDOL and other non-steroidal anti-inflammatory drugs should be avoided.
Corticosteroids: increased risk of gastrointestinal ulceration or bleeding (see section 4.4).
Anti-aggregating agents and selective serotonin re-uptake inhibitors (SSRIs): increased risk of gastrointestinal bleeding (see section 4.4). In patients treated concomitantly with ASA or other NSAIDs, the risk of NSAID-related serious adverse events appears to be increased.
KEVINDOL 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 KEVINDOL. .
Anticoagulants: NSAIDs may amplify the effects of anticoagulants, such as warfarin (see section 4.4).
In vitro KEVINDOL causes negligible reduction in the binding of warfarin to plasma proteins.
Although studies do not indicate a significant interaction between KEVINDOL and warfarin or heparin, concomitant use of KEVINDOL and drugs that affect haemostasis, including therapeutic doses of anticoagulants such as warfarin, low dose heparin (2500-5000 units every 12 hours ) administered prophylactically and dextrans may be associated with an increased risk of haemorrhage.
Pentoxifylline: Simultaneous use of pentoxifylline may increase the risk of bleeding.
Probenecid: Concomitant administration of probenecid and KEVINDOL leads to decreased clearance of the latter and to an increase in the volume of distribution, increased plasma concentrations and increased half-life of ketorolac.
Methotrexate: Some drugs that inhibit prostaglandin synthesis have been reported to reduce the synthesis 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 lithium plasma concentrations. There have been reports of increased plasma lithium concentrations during therapy with KEVINDOL.
Ketorolac tromethamine does not modify the protein binding of digoxin. In vitro studies indicate that, at therapeutic concentrations of salicylate (300 mcg / mL), ketorolac binding was reduced from approximately 99.2 to 97.5%, representing a potential two-fold increase in plasma ketorolac concentration not tied up.
Therapeutic concentrations of digoxin, warfarin, ibuprofen, naproxen, piroxicam, acetaminophen, phenytoin and tolbutamide do not modify the protein binding of ketorolac tromethamine.
Furosemide: KEVINDOL solution for injection can interact with furosemide, decreasing its diuretic action, in healthy normovolemic subjects, by about 20%, therefore special attention should be paid in patients with heart failure.
Diuretics, ACE inhibitors and angiotensin II antagonists: NSAIDs may reduce the effect of diuretics and other antihypertensive drugs. The risk of acute renal failure, which is usually reversible, may be increased 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. These interactions should be considered in patients taking ketorolac 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 and periodically thereafter.
KEVINDOL has been shown to reduce the need for concomitant opioid analgesics for post-operative pain relief.
Antacids do not affect the degree of absorption.
For incompatibilities see paragraph 6.2.
04.6 Pregnancy and breastfeeding
Pregnancy
KEVINDOL is contraindicated in the third trimester of pregnancy, during labor, delivery and lactation (see section 4.3).
KEVINDOL should only be used during pregnancy if the potential benefit to the mother justifies the potential risk to the fetus.
Inhibition of prostaglandin synthesis can adversely affect pregnancy and / or embryo / fetal development.
Results of epidemiological studies suggest an increased risk of abortion, 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% up 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 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, KEVINDOL should only be given if strictly necessary. If KEVINDOL is used in women attempting to conceive, or during the first and second trimester of pregnancy, the dose should be kept low and the duration of treatment as short 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 concentrations resulting in delayed or prolonged labor.
Consequently, KEVINDOL is contraindicated during the third trimester of pregnancy.
KEVINDOL should only be administered during the first two trimesters of pregnancy if strictly necessary.
KEVINDOL crosses the placenta to the extent of about 10%.
Fertility
The use of KEVINDOL, as with any prostaglandin synthesis and cyclooxygenase inhibitor drug, is not recommended in women planning to become pregnant (see section 4.4).
KEVINDOL administration should be discontinued in women who have fertility problems or who are undergoing fertility investigations.
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
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.
KEVINDOL is contraindicated during labor and delivery because, through its effect of inhibition of prostaglandin synthesis, it can have negative effects on the circulation of the fetus and inhibit uterine contractions, thus increasing the risk of uterine bleeding.
Feeding time
KEVINDOL and its metabolites were detected in the fetus and milk of animals.
KEVINDOL is excreted in small quantities in breast milk, therefore it is contraindicated in breastfeeding mothers.
04.7 Effects on ability to drive and use machines
Some patients may experience somnolence, dizziness, vertigo, insomnia or depression with the use of KEVINDOL. If patients experience these, or other similar side effects, they should be careful in performing activities that require attention.
It is therefore advisable to exercise caution when driving cars and using machines.
04.8 Undesirable effects
Post-marketing experience
The following side effects may occur in patients receiving KEVINDOL; the frequencies of the reported events are not known, because they were reported voluntarily by an unquantifiable number of people.
Gastrointestinal disorders: the most commonly observed adverse events are gastrointestinal in nature. Peptic ulcers, ulcer, perforation or gastrointestinal haemorrhage, sometimes fatal, may occur, particularly in the elderly (see section 4.4.
Following administration of KEVINDOL the following have been reported: nausea, vomiting, diarrhea, flatulence, constipation, dyspepsia, abdominal pain / discomfort, fullness, melaena, rectal bleeding, haematemesis, ulcerative stomatitis, oesophagitis, belching, gastrointestinal ulceration, pancreatitis, dryness of the mouth, exacerbation of colitis and Crohn's disease (see section Precautions for use).
Gastritis has been observed less frequently.
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 be fatal; hypersensitivity reactions such as bronchospasm, vasodilation, flushing, rash, hypotension, laryngeal edema).
Metabolism and nutrition disorders: anorexia, hyperkalaemia, hyponatremia.
Psychiatric disorders: abnormal ideation of thought, depression, insomnia, anxiety, irritability, psychotic reactions, abnormal dream activity, hallucinations, euphoria, difficulty concentrating, drowsiness, lethargy, confusion.
Nervous system disorders: headache, dizziness, convulsions, paraesthesia, hyperkinesia, altered taste.
Eye disorders: visual 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, bruising, redness, pallor, post-operative bleeding from wounds.
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 (eg myocardial infarction or stroke ) (see section 4.4) Although KEVINDOL has not been shown to increase thrombotic events, such as myocardial infarction, there are insufficient data to exclude a similar risk for KEVINDOL.
Diseases of the reproductive system and breast: female infertility.
Respiratory thoracic and mediastinal disorders: pulmonary edema, dyspnoea, asthma.
Hepatobiliary disorders: hepatitis, cholestatic jaundice, liver failure.
Skin and subcutaneous tissue disorders: angioedema, exfoliative dermatitis, sweating increased, maculo-papular rash, urticaria, pruritus, purpura, bullous reactions including Stevens-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 (with or without hematuria, +/- of azotemia). As with other drugs that inhibit synthesis of renal prostaglandins, after administration of ketorolac, signs of renal impairment may occur, for example, increased levels of creatinine and potassium.
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.
Lab test
See section Post-marketing experience (Undesirable effects).
Reporting of suspected adverse reactions.
Reporting of suspected adverse reactions occurring after authorization of the medicinal product is important as it allows continuous monitoring of the benefit / risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system. "address www.agenziafarmaco.gov.it/it/responsabili.
04.9 Overdose
Symptoms and signs
Following an overdose of KEVINDOL, the following were found: erosive gastritis, peptic ulcer, abdominal pain, nausea, vomiting, hyperventilation and renal dysfunction, which disappeared upon discontinuation of the drug.
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 intake of NSAIDs; this can happen as a result of overdose.
Treatment
There are no specific antidotes.
In the event of an overdose of NSAIDs, symptomatic and supportive therapy should be used. In case of accidental ingestion, normal safety measures must be added to this (induction of vomiting, gastric lavage, administration of activated charcoal).
Dialysis does not significantly eliminate KEVINDOL 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 KEVINDOL 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.
Ketorolac also showed anti-inflammatory (superior to phenylbutazone) and antipyretic (superior to aspirin) activity.
Ketorolac was 37 times more active than aspirin in inhibiting collagen-induced aggregation of human platelets.
Ketorolac has no effect on the Central Nervous System; the effects on the cardiovascular and respiratory systems are minimal.
From the clinical studies it emerged that the analgesic activity of ketorolac 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; with glafenine 400 mg, with ibuprofen 400 mg, with diclofenac 50 mg.
Ketorolac 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.
Ketorolac administered i.m. at the dose of 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.
Ketorolac has no morphine-like effects, does not cause respiratory depression and, compared to morphine, the incidence of central nervous system side effects (somnolence) is significantly lower.
05.2 Pharmacokinetic properties
Absorption
KEVINDOL 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% oral solution were found to be bioequivalent in terms of AUC and half-life.
Likewise, after intramuscular administration of 30 mg, KEVINDOL 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 KEVINDOL 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 ketorolac.
Distribution
The plasma protein binding of ketorolac is 99%.
Therapeutic concentrations of digoxin, warfarin, ibuprofen, naproxen, piroxicam, acetaminophen, phenytoin and tolbutamide do not alter the protein binding of ketorolac.
The 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 ketorolac and its metabolites is via the urine and the remainder is eliminated in the faeces. The 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
Studies of: teratogenesis in the rat (10 mg / kg) and in the rabbit (3.6 mg / kg), peri-postnatal (9 mg / kg) and fertility (16 mg / kg female, 9 mg / kg male) in the rat , did not show teratogenic effects or changes in fertility and reproductive capacity.
Prolonged pregnancy and / or maternal dystocia and subsequent perinatal mortality were noted in the rat at higher doses.
Mutagenesis, carcinogenesis, tolerability
Ketorolac 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
KEVINDOL 30 mg solution for injection: Ethyl alcohol, sodium chloride, water for injections.
KEVINDOL 20 mg / ml oral drops, solution:
citric acid anhydrous, sodium dihydrogen phosphate dihydrate, methyl parahydroxybenzoate, propyl parahydroxybenzoate, sodium hydroxide, purified water.
06.2 Incompatibility
KEVINDOL is compatible with aminophylline, xylocaine, morphine, meperidine, dopamine, insulin and heparin administered simultaneously in solution contained in a drip bag for i.v. administration, but cannot be mixed with morphine, meperidine, promethazine or hydroxyzine in a syringe.
06.3 Period of validity
2 years.
Shelf life after opening the bottle of oral solution drops:
The shelf life after first opening the bottle is 6 months.
Shelf-life after reconstitution of the solution for injection:
In accordance with the rules of good pharmaceutical practice, the intravenous solutions must be prepared at the time of infusion. The reconstituted solution must be used immediately and any residues discarded.
06.4 Special precautions for storage
Store in the original packaging to protect the product from light.
06.5 Nature of the immediate packaging and contents of the package
KEVINDOL 30 mg / ml solution for injection: amber type I glass vials; pack of 3 ampoules of 1 ml
KEVINDOL 20 mg / ml oral drops solution: 10ml amber type III glass bottle.
06.6 Instructions for use and handling
No special instructions.
07.0 MARKETING AUTHORIZATION HOLDER
So.Se.PHARM S.r.l. Via dei Castelli Romani, 22 - 00040 Pomezia (Rome).
08.0 MARKETING AUTHORIZATION NUMBER
KEVINDOL 30 mg / mI solution for injection - 3 ampoules 1 ml A.I.C. n. 037746017
KEVINDOL 20mg / ml oral drops solution - bottle 10 ml A.I.C. n. 037746029
09.0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION
First authorization: 29 January 2009
Unlimited Renewal: January 29, 2014
10.0 DATE OF REVISION OF THE TEXT
AIFA Determination of May 18, 2015
