LIXIDOL - PACKAGE LEAFLET - LEAFLETS

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Lixidol - Package Leaflet

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

Active ingredients: Ketorolac (ketorolac trometamine)

Lixidol 10 mg film-coated tablets
Lixidol 20 mg / ml oral drops solution

Lixidol package inserts are available for pack sizes:

Lixidol 10 mg film-coated tablets, Lixidol 20 mg / ml oral drops solution
Lixidol 30 mg / ml solution for injection

Why is Lixidol used? What is it for?

Lixidol contains the active substance ketorolac tromethamine belonging to a group of medicines known as non-steroidal anti-inflammatory drugs (NSAIDs) used to reduce inflammation and pain.

Lixidol is indicated in adults and adolescents over 16 years of age only for the short-term (maximum 5 days) treatment of moderate pain after surgery.

Contraindications When Lixidol should not be used

Do not take Lixidol

if you are allergic to ketorolac trometamine or any of the other ingredients of this medicine (listed in section 6);
if you are allergic to other substances similar to ketorolac trometamine;
if you have had an allergic reaction in the past after using acetylsalicylic acid (medicine to treat inflammation, pain, fever and to thin the blood) and / or other non-steroidal anti-inflammatory drugs (NSAIDs). This is to avoid the risk of severe allergic reactions;
if you have lumps inside the nose (nasal polyposis);
if you have ever had swelling of the hands, feet, ankles, face, lips, tongue and / or throat (angioedema);
if you have difficulty breathing (bronchospasm);
if you suffer from asthma;
if you have or have had stomach or bowel problems such as active peptic ulcer (injury to the stomach and the first part of the intestine); gastrointestinal bleeding, ulceration or perforation;
if you have severe heart problems (heart failure);
if you have suffered in the past, are suffering or suspect that you are suffering from bleeding in the brain;
if you have a decrease in the volume of blood in your circulation (hypovolaemia);
if you suffer from dehydration (severe loss of water from the body);
if you have kidney problems (moderate or severe kidney failure);
if you are at risk of kidney problems (kidney failure) due to low blood volume or dehydration;
if you have severe liver problems (liver cirrhosis or severe hepatitis);
if you have a predisposition to blood loss (haemorrhagic diathesis);
if you suffer from bleeding problems (bleeding disorders)
if you are taking or are being treated with the following medicines (see section "Other medicines and Lixidol"):
- other non-steroidal anti-inflammatory drugs (NSAIDs), including high-dose acetylsalicylic acid
- anticoagulants
- lithium salts (medicines used to treat depression and mental disorders)
- probenecid (to treat gout)
- pentoxifylline (for blood circulation)
- intensive diuretic therapy (medicines used to facilitate the elimination of fluids in the urine);
you are about to undergo surgery;
if you have recently undergone surgery with a high risk of bleeding
if you are in the last 3 months of pregnancy, near or during childbirth (see "Pregnancy, breastfeeding and fertility")
if you are breastfeeding.

Lixidol should not be given to children and adolescents under the age of 16

This medicine is not indicated for mild or chronic pain.

Precautions for use What you need to know before taking Lixidol

Talk to your doctor or pharmacist before taking Lixidol.

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

Your doctor will prescribe the dose and duration of the minimum therapy suited to your problem, in order to reduce the occurrence of side effects.

In particular, tell your doctor:

if you have or think you have fertility problems and are planning to become pregnant (see section "Pregnancy, breast-feeding and fertility");
if you have / have had inflammation of the stomach and intestines, because in this case the treatment with Lixidol should only take place under strict medical supervision;
if you have suffered in the past from peptic ulcer (injury to the stomach and the first part of the intestine), especially if complicated by bleeding or perforation, as there is a risk that these disorders may recur, especially with high doses of the medicine. In these cases, your doctor may prescribe medicines to protect your stomach and intestines (misoprostol or proton pump inhibitors) and / or start treatment with low doses of Lixidol (see section 3 "Do not take Lixidol"). If you experience any stomach side effect, especially at the start of treatment, tell your doctor immediately who will stop treatment with Lixidol (see section 4 "Possible side effects");
if you have suffered in the past from severe chronic bowel disease (ulcerative colitis, Crohn's disease), as these diseases can get worse;
if you have suffered from asthma in the past or are prone to asthma attacks, as it increases the risk of having bronchospasm attacks (narrowing of the bronchi which causes severe breathing difficulties) or other severe allergic reactions;
if you have suffered in the past from bronchospasm (difficulty in breathing), nasal polyps (lumps that form inside the nose), angioedema (swelling of the hands, feet, ankles, face, lips, tongue and / or throat), as the risk of allergic reactions increases.If you experience any allergic reaction, please inform your doctor immediately who will stop treatment with Lixidol (see section 4 "Possible side effects");
if you suffer or have suffered in the past from hypertension (high blood pressure) and / or heart problems (mild to moderate heart failure), as this increases the risk of having a tendency to retain fluid in the body and edema (swelling due to accumulation of liquids);
if you have or have suffered from heart problems, or have had a heart attack or stroke (sudden closure or rupture of a blood vessel in the brain) or think you may be at risk (for example if you have high blood pressure, diabetes or cholesterol high or smoke); In these cases, the risk of heart attack or stroke may increase;
if you have kidney problems (impaired kidney function) and / or have suffered from kidney disease in the past, as this increases the risk of having side effects on the kidneys;
if you suffer from hypovolaemia (reduced volume of blood circulating) and / or reduced blood flow to the kidneys, as this increases the risk of having side effects in the kidneys;
if you have or have suffered in the past from liver problems (reduced liver function). In this case the doctor will keep you under control with appropriate tests to evaluate the functionality of the liver. If you experience severe liver impairment, tell your doctor immediately who will stop treatment with Lixidol (see section 4 "Possible side effects")
if you have a blood clotting disorder, as this medicine may increase the risk of bleeding

Attention:

Lixidol is not a simple pain reliever and its use requires close medical supervision.
The use of ketorolac may be associated with a higher risk of severe toxicity to the stomach and intestines, compared to other non-steroidal anti-inflammatory drugs (NSAIDs), especially when used outside the intended indications (see section 1 "What is "is Lixidol and what it is used for") and / or for prolonged periods. Your doctor will ask you before starting Lixidol therapy if you have ever had an allergic reaction to ketorolac, acetylsalicylic acid and / or other non-steroidal anti-inflammatory drugs (NSAIDs) ).

Before taking this medicine tell your doctor:

if you are taking medicines that can cause stomach or bowel problems (oral corticosteroids, selective serotonin re-uptake inhibitors), medicines that help eliminate fluid in the urine (diuretics) and medicines that interfere with blood clotting ( see section "Other medicines and Lixidol").

Interactions Which drugs or foods can modify the effect of Lixidol

Tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines.

In particular, tell your doctor if you are taking the following medicines.

Medicines not to be taken together with Lixidol (see section "Do not take Lixidol")

other non-steroidal anti-inflammatory drugs (NSAIDs), including 'acetylsalicylic acid and' selective cyclooxygenase-2 (COX-2) inhibitors' (a class of NSAIDs), because they increase the risk of side effects;
anticoagulants (medicines used to thin the blood and prevent clots) including warfarin and low-dose heparin given as a preventative measure, as they can cause bleeding;
lithium salts (used to treat depression and mental disorders), as it can increase the toxicity of these medicines;
probenecid (medicine used to treat gout), as it increases the time and amount of Lixidol in the blood, causing an increase in side effects;
pentoxifylline (medicine that improves blood flow), as it may increase the risk of bleeding.

Medicines to be used with caution

medicines that may increase the risk of side effects affecting the stomach and intestines (injury and bleeding), such as:
- oral corticosteroids (medicines to treat inflammation and allergies)
- selective serotonin re-uptake inhibitors (medicines to treat anxiety and behavioral disorders)
- methotrexate (a medicine used to treat some cancers and autoimmune diseases)
diuretics (such as furosemide) and medicines used to treat high blood pressure (angiotensin converting enzyme inhibitors and angiotensin II antagonists)
pain relievers (analgesics)

Lixidol with food

Note that a high fat meal may delay the effect of ketorolac by approximately 1 hour.

Warnings It is important to know that:

Elderly (65 years of age or older) and / or debilitated

If you are elderly and / or debilitated you may have an increased frequency of side effects, especially bleeding and perforation of the stomach and intestines, which can be fatal (see section 4 "Possible side effects"). In this case your doctor may decide to reduce the dose or increase the time interval between doses (see section "How to use Lixidol")

Your doctor may also prescribe medicines to protect your stomach and intestines (misoprostol or proton pump inhibitors).

Also, if you are elderly and have kidney problems, you may have a higher risk of experiencing possible side effects affecting the kidneys.

There have been reports of bruising (hematoma) after surgery (postoperative period) and bleeding from wounds following the use of Lixidol before or after surgery (perioperative period). Therefore tell your doctor if you need to undergo to surgical removal of the tonsils, prostate surgery (prostate resection) or cosmetic surgery.

Children and adolescents

Do not give Lixidol to children and adolescents under 16 years of age, as safety and efficacy in children and adolescents under 16 years of age have not been established (see section "Do not take Lixidol").

Pregnancy, breastfeeding and fertility

If you are planning to become pregnant ask your doctor or pharmacist for advice before taking this medicine.

Pregnancy

Do not take Lixidol if you are in the last trimester of pregnancy, during labor and delivery (see section "Do not take Lixidol").

Your doctor may prescribe Lixidol in the first 6 months of pregnancy, only if strictly necessary.

In this case, your doctor will prescribe the lowest dose and the shortest possible duration of treatment.

Feeding time

Do not take Lixidol if you are breast-feeding (see section "Do not take Lixidol").

Fertility

The use of Lixidol, as with any medicine similar to Lixidol, is not recommended in women who intend to become pregnant. Therefore, if you are of childbearing age, your doctor will advise you to exclude a possible pregnancy, therefore before the start of treatment and during the treatment he will advise you on the use of contraceptives (methods for avoiding pregnancy).

If you have or think you have fertility problems, your doctor may have you stop taking Lixidol.

Driving and using machines

Lixidol can make you sleepy, dizzy, sleepless or depressed. If you experience these symptoms, avoid driving and using machines.

Lixidol contains lactose

If you have been told by your doctor that you have an intolerance to some sugars (such as lactose), contact your doctor before taking this medicinal product.

Dosage and method of use How to use Lixidol: Dosage

Always take this medicine exactly as your doctor or pharmacist has told you. If in doubt, consult your doctor or pharmacist.

Using the lowest dose for the shortest possible treatment duration needed to control symptoms reduces side effects.

Adults

The recommended dose is 10 mg (1 tablet) every 4-6 hours, as determined by your doctor.
Your doctor will reduce your dose appropriately if you weigh less than 50 kg.
The maximum dose is 40 mg / day (4 tablets).
Do not exceed the dose and duration of treatment prescribed by your doctor, especially if you have or have suffered from heart problems, or have had a heart attack or stroke.
If you need to switch to oral Lixidol therapy, your doctor will advise you on the dose to take on the changeover day.

If you are elderly (age 65 or over)

If you are elderly, your doctor will evaluate a possible reduction in the dosages indicated above and an increase in the interval between doses.

Use in children and adolescents

The use of Lixidol is contraindicated in children and adolescents under the age of 16 years.

Duration of treatment

Do not exceed 5 days of treatment.

If you forget to take Lixidol

Do not take a double dose to make up for a forgotten dose.

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 Lixidol

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

Symptoms

If you take too much Lixidol you may experience the following symptoms:

erosive gastritis (inflammation of the stomach characterized by the flaking of the lining of the stomach), pain in the stomach, peptic ulcer (stomach injury), abdominal pain which disappears when treatment is stopped
stomach and intestinal bleeding
hypertension (high blood pressure)
acute kidney failure (decreased kidney function)
respiratory depression (reduction and / or block of breathing)
coma
severe allergic reactions.

Side Effects What are the side effects of Lixidol

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

If you experience any of the following side effects, contact your doctor or the nearest hospital immediately:

Allergic reactions, such as:
- anaphylactic reactions (allergic reactions which can be fatal)
- bronchospasm (narrowing of the bronchi which causes severe breathing difficulties due to a reduced passage of air)
- vasodilation (increase in the caliber of blood vessels which causes a decrease in blood pressure)
- hot flashes
- rash (skin eruptions)
- hypotension (low blood pressure)
- laryngeal edema (swelling of the throat).
haematemesis (bleeding in the stomach which manifests itself in the presence of blood in the vomit or dark parts that look like coffee grounds
melaena (sticky black stools or bloody diarrhea)
peptic ulcers, ulcers or perforations or gastrointestinal bleeding
pancreatitis (pancreas problems)
worsening of ulcerative colitis or Crohn's disease
hepatitis (inflammation of the liver)
cholestatic jaundice (yellowing of the skin and whites of the eyes)

Other undesirable effects with a frequency not known (the frequency of which cannot be estimated from the available data) are:

thrombocytopenia (reduction in the number of platelets in the blood)
purpura (appearance of red patches on the skin due to accumulation of blood under the skin)
epistaxis (nose bleeding)
anorexia (weight loss)
hyperkalaemia (high levels of potassium in the blood)
hyponatremia (low levels of sodium in the blood)
abnormal thinking (thought disorder)
depression
insomnia
anxiety
irritability
nervousness
psychotic reactions (mental disorders, resulting in a loss of relationship with reality)
sleep disorders
hallucinations (perception of things that do not exist in reality)
euphoria
reduced ability to concentrate
lethargy (physical or mental listlessness)
confusion
headache
dizziness
seizures and hyperkinesis (uncontrolled body movements)
paraesthesia (numbness in the arms, legs or other parts of the body)
changes in taste
abnormal vision
swelling around the eyes
tinnitus (ringing in the ears)
hearing loss
dizziness
palpitations (feeling of increased heartbeat)
bradycardia (decrease in heart rate, i.e. the number of heart beats per minute)
heart failure (reduced heart function)
edema (fluid buildup)
hypertension (high blood pressure)
vasodilation (increase in the caliber of blood vessels which causes a decrease in blood pressure)
hypotension (low blood pressure)
hematomas (accumulation of blood under the skin that appears as a bruise-like patch on the skin)
flushing
pallor
postoperative wound bleeding
risk of blood clot formation, especially at high doses and for long-term treatments which (arterial thrombotic events) can cause e.g. heart attack or stroke
pulmonary edema (accumulation of fluid in the lungs)
wheezing (shortness of breath)
asthma
nausea
He retched
diarrhea
flatulence (emission of air from the intestine)
constipation
dyspepsia (stomach upset)
belly pain / discomfort
sense of fullness
bleeding from the rectum
ulcerative stomatitis (infections of the oral cavity)
esophagitis (inflammation of the esophagus, the tube that carries food from the mouth to the stomach)
belching
dry mouth
gastrointestinal ulceration
gastritis (inflammation of the stomach)
liver failure (impaired liver function)
angioedema
exfoliative dermatitis
increased sweating
maculo-papular rash (skin rash that presents with flat or raised red patches on the skin)
hives (redness of the skin accompanied by itching)
itch
purpura (appearance of red patches on the skin due to accumulation of blood under the skin)
bullous reactions (including very rarely Stevens-Johnson syndrome and toxic epidermal necrolysis)
myalgia (muscle pain)
polyuria (excessive production and elimination of urine) - increased frequency to urinate
oliguria (decreased urine output)
uraemic-haemolytic syndrome (syndrome characterized by the presence of disorders in the blood and kidneys)
kidney disease (acute renal failure, interstitial nephritis, nephrotic syndrome)
urinary retention (inability of the urinary bladder to empty completely)
flank pain
increase of creatinine in the blood (a protein whose increase indicates the presence of reduced function of the kidneys)
increased potassium in the blood (sign of impaired kidney function)
female infertility
aseptic meningitis (infection with e.g. pain, drowsiness, fever, general malaise, headache, nausea, vomiting)
tiredness
fever
edema (swelling)
chest pain
excessive thirst
weight gain
increased bleeding time
increased blood urea
increase in creatinine and potassium in the blood
abnormal tests to evaluate liver function.

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. You can also report side effects directly via the national reporting system at www.agenziafarmaco.gov.it/it/responsabili. By reporting side effects you can help provide more information on the safety of this medicine.

Expiry and Retention

Keep this medicine out of the sight and reach of children.

Do not use this medicine after the expiry date which is stated on the carton after EXP. The expiry date refers to the last day of that month.

Store in the original package to protect from light and moisture.

Do not throw any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. This will help protect the environment.

Deadline "> Other information

What Lixidol contains

the active ingredient is: ketorolac trometamine (each tablet contains 10 mg of ketorolac trometamine)
the other ingredients are: microcrystalline cellulose, lactose (see section "Lixidol contains lactose"), magnesium stearate, hypromellose, titanium dioxide, macrogol 8000.

What Lixidol looks like and contents of the pack

Lixidol are round, off-white tablets packed in blisters of 10 tablets.

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.

More information on Lixidol 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 interaction - 04.6 Pregnancy and lactation - 04.7 Effects on the ability to drive and use machines - 04.8 Undesirable effects - 04.9 Overdose - 05.0 PHARMACOLOGICAL PROPERTIES - 05.1 "Pharmacodynamic properties - 05.2 Pharmacokinetic properties" - 05.3 Preclinical safety data - 06.0 PHARMACEUTICAL PARTICULARS - 06.1 Excipients - 06.2 Incompatibility "- 06.3 Shelf life" - 06.4 Special precautions for storage - 06.5 Nature of the primary packaging and contents of the package - 06.6 Instructions for use and handling - 07.0 AUTHORIZATION HOLDER ALL "PLACING ON THE MARKET - 08.0 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 RADIO DRUGS, COMPLETE DATA ON INTERNAL RADIATION DOSIMETRY - 12.0 INSTRUCTIONS FOR RADIOPHONES ON EXTEMPORARY PREPARATION AND QUALITY CONTROL -

01.0 NAME OF THE MEDICINAL PRODUCT -

LIXIDOL

02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION -

Lixidol 10 mg film-coated tablets

Each film-coated tablet contains: ketorolac trometamine 10 mg.

Excipients: Lactose

Lixidol 30 mg / ml solution for injection

Each ampoule contains: ketorolac trometamine 30 mg.

Excipients: Ethanol

For the full list of excipients, see section 6.1.

03.0 PHARMACEUTICAL FORM -

Lixidol is available as film-coated tablets, solution for injection for IM use. or i.v.

04.0 CLINICAL INFORMATION -

04.1 Therapeutic indications -

Lixidol film-coated tablets

Lixidol is only indicated for the short-term (maximum 5 days) treatment of moderate post-operative pain.

Lixidol solution for injection

Lixidol 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 Lixidol can be used as a complement to an opioid analgesic.

Lixidol 30 mg / ml solution for injection is also indicated in the treatment of pain due to renal colic.

04.2 Posology and method of administration -

Lixidol film-coated tablets

Warning: The treatment duration should not exceed 5 days.

ADULTS

Undesirable effects can be minimized by using the lowest effective dose for the shortest possible duration of treatment needed to control symptoms (see section 4.4).

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.

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).

Lixidol 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.

Undesirable effects can be minimized by using the lowest effective dose for the shortest possible duration of treatment needed to control symptoms (see section 4.4).

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 other closely related substances from a chemical point of view and / or to any of the excipients.

- Due to the possibility of cross-sensitivity Lixidol 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-type 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.

- Patients with moderate or severe renal insufficiency (serum creatinine> 442 μmol / l) or patients at risk of renal insufficiency due to hypovolaemia or dehydration.

- Cirrhosis of the liver or severe hepatitis.

- Hemorrhagic diathesis.

- Coagulation disorders.

- Patients on anticoagulant therapy.

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

- 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 Lixidol is contraindicated during the third trimester of pregnancy, labor, delivery and during lactation (see section 4.6).

Warning: the solution for injection contains ethanol therefore use by neuraxial route (epidural or intrathecal) is contraindicated.

04.4 Special warnings and appropriate precautions for use -

Warning: Lixidol 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 sections 4.1, 4.2 and 4.3).

The concomitant use of Lixidol with other non-steroidal anti-inflammatory drugs (NSAIDs), including selective cyclooxygenase-2 (COX-2) inhibitors, should be avoided.

Undesirable effects can be minimized with the use of the lowest effective dose for the shortest possible duration of treatment needed to control symptoms (see section 4.2 and the paragraphs below on gastrointestinal and cardiovascular risks).

Before initiating Lixidol therapy, it must 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 Lixidol is not addictive. No withdrawal symptoms have been observed following an abrupt discontinuation of injectable Ketorolac.

Fertility related precautions:

The use of Lixidol, as with any prostaglandin synthesis and cyclooxygenase inhibitor drug, is not recommended for women intending to become pregnant.

Lixidol administration should be discontinued in women who have fertility problems or who are undergoing fertility investigations. In women who have difficulty conceiving or who are undergoing examination for infertility, discontinuation of ketorolac should be considered.

Use in the 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. In elderly subjects, there may also be an increase in the elimination half-life of the drug and a simultaneous reduction in clearance. Therefore, in addition to a reduction in the overall dose, a longer interval between doses may be appropriate (see section 4.2).

Gastrointestinal Effects Lixidol 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. The risk of clinically severe gastrointestinal bleeding is dose-dependent, especially in elderly patients receiving a mean daily dose of more than 60 mg / day of Ketorolac injection. A history of peptic ulcer increases the possibility of developing serious gastrointestinal complications during therapy with ketorolac.

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

Gastrointestinal ulcer, bleeding and perforation Gastrointestinal bleeding, ulceration and perforation, which can be fatal, have been reported at any time during treatment with all NSAIDs, 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

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 re-uptake inhibitors or antiplatelet agents such as aspirin (see section 4.5).

When gastrointestinal bleeding or ulceration occurs in patients taking Lixidol, 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.

Anaphylactic (anaphylactoid) reactions Anaphylactic reactions (including but not limited to anaphylaxis, bronchospasm, flushing, rash, hypotension, larynx 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, Lixidol 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 Adequate monitoring and instruction are required 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 treatment.

Clinical studies and epidemiological data suggest that the use of selective cyclooxygenase-2 inhibitors and some NSAIDs (especially at high doses and for long-term treatment) may be associated with a slightly increased risk of arterial thrombotic events (eg heart attack 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, established ischemic heart disease, peripheral arterial disease and / or cerebrovascular disease should only be treated with keterolac after careful consideration. Similar considerations should be made before initiating long-term treatment in patients with risk factors for cardiovascular disease (e.g. hypertension, hyperlipidaemia, diabetes mellitus, 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, and may 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, the 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 impaired renal function. states of kidney hypoperfusion, 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 of the pre-treatment state.

In particular, the use of Lixidol is contraindicated in patients with serum creatinine values greater than 1.8 mg / dl.

The drug is contraindicated in intensive diuretic therapy

Patients with impaired renal function

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

The drug is contraindicated in intensive diuretic therapy.

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

Due to the potential water retention effect, Lixidol 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.

Ketorolac should not be administered concomitantly with probenecid, as alterations in the pharmacokinetics of the drug have been reported with this combination.

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

Patients with impaired liver function

Use in patients with impaired hepatic function: Patients with impaired hepatic function due to cirrhosis do not experience any clinically important changes in the clearance or half-life of ketorolac. Borderline elevations of one or more liver function tests may occur. These abnormalities may be transient. , remain unchanged, or progress with continued therapy. Significant serum elevations (more than 3 times above normal) of glutamate pyruvate transaminase (SGPT / ALT) or glutamate oxaloacetate transaminase (SGOT / AST) occurred in less than "1% of patients. Lixidol should be discontinued if consistent clinical signs and symptoms of liver disease develop or if systemic manifestations occur.

Haematological Effects Lixidol inhibits platelet function and may prolong bleeding time.

Lixidol should not be administered to patients with coagulation disorders or to patients treated with drugs that interfere with haemostasis, including warfarin and low-dose heparin (2500-5000 IU) administered 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 Lixidol 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 i patients appear to be at higher risk: the onset of the reaction occurs in most cases within the first month of treatment. Lixidol should be discontinued at the first appearance of skin rash, mucosal lesions or any other signs of hypersensitivity.

The film-coated tablets contain lactose therefore patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency, or glucose-galactose malabsorption should not take this medicine.

The solution for injection contains small amounts of ethanol (alcohol) less than 100 mg per dose.

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 Lixidol and other non-steroidal anti-inflammatory drugs should be avoided.

Concomitant use of Lixidol and corticosteroids increases the risk of gastrointestinal ulceration or bleeding (see section 4.4).

Concomitant use of Lixidol and antiplatelet agents and selective serotonin re-uptake inhibitors (SSRIs) increases the risk of gastrointestinal bleeding (see section 4.4).

NSAIDs may amplify the effects of anticoagulants, such as warfarin (see section 4.4). Lixidol 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 Lixidol treatment. . In vitro Lixidol causes a negligible reduction in the binding of warfarin to plasma proteins. Ketorolac does not modify the protein binding of digoxin. In vitro studies indicate that, at therapeutic concentrations of salicylate (300 mcg / 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. As with other drugs that inhibit prostaglandin synthesis, the concomitant administration of Lixidol 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.

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. 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), 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 Lixidol 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.

Ketorolac should not be administered concomitantly with pentoxifylline as it may increase the risk of bleeding.

Ketorolac should not be administered concomitantly with probenecid as the concomitant administration of probenecid and Lixidol leads to decreased clearance of the latter and consequently to higher and prolonged plasma concentrations.

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

Oral administration of Lixidol 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.

For incompatibilities see section 6.2.

04.6 Pregnancy and breastfeeding -

The use of Lixidol is contraindicated during the third trimester of pregnancy, labor, delivery and during lactation (see section 4.4).

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

During the first and second trimester of pregnancy, Lixidol should not be administered unless strictly necessary.

If Lixidol is administered to women intending to become pregnant or during the first or second trimester of pregnancy, the dose should be the lowest 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.

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

Consequently, ketorolac is contraindicated during the third trimester of pregnancy.

Ketorolac should only be given as needed during the first two trimesters of pregnancy.

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 because, 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 :

Lixidol and its metabolites have been shown to be able to pass into the fetal circulation and into the milk of experimental animals.

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

Fertility:

The use of Lixidol, as with any prostaglandin synthesis and cyclooxygenase inhibitor drug, is not recommended for women intending to become pregnant.

Lixidol administration 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 -

Lixidol, while having no narcotic effect or central nervous system effect, may cause some patients to feel drowsy, dizzy, insomnia or depressed.

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

04.8 Undesirable effects -

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.

Disorders of the immune system: anaphylaxis; anaphylactoid reactions, such as anaphylaxis, can have a fatal outcome; hypersensitivity reactions (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 dream activity, hallucinations, euphoria, reduced ability to concentrate, lethargy, confusion.

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

Eye disorders: abnormal vision, swelling around the eyes

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) 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 system: the most commonly observed adverse events are gastrointestinal in nature. Peptic ulcers, ulcer, 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, flatulence, gastrointestinal ulceration, pancreatitis, have been reported following administration of Lixidol. 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, 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 haematuria ± azotemia). As with other drugs that inhibit prostaglandin synthesis, signs of kidney failure, such as increases in creatinine and potassium

Diseases of the reproductive system and breast: female infertility.

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

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

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 -

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.

Treatment

There are no specific antidotes. If necessary, symptomatic and supportive therapy should be adopted. 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 eliminate ketorolac from the bloodstream significantly.

05.0 PHARMACOLOGICAL PROPERTIES -

05.1 "Pharmacodynamic properties -

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

ATC code: M01AB15.

The active ingredient of Lixidol 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.

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

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

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

Clinical studies showed that the analgesic activity of Lixidol 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.

Lixidol 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.

Lixidol 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.

Lixidol 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

Lixidol 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, Lixidol 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 Lixidol 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. administration.

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

The intake of antacids does not affect the absorption of Lixidol.

Distribution

The plasma protein binding of keterolac is 99%.

Therapeutic concentrations of digoxin, warfarin, ibuprofen, naproxen, piroxicam, acetaminophen, phenytoin and tolbutamide do not alter the protein binding of Lixidol.

The volume of distribution is 0.11 l / kg.

Metabolism

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

Elimination

The major route of elimination for Lixidol and its metabolites is via urine and the remainder is eliminated in the faeces. Renal clearance of keterolac 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

Prolonged pregnancy and / or maternal dystocia and subsequent perinatal mortality were noted in the rat at higher doses.

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 -

Lixidol 10 mg film-coated tablets

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

Lixidol 30 mg / ml solution for injection

ethanol, sodium chloride, water for injections.

06.2 Incompatibility "-

Lixidol 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.