PATROL - PACKAGE LEAFLET - LEAFLETS

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Patrol - Package Leaflet

Indications Contraindications Precautions for use Interactions Warnings Dosage and method of use Overdose Undesirable Effects Shelf life and Storage Composition and pharmaceutical form

Active ingredients: Tramadol (Tramadol hydrochloride), Paracetamol

PATROL 37.5 mg / 325 mg film-coated tablets
PATROL 37.5 mg / 325 mg effervescent tablets

Why is Patrol used? What is it for?

PHARMACOTHERAPEUTIC CATEGORY

Analgesics, other opioids

THERAPEUTIC INDICATIONS

PATROL is indicated for the symptomatic treatment of acute mild to moderate pain.

Contraindications When Patrol should not be used

Hypersensitivity to the active substances or to any of the excipients
Acute alcohol intoxication
Taking hypnotic drugs, central analgesics, opioids or psychotropic substances - PATROL must not be given to patients who are being treated with antidepressant drugs (monoamine oxidase inhibitors) or who have taken them within the last 2 weeks (see "Interactions")
Severe hepatic insufficiency
Epilepsy not controlled by treatment (see "Special warnings")
Patients with severe haemolytic anemia

Precautions for use What you need to know before taking Patrol

Physical and / or psychological tolerance and dependence may develop, even at therapeutic dosages. The clinical need for analgesic treatment should be reassessed at regular intervals (see "Dose, method and time of administration"). In opioid-dependent patients and in patients with a previous history of drug abuse or dependence, treatment should be given for short periods and under medical supervision.

PATROL should be used with caution in patients with head trauma, in patients with a tendency to seizure, biliary tract disorders, in shock, in patients with changes in consciousness of unknown causes, in patients with severe respiratory disorders (disorders center of breath or respiratory function), in patients with increased intracranial pressure.

Symptoms of a withdrawal reaction, similar to those that occur during opioid detox, can also occur at therapeutic dosages and with treatments conducted for short periods of time (see "Undesirable Effects"). Withdrawal symptoms can be avoided by gradually reducing the dose upon discontinuation of therapy, especially after long periods of treatment.

In some patients, paracetamol overdose can cause liver toxicity.

At therapeutic dosages, tramadol has the potential to cause withdrawal symptoms.

Cases of dependence and abuse have rarely been reported (see "Undesirable Effects").

Withdrawal symptoms, similar to those induced by opioids, are: agitation, anxiety, nervousness, insomnia, hyperkinesis, tremor and gastrointestinal symptoms. Other symptoms, very rarely seen after abrupt discontinuation of tramadol, include: panic attacks, severe anxiety, hallucinations, paraesthesia, tinnitus and unusual CNS symptoms.

The use of the product should be avoided during anesthesia.

Interactions Which drugs or foods can modify the effect of Patrol

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

The concomitant use of:

Non-selective monoamine oxidase inhibitors, for the risk of serotonin syndrome: diarrhea, tachycardia, sweating, tremors, confusion and coma.
Selective monoamine oxidase A inhibitors, for the risk of serotonin syndrome: diarrhea, tachycardia, sweating, tremors, confusion and coma.
Selective monoamine oxidase B inhibitors, for the onset of central excitation symptoms evoking a serotonin syndrome: diarrhea, tachycardia, sweating, tremors, confusion and coma. In case of recent monoamine oxidase inhibitor therapy, 2 weeks should elapse before treatment with tramadol.

The concomitant use of:

Alcohol: Alcohol increases the sedative effect of opioid analgesics. The effect on alertness can make driving vehicles or using machines dangerous. Avoid the intake of alcoholic beverages and medicines containing alcohol.
Carbamazepine and other enzyme inducers, due to a reduction in efficacy and a shorter duration of action, due to a decrease in plasma concentrations of tramadol.
Opioid agonist-antagonists (buprenorphine, nalbuphine, pentazocine), for the reduction of the analgesic effect following the competitive block of receptors, with the risk of the onset of withdrawal syndrome.

The risk of side effects increases:

If you are taking medicines that can cause fits (fits), such as certain antidepressants or antipsychotics. The risk of having a seizure may increase if you take PATROL at the same time. Your doctor will tell you if PATROL is suitable for you.
if you are taking certain antidepressants. PATROL can interact with these drugs and may experience symptoms such as: involuntary rhythmic contractions of the muscles, including the muscles that control the movement of the eyes, agitation, excessive sweating, tremor, exaggerated reflexes, increased muscle tension, body temperature above 38 ° C ..
Other opioid derivatives (including antitussive drugs and substitution treatments), benzodiazepines and barbiturates: increase the risk of respiratory depression which can be fatal in the event of an overdose.
Other central nervous system sedative drugs such as opioid derivatives (including antitussive drugs and replacement treatments), barbiturates, benzodiazepines, other anxiolytics, hypnotics, sedative antidepressants, sedative antihistamines, neuroleptics, centrally acting antihypertensive drugs, thalidomide, baclofen. These drugs can cause increased central depression. The effect on alertness can make driving vehicles or using machines dangerous.
For proper clinical practice, periodic evaluation of prothrombin time should be performed if PATROL is used concomitantly with similar warfarin drugs, as increased INR values have been reported.
Other drugs known as CYP3A4 inhibitors, such as ketoconazole and erythromycin, may inhibit the metabolism of tramadol (N-dealkylation) and possibly also the metabolism of the active O-demethylated metabolite. The clinical relevance of this interaction has not been studied.
Drugs that lower the seizure threshold, such as bupropion, serotonin re-uptake inhibitor antidepressants, tricyclic antidepressants and neuroleptics. Concomitant use of tramadol with these drugs may increase the risk of seizures.
The absorption rate of paracetamol can be increased by metoclopramide and domperidone or reduced by cholestyramine.

Warnings It is important to know that:

In adults and children over 12 years of age, the maximum dosage of 8 PATROL tablets per day should not be exceeded. To avoid overdose problems, do not exceed the recommended dosage and do not use other medications containing acetaminophen (including over-the-counter products) or tramadol at the same time without a doctor's advice.
In case of severe renal insufficiency (creatinine clearance
In patients with severe hepatic impairment, PATROL should not be used (see "Contraindications"). The risk of paracetamol overdose is greater in patients with non-cirrhotic alcoholic liver disease. In case of moderate insufficiency, prolongation of the dosing interval should be carefully considered.
PATROL is not recommended in case of severe respiratory insufficiency.
Tramadol is not suitable for substitution treatment in opioid-dependent patients. Tramadol, although an opioid agonist, is unable to suppress morphine withdrawal symptoms.
Seizures have been observed in patients predisposed to or treated with drugs that can lower the seizure threshold, particularly selective serotonin re-uptake inhibitors, tricyclic antidepressants, antipsychotics, central analgesics or local anesthetics. Epileptic patients in good drug control or patients predisposed to seizures should only be treated with PATROL if absolutely necessary. Convulsions have been reported in patients receiving tramadol at recommended doses. The risk may increase if the recommended doses of tramadol are exceeded.
The concomitant use of opioid agonist-antagonists (nalbuphine, buprenorphine, pentazocine) is not recommended (see "Interactions").

PATROL effervescent tablets contain sunset yellow E110 which may cause allergic reactions.

Pregnancy and breastfeeding

Ask your doctor or pharmacist for advice before taking any medicine. You should not use PATROL during pregnancy due to the presence of tramadol. Its use should also be avoided in case of suspicion of pregnancy or if you wish to plan a maternity leave.

As tramadol passes into breast milk in small amounts, PATROL should not be used during breastfeeding.

Driving and using machines

Do not drive or use any tools or machines because tramadol can cause drowsiness and dizziness, particularly when the medicine is combined with alcohol or other CNS depressant drugs.

Dosage and method of use How to use Patrol: Dosage

Adults and adolescents (over 12 years of age)

The use of PATROL should be reserved for those patients in which the combination of tramadol and paracetamol is required for the treatment of pain. The dosage should be chosen based on the intensity of the pain and your personal sensitivity to pain. In general, the lowest pain-reducing dose should be taken.

PATROL film-coated tablets: The recommended starting dosage of PATROL is 2 tablets. If necessary, further doses of up to 8 tablets per day (equivalent to 300 mg of tramadol and 2600 mg of paracetamol) can be administered.

PATROL effervescent tablets: the recommended starting dosage of PATROL is 2 tablets. If necessary, further doses of up to 8 tablets per day (equivalent to 300 mg of tramadol and 2600 mg of paracetamol) can be administered. The effervescent tablets are dissolved in a glass of water.

The interval between administrations should not be less than 6 hours. PATROL should under no circumstances be administered for longer than strictly necessary (see also "Special warnings"). If, given the nature and severity of the disease, repeated or long-term analgesic treatment with PATROL is required, careful and regular monitoring (with treatment withdrawal periods when possible) should be performed to assess whether continuation of therapy is necessary.

Children

The safety and efficacy of PATROL have not been evaluated in children under the age of 12. Therefore, treatment is not recommended in this age group.

Elderly patients

In elderly people (over 75 years) the elimination of tramadol may be delayed. If this applies to you, your doctor may advise you to lengthen the time interval between one dose and the next.

Patients with severe hepatic or renal insufficiency / dialysis

Patients with severe hepatic and / or renal insufficiency should not take PATROL. In case of mild or moderate insufficiency, your doctor may advise you to lengthen the time interval between one dose and the next.

Since tramadol is removed very slowly by hemodialysis or haemofiltration, post dialysis administration is usually not required to maintain analgesia.

Patients with hepatic insufficiency

In patients with severe hepatic insufficiency, PATROL should not be used (see "Contraindications"). In case of moderate insufficiency, prolongation of the dosing interval should be carefully considered (see "Special warnings").

Overdose What to do if you have taken too much Patrol

OVERDOSE

In case of accidental ingestion / intake of an overdose of PATROL, notify your doctor immediately or go to the nearest hospital.

EFFECTS DUE TO THE SUSPENSION OF THE TREATMENT

The risk of a withdrawal syndrome after prolonged use is small, but it cannot be excluded (see "Undesirable Effects"). IF YOU HAVE ANY DOUBTS ABOUT THE USE OF PATROL, PLEASE ASK YOUR DOCTOR OR PHARMACIST.

Side Effects What are the side effects of Patrol

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

Very common side effects (reported in more than 10% of patients): nausea, dizziness, drowsiness.
Common side effects (1-10% of patients): vomiting, constipation, digestive problems, bloating, diarrhea, stomach pain, increased sweating, itching, dry mouth, headache, tremors, confusion, sleep disturbances, "mood (anxiety, nervousness, euphoria).
Uncommon side effects (0.1-1% of patients): heart rhythm disturbances (tachycardia, palpitations, arrhythmia), changes in blood pressure (hypertension), involuntary muscle contractions, tingling sensation in the limbs (paraesthesia), buzzing in the ear (tinnitus), difficulty urinating (dysuria and urinary retention), skin irritation (e.g. redness, hives), chills, flushing, chest pain, difficulty breathing (dyspnoea), depression, nightmares, hallucinations ( perception of things that do not exist in reality), memory loss, difficulty swallowing, blood in the stool.
At the biological level, an increase in the level of liver enzymes or the presence of albumin in the urine has been reported.
There have been reports of increased prothrombin time in patients taking concomitant anticoagulants (warfarin).
Rare side effects (less than 0.1% of patients): convulsions, ataxia (difficulty coordinating movements), speech disturbances, drug addiction, muscle weakness, altered appetite, blurred vision, allergic reactions, worsening of asthma. Syncope (transient loss of consciousness).
In some rare cases the skin reaction or allergic reaction can cause breathing problems. In this case, stop therapy immediately and consult your doctor.
In exceptional cases, biological changes have been reported, it is therefore necessary to do some blood tests: abnormal low levels of certain elements of the blood (blood dyscrasia), a lowering of platelet levels (thrombocytopenia) which can lead to nosebleeds or bleeding gums, or lowering of the number of white blood cells (agranulocytosis).
When abruptly interrupting a long period of treatment, in rare cases, there may be a withdrawal syndrome with anxiety, agitation, nervousness (insomnia in particular), tremors and gastrointestinal disturbances.
Side effects with frequency not known: decreased blood sugar level.

If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please tell your doctor or pharmacist.

Expiry and Retention

Keep PATROL out of the reach and sight of children.

Do not use PATROL after the expiry date which is stated on the label. The expiry date refers to the last day of the month.

PATROL film-coated tablets: the medicine does not require any special storage conditions.

PATROL effervescent tablets in blister packs: the medicine must be stored at a temperature not exceeding 25 ° C.

PATROL effervescent tablets in tube: the medicine must be stored at a temperature not exceeding 30 ° C. Shelf life after first opening the tube: 1 year.

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.

Composition and pharmaceutical form

COMPOSITION

PATROL film-coated tablets: one tablet contains:

Active ingredients: tramadol hydrochloride 37.5 mg, paracetamol 325 mg.

Excipients: pulverized cellulose, pregelatinised starch, sodium carboxymethyl starch, maize starch, magnesium stearate, Opadry yellow YS-1-6382 G [hypromellose, titanium dioxide (E 171), macrogol 400, yellow iron oxide (E 172), polysorbate 80 ], carnauba wax.

PATROL effervescent tablets: one tablet contains:

Active ingredients: tramadol hydrochloride 37.5 mg, paracetamol 325 mg.

Excipients: anhydrous sodium citrate, anhydrous citric acid, povidone K30, sodium bicarbonate, macrogol 6000, anhydrous colloidal silica, magnesium stearate, orange flavor, acesulfame potassium, sodium saccharin, sunset yellow E110

PHARMACEUTICAL FORM AND CONTENT

Film-coated tablets. Packs of 10, 16, 20, 30, 60 tablets.

Effervescent tablets. Packs of 10, 20, 30, 40 tablets in blister and tube.

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 about Patrol can be found in the "Summary of Features" 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 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 Incompatibilities 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 MARKETING AUTHORIZATION HOLDER 08.0 MARKETING AUTHORIZATION NUMBER CIO 09.0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION 10.0 DATE OF REVISION OF THE TEXT 11.0 FOR RADIO DRUGS, FULL DATA ON INTERNAL RADIATION DOSIMETRY 12.0 FOR RADIO DRUGS, FURTHER DETAILED INSTRUCTIONS ON PREPARATION AND QUALITY CONTROL

01.0 NAME OF THE MEDICINAL PRODUCT

PATROL 37.5 MG / 325 MG

02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION

One film-coated tablet contains: 37.5 mg of Tramadol hydrochloride and 325 mg of Paracetamol.

An effervescent tablet contains: 37.5 mg of Tramadol hydrochloride and 325 mg of Paracetamol.

Excipients: One effervescent tablet contains 0.4 mg of sunset yellow E110 and 7.8 mmol (or 179.4 mg) of sodium (as sodium citrate, sodium bicarbonate and sodium saccharin).

For the full list of excipients, see section 6.1.

03.0 PHARMACEUTICAL FORM

Film-coated tablets: pale yellow tablets.

Effervescent tablets: off-white to slightly pink tablets with colored patches, round in shape, with flat rounded edges.

04.0 CLINICAL INFORMATION

04.1 Therapeutic indications

PATROL is indicated for the symptomatic treatment of moderate acute pain.

04.2 Posology and method of administration

Dosage

Adults and adolescents (over 12 years of age)

The use of PATROL should be reserved for those patients in which the combination of tramadol and paracetamol is required for the treatment of pain.

The dosage should be adapted to the intensity of the pain and the individual sensitivity of the patient. In general, the minimum effective dose should be chosen.

PATROL film-coated tablets: the recommended starting dosage of PATROL is 2 tablets. If necessary, further doses of up to 8 tablets per day (equivalent to 300 mg of tramadol and 2600 mg of paracetamol) can be administered.

The interval between administrations should not be less than 6 hours.

Under no circumstances should PATROL be administered for longer than strictly necessary (see also section 4.4 "Special warnings and precautions for use"). If, given the nature and severity of the disease, repeated or long-term analgesic treatment with PATROL is required, careful and regular monitoring (with treatment withdrawal periods when possible) should be performed to assess whether continuation is necessary. of therapy.

Pediatric population

The safety and efficacy of PATROL have not been evaluated in children below 12 years of age. Hence, treatment is not recommended in this age group.

Elderly patients

No dose adjustment is usually necessary in patients up to 75 years in the absence of clinically manifest hepatic or renal insufficiency. In elderly subjects over 75 years of age, drug elimination may be slower. Therefore, if necessary, the dosing interval should be increased according to the patient's needs.

Renal failure / dialysis and hepatic impairment

Elimination of tramadol is delayed in patients with renal and / or hepatic insufficiency. In these patients, prolongation of the dosing intervals should be carefully considered, taking into account the patient's needs.

The use of PATROL is not recommended in patients with severe hepatic insufficiency (see section 4.3 "Contraindications").

Method of administration

Oral use.

The film-coated tablets they must be swallowed whole with a sufficient amount of fluids. They must not be broken or chewed.

The effervescent tablets must be dissolved in a glass of water.

04.3 Contraindications

• Hypersensitivity to the active substances or to any of the excipients (see section 6.1 "List of excipients");

• Acute intoxication with alcohol, hypnotic drugs, central analgesics, opioids or psychotropic substances;

• PATROL must not be given to patients who are being treated with monoamine oxidase inhibitors or who have taken them within the last 2 weeks (see section 4.5 "Interactions with other medicinal products or other forms of interaction");

• Severe hepatic insufficiency;

• Severe haemolytic anemia;

• Epilepsy not controlled by treatment (see section 4.4 "Special warnings and precautions for use").

04.4 Special warnings and appropriate precautions for use

Warnings

• In adults and children over 12 years of age, the maximum dosage of 8 PATROL tablets per day should not be exceeded. To avoid overdose problems, the patient should be advised not to exceed the recommended dosage and not to use other medications containing acetaminophen (including over-the-counter products) or tramadol at the same time without the advice of a physician.

• In case of severe renal insufficiency (clearance of creatinine

• In patients with severe hepatic impairment, PATROL must not be used (see section 4.3 "Contraindications"). The risk of paracetamol overdose is greater in patients with non-cirrhotic alcoholic liver disease. In case of moderate insufficiency, prolongation of the dosing interval should be carefully considered.

• PATROL is not recommended in case of severe respiratory insufficiency.

• Tramadol is not suitable for substitution treatment in opioid-dependent patients. Tramadol, although an opioid agonist, is unable to suppress morphine withdrawal symptoms.

• Seizures have been observed in patients predisposed to or treated with drugs that can lower the seizure threshold, particularly selective serotonin re-uptake inhibitors, tricyclic antidepressants, antipsychotics, central analgesics or local anesthetics. Epileptic patients in good drug control or patients predisposed to seizures should only be treated with PATROL if absolutely necessary. Convulsions have been reported in patients receiving tramadol at recommended doses. The risk may increase if the recommended doses of tramadol are exceeded.

• The effervescent tablets contain E110 sunset yellow dye which can cause allergic reactions; the effervescent tablets also contain 7.8 mmol (or 179.4 mg) of sodium per dose unit. This should be taken into consideration in patients on a controlled sodium diet.

Precautions for use

Physical and / or psychic tolerance and dependence may develop, even at therapeutic dosages. The clinical need for analgesic treatment should be reassessed at regular intervals (see section 4.2). In opioid-dependent patients and in patients with a previous history of drug abuse or dependence, treatment should be given for short periods and under medical supervision.

PATROL should be used with caution in patients with head trauma, in patients with a tendency to seizure, biliary tract disorders, in shock, in patients with changes in consciousness for unknown causes, in patients with disturbances of the center of breath or respiratory function, in patients with increased intracranial pressure.

Symptoms of a withdrawal reaction, similar to those occurring during opioid detoxification, may also occur at therapeutic dosages and with treatments conducted for short periods of time (see section 4.8). Withdrawal symptoms can be avoided by gradually reducing the dose upon discontinuation of therapy, especially after long periods of treatment.

In some patients, paracetamol overdose can cause liver toxicity.

Cases of dependence and abuse have been reported rarely (see section 4.8 "Undesirable effects").

An increase in intraoperative memories following administration of tramadol during general anesthesia with enfluorane and nitric oxide was reported in one study. Until further information is available, the use of tramadol during anesthesia should be avoided.

Tramadol should be used with caution in diabetic patients due to the possible occurrence of hypoglycaemia.

04.5 Interactions with other medicinal products and other forms of interaction

The concomitant use of:

• Non-selective inhibitors of monoamine oxidase

Risk of serotonin syndrome: diarrhea, tachycardia, hyperhidrosis, tremors, confusion and coma.

• Selective inhibitors of monoamine oxidase A

Extrapolation from non-selective monoamine oxidase inhibitors

Risk of serotonin syndrome: diarrhea, tachycardia, hyperhidrosis, tremors, confusion and coma.

• Selective monoamine oxidase B inhibitors

Central excitation symptoms evoking a serotonin syndrome: diarrhea, tachycardia, hyperhidrosis, tremors, confusion and coma.

In case of recent monoamine oxidase inhibitor therapy, 2 weeks should elapse before treatment with tramadol.

The concomitant use of:

• Alcohol

Alcohol increases the sedative effect of opioid analgesics.

The effect on alertness can make driving vehicles or using machines dangerous.

Avoid the intake of alcoholic beverages and medicines containing alcohol.

• Carbamazepine and other enzyme inducers

Risk of reduced efficacy and shorter duration of action due to decreased plasma concentrations of tramadol.

Concomitant uses that need to be considered:

• Tramadol can induce seizures and potentiate the effect of selective serotonin reuptake inhibitors, serotonin-norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants, antipsychotics and other drugs (such as bupropion, mirtazapine, tetrahydrocannabinol) which lower the anticonvulsant threshold.

• The therapeutic use of tramadol in combination with serotonergic drugs such as selective serotonin reuptake inhibitors (SSRIs), serotonin-noradrenaline reuptake inhibitors (SNRIs), MAO inhibitors (see section 4.3), tricyclic antidepressants and mirtazapine, can cause serotonin toxicity.Signs of serotonin syndrome can be:

- spontaneous clone

- inducible or ocular clonus with a state of agitation or diaphoresis

- tremor and hyperreflexia

- hypertonia and body temperature above 38 ° C with inducible or ocular clonus.

Discontinuation of serotonergic drugs generally results in rapid improvement. Treatment depends on the type and severity of the symptoms.

• Other opioid derivatives (including antitussive drugs and replacement treatments), benzodiazepines and barbiturates.

Increased risk of respiratory depression which can be fatal in case of overdose.

• Other central nervous system sedative drugs such as opioid derivatives (including antitussive drugs and replacement treatments), barbiturates, benzodiazepines, other anxiolytics, hypnotics, sedative antidepressants, sedative antihistamines, neuroleptics, centrally acting antihypertensive drugs, thalidomide, baclofen.

These drugs can cause increased central depression. The effect on alertness can make driving vehicles or using machines dangerous.

• For proper clinical practice, periodic evaluation of prothrombin time should be performed if PATROL is used concomitantly with similar warfarin drugs, as increased INR values have been reported.

Other drugs known as CYP3A4 inhibitors, such as ketoconazole and erythromycin, may inhibit the metabolism of tramadol (N-dealkylation) and possibly also the metabolism of the active O-demethylated metabolite. The clinical relevance of this interaction has not been studied.

• In a limited number of studies, pre- and post-operative administration of the antiemetic ondansetron, the 5-HT3 antagonist, increased the demand for tramadol by patients with postoperative pain.

04.6 Pregnancy and lactation

Pregnancy

PATROL is a "fixed combination of active substances including tramadol, therefore it should not be used during pregnancy.

• Data regarding paracetamol:

the results of epidemiological studies in humans have shown no teratogenic or foetotoxic effects of paracetamol used at recommended doses.

• Data regarding tramadol:

Tramadol should not be used in pregnancy as there are insufficient data to establish its safety. Tramadol administered before or during childbirth does not affect uterine motility. In neonates, it may change the respiratory rate in a way that is generally not clinically relevant. Chronic use during pregnancy can lead to a neonatal abstinence syndrome.

Feeding time

PATROL is a fixed combination of active substances including tramadol, therefore it should not be used during breastfeeding.

• Data regarding paracetamol:

paracetamol is excreted in breast milk but not in clinically relevant quantities. The available published data do not lead to contraindicating the use of medicines containing paracetamol, as the sole ingredient, during breastfeeding.

• Data regarding tramadol:

tramadol and its metabolites are found in small quantities in breast milk. The newborn can absorb approximately 0.1% of the dose administered to the mother. Tramadol should not be used while breastfeeding.

Fertility

Post-marketing data suggest no effects of tramadol on fertility. Animal studies do not show an effect of tramadol on fertility. Fertility studies have not been conducted with the tramadol-paracetamol combination.

04.7 Effects on ability to drive and use machines

Tramadol can cause drowsiness and dizziness, which can be aggravated by alcohol or other CNS depressant drugs, in which case the patient should not drive or operate machinery.

04.8 Undesirable effects

The most frequently reported undesirable effects during clinical trials with the tramadol / paracetamol combination were nausea, dizziness and somnolence, observed in more than 10% of patients.

Within each frequency group, undesirable effects are listed in descending order of severity.

Cardiac pathologies:

• Uncommon (≥ 1/1000 and palpitations, tachycardia, arrhythmia.

Vascular pathologies:

• Uncommon (≥ 1/1000 and hypertension, hot flashes.

Nervous system disorders:

• Very common (≥ 1/10): dizziness, somnolence.

• Common (≥ 1/100 and headache and tremors.

• Uncommon (≥ 1/1000 and involuntary muscle contractions and paraesthesia.

• Rare (≥ 1/10000 and ataxia, convulsions, speech disturbances, syncope.

Psychiatric disorders:

• Common (≥ 1/100 and anxiety, nervousness, euphoria, sleep disturbances.

• Uncommon (≥ 1/1000 and hallucinations, nightmares, amnesia.

• Rare (≥ 1/10000 and delirium, drug addiction.

Post-marketing surveillance:

• Very rare (

Eye disorders:

• Rare (≥ 1/10000 and blurred vision, miosis, mydriasis.

Ear and labyrinth disorders:

• Uncommon (≥ 1/1000 and tinnitus.

Respiratory, thoracic and mediastinal disorders:

• Uncommon (≥ 1/1000 and dyspnoea.

Gastrointestinal disorders:

• Very common (≥ 1/10): nausea.

• Common (≥ 1/100 and vomiting, constipation, dry mouth, diarrhea, abdominal pain, dyspepsia, flatulence.

• Uncommon (≥ 1/1000 and dysphagia, melaena.

Diagnostic tests:

• Uncommon (≥ 1/1000 and increased hepatic transaminases.

Metabolism and nutrition disorders:

• Frequency not known: hypoglycemia.

Skin and subcutaneous tissue disorders:

• Common (≥ 1/100 and pruritus.

• Uncommon (≥ 1/1000 and urticaria).

Renal and urinary disorders:

• Uncommon (≥ 1/1000 and albuminuria, urination disturbances (dysuria and urinary retention).

General disorders and administration site conditions:

• Uncommon (≥ 1/1000 chills, chest pain.

Although not observed in clinical studies, the occurrence of the following undesirable effects related to the individual components cannot be excluded:

Tramadol

• Hypotension, bradycardia, collapse.

• The possibility of drug interaction between tramadol and warfarin, with modification of the effect of the latter drug, including an increase in prothrombin time, has rarely emerged from post-marketing surveillance PMS.

• Rare cases (≥ 1/10000 and bronchospasm, respiratory distress, angioneurotic edema) and anaphylaxis.

• Rare cases (≥ 1/10000 and appetite, muscle weakness and respiratory depression.

• After administration of tramadol, psychological side effects may appear, with inter-individual variability in intensity and nature (in relation to the personality and duration of therapy). These effects include alterations in mood (usually euphoria, occasionally dysphoria), in activity (generally decrease, occasionally increase) and in cognitive and sensory abilities (eg, in decision-making behavior, perception disturbances).

• Worsening of asthma has been observed although a causal relationship has not been demonstrated.

• Withdrawal symptoms similar to those induced by opioids may appear: agitation, anxiety, nervousness, insomnia, hyperkinesia, tremor and gastrointestinal symptoms. Other symptoms, very rarely seen after abrupt discontinuation of tramadol, include: panic attacks, severe anxiety, hallucinations, paraesthesia, tinnitus and unusual CNS symptoms.

Paracetamol

• Side effects are rare but hypersensitivity symptoms including skin rash may occur. Very rare cases of severe skin reactions have been reported. There have been reports of blood dyscrasia, including thrombocytopenia and agranulocytosis, but definitely not related to paracetamol.

• Numerous cases have been reported suggesting that paracetamol may cause hypoprothrombinemia when administered concomitantly with similar warfarin drugs. In other studies, prothrombin time did not change.

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: http://www.agenziafarmaco.gov.it/it/responsabili.

04.9 Overdose

PATROL is a fixed combination of active substances. In the event of an overdose, symptoms may include signs and symptoms of toxicity from tramadol, acetaminophen or both.

• Symptoms of tramadol overdose:

In principle, tramadol intoxication can cause symptoms similar to those of other central analgesic drugs (opioids). In particular: miosis, vomiting, cardiovascular collapse, disturbances of consciousness up to coma, convulsions and respiratory depression up to arrest. respiratory.

• Symptoms of paracetamol overdose:

Overdose can be especially dangerous in children. Symptoms of paracetamol overdose during the first 24 hours are: paleness, nausea, vomiting, anorexia, abdominal pain. Liver damage may occur 12 to 48 hours after ingestion. Alterations in glucose metabolism and metabolic acidosis may appear. In case of severe poisoning, liver failure may progress to encephalopathy, coma and death. Acute renal failure may develop. with tubular necrosis even in the absence of severe hepatic damage Cardiac arrhythmia and pancreatitis have been observed.

In adults, liver damage is possible after taking 7.5 - 10 g or more of paracetamol. It should be considered that excessive quantities of toxic metabolite (normally sufficiently detoxified by glutathione after taking normal doses of paracetamol), bind irreversibly to the liver tissue.

Emergency treatment:

• Immediate transfer to a specialized unit.

• Maintenance of respiratory and circulatory functions.

• Before starting treatment, a blood sample must be taken as soon as possible to measure the plasma concentrations of paracetamol and tramadol and perform liver tests.

• Liver tests should be performed at the start and every 24 hours after the overdose occurs. An increase in liver enzymes (ASAT, ALAT) is usually observed and normalizes after one or two weeks.

• Promote gastric emptying by vomiting (if the patient is conscious) with stimulants or gastric lavage.

• All supportive measures such as keeping the airway open and supporting cardiovascular function should be in place. Naloxone must be used to antagonize respiratory depression; seizures can be controlled with Diazepam.

• Tramadol is eliminated only to a small extent by hemodialysis or haemofiltration, so such procedures are not useful in case of acute PATROL intoxication.

Immediate intervention is essential for the treatment of cases of acetaminophen overdose. Despite the lack of significant early symptoms, the patient must be rushed to hospital for immediate medical check-ups.Adults and adolescents who have ingested approximately 7.5 g or more of paracetamol in the previous 4 hours or children who have ingested doses of 150 mg / kg or more of paracetamol should undergo gastric lavage. Plasma concentrations of paracetamol should be measured 4 hours after the overdose in order to assess the risk of developing liver damage (using the nomogram for paracetamol overdose). The administration of oral methionine or N-acetylcysteine (NAC ), intravenously can have a favorable effect within 48 hours of overdose. Intravenous administration of NAC is much more effective when it starts within 8 hours of the overdose.

However, NAC should be administered even if more than 8 hours have elapsed since overdosing and continued throughout therapy. NAC treatment should be initiated immediately when overdose is suspected. General supportive measures should be available.

Regardless of the amount of paracetamol taken, acetylcysteine, the antidote to paracetamol, should be administered orally or intravenously as soon as possible, if possible within 8 hours of the overdose.

05.0 PHARMACOLOGICAL PROPERTIES

05.1 Pharmacodynamic properties

Pharmacotherapeutic group: Analgesics, other opioids.

ATC code: N02AX52.

Tramadol is an opioid analgesic that acts on the central nervous system. Tramadol is a pure, non-selective agonist of the µ, δ and κ opioid receptors with higher affinity for the mc receptors. Other mechanisms contributing to its analgesic effect are inhibition of noradrenaline re-uptake and increased release of serotonin. Tramadol has an anti-cough effect. Unlike morphine, tramadol in the wide range of analgesic doses does not depress respiratory function. Similarly, gastrointestinal motility is not impaired. Cardiovascular effects are generally mild. The potency of tramadol is considered to be 1/10 - 1 / 6 than that of morphine.

The exact mechanism of the analgesic action of paracetamol is unknown and could include central and peripheral effects.

PATROL ranks on the 2nd step of the WHO pain scale and must be administered according to medical prescription.

05.2 Pharmacokinetic properties

Tramadol is administered in racemic form. Both the [-] and [+] isomers of tramadol and its metabolite M1 are detectable in the blood. Although tramadol is rapidly absorbed, its absorption is slower (and its half-life longer) than acetaminophen.

Film-coated tablets: after single oral administration of the tramadol / paracetamol combination (37.5 mg / 325 mg), peak plasma concentrations equal to 64.33 / 55.5 ng / ml [(+) - tramadol / (-) - tramadol ] and 4.2 mcg / ml (paracetamol) are reached after 1.8 h [(+) - tramadol / (-) - tramadol] and 0.9 h (paracetamol) respectively. The mean elimination half-life (t½) is equal to 5.1 / 4.7 h [(+) - tramadol / (-) - tramadol] and 2.5 h (paracetamol).

Effervescent tablets: after single oral administration of the combination tramadol / paracetamol in effervescent tablets (37.5 mg / 325 mg), peak plasma concentrations equal to 94.1 ng / ml of racemic tramadol and 4.0 mcg / ml of paracetamol are reached after 1.1 h (racemic tramadol) and 0.5 h (paracetamol) respectively. The mean elimination half-life (t½) is 5.7 h for racemic tramadol and 2.8 h for paracetamol.

Film-coated tablets and effervescent tablets: During the pharmacokinetic studies in healthy volunteers, no significant changes in the pharmacokinetic parameters were observed after single and repeated oral administration of PATROL compared to the parameters of the active substances used individually.

Absorption:

Racemic tramadol is rapidly and almost completely absorbed after oral administration. The mean absolute bioavailability of a single 100 mg dose is approximately 75%. After repeated administration, the bioavailability increases and reaches approximately 90%.

After administration of PATROL the oral absorption of paracetamol is rapid and almost complete and occurs mainly in the small intestine. Peak plasma concentrations of paracetamol are reached within 1 hour and are not affected by concomitant administration of tramadol.

Administration of PATROL with food has no significant effect on the peak plasma concentration and absorption rate of either tramadol or paracetamol; consequently PATROL can be administered independently of meals.

Distribution:

Tramadol has a high affinity for tissues (Vα, β = 203 ± 40 l). Plasma protein binding is approximately 20%.

Paracetamol appears widely distributed in most tissues with the exception of adipose tissue. Its apparent volume of distribution is approximately 0.9 l / kg. A relatively small portion (± 20%) of paracetamol binds to plasma proteins.

Metabolism:

Tramadol is extensively metabolised after oral administration. About 30% of the dose is excreted unchanged in the urine while 60% of the dose is excreted as a metabolite.

Tramadol is transformed into the metabolite M1 via O-demethylation (catalyzed by the CYP2D6 enzyme), and into the metabolite M & SUP2; via N-demethylation (catalysed by the CYP3A enzyme). M1 is further metabolised through N-demethylation and conjugation with glucuronic acid. The elimination half-life of M1 is 7 hours. The metabolite M1 has analgesic activity and is more potent than the parent molecule. The plasma concentration of M1 is much lower than that of tramadol and the clinical effect is unlikely to change after administration. repeated.

Paracetamol is mainly metabolised in the liver through the 2 main pathways of hepatic metabolism: glucuronidation and sulfuronation. The second route is rapidly saturated with higher than therapeutic doses. A small fraction (less than 4%) is metabolized by cytochrome P 450 into an active intermediate (N-acetylbenzoquinoneimine) which, under normal conditions of use, is rapidly detoxified from the reduced glutathione and excreted in the urine conjugated to the cistern and acid. mercapturic. However, in the event of a massive overdose, the amount of this metabolite increases.

Elimination:

Tramadol and its metabolites are mainly eliminated by the kidney. The half-life of paracetamol is approximately 2-3 hours in adults. The half-life is shorter in children and slightly longer in neonates and cirrhotic patients. Paracetamol is eliminated mainly by the dose dependent formation of glucuro- and sulpho-conjugated derivatives. Less than 9% of paracetamol is excreted unchanged in the urine. In case of renal insufficiency, the half-life of both components is prolonged.

05.3 Preclinical safety data

No preclinical studies have been performed with the fixed combination (tramadol and paracetamol) to evaluate its carcinogenic or mutagenic effects or its effects on fertility.

No teratogenic effects attributable to the drug were observed in the offspring of rats treated orally with the tramadol / paracetamol combination.

The tramadol / paracetamol combination has been shown to be embryotoxic and foetotoxic in rats at maternally toxic doses (50/434 mg / kg tramadol / paracetamol), ie 8.3 times the maximum therapeutic dose in humans. . No teratogenic effects have been demonstrated at this dose. The toxicity for the embryo and the fetus determines a decrease in the weight of the fetus itself and an increase in the number of supernumerary ribs. Lower doses, which can cause a less severe toxic effect in the mother (10/87 and 25/217 mg / kg tramadol / paracetamol) did not cause toxic effects in the embryo or fetus.

The results of standard mutagenicity studies did not reveal a potential genotoxic risk of tramadol in humans.

The results of carcinogenicity tests do not suggest a potential risk of tramadol in humans.

Animal studies with extremely high doses of tramadol have revealed effects on organ development on ossification and neonatal mortality associated with maternal toxicity. Fertility and development of newborns are not affected. Tramadol crosses the placental barrier. Fertility. of males and females it did not undergo any alteration.

Numerous studies have shown that paracetamol does not present genotoxic risks at therapeutic (non-toxic) doses.

Long-term studies in rats and mice show that there are no relevant carcinogenic effects for non-hepatotoxic dosages of paracetamol.

Animal studies and extensive clinical experience show that there is no evidence of reproductive toxicity.

06.0 PHARMACEUTICAL INFORMATION

06.1 Excipients

PATROL film-coated tablets: Pulverized cellulose, pregelatinised starch, sodium carboxymethyl starch, maize starch, magnesium stearate. Coating: Opadry yellow YS-1-6382 G [hypromellose, titanium dioxide (E171), macrogol 400, yellow iron oxide (E172), polysorbate 80], carnauba wax.

PATROL effervescent tablets: anhydrous sodium citrate, anhydrous citric acid, povidone K30, sodium bicarbonate, macrogol 6000, anhydrous colloidal silica, magnesium stearate, orange flavor, acesulfame potassium, sodium saccharin, sunset yellow E110.

06.2 Incompatibility

Not relevant.

06.3 Period of validity

PATROL film-coated tablets 3 years.

PATROL effervescent tablets in blister packs 2 years.

PATROL effervescent tablets in tube 2 years; Shelf life after first opening the tube: 1 year.

06.4 Special precautions for storage

PATROL film-coated tablets: no special storage precautions.

PATROL effervescent tablets in blister packs: store at a temperature not exceeding 25 ° C.

PATROL effervescent tablets in tube: store at a temperature not exceeding 30 ° C.

06.5 Nature of the immediate packaging and contents of the package

PATROL film-coated tablets Packs of 10, 16, 20, 30, 60 tablets.

Paper / PET / Aluminum - PVC blisters.

PATROL effervescent tablets Packs of 10, 20, 30, 40 tablets in aluminum blisters, externally coated with polyethylene terephthalate and internally with polyethylene.

PATROL effervescent tablets Packs of 10, 20, 30, 40 tablets in polypropylene tube with desiccant.