Active ingredients: Tramadol (tramadol hydrochloride)
CONTRAMAL 50 mg hard capsules
Contramal package inserts are available for pack sizes:- CONTRAMAL 50 mg hard capsules
- CONTRAMAL 100 mg prolonged release tablets
- CONTRAMAL 150 mg prolonged-release tablets, CONTRAMAL 200 mg prolonged-release tablets
- CONTRAMAL 100 mg / ml oral drops, solution with dropper
- CONTRAMAL 100 mg / ml oral solution with dispenser CONTRAMAL 30 ml bottle with dispenser
- CONTRAMAL 50 mg / 1 ml solution for injection, CONTRAMAL 100 mg / 2 ml solution for injection
Indications Why is Contramal used? What is it for?
Tramadol - the active ingredient in Contramal is an analgesic (against pain) that comes from the class of opioids, it acts on the central nervous system. It reduces pain by acting on specific nerve cells in the spinal cord and brain.
Contramal is used for the treatment of moderate to severe pain of various types and causes, as well as for pain caused by diagnostic and surgical procedures.
Contraindications When Contramal should not be used
Do not take Contramal
- if you are allergic to tramadol or any of the other ingredients of this medicine
- in acute poisoning with alcohol, sleeping drugs, pain relievers or other psychotropic drugs (drugs that affect mood and emotions);
- if you are also taking MAO inhibitors (some medicines used to treat depression) or if you have taken them in the last 14 days before treatment with Contramal
- if you are epileptic and your seizures are not sufficiently controlled by therapy;
- as a substitute in drug detox therapy.
Precautions for use What you need to know before taking Contramal
Talk to your doctor or pharmacist before taking Contramal,
- if you think you overuse other pain relievers (opioids);
- if you suffer from disturbances of consciousness (if you feel faint);
- if you are in a state of shock (cold sweats can be a sign of this);
- if you have increased pressure in the brain (possible after head trauma or brain disease);
- if you have difficulty breathing;
- if you have a tendency to epilepsy or seizures as the risk of a seizure may increase;
- if you suffer from liver or kidney disease.
Interactions Which drugs or foods may change the effect of Contramal
Tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines.
Contramal must not be taken together with MAO inhibitors (some medicines used for depression).
The intensity and duration of the analgesic effect of Contramal may be reduced if you are taking medicines that contain
- carbamazepine (for seizures);
- ondansetron (to prevent nausea).
Your doctor will inform you if and what dosages of Contramal you should take.
The risk of side effects increases,
- if you are taking tranquilizers, sleeping medications, other pain relievers such as morphine and codeine (including when taken for cough), and alcohol together with Contramal. You may feel drowsy or faint. In these cases, consult your doctor.
- if you are taking medicines that can cause fits (fits), such as some antidepressants or antipsychotics. The risk of having a seizure may increase if you take Contramal at the same time. Your doctor will tell you if Contramal is suitable for you.
- if you are taking certain antidepressants. Contramal 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.
- if you are taking coumarin anticoagulants (medicines that thin the blood), such as warfarin, together with Contramal. The effect of these medicines on blood clotting can be affected and bleeding can occur.
Warnings It is important to know that:
Seizures have been reported in patients taking tramadol at recommended dosages. The risk may increase when tramadol dosages exceed those recommended, beyond the daily limit dose of 400 mg.
Contramal can lead to physical and psychological addiction. When Contramal is administered for a long time, its effect may decrease, therefore higher doses should be given (development of tolerance). In patients with a tendency to drug abuse or who are drug addicts, Contramal should be taken for short periods and under close medical supervision.
Tell your doctor if any of these problems occur during treatment with Contramal or have occurred previously.
CONTRAMAL with food, drink and alcohol
Do not drink alcohol while taking Contramal, as its effect may be increased.
Food intake does not influence the effect of Contramal.
Pregnancy, breastfeeding and fertility
If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask your doctor or pharmacist for advice before taking this medicine.
There is little information regarding the safety of tramadol in pregnant women. Therefore, if you are pregnant, you should not use Contramal capsules. Chronic use during pregnancy could lead to withdrawal symptoms in infants.
Generally, the use of tramadol is not recommended while breastfeeding. Small amounts of tramadol are secreted into breast milk. There is usually no need to interrupt breastfeeding after a single administration.
There are insufficient fertility data in humans. Animal studies do not show an effect of tramadol on male fertility while showing high dose effects in female.
Driving and using machines
Contramal can cause drowsiness, dizziness and vision problems (blurred vision) and therefore can affect your reactions. If you feel that your ability to react is affected, do not drive cars or other vehicles, do not use electrical tools or operate machinery, and do not work without secure support.
Dosage and method of use How to use Contramal: Dosage
Always take this medicine exactly as your doctor has told you. If in doubt, consult your doctor or pharmacist.
The dosage should be chosen based on the intensity of the pain and your personal sensitivity to pain. The lowest pain-reducing dose should generally be taken. Do not take more than 400 mg (8 capsules) of tramadol hydrochloride per day. unless your doctor has given you different instructions.
Unless otherwise prescribed, the usual dose is:
Adults and adolescents over 12 years of age:
Contramal 50 mg hard capsules: one or two capsules (equivalent to 50 or 100 mg of tramadol hydrochloride) every 4 - 6 hours.
Use in children and adolescents
Contramal 50 mg capsules are not recommended for children under 12 years of age
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 Contramal. In case of mild or moderate insufficiency, your doctor may advise you to lengthen the time interval between one dose and the next.
How and when you should take Contramal 50 mg hard capsules
Contramal capsules 50 mg are for oral use. Swallow the capsules whole, not divided or chewed with a sufficient amount of liquid, preferably in the morning and evening. You can take the capsules both with and away from meals.
How long should you take Contramal
Do not take Contramal longer than necessary. If you need to continue treatment for a long time, your doctor will check you at short and regular intervals (if necessary by temporarily stopping the therapy) to determine if you should continue the treatment and at what dose.
If you feel that the analgesic effect of Contramal is too much or too little, consult your doctor or pharmacist.
Overdose What to do if you have taken too much Contramal
If you have taken an extra dose by mistake, this should not have any adverse effects. You can continue to take the medicine as prescribed
After taking very high doses the following may occur: pinched pupils, vomiting, drop in blood pressure, fast heartbeat, collapse, disturbances of consciousness up to coma (profound unconsciousness), seizures, and difficulty in breathing up to "stop. respiratory In such cases call a doctor immediately.
If you forget to take Contramal
If you forget to take Contramal, the pain is likely to return. Do not double the dosage to make up for this forgetfulness, just continue taking the capsules as before.
If you stop taking Contramal
If you stop or finish treatment too soon, the pain is likely to return.
If you wish to stop treatment due to side effects, please consult your doctor.
There is generally no withdrawal effect when treatment with Contramal is terminated.
However, in rare cases, some people may feel unwell when they suddenly stop taking Contramal after a certain period of time. They may feel agitated, anxious, nervous or weak. They may be hyperactive, have difficulty sleeping, or have stomach or bowel upset. Very few people may have panic attacks, hallucinations, unusual sensations such as itching, tingling, numbness, and noise in the ears (tinnitus). Also, very rarely, unusual CNS symptoms such as confusion, delusion, change in perception of one's personality (depersonalization) and changes in perception of reality (derealization) and persecution (paranoia) have been reported. treatment with Contramal, consult your doctor.
If you have any further questions on the use of this medicine, ask your doctor or pharmacist.
Side Effects What are the side effects of Contramal
Like all medicines, this medicine can cause side effects, although not everybody gets them.
- very common (may affect more than 1 in 10 people)
- common (may affect up to 1 in 10 people)
- uncommon (may affect up to 1 in 100 people)
- rare (may affect up to 1 in 1,000 people)
- very rare (may affect up to 1 in 10,000 people)
- not known (impossible to quantify based on available information)
See a doctor immediately if you experience symptoms of an allergic reaction such as swelling of the face, tongue and / or throat and / or difficulty in swallowing or hives together with difficulty in breathing.
The most common side effects during treatment with Contramal are nausea and dizziness, in more than 1 in 10 people.
Disorders of the immune system:
Rare: allergic reactions (e.g. difficulty in breathing, wheezing, hives) and shock (sudden drop in blood pressure).
Cardiac and circulation disorders
Uncommon: effects on the heart and blood circulation (palpitations, fast heart beat, feeling faint or collapsing). These side effects may occur in particular in patients who are standing or undergoing physical exertion.
Rare: slow heartbeat.
Investigations: increased blood pressure.
Nervous system disorders
Very common: dizziness.
Common: headache, drowsiness.
Rare: unusual sensations (itching, tingling, numbness), tremors, slowed breathing, seizures, muscle spasms, uncoordinated movements, transient loss of consciousness (syncope), speech disturbances.
Seizures occurred mainly after the administration of high doses of tramadol or after concomitant treatment with drugs that predispose to seizures.
Metabolism and nutrition disorders
Rare: changes in appetite Frequency not known: decrease in blood sugar level
Psychiatric disorders
Rare: hallucinations, confusion, sleep disturbances, delirium, anxiety and nightmares.
Psychological disturbances may occur after treatment with Contramal. Their intensity and nature can vary (depending on the patient's personality and the duration of therapy).
They can manifest as a change in mood (usually euphoria, rarely irritation), activity (usually reduction, rarely increase) and reduction of sensory and cognitive perceptions (alterations in sensations and the ability to distinguish, which can lead to errors of assessment).
Addiction may appear. Dependence may occur when Contramal is administered for a long time, although the risk is very low. When treatment is stopped abruptly, withdrawal symptoms may occur (see "If you stop taking Contramal").
Eye disorders
Rare: vision problems (blurred vision).
Excessive dilation of the pupils (mydriasis), narrowing of the pupil (miosis).
Diseases of the respiratory system
Rare: slowed breathing, shortness of breath (dyspnoea)
If recommended doses are exceeded, or other drugs that depress brain function are taken at the same time, breathing may slow down.
Worsening of bronchial asthma has been observed, however it has not been established whether it may have been caused by tramadol
Gastrointestinal disorders
Very common: nausea.
Common: constipation, dry mouth, vomiting.
Uncommon: retching, stomach upset (feeling of weight, bloating), diarrhea.
Skin pathologies
common: profuse sweating (hyperhidrosis).
Uncommon: skin reactions (for example: itching, rash).
Muscle pathologies
Rare: muscle weakness.
Liver and biliary disorders
Very rare: increase in liver enzyme values.
Urinary disorders
Rare: difficulty or pain in passing urine, decreased amount of urine (dysuria).
Disorders of the organism in general
common: tiredness.
Reporting of side effects
If you get any side effects, talk to your doctor or pharmacist or nurse. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the national reporting system at https: // www. aifa.gov.it/content/segnalazioni-reazioni-avverse.
By reporting side effects you can help provide more information on the safety of this medicine.
Expiry and Retention
Store at a temperature not exceeding 30 ° C.
Keep out of the sight and reach of children.
Do not use Contramal 50 mg hard capsules after the expiry date which is stated on the carton and blister. The expiry date refers to the last day of the month.
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.
Package Contents
What Contramal 50 mg hard capsules contains
The active ingredient is tramadol hydrochloride.
One capsule contains 50 mg of tramadol hydrochloride. The other ingredients are: microcrystalline cellulose, sodium carboxymethyl starch sodium (type A), magnesium stearate, anhydrous colloidal silica, gelatin, titanium dioxide (E171), yellow iron oxide (E172), indigo carmine.
What Contramal 50 mg hard capsules look like and contents of the pack
Hard, oblong two-colored (green / yellow) capsules. The pack is 20 hard capsules
Source Package Leaflet: AIFA (Italian Medicines Agency). Content published in January 2016. The information present may not be up-to-date.
To have access to the most up-to-date version, it is advisable to access the AIFA (Italian Medicines Agency) website. Disclaimer and useful information.
01.0 NAME OF THE MEDICINAL PRODUCT
CONTRAMAL
02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION
CONTRAMAL 50 mg hard capsules
One hard capsule contains 50 mg of tramadol hydrochloride
CONTRAMAL 100 mg / ml oral drops solution with dropper
20 drops (equivalent to 0.5 ml) of dropper solution contain 50 mg of tramadol hydrochloride.
Excipients with known effect : 0.5 ml of solution contains 100 mg of sucrose (see section 4.4) and 0.5 mg of macrogolglycerol hydroxystearate
(the 10 ml bottle is supplied with a dropper: 1 drop corresponds to 2.5 mg of tramadol)
CONTRAMAL 100 mg prolonged release tablets
one tablet contains 100 mg of tramadol hydrochloride
Excipients with known effect: each prolonged-release tablet contains 2.5 mg of lactose monohydrate (see section 4.4).
CONTRAMAL 50 mg / ml solution for injection and 100mg / 2ml solution for injection
1 ampoule of 1 ml contains 50 mg of tramadol hydrochloride
1 ampoule of 2 ml contains 100 mg of tramadol hydrochloride.
Excipients with known effect: 1 ml of solution for injection contains 0.7 mg of sodium.
For the full list of excipients see section 6.1.
03.0 PHARMACEUTICAL FORM
Oral use: hard capsules (two-tone green / light yellow), oral drops solution (clear, slightly viscous, colorless to pale yellow solution),prolonged-release tablets (round, biconvex tablets embossed with the company logo on one side and T1 on the other).
Use intramuscular, intravenous and subcutaneous: solution for injection (clear, colorless solution).
04.0 CLINICAL INFORMATION
04.1 Therapeutic indications
Acute and chronic painful states of various types and causes and of medium and severe intensity, as well as in pain induced by diagnostic and surgical interventions.
04.2 Posology and method of administration
CONTRAMAL 50 MG HARD CAPSULES
Dosage
The posology should be adapted to the intensity of pain and the individual sensitivity of the patient. In general, the minimum effective dose should be selected. The total daily dose should not exceed 400 mg of tramadol hydrochloride, except in special clinical conditions.
Unless otherwise prescribed, Contramal hard capsules should be administered as follows:
Adults and adolescents over 12 years :
50-100 mg of tramadol hydrochloride every 4-6 hours.
Pediatric population :
in consideration of the high dosage the capsules are not suitable for children under 12 years of age.
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, elimination of the drug may be slower. Therefore, if necessary, the dosing interval should be increased according to the patient's needs.
Patients with renal insufficiency / dialysis and hepatic impairment
In patients with renal and / or hepatic insufficiency the elimination of tramadol is delayed. In these patients, prolongation of the dosing intervals should be carefully considered taking into account the patient's needs.
Method of administration
The hard capsules they should be swallowed whole, not divided or chewed, with a sufficient amount of liquid, regardless of meals.
Duration of therapy
Tramadol should never be given for longer than absolutely necessary. If, based on the type and severity of the disease, long-term analgesic therapy with Contramal is required, careful and regular checks (if necessary temporarily interrupting the therapy) should be carried out to determine whether and to what extent it is necessary to continue treatment. .
CONTRAMAL 100 MG / ML ORAL DROPS SOLUTION WITH DROPPER
Dosage :
The posology should be adapted to the intensity of pain and the individual sensitivity of the patient. In general, the minimum effective dose should be selected. The total daily dose should not exceed 400 mg of tramadol hydrochloride, except in special clinical conditions.
Unless otherwise prescribed, Contramal oral drops solution with dropper should be administered as follows:
Adults and adolescents over 12 years :
50-100 mg of tramadol hydrochloride every 4-6 hours.
Pediatric population over 1 year of age :
the single dose is 1-2 mg / kg of body weight.
Daily dosages of 8 mg of active substance per kg of body weight or 400 mg of active substance in any case should not be exceeded.
Note on dosage of Contramal 100 mg / ml oral drops, solution with dropper in children over 1 year of age
Table of dosage in relation to body weight in children over 1 year of age:
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, elimination of the drug may be slower. Therefore, if necessary, the dosing interval should be increased according to the patient's needs.
Patients with renal insufficiency / dialysis and hepatic impairment
In patients with renal and / or hepatic insufficiency the elimination of tramadol is delayed. In these patients, prolongation of the dosing intervals should be carefully considered taking into account the patient's needs.
Method of administration
Contramal oral drops solution with dropper, should be taken with some liquid or sugar, regardless of meals.
See the table below for further details.
Duration of therapy
Tramadol should never be given for longer than absolutely necessary. If, based on the type and severity of the disease, long-term analgesic therapy with Contramal is required, careful and regular checks (if necessary temporarily interrupting the therapy) should be carried out to determine whether and to what extent it is necessary to continue treatment. .
CONTRAMAL 100 MG EXTENDED RELEASE TABLETS
Dosage :
The posology should be adapted to the intensity of pain and the individual sensitivity of the patient. In general, the minimum effective dose should be selected. The total daily dose should not exceed 400 mg of tramadol hydrochloride, except in special clinical conditions.
Unless otherwise prescribed, Contramal prolonged-release tablets should be administered as follows:
Adults and adolescents over 12 years :
The usual starting dose is 100 mg twice a day, morning and evening: if pain relief is insufficient the dose can be increased up to 200 mg twice a day.
Pediatric population:
In view of the high dosage, the prolonged-release tablets are not suitable for children under 12 years of age.
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, elimination of the drug may be slower. Therefore, if necessary, the dosing interval should be increased according to the patient's needs.
Patients with renal insufficiency / dialysis and hepatic impairment :
In patients with renal and / or hepatic insufficiency the elimination of tramadol is delayed. In these patients, prolongation of the dosing intervals should be carefully considered taking into account the patient's needs. Contramal prolonged-release tablets are not recommended in case of severe renal insufficiency or hepatic
Method of administration
The prolonged-release tablets should be swallowed whole, not divided or chewed, with a sufficient amount of liquid, regardless of meals.
Duration of therapy
Tramadol should never be given for longer than absolutely necessary. If, based on the type and severity of the disease, long-term analgesic therapy with Contramal is required, careful and regular checks (if necessary temporarily interrupting the therapy) should be carried out to determine whether and to what extent it is necessary to continue treatment. .
CONTRAMAL 50 MG / ML AND 100 MG / 2 ML SOLUTION FOR INJECTION
Dosage :
The posology should be adapted to the intensity of pain and the individual sensitivity of the patient. In general, the minimum effective dose should be selected. The total daily dose should not exceed 400 mg of tramadol hydrochloride, except in special clinical conditions.
Unless otherwise prescribed, Contramal solution for injection should be administered as follows:
Adults and adolescents over 12 years :
50-100 mg of tramadol hydrochloride every 4-6 hours.
Pediatric population over 1 year of age:
the single dose is 1-2 mg / kg of body weight.
Daily dosages of 8 mg of active substance per kg of body weight or 400 mg of active substance in any case should not be exceeded.
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, elimination of the drug may be slower. Therefore, if necessary, the dosing interval should be increased according to the patient's needs.
Patients with renal insufficiency / dialysis and hepatic impairment :
In patients with renal and / or hepatic insufficiency the elimination of tramadol is delayed. In these patients, prolongation of the dosing intervals should be carefully considered taking into account the patient's needs.
Method of administration
The solution for injection should be injected slowly or infused diluted into the infusion solutions. For instructions on dilution, see section 6.6.
Duration of therapy
Tramadol should never be given for longer than absolutely necessary. If, based on the type and severity of the disease, long-term analgesic therapy with Contramal is required, careful and regular checks (if necessary temporarily interrupting the therapy) should be carried out to determine whether and to what extent it is necessary to continue treatment. .
04.3 Contraindications
Contramal is contraindicated
• in hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
• in acute intoxication with alcohol, hypnotics, analgesics, opioids or psychotropic drugs.
• in patients on MAO inhibitors or who have taken them within the last 14 days (see section 4.5).
• in patients with epilepsy not adequately controlled by treatment.
• in use as a drug cessation therapy.
04.4 Special warnings and appropriate precautions for use
Tramadol should only be used with particular caution in opioid-dependent patients, in case of head trauma, shock, disturbances of consciousness of questionable origin, disturbances of the respiratory center or respiratory function, increased intracranial pressure.
The drug should be used with caution in opioid sensitive patients.
Caution should be exercised in treating patients with respiratory depression when CNS depressant drugs are administered concomitantly (see section 4.5) or when recommended dosages are significantly exceeded (see section 4.9) as, in such cases, the onset of respiratory depression does not it can be excluded.
Convulsions have been reported in patients treated with tramadol at recommended doses. The risk of seizures may increase when tramadol doses exceed the maximum recommended daily dose (400 mg). Furthermore, tramadol may increase the risk of seizures in patients treated with other drugs that lower the seizure threshold (see section 4.5). Patients with epilepsy or at risk of seizures should only be treated with tramadol when clinical conditions dictate it.
Tramadol has a low addictive potential. In case of long-term therapy, tolerance, psychic and physical dependence can develop. In patients with a tendency to drug abuse or drug addiction, Contramal can only be administered for short periods, under strict medical supervision.
Tramadol is not suitable for use as a substitution treatment in drug addicts. Although it is an opioid agonist, tramadol is unable to suppress morphine withdrawal symptoms.
Important information about some of the ingredients
Contramal oral drops solution with dropper contains sucrose : Patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption or sucrase isomaltase insufficiency should not take this medicine.
Contramal prolonged-release tablets : contains lactose. Patients with rare hereditary forms of galactose intolerance, lactase deficiency or glucose-galactose malabsorption should not take this drug.
Contramal oral drops solution with dropper contains macrogolglycerol hydroxystearate, a derivative of castor oil which may cause stomach upset and diarrhea.
Contramal solution for injection contains less than 1 mmol sodium (23 mg) per ml, it can be considered "sodium free".
04.5 Interactions with other medicinal products and other forms of interaction
Tramadol must not be combined with MAO inhibitors (see section 4.3).
In patients treated with MAO inhibitors in the 14 days prior to the administration of the opioid pethidine, life-threatening interactions have been observed at the level of the central nervous system and respiratory and cardiovascular function. MAO inhibitors and Contramal.
Concomitant administration of Tramadol with other central nervous system depressant drugs, including alcohol, may potentiate CNS effects (see section 4.8).
The results of the pharmacokinetic studies available so far show that clinically relevant interactions are unlikely in case of concomitant or previous administration of cimetidine (enzyme inhibitor). Concomitant or previous administration of carbamazepine (enzyme inducer) may decrease the analgesic effect and shorten the duration of action of tramadol.
Tramadol can induce seizures and potentiate the effect of selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants, antipsychotics and other drugs (such as bupropion, mirtazapine, tetrahydrocannol ) which lower the seizure threshold.
The therapeutic use of tramadol in combination with serotonergic drugs such as selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), MAO inhibitors (see section 4.3), tricyclic antidepressants and mirtazapine , can cause serotonin toxicity.Signs of serotonin syndrome can be:
• spontaneous cloning
• 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.
Caution should be used during concomitant treatment with tramadol and coumarin derivatives (eg warfarin) due to reports of increased INR with major bleeding and bruising in some patients.
Other drugs, known as CYP3A4 inhibitors, such as ketoconazole and erythromycin, may inhibit the metabolism of tramadol (N demethylation), and possibly also of the active O-desmethyl metabolite. The clinical relevance of this interaction has not yet been definitively studied (see section 4.8).
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 post-operative pain.
04.6 Pregnancy and lactation
Pregnancy
Animal studies have revealed that tramadol in very high doses has effects on organ development, ossification and neonatal mortality. Tramadol passes the placental barrier. There is not yet sufficient data on the safety of tramadol during pregnancy, therefore Tramadol does not it must be used during pregnancy of the woman.
Tramadol, administered before or during childbirth, does not change uterine contractility. In neonates it can cause changes in respiratory rate that are usually not clinically relevant. Chronic use during pregnancy can lead to a neonatal abstinence syndrome.
Feeding time:
During breastfeeding approximately 0.1% of the dose of tramadol administered to the mother passes into the milk. Therefore, its use is not recommended in breastfeeding women. Usually, if the therapy consists of the administration of a single dose of tramadol, it is not necessary to interrupt breastfeeding.
Fertility:
There are insufficient fertility data in humans. Animal studies do not show an effect of tramadol on male fertility while showing high dose effects in female (see section 5.3).
04.7 Effects on ability to drive and use machines
Tramadol, even if taken according to instructions, can cause effects such as drowsiness or dizziness and consequently affect the reactions of those who drive and operate machines. This is especially true in the case of association with alcohol or other psychotropic substances.
04.8 Undesirable effects
The most frequently reported adverse events are nausea and dizziness, both occurring in over 10% of patients.
The frequency is defined as follows:
Very common: ≥ 1/10
Common: ≥ 1/100 e
Uncommon: ≥ 1/1000 e
Rare: ≥ 1 / 10,000 e
Very rare:
Not known: frequency cannot be estimated from the available data
Cardiac pathologies
Uncommon: dependent on cardiovascular regulation (palpitations, tachycardia). These side effects can occur especially during intravenous administration and in patients under physical stress conditions.
Rare: bradycardia.
Diagnostic tests
Rare: increase in blood pressure
Vascular pathologies
Uncommon: dependent on cardiovascular regulation (postural hypotension or cardiovascular collapse). These side effects can occur especially during intravenous administration and in patients under physical stress conditions.
Metabolism and nutrition disorders
Rare: changes in appetite.
Frequency not known: hypoglycemia
Respiratory, thoracic and mediastinal disorders
Rare: respiratory depression, dyspnoea. If the recommended doses have been significantly exceeded and if other centrally depressant substances have been administered at the same time (see section 4.5), respiratory depression may occur. Worsening of asthma has been observed, although a causal relationship has not been established.
Nervous system disorders
Very common: dizziness.
Common: headache, somnolence.
Rare: speech disorders, paraesthesia, tremor, epileptic seizures, involuntary muscle contractions, motor incoordination, syncope.
Convulsions may occur mainly after administration of high doses of tramadol or following concomitant therapy with drugs that may lower the seizure threshold (see sections 4.4 and 4.5).
Psychiatric disorders
Rare: hallucinations, confusion, sleep disturbances, delirium, anxiety and nightmares. The psychiatric side effects that may appear following the administration of tramadol may vary in the individual by type and severity (in relation to personality and duration of treatment). They include changes in mood (usually euphoria, occasionally dysphoria), changes in activity (usually decrease, occasionally increase), and changes in cognitive and sensory abilities (eg in decision-making behavior, perception disturbances).
Addiction may appear. Stinence symptoms, similar to those of opioid withdrawal, may present as follows: agitation, anxiety, nervousness, insomnia, hyperkinesis, tremors, and gastrointestinal symptoms. Other symptoms very rarely seen after discontinuation of tramadol are: panic attacks, severe anxiety, hallucinations, paraesthesia, tinnitus and unusual CNS symptoms (such as confusion, hallucinations, depersonalization, perception disturbances, paranoia).
Eye disorders
Rare: myosis, mydriasis, blurred vision.
Gastrointestinal disorders
Very common: nausea.
Common: constipation, dry mouth. He retched.
Uncommon: retching, gastrointestinal irritation (feeling of gastric tension, bloating), diarrhea.
Skin and subcutaneous tissue disorders
Common: hyperhidrosis.
Uncommon: skin reactions (e.g. itching, rash, urticaria).
Musculoskeletal and connective tissue disorders
Rare: muscle weakness.
Hepatobiliary disorders
In a few isolated cases, an increase in liver enzyme values was observed in temporal relationship with the therapeutic use of tramadol.
Renal and urinary disorders
Rare: disturbances in urination (dysuria and urinary retention).
Disorders of the immune system
Rare: allergic reactions (e.g. dyspnoea, bronchospasm, wheezing, angioneurotic edema) and anaphylaxis.
General disorders and administration site conditions
Common: a sense of fatigue.
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
Symptoms: Basically, in intoxications with tramadol a symptomatology similar to that observed with other centrally acting analgesics (opiates) is to be expected. It includes, in particular, miosis, vomiting, cardiovascular collapse, disturbances of consciousness up to coma, convulsions and respiratory depression up to respiratory arrest.
Treatment: general emergency measures apply: keep the respiratory tract clear (aspiration), support cardiac and respiratory function according to the symptoms. In case of respiratory depression the antidote is naloxone. In animal experiments, naloxone had no effect on seizures; in these cases administer intravenous diazepam.
In case of intoxication with oral formulations, elimination with activated charcoal or gastric lavage is recommended only in the 2 hours following the ingestion of tramadol, subsequently these procedures can be useful only in case of ingestion of exceptionally high quantities of tramadol or sustained release formulations.
Tramadol is eliminated only to a small extent by hemodialysis or hemofiltration, so hemodialysis or hemofiltration alone are not suitable treatments for acute tramadol intoxication.
05.0 PHARMACOLOGICAL PROPERTIES
05.1 Pharmacodynamic properties
Pharmacotherapeutic group: opioid analgesics. ATC code: N02AX02.
Tramadol is a centrally acting opioid analgesic. It is a pure non-selective agonist of the µ, δ, and κ opioid receptors with greater affinity for the µ receptors. Other mechanisms contributing to its analgesic effect are the inhibition of the neuronal reuptake of noradrenaline and the increase of the release of serotonin.
Tramadol has an antitussive effect. Unlike morphine, tramadol has no depressive effects on respiration when administered in the analgesic dose range. Likewise, it does not affect gastrointestinal motility. Effects on the cardiovascular system tend to be mild. The potency of tramadol ranges from 1/10 to 1. 1/6 compared to that of morphine.
05.2 Pharmacokinetic properties
After intramuscular administration in humans, tramadol is rapidly and completely absorbed: peak plasma is reached after 45 minutes and bioavailability is approximately 100%. In humans approximately 90% of tramadol is absorbed after oral administration (Contramal hard capsules ); the absorption half-life is 0.38 ± 0.18 h.
Comparison of the areas under the tramadol serum concentration curve (AUC) after oral and intravenous administration demonstrates a bioavailability of 68 ± 13% of Contramal hard capsules. Compared to other opioid analgesics, the absolute bioavailability of Contramal hard capsules is very high.
The plasma peak is reached within 2 hours after administration of Contramal hard capsules. After administration of Contramal prolonged-release tablets 100 mg, the peak plasma concentration Cmax = 141 ± 40 ng / ml is reached after 4.9 h; after administration of Contramal prolonged-release tablets 200 mg, Cmax 260 ± 62 ng / ml is reached after 4.8 h.
The pharmacokinetics of Contramal oral drops solution do not differ significantly from that of Contramal hard capsules with regard to the bioavailability measured with AUC. The time to reach Cmax is 1 hour for Contramal oral drops solution and 2.2 hours for Contramal capsules. rigid, reflecting the rapid absorption of liquid oral forms.
Tramadol has a high affinity for tissues (V d, b = 203 ± 40 L.). Plasma protein binding is approximately 20%. Tramadol crosses the blood-brain and placental barrier. Very small amounts of the substance and of its O-demethyl derivative are found in breast milk (0.1% and 0.02% of the administered dose, respectively).
Inhibition of one or both types of the isoenzymes CYP3A4 and CYP2D6 involved in the biotransformation of tramadol may alter the plasma concentration of tramadol or its active metabolite. To date, no clinically relevant interactions have been reported.
Elimination of tramadol and its metabolites is almost completely via the kidney. Cumulative urinary excretion is 90% of the total radioactivity of the administered dose. The elimination half-life t ½, b is approximately 6 h, regardless of the route of administration. In patients over 75 years, it may increase by a factor of approximately 1.4. In the case of impaired hepatic or renal function, there is a modest prolongation of the half-life.
Elimination half-lives of 13.3 ± 4.9 h (tramadol) and 18.5 ± 9.4 h (O-desmethyltramadol) were determined in patients with liver cirrhosis, maximum values of 22.3 h and 36 h, respectively. In patients with renal insufficiency (creatinine clearance
In humans, tramadol is metabolised essentially by means of demethylation into N and O and conjugation of the products of demethylation in O with glucuronic acid. Only O-desmethyltramadol is pharmacologically active. For the other metabolites, from a quantitative point of view, there are significant interindividual differences. 11 metabolites have so far been found in urine. Animal experiments have shown that O-desmethyltramadol has a potency 2-4 times higher than that of the parent substance. Its half-life t½, b (in 6 healthy volunteers) is 7.9 h (5.4 to 9.6 h) and approximately equal to that of tramadol.
In the therapeutic dose range, tramadol has a linear pharmacokinetic profile.
The relationship between serum concentrations and analgesic effect is dose-dependent, however with considerable variations from case to case. A serum concentration of 100-300 ng / mL is usually effective.
05.3 Preclinical safety data
After repeated oral and parenteral administrations of tramadol for 6-26 weeks to rats and dogs and after oral administrations to dogs for 12 months, no changes in the haematological, clinical chemistry and histological tests attributable to the drug were highlighted. Only with high doses, significantly higher than the therapeutic doses, did symptoms affecting the central nervous system occur: agitation, salivation, convulsions and reduced weight gain. Rats and dogs tolerated, respectively, oral doses of 20 mg / kg and 10 mg / kg body weight and rectal doses of 20 mg / kg body weight dogs, without any reaction.
In rats, doses of tramadol starting from 50 mg / kg / day caused toxic effects in pregnant females and increased neonatal mortality. Growth delays occurred in the offspring such as alterations in ossification and delayed opening of the vagina and eyes. The fertility of males did not undergo any alteration. In females, after administration of high doses (starting from 50 mg / kg / day) a lower percentage of pregnancies were observed In rabbits, starting from 125 mg / kg, toxic effects occurred in pregnant females and skeletal anomalies in the offspring.
Mutagenic effects have been shown in some in vitro tests. In vivo research has not revealed any such effects. On the basis of currently available knowledge, tramadol can be classified as a non-mutagenic substance.
Studies concerning the carcinogenic potential of tramadol hydrochloride were carried out in rats and mice. The study in rats did not show any increase in the incidence of tumors attributable to the drug. In the study in mice, an increased incidence of liver cell adenomas in male animals (non-significant increase, dose-dependent, starting from 15 mg / kg) and an increase in lung tumors in female animals in all dose groups (significant, but not dose-dependent).
06.0 PHARMACEUTICAL INFORMATION
06.1 Excipients
Hard capsules: microcrystalline cellulose, sodium carboxymethyl starch (Type A), magnesium stearate, colloidal silica, gelatin, titanium dioxide (E171), yellow iron oxide (E172), indigo carmine.
Oral drops solution with dropper: sucrose, propylene glycol, glycerol, sodium cyclamate, sodium saccharinate, potassium sorbate, macrogolglycerol hydroxystearate, mint essence, anise aroma, purified water.
Prolonged-release tablets: nucleus: microcrystalline cellulose, hypromellose 100,000 mPa S, colloidal anhydrous silica, magnesium stearate;
coating : hypromellose 6 mPa s, lactose monohydrate, macrogol 6000, propylene glycol, talc, titanium dioxide (E171).
Injectable solution: sodium acetate, water for injections.
06.2 Incompatibility
The injectable solution is incompatible (not miscible) with injectable solutions of diclofenac, piroxicam, indomethacin, phenylbutazone, diazepam, flunitrazepam, midazolam, nitroglycerin.
06.3 Period of validity
Hard capsules, ampoules, prolonged-release tablets: 5 years.
Oral drops solution with dropper: 4 years.
06.4 Special precautions for storage
This medicine does not require any special storage conditions.
06.5 Nature of the immediate packaging and contents of the package
Hard capsules: blisters made up of white PVC / Aluminum
20 hard capsules of 50 mg -
Oral drops solution: amber glass bottle with polythene dropper and cap with closure
safety of 10 ml of 100 mg / ml solution
Prolonged-release tablets:
blisters made of PVC-PVDC / Aluminum
20 prolonged-release tablets of 100 mg -
Injectable solution: type I colorless neutral glass vials with pre-breaking engraved
5 ampoules 50 mg / 1 ml -
5 vials 100 mg / 2 ml
06.6 Instructions for use and handling
Unused medicine and waste derived from this medicine must be disposed of in accordance with local regulations
Instructions for opening Contramal oral drops solution with dropper
The bottle has a safety closure that protects it from manipulation by children. To open: press on the cap and turn it. To release the drops, the bottle must be held vertically with the opening at the bottom (the 10 ml bottle is equipped with a dropper: 1 drop corresponds to 2.5 mg). After use, close the bottle with the cap which must be turned until it is hermetically sealed.
07.0 MARKETING AUTHORIZATION HOLDER
GRÜNENTHAL ITALIA S.r.l. - Via Carlo Bo, 11 - 20143 Milan
08.0 MARKETING AUTHORIZATION NUMBER
Contramal 50 mg hard capsules, 20 hard capsules - A.I.C. n. 028853012
Contramal 100 mg / ml oral drops solution, 10 ml bottle with dropper - A.I.C. n. 028853024
Contramal 100 mg prolonged release tablets, 20 tablets - A.I.C. n. 028853036
Contramal 50 mg / ml solution for injection, 5 ampoules 1 ml - A.I.C. n. 028853051
Contramal 100 mg / 2ml solution for injection, 5 ampoules 2ml - A.I.C. n. 028853063
09.0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION
Date of first registration: October 1994
Date of last renewal: November 15, 2009
10.0 DATE OF REVISION OF THE TEXT
May 2014
