Tramal - instructions for use, dose, side effects, contraindications

Pharmacodynamics:Tramadol - opioid analgesic with a central mechanism of action. It is a nonselective complete agonist of μ-, δ- and k-opioid receptors with a high affinity for μ-receptors. The second mechanism of action of tramadol, which enhances its analgesic effect, is suppression of norepinephrine reuptake by neurons and increased release of serotonin.

Tramadol has antitussive action. In contrast to morphine, in therapeutic doses does not depress respiration and to a lesser extent affect intestinal motility. Influence on the cardiovascular system is weakly expressed. The analgesic potential of tramadol is 1/10 - 1/6 of the activity of morphine.

Pharmacokinetics:

After intramuscular injection tramadol absorbed quickly and completely, the maximum concentration in the blood plasma is reached after 45 minutes. Bioavailability is close to 100%. Binding to plasma proteins is about 20%. Tramadol has a high affinity for tissues (Vd, p = 203 ± 40 L). Penetrates through blood-brain and placental barriers.Insignificant amounts of tramadol and its O-demethylated derivative (0.1% and 0.02%, respectively) are excreted in breast milk.

In the metabolism of tramadol, the isozymes CYP3A4 and CYP2D6 are involved, the suppression of these isoenzymes by other substances can affect the concentration of tramadol and its active metabolite in the blood. To date, clinically significant interactions with other drugs mediated by this mechanism have not been identified.

Tramadol and its metabolites are excreted mainly with urine, the average cumulative index of renal excretion is 90%.

The half-life of tramadol (T1 / 2) is approximately 6 hours, regardless of the route of administration. In patients older than 75 years, the elimination half-life can be increased by a factor of 1.4; with cirrhosis of the liver to 13.3 ± 4.9 h (tramadol), 18.5 ± 9.4 h (O-demethyltramadol), in severe cases - 22.3 h and 36 h respectively. T1 / 2 with renal insufficiency (creatinine clearance less than 5 ml / min) - 11 ± 3.2 h (tramadol), 16.9 ± 3 h (O-demethyltramadol), in severe cases - 19.5 h and 43.2 h respectively.

In the liver, it is metabolized by N- and O-demethylation followed by conjugation with glucuronic acid. Only O-demethyltramadol has pharmacological activity.There are significant individual differences in the concentration of other metabolites. 11 metabolites of tramadol were found in urine.

In therapeutic doses tramadol has a linear pharmacokinetic profile. The ratio of the concentration of tramadol in the blood serum and the analgesic effect is dose-dependent, which varies in individual individuals. The concentration of tramadol in the blood serum of 100-300 ng / ml is usually effective.

Indications:Treatment of pain of medium and high intensity.

Contraindications:

- hypersensitivity to tramadol or any of the components of the drug;

- acute intoxication with alcohol, hypnotics, analgesics, opioids or other psychotropic drugs;

- contraindicated the joint use of tramadol with monoamine oxidase (MAO) inhibitors, and also within 14 days after the end of their admission;

- epilepsy, not amenable to adequate drug control;

- contraindicated the use of tramadol as a drug for the treatment of the syndrome of "withdrawal" of drugs;

- contraindicated during pregnancy. During breastfeeding the drug can be prescribed only for vital indications.In the case of a single dose, there is no need to interrupt breastfeeding;

- children under 1 year.

Carefully:

Tramadol should be used with caution:

- in patients with opioid dependence;

- with craniocerebral trauma, in patients with shock, in patients with impaired consciousness of unclear genesis, in patients with respiratory distress and disruption of the respiratory center, with increased intracranial pressure;

- the drug should be used with caution in patients with established severe intolerance to opioids of allergic and non-allergic genesis;

- with epilepsy, amenable to adequate drug control, or in patients prone to developing seizures, tramadol can only be used for life indications (see "Special instructions");

- In patients with a tendency to abuse drugs or drug dependence, tramadol should be treated with short courses and under medical supervision (see "Special instructions").

Pregnancy and lactation:

Pregnancy

Studies in animals have shown that in very high doses tramadol affects the development of internal organs, ossification and neonatal mortality. Tramadol penetrates the placental barrier. Convincing evidence of the safety of the use of tramadol during pregnancy in humans is not obtained, therefore tramadol Do not use during pregnancy. Long-term use of tramadol in pregnancy can lead to the development of symptoms of "cancellation" in a newborn. Tramadol, used before and during labor, does not affect the contractility of the uterus during childbirth. In newborns tramadol can cause a change in respiratory rate, which is usually not clinically significant.

Lactation

About 0.1% of the dose of tramadol administered to the mother is excreted with milk during lactation. Tramadol should not be used during breastfeeding. After a single dose of tramadol, there is usually no need to interrupt breastfeeding.

Fertility

Studies on animals and post-registration observations did not reveal the effect of tramadol on fertility.

Dosing and Administration:

Tramal® injection 50 mg / ml is for intravenous, intramuscular, subcutaneous and intravenous drip administration.Intravenous injection of the injection solution is carried out either slowly or driply after dilution in an injection solution. The method of preparation of Tramal® for injection is described in the section "Calculating the volume of solution for injection". The doses used depend on the severity of the pain syndrome and the individual sensitivity of the patient. It is necessary to select the minimum effective dose of the drug. In the treatment of chronic pain syndrome should adhere to a specific schedule for the administration of the drug.

Adults and teenagers over 12 years of age

Single dose for single administration of 50-100 mg of tramadol (1-2 ml of solution for injection). If 30-60 minutes after the first administration there is no satisfactory analgesia, 50 mg (1 ml) of tramadol can be re-administered.

In severe pain, the administration of 100 mg of tramadol is recommended as the initial dose. Depending on the intensity of the pain syndrome, the analgesic effect of tramadol lasts 4-8 hours. In the postoperative period, short-term use of tramadol in doses exceeding the indicated ones is possible. The maximum daily dose of tramadol should not exceed 400 mg,except for some clinical cases (for example, in the treatment of pain syndrome in cancer patients and in the postoperative period).

Children aged 1 to 12 years

Tramal® in the form of a solution for injection is prescribed in a single dose at the rate of 1 - 2 mg / kg of the child's body weight. It is necessary to select the minimum effective dose. The total daily dose of tramadol should not exceed 8 mg / kg of the body weight of the child or not more than 400 mg per day, the calculation is carried out at the lowest value.

Elderly patients

In elderly patients (up to 75 years old) who do not have clinically expressed hepatic or renal insufficiency, dose adjustment is usually not required. In patients older than 75 years, excretion of the drug may be delayed. Therefore, if necessary, increase the interval in the appointment of the drug in accordance with the characteristics of the patient.

Patients with renal insufficiency or on dialysis and patients with hepatic impairment

If the renal and / or liver function is impaired, the excretion of tramadol from the body is slowed. If necessary, the interval between doses of the drug should be increased.

Calculation of the volume of solution for injection:

1. To calculate the full dose of tramadol (mg), it is required: body weight (kg) x dose (mg / kg).

2. The volume (ml) of the diluted solution for administration is calculated as follows: divide the total dose (mg) by the appropriate concentration of the diluted solution (mg / ml, see table below).

Tramal® 50 mg (50 mg / ml - 1 ml) solution for injection + added solvent	Tramal® 100 mg (50 mg / mg-2 mL) injection solution + added solvent	The concentration of diluted solution for injection (mg tramadol / ml)
1 ml + 1 ml	2 ml + 2 ml	25.0 mg / ml
1 ml + 2 ml	2 ml + 4 ml	16.7 mg / ml
1 ml + 3 ml	2 ml + 6 ml	12.5 mg / ml
1 ml + 4 ml	2 ml + 8 ml	10.0 mg / ml
1 ml + 5 ml	2 ml + 10 ml	8.3 mg / ml
1 ml + 6 ml	2 ml + 12 ml	7.1 mg / ml
1 ml + 7 ml	2 ml + 14 ml	6.3 mg / ml
1 ml + 8 ml	2 ml + 16 ml	5.6 mg / ml
1 ml + 9 ml	2 ml + 18 ml	5.0 mg / ml

In accordance with the calculation, dilute the contents of the ampoule by adding a solvent, mix and enter the calculated volume of the finished solution. Dispose of unused residue of injection solution.

Duration of therapy

Tramadol should never be used for longer than necessary. With long-term use of tramadol, due to the intensity or etiology of pain,Periodic monitoring is necessary (if necessary with interruptions in taking the drug) to determine the need for further therapy and optimize the dosing regimen.

Side effects:

The most common side effects are nausea and dizziness, noted in more than 10% of patients.

The frequency is defined as follows:

Often: >1/10;

Often: >1/100, <1/10;

Infrequently: >1/1000, <1/100;

Rarely: >1/10 000, <1/1000;

Very rarely: <1/10 000;

Insufficient data: can not be determined based on available data.

Heart Disease:

Infrequently: the effect on cardiovascular regulation (palpitation, tachycardia). These side effects are mainly observed with intravenous administration of the drug or with significant physical exertion.

Rarely: aetiology.

Vascular disorders:

Infrequently: effects on cardiovascular regulation (orthostatic hypotension or collapse). These side effects are mainly observed with intravenous administration drug or with significant physical exertion.

Rarely: increased blood pressure.

Disorders from the metabolism and nutrition:

Rarely: changes in appetite.

Disturbances from the respiratory system, chest and mediastinal organs:

Rarely: respiratory depression, shortness of breath.

At a significant excess of the recommended doses with simultaneous use of other drugs that depress the central nervous system (CNS), respiratory depression is possible.

There was a deterioration in bronchial asthma, but the cause-the investigational link with the use of the drug was not established.

Impaired nervous system:

Very often: dizziness.

Often: headache, drowsiness.

Rarely: speech disorders, paresthesia, tremor, epileptiform seizures, involuntary muscle contractions, coordination disorders, fainting. Epileptiform seizures are possible after application of high doses of tramadol or with simultaneous use with drugs that lower the threshold of convulsive readiness.

Disorders of the psyche:

Rarely: hallucinations, confusion, sleep disturbances, anxiety, delirium and nightmares. After the use of tramadol, various rarely observed undesirable reactions from the psyche are possible (depending on the patient's personal characteristics and duration of treatment).These side effects include mood changes (usually euphoria, sometimes dysphoria), changes in activity (usually a decrease, sometimes an increase), impairment of cognitive functions and perception (eg, decision-making, perceptual disorders). Perhaps the development of drug dependence. Possible symptoms of "withdrawal" are similar to the symptoms of "withdrawal" of opioids: agitation, anxiety, nervousness, sleep disorders, hyperkinesia, tremor and gastrointestinal symptoms.

Other symptoms that are very rare with the cancellation of tramadol include:

panic attacks, severe anxiety, hallucinations, paresthesia, ringing in the ears and others extremely rare symptoms from the side of the central nervous system (confusion, hallucinations, depersonalization, derealization, paranoia).

Disorders from the side of the organ of vision:

Rarely: miosis, mydriasis, blurred vision.

Disorders from the gastrointestinal tract:

Very often: nausea.

Often: constipation, dry mouth, vomiting.

Infrequent: vomiting, a feeling of heaviness in the epigastrium, flatulence, diarrhea.

Disturbances from the skin and subcutaneous tissues:

Often: sweating.

Infrequent: skin reactions (eg, itching, erythema, urticaria).

Disturbances from the musculoskeletal and connective tissue:

Rarely: muscle weakness.

Disorders from the liver and bile ducts:

In some cases there was an increase in the activity of liver enzymes, in time coinciding with therapy tramadol.

Disorders from the kidneys and urinary tract:

Rarely: disturbances of urination (dysuria and urinary retention).

Immune system disorders:

Rarely: allergic reactions (dyspnoea, bronchoconstriction, wheezing, angioedema) and anaphylaxis.

General disorders and disorders at the site of administration:

Often: fatigue.

If any of the following side effects occur, or if there are other side effects not indicated in the instructions, tell your doctor.

Overdose:

In case of an overdose of tramadol, symptoms characteristic of narcotic analgesics should be expected.

Possible Symptoms: miosis, vomiting, collapse, consciousness up to the coma, convulsions, depression of the respiratory center to respiratory paralysis.

Treatment. Providing airway patency. Maintaining respiration and activity of the cardiovascular system depending on the symptomatology. If breathing is disturbed, enter naloxone. When convulsions should be administered intravenously diazepam. When an overdose of the drug in oral dosage forms, it is necessary to wash the stomach and prescribe Activated carbon within the first two hours after an overdose. After taking especially large doses of the drug in capsules, removing the contents of the stomach can be effective at a later date. Hemodialysis and hemofiltration are ineffective in overdose.

Interaction:

Tramal® injection solution is pharmaceutically incompatible with injectable solutions of diclofenac, indomethacin, phenylbutazone, diazepam, flunitrazepam, midazolam, nitroglycerin.

Tramadol can not be administered simultaneously or within 14 days after the abolition of monoamine oxidase inhibitors (MAO). In patients treated with MAO inhibitors, life-threatening drug interactions, manifested by symptoms from the central nervous system, respiratory and cardiovascular systems, were noted 14 days prior to the onset of the use of the opioid analgesic pethidine. Similar interactions with MAO inhibitors are possible with the administration of tramadol.

The simultaneous use of tramadol and substances that suppress the activity of the central nervous system, including alcohol, can increase the side effects of the central nervous system.

It is noted that with the joint or previous use of cimetidine (an inhibitor of microsomal liver enzymes) clinically significant interactions are unlikely. Concurrent or previous use of carbamazepine (an inducer of microsomal liver enzymes) can reduce the analgesic effect of tramadol and shorten its duration.

Tramadol may induce convulsions and increase the effects of selective serotonin reuptake inhibitors (SSRIs), serotonin reuptake inhibitors, norepinephrine (SNRI), tricyclic antidepressants, neuroleptics, and other medications that lower seizure threshold (e.g., bupropion, mirtazapine), thus leading to the development of seizures.

The simultaneous use of tramadol with other serotonergic drugs such as selective serotonin reuptake inhibitor, ingibitoryobratnogo serotonin-noradrenaline, MAO inhibitors, tricyclic antidepressants, and mirtazapine can lead to the development of serotonin syndrome. The probability of developing a serotonin syndrome exists when one of the following symptoms / syndromes is observed:

- spontaneous muscular clone;

- Induced or ocular myoclonus with excitation or increased sweating;

- tremor and hyperreflexia;

- hypertension, an increase in body temperature> 38 ° C and inducible or ocular myoclonus.

The abolition of serotonergic drugs causes rapid disappearance of symptoms. The necessary therapy is determined by the clinical picture and the severity of the symptoms. With the simultaneous use of tramadol and coumarin derivatives (eg warfarin), careful monitoring of patients is necessary, as some have an increase in the international normalized ratio (MHO) with the development of bleeding and ecchymosis.

Other inhibitors of the isoenzyme CYP3A4, for example, ketoconazole and erythromycin, can slow down the metabolism of tramadol (N-demethylation) and, possibly, active O-demethyltramadol. The clinical significance of this interaction has not been studied.There is limited evidence that pre- or post-operative use of the 5-HTs receptor blocker-ondansetron has increased the need for tramadol in patients with postoperative pain syndrome.

Special instructions:

In patients with opioid dependence, head trauma, shock, in patients with impaired consciousness of unclear etiology, breathing disorders or respiratory center damage, increased intracranial pressure tramadol should only be used with extreme caution.

The drug should be used with caution in patients with known cases of severe intolerance to opioids of allergic and non-allergic origin.

There have been cases of seizures in patients taking tramadol in recommended doses. The risk of seizures may increase if the recommended maximum daily dose of the drug is exceeded (400 mg). The administration of tramadol may increase the risk of seizures in patients taking drugs that reduce the convulsive threshold. Patients with epilepsy and patients prone to developing seizures should take tramadol only for life indications.

Tramal® has a low potential for drug dependence.However, with prolonged use, addiction, physical and mental dependence are possible. In patients prone to drug abuse, or to the development of drug dependence, treatment with Tramal® should only be carried out with short courses and under medical supervision.

Tramal® is not applicable as a substitute therapy for patients with opioid dependence. Although tramadol is an agonist of opioid receptors, it can not suppress the symptoms of "withdrawal" of morphine.

Effect on the ability to drive transp. cf. and fur:Even at recommended doses tramadol can cause effects such as drowsiness and dizziness and can therefore disrupt the reaction of car drivers and machine operators. When using Tramal®, it is necessary to refrain from managing motor vehicles and practicing potentially dangerous activities that require increased concentration of attention and rapid psychomotor reactions, especially when combined with other psychotropic drugs or alcohol.

Form release / dosage:Solution for injection 50 mg / ml.

Packaging:For 1 or 2 ml in glass ampoules (type I).5 ampoules in a contour acheive box along with instructions for use in a cardboard pack.

Storage conditions:At a temperature of no higher than 25 ° C. Keep out of the reach of children.

Shelf life:

5 years. Do not use after the expiry date printed on the package.

Terms of leave from pharmacies:On prescription

Registration number:П N014289 / 03

Date of registration:12.12.2008

Date of cancellation:2017-09-26

The owner of the registration certificate:SHTADA Artznajmittel AGSHTADA Artznajmittel AG Germany

Manufacturer: & nbsp

SHTADA Artznajmittel AG

Representation: & nbspNizhpharm, JSCNizhpharm, JSCRussia

Information update date: & nbsp26.09.2017

Illustrated instructions

Instructions

Tramal® (Tramal®)