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

Pharmacodynamics:Opioid synthetic analgesic, a non-selective complete agonist of μ-, δ- and k-opioid receptors with a high affinity for μ-receptors. Inhibits the reuptake of norepinephrine and increases the release of serotonin. Tramadol also has antitussive effect, but, unlike morphine, does not exert a depressant effect on the respiratory system in a wide range of therapeutic doses. Slightly slows the peristalsis of the intestine without causing constipation, slightly affects hemodynamics, excites the start zone of the vomiting center, the nucleus of the oculomotor nerve. With prolonged use, the development of tolerance is possible.

Pharmacokinetics:

Absorption when administered intramuscularly - 100%. The maximum concentration (C_m_Oh) in the blood plasma is determined after 45 minutes, the metabolite mono-O-desmethyltramadol - after 3 hours. It penetrates through the blood-brain and placental barriers.

Insignificant amounts of tramadol and its O-demethylated derivative (OD% and 0.02%, respectively) are excreted in breast milk.

In the metabolism of tramadol, isozymes CYP3A4 and CYP2D6, 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.

The volume of distribution for intravenous administration is 203 ± 40 liters. Connection with blood plasma proteins - 20%.

Metabolized in the liver by N- and O-demethylation followed by conjugation with glucuronic acid. 11 metabolites have been identified, of which mono-O-desmethyltramadol has pharmacological activity. Inhibition of cytochrome P-450 isoenzymes (CYP3A4 and / or CYP2D6), involved in biotransformation of tramadol, can affect the concentration of tramadol and its active metabolites in blood plasma.

Displayed kidneys (25 - 35% unchanged), the average cumulative index of renal excretion - 94%. Half-life (T_1/2) in the second phase -6h (tramadol); 7.9 hours (mono-O-desmethyltramadol); in patients older than 75 years - 7.4 h (tramadol); with cirrhosis of the liver - 13.3 ± 4.9 h (tramadol), 18.5 ± 9.4 h (mono-O-desmethyltramadol), in severe cases - 22.3 and 36 h, respectively; with chronic renal failure (creatinine clearance less than 5 ml / min) - 11 ± 3.2 h (tramadol); 16.9 ± 3 hours (mono-O-desmethyltramadol); in severe cases - 19.5 and 43.2 hours, respectively.

About 7% is excreted by hemodialysis.

Indications:- Treatment of pain of medium and high intensity.

Contraindications:

- increased sensitivity to tramadol and other components of the drug;

- acute alcohol poisoning, hypnotics, narcotic analgesics, psychotropic drugs;

- simultaneous administration of monoamine oxidase inhibitors (MAO) (and two weeks after their withdrawal);

- epilepsy, which is not amenable to pharmacological correction;

- pregnancy;

- breastfeeding (a single application is only possible according to vital indications);

- as a means of treating the syndrome of "withdrawal" of narcotic drugs;

- children's age (up to 1 year).

Carefully:With caution and under the supervision of a doctor, the drug should be used in patients with impaired renal and hepatic function, with craniocerebral trauma, increased intracranial pressure, with epileptic syndrome (central genesis), drug dependence for opioids (opioid addiction), with a violation of the consciousness of various genesis, in patients with suicidal tendencies; on the background of pain in the abdominal cavity of an unknown genesis ("acute abdomen"), with a violation of consciousness of different genesis,with simultaneous use with selective serotonin reuptake inhibitors (some antidepressants, drugs that reduce appetite), tricyclic antidepressants, other tricyclic compounds (for example, promethazine), antimigraine drugs (triptans), narcotic analgesics, neuroleptics and other drugs that reduce the threshold of convulsive readiness; with hypersensitivity to other opioids, shock, respiratory center disorders or respiratory function.

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, so the use of tramadol during pregnancy is contraindicated.

Long-term use of tramadol in pregnancy can lead to the development of symptoms of "cancellation" in a newborn.

When applied immediately before or during labor tramadol does not affect the contractility of the uterus. The drug can cause a change in the respiratory rate in a newborn, which however, as a rule, has no clinical significance.

Lactation

The drug is excreted in breast milk at low concentrations (0.1% of the dose taken). Tramadol should not be used during breastfeeding. Single application is possible only for vital indications. After a single dose of tramadol, there is usually no need to interrupt breastfeeding.

With prolonged intake of the drug, it is necessary to resolve the issue of termination

breastfeeding.

Fertility

Studies in animals and post-registration studies have not revealed the effect of tramadol on fertility.

Dosing and Administration:

Tramadol is used according to the doctor's prescription, the dosage regimen is selected individually depending on the severity of the pain syndrome and the patient's sensitivity.

Tramadol is intended for intravenous (inject slowly - 1 ml for a minute), intramuscular or subcutaneous injection. Immediately before intravenous injection tramadol can be diluted in a 0.9% solution of sodium chloride or in a 5% solution of glucose.In the absence of other regulations tramadol should be given in the following doses:

children over 1 year old: a solution for injections can be prescribed in a single dose at a rate of 1 - 2 mg / kg of body weight of the child. For more accurate dosing, it is recommended to dilute the preparation with water for injection immediately before administration. Daily dose at calculation 4-8 mg / kg of body weight of the child;

adults and children over 12 years: single administration of 50-100 mg of tramadol hydrochloride (1 - 2 ml of injection solution). If there is no satisfactory analgesia, after 30 - 60 min, a second dose of 50 mg (1 ml) may be prescribed.

In severe pain, a single dose can be 100 mg (2 ml) of tramadol. 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).

It is necessary to select a minimally effective dose of the drug.The total daily dose 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.

In elderly patients (at the age of 75 and over) who do not have clinically expressed hepatic or renal failure, dose adjustment is not required. In connection with the possibility of delayed excretion, the interval between administration of the drug can be increased in accordance with individual characteristics.

Have nacitients with kidney and liver diseases tramadol may last longer. These patients the doctor can recommend an increase in the interval between the administration of single doses. Calculation of the volume of the solvent for injections

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)

50 mg (50 mg / ml-1 ml)	100 mg (50 mg / ml - 2 ml)	Concentration
solution for injection +	solution for injection +	diluted solution
solvent	solvent	for injections (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 under no circumstances should be used beyond the term justified from a therapeutic point of view. With long-term use of tramadol, due to the intensity or etiology of the pain syndrome, periodic monitoring (if necessary, with interruptions in the administration of tramadol) is necessary to determine the need for further therapy and the optimization of the dosing regimen.

Side effects:

According to the World Health Organization (WHO), undesirable effects are classified according to their frequency of development as follows: very often (>1/10), often (from >1/100 to <1/10), infrequently (from >1 / 1,000 to <1/100), rarely (from >1 / 10,000 to <1 / 1,000), very rarely (<1 / 10,000); frequency is unknown - according to available data, it was not possible to establish the frequency of occurrence.

From the side of the cardiovascular system

infrequently: tachycardia, orthostatic hypotension, palpitation,

cardiovascular failure, collapse;

rarely: fainting, bradycardia, increased blood pressure.

From the digestive system

Often: nausea;

often: dryness of the oral mucosa, vomiting, constipation;

infrequently: vomiting, diarrhea, irritation of the gastrointestinal tract,

feeling of heaviness in the stomach;

rarely: flatulence, pain in the abdomen, difficulty in swallowing.

From the nervous system

Often: dizziness; often: headache, drowsiness;

rarely: speech disorders, epileptiform seizures, involuntary muscular contractions, weakness, fatigue, paradoxical stimulation of the central nervous system (nervousness, agitation, anxiety, tremor, muscle spasms, euphoria, dysphoria, emotional lability, hallucinations), sweating, confusion, impaired coordination of movement , convulsions of the central genesis (with intravenous administration in high doses or with the simultaneous administration of antipsychotics), depression, amnesia, paresthesia, instability odki, blurred vision, anorexia, respiratory depression.

Epileptiform seizures are possible after applying high doses of tramadol or with simultaneous use with drugs that reduce 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 tramadol are: panic attacks, severe anxiety, hallucinations, paresthesia, ringing in the ears and other extremely rare symptoms from the central nervous system (confusion, hallucinations, depersonalization, derealization, paranoia).

From the skin and subcutaneous tissues

often: increased sweating;

infrequently: itching, redness, hives, rashes, including bullous.

From the musculoskeletal and connective tissue

rarely: motor weakness.

From the side of the urinary system

rarely: different types of dysuria.

From the side of the liver and bile ducts

rarely: increased activity of "liver" transaminases.

From the sense organs

rarely: impaired vision, taste, miosis, mydriasis.

From the respiratory system

rarely: dyspnea

Local Reactions

often: pain, compaction at the injection site;

rarely: local necrosis in the area of injection.

From the immune system

rarely: bronchospasm, angioedema (Quincke's edema), anaphylaxis.

From the side of metabolism

frequency unknown: hypoglycemia.

Other

rarely: withdrawal reaction symptoms similar to the opiate withdrawal reaction: agitation, anxiety, increased excitability, sleep disorders, hyperkinesia, tremor and symptoms of gastrointestinal disorders

rarely: withdrawal symptoms: panic attack, violent excitability, hallucinations, parasthesia, tinnitus and unusual symptoms from the central nervous system; violation of the menstrual cycle.

Overdose:

Symptoms: miosis, vomiting, collapse, oppression of consciousness, coma, convulsions, respiratory center depression, respiratory paralysis.

Treatment: ensuring airway patency, supporting breathing and cardiovascular activity. When spasms should be administered intravenously diazepam. If breathing is disturbed, enter naloxone. Tramadol only to a small extent is excreted during dialysis, so the use of only hemodialysis or hemofiltration with acute intoxication with tramadol is not enough.

In case of an overdose, the patient should be under the supervision of a physician, treatment - symptomatic.

Interaction:

Tramadol is pharmaceutically incompatible with injection solutions diclofenac, indomethacin, phenylbutazone, diazepam, flunitrazepam, midazolam, nitroglycerin.

Contraindicated simultaneous use of tramadol and monoamine oxidase inhibitors (MAO) (and two weeks after their withdrawal) due to the development of severe side effects from the central nervous system and the cardiovascular system. Patients treated with MAO inhibitors within 14 days before the onset of opioid analgesic use of pethidine were notedlife-threatening drug interactions, manifested by symptoms from the central nervous system, the respiratory system and the cardiovascular system. Similar interactions with MAO inhibitors are possible with the appointment of tarmadol.

Strengthens the action ethanol and the means, which exert a depressing influence on the central nervous system.

Inducers of microsomal liver enzymes (including carbamazepine, barbiturates) reduce the severity of the analgesic effect and the duration of action, increase the risk of seizures. Prolonged use of opioid analgesics and barbiturates also stimulates the development of cross tolerance.

Naloxone eliminates respiratory depression, eliminating analgesia after the use of opioid analgesics.

Quinidine increases the concentration in the blood plasma tramadol and reduces the metabolite tramadol (mono-O-desmethyltramadol) due to competitive inhibition of isofemant CYP2D6.

Inhibitor inhibitors CYP2D6 (such as fluoxetine, paroxetine and amitriptyline) reduce the metabolism of tramadol.

Inhibitor inhibitors CYP3A4 (ketoconazole, erythromycin) inhibit the metabolism of tramadol (N-detylation) and active (3-demethylated metabolite.

Simultaneous application with antagonists of serotonin 5HT3 receptors (ondansetron) increases the patient's need for tramadol in the treatment of postoperative pain.

When used simultaneously with coumarin derivatives (warfarin), careful monitoring of patients is necessary, since in some of them the prothrombin time increases with the development of bleeding and subcutaneous hemorrhage.

Tramadol can cause seizures and increase the effect of selective serotonin reuptake inhibitors (SSRIs), serotonin-noradrenaline reuptake inhibitors (SSRIs), tricyclic antidepressants, neuroleptics and other drugs that reduce the threshold of convulsive alertness (eg, bupropion, mirtazapine), thus leading to the development of seizures.

Simultaneous use of tramadol with other serotonergic drugs, such as selective serotonin reuptake inhibitors, serotonin-noradrenaline reuptake inhibitors, 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.

Special instructions:

Tramadol has a low potential for dependence formation. However, with its continued use, drug, psychological and physical dependence may develop. Patients who are inclined to develop addiction or drug dependence, should receive Tramadol only for a short time and under medical supervision. With a sharp discontinuation of tramadol, development of the "withdrawal" syndrome is not ruled out. With extended time intervals tramadol used in elderly patients.Under careful medical supervision and in reduced doses should be used tramadol against the background of the action of funds for anesthesia, sleeping pills and psychotropic drugs. It is forbidden to drink alcohol during treatment.

When using the drug Tramadol in the recommended doses, cases of seizures are noted. The administration of a dose exceeding the recommended daily dose of the drug (400 mg) increases the risk of seizures. With epilepsy or a tendency to convulsive seizures appoint tramadol patients should only in exceptional cases.

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). Admission tramaloda can increase the risk of seizures in patients taking drugs that reduce the threshold of convulsive readiness. Do not use for the treatment of the syndrome of "withdrawal" of drugs. Tramadol Do not prescribe instead of opioid drugs. Being an agonist of opioid receptors, tramadol can not suppress the symptoms of "cancellation" of drugs containing morphine.

The drug is not recommended for patients with severe intolerance of opioids of allergic and non-allergic origin.

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 the drug Tramadol it is necessary to refrain from driving vehicles and practicing potentially dangerous activities that require an increased concentration of attention and speed of psychomotor reactions, especially when combined with other psychotropic drugs and alcohol.

Form release / dosage:

Solution for injection 50 mg / ml.

Packaging:

By 1 ml or 2 ml in ampoules of colorless glass with a break point of blue.

5 ampoules per carton tray. One or two cardboard trays, along with instructions for use in a cardboard box.

5 ampoules per open blister of PVC. One or two blisters together with instructions for use in a cardboard box.

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

List No. 1 of the strong BACC substances.

Shelf life:

5 years.

Do not use after the expiration date.

Terms of leave from pharmacies:On prescription

Registration number:P N 015731/04

Date of registration:25.05.2009

The owner of the registration certificate:HEXAL AG HEXAL AG Germany

Manufacturer: & nbsp

HEXAL AG Germany

Representation: & nbspHEXAL AG HEXAL AG Germany

Information update date: & nbsp17.09.2015

Illustrated instructions

Instructions

Tramadol (Tramadol)