Dyurogezik Matriks

General characteristics. Structure:

Active agent – fentanyl (TTS of 12,5 mkg/h contains 2,1 mg of fentanyl, TTS of 25 mkg/h contains 4,2 mg of fentanyl, TTS of 50 mkg/h contains 8,4 mg of fentanyl, TTS of 75 mkg/h contains 12,6 mg of fentanyl, TTS of 100 mkg/h contains 16,8 mg of fentanyl).

Excipients: a substrate – copolymer of polyethyleneterephthalate (PET) and an etilenvinilatsetat (EVA); adherent layer – polyacrylate (Duro-Tak® 87-4287); a protective film – silikonizirovanny polyethyleneterephthalate (PET).

Pharmacological properties:

Pharmacodynamics.

Fentanyl – the synthetic analgetic interacting preferential with μ-opioid receptors. Treats the list II of drugs, psychotropic substances and their precursors approved by the Resolution of the Government of the Russian Federation No. 681 of 30.06.98. Increases activity of anti-nociceptive system, increases a threshold of painful sensitivity. Breaks transfer of excitement on specific and nonspecific painful ways to kernels of a thalamus, a hypothalamus, an amygdaloid complex.

The main therapeutic effects of drug are anesthetizing and sedative. The minimum effective anesthetizing concentration of fentanyl in plasma at the patients who were not applying earlier opioid analgetics makes 0,3–1,5 ng/ml. The general time of effect of drug – 72 hours.

Has the oppressing effect on a respiratory center, slows down a cordial rhythm, excites the centers of a vagus nerve and the emetic center. Raises a tone of unstriated muscles of biliary tract, sphincters (including an urethra, a bladder, Oddi's sphincter), reduces an intestines peristaltics, improves absorption of water from the digestive tract (DT). Practically does not exert impact on the arterial pressure (AP), reduces a renal blood stream. In blood increases the content of amylase and a lipase. Promotes approach of a dream.

Causes euphoria.

Speed of development of medicinal dependence and tolerance to analgetic action has significant individual differences.

Pharmacokinetics.

Absorption. The Matrix Transdermal Therapeutic System (TTS) Dyurogezik® provides continuous system release of fentanyl within 72 hours after application. Fentanyl is released with rather constant speed. The concentration gradient between TTS and low concentration in skin provides fentanyl release. After application of the drug Dyurogezik® Matrix concentration of fentanyl in a blood plasma gradually increases within the first 12-24 hours and remains concerning a constant during the remained span. Level of concentration of fentanyl in a blood plasma is proportional to the TTS size.

By the end of the second 72-hour application equilibrium concentration in a blood plasma which is supported by means of the subsequent applications of TTS of the same size is reached. The pharmacokinetic model shows that concentration of fentanyl in plasma can increase on average by 14% (ranging from 0 to 26%) if new TTS is pasted in 24 hours in comparison with pasted in 72 hours as it is recommended.

Distribution. Linkng of fentanyl with proteins of a blood plasma makes about 84%.

Metabolism. Fentanyl is a connection with high clearance which is quickly metabolized in a liver, preferential CYP3A4 enzyme. The main metabolite, norfentanit, is inactive. At transdermalny introduction fentanyl is not metabolized in skin that was defined in researches on keratotsita of the person and in clinical tests (92% of a dose of fentanyl (TTS), in not changed look came to a blood stream).

Removal. After removal of TTS Dyurogezik® the Matrix concentration of fentanyl in a blood plasma gradually decreases, at the same time the elimination half-life makes about 17 (13-22) hours after 24-hour application of TTS. After 72-hour application of TTS the elimination half-life makes about 20-27 hours.

The continuing absorption of fentanyl from skin explains slower disappearance of drug from a blood plasma in comparison with intravenous administration of fentanyl when the elimination half-life makes about 7 (3-12) hours.

In 72 hours after intravenous administration of fentanyl about 75% of a dose of fentanyl it is removed with urine, generally in the form of metabolites and less than 10% in not changed look. About 9% are removed with a stake, generally in the form of metabolites.

Special groups of patients.

Elderly patients. The data received at fentanyl researches at intravenous administration allow to assume that at elderly patients the clearance can decrease and be extended a drug elimination half-life, but also, such patients can be more sensitive to fentanyl, than young patients. In researches of the drug Dyurogezik® Matrix on healthy volunteers of advanced age it is established that the pharmacokinetics of fentanyl of upozhily people does not differ considerably from pharmacokinetics at young healthy people though at elderly the peak of concentration is lower and the elimination half-life is extended approximately till 34 o'clock. Elderly patients should be observed carefully for identification of symptoms of toxicity of fentanyl and if necessary to lower a dose of the drug Dyurogezik® Matrix.

Patients with a liver failure. The pharmacokinetics of a single dose of 50 mkg/h was studied at patients with cirrhosis. In spite of the fact that time of achievement of the maximum concentration and an elimination half-life did not change, average values of the maximum concentration and the area under a curve concentration time increased by 35% and 73% respectively. Patients with a liver failure should be observed carefully for identification of symptoms of toxicity of fentanyl and if necessary to lower a dose of the drug Dyurogezik® Matrix.

Patients with a renal failure. The data received at fentanyl researches at intravenous administration on patients after transplantation of a kidney allow to assume that this group of patients can have a reduced clearance of fentanyl. The patients with a renal failure accepting Dyurogezik® the Matrix should be observed carefully for identification of symptoms of toxicity of fentanyl and if necessary to lower a dose of the drug Dyurogezik® Matrix.

Indications to use:

Chronic pain syndrome of strong and average expressiveness: - the pains caused by an oncological disease; - the pain syndrome of not oncological genesis demanding repeated anesthesia by narcotic analgetics, for example neyropatichesky pains (a pain syndrome at diabetic polyneuropathy, injuries of a nerve, a myelosyringosis, multiple sclerosis, shingles (Herpes zoster)), arthritises and arthroses, stump neuralgias after amputation of extremities, etc.

Route of administration and doses:

The dose of the drug Dyurogezik® Matrix is selected individually depending on a condition of the patient and has to be estimated regularly after application of TTS.
Дюрогезик® the Matrix should be applied on the flat surface of skin of a trunk or upper parts of hands. For application it is recommended to choose the place with the minimum indumentum. Before application hair on site applications should be sheared (not to shave off!).
If before application of a plaster the place of application needs to be washed up, then it should be made by means of clear water. It is not necessary to use soap, lotions, oils or other means as they can cause irritation of skin or change its properties. Before application skin has to be absolutely dry.
Before use the transdermal system needs to be checked carefully regarding damages. TTS divided into the parts cut or otherwise damaged in any case should not be used.
Дюрогезик® the Matrix should be pasted right after extraction from the soldered package. For extraction of a transdermal system from a package put an upper part of a bag along a cut (it is designated by an arrow) and tear off it. Then open a package as open the book. The protective film has a section in the middle. Put a transdermal system in half in the middle and remove each half of a protective film, without touching with fingers a sticky layer.
The transdermal system needs to be pressed densely a palm on site of application for 30 seconds. It is necessary to be convinced that the plaster densely adjoins to skin, especially at the edges. After gluing of TTS wash up hands clear water.
Дюрогезик® the Matrix is counted on continuous use within 72 hours. The new system can be pasted on other site of skin after removal of earlier pasted plaster. On the same site of skin transdermalny systems it can be pasted only at an interval of several days.

Selection of an initial dose
The initial dose of the drug Dyurogezik® Matrix is selected, proceeding from the previous use of opioid analgetics. It is recommended to appoint Dyurogezik® the Matrix to the patients showing opioid tolerance. Also other factors are considered: general condition of the patient, including body size, age, degree of exhaustion and degree of opioid tolerance.
- The patients who were earlier accepting opioids
For transition from peroral or parenteral forms of opioids to the drug Dyurogezik® Matrix at patients with tolerance to opioids it is necessary to be guided by the "Transfer in the equivalent anesthetizing dose" given below. The dosage can be reduced or increased afterwards if necessary by 12 or 25 mkg/h for achievement of the smallest dose of the drug Dyurogezik® Matrix depending on reaction and additional requirements to anesthesia.
- The patients who were earlier not accepting opioids
Experience of use of the drug Dyurogezik® Matrix for the patients who were earlier not accepting opioids is limited. In cases when patients need purpose of the drug Dyurogezik® Matrix, earlier not accepting opioids, it is recommended to begin with small doses of opioids of bystry release (for example, morphine, трамадол and codeine), equivalent 25 mkg/h of the drug Dyurogezik® Matrix. After that patients can be transferred to a dose of 25 mkg/h of the drug Dyurogezik® Matrix. The dosage can be reduced or increased afterwards if necessary by 12 or 25 mkg/h for achievement of the smallest dose of the drug Dyurogezik® Matrix depending on reaction and additional requirements to anesthesia (see. "Transfer in the equivalent anesthetizing dose").

Transfer in the equivalent anesthetizing dose
1. 1. To calculate the previous 24-hour need for an analgesia
2. 2. To transfer this quantity to an equivalent peroral dose of morphine by means of Table 1. All intramuscular and peroral doses of the opioid analgetics given in this table are equivalent on analgesic effect 10 mg of morphine in oil.
3. 3. To find the dose of the drug Dyurogezik® Matrix equivalent to a 24-hour dose of morphine which is required for the patient, by means of table 2 or 3:
a) Table 2 is applicable for the patients demanding transfer from other mode of administration of opioids (the relation of a dose of peroral morphine to a transdermalny form of fentanyl about 150:1).
b) Table 3 is applicable for the patients who are on stable, well transferable opioid therapy (the relation of a dose of peroral morphine to a transdermalny form of fentanyl about 100:1).

Table 1: Transfer in the equivalent anesthetizing dose

Name of drug	The equivalent anesthetizing dose (mg)
	in oil *	inside
Morphine	10	30 (at regular introduction) ** 60 (at single or intermittent introduction)
Omnoponum	45	-
Hydromorphone	1.5	7.5
Methadone	10	20
Oxycodone	15	30
Levorphanol	2	4
Oxymorphone	1	10 (rektalno)
Diamorphine	5	60
Pethidine	75	-
Codeine	130	200
Buprenorphine	0.3	0.8 (sublingual)

* These peroral doses are recommended upon transition from introduction, parenteral to a peroral way.
** The ratio of force of effect of morphine at an intramuscular/peroral way of introduction, is based on the clinical experience got at treatment of patients with chronic pains.

Table 2: The recommended dose of the drug Dyurogezik® Matrix (depending on a daily peroral dose of morphine) *

Peroral daily dose of morphine (mg/days)	Dose of the drug Dyurogezik® Matrix (Mkg/h)
<135	25
135-224	50
225-314	75
315-404	100
405-494	125
495-584	150
585-674	175
675-764	200
765-854	225
855-944	250
945-1034	275
1035-1124	300

* During clinical tests these values of daily doses of morphine were used as a basis for transition to Dyurogezik® the Matrix.

The table 3 The Recommended Initial Dose of Drug Dyurogezik® Matrix on the basis of a daily peroral dose of morphine (for the patients who are on stable, well transferable opioid therapy)
<44 (Morphine mg/days) - 12,5 (mkg/h of Dyurogezik® of the Matrix)
45-89 (Morphine mg/days) - 25 (mkg/h of Dyurogezik® of the Matrix)
90-149 (Morphine mg/days) - 50 (mkg/h of Dyurogezik® of the Matrix)
150-209 (Morphine mg/days) - 75 (mkg/h of Dyurogezik® of the Matrix)
210-269 (Morphine mg/days) - 100 (mkg/h of Dyurogezik® of the Matrix)
270-329 (Morphine mg/days) - 125 (mkg/h of Dyurogezik® of the Matrix)
330-389 (Morphine mg/days) - 150 (mkg/h of Dyurogezik® of the Matrix)
390-449 (Morphine mg/days) - 175 (mkg/h of Dyurogezik® of the Matrix)
450-509 (Morphine mg/days) - 200 (mkg/h of Dyurogezik® of the Matrix)
510-569 (Morphine mg/days) - 225 (mkg/h of Dyurogezik® of the Matrix)
570-629 (Morphine mg/days) - 250 (mkg/h of Dyurogezik® of the Matrix)
630-689 (Morphine mg/days) - 275 (mkg/h of Dyurogezik® of the Matrix)
690-749 (Morphine mg/days) - 300 (mkg/h of Dyurogezik® of the Matrix)

Initial assessment of the maximum analgesic effect of the drug Dyurogezik® Matrix cannot be made less than in 24 hours after application. This period is caused by gradual increase in concentration of fentanyl in serum after application.
For successful transition from one drug to another the previous anesthetizing therapy has to be cancelled gradually after application of an initial dose of the drug Dyurogezik® Matrix.
Selection of a dose and maintenance therapy.
For selection of a dose use TTS Dyurogezik® the Matrix 12,5 MSC/h TTS Dyurogezik® the Matrix should be replaced new each 72 hours. The dose is selected individually, observing balance between achievement of necessary anesthesia and portability by the patient. If after application of an initial dose adequate anesthesia is not reached, then in 3 days the dose can be increased. Further the dose can be increased every 3 day.
At the beginning of therapy at some patients the adequate analgesia can be not reached during the day before yesterday application of TTS at this interval of dosing, and in this case replacement of TTS in 48 hours, but not in 72 hours can be required. At reduction of duration of application by early removal of TTS concentration of fentanyl in plasma can increase. Usually for once the dose increases by 12,5 mkg/h or 25 mkg/h, however it is necessary to consider a condition of the patient and the need for additional anesthesia (peroral doses of morphine of 45 mg/days and 90 mg/days are approximately equivalent to doses of the drug Dyurogezik® Matrix of 12,5 Mkg/h and 25 Mkg/h respectively).
For achievement of a dose more than 100 mkg/h can be used by several TTS at the same time.
Additional doses of analgetics of short action when developing of the "breaking" pains can periodically be required for patients. Additional or alternative ways of introduction of opioid analgetics when using the dose of the drug Dyurogezik® Matrix exceeding 300 mkg/h can be required by some patients.

Features of use:

Patients at whom heavy side effects were noted have to be under careful observation not less than 24 hours (depending on symptoms) after removal of TTS Dyurogezik® the Matrix as concentration of fentanyl in plasma decreases gradually and its 50% decrease are reached within about 17 (13-22) hours.

Дюрогезик® the Matrix should be stored in places, unavailable to children, both to, and after use.

TTS Dyurogezik® the Matrix cannot be cut.

Use for the patients who were earlier not accepting opioids and at the patients who are not possessing a toleranstnost to opioids. At use of TTS Dyurogezik® the Matrix at the patients who were earlier not accepting opioids very seldom cases of considerable respiratory depression and/or death at use as initial opioid therapy were noted. The possibility of development of serious or life-threatening hypoventilation of lungs exists even in case of use of the minimum dose of TTS Dyurogezik® the Matrix as initial opioid therapy at the patients who were earlier not accepting opioids. It is recommended to appoint Dyurogezik® the Matrix to the patients showing opioid tolerance.

Respiratory depression. As well as when using other strong opioid analgetics, at use of the drug Dyurogezik® Matrix for some patients considerable respiratory depression can be noted. Patients should be inspected carefully for identification of similar effects. Respiratory depression can proceed also after removal of TTS Dyurogezik® the Matrix. Degree of respiratory depression increases with increase in a dose of the drug Dyurogezik® Matrix. The medicines influencing TsNS can strengthen respiratory depression.

Chronic diseases of lungs. Дюрогезик® the Matrix can cause a number of heavy side effects in patients with chronic obstructive and other diseases of lungs. At such patients opioids can reduce excitability of a respiratory center and increase respiratory resistance.

Increase in intracranial pressure. Дюрогезик® the Matrix should be applied with care at patients who can be especially sensitive to increase in maintenance of CO2. Such patients are at what increase in intracranial pressure, disturbance of consciousness or a lump was noted. Дюрогезик® the Matrix should be applied with care at patients with a brain tumor.

Cardiovascular diseases. Fentanyl can cause bradycardia and, thus, it should be applied with care at patients with bradyarrhythmias. It is necessary to apply with care Dyurogezik® the Matrix at patients with arterial hypotension.

Liver failure. As fentanyl is metabolized to inactive metabolites in a liver, the abnormal liver function can lead to a drug removal delay. The patients with a liver failure accepting Dyurogezik® the Matrix have to be under constant observation for identification of symptoms of possible toxicity of fentanyl, and if necessary the dose of the drug Dyurogezik® Matrix has to be lowered. Opioid analgetics can raise a tone of smooth muscles of digestive tract and biliary tract. Дюрогезик® the Matrix should be applied with care at patients with hepatic colic in the anamnesis.

Renal failure. Less than 10% of fentanyl are removed by kidneys in an invariable look, fentanyl has no known active metabolites which would be removed by kidneys. The patients with a renal failure accepting Dyurogezik® the Matrix have to be under constant observation for identification of symptoms of possible toxicity of fentanyl and if necessary the dose of the drug Dyurogezik® Matrix has to be lowered.

Serotoninovy syndrome. It is necessary to be careful at combined use of the drug Dyurogezik® Matrix with the drugs influencing serotonergic neyrotransmitterny system. Combined use with serotonergic drugs, such as the selective serotonin reuptake inhibitors (SSRI) and inhibitors of the return serotonin reuptake and noradrenaline (IOZSN), and also with the drugs reducing serotonin metabolism (including monoamine oxidase inhibitors) can lead to development of potentially life-threatening serotoninovy syndrome. This syndrome can arise at reception of the recommended doses. The Serotoninovy syndrome can include mental disturbances (agitation, hallucinations, a coma), vegetative disturbances (tachycardia, fluctuations of arterial pressure, a hyperthermia), nervnomyshechny disturbances (a hyperreflexia, a lack of coordination, rigidity) and/or disturbances from gastrointestinal system (nausea, vomiting, diarrhea). At suspicion on development of a serotoninovy syndrome therapy by the drug Dyurogezik® Matrix should be cancelled.

Interaction with CYP3A4 cytochrome inhibitors. At combined use with CYP3A4 cytochrome inhibitors (for example, ритонавир, кетоконазол, итраконазол, тролеандомицин, кларитромицин, нелфинавир, нефадозон, verapamil, diltiazem and Amiodaronum) increase in concentration of fentanyl in plasma is possible. Strengthening or lengthening as therapeutic action, and development of possible side effects is a consequence of it (respiratory depression). The patient has to be in these cases under constant observation of the doctor. Therefore, combined use of transdermalny forms of fentanyl with inhibitors of CYP3A4 cytochrome is not recommended, except for cases when patients are under observation of the doctor. In case of symptoms of oppressed breath, a dozapreparat it has to be reduced.

Accidental influence of TTS. Accidental impact of the drug Dyurogezik® Matrix on skin (especially at children) at close physical contact with the patient using TTS can lead to opioid overdose. Patients have to be warned that at accidental impact on skin of the person who is not accepting drug, TTS has to be immediately removed. At overdose symptoms see the Section "Overdose".

Use for elderly patients. The data received at researches of intravenous administration of fentanyl allow to assume that at elderly patients the clearance can decrease and be extended a drug elimination half-life, but also, such patients can be more sensitive to fentanyl, than young patients. The elderly patients accepting Dyurogezik® the Matrix have to be under constant observation for identification of symptoms of possible overdose of fentanyl and if necessary the dose of the drug Dyurogezik® Matrix has to be lowered.

Influence on a GIT. Opiates raise a tone and reduce propulsive reductions of smooth muscles of digestive tract. As a result time of gastrointestinal transit increases that can be the cause of locks. Patients have to be informed on measures of prevention of locks and preventive use of purgatives. Additional precautionary measures should be applied to the patients suffering from chronic locks. If paralytic intestinal impassability is present or is suspected, treatment by the drug Dyurogezik® Matrix has to be stopped. Use for the exhausted and weakened patients. As at the exhausted and weakened patients the clearance can decrease and be extended a drug elimination half-life, the exhausted and weakened patients have to be under constant observation of the doctor for identification of symptoms of possible overdose, in this case the dose of the drug Dyurogezik® Matrix has to be lowered.

Medicinal dependence and possibility of abuse. At repeated administration of opioids tolerance, and also physical and mental dependence can develop. Iatrogenic dependence at use of opioids is noted seldom. As well as at use of other agonists of opioid receptors, fentanyl abuse chances. Abuse or deliberate use of the drug Dyurogezik® Matrix not to destination can lead to overdose and/or by death. The patients who are in group of the increased risk of abuse of opioids can still receive adequate therapy by opioids of the modified release, however have to be under observation for identification of possible signs of use not to destination, to abuse or dependence emergence.

Fever / external sources of heat. The pharmacokinetic model allows to assume that concentration of fentanyl in serum can increase approximately on one third if body temperature increases to 40 °C. Therefore, patients with fever have to be under constant observation for identification of side effects, characteristic of opioids, and, if necessary, the subsequent dose adjustment. Increase in release of fentanyl from TTS at temperature increase as a result of which the overdose and the death of the patient are possible is noted. The research on healthy volunteers showed that when heating of the pasted TTS Dyurogezik® the Matrix increase in average AUC values by 120% and Cmax by 61% was observed. All patients need to avoid direct influence of external sources of heat, such as heating lamps, lamps for suntan, intensive solar bathtubs, hot-water bottles, saunas, a sunbed, bathtubs with hot water, etc., to the place of application of TTS Dyurogezik® the Matrix.

Phase-out of the drug Dyurogezik® Matrix. In need of phase-out of the drug Dyurogezik® Matrix, replacement of this drug with others of an opioidamidolzhn to pass gradually, since low doses. Such mode of replacement of drugs is necessary because of gradual decrease in concentration of fentanyl after removal of TTS Dyurogezik® the Matrix, at the same time decrease in concentration of fentanyl by 50% in blood serum takes 17 hours. Cancellation of an opioid analgesia always has to be gradual to prevent development of "withdrawal".

Impact on ability to drive the car and to work with the equipment. Дюрогезик® the Matrix can influence the mental and/or physical functions necessary for performance of potentially dangerous work, such as driving or work with the equipment. During treatment it is necessary to refrain from driving of transport and occupations potentially dangerous types of activity demanding the increased concentration of attention and speed of psychomotor reactions.

Removal of TTS. The used TTS should be put in half the sticky party inside and to return to the doctor for destruction in accordance with the established procedure. Unused TTS need also to be returned to the doctor for destruction. Prior to use drug should be stored in the sealed package.

Side effects:

Side effects are given with distribution on the frequency and systems of bodies. Frequency of side effects was classified as follows: very frequent (≥ 1/10), frequent (≥ 1/100, <1/10) and infrequent (≥ 1/1000, <1/100), rare (≥1/10000, <1/1000 and very rare (<1/10000, including separate cases).

From a nervous system:

- very often – drowsiness, dizziness, a headache;

- infrequently - a gipoesteziya;

- very seldom – spasms (including clonic spasms and a big epiletichesky attack), amnesia, confusion of consciousness, a loss of consciousness.

Disturbances of mentality:

- very often - sleeplessness;

- often – a depression, an alarming condition, confusion of consciousness, a hallucination;

- infrequently - a disorientation, euphoria;

- very seldom – agitation.

From sense bodys:

- often – вертиго;

- infrequently – a miosis;

- very seldom – a sight illegibility.

From respiratory system:

- infrequently - respiratory depression;

- very seldom – a respiratory distress syndrome, an apnoea, брадипноэ, hypoventilation, диспноэ (see the section "Overdose").

From the alimentary system:

- very often - nausea, vomiting;

- often – a lock, pains in a stomach, diarrhea, dryness in a mouth;

- infrequently – partial intestinal obstruction;

- very seldom - intestinal impassability, dyspepsia.

Disturbances of metabolism and food:

- often – anorexia.

From cardiovascular system:

- often – heartbeat;

- infrequently – cyanosis;

- very seldom - tachycardia, bradycardia, increase or a lowering of arterial pressure.

From a musculoskeletal system:

- often – muscular spasms;

- infrequently - twitchings of muscles.

From skin and hypodermic fabrics:

- often – an erythema;

- infrequently – dermatitis (including allergic and contact), eczema, etc. disturbances of skin.

From an urinary system:

- infrequently – an ischuria.

From immune system:

- often - hypersensitivity;

- very seldom – an acute anaphylaxis, anaphylactic reactions, anaphylactoid reactions.

From a reproductive system:

- infrequently – erectile dysfunction, sexual dysfunction.

Others:

- often – fatigue, a fever, an indisposition, an adynamy, peripheral hypostases;

- infrequently – reactions in the place of application (including dermatitis, eczema, hypersensitivity), "withdrawal", grippopodobny symptoms,

- very seldom – feeling of change of body temperature, a pyrexia.

As for other opioid analgetics, at repeated use of the drug Dyurogezik® Matrix physical and mental dependence and tolerance can develop.

Upon transition from earlier accepted narcotic analgetics to use of the drug Dyurogezik® Matrix or in case of the sudden termination of therapy the symptoms characteristic of cancellation of opioids (nausea, vomiting, diarrhea, an alarming state, a fever) are possible. Very exceptional cases of a withdrawal at newborn children whose mothers chronically applied Dyurogezik® the Matrix during pregnancy were celebrated.

Interaction with other medicines:

Simultaneous use of other drugs having the oppressing effect on TsNS including opioids, sedative and somnolent drugs, means for the general anesthesia, a fenotiazina, the tranquilizers, the central muscle relaxants, antihistaminic drugs possessing sedation and alcoholic beverages, can increase risk of emergence of the additive suppressive effect, hypoventilation of lungs, decrease in the ABP, excessive sedation, a coma or to lead to a lethal outcome (reception of any of the specified drugs along with use of the drug Dyurogezik® Matrix, demands special observation of the patient).

The concomitant use of inhibitors of P450 CYP3A4 cytochrome, can lead to increase in concentration of fentanyl in plasma. Strengthening or lengthening of both therapeutic action, and possible side effects, development of serious respiratory depression is a consequence of it. In these cases it is necessary to control a condition of the patient carefully.

Combined use of transdermalny forms of fentanyl with inhibitors of CYP3A4 cytochrome is not recommended, except for careful monitoring of patients (see the section "Special Instructions"). Combined use of drug with CYP3A4 isoenzyme inductors (for example, rifampicin, carbamazepine, phenobarbital, Phenytoinum) can lead to decrease in concentration of fentanyl in a blood plasma and to reduction of therapeutic effect. Dose adjustment of transdermalny fentanyl can be required. After the therapy termination by CYP3A4 isoenzyme inductors, effects of the inductor decrease gradually that can cause increase in concentration of fentanyl in a blood plasma. It, in turn, can cause strengthening or extension of therapeutic effect and expressiveness of side effects that can lead to serious respiratory depression. In case of need carry out careful monitoring of a condition of the patient and correction of a dose of drug.

Fentanyl strengthens effect of hypotensive medicines. Beta adrenoblockers can reduce the frequency and weight of hypertensive reaction in a heart surgery (including at a sternotomy), but increase risk of bradycardia.

Buprenorphine, налбуфин, pentazocine, Naloxonum, naltrexone reduce analgeziruyushchy effect of fentanyl and eliminate its oppressing influence on a respiratory center.

Muscle relaxants prevent or eliminate muscular rigidity; muscle relaxants with vagolytic activity (including a pankuroniya bromide) reduce risk of bradycardia and hypotension (especially against the background of use of beta adrenoblockers and other vazodilatator) and can increase risk of tachycardia and hypertensia; the muscle relaxants which do not have vagolytic activity (including сукцинилхолин), do not reduce risk of bradycardia and hypertensia (especially against the background of the burdened cardiological anamnesis) and increase risk of heavy side effects from cardiovascular system.

Nitrous oxide increases muscular rigidity; the effect reduces buprenorphine.

It is necessary to reduce a fentanyl dose at simultaneous use with insulin, glucocorticosteroids and hypotensive drugs.

Monoamine oxidase inhibitors (MAO). Joint purpose of fentanyl with MAO inhibitors is not recommended. Serious and unpredictable interactions with MAO inhibitors, with strengthening of effects of opioids or strengthening of serotonergic effects were noted. Therefore it is not recommended to appoint Dyurogezik® the Matrix earlier, than in 14 days after cancellation of MAO inhibitors.

Serotonergic drugs. Combined use of fentanyl with serotonergic drugs, such as the selective serotonin reuptake inhibitors (SSRI), inhibitors of the return serotonin reuptake and noradrenaline (IOZSN), monoamine oxidase inhibitors (IMAO) can increase risk of emergence of a serotoninovy syndrome – potentially life-threatening state.

Contraindications:

- hypersensitivity to fentanyl or to the adhesive substances which are a part of system;

- children's age up to 18 years;

- oppression of a respiratory center, including acute respiratory depression;

- the acute pain or postoperative pains demanding the short period of treatment;

- pregnancy and period of a lactation;

- diarrhea against the background of the pseudomembranous colitis caused by cephalosporins, linkozamida, penicillin;

- toxic diarrhea;

- the angry, irradiated or injured skin in the place of application.

With care:

- at chronic diseases of lungs;

- at intracranial hypertensia;

- at brain tumors;

- at craniocereberal injuries;

- at bradyarrhythmias;

- at arterial hypotension;

- at a renal and liver failure;

- at patients with hepatic or renal colic, including in the anamnesis;

- at cholelithiasis;

- at a hypothyroidism;

- at the elderly, exhausted and weakened patients (see the section "Special Instructions");

- at acute surgical diseases of abdominal organs before establishment of the diagnosis;

- at the general serious condition;

- at a high-quality prostatauxe;

- at urethra strictures;

- at medicinal dependence;

- at alcoholism;

- at suicide bent;

- at a hyperthermia;

- at a concomitant use of insulin, glucocorticoids, hypotensive medicines and MAO inhibitors.

Overdose:

Symptoms: брадипноэ, apnoea, muscle tension, oppression of a respiratory center, decrease in the ABP, bradycardia. Treatment: removal of TTS, physical and verbal stimulation (the patient should be "patted" on cheeks, to call by name, etc.), if necessary – auxiliary and the artificial ventilation of the lungs (AVL). Introduction of the specific antagonist – Naloxonum. Respiratory depression at overdose can longer last the period of action of the antagonist of opioids therefore there can be a need for repeated introduction of Naloxonum. The symptomatic and supporting important vital signs therapy (including introduction of muscle relaxants, IVL, at bradycardia – atropine, at decrease in the ABP – completion of volume of the circulating blood. Disappearance of analgetic effect can lead to development of a sharp painful attack and emission of catecholamines.

Storage conditions:

To store at a temperature of 15-25 °C. To store in the place unavailable to children.

Issue conditions:

According to the recipe

Packaging:

On 1 TTC in a package from the combined material (polyethyleneterephthalate, polyethylene of low density, aluminum foil). On 5 packages together with the application instruction are enclosed in a cardboard pack.