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

Excipients: lauryl alcohol (1-dodecanol) 10.2 mg / 20.4 mg / 30.6 mg / 40.8 mg, acrylic polymer (DURO TAK 87- 4098) 83.3 mg / 166.7 mg / 250.0 mg /333.3 mg, acrylic polymer (DURO TAK 87-2353) 3.7 mg / 7.3 mg / 11.0 mg / 14.7 mg;

protective film: polyester / ethyl vinyl acetate laminated film 15 cm²/ 30 cm²/ 45 centimeters²/ 60 cm², siliconized film 15 cm²/30 cm²/ 45 centimeters²/60 cm².

Description:

The patch is rectangular with a colorless and opaque adhesive matrix that contains the active ingredient, and is covered with a protective transparent easily removable film.There should be no residual tack on any of the surfaces.

On one side of the patch there is an international non-proprietary name and dosage of the preparation in English (the inscription may be incomplete).

Pharmacotherapeutic group:analgesic narcotic

ATX: & nbsp

N.01.A.H.01 Fentanyl

Pharmacodynamics:

Fentanyl - a synthetic analgesic, interacting predominantly with µ-opioid receptors. Increases the activity of the antinociceptive system, increases the threshold of pain sensitivity. Violates the transmission of excitation by specific and nonspecific painful pathways to the nuclei of the thalamus, the hypothalamus, the amygdala complex. In addition to the main therapeutic effects (analgesic and sedative), it has a depressing effect on the respiratory center, reduces the heart rate, excites the centers of the vagus nerve and vomiting center, increases the tone of the smooth muscles of the bile ducts, sphincters (including the urethra, bladder, sphincter of Oddi), reduces peristalsis of the intestine, improves the absorption of water from the gastrointestinal tract.Virtually no effect on blood pressure, reduces renal blood flow, increases the activity of amylase and lipase in the blood, promotes the onset of sleep, causes euphoria. The rate of development of drug dependence and tolerance to analgesic effect has significant individual differences.

Pharmacokinetics:

The minimum effective anesthetic concentration of fentanyl in blood plasma in patients not previously used opioid analgesics is 0.3-1.5 ng / ml. Dolforin® provides a constant release of fentanyl within 72 hours after application. After the first application, the fentanyl concentration in the blood plasma gradually increases during the first 12-24 hours and remains relatively constant over the remainder of the time. The concentration of fentanyl in blood plasma is proportional to the size of the TTS. After repeated applications, an equilibrium concentration in the blood plasma is achieved, which is maintained by subsequent TTS applications of the same size. The mean values of the content of fentanyl fractions unrelated to plasma proteins in plasma are 13-21%.

After removal of the TTS, the fentanyl concentration in the blood plasma gradually decreases, with a half-life of about 17 (13-22) hours. The continued absorption of fentanyl from the skin (more typically after 4 injections) explains a slower elimination of the drug from the blood plasma. In elderly, debilitated or weakened patients, the clearance of fentanyl may be reduced, which leads to an elongation of the half-life.

Fentanyl Metabolism occurs predominantly in the liver primarily by cytochrome CYP3A4 (N-dealkylation and hydroxylation), and in the kidneys, intestines and the adrenal glands. About 75% of fentanyl is excreted in the urine, mainly in the form of metabolites, while less than 10% of the drug is excreted unchanged. About 9% of the drug is excreted with feces, mainly in the form of metabolites. Penetrates into breast milk.

Indications:

Chronic pain syndrome of strong and moderate severity:

- pain caused by an oncological disease;

- pain than cancer genesis, which requires repeated anesthesia narcotic analgesics (neuropathic pain, arthritis and arthrosis, phantom pain after amputation, infection Varicella zoster).

Contraindications:

- Hypersensitivity to any of the components of the drug;

- depression of the respiratory center;

- acute pain or postoperative pain requiring a short period of treatment;

- diarrhea on the background of pseudomembranous colitis caused by the intake of cephalosporins, lincosamides, penicillins;

- toxic diarrhea;

- damage to the skin in the place of the intended application;

- pregnancy and the period of breastfeeding;

- children's age till 18 years;

- co-administration with barbituric acid derivatives;

- joint intake with MAO inhibitors and within 14 days after their cancellation.

Carefully:

Chronic lung diseases; increased intracranial pressure, incl. with tumors of the brain, bradyarrhythmia, arterial hypotension; renal and hepatic impairment; simultaneous reception of insulin, glucocorticoids and antihypertensive drugs; patients with a history of hepatic colic; old age, exhausted and weakened patients.

Pregnancy and lactation:

The safety of Dolforin® is not established. Studies in animals have shown the presence of reproductive toxicity.Cases of withdrawal syndrome in newborns, whose mothers have been used for a long time fentanyl. It is not recommended to use during childbirth, tk. fentanyl penetrates the placental barrier and can cause respiratory depression in the newborn.

Fentanyl is excreted in breast milk and can cause sedation and respiratory depression in children. In this regard, when using Dolforin®, it is necessary to stop breastfeeding!

Dosing and Administration:

Transdermally. The dose is selected individually depending on the patient's condition and should be evaluated regularly after the application of the TTS.

Dolphinin® should be applied to the flat surface of the skin of the trunk or upper parts of the hands immediately after removal from the package and removal of the protective film. For the application it is recommended to choose a place with a minimal hair cover. Before the application, the hair is in place applications should shear, and not shave. If the application site needs to be cleaned before applying the patch, then this should be done with clean water only. Do not use soap, lotions, oils or other products, as they can cause skin irritation or alter its properties.Before applique the skin should be absolutely dry.

The transdermal system should be pressed firmly with the palm of the hand in place of the application for 30 seconds. Should make sure that it is snug against the skin, especially around the edges. Dolphinin® is designed for continuous use within 72 hours. A new system can be glued to another area of the skin only after removing the previously pasted patch. For the same skin area, the transdermal system can be glued only at intervals of several days. TTS is protected by an external waterproof protective film, so it can not be removed while taking a shower.

In patients who had not previously taken opioids, the initial dose is 25 μg / h. The same dose is used if the patient has previously received trimeridine (promedol).

When a patient passes from oral or parenteral forms of opioids to fentanyl treatment, its initial dose is calculated as follows:

1. Determine the previous daily dose of analgesic.

2. The resulting value is converted to an equivalent oral dose of morphine using Table 1. All intramuscular and oral doses of opioid analgesics given in this table are equivalent to the analgesic effect of 10 mg of morphine administered intramuscularly.

3. In Table 2, find the 24-hour dose of morphine required for the patient and the corresponding dose of Dolphin®.

Table. 1. Equivalent doses of drugs on the effectiveness of analgesia.

	Therapeutically equivalent doses (mg)
Name of the drug	in / m *	orally
Morphine	10	30 (with regular administration) ** 60 (with a single or intermittent introduction
Omnompon	45
Hydromorphone	1,5	7,5
Methadone	10	20
Oxycodone	15	30
Levorphanol	2	4
Oxymorphone	1	10 (rectally)
Pethidine	75	-
Codeine	130	200
Buprenorphine	0,4	0.8 (sublingually)

* these oral doses are recommended for the transition from parenteral to oral administration.

** The ratio of morphine action strength to intramuscular / oral administration is 1: 3, based on the clinical experience obtained in the treatment of patients with chronic pain.

Table. 2. The recommended dose of Dolphorin, depending on the daily oral dose of morphine.

The oral daily dose of morphine (mg / day)	The dose of Dolforin® (μg / 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

An initial evaluation of the maximum analgesic effect of Dolphorin® can be made no earlier than 24 hours after the application. This time interval is due to a gradual increase in serum fentanyl concentration after application.For a successful transition from one drug to another, previous analgesic therapy should be discontinued gradually after the initial dose of Dolphorin® is applied.

TTC Dolphin® should be replaced every 72 hours. The dose is selected individually depending on the achievement of the necessary anesthesia. If after the application of the initial dose adequate anesthesia is not achieved, then in 3 days the dose may beь thegrand. Further the dose can be increase every 3 days. Usually, the dose is increased by 25 μg / h at a time, but the patient's condition and the need for additional pain relief must be taken into account (oral dose of morphine 90 mg / day approximately corresponds to a dose of Dolphorin® 25 μg / h). To achieve a dose of more than 100 μg / h, several TTS can be used simultaneously. Patients may occasionally require additional doses of short-acting analgesics in the event of "breakthrough" pain. Some patients may require additional or alternative methods of administering opioid analgesics when using a dose of Dolphin® greater than 300 μg / h.

Side effects:

From the nervous system, psyche and organs feelings: drowsiness or insomnia, headache, dizziness, confusion, convulsions (including clonic convulsions and a large epileptic fit), depression, anorexia, hallucinations, anxiety, euphoria, agitation, amnesia, tremor, paresthesia, involuntary muscular contractions, hypoesthesia, conjunctivitis.

From the respiratory system: yawning, rhinitis, hypoventilation, bronchospasm and respiratory depression (up to apnea), dyspnea, hypoventilation.

From the digestive system: very rarely - nausea, vomiting, constipation, anorexia, diarrhea, abdominal pain, dry mouth, indigestion, diarrhea.

From the side of the cardiovascular system: bradycardia, tachycardia, palpitation, increase or decrease in blood pressure.

From the side of the urinary system: urinary tract infections, spasm of ureters, urinary retention.

Allergic reactions: itching, rash, anaphylactic shock, anaphylactic or anaphylactoid reactions.

Proche: increased sweating, sensation of body temperature changes, general fatigue, flu-like symptoms, peripheral edema, asthenia, erythema,local skin reactions at the site of application, sexual dysfunction, tolerance, as well as physical and mental dependence, and "withdrawal syndrome".

Overdose:

Symptoms: respiratory depression up to apnea (the main symptom), rigidity of muscles, lowering of arterial pressure, bradycardia.

Treatment: removal of TTS, physical and verbal stimulation, if necessary - auxiliary and artificial ventilation of the lungs, the introduction of a specific antagonist - naloxone (respiratory depression during an overdose may last longer than the period of naloxone, so it may be necessary to re-introduce it), symptomatic therapy. The disappearance of the analgesic effect can lead to the development of a sharp pain attack and the release of catecholamines.

Interaction:

The simultaneous use of other drugs that exert a depressing effect on the central nervous system, including opioids, sedatives and hypnotics, general anesthetics, phenothiazines, tranquilizers, central muscle relaxants, antihistamines with sedatives, and alcoholic beverages can increase the risk of developing, inducing and enhancing hypoventilation,reduction of blood pressure, excessive sedation, to whom or to lead to death (taking any of these drugs simultaneously with Dolphinin®, requires constant monitoring of the patient).

Simultaneous administration of cytochrome P450 inhibitors CYP3A4 (e.g., ritonavir, ketoconazole, itraconazole, troleandomycin, clarithromycin, nelfinavir, nefadozone, verapamil, diltiazem, amiodarone), can lead to an increase in plasma concentrations of fentanyl. In this regard, the combined use of Dolforin® with cytochrome P450 inhibitors CYP3A4 is not recommended.

Fentanyl enhances the effect of antihypertensive drugs. Beta-adrenoblockers can reduce the frequency and severity of hypertensive reaction in cardiac surgery (including sternotomy), but increase the risk of bradycardia.

Buprenorphine, nalboufine, pentazocine, naloxone, naltrexone reduce the analgesic effect of fentanyl and eliminate its depressing effect on the respiratory center.

Muscle relaxants prevent or eliminate muscle rigidity. Miorelaxants with vagolytic activity (including pancuronium bromide) reduce the risk of bradycardia and hypotension (especially when using beta-blockers and vasodilators) and may increase the risk of tachycardia and hypertension.Miorelaxants that do not have vagolytic activity (including suxamethonium) do not reduce the risk of bradycardia and hypertension (especially in the background of an aggravated cardiological history) and increase the risk of serious side effects from the cardiovascular system.

Dinitrogen oxide increases muscle rigidity; effect reduces buprenorphine.

It is necessary to reduce the dose of fentanyl with simultaneous use with insulin, glucocorticosteroids and antihypertensive drugs.

Serious and unpredictable interactions of fentanyl with MAO inhibitors were observed with an increase in the effects of opioids or an increase in serotonergic effects.

Special instructions:

Patients with severe side effects should be under medical observation within 24 hours after Dolphorin® is removed, as the fentanyl concentration in the plasma decreases gradually and its 50% reduction is achieved within approximately 17 (13-22) hours.

TTS Dolforin® can not be cut.

In patients who had not previously taken opioids, when Dolforin® was used, cases of severe oppression were very rare breathing and death even when the minimum dose is applied TTC. Degree of oppression breathing increases with increasing dose of the drug.

Chronic lung diseases. Dolphinin® can cause a number of severe side effects in patients with chronic obstructive and other lung diseases. In such patients, opioids can reduce the excitability of the respiratory center and increase resistance breathing

Increased intracranial pressure. Dolphinin® should be used with caution in patients who may be particularly sensitive to an increase in carbon dioxide (CO₂). Such patients are patients who previously had increased intracranial pressure, impaired consciousness or coma.

Diseases of the liver. As fentanyl metabolized to inactive metabolites in the liver, liver disease can lead to a delay in removing the drug. In patients with cirrhosis of the liver, there was no change in pharmacokinetics in a single application of TTS fentanyl, although the concentration of the drug in the serum tended to increase. Patients with hepatic impairment need careful monitoring to identify symptoms of fentanyl overdose. In this case, it is necessary to reduce the dose of the drug.Opioid analgesics can increase the tone of the smooth muscles of the gastrointestinal tract and bile ducts.

Kidney Diseases. Less than 10% of fentanyl is excreted by the kidneys in an unchanged form, fentanyl has no known active metabolites that would be excreted by the kidneys. The data obtained with intravenous administration of fentanyl in patients with renal insufficiency suggest that the volume of fentanyl distribution may change during hemodialysis, and this may affect the concentration of the drug in the serum. Patients with renal failure need careful monitoring. If you notice symptoms of an overdose, you need to reduce the dose of the drug.

Use in elderly patients. Data from fentanyl studies for intravenous administration suggest that elderly patients may experience reduced clearance and longer half-life, and in addition, such patients may be more sensitive to fentanyl than younger patients. During the studies, the pharmacokinetics of fentanyl in elderly patients did not differ significantly from the pharmacokinetics in young patients, although serum concentrations were slightly higher.Elderly patients need careful monitoring to identify symptoms of a possible fentanyl overdose, which will require a reduction in the dose of the drug.

Drug addiction and possible abuse. With the re-introduction of opioids, tolerance can develop, as well as physical and mental dependence. Iatrogenic dependence when using opioids is rarely observed. There are cases of abuse.

Fever / external heat sources. It is possible that serum fentanyl concentrations may increase by about one-third if the body temperature rises to 40 ° C. Consequently, patients with fever should be closely monitored to identify opioid-specific side effects and, if necessary, subsequent dose adjustments. All patients should avoid direct exposure to external heat sources such as heating lamps, intense sun baths, hot water bottles, saunas, hot water baths, etc., in the place of application.

Termination of Dolforin application®. If it is necessary to stop the use, the replacement of this drug with other opioids should be gradual, starting with low doses.This mode of drug substitution is necessary due to a gradual decrease in the concentration of fentanyl after removal of the TTS, while a 50% reduction in serum fentanyl concentration takes 17 hours. The abolition of opioid analgesia should always be gradual in order to prevent the development of a "withdrawal syndrome".

Removal of TTS. The used TTS should be folded in half an adhesive side inside and returned to the doctor for destruction in the prescribed manner. Unused TTS should also be returned to the doctor for destruction.

Effect on the ability to drive transp. cf. and fur:Dolphinin® can affect the mental and / or physical functions necessary to carry out potentially dangerous work, such as driving a car or working with machinery. During the period of treatment, it is necessary to refrain from driving and practicing potentially dangerous activities that require an increased concentration of attention and speed of psychomotor reactions.

Form release / dosage:

Transdermal therapeutic system, 25 μg / h, 50 μg / h, 75 μg / h, 100 μg / h.

Packaging:

According to one transdermal therapeutic system, a packet consisting of polyester / Al/ polypropylene.

For 5 and 10 bags together with instructions for use in a cardboard box.

Storage conditions:

Store at a temperature not exceeding 30 ° C. The drug belongs to list II of the List of narcotic drugs, psychotropic substances and their precursors subject to control in the Russian Federation in accordance with the Federal Law of the Russian Federation "On narcotic drugs and psychotropic substances".

Keep out of the reach of children.

Shelf life:

3 years.

Do not use after the expiration date printed on the package.

Terms of leave from pharmacies:On prescription

Registration number:LSR-008338/10

Date of registration:18.08.2010

The owner of the registration certificate:GEDEON RICHTER, OJSC GEDEON RICHTER, OJSC Hungary

Manufacturer: & nbsp

GEDEON RICHTER, Ltd. Hungary

Representation: & nbspGEDEON RICHTER OJSC GEDEON RICHTER OJSC Hungary

Information update date: & nbsp22.09.2015

Illustrated instructions

Instructions

Dolphinin® (DOLFORIN®)