Symptoms: bradypnea, apnea, muscle rigidity, respiratory depression, decreased blood pressure, bradycardia.
Treatment: removal of TTS, physical and verbal stimulation (the patient should be "patted" on the cheeks, called by name, etc.).d.), if necessary — auxiliary and artificial lung ventilation (ventilator). Introduction of a specific antagonist — naloxone. Respiratory depression in overdose may last longer than the period of action of the opioid antagonist, so it may be necessary to re-administer naloxone. Symptomatic and vital function-supporting therapy (in t.tsch. administration of muscle relaxants, ventilator, atropine for bradycardia, and BCC replacement for decreased blood pressure. The disappearance of the analgesic effect can lead to the development of a sharp pain attack and the release of catecholamines
An overdose of fentanyl manifests itself in the form of an increase in its pharmacological effects, the most serious of which is respiratory depression.
Symptoms: lethargy, comatose state, depression of the respiratory center with Chain-Stokes breathing and / or cyanosis. Other symptoms may include hypothermia, decreased muscle tone, bradycardia,and hypotension. Signs of toxicity include deep sedation, ataxia, miosis, convulsions, and respiratory depression.
Treatment: removal of the transdermal patch, administration of a specific antagonist — naloxone, physical or verbal impact on the patient, symptomatic and supportive of vital functions therapy (including the introduction of muscle relaxants, artificial ventilation, with bradycardia-the introduction of atropine, with a pronounced decrease in blood pressure-replenishment of BCC).
The recommended starting dose for adults is 0.4-2 mg of naloxone IV. If necessary, you can give the same dose every 2-3 minutes or prescribe a long-term administration of 2 mg of naloxone dissolved in 500 ml of 0.9% sodium chloride solution or 5% dextrose solution (0.004 mg/ml). The rate of administration should be adjusted based on previous bolus infusions and the individual patient response.
If intravenous administration is not possible, then naloxone can be administered in / m or n / K. After intravenous or subcutaneous administration of naloxone, the onset of action will be slower compared to intravenous administration. I / m administration gives a more prolonged effect than I / v administration.
Respiratory depression due to overdose may persist longer than the effect of an opioid antagonist. Removing the analgesic effect can lead to an increase in acute pain and the release of catecholamines. If necessary, the patient should be treated in the intensive care unit.
2 years
Hypersensitivity, obstetric operations, bronchial asthma, respiratory depression, drug addiction.
hypersensitivity to fentanyl or to the adhesive substances that are part of the system,
children under 18 years of age,
depression of the respiratory center,
acute pain or postoperative pain requiring a short period of treatment,
pregnancy and lactation,
the drug should not be applied to irritated, irradiated or damaged skin.
With caution:
chronic lung diseases,
increased intracranial pressure, including in brain tumors,
with bradyarrhythmias,
arterial hypotension,
renal and hepatic insufficiency,
a history of hepatic colic,
elderly patients,
acute surgical diseases of the abdominal cavity (before diagnosis),
cesarean section and other obstetric operations (before fetal extraction),
simultaneous administration of insulin, corticosteroids and antihypertensive drugs.
hypersensitivity to the active substance or excipients,
depression of the respiratory center, including acute respiratory depression,
irritated, irradiated or damaged skin at the application site,
diarrhea on the background of pseudomembranous colitis caused by cephalosporins, lincosamides, penicillins,
toxic dyspepsia,
treatment of acute or postoperative pain due to the lack of possibility of dose adjustment in a short period of time and the likelihood of developing life-threatening respiratory depression,
severe CNS lesions,
simultaneous use of MAO or pediod inhibitors for 14 days after their withdrawal,
children under 2 years of age (efficacy and safety have not been established).
With caution: chronic lung diseases, intracranial hypertension, brain tumor, traumatic brain injury, bradyarrhythmia, arterial hypotension, renal and hepatic insufficiency, hepatic or renal colic (including in the anamnesis), cholelithiasis, hypothyroidism, elderly, emaciated and weakened patients, acute surgical diseases of the abdominal cavity before diagnosis, general serious condition, benign prostatic hypertrophy, stricture urethra, drug dependence, alcoholism, suicidal tendencies, hyperthermia, simultaneous administration of insulin, corticosteroids, hypotensive drugs.
The simultaneous use of other drugs that have a depressing effect on the central nervous system, including opioids, sedatives and hypnotics, general anesthesia, phenothiazines, tranquilizers, central muscle relaxants, antihistamines that have a sedative effect, and alcoholic beverages, may increase the risk of, cause and increase hypoventilation, lowering blood pressure, excessive sedation (taking any of these drugs simultaneously with the use of Durogesic®, requires special patient supervision).
Oral administration of itraconazole (a potential cytochrome P450 CYP3A4 inhibitor) at a dose of 200 mg per day for 4 days does not significantly affect the pharmacokinetic characteristics of fentanyl.
Concomitant administration of potential cytochrome P450 CYP3A4 inhibitors, such as ritonavir, may lead to an increase in the concentration of fentanyl in plasma. The consequence of this is an increase or prolongation of both the therapeutic effect and possible side effects.
Nitrous oxide increases muscle rigidity, the effect reduces buprenorphine.
It is necessary to reduce the dose of fentanyl when used simultaneously with insulin, corticosteroids and antihypertensive drugs.
MAO inhibitors increase the risk of severe complications.
CYP3A4 inhibitors
Fentanyl has a high clearance, it is rapidly and largely metabolized, mainly by cytochrome CYP3A4.
Concomitant use of a transdermal patch with fentanyl and cytochrome P450 3A4 (CYP3A4) inhibitors (including ritonavir, ketoconazole, itraconazole, fluconazole, voriconazole, clarithromycin, erythromycin, nelfinavir, nefazodone, verapamil, diltiazem, cimetidine, amiodarone) may lead to an increase in the concentration of fentanyl in the blood plasma. This may enhance or prolong both the therapeutic effect and the side effects of the drug Abstral (buccal/sublingual)™ and cause severe respiratory depression. In such cases, intensive care should be provided and the patient should be monitored more closely. If necessary, reduce the dose of fentanyl or stop using the drug Abstract (buccal/sublingual)™.
Concomitant use of a transdermal patch with fentanyl and CYP3A4 inhibitors is not recommended, except in cases where the benefit exceeds the risk. Patients should take a break for at least 48 hours between discontinuation of cytochrome P450 3A4 (CYP3A4) inhibitors and the first application of the drug Abstract (buccal/sublingual)™.
It is assumed that the degree of interaction with strong CYP3A4 inhibitors will be higher compared to weak or moderate CYP3A4 inhibitors. After the combined use of weak, moderate, or strong CYP3A4 inhibitors with short-acting forms of fentanyl, the decrease in the rate of fentanyl elimination, as a rule, did not exceed 25%. However, when taken with ritonavir (a strong CYP3A4 inhibitor), the elimination rate of fentanyl decreased by an average of 67%.
The degree of interaction of CYP3A4 inhibitors with fentanyl in transdermal patches is unknown, but it may be more pronounced than with short-acting forms of fentanyl in IV administration.
CYP3A4 Inducers
Simultaneous use of a transdermal patch with fentanyl and inducers of CYP3A4 (including rifampicin, carbamazepine, phenobarbital, phenytoin) can lead to a decrease in the concentration of fentanyl in the blood plasma and a decrease in the therapeutic effect. With the simultaneous use of CYP3A4 inducers and the drug Abstral (buccal/sublingual)™ you should be careful. You may need to increase the dose of fentanyl or transfer the patient to another analgesic. The planned withdrawal of concomitant therapy with a CYP3A4 inducer will require a reduction in the dose of fentanyl and careful monitoring of the patient. After discontinuation of CYP3A4 inducers, their effects are gradual, which can cause prolongation of the therapeutic and side effects of fentanyl and severe respiratory depression. In such cases, intensive care should be provided and the patient should be monitored more closely, and the dose should be adjusted if necessary.
Simultaneous administration with barbituric acid derivatives should be excluded, as they may increase the effect of respiratory depression of fentanyl.
Concomitant use of other CNS suppressants, including other opioids, sedatives, hypnotics, general anesthetics, phenothiazine derivatives, tranquilizers, muscle relaxants, antihistamines with sedative effects, alcohol, may cause additive sedative effects, respiratory depression, hypotension, deep sedation, coma, or death.
Therefore, taking any of the above drugs requires careful monitoring of the patient.
MAO inhibitors
It is not recommended to use a transdermal patch with fentanyl in patients who require simultaneous administration of MAO inhibitors. Serious and unpredictable interaction effects have been reported, including increased effects of narcotic analgesics or serotonergic effects. Therefore, you should not take fentanyl during the entire period of use of MAO inhibitors, as well as for 14 days after their withdrawal.
Serotonergic agents
Concomitant use of the transdermal patch with SSRIs or SSRIs, or MAO inhibitors, is not recommended. Co-administration may increase the risk of developing serotonin syndrome, which is potentially life-threatening.
Mixed agonists/antagonists
The simultaneous use of a transdermal patch with fentanyl and buprenorphine, nalbufin, pentazocin is not recommended, since they reduce the analgesic effect of fentanyl and can cause withdrawal syndrome in patients with opioid dependence.
It is necessary to reduce the dose of fentanyl when used simultaneously with insulin, corticosteroids and antihypertensive drugs.
Muscle relaxants prevent or eliminate muscle rigidity. Muscle relaxants with vagolytic activity (including pancuronium bromide) reduce the risk of bradycardia and hypotension (especially when using beta-blockers and other vasodilators) and may increase the risk of tachycardia and hypertension. Muscle relaxants that do not have vagolytic activity (including succinylcholine) do not reduce the risk of developing bradycardia and arterial hypotension (especially against the background of a burdened cardiac history) and increase the risk of severe side effects from CCC.
Mannitol (E421)
Silicified microcrystalline cellulose
Croscarmellose sodium
Magnesium stearate
Sublingual tablets
Respiratory depression (in high doses), bradycardia, muscle rigidity, bronchospasm.
From the nervous system: drowsiness, confusion, depression, anorexia, hallucinations, anxiety, headache, rarely-euphoria, insomnia, agitation, amnesia, tremor, paresthesia.
From the respiratory system: hypoventilation, bronchospasm and respiratory depression (in case of overdose), in rare cases — shortness of breath,
From the digestive system: nausea, vomiting, constipation, bile colic (in patients with a history of them), dry mouth, dyspepsia, rarely-diarrhea,
Other: bradycardia, tachycardia, hypertension, decreased blood pressure, urinary retention, itching, increased sweating, short-term muscle rigidity (including chest), tolerance, as well as physical and mental dependence, very rarely — asthenia, sexual dysfunction and "withdrawal syndrome".
Sometimes there are local reactions, such as skin rash, erythema and itching at the application site. These reactions usually resolve within 24 hours after removal of the TTS.
When switching from previously taken narcotic analgesics to the use of Durogesic® or in the case of sudden discontinuation of therapy, symptoms characteristic of opioid withdrawal (nausea, vomiting, diarrhea, anxiety, chills) may occur. Slowly lowering the dose helps to reduce the severity of such symptoms.
The safety of transdermal patches with fentanyl was evaluated in 1565 adults and 289 children who participated in 11 clinical trials on the use of the drug for the treatment of chronic pain of oncological and non-oncological origin. These patients received at least 1 dose of a transdermal patch with fentanyl, after which the safety of the drug was evaluated. Based on the combined safety data obtained from these clinical trials, the most common (with a frequency of at least 10%) adverse reactions were: nausea (35.7%), vomiting (23.2%), constipation (23.1%), drowsiness (15%), dizziness (13.1%) and headache (11.8%)
Adverse reactions are classified according to frequency of occurrence: very common (>1/10), common (>1/100, <1/10), infrequent (>1/1000, <1/100), rare (>1/10000, <1/1000), very rare (<1/10000), frequency unknown, including individual reports.
The most dangerous adverse reaction is respiratory depression.
Mental disorders: often-confusion, depression, anxiety, hallucinations, insomnia, infrequently-euphoria, agitation, disorientation.
From the side of metabolism and nutrition: often-anorexia.
From the nervous system: very often-drowsiness, headache, dizziness, often-tremor, paresthesia, infrequently-hypesthesia, convulsions (including clonic and grand mal), amnesia, decreased consciousness, loss of consciousness.
On the part of the visual organ: infrequently-decreased visual acuity, rarely-miosis.
On the part of the organ of hearing and labyrinth disorders: often-vertigo.
From the heart:
From the side of the vessels: often-arterial hypertension, infrequently-arterial hypotension.
From the respiratory system, chest and mediastinal organs: often-dyspnea, infrequently-respiratory depression, respiratory failure, rarely-apnea, hypoventilation, frequency unknown-bradypnea.
From the gastrointestinal tract: very often-nausea, vomiting, constipation, often-diarrhea, abdominal pain, epigastric pain, dry mouth, dyspepsia, infrequently-intestinal obstruction, rarely-partial intestinal obstruction.
On the part of the immune system: often-hypersensitivity, frequency unknown-anaphylactic shock, anaphylactic reactions, anaphylactoid reactions.
From the skin and subcutaneous tissues: often-sweating, itching, rash, erythema, infrequently-eczema, allergic dermatitis, skin inflammation, dermatitis, contact dermatitis.
From the musculoskeletal system and connective tissue: often-muscle spasms, infrequently-muscle twitching.
From the kidneys and urinary tract: often-urinary retention.
From the genitals and breast: infrequently-erectile dysfunction, sexual dysfunction.
General disorders and disorders at the injection site: often-fatigue, peripheral edema, asthenia, malaise, a feeling of cold, infrequently-skin reaction at the application site, flu-like symptoms, a feeling of changes in body temperature, hypersensitivity at the application site, withdrawal syndrome, fever, rarely-dermatitis at the application site, eczema at the application site.
With long-term use of fentanyl, tolerance, physical and mental dependence, short-term rigidity of the muscles (including the chest) can develop.
If previously prescribed opioid analgesics are replaced with a transdermal patch with fentanyl, or if therapy is suddenly discontinued, withdrawal symptoms may develop, including, for example, nausea, vomiting, diarrhea, anxiety, trembling, and fever.
Very rarely, withdrawal symptoms have been reported in newborns whose mothers have consistently used a transdermal patch with fentanyl during pregnancy.
Children
The profile of adverse reactions in children and adolescents was similar to that in adults.
When using a transdermal patch with fentanyl in children, the most common adverse reactions were nausea, vomiting, headache, constipation, diarrhea, and itching.
Safety pharmacology and repeated dose toxicity data reveal no special hazard for humans that is not already covered by other sections of this SPC. Animal studies have shown reduced fertility and increased mortality in rat foetuses. Teratogenic effects have, however, not been demonstrated.
Mutagenicity testing in bacteria and in rodents yielded negative results. Like other opioids fentanyl showed mutagenic effects in vitro in mammalian cells. A mutagenic risk with therapeutic use seems unlikely since effects were induced only at very high concentrations.
Carcinogenicity studies (26-week dermal alternative bioassay in Tg.AC transgenic mice; two-year subcutaneous carcinogenicity study in rats) with fentanyl did not reveal any findings indicative of oncogenic potential. Evaluation of brain slides from the carcinogenicity study in rats revealed brain lesions in animals administered high doses of fentanyl citrate. The relevance of these findings to humans is unknown.
Premedication, neuroleptanalgesia, severe pain syndrome.
Severe and moderate chronic pain syndrome:
pain caused by cancer,
pain syndrome of non-oncological origin, requiring anesthesia with narcotic analgesics: neuropathic pain-for example, pain syndrome in diabetic polyneuropathy, nerve injuries, syringomyelia, multiple sclerosis, shingles (Herpes zoster), phantom pain after amputation of limbs.
chronic severe pain syndrome requiring long-term continuous anesthesia with opioid analgesics, in adults,
long-term analgesia of chronic pain syndrome in children from 2 years of age receiving opioid analgesic therapy.
Fentanyl is a synthetic analgesic that interacts primarily with the µ-opioid receptors. It belongs to the list II of narcotic drugs, psychotropic substances and their precursors, approved by the Decree of the Government of the Russian Federation No. 681 of 30.06.98. It increases the activity of the antinociceptive system, increases the threshold of pain sensitivity. It disrupts the transmission of arousal along specific and non-specific pain pathways to the nuclei of the thalamus, hypothalamus, and amygdala complex.
The main therapeutic effects of the drug are analgesic and sedative. The minimum effective analgesic concentration of fentanyl in plasma in patients who have not previously used opioid analgesics is 0.3-1.5 ng / ml. The total duration of the drug is 72 hours.
It has a depressing effect on the respiratory center, slows down the heart rate, excites the centers of the vagus nerve and the emetic center. Increases the tone of the smooth muscles of the biliary tract, sphincters (including the urethra, bladder, sphincter Oddi), reduces intestinal peristalsis, improves the absorption of water from the gastrointestinal tract. It has almost no effect on blood pressure, reduces renal blood flow. In the blood increases the content of amylase and lipase.
Promotes the onset of sleep. Causes euphoria.
The rate of development of drug dependence and tolerance to analgesic action has significant individual differences.
Abstral (buccal/sublingual)™ - a transdermal patch that provides a constant systemic supply of fentanyl for 72 hours. Fentanyl is an opioid analgesic with an affinity mainly for opiate µ-receptors of the central nervous system, spinal cord and peripheral tissues. Increases the activity of the antinociceptive system, increases the threshold of pain sensitivity. Preparation of Abstract (buccal/sublingual)™ it mainly has analgesic and sedative effects. Fentanyl has a depressing effect on the respiratory center, slows down the heart rate, and excites the centers n.vagus and the emetic center, increases the tone of the smooth muscles of the biliary tract, sphincters (including the urethra, bladder and sphincter of Oddi), improves the absorption of water from the gastrointestinal tract. Reduces blood pressure, intestinal peristalsis and renal blood flow. Increases the concentration of amylase and lipase in the blood, reduces the concentration of STH, catecholamines, ACTH, cortisol, prolactin. Promotes the onset of sleep (mainly in connection with the removal of pain). Causes euphoria. The rate of development of drug dependence and tolerance to analgesic action has significant individual differences. Rarely causes histamine reactions
The minimum effective analgesic concentration of fentanyl in the blood plasma in patients who have not previously used opioid analgesics is 0.3-1.5 ng / ml. Durogesic® provides continuous systemic release of fentanyl for 72 hours after application. Fentanyl is released at a relatively constant rate, which is determined by the copolymer membrane and the diffusion of fentanyl through the skin. After applying Durogesic® the concentration of fentanyl in the blood plasma gradually increases during the first 12-24 hours and remains relatively constant for the remaining period of time. The level of fentanyl concentration in the 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 applications of TTS of the same size.
The average content of the fentanyl fraction unbound to blood proteins in the plasma is 13-21%.
After removing the Durogesic® the concentration of fentanyl in the blood plasma gradually decreases, while T1/2 it is approximately 17 (13-22) hours. The continued absorption of fentanyl from the skin (more typical after 4 injections) explains the slow disappearance of the drug from the blood plasma. In elderly, emaciated or debilitated patients, the clearance of fentanyl may be reduced, resulting in an elongation of the T1/2 the drug. Fentanyl metabolism occurs primarily in the liver (N-disalkylation and hydroxylation), as well as in the kidneys, intestines, and 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 in the feces, mainly in the form of metabolites. Penetrates into breast milk.
The minimum effective analgesic concentration of fentanyl in the blood serum in patients who have not previously used opioid analgesics is 0.3-1.5 ng / ml. The frequency of adverse effects in such patients increases when the concentration of fentanyl in the blood serum is higher than 2 ng / ml. With the development of tolerance, both the minimum effective analgesic concentration of fentanyl increases, and the concentration at which undesirable reactions occur.
Suction. After the first application of the transdermal patch, the concentration of fentanyl in the blood serum increases gradually, usually equalizing between 12 and 24 hours, and then remains relatively constant for the rest of the 72-hour period of time. By the second 72-hour application of the transdermal patch, a constant concentration of fentanyl in the blood serum is achieved, which is maintained during subsequent applications of the patch of the same size. The concentration of fentanyl in the blood is proportional to the size of the transdermal patch. The absorption of fentanyl may vary slightly depending on the application site. A slightly reduced absorption of fentanyl (approximately 25%) was observed in studies conducted with healthy volunteers during the application of the patch to the chest compared to the application to the upper arm and back
Distribution. Fentanyl binds to plasma proteins by 84%, penetrates through the BBB, placenta and breast milk.
Metabolism. Fentanyl has linear biotransformation kinetics and is primarily metabolized in the liver by CYP3A4 enzymes. The main metabolite of fentanyl is norfentanyl, which is not active.
Output. After removal of the transdermal patch, the concentration of fentanyl in the blood serum decreases gradually. T1/2 fentanyl after application of the transdermal patch is 17 hours (13-22 hours) in adults and 22-25 hours in children. The continued absorption of fentanyl from the skin surface causes a slower elimination of the drug from the blood serum compared to intravenous administration. About 75% of fentanyl is excreted in the urine, mainly in the form of metabolites, less than 10% - in unchanged form, about 9% is excreted in the feces, mainly in the form of metabolites.
Special patient groups
Impaired liver or kidney function may cause an increase in the serum concentration of fentanyl. In elderly, emaciated, or debilitated patients, there may be a decrease in fentanyl clearance, which may lead to a longer T1/2 fentanyl.
Children. Depending on body weight, clearance (l / h / kg) is 82% higher in children 2 to 5 years old and 25% higher in children 6 to 10 years old compared to children 11 to 16 years old, who have the same clearance as adults.
March 2018
Abstral (buccal/sublingual)
Kyowa Kirin Ltd
Galabank Business Park
Galashiels
TD1 1QH
United Kingdom
At a temperature of 15-25 °C.
Keep out of reach of children.
Shelf life of the drug Durogesic® Matrix2 года.Do not use after the expiration date indicated on the package.
| Transdermal Therapeutic System (TTS) | 1 system |
| active substance: | |
| fentanyl | |
| with release: | |
| 12.5 mcg/h | 2.1 mg |
| 25 mcg/h | 4.2 mg |
| 50 mcg/h | 8.4 mg |
| 75 mcg/h | 12.6 mg |
| 100 mcg/h | 16.8 mg |
| excipients: background - copolymer of polyethylene terephthalate (PET) and ethylene vinyl acetate (EVA), adhesive layer - polyacrylate (Duro-Tak® 87-4287), protective film - siliconized PET |
Transdermal therapeutic system, 12.5 mcg/h, 25 mcg/h, 50 mcg/h, 75 mcg/h or 100 mcg/h. 1 TTS in a package made of a combined material (PET, LDPE, aluminum foil), 5 packages in a cardboard pack.
Abstral 100 microgram sublingual tablets: PL 16508/0030
Abstral 200 microgram sublingual tablets: PL 16508/0031
Abstral 300 microgram sublingual tablets: PL 16508/0032
Abstral 400 microgram sublingual tablets: PL 16508/0033
Abstral 600 microgram sublingual tablets: PL 16508/0034
Abstral 800 microgram sublingual tablets: PL 16508/0035
The safety of transdermal patches with fentanyl during pregnancy has not been established. Some reproductive toxicity has been established in animal studies.
Fentanyl during pregnancy should only be used if absolutely necessary. Prolonged use during pregnancy may cause withdrawal symptoms in newborns. Very rarely, withdrawal symptoms have been reported in newborns whose mothers constantly used a transdermal patch with fentanyl during pregnancy.
Fentanyl should not be used during labor and delivery (including caesarean section), because it passes through the placenta and can cause respiratory depression in the fetus or newborn.
Fentanyl is released into breast milk and can cause sedation and respiratory depression in a breastfed baby. Therefore, if it is necessary to prescribe the drug Fendivia™ during lactation, breastfeeding should be discontinued (for the entire duration of use and for at least 72 hours after the last use).
Fentanyl
Patients and their carers must be instructed that Abstral contains an active substance in an amount that can be fatal to a child, and therefore to keep all tablets out of the reach and sight of children.
Due to the potentially serious undesirable effects that can occur when taking an opioid therapy such as Abstral, patients and their carers should be made fully aware of the importance of taking Abstral correctly and what action to take should symptoms of overdose occur.
Before Abstral therapy is initiated, it is important that the patient's long-acting opioid treatment used to control their persistent pain has been stabilised.
Upon repeated administration of opioids such as fentanyl, tolerance and physical and/or psychological dependence may develop. Iatrogenic addiction following therapeutic use of opioids is rare.
In common with all opioids, there is a risk of clinically significant respiratory depression associated with the use of Abstral. Particular caution should be exercised during dose titration with Abstral in patients with chronic obstructive pulmonary disease or other medical conditions predisposing them to respiratory depression (e.g. myasthenia gravis) because of the risk of further respiratory depression, which could lead to respiratory failure.
Abstral should only be administered with extreme caution in patients who may be particularly susceptible to the intracranial effects of hyperkapnia, such as those showing evidence of raised intracranial pressure, reduced consciousness, coma or brain tumours. In patients with head injuries, the clinical course may be masked by the use of opioids. In such a case, opioids should be used only if absolutely necessary.
Cardiac disease
Fentanyl may produce bradycardia. Fentanyl should be used with caution in patients with previous or pre-existing bradyarrythmias.
Data from intravenous studies with fentanyl suggest that older patients may have reduced clearance, a prolonged half-life and they may be more sensitive to the active substance than younger patients. Older, cachectic, or debilitated patients should be observed carefully for signs of fentanyl toxicity and the dose reduced if necessary.
Abstral should be administered with caution to patients with liver or kidney dysfunction, especially during the titration phase. The use of Abstral in patients with hepatic or renal impairment may increase the bioavailability of fentanyl and decrease its systemic clearance, which could lead to accumulation and increased and prolonged opioid effects.
Care should be taken in treating patients with hypovolaemia and hypotension.
Abstral has not been studied in patients with mouth wounds or mucositis. There may be a risk of increased systemic drug exposure in such patients and therefore extra caution is recommended during dose titration.
There should be no noticeable effects on cessation of treatment with Abstral, but possible symptoms of withdrawal are anxiety, tremor, sweating, paleness, nausea and vomiting.
Serotonin Syndrome
- Caution is advised when Abstral is coadministered with drugs that affect the serotoninergic neurotransmitter systems.
The development of a potentially life-threatening serotonin syndrome may occur with the concomitant use of serotonergic drugs such as Selective Serotonin Re-uptake Inhibitors (SSRIs) and Serotonin Norepinephrine Re-uptake Inhibitors (SNRIs), and with drugs which impair metabolism of serotonin (including Monoamine Oxidase Inhibitors [MAOIs]). This may occur within the recommended dose.
Serotonin syndrome may include mental-status changes (e.g., agitation, hallucinations, coma), autonomic instability (e.g., tachycardia, labile blood pressure, hyperthermia), neuromuscular abnormalities (e.g., hyperreflexia, incoordination, rigidity), and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhoea).
If serotonin syndrome is suspected, treatment with Abstral should be discontinued.
No studies on the effects on the ability to drive and use machines have been performed with Abstral.
However, opioid analgesics are known to impair the mental or physical ability to perform potentially hazardous tasks such as driving or operating machinery. Patients should be advised not to drive or operate machinery if they become dizzy or drowsy or experience blurred or double vision while taking Abstral.
This medicine can impair cognitive function and can affect a patient's ability to drive safely. This class of medicine is in the list of drugs included in regulations under 5a of the Road Traffic Act 1988. When prescribing this medicine, patients should be told:
- The medicine is likely to affect your ability to drive
- Do not drive until you know how the medicine affects you
- It is an offence to drive while under the influence of this medicine
- However, you would not be committing an offence (called 'statutory defence') if:
o The medicine has been prescribed to treat a medical or dental problem and
o You have taken it according to the instructions given by the prescriber and in the information provided with the medicine and
o It was not affecting your ability to drive safely
I / v, I / m, adults, in preparation for surgery: I / v-0.05-0.1 mg (in combination with 2.5-5 mg of droperidol) for 10-15 minutes before anesthesia, for surgical anesthesia: I / v-0.05–0.2 mg every 20-30 minutes. Children in preparation for surgery-0.002 mg / kg of body weight, for surgical anesthesia: in / in-0.01-0.15 mg/kg or in / m 0.15-0.25 mg/kg, for maintaining surgical anesthesia: in / m-0.001–0.002 mg/kg.
Dose of Durogesic® it is selected individually depending on the patient's condition and should be regularly evaluated after the application of TTS.
Locally. Durogesic® it should be applied to the flat surface of the skin of the trunk or upper arms. For the application, it is recommended to choose a place with minimal hair cover. Before applying, the hair on the site of the application should be cut (do not shave!). If the application site needs to be washed before applying the patch, then this should be done with clean water. Do not use soaps, lotions, oils or other products, as they can irritate the skin or change its properties. Before applying, the skin should be completely dry.
Durogesic® it should be pasted immediately after removing it from the sealed package. TTS must be pressed firmly with the palm of your hand on the application site for 30 seconds. Make sure that the patch fits snugly to the skin, especially at the edges.
Durogesic® designed for continuous use for 72 hours. The new system can be applied to another area of the skin after removing the previously applied patch. On the same area of the skin, the TTS can be pasted only at intervals of several days.
The initial dose. At the first use, the dose (system size) is selected based on the previous use of opioid analgesics, the degree of tolerance and the patient's condition. In patients who have not previously taken opioids, the lowest dose of Durogesic is used as the initial dose® — 25 mcg/h. The same dose is used if the patient has previously received Promedol.
For the transition from oral or parenteral forms of opioids to Durogesic®in patients with opioid tolerance please refer to Table 1 "Conversion to an equivalent analgesic dose" and Table 2 " Recommended dose of Durogesic® (depending on the daily oral dose of morphine)".
Conversion to an equivalent painkiller dose
1. Calculate the previous 24-hour analgesia requirement.
2. Convert this amount to an equivalent oral dose of morphine using Table 1. All intramuscular and oral doses of opioid analgesics listed in this table are equivalent in analgesic effect to 10 mg of morphine/m.
3. In Table 2, find the required 24-hour dose of morphine for the patient and the corresponding dose of Durogesic®.
Table 1
Conversion to an equivalent painkiller dose
| Name of the drug | Equivalent analgesic dose, mg | |
| in/m* | inside | |
| Morphine | 10 | 30 — with regular administration** |
| 60 — with a single or intermittent administration | ||
| Omnopon | 45 | - |
| Hydromorphone | 1,5 | 7,5 |
| Methadone | 10 | 20 |
| Oxycodone | 15 | 30 |
| Levorphanol | 2 | 4 |
| Oxymorphone | 1 | 10 (rectally) |
| Diamorphine | 5 | 60 |
| Pethidine | 75 | - |
| Codeine | 130 | 200 |
| Buprenorphine | 0,3 | 0.8 (sublingual) |
* These oral doses are recommended when switching from parenteral to oral administration.
** The ratio of the strength of morphine in the iv / m / oral method of administration, equal to 1:3, is based on clinical experience obtained in the treatment of patients with chronic pain.
Table 2
Recommended dose of Durogesic® (depending on the daily oral dose of morphine*)
| Oral 24-hour dose of morphine, mg / day | Dose of Durogesic®, mcg/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 |
* In clinical trials, these values of daily morphine doses were used as the basis for switching to Durogesic®.
Initial assessment of the maximum analgesic effect of Durogesic® it can not be made less than 24 hours after application. This period of time is due to a gradual increase in the concentration of fentanyl in the serum after application.
For a successful transition from one drug to another, the previous analgesic therapy should be discontinued gradually after the application of the initial dose of Durogesic®.
Dose selection and maintenance therapy
TTS Durogesic® it should be replaced with a new one every 72 hours. The dose is selected individually, depending on the achievement of the necessary analgesia. If adequate analgesia is not achieved after the initial dose, the dose may be increased after 3 days. Further, the dose can be increased every 3 days. Usually, the dose is increased by 25 mcg / h at a time, but it is necessary to take into account the patient's condition and the need for additional anesthesia (an oral dose of morphine 90 mg/day approximately corresponds to the dose of Durogesic® 25 mcg/h). To achieve a dose of more than 100 mcg/h, several TTS can be used simultaneously. Patients may periodically require additional doses of short-acting analgesics in the event of "bursting" pain. Some patients may require additional or alternative methods of administration of opioid analgesics when using a dose of Durogesic® exceeding 300 µg/h.
Transdermal.
The transdermal patch releases fentanyl within 72 hours. The release rate of fentanyl is 12.5, 25, 50, 75, and 100 mcg / h, which is approximately 0.3, 0.6, 1.2, 1.8, and 2.4 mg / day, respectively.
The required dosage of fentanyl is selected individually, taking into account the patient's condition, and should be reviewed regularly. The lowest effective dosage should be used.
Choosing the initial dosage
The initial dosage of fentanyl is set depending on the level of opioid intake in the previous period, as well as taking into account the possible development of tolerance, concomitant medication, the general health and medical status of the patient, i.e. body size, age and degree of exhaustion, and the severity of the disease.
Adults who have previously received opioids
To transfer patients who have previously received opioids from oral or parenteral use of opioids to a transdermal patch, use Table 1. If necessary, the dosage can be adjusted both downward and upward by 12.5 or 25 mcg / h in order to select the lowest effective dose, depending on the patient's response and the need for additional anesthesia.
Adults who have not previously received opioids
As a rule, patients who have not previously received opioids are not recommended for transdermal use. Alternative methods of administration (oral, parenteral) should be considered. To prevent overdose in patients who have not previously received opioids, it is recommended to prescribe low doses of immediate-release opioids (including morphine, hydromorphone, oxycodone, tramadol and codeine), the dose of which should be selected so that it corresponds to the effectiveness of analgesia to the transdermal patch at a dosage of 12.5 or 25 mcg/h. After that, patients can switch to the use of the drug Abstract (buccal/sublingual)™.
In conditions where oral administration of opioids is not possible and the use of a transdermal patch is recognized as the only possible treatment method, the use of the drug Abstral (buccal/sublingual)™ you should start with a minimum dosage of 12.5 mcg/h. In such cases, special monitoring of the patient is required.
The risk of developing serious or life-threatening respiratory depression exists even with the use of a minimum dosage of 12.5 mcg / h of the drug Abstral (buccal/sublingual)™ in patients who have not previously received opioids.
Switching from taking other opioids
When a patient switches from oral or parenteral opioid analgesics to fentanyl treatment, the initial dosage of the drug is Abstract (buccal/sublingual)™ calculated as follows.
1) Determine the number of opioid analgesics required by the patient in the last 24 hours (mg / day).
2) The amount received should be converted to the appropriate oral daily dose of morphine (mg / day), using Table 1.
3) The appropriate dose of fentanyl is determined using Tables 2 and 3.
Tables 2 and 3 should not be used to switch from a transdermal patch to other opioids in order to avoid prescribing too high a dose. This can lead to an overdose.
Table 1
Conversion table — coefficients for converting the daily dose of previously used opioids to the equivalent analgesic daily oral dose of morphine (mg/day of previously used opioid × coefficient = equivalent analgesic daily oral dose of morphine)
| Previously used opioid | Method of application | Coefficient |
| morphine | oral | 1a |
| parenteral | 3 | |
| buprenorphine | sublingual | 75 |
| parenteral | 100 | |
| codeine | oral | 0,15 |
| parenteral | 0,23b | |
| diamorphine | oral | 0,5 |
| parenteral | 6b | |
| fentanyl | oral | — |
| parenteral | 300 | |
| hydromorphone | oral | 4 |
| parenteral | 20b | |
| ketobemidone | oral | 1 |
| parenteral | 3 | |
| levorphanol | oral | 7,5 |
| parenteral | 15b | |
| methadone | oral | 1,5 |
| parenteral | 3b | |
| oxycodone | oral | 1,5 |
| parenteral | 3 | |
| oxymorphine | rectally | 3 |
| parenteral | 30b | |
| pethidine | oral | — |
| parenteral | 0,4b | |
| tapentadol | oral | 0,4 |
| parenteral | — | |
| tramadol | oral | 0,25 |
| parenteral | 0,3 |
butThe activity of oral or intravenous morphine is based on clinical experience in patients with chronic pain syndrome.
bBased on studies with a single intravenous administration of each of the listed opioid analgesics, conducted in order to establish their relative activity in comparison with morphine. Doses for oral administration — the doses recommended during the transition from parenteral to oral administration of the drug.
Table 2
Recommended starting dose of Abstral (buccal/sublingual)™ depending on the daily oral dose of morphine (for clinically less stable adult patients requiring opioid replacement: the ratio of transition from oral morphine to transdermal use of fentanyl is 150:1)but
| Oral daily dose of morphine, mg / day | Dose of the drug Abstral (buccal/sublingual)™, mcg/h |
| <90 | 12,5 |
| 90–134 | 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 |
butIn clinical studies, these limits of oral daily doses of morphine were used to calculate the patient's transfer to the drug Abstract (buccal/sublingual)™.
Table 3
Recommended starting dose of Abstral (buccal/sublingual)™ depending on the daily oral dose of morphine (for adults who are on stable, well-tolerated opioid therapy: the ratio of transition from oral morphine to transdermal use of fentanyl is 100:1)
| Oral daily dose of morphine, mg / day | Dose of the drug Abstral (buccal/sublingual)™, mcg/h |
| ≤44 | 12,5 |
| 45–89 | 25 |
| 90–149 | 50 |
| 150–209 | 75 |
| 210–269 | 100 |
| 270–329 | 125 |
| 330–389 | 150 |
| 390–449 | 175 |
| 450–509 | 200 |
| 510–569 | 225 |
| 570–629 | 250 |
| 630–689 | 275 |
| 690–749 | 300 |
Initial assessment of the maximum analgesic effect of the drug Abstract (buccal/sublingual)™ it can be performed no earlier than 24 hours after application. This restriction is due to the fact that the increase in the concentration of fentanyl in the blood serum in the first 24 hours after the application of the transdermal patch occurs gradually. Therefore, when switching from one drug to another, the previous analgesic therapy should be discontinued gradually after the application of the initial dose of the drug Abstract (buccal/sublingual)™ until its analgesic effect is stabilized.
Dose selection and maintenance therapy
The transdermal patch should be replaced with a new one every 72 hours.
The dose is selected individually to achieve the optimal ratio of the level of pain relief and tolerability of the drug Abstract (buccal/sublingual)™. Usually, for 1 time, the dose is increased by 12.5 or 25 mcg/h. However, when adjusting the dose, it is necessary to take into account the patient's condition and the need for additional anesthesia (oral doses of morphine 45 and 90 mg / day are approximately equivalent to dosages of 12.5 and 25 mcg / h of the drug Abstral (buccal/sublingual)™ respectively). After increasing the dose, the patient may need up to 6 days to achieve stable pain relief.
For this reason, after increasing the dose, it is necessary to use a transdermal patch of an increased dosage at least 2 times for 72 hours. Only after this, the next increase in the dose is possible, if the anesthesia was insufficient.
To achieve a dose of more than 100 mcg/h, several transdermal patches can be used simultaneously. If breakthrough pain occurs, patients may periodically require additional doses of short-acting analgesics. If the dose of the drug is Abstract (buccal/sublingual)™ If the dose exceeds 300 mcg/h, additional or alternative methods of pain relief or alternative methods of administration of opioid analgesics should be considered.
Only at the beginning of therapy, if after the application of the initial dose there is a significant decrease in the analgesic effect, the patch can be replaced after 48 hours with a patch of a similar dosage, and after 72 hours the dose can be increased.
If you need to replace the transdermal patch for up to 72 hours (for example, if the patch has come off), a patch of a similar dosage should be applied to another area of the skin. This situation can lead to an increase in the concentration of fentanyl in the blood plasma, and therefore the patient needs close monitoring.
When switching from long-term treatment with morphine to a transdermal patch with fentanyl, a withdrawal syndrome may occur, despite the adequate analgesic effect. When withdrawal symptoms occur, it is recommended to administer short-acting morphine in low doses to patients.
Discontinuation of treatment with Abstract (buccal/sublingual)™
If it is necessary to interrupt the use of the transdermal patch, then replacement with any other opioids should be carried out gradually, starting with a low dose and slowly increasing it. This is due to the fact that the content of fentanyl in the blood serum after removal of the transdermal patch decreases gradually. To reduce the concentration of fentanyl in the blood serum by 50%, it takes at least 20 hours. There is a general rule: the withdrawal of pain relief with opioid analgesics should be carried out gradually to prevent the appearance of withdrawal symptoms (nausea, vomiting, diarrhea, anxiety and muscle tremor).
Use in elderly patients
Elderly patients should be carefully examined and monitored. If necessary, the dose of the drug Abstral (buccal/sublingual)™ it should be reduced (see "Special instructions"). In elderly patients who have not previously received opioids, the drug Abstral (buccal/sublingual)™ it should be used only if the benefit exceeds the risk. As an initial dosage, only 12.5 mcg/h should be used.
Use in patients with impaired liver and kidney function
Patients with impaired liver and kidney function should be carefully examined and monitored for symptoms of fentanyl overdose and, if necessary, the dose of the drug Abstral (buccal/sublingual)™ it should be reduced (see "Special instructions").
In patients with impaired liver and kidney function, previously not treated with opioids, the drug Abstral (buccal/sublingual)™ it should be used only if the benefit exceeds the risk. As an initial dosage, only 12.5 mcg/h should be used.
Use in patients with elevated body temperature/exposed to external heat sources
Patients with elevated body temperature may need to adjust the dose of fentanyl (see "Special Instructions").
Use in children 16 years and older
The dosage regimen for children over 16 years of age is similar to that for adults.
Use in children from 2 to 16 years of age
Preparation of Abstract (buccal/sublingual)™ it should be used only in children who have already received an equivalent amount of morphine orally at a dosage of at least 30 mg / day. When switching from oral or parenteral opioid analgesics to a transdermal patch with fentanyl in children, the initial dose is calculated using Tables 1 and 4.
Table 4
Recommended starting dose of Abstral (buccal/sublingual)™ for children from 2 to 16 years olda depending on the daily oral dose of morphineb
| Oral daily dose of morphine for children, mg / day | Dose of the drug Abstract (buccal/sublingual)™ for children, mcg/h |
| 30–44 | 12,5 |
| 45–134 | 25 |
aSwitching to fentanyl doses exceeding 25 mcg / h is not different for children and adults (see Table 2).
bIn clinical studies, these limits of oral daily doses of morphine were used to calculate the patient's transfer to the drug Abstract (buccal/sublingual)™.
In two studies in children, the required dosage of the transdermal patch was calculated with caution: from 30 to 44 mg / day of morphine orally or an equivalent amount of other opioid analgesics were replaced with a single transdermal patch at a dosage of 12.5 mcg/h. Such a transfer scheme for children is used only when replacing oral morphine (or its equivalent) with a transdermal patch. The scheme cannot be used to switch from fentanyl to other opioid analgesics, since an overdose may occur in this case.
The analgesic effect of the first dose of the transdermal patch with fentanyl does not reach the optimal level during the first 24 hours. Therefore, during the first 12 hours after switching to the drug Abstract (buccal/sublingual)™ the patient should receive previous doses of analgesics. For the next 12 hours, patients should be provided with analgesics based on clinical need.
Since the level of fentanyl in the blood reaches its maximum values after 12-24 hours, it is recommended to monitor patients for adverse events, which may include respiratory depression for at least 48 hours after starting therapy with a transdermal patch or after increasing the dose (see "Special Instructions").
Dose selection and maintenance therapy in children from 2 to 16 years of age
The transdermal patch should be replaced with a new one every 72 hours. The dose is selected individually to achieve the optimal ratio of the level of pain relief and tolerability of the drug Abstract (buccal/sublingual)™. If the analgesic effect of the drug is Abstract (buccal/sublingual)™ if it is insufficient, you should additionally prescribe morphine or another short-acting opioid analgesic. Depending on the additional need for pain relief and the severity of the pain syndrome in the child, it is possible to increase the dose. Dose adjustment should be carried out gradually, in increments of 12.5 mcg/h. The dose should not be increased more often than once every 72 hours.
Method of application
The transdermal patch should be applied to the flat surface of the intact and unirradiated skin of the torso or shoulder. The upper back is the optimal place for applying a transdermal patch in young children. With this application, the probability of self-removal of the transdermal patch by children decreases.
For the application, it is recommended to choose a place with minimal hair cover (preferably without hair cover). Before applying, the hair on the application site should be cut (not shaved). If the application site needs to be washed before applying the transdermal patch, then this should be done with clean water. Do not use soap, lotions, oils, alcohol or other products, as they can cause skin irritation or change its properties. Before applying, the skin should be completely dry.
Since the transdermal patch is protected by a waterproof outer protective film, it can not be removed during a short stay in the shower.
The transdermal patch is removed from the package by bending the section with an incision located close to the tip of the arrow, and carefully tearing the package material.
The transdermal patch should be applied immediately after removal from the package, without touching its adhesive side. After removing the protective film, the transdermal patch should be pressed firmly with the palm of your hand to the application site for about 30 seconds. Make sure that the transdermal patch fits snugly to the skin, especially at the edges. Additional fixation of the patch may be required. Then wash your hands with clean water.
The patch should be worn continuously for 72 hours, after which it must be replaced with a new transdermal patch. A new transdermal patch should always be applied to another area of the skin, without capturing the place of the previous application. At the same place of application, the transdermal patch can be applied again no earlier than 7 days later.
The transdermal patch should be examined before use.
The transdermal patch should not be divided or cut (see "Special Instructions").
Waste material should be disposed of safely. Patients/carers should be encouraged to return any unused product to the Pharmacy, where it should be disposed of in accordance with national and local requirements.
Date of first authorisation: 19/09/2008
Date of latest renewal: 28/02/2013
Fentanyl is metabolised by CYP3A4. Active substances that inhibit CYP3A4 activity such as macrolide antibiotics (e.g. erythromycin), azole antifungal agents (e.g. ketoconazole, itraconazole) or certain protease inhibitors (e.g. ritonavir) may increase the bioavailability of fentanyl by decreasing its systemic clearance, potentially enhancing or prolonging opioid effects. Grapefruit juice is also known to inhibit CYP3A4. Coadministration with agents that induce CYP3A4 activity such as antimycobacterials (e.g. rifampin, rifabutin), anticonvulsants (e.g. carbamazepine, phenytoin, and phenobarbital) herbal products (e.g. St John's wort, Hypericum perforatum) may reduce the efficacy of fentanyl. CYP3A4 inducers exert their effect in a time-dependent manner, and may take at least 2 weeks to reach maximal effect after introduction. Conversely, on discontinuation, CYP3A4 induction may take at least 2 weeks to decline. Patients receiving fentanyl who stop therapy with, or decrease the dose of CYP3A4 inducers may be at risk of increased fentanyl activity or toxicity. Fentanyl should therefore be given to patients with caution if administered concomitantly with CYP3A4 inhibitors and/or inducers.
Concomitant use of other CNS depressants, such as other morphine derivatives (analgesics and antitussives), general anaesthetics, skeletal muscle relaxants, sedative antidepressants, sedative H1 antihistamines, barbiturates, anxiolytics (ie benzodiazepines), hypnotics, antipsychotics, clonidine and related substances may produce increased CNS depressant effects. Respiratory depression, hypotension and profound sedation may occur.
Alcohol potentiates the sedative effects of morphine-based analgesics, therefore concomitant administration of alcoholic beverages or medicinal products containing alcohol with Abstral is not recommended.
Abstral is not recommended for use in patients who have received monoamine oxidase (MAO) inhibitors within 14 days because severe and unpredictable potentiation by MAO inhibitors has been reported with opioid analgesics.
The concomitant use of partial opioid agonists/antagonists (e.g. buprenorphine, nalbuphine, pentazocine) is not recommended. They have high affinity to opioid receptors with relatively low intrinsic activity and therefore partially antagonise the analgesic effect of fentanyl and may induce withdrawal symptoms in opioid dependent patients.
Serotoninergic Drugs
Coadministration of fentanyl with a serotoninergic agent, such as a Selective Serotonin Re-uptake Inhibitor (SSRI) or a Serotonin Norepinephrine Re-uptake Inhibitor (SNRI) or a Monoamine Oxidase Inhibitor (MAOI), may increase the risk of serotonin syndrome, a potentially life-threatening condition.
