ZOLEUM

INSTRUCTIONS for medical use of the medicinal product FENTAVERA 12 mcg/h, FENTAVERA 25 mcg/h, FENTAVERA 50 mcg/h, FENTAVERA 75 mcg/h, FENTAVERA 100 mcg/h

Composition

The active substance is fentanyl; Fentavera 12 mcg/h: 1 transdermal patch of size 4.25 cm2 contains 2.55 mg of fentanyl with a release of 12.5 mcg of fentanyl per hour; Fentavera 25 mcg/h: 1 transdermal patch of size 8.5 cm2 contains 5.1 mg of fentanyl with a release of 25 mcg of fentanyl per hour; Fentavera 50 mcg/h: 1 transdermal patch of size 17 cm2 contains 10.2 mg of fentanyl with a release of 50 mcg of fentanyl per hour; Fentavera 75 mcg/h: 1 transdermal patch of size 25.5 cm2 contains 15.3 mg of fentanyl with a release of 75 mcg of fentanyl per hour; Fentavera 100 mcg/h: 1 transdermal patch of size 34 cm2 contains 20.4 mg of fentanyl with a release of 100 mcg of fentanyl per hour; excipients: poly (2-ethylhexyl acrylate, vinyl acetate), aloe vera leaf extract (soybean oil, alpha-tocopherol), hydrogenated canola oil, polyether film, polyethylene terephthalate (PET) film with ink printing.

Pharmaceutical form

Transdermal patch.

Main physical and chemical properties

A non-transparent, colorless, rectangular patch with rounded corners and an imprint on the foil base: "Fentanyl 12 µg/h" for Fentavera 12 mcg/h; "Fentanyl 25 µg/h" for Fentavera 25 mcg/h; "Fentanyl 50 µg/h" for Fentavera 50 mcg/h; "Fentanyl 75 µg/h" for Fentavera 75 mcg/h; "Fentanyl 100 µg/h" for Fentavera 100 mcg/h.

Pharmacotherapeutic group

Analgesics. Opioids. Phenylpiperidine derivatives.

ATC code N02A B03.

Pharmacological properties

Pharmacodynamics

Mechanism of action

Fentanyl is an opioid analgesic that interacts mainly with the mu-opioid receptor. The main therapeutic effects are analgesia and sedation.

Pharmacokinetics

Fentanyl is continuously absorbed through the skin for 72 hours after applying the Fentavera patch. After applying the Fentavera patch, fentanyl is absorbed through the skin, and a fentanyl depot is concentrated in the upper layers of the skin. Then, fentanyl enters the systemic circulation. The polymer matrix and the distribution of fentanyl through the skin layers provide a relatively constant release rate. The difference between the concentrations of fentanyl in the patch and in the skin leads to the release of the medicinal product. The average bioavailability of fentanyl after transdermal administration is 92%. After the first application of the Fentavera patch, the serum concentration of fentanyl increases gradually, reaching a steady state between 12 and 24 hours after patch application, and remains relatively constant throughout the remaining 72-hour application period. By the end of the second 72-hour application period, the concentration in the blood plasma reaches a steady state, which is maintained with subsequent applications of the patch of the same dosage. Due to accumulation, the values of the area under the pharmacokinetic curve "concentration-time" (AUC) and the maximum concentration (Cmax) during the interval between applications in a steady state are approximately 40% higher than after single application. Achieving and maintaining a constant concentration in the blood plasma is determined by the individual skin permeability of the patient and the clearance of fentanyl in the body. A high interindividual variability of fentanyl concentration in blood plasma was observed.

A pharmacokinetic model suggests that serum fentanyl concentrations may increase by 14% (range 0-26%) if a new patch is used 24 hours instead of the recommended 72-hour interval.

An increase in skin temperature may increase the absorption of fentanyl during transdermal administration (see "Special instructions for use"). An increase in skin temperature using an electric heating pad at the site of application of the Fentavera patch during the first 10 hours of single patch application increased the average AUC of fentanyl by 2.2 times, and the average concentration at the end of the heating pad use by 61%.

Distribution

Fentanyl is rapidly distributed to various tissues and organs, as indicated by a large volume of distribution (3-10 L/kg after intravenous administration to patients). Fentanyl accumulates in skeletal muscles and fatty tissue and is slowly released into the blood.

It is known that in a study involving patients with cancer who used transdermal fentanyl, the binding of the drug to plasma proteins was on average 95% (range 77-100%). Fentanyl easily passes through the blood-brain barrier, placenta, and into breast milk.

Metabolism

Fentanyl is a high-clearance drug, it is rapidly and extensively metabolized, mainly by CYP3A4 in the liver. The main metabolite, norfentanyl, and other metabolites are inactive. In the skin, fentanyl delivered transdermally is not metabolized. This was determined in an experiment with human keratinocytes, as well as in clinical studies, in which 92% of the dose that entered the transdermal patch was found in the systemic circulation as unchanged fentanyl.

Excretion

The half-life of fentanyl is between 20-27 hours after 72-hour application of the patch. As a result of continuous absorption of fentanyl from the skin after removal of the patch, the half-life of fentanyl after transdermal administration is approximately 2-3 times longer than after intravenous administration.

It is known that in studies after intravenous administration, the average values of total clearance of fentanyl were in the range from 34 to 66 L/hour. During 72 hours of intravenous infusion of fentanyl, approximately 75% of the fentanyl dose is excreted in the urine and approximately 9% of the dose is excreted in the feces. Excretion occurs mainly in the form of metabolites, with less than 10% of the drug being excreted unchanged.

Linearity/Nonlinearity

The concentration of fentanyl in the blood plasma is proportional to the size of the Fentavera patch. The pharmacokinetics of transdermal fentanyl does not change with repeated application.

Pharmacokinetic/Pharmacodynamic Relationship

The pharmacokinetics of fentanyl, the relationship between fentanyl concentrations and therapeutic and side effects, as well as tolerance to opioids, have a high interindividual variability. Both the minimum effective concentration and the toxic concentration increase with increasing tolerance. Thus, it is impossible to establish an optimal therapeutic concentration range for fentanyl. Adjustment of the individual dose of fentanyl should be based on the patient's response and level of tolerance. The period of delayed action, which is 12-24 hours after applying the first patch or after increasing the dose, should also be taken into account.

Special patient groups

Elderly patients

Data from studies of intravenous administration of fentanyl indicate that in elderly patients, clearance decreases, the half-life is prolonged, and they may be more sensitive to the drug than younger patients. In a study conducted with transdermal fentanyl patches in healthy elderly volunteers, the pharmacokinetics of fentanyl did not differ significantly from that in healthy young volunteers, although the maximum concentration in the blood plasma was lower, and the average half-life was prolonged to approximately 34 hours. Elderly patients should be closely monitored for signs of fentanyl toxicity and, if necessary, the dose should be reduced (see "Special instructions for use").

Renal impairment

It is expected that renal impairment will have a limited effect on the pharmacokinetics of fentanyl, as the excretion of unchanged fentanyl in the urine is less than 10%, and there are no known active metabolites excreted by the kidneys. However, since the effect of renal impairment on the pharmacokinetics of fentanyl has not been evaluated, caution is recommended (see "Special instructions for use" and "Method of administration and dosage").

Hepatic impairment

Elderly patients with impaired liver function should be closely monitored for signs of fentanyl toxicity and, if necessary, the dose should be reduced (see "Special instructions for use"). Data from patients with cirrhosis and modeling data suggest that in patients with various degrees of liver impairment who underwent treatment with transdermal fentanyl, the concentration of fentanyl may increase, and the clearance of fentanyl may decrease compared to patients without liver impairment. Modeling suggests that the AUC at steady state in patients with moderate liver impairment (Child-Pugh score 8) will be approximately 1.36 times higher compared to patients without liver impairment (Child-Pugh score 5.5). In patients with severe liver impairment (Child-Pugh score 12.5), the concentration of fentanyl accumulates with each application, leading to an increase in AUC (approximately 3.72 times) at steady state.

Children

It is known that the concentration of fentanyl was measured in more than 250 children aged 2 to 17 years who used fentanyl patches in doses ranging from 12.5 to 300 mcg/hour. With correction for body weight, it was found that clearance (L/h/kg) in children aged 2 to 5 years was approximately 80% higher, and in children aged 6 to 10 years, it was 25% higher compared to children aged 11 to 16 years, in whom clearance is similar to that in adults. These findings were taken into account when determining dosage recommendations for children (see "Special instructions for use" and "Method of administration and dosage").

Clinical characteristics

Indications

Adults: Long-term treatment of severe chronic pain that can only be adequately controlled with opioid analgesics.

Children: Long-term treatment of severe chronic pain in children aged 2 years and older who are already using opioid therapy.

Contraindications

Hypersensitivity to the active substance or to any of the excipients of the medicinal product.

The Fentavera preparation should not be used in the following cases:

• acute or postoperative pain, as dose titration is not possible during short-term use, and severe or life-threatening respiratory depression may occur;
• severe respiratory failure.

Due to the risk of life-threatening respiratory depression, Fentavera is contraindicated:

• in patients who are not opioid-tolerant;
• in patients with acute or severe asthma;
• in patients with intestinal obstruction;
• for the treatment of moderate pain.

Interactions with other medicinal products and other forms of interaction

Interactions related to pharmacodynamics

Central-acting medicinal products / central nervous system (CNS) depressants, including alcohol and narcotic CNS depressants: Concomitant use of Fentavera with other CNS depressants (including benzodiazepines and other sedative/hypnotic agents, opioids, general anesthetics, phenothiazines, tranquilizers, sedative antihistamines, alcohol, and narcotic drugs that depress the CNS) may result in respiratory depression, arterial hypotension, deep sedative effect, coma, or death.

Concomitant treatment with CNS depressants and fentanyl should only be prescribed to patients for whom alternative treatment options are not possible. The use of any of these medicinal products concomitantly with fentanyl requires special care and monitoring of the patient. The dose and duration of such concomitant use should be limited (see "Special instructions for use").

Monoamine oxidase inhibitors (MAOIs)

Fentavera is not recommended for use in patients who require concomitant treatment with MAOIs. Severe and unpredictable interactions with MAOIs have been reported, including enhanced opioid effects or serotonergic effects. Therefore, Fentavera should not be used within 14 days after stopping MAOI treatment.

Serotoninergic agents

Concomitant use of fentanyl with other serotoninergic agents, such as selective serotonin reuptake inhibitors (SSRIs) or serotonin-norepinephrine reuptake inhibitors (SNRIs), or MAOIs may increase the risk of serotonin syndrome, a potentially life-threatening condition. Therefore, concomitant use of these agents should be done with caution. Patients should be closely monitored, especially at the beginning of treatment and during dose adjustment (see "Special instructions for use").

Concomitant use with mixed agonist/antagonist opioids

Concomitant use of buprenorphine, nalbuphine, or pentazocine is not recommended. They have a high affinity for opioid receptors with relatively low intrinsic activity, so they can partially antagonize the analgesic effect of fentanyl and cause withdrawal symptoms in opioid-dependent patients (see "Special instructions for use").

Interactions related to pharmacokinetics

CYP3A4 enzyme inhibitors

Fentanyl is a high-clearance substance that is rapidly and extensively metabolized, mainly by CYP3A4.

Concomitant use of transdermal fentanyl patches and CYP3A4 inhibitors may lead to an increase in fentanyl plasma concentration, which may enhance or prolong both therapeutic and side effects and cause severe respiratory depression.

The degree of interaction with strong CYP3A4 inhibitors is expected to be greater than with weak or moderate CYP3A4 inhibitors. Cases of severe respiratory depression have been reported after concomitant use of CYP3A4 inhibitors with transdermal fentanyl, including a fatal case after concomitant use with a moderate CYP3A4 inhibitor. Concomitant use of CYP3A4 inhibitors and fentanyl is not recommended, except in cases where the expected benefit outweighs the increased risk of side effects. Such active substances as amiodarone, cimetidine, clarithromycin, diltiazem, erythromycin, fluconazole, itraconazole, ketoconazole, nefazodone, ritonavir, verapamil, and voriconazole (this list is not exhaustive) may increase the concentration of fentanyl.

CYP3A4 enzyme inducers

Concomitant use of CYP3A4 inducers may cause a decrease in fentanyl plasma concentration and a decrease in therapeutic efficacy. Caution is recommended when concomitantly using CYP3A4 inducers and Fentavera patches. There may be a need to increase the dose of fentanyl or switch to another analgesic agent. Before stopping concomitant use of CYP3A4 inducers, it is necessary to ensure a decrease in the dose of fentanyl and close monitoring. After stopping treatment with CYP3A4 inducers, their effect gradually decreases, resulting in a possible increase in fentanyl plasma concentration, which may lead to enhanced or prolonged therapeutic effects and side effects, including severe respiratory depression. In such cases, the patient requires special monitoring until a stable effect of the medicinal product is achieved. Such active substances as carbamazepine, phenobarbital, phenytoin, and rifampicin (this list is not exhaustive) may decrease the concentration of fentanyl in the blood plasma.

Children

Interaction studies were conducted in adult patients.

Special instructions for use

Patients who have developed serious side effects after removal of the patch should be monitored for at least 24 hours or longer, depending on clinical symptoms. The serum concentration of fentanyl decreases gradually and after 20-27 hours reaches approximately 50% of the initial level.

Patients and their caregivers should be informed that Fentavera patches contain an active substance in a quantity that can be lethal, especially for children. Therefore, patches should be stored in a place inaccessible to children, both before and after use.

Due to the risks, including fatal consequences, associated with accidental ingestion, improper use, and abuse, patients and their caregivers should be advised to store Fentavera patches in a safe and secure place, inaccessible to others.

Patients who have not previously received opioid therapy and are not tolerant to opioids

The use of fentanyl in patients who have not previously received opioid therapy is very rarely associated with significant respiratory depression and/or fatal consequences, especially in patients whose pain is not caused by cancer. The possibility of severe or life-threatening respiratory depression exists even when using the smallest dose of fentanyl as initial therapy, especially in elderly patients and patients with impaired liver or kidney function. The tendency to develop tolerance varies among patients. Fentanyl is recommended for use in patients who have developed tolerance to opioids (see "Method of administration and dosage").

Respiratory depression

Since the use of Fentavera patches can cause significant respiratory depression in some patients, patients should be monitored for the development of this effect. Respiratory depression can persist after patch removal. The frequency of respiratory depression increases with increasing doses of fentanyl (see "Overdose").

Opioids can cause sleep-related breathing disorders, including central sleep apnea (CSA) and sleep-related hypoxemia. Opioid use increases the risk of developing CSA, depending on the dose. In patients with CSA, it is necessary to consider reducing the overall dose of opioids.

Risk of concomitant use of CNS depressants, including sedative agents, such as benzodiazepines or related agents, alcohol, and narcotic drugs that depress the CNS

Concomitant use of fentanyl and sedative agents, such as benzodiazepines or related agents, alcohol, and narcotic drugs that depress the CNS, can lead to sedation, respiratory depression, coma, and fatal consequences. Due to this risk, concomitant prescription of such sedative agents is indicated only for patients for whom there are no alternative treatment options. However, if concomitant prescription of fentanyl and sedative agents is considered necessary, the minimum effective dose should be used for the shortest possible period. Patients should be closely monitored to detect signs and symptoms of respiratory depression and sedation. In this regard, it is strongly recommended to inform patients and their caregivers about these symptoms (see "Interactions with other medicinal products and other forms of interaction").

Chronic lung disease

In patients with chronic obstructive or other lung disease, fentanyl may cause more severe adverse reactions. In such patients, opioids can reduce the activity of the respiratory center and increase airway resistance.

Long-term treatment effect and tolerance

Tolerance to the analgesic effect, hyperalgesia, physical dependence, and psychological dependence may develop in all patients with repeated use of opioids, while with some side effects, such as opioid-induced constipation, incomplete tolerance develops. In particular, in patients with chronic non-cancer pain, it has been reported that they may not experience significant pain relief due to constant opioid treatment during long-term treatment. During treatment, there should be constant contact between the doctor and the patient to assess the need to continue treatment (see "Method of administration and dosage"). When it is decided that the benefits of continuing therapy are not available, the dose should be gradually reduced to avoid withdrawal symptoms.

Patients who are physically dependent on opioids should not abruptly stop using Fentavera patches. Abrupt cessation of therapy or dose reduction can lead to withdrawal syndrome.

There have been reports that abrupt cessation of fentanyl use in patients who are physically dependent on opioids has led to the development of severe withdrawal symptoms and uncontrolled pain (see "Method of administration and dosage" and "Side effects"). When the patient no longer needs therapy, it is advisable to gradually reduce the dose to minimize withdrawal symptoms. Reducing a high dose can take several weeks to several months.

Opioid withdrawal syndrome is characterized by some or all of the following symptoms: anxiety, lacrimation, rhinorrhea, yawning, sweating, chills, myalgia, mydriasis, and tachycardia. Other symptoms may also occur, including irritability, agitation, anxiety, hyperkinesia, tremor, weakness, insomnia, anorexia, abdominal cramps, nausea, vomiting, diarrhea, increased blood pressure, and increased respiratory rate.

Opioid use disorder (addiction and abuse)

Repeated use of fentanyl can lead to opioid use disorder (OUD). A higher dose and longer duration of opioid treatment may increase the risk of developing OUD. Abuse or improper use of Fentavera patches can lead to overdose and/or fatal consequences. Patients with a personal or family history (parents, siblings) of substance use disorder, current smokers, or patients with a history of other mental health disorders (e.g., major depression, anxiety, and personality disorders) are at higher risk of developing OUD.

Before starting fentanyl treatment and during treatment, it is necessary to agree with the patient on the treatment goals and the plan for stopping treatment (see "Method of administration and dosage"). During treatment, patients should also be informed about the risks and signs of OUD. If these signs appear, patients should be advised to consult their doctor.

Patients receiving opioids should be monitored for signs of OUD, such as behavior related to drug seeking (e.g., too early requests for re-administration of the drug), especially in patients at high risk. This includes reviewing concomitant opioids and psychoactive substances (such as benzodiazepines). For patients with signs and symptoms of OUD, it is necessary to consider consulting a specialist in addiction medicine. If it is planned to stop taking opioids, see "Special instructions for use".

CNS disorders, including increased intracranial pressure

Fentanyl should be used with caution in patients who may have increased sensitivity to increased CO2 levels, such as in cases of increased intracranial pressure, impaired consciousness, or coma. Patients with brain tumors should use Fentavera patches with caution.

Cardiovascular disorders

Fentanyl may cause bradycardia, so Fentavera patches should be used with caution in patients with bradyarrhythmia.

Arterial hypotension

Opioids can cause arterial hypotension, especially in patients with acute hypovolemia. Considering this, before starting treatment with transdermal fentanyl patches, it is necessary to correct symptomatic hypotension and/or hypovolemia.

Liver function disorders

Since fentanyl is metabolized to inactive metabolites in the liver, liver function disorders may cause a delay in their elimination. If patients with liver function disorders use fentanyl, they should be closely monitored for signs of fentanyl toxicity and, if necessary, the dose should be reduced (see "Pharmacological properties").

Kidney function disorders

Although kidney function disorders are not expected to affect the excretion of fentanyl in clinically significant amounts, caution is recommended, as the pharmacokinetics of fentanyl have not been evaluated in this patient population (see "Pharmacological properties"). Fentanyl treatment should only be started when the benefits outweigh the risks. If patients with kidney function disorders use Fentavera patches, they should be closely monitored for signs of fentanyl toxicity and, if necessary, the dose should be reduced. Additional restrictions apply to patients with kidney function disorders who have not previously received opioid therapy (see "Method of administration and dosage").

Fever/external heat use

An increase in skin temperature may increase the concentration of fentanyl. Therefore, patients with fever should be closely monitored for side effects, and the dose of fentanyl should be adjusted if necessary. A temperature-dependent increase in fentanyl release from the patch is possible, which can lead to overdose and fatal consequences. All patients should avoid exposure to external heat sources, such as electric heating pads, electric blankets, water beds with hot water, heat lamps, sunbathing, hot water bottles, saunas, prolonged hot baths, or hot whirlpools, at the site of application of the Fentavera patch.

Serotonin syndrome

Caution is recommended if fentanyl is used concomitantly with agents that affect the serotonergic neurotransmitter system.

The development of a potentially life-threatening serotonin syndrome is possible with concomitant use of serotonergic agents, such as SSRIs and SNRIs, and agents that disrupt serotonin metabolism (including MAOIs), even when used within the recommended dose (see "Interactions with other medicinal products and other forms of interaction").

Serotonin syndrome can be characterized by one or more of the following symptoms: changes in mental status (e.g., agitation, hallucinations, coma), autonomic nervous system disorders (e.g., tachycardia, blood pressure fluctuations, hyperthermia), neuromuscular disorders (e.g., hyperreflexia, discoordination, rigidity), and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea).

If serotonin syndrome is suspected, it is necessary to decide on the rapid cessation of Fentavera patch use.

Interactions with other medicinal products

CYP3A4 inhibitors

Concomitant use of Fentavera patches with CYP3A4 inhibitors may lead to an increase in fentanyl plasma concentration, which may enhance or prolong both therapeutic and side effects and cause severe respiratory depression. Therefore, concomitant use of transdermal fentanyl and CYP3A4 inhibitors is not recommended, except in cases where the expected benefit outweighs the increased risk of side effects. Fentavera patches should not be used within 2 days after stopping CYP3A4 inhibitor treatment and before applying the first Fentavera patch. However, the duration of respiratory depression may vary, and for some CYP3A4 inhibitors with a long half-life, such as amiodarone, or time-dependent inhibitors, such as erythromycin, idelalisib, nicardipine, and ritonavir, a longer period may be necessary. Therefore, before applying the first Fentavera patch, it is necessary to familiarize yourself with the instructions for the CYP3A4 inhibitor regarding its half-life and duration of the inhibitory effect. A patient who is receiving fentanyl treatment should wait at least 1 week after removing the last patch before starting CYP3A4 inhibitor therapy. If concomitant use of fentanyl and CYP3A4 inhibitors is unavoidable, it is necessary to ensure close monitoring for the development of symptoms of enhanced or prolonged therapeutic effects and side effects of fentanyl (including respiratory depression). In addition, if necessary, the dose of fentanyl should be reduced or its use should be discontinued (see "Interactions with other medicinal products and other forms of interaction").

Accidental application of the patch

Accidental application of a fentanyl patch to a person for whom it is not intended (especially a child) during co-sleeping or in case of close physical contact with the patch wearer can lead to opioid overdose. In case of accidental transfer of the patch, it should be immediately removed from the skin (see "Overdose").

Elderly patients

Data from studies of intravenous administration of fentanyl indicate that elderly patients may be more sensitive to the drug than younger patients. In elderly patients, the clearance of fentanyl is lower, and the half-life is longer. If elderly patients use Fentavera patches, they should be closely monitored for signs of fentanyl toxicity, and the dose should be reduced if necessary.

Gastrointestinal tract

Opioids increase the tone and reduce the propulsive peristalsis of the smooth muscles of the gastrointestinal tract. As a result, the passage time through the gastrointestinal tract is prolonged, which may explain the occurrence of constipation when using fentanyl. Patients should be informed about measures to prevent constipation and recommended to use prophylactic laxatives. Particular caution should be exercised in patients with chronic constipation. If intestinal obstruction is suspected, Fentavera use should be discontinued.

Patients with myasthenia gravis

Non-epileptic myoclonic reactions may occur. Patients with myasthenia gravis should be treated with caution.

Concomitant use with mixed agonist/antagonist opioids

Concomitant use of buprenorphine, nalbuphine, or pentazocine is not recommended (also see "Interactions with other medicinal products and other forms of interaction").

Children

Fentavera patches should not be used in children who have not previously received opioid therapy (see "Method of administration and dosage"). There is a possibility of severe or life-threatening respiratory depression, regardless of the prescribed dose of the transdermal Fentavera patch, especially in children and patients with impaired liver or kidney function.

The use of Fentavera patches has not been studied in children under 2 years of age. Fentavera patches should only be prescribed to children with opioid tolerance aged 2 years and older (see "Method of administration and dosage"). Fentavera patches should not be used in children under 2 years of age.

To prevent accidental ingestion by children, caution should be exercised when choosing the site for attaching the Fentavera patch, and the attachment of the patch should be closely monitored.

Overdose

Symptoms and signs

The manifestations of fentanyl overdose are a prolongation of its pharmacological actions, the most serious effect being respiratory depression. Toxic leukoencephalopathy has also been observed with fentanyl overdose.

Treatment

In case of respiratory depression, the Fentavera patch should be removed immediately, and the patient should be encouraged to breathe verbally or physically. A specific antagonist, such as naloxone, can be administered, but respiratory depression may persist longer than the action of the opioid antagonist. The interval between intravenous injections of antagonist doses should be carefully selected due to the possibility of re-narcotization after patch removal; repeated administration or continuous infusion of naloxone may be necessary. Sudden pain and release of catecholamines may be a consequence of antagonist administration.

If clinically justified, it is necessary to establish and maintain a free airway, possibly by inserting an oropharyngeal or endotracheal tube. It is necessary to maintain adequate body temperature and fluid intake.

If severe or persistent hypotension occurs, it is necessary to consider the possibility of hypovolemia and treat this condition with appropriate infusion therapy.

Side effects

The safety of fentanyl was evaluated in 1565 adult and 289 pediatric patients who participated in 11 clinical trials of the drug for the treatment of chronic pain, both cancer-related and non-cancer-related. Each study participant received at least one dose of the medicinal product. Based on the combined safety data, the most common (≥10% of cases) side effects were nausea (35.7%), vomiting (23.2%), constipation (23.1%), somnolence (15.0%), dizziness (13.1%), and headache (11.8%).

Side effects reported during these clinical trials and during post-marketing surveillance are listed below.

Side effects are classified by system organ class and frequency: very common (≥1/10); common (≥1/100, <1/10); uncommon (≥1/1000, <1/100); rare (≥1/10000, <1/1000); very rare (<1/10000); frequency not known (cannot be estimated from the available data).

Immune system disorders: common - hypersensitivity; frequency not known - anaphylactic shock, anaphylactic reaction, anaphylactoid reaction.

Endocrine system disorders: frequency not known - androgen deficiency.

Metabolic and nutritional disorders: common - anorexia.

Psychiatric disorders: common - insomnia, depression, anxiety, confusion, hallucinations; uncommon - agitation, disorientation, euphoria; frequency not known - delirium, drug dependence.

Nervous system disorders: very common - somnolence, dizziness, headache; common - tremor, paresthesia; uncommon - hypesthesia, seizures (including clonic seizures and grand mal seizures), amnesia, impaired consciousness, loss of consciousness.

Eyes: uncommon - blurred vision; rare - miosis.

Ears and labyrinth: common - vertigo.

Cardiac disorders: common - tachycardia; uncommon - bradycardia, cyanosis.

Vascular disorders: common - arterial hypertension; uncommon - arterial hypotension.

Respiratory, thoracic, and mediastinal disorders: common - dyspnea; uncommon - respiratory depression, respiratory distress syndrome; rare - apnea, hyperventilation; frequency not known - bradypnea.

Gastrointestinal disorders: very common - nausea, vomiting, constipation; common - diarrhea, dry mouth, abdominal pain, upper abdominal pain, dyspepsia; uncommon - intestinal obstruction, dysphagia; rare - partial intestinal obstruction.

Skin and subcutaneous tissue disorders: common - hyperhidrosis, pruritus, rash, erythema; uncommon - eczema, allergic dermatitis, skin reactions, dermatitis, contact dermatitis.

Musculoskeletal and connective tissue disorders: common - muscle spasms; uncommon - muscle cramps.

Renal and urinary disorders: common - urinary retention.

Reproductive system and breast disorders: uncommon - erectile dysfunction, sexual dysfunction.

General disorders and administration site conditions: common - fatigue, peripheral edema, asthenia, malaise, feeling cold; uncommon - application site reaction, flu-like illness, feeling of temperature change, increased sensitivity at the application site, withdrawal syndrome, pyrexia*; rare - application site dermatitis, application site eczema; frequency not known - tolerance.

*The frequency (uncommon) was determined based on the incidence in clinical trials in adult patients and children with pain not related to cancer.

Fentavera medicinal product contains soybean oil

In very rare cases, soybean oil can cause allergic reactions.

Children

The safety of fentanyl was evaluated in 289 pediatric patients (<18 years) who participated in 3 clinical trials for the treatment of chronic or persistent pain of malignant or non-malignant origin. These patients received at least one dose of fentanyl. The profile of undesirable effects in children and adolescents who used transdermal fentanyl patches was similar to that in adults. No risks were identified in children, except for those expected with the use of opioids for pain relief in severe illness. No characteristic risks for children associated with fentanyl use were identified in children aged 2 years and older when used as indicated. Very common undesirable effects reported in pediatric clinical trials were headache (16.3%), vomiting (33.9%), nausea (23.5%), constipation (13.5%), diarrhea (12.8%), and pruritus (12.8%).

Tolerance

Tolerance may develop with repeated use.

Drug dependence

Repeated use of fentanyl can lead to drug dependence, even at therapeutic doses. The risk of developing drug dependence may vary depending on individual patient risk factors, dosage, and duration of opioid treatment (see "Special instructions for use").

Opioid withdrawal symptoms (nausea, vomiting, diarrhea, anxiety, and tremors) are possible in some patients after switching from a previous opioid analgesic to fentanyl or after abrupt cessation of therapy (see "Method of administration and dosage" and "Special instructions for use").

Very rarely, there have been reports of newborns with neonatal withdrawal syndrome whose mothers constantly used fentanyl during pregnancy (see "Use during pregnancy or breastfeeding").

There have been reports of the development of serotonin syndrome when fentanyl is used concomitantly with serotonergic agents (see "Interactions with other medicinal products and other forms of interaction" and "Special instructions for use").

Shelf life

2 years.

Storage conditions

No special storage conditions are required. Store in a place inaccessible to children.

Incompatibilities

To prevent deterioration of the adhesive properties of the patch, creams, oils, lotions, or powders should not be applied to the skin area where the patch will be attached.

Packaging

1 transdermal patch per child-resistant pouch; 5 pouches per carton with a first-opening control.

Release category

Prescription only.

Manufacturer

Asino AG.

Manufacturer's location and address

Leopoldstrasse 115, 80804 Munich, Germany.