Fentavera 12 mcg/hour

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT FENTAVERA 12 µg/h FENTAVERA 25 µg/h FENTAVERA 50 µg/h FENTAVERA 75 µg/h FENTAVERA 100 µg/h (FENTAVERA® 12 µg/h) (FENTAVERA® 25 µg/h) (FENTAVERA® 50 µg/h) (FENTAVERA® 75 µg/h) (FENTAVERA® 100 µg/h)

Composition:

Active substance: fentanyl;

FENTAVERA 12 µg/h:

1 transdermal patch of 4.25 cm² contains fentanyl 2.55 mg, releasing 12.5 µg of fentanyl per hour;

FENTAVERA 25 µg/h:

1 transdermal patch of 8.5 cm² contains fentanyl 5.1 mg, releasing 25 µg of fentanyl per hour;

FENTAVERA 50 µg/h:

1 transdermal patch of 17 cm² contains fentanyl 10.2 mg, releasing 50 µg of fentanyl per hour;

FENTAVERA 75 µg/h:

1 transdermal patch of 25.5 cm² contains fentanyl 15.3 mg, releasing 75 µg of fentanyl per hour;

FENTAVERA 100 µg/h:

1 transdermal patch of 34 cm² contains fentanyl 20.4 mg, releasing 100 µg of fentanyl per hour;

Excipients: poly(2-ethylhexyl acrylate, vinyl acetate), oil extract of aloe vera leaves (soybean oil, alpha-tocopherol), hydrogenated rosin ether, polyester film, polyethylene terephthalate (PET) film with printed text in ink.

Pharmaceutical form. Transdermal patch.

Main physicochemical properties:

A translucent, colorless, rectangular patch with rounded corners and printed marking on the backing film:

«Fentanyl 12 µg/h» for FENTAVERA 12 µg/h;

«Fentanyl 25 µg/h» for FENTAVERA 25 µg/h;

«Fentanyl 50 µg/h» for FENTAVERA 50 µg/h;

«Fentanyl 75 µg/h» for FENTAVERA 75 µg/h;

«Fentanyl 100 µg/h» for FENTAVERA 100 µg/h.

Pharmacotherapeutic group. Analgesics. Opioids. Phenylpiperidine derivatives.

ATC code: N02A B03.

Pharmacological Properties.

Pharmacodynamics.

Mechanism of action

Fentanyl is an opioid analgesic that interacts primarily with the μ-opioid receptor. The principal therapeutic effects are analgesia and sedation.

Pharmacokinetics.

Absorption

Fentanyl is continuously absorbed through the skin for 72 hours following application of the Fentavere patch. After application of the Fentavere patch, fentanyl is absorbed through the skin, and a fentanyl depot accumulates in the upper layers of the skin. Subsequently, fentanyl enters the systemic circulation. The polymer matrix and diffusion of fentanyl through the skin layers ensure a relatively constant rate of release. The concentration gradient between fentanyl in the patch and in the skin drives drug release. The mean bioavailability of fentanyl following transdermal administration is 92%. After the first application of the Fentavere patch, serum fentanyl concentrations increase gradually, reaching steady-state levels between 12 and 24 hours after patch application, and remain relatively constant throughout the remainder of the 72-hour application period. By the end of the second 72-hour application period, serum concentrations reach equilibrium, which is maintained with subsequent applications of patches at the same dosage. Due to accumulation, the area under the plasma concentration-time curve (AUC) and maximum concentration (Cmax) during the dosing interval at steady state are approximately 40% higher than after a single dose. The achievement and maintenance of steady-state serum concentrations are determined by the individual patient's skin permeability and fentanyl clearance. High inter-individual variability in plasma fentanyl concentrations has been observed.

Pharmacokinetic modeling suggests that serum fentanyl concentrations may increase by 14% (range 0–26%) if a new patch is applied after 24 hours instead of the recommended 72-hour interval.

Elevated skin temperature may increase fentanyl absorption following transdermal administration (see section "Special precautions"). Increasing skin temperature by using an electric heating pad at the Fentavere patch application site during the first 10 hours of single patch application increased the mean AUC of fentanyl by a factor of 2.2 and the mean concentration at the end of the heating period by 61%.

Distribution

Fentanyl rapidly distributes into various tissues and organs, as indicated by its large volume of distribution (3–10 L/kg after intravenous administration in patients). Fentanyl accumulates in skeletal muscle and adipose tissue and is slowly released back into the bloodstream.

In studies involving cancer patients receiving transdermal fentanyl, plasma protein binding of the drug was found to average 95% (range 77–100%). Fentanyl readily crosses the blood-brain barrier, placenta, and into breast milk.

Biological transformation

Fentanyl is a high-clearance drug that is rapidly and extensively metabolized, primarily by CYP3A4 in the liver. The main metabolite, norfentanyl, and other metabolites are inactive. Fentanyl delivered transdermally is not metabolized in the skin. This has been demonstrated in experiments with human keratinocytes and in clinical studies, where 92% of the dose absorbed from the transdermal patch was found in the systemic circulation as unchanged fentanyl.

Elimination

The elimination half-life of fentanyl ranges from 20 to 27 hours after 72-hour patch application. Due to continuous absorption of fentanyl from the skin following patch removal, the elimination half-life after transdermal administration is approximately 2–3 times longer than after intravenous administration.

After intravenous administration, mean values of total fentanyl clearance have been reported to range from 34 to 66 L/hour. During 72 hours of intravenous infusion, approximately 75% of the fentanyl dose is excreted in urine and about 9% is eliminated in feces. Elimination occurs primarily as metabolites, with less than 10% of the drug excreted unchanged.

Linearity/non-linearity

Serum fentanyl concentrations are proportional to the size of the Fentavere patch. The pharmacokinetics of transdermal fentanyl do not change with repeated administration.

Pharmacokinetic/pharmacodynamic relationship

Fentanyl pharmacokinetics, the relationship between fentanyl concentrations and therapeutic or adverse effects, and opioid tolerance exhibit considerable inter-individual variability. Both the minimum effective concentration and the toxic concentration increase with increasing tolerance. Therefore, it is not possible to define an optimal therapeutic concentration range for fentanyl. Individual dose titration of fentanyl should be based on patient response and level of tolerance. The delayed onset period of 12–24 hours after application of the first patch or after dose escalation should also be taken into account.

Special patient groups

Elderly patients

Data from studies of intravenous fentanyl administration indicate that elderly patients have reduced clearance, prolonged elimination half-life, and may be more sensitive to the drug than younger patients. In a study with transdermal fentanyl patches, the pharmacokinetics of fentanyl in healthy elderly volunteers did not differ significantly from those in healthy young volunteers, although maximum serum concentration was lower and the mean elimination half-life was prolonged to approximately 34 hours. Elderly patients should be closely monitored for signs of fentanyl toxicity, and dose reduction may be necessary (see section "Special precautions").

Renal impairment

The impact of renal impairment on fentanyl pharmacokinetics is expected to be limited, as less than 10% of unchanged fentanyl is excreted in urine and there are no known active metabolites eliminated by the kidneys. However, since the effect of renal impairment on fentanyl pharmacokinetics has not been formally evaluated, caution is recommended (see sections "Special precautions" and "Dosage and administration").

Hepatic impairment

Patients with hepatic impairment should be closely monitored for signs of fentanyl toxicity, and dose reduction may be necessary (see section "Special precautions"). Data from patients with cirrhosis and modeling data suggest that patients with varying degrees of hepatic dysfunction receiving transdermal fentanyl may have increased fentanyl concentrations and reduced fentanyl clearance compared to patients with normal liver function. Modeling indicates that steady-state AUC in patients with moderate hepatic impairment (Child-Pugh class B, score = 8) is approximately 1.36 times higher than in patients with normal liver function (Child-Pugh class A, score = 5.5). In patients with severe hepatic impairment (Child-Pugh class C, score = 12.5), fentanyl accumulates with each patch application, resulting in increased AUC (approximately 3.72 times higher) at steady state.

Children

Fentanyl concentrations have been measured in more than 250 children aged 2 to 17 years who received fentanyl patches at doses ranging from 12.5 to 300 mcg/hour. When adjusted for body weight, clearance (L/h/kg) was found to be approximately 80% higher in children aged 2 to 5 years and 25% higher in children aged 6 to 10 years compared to children aged 11 to 16 years, in whom clearance is similar to that in adults. These findings were taken into account when establishing dosage recommendations for children (see sections "Special precautions" and "Dosage and administration").

Clinical characteristics.

Indications.

Adults

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

Children

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

Contraindications.

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

Fentavera should not be used in the following cases:

• Acute or postoperative pain, as dose titration is not feasible during short-term use and may result in serious or life-threatening hypoventilation;
• Severe respiratory insufficiency.

Due to the risk of fatal respiratory depression, Fentavera is contraindicated:

• In patients who are not opioid-tolerant;
• In patients with acute or severe asthma;
• In patients with paralytic ileus;
• For the treatment of moderate pain.

Interaction with other medicinal products and other forms of interaction.

Types of interactions related to pharmacodynamics

Medicinal products with central action / 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 substances that depress the CNS), muscle relaxants, and gabapentinoids (gabapentin and pregabalin) may result in respiratory depression, hypotension, profound sedation, coma, or death.

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

Monoamine oxidase inhibitors (MAOIs)

Fentavera is not recommended for use in patients requiring concomitant treatment with MAOIs. Severe and unpredictable interactions, including potentiation of opioid effects or serotonergic effects, have been reported. Therefore, Fentavera should not be administered within 14 days after discontinuation of MAOI therapy.

Serotonergic agents

Concomitant use of fentanyl with other serotonergic agents, such as selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), or MAOIs, may increase the risk of serotonin syndrome, a potentially life-threatening condition. Therefore, such concomitant use should be done with caution. Close monitoring of the patient is required, especially at the beginning of treatment and during dose adjustments (see section "Special warnings and precautions for use").

Concomitant use with mixed opioid agonist/antagonist agents

Concomitant use of buprenorphine, nalbuphine, or pentazocine is not recommended. These agents have high affinity for opioid receptors with relatively low intrinsic activity and may therefore partially antagonize the analgesic effect of fentanyl and may precipitate withdrawal symptoms in opioid-dependent patients (see section "Special warnings and precautions for use").

Types of interactions related to pharmacokinetics

Inhibitors of cytochrome P450 3A4 (CYP3A4) enzymes

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

Concomitant use of transdermal fentanyl patches and CYP3A4 inhibitors may lead to increased plasma concentrations of fentanyl, which may enhance or prolong both therapeutic effects and adverse reactions, and may cause severe respiratory depression.

The degree of interaction is expected to be greater with strong CYP3A4 inhibitors than with weak or moderate inhibitors. Cases of severe respiratory depression have been reported following 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 when the patient is under close supervision (see section "Special warnings and precautions for use"). Such active substances as amiodarone, cimetidine, clarithromycin, diltiazem, erythromycin, fluconazole, itraconazole, ketoconazole, nefazodone, ritonavir, verapamil, and voriconazole (this list is not exhaustive) may increase fentanyl concentrations. Following concomitant use of weak, moderate, or strong CYP3A4 inhibitors with short-term intravenous administration of fentanyl, reduction in its clearance was typically ≤25%, but with concomitant use of ritonavir (a strong CYP3A4 inhibitor), fentanyl clearance was reduced by an average of 67%. The extent of interaction between CYP3A4 inhibitors and long-term transdermal fentanyl use is unknown but may be greater than with short-term intravenous administration.

Inducers of cytochrome P450 3A4 (CYP3A4) enzymes

Concomitant use of CYP3A4 inducers may lead to decreased plasma concentrations of fentanyl and reduced therapeutic efficacy. Caution is recommended when using CYP3A4 inducers concomitantly with the Fentavera patch. It may be necessary to increase the fentanyl dose or switch to another analgesic. Prior to discontinuation of concomitant CYP3A4 inducers, fentanyl dose reduction and careful monitoring should be ensured. After stopping treatment with CYP3A4 inducers, their effect gradually diminishes, potentially leading to increased fentanyl plasma concentrations, which may enhance or prolong therapeutic effects and adverse reactions, including severe respiratory depression. In such cases, close monitoring of the patient is required until a stable drug effect is achieved. Such active substances as carbamazepine, phenobarbital, phenytoin, and rifampicin (this list is not exhaustive) may lead to decreased fentanyl plasma concentrations.

Children.

Interaction studies were conducted in adult patients.

Special precautions for use.

Patients who have experienced serious adverse reactions should remain under observation for at least 24 hours or longer depending on clinical symptoms after removal of the patch. Serum fentanyl concentration decreases gradually and reaches approximately 50% of the initial level within 20–27 hours.

Patients and caregivers should be informed that Fentavera patch contains an amount of active substance that may be lethal, especially for children. Therefore, patches must be stored out of reach of children both before and after use.

Due to risks, including fatal outcomes associated with accidental ingestion, misuse, and abuse, patients and caregivers should be advised to store Fentavera patch in a safe and secure place inaccessible to others.

Patients who have not previously received opioid therapy and who are opioid-naïve

Use of fentanyl in opioid-naïve patients has very rarely been associated with significant respiratory depression and/or fatal outcomes when fentanyl is used as initial therapy, especially in patients whose pain is not cancer-related. The potential for severe or life-threatening hypoventilation exists even when the lowest dose of fentanyl is used as initial therapy in opioid-naïve patients, particularly in elderly patients and in patients with hepatic or renal impairment. The tendency to develop tolerance varies among individual patients. Fentanyl is recommended for use in patients who are opioid-tolerant (see section "Dosage and administration").

Respiratory depression

Since significant respiratory depression may occur in some patients using Fentavera patch, patients should be monitored for this effect. Respiratory depression may persist after removal of the patch. The frequency of respiratory depression increases with increasing fentanyl dose (see section "Overdose").

Opioids may cause sleep-related breathing disorders, including central sleep apnea (CSA) and sleep-related hypoxemia. Opioid use increases the risk of developing CSA in a dose-dependent manner. In patients with CSA, consideration should be given to reducing the total opioid dose.

Risk of concomitant use of CNS depressants, including sedatives such as benzodiazepines or related drugs, alcohol, and other CNS depressant medications

Concomitant use of fentanyl with sedatives such as benzodiazepines or related drugs, alcohol, and other CNS depressant medications may lead to sedation, respiratory depression, coma, and fatal outcomes. Because of this risk, concomitant prescribing of such sedatives is indicated only for patients for whom no alternative treatment options are available. However, if concomitant use of fentanyl and sedatives is considered necessary, the lowest effective dose should be used for the shortest possible duration. Patients must be closely monitored for signs and symptoms of respiratory depression and sedation. Therefore, patients and caregivers should be strongly advised to be informed about these symptoms (see section "Interaction with other medicinal products and other forms of interaction").

Chronic lung disease

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

Prolonged treatment effect and tolerance

Tolerance to analgesic effects, hyperalgesia, physical dependence, and psychological dependence may develop in all patients with repeated use of opioids, while incomplete tolerance may develop to some adverse effects, such as opioid-induced constipation. In particular, patients with chronic non-malignant pain have reported inability to achieve significant pain reduction with continued opioid therapy during long-term treatment. During treatment, continuous communication between physician and patient is necessary to assess the need for continued therapy (see section "Dosage and administration"). When it is determined that no benefit is derived from continuing therapy, the dose should be gradually reduced to avoid withdrawal symptoms.

Patients who are physically dependent on opioids should not abruptly discontinue use of Fentavera patch. Abrupt discontinuation or dose reduction may lead to withdrawal syndrome.

There have been reports of abrupt discontinuation of fentanyl in patients physically dependent on opioids resulting in severe withdrawal symptoms and uncontrolled pain (see sections "Dosage and administration" and "Adverse reactions"). When a patient no longer requires therapy, gradual dose reduction is advisable to minimize withdrawal symptoms. Reduction from a high dose may 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, miosis, and tachycardia. Other symptoms may also occur, including irritability, agitation, anxiety, hyperkinesis, tremor, weakness, insomnia, anorexia, abdominal cramps, nausea, vomiting, diarrhea, elevated blood pressure, increased respiratory rate, or tachycardia.

Opioid use disorder (dependence and abuse)

Repeated use of fentanyl may lead to opioid use disorder (OUD). Higher doses and longer duration of opioid therapy may increase the risk of developing OUD. Abuse or improper use of Fentavera patch may lead to overdose and/or fatal outcomes. Patients with personal or family history (parents, siblings) of substance use disorder, current tobacco users, or patients with personal history of other mental health disorders (e.g., major depression, anxiety, and personality disorders) have a higher risk of developing OUD.

Prior to initiating fentanyl therapy and during treatment, treatment goals and a plan for discontinuation should be discussed with the patient (see section "Dosage and administration"). Patients should also be informed about the risks and signs of OUD before and during treatment. If such signs occur, patients should be advised to contact their physician.

Patients receiving opioids should be monitored for signs of OUD, such as drug-seeking behavior (e.g., early requests for medication renewal), especially in patients at increased risk. This includes review of concomitant opioid and psychoactive medications (such as benzodiazepines). For patients showing signs and symptoms of OUD, consultation with a specialist in addiction medicine should be considered. For discontinuation of opioid therapy, see section "Special precautions for use".

CNS disorders, including increased intracranial pressure

Fentanyl should be used with caution in patients who may have increased sensitivity to elevated CO₂ levels, for example, in cases of increased intracranial pressure, impaired consciousness, or coma. Fentavera patch should be used with caution in patients with brain tumors.

Cardiac disorders

Fentanyl may cause bradycardia; therefore, Fentavera patch should be used with caution in patients with bradyarrhythmias.

Arterial hypotension

Opioids may cause arterial hypotension, especially in patients with acute hypovolemia. Therefore, symptomatic hypotension and/or hypovolemia should be corrected prior to initiating transdermal fentanyl therapy.

Hepatic impairment

Since fentanyl is metabolized to inactive metabolites in the liver, hepatic impairment may result in slower elimination. Patients with hepatic impairment receiving fentanyl should be closely monitored for signs of fentanyl toxicity and the dose should be reduced if necessary (see section "Pharmacological properties").

Renal impairment

Although renal impairment is not expected to affect fentanyl elimination in clinically significant amounts, caution is recommended since the pharmacokinetics of fentanyl have not been evaluated in this patient population (see section "Pharmacological properties"). Fentanyl therapy should only be initiated when benefits outweigh the risks. Patients with renal impairment receiving Fentavera patch should be closely monitored for signs of fentanyl toxicity, and the dose should be reduced if necessary. Additional restrictions apply to opioid-naïve patients with renal impairment (see section "Dosage and administration").

Fever/Use of external heat

Increased skin temperature may increase fentanyl concentration. Therefore, patients with fever should be closely monitored for adverse reactions. Fentanyl dose should be adjusted if necessary. Temperature-dependent increase in fentanyl release from the patch may lead to overdose and fatal outcomes. All patients should avoid exposure to external heat sources such as heating pads, electric blankets, waterbeds, heat lamps, sunlamps, prolonged sunbathing, hot water bottles, saunas, prolonged hot baths, or hot tubs, on the site where Fentavera patch is applied.

Serotonin syndrome

Caution is recommended when fentanyl is used concomitantly with drugs affecting the serotonergic neurotransmitter system.

Potentially life-threatening serotonin syndrome may occur with concomitant use of serotonergic drugs, e.g., SSRIs and SNRIs, and drugs that impair serotonin metabolism (including MAOIs), even within recommended dosage ranges (see section "Interaction with other medicinal products and other forms of interaction").

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

If serotonin syndrome is suspected, prompt discontinuation of Fentavera transdermal patch should be considered.

Interaction with other medicinal products

Inhibitors of CYP3A4

Concomitant use of Fentavera patch with inhibitors of cytochrome P450 3A4 (CYP3A4) may increase plasma fentanyl concentrations, which may enhance or prolong both therapeutic effects and adverse reactions and may cause serious respiratory depression. Therefore, concomitant use of transdermal fentanyl and CYP3A4 inhibitors is not recommended, except when expected benefit outweighs the increased risk of adverse reactions. Fentavera patch should not be used within 2 days after discontinuation of a CYP3A4 inhibitor and before application of the first Fentavera patch. However, duration of respiratory depression may vary, and for some CYP3A4 inhibitors with long half-lives, e.g., amiodarone, or time-dependent inhibitors such as erythromycin, idelalisib, nicardipine, and ritonavir, a longer interval may be required. Therefore, prior to applying the first Fentavera patch, the prescribing information for the CYP3A4 inhibitor should be consulted regarding its half-life and duration of inhibitory effect. A patient receiving fentanyl therapy should wait at least 1 week after removal of the last patch before starting treatment with a CYP3A4 inhibitor. If concomitant use of fentanyl and a CYP3A4 inhibitor cannot be avoided, careful monitoring for symptoms of increased or prolonged fentanyl effects and adverse reactions (especially respiratory depression) is required. In addition, fentanyl dose should be reduced or discontinued if necessary (see section "Interaction with other medicinal products and other forms of interaction").

Accidental application of the patch

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

Elderly patients

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

Gastrointestinal tract

Opioids increase tone and reduce propulsive peristalsis of gastrointestinal smooth muscle. This results in prolonged gastrointestinal transit time, which may explain constipation associated with fentanyl use. Patients should be informed about measures to prevent constipation and advised to use laxatives prophylactically. Particular caution is required in patients with chronic constipation. If paralytic ileus is suspected, Fentavera should be discontinued.

Patients with myasthenia gravis

Non-epileptic myoclonic reactions may occur. Caution should be exercised in patients with myasthenia gravis.

Concomitant use with mixed opioid agonists/antagonists

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

Children

Fentavera patch should not be used in children who have not previously received opioids (see section "Dosage and administration"). There is a risk of serious or life-threatening hypoventilation, regardless of the prescribed dose of Fentavera transdermal patch.

Use of Fentavera patch has not been studied in children under 2 years of age. Fentavera patch should only be prescribed to children aged 2 years and older who are opioid-tolerant (see section "Dosage and administration"). Fentavera patch should not be used in children under 2 years of age.

To prevent accidental ingestion by children, caution should be exercised in selecting the site for application of Fentavera patch, and the attachment of the patch should be carefully monitored.

Opioid-induced hyperalgesia

Opioid-induced hyperalgesia (OIH) is a paradoxical response to opioids, characterized by increased pain sensitivity despite stable or increased opioid exposure. It differs from tolerance, where higher opioid doses are required to achieve the same analgesic effect or to treat pain recurrence. OIH may manifest as increased pain, more generalized pain (i.e., less localized), or pain from normally non-painful stimuli (allodynia), without signs of disease progression. In suspected OIH, opioid dose should be reduced immediately or gradually, if possible.

Use during pregnancy or breastfeeding

Pregnancy

There are insufficient data on the use of fentanyl in pregnant women. Animal studies have shown some reproductive toxicity. The potential risk to humans is unknown. Fentanyl crosses the placenta. Neonatal withdrawal syndrome has been reported in newborns whose mothers received long-term transdermal fentanyl during pregnancy. Fentavera patch should not be used during pregnancy except in cases of urgent medical need.

Use of Fentavera patch during labor (including cesarean section) is not recommended; therefore, the drug should not be used for treatment of acute or postoperative pain (see section "Contraindications").

Breastfeeding

Fentanyl is excreted in breast milk and may cause sedation and/or respiratory depression in the breastfed infant. Therefore, breastfeeding should be discontinued during fentanyl therapy and for at least 72 hours after removal of the patch.

Fertility

There are no clinical data on the effect of fentanyl on fertility. Animal studies in rats have shown reduced fertility and increased embryonic lethality at doses toxic to the dams.

Ability to affect reaction speed when driving or operating machinery

Fentavera patch may impair mental and/or physical abilities required for performing potentially hazardous tasks such as driving a car or operating machinery.

Method of Administration and Dosage

Dose Selection

The dose of Fentavera should be individually titrated according to the patient's condition, with regular assessment following patch application. The lowest effective dose should be used. The patches are designed to release 12.5 mcg, 25 mcg, 50 mcg, 75 mcg, and 100 mcg of fentanyl per hour into the systemic circulation, corresponding approximately to 0.3 mg, 0.6 mg, 1.2 mg, 1.8 mg, and 2.4 mg per day, respectively.

Selection of Initial Dose

When determining the appropriate dose for the treatment of chronic pain, consideration should be given to the type of analgesic (particularly opioids) previously used. Fentavera is recommended for use in opioid-tolerant patients. Other factors to consider include the patient’s current general health and medical status, including body size, age, degree of debilitation, and level of opioid tolerance.

Adults

Opioid-Tolerant Patients

To determine the dosage of Fentavera when switching a patient from oral or intravenous opioids, refer to the equianalgesic dose conversion table provided below. Subsequently, the dose may be titrated by increasing or decreasing in increments of 12.5 mcg/hour or 25 mcg/hour to achieve the lowest effective dose, based on the patient’s response to treatment and additional analgesic requirements.

Opioid-Naïve Patients

The use of transdermal fentanyl is generally not recommended in opioid-naïve patients. In such cases, alternative routes of administration (oral, parenteral) should be considered. To prevent overdose, opioid-naïve patients should be initiated on the lowest possible dose of immediate-release opioids (morphine, hydromorphone, oxycodone, tramadol, or codeine), with gradual titration until a dose equivalent to 12.5 mcg/hour of Fentavera is reached. The patient may then be transitioned to the Fentavera patch at a dose of 12.5 mcg/hour. In situations where oral opioid medications cannot be used at the beginning of therapy and the Fentavera patch is the only available option for opioid-naïve patients, the lowest dose of Fentavera—12.5 mcg/hour—should be used. In such cases, the patient must be under close monitoring. There is a risk of developing severe or life-threatening hypoventilation, even when using the lowest dose of the drug during initial therapy (see sections "Special Warnings and Precautions" and "Adverse Reactions").

Equianalgesic Dose Conversion

For patients currently receiving opioid analgesics, the initial dose of Fentavera should be determined based on the patient’s prior daily opioid dose. When switching from an oral or parenteral opioid to Fentavera, the initial dose should be calculated as follows:

1. Calculate the previous total daily dose of the opioid analgesic.
2. Convert this value to the equianalgesic 24-hour oral morphine dose using the multiplication factor from Table 1, corresponding to the route of administration.
3. To determine the Fentavera dose corresponding to the calculated equianalgesic 24-hour oral morphine dose, use Table 2 or Table 3 as follows:

a) Table 2 – for patients requiring opioid analgesic switch and who have a less stable clinical condition (the conversion ratio from oral morphine to transdermal fentanyl is approximately 150:1);

b) Table 3 – for determining the dose in adult patients who are on a stable and well-tolerated treatment regimen (the conversion ratio from oral morphine to transdermal fentanyl is approximately 100:1).

Dose Conversion Table: Multiplication factors for converting the daily dose of prior opioid analgesics to equianalgesic 24-hour oral morphine dose
(dose in mg/day of prior analgesic × factor = equianalgesic 24-hour oral morphine dose)

Table 1

Previous opioid analgesic	Route of administration	Multiplication factor
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
Oxymorphone	Rectal	3
	Parenteral	30b
Pethidine	Oral
	Parenteral	0.4b
Tapentadol	Oral	0.4
	Parenteral
Tramadol	Oral	0.25
	Parenteral	0.3

a The ratio of oral to intramuscular morphine doses is based on clinical experience in patients with chronic pain.

b Based on single-dose studies comparing intramuscular administration of each substance with morphine to determine relative potency. Oral doses correspond to recommendations for switching from parenteral to oral administration.

The recommended initial dose of Fentavera based on the daily oral morphine dose (for patients requiring a switch from one opioid to another due to adverse drug reactions) is a conversion ratio of 150:11.

Table 2

Oral morphine dose (mg/day)	Fentavera (mcg/hour)
< 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

1 The daily oral morphine doses listed were used in clinical studies for conversion to Fentavera patch.

Recommended initial dose of Fentavera based on daily oral morphine dose (for patients receiving stable and well-tolerated opioid therapy): the conversion ratio of oral morphine to transdermal fentanyl is approximately 100:1.

Table 3

Oral morphine dose (mg/day)	Fentavera (mcg/hour)
≤ 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

The initial assessment of the maximum analgesic effect of Fentavera patch cannot be made earlier than 24 hours after patch application. This time interval is due to the gradual increase in serum fentanyl concentration following application. Previous analgesic therapy should be tapered off gradually starting from the moment of application of the first patch until the analgesic effect of Fentavera is achieved.

Dosage Titration and Maintenance Therapy

Fentavera patches should be replaced every 72 hours. The dose should be individually adjusted based on the daily use of supplemental analgesics until a balance between adequate pain relief and treatment tolerability is achieved. For dose titration of Fentavera, patches with the lowest available dosage strengths — 12.5 mcg/hour or 25 mcg/hour — should be used. However, the patient's condition, need for additional analgesia (oral morphine dose of 45/90 mg/day approximately corresponds to fentanyl dose of 12.5/25 mcg/hour), and the patient's pain status must be taken into account. After a dose increase, up to 6 days may be required to reach equilibrium at the new dosage level. Therefore, after increasing the dose, patients should use the higher-dose patch for two consecutive 72-hour periods before any further dose escalation.

For doses exceeding 100 mcg/hour, multiple patches may be used simultaneously. Patients may periodically require supplemental doses of short-acting analgesics for breakthrough pain. In some patients, additional or alternative analgesic methods may be needed when fentanyl doses exceeding 300 mcg/hour are used.

In the absence of adequate pain relief, consider the possibility of hyperalgesia, tolerance, or progression of the underlying disease (see section "Special Warnings and Precautions for Use").

If adequate analgesia is not achieved after initial patch application, the patch may be replaced after 48 hours with a patch of the same strength or the dose may be increased after 72 hours.

If replacement of the patch (e.g., due to poor adhesion) is necessary before 72 hours, a patch of the same strength should be applied to a different skin site. This may lead to increased fentanyl blood concentration (see section "Pharmacological Properties"); in such cases, careful patient monitoring is required.

Duration and Goals of Therapy

Prior to initiating fentanyl therapy, the treatment strategy — including duration, treatment goals, and a plan for discontinuation — should be discussed and agreed upon with the patient, in accordance with pain management guidelines. During treatment, regular communication between the physician and patient is essential to assess the need for continued therapy, consider discontinuation, and, if necessary, adjust dosing. Inadequate pain control should prompt consideration of possible hyperalgesia, tolerance, or progression of the underlying disease (see section "Special Warnings and Precautions for Use").

Discontinuation of Fentavera

When discontinuing Fentavera, any switch to another opioid should be initiated gradually, starting with a low dose and slowly increasing it. This is because fentanyl concentrations decline gradually after patch removal. It takes at least 20 hours or longer for serum fentanyl concentration to decrease by 50%. Opioid analgesics should be discontinued gradually to prevent withdrawal symptoms (see sections "Special Warnings and Precautions for Use" and "Side Effects"). There have been reports of rapid discontinuation of opioid analgesics in opioid-dependent patients resulting in severe withdrawal symptoms and uncontrolled pain. During gradual dose reduction, individual dose, duration of treatment, and patient response to pain and withdrawal symptoms should be considered. Patients on long-term therapy may require a more gradual dose taper. For patients treated over a short period, a more rapid dose reduction schedule may be considered.

Opioid withdrawal symptoms may occur in some patients after conversion or dose adjustment (see section "Side Effects"). Tables 1, 2, and 3 should be used only for dose conversion when switching from other opioid analgesics to Fentavera, and not when switching from Fentavera to another analgesic, to avoid overdose of the new analgesic and potential toxicity.

Special Patient Populations

Elderly Patients

Elderly patients should be closely monitored, and dosage should be individually adjusted according to the patient's condition (see section "Special Warnings and Precautions for Use"). Opioid-naïve elderly patients should not receive Fentavera, except when the expected benefit outweighs the potential risk. In such cases, only the 12.5 mcg/hour dose should be considered for initial therapy.

Hepatic and Renal Impairment

Patients with hepatic or renal impairment should be closely monitored, and dosage should be individually adjusted based on the patient's condition (see sections "Pharmacological Properties" and "Special Warnings and Precautions for Use"). Opioid-naïve patients with hepatic or renal impairment should not receive Fentavera, except when the expected benefit outweighs the potential risk. In such cases, only the 12.5 mcg/hour dose should be considered for initial therapy.

Children

Patients Aged 16 Years

Follow adult dosing recommendations.

Children Aged 2 to 16 Years

Fentavera should be prescribed only for opioid-tolerant children (aged 2 to 16 years) who are already receiving at least the equivalent of 30 mg/day of oral morphine.

To switch from an oral or parenteral opioid to Fentavera, refer to Table 1. Recommendations for determining the Fentavera dosage based on daily oral morphine dose are provided in Table 4.

Recommended Fentavera dosage for children¹ according to daily oral morphine dose²

Table 4

Daily dose of oral morphine (mg/day)	Dose of Fentavera preparation (mcg/hour)
30−44	12.5
45−134	25

1 Dose conversion for doses exceeding 25 mcg/h of Fentavera corresponds to that for adult patients (see Table 2).

2 The daily oral morphine doses listed were used during clinical studies when switching to Fentavera patch.

During pediatric studies, the required transdermal fentanyl patch strength was conservatively calculated: 30 to 44 mg of oral morphine per day or an equivalent opioid dose was replaced by one Fentavera patch 12.5 mcg/h. It should be noted that this conversion table for children applies only when switching from oral morphine (or its equivalent) to the Fentavera patch. The conversion table should not be used to switch from Fentavera to another opioid, as overdose may occur.

The analgesic effect of the first Fentavera patch dose will not be optimal during the first 24 hours. Therefore, during the first 12 hours after switching to the Fentavera patch, the patient should continue using their usual doses of previous analgesics. During the subsequent 12 hours, previous analgesics should be administered based on clinical need.

Since peak fentanyl levels are reached after 12–24 hours of treatment, monitoring of the patient for adverse events such as hypoventilation is recommended for at least 48 hours after initiating fentanyl therapy or after dose titration (see also section "Special precautions").

Fentavera must not be used in children under 2 years of age, as safety and efficacy in this patient group have not been established.

Titration and maintenance therapy in children

The patch should be replaced every 72 hours.

The dose should be individually titrated based on daily use of supplemental analgesics, balancing adequate pain relief against treatment tolerability. Dosage adjustments must not be made at intervals shorter than 72 hours. If analgesia provided by the Fentavera patch is insufficient, children should be given supplemental morphine or another short-acting opioid. Depending on additional analgesic requirements and the child's pain status, the dose may be increased. Dose adjustments should be made in 12 mcg/h fentanyl increments.

Method of administration

For transdermal use.

The Fentavera patch should be applied to an intact, non-irradiated, flat area of skin on the trunk or upper parts of the arms. In younger children, the upper back is the preferred site for patch application to minimize the risk of the child removing the patch.

Before patch application, hair at the application site (preferably on a hairless area) should be clipped (not shaved). If the application site needs to be cleaned before patch application, it should be done using plain water only. Do not use soap, lotions, oils, or other agents, as they may irritate the skin or alter its properties. The skin must be completely dry before patch application. The patch should be inspected before use. Do not use patches that have been cut, divided, or otherwise damaged.

The Fentavera patch should be applied immediately after opening the sealed pouch. To remove the Fentavera patch from the protective pouch, cut along the two notches at the edges of the pouch (located near the edge of the arrow on the pouch label), then carefully tear open the pouch material. Hold both sides of the opened pouch and remove the patch. The protective liner has a central slit. Fold the patch in half along the center and remove each half of the protective liner, taking care not to touch the adhesive side of the patch with fingers. Press the patch firmly with the palm of the hand onto the application site for 30 seconds. Ensure that the patch adheres completely to the skin, especially at the edges. Then wash hands thoroughly with plain water.

The Fentavera patch must be used continuously for 72 hours. A new patch should be applied to a different skin site after removal of the used patch. The same skin site should not be reused until several days have passed.

Children

The medicinal product is indicated for use in children aged 2 years and older.

Overdose

Symptoms and signs

Manifestations of fentanyl overdose are an extension of its pharmacological effects, the most serious of which is respiratory depression. Toxic leukoencephalopathy has also been observed in cases of 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 may be administered, but respiratory depression may persist longer than the duration of action of the opioid antagonist. The interval between intravenous doses of the antagonist should be carefully selected due to the risk of recurrent narcotization after patch removal; repeated administration or continuous naloxone infusion may be required. Sudden pain and catecholamine release may occur following administration of the antagonist.

If clinically indicated, the airway should be established and maintained, possibly by insertion of an oropharyngeal or endotracheal tube. Adequate body temperature and fluid intake should be maintained.

If severe or persistent hypotension occurs, hypovolemia should be considered and treated appropriately with infusion therapy.

Adverse Reactions

The safety of fentanyl has been evaluated in 1565 adults and 289 children who participated in 11 clinical trials of the drug for the treatment of chronic pain, both related and unrelated to oncological conditions. Each study participant received at least one dose of the medicinal product. Based on pooled safety data, the most frequently reported adverse reactions (with frequency %) were: nausea (35.7%), vomiting (23.2%), constipation (23.1%), somnolence (15.0%), dizziness (13.1%), and headache (11.8%).

Adverse reactions reported during these clinical studies and during post-marketing surveillance are listed below.

Adverse reactions are categorized by system organ class and grouped by 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 available data).

Immune system disorders:
Common – hypersensitivity;
Frequency not known – anaphylactic shock, anaphylactic reaction, anaphylactoid reaction.

Endocrine system disorders:
Frequency not known – androgen deficiency.

Metabolism and nutrition 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, paraesthesia;
Uncommon – hypaesthesia, convulsions (including clonic convulsions and grand mal seizures), amnesia, depressed level of consciousness, loss of consciousness.

Eye disorders:
Uncommon – blurred vision;
Rare – miosis.

Ear and labyrinth disorders:
Common – vertigo.

Cardiac disorders:
Common – palpitations, tachycardia;
Uncommon – bradycardia, cyanosis.

Vascular disorders:
Common – hypertension;
Uncommon – hypotension.

Respiratory, thoracic and mediastinal disorders:
Common – dyspnoea;
Uncommon – respiratory depression, respiratory distress syndrome;
Rare – apnoea, hypoventilation;
Frequency not known – bradypnoea.

Gastrointestinal disorders:
Very common – nausea, vomiting, constipation;
Common – diarrhoea, 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 twitching.

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 oedema, asthenia, malaise, feeling cold;
Uncommon – application site reaction, influenza-like illness, sensation of body temperature change, application site hypersensitivity, withdrawal syndrome, pyrexia*;
Rare – application site dermatitis, application site eczema;
Frequency not known – tolerance.

*Frequency (uncommon) was determined based on analysis of treatment-emergent adverse events in clinical trials in adult and paediatric patients with non-cancer-related pain.

The medicinal product Fentavera contains soybean oil.

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

Children

The safety of fentanyl was evaluated in 289 paediatric patients (<18 years of age) who participated in 3 clinical trials for the treatment of chronic or continuous pain of malignant or non-malignant origin. These patients received at least one dose of fentanyl. The adverse event profile in children and adolescents using fentanyl transdermal patches was similar to that in adults. No risks specific to children were identified beyond those expected with opioid use for pain associated with severe illness. No age-specific risks associated with fentanyl were identified when administered to children aged 2 years and older for approved indications. Very common adverse events reported in paediatric clinical trials included headache (16.3%), vomiting (33.9%), nausea (23.5%), constipation (13.5%), diarrhoea (12.8%), and pruritus (12.8%).

Tolerance

Tolerance may develop with repeated administration.

Drug dependence

Repeated use of fentanyl may 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 section "Special warnings and precautions for use").

Symptoms of opioid withdrawal (nausea, vomiting, diarrhoea, anxiety, and tremor) may occur in some patients after switching from a previous opioid analgesic to fentanyl or following abrupt discontinuation of therapy (see sections "Dosage and administration" and "Special warnings and precautions for use").

Very rare cases of neonates with neonatal withdrawal syndrome have been reported in mothers who used fentanyl continuously during pregnancy (see section "Pregnancy and lactation").

Cases of serotonin syndrome have been reported with concomitant use of fentanyl and serotonergic agents (see sections "Interaction with other medicinal products and other forms of interaction" and "Special warnings and precautions for use").

Shelf life

2 years.

Storage conditions

No special storage conditions required. Keep out of reach and sight of children.

Incompatibilities

To prevent impairment of the adhesive properties of the patch, do not apply creams, oils, lotions, or powders to the area of skin where the patch will be applied.

Packaging

1 transdermal patch per child-resistant sachet; 5 sachets in a cardboard box with tamper-evident seal.

Prescription status

Prescription only.

Manufacturer

Asino AG.

Manufacturer's address and place of business

Leopoldstrasse 115, 80804 Munich, Germany.