Fentanyl m sandoz®
UkraineTable of Contents
INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT FENTANYL M SANDOZ®
Composition:
Active substance: fentanyl;
1 patch with fentanyl release rate of 25 µg/h (absorption area = 10.5 cm²),
50 µg/h (absorption area = 21 cm²), 75 µg/h (absorption area = 31.5 cm²) and
100 µg/h (absorption area = 42 cm²) contains fentanyl 5.78 mg, 11.56 mg, 17.34 mg and
23.12 mg, respectively;
Excipients: refined soybean oil, hydrogenated rosin, poly-(2-ethylhexyl acrylate-co-vinyl acetate), polyethylene terephthalate fabric, polyethylene terephthalate silicone release liner.
Pharmaceutical form. Transdermal patch.
Main physicochemical properties: white milky-colored rectangular transdermal patch with rounded edges, on a transparent protective film with individual crystals. Labeling on the liner according to release rate: «fentanyl 25 µg/h», «fentanyl 50 µg/h», «fentanyl 75 µg/h» or «fentanyl 100 µg/h».
Pharmacotherapeutic group. Analgesics. Opioids. Phenylpiperidine derivatives.
ATC code N02AB03.
Pharmacological properties.
Pharmacodynamics.
Fentanyl is a synthetic opioid analgesic that interacts primarily with the μ-opioid receptor. The main therapeutic effects of fentanyl are analgesia and sedation.
Children. The safety of fentanyl patches was evaluated in three open-label studies involving 289 children aged 2 to 17 years inclusive, suffering from chronic pain. Eighty children were aged 2 to 6 years inclusive. Of the 289 patients included in these three studies, 110 patients initiated fentanyl treatment at a dose of 12 mcg/hour. Of these 110 patients, 23 (20.9%) had previously received an opioid dose equivalent to <30 mg oral morphine per day, 66 (60.0%) had received an equivalent of 30–44 mg oral morphine per day, and 12 (10.9%) had received at least an equivalent of 45 mg oral morphine per day (data missing for 9 [8.2%] patients). Initial doses of 25 mcg/hour or higher were administered to the other 179 patients, 174 (97.2%) of whom were receiving opioids at doses equivalent to at least 45 mg oral morphine per day. Of the remaining 5 patients who started at an initial dose of at least 25 mcg/hour and whose prior opioid exposure was less than the equivalent of 45 mg oral morphine per day, 1 (0.6%) had previously received less than the equivalent of 30 mg oral morphine per day, and 4 (2.2%) had received the equivalent of 30–44 mg oral morphine per day.
Pharmacokinetics.
Absorption.
FENTANYL M SANDOZ*®* provides continuous systemic release of fentanyl for 72 hours following application. After application of the fentanyl patch, the skin beneath the patch absorbs fentanyl, and a depot of fentanyl accumulates in the upper layers of the skin. Fentanyl then enters the systemic circulation. The release rate is relatively constant, driven by the polymer matrix and diffusion of fentanyl through the skin layers. The concentration gradient between the matrix and the lower concentration in the skin promotes drug release. The mean bioavailability of fentanyl after application of the transdermal patch is 92%.
Following the first application of FENTANYL M SANDOZ®*, serum fentanyl concentrations increase gradually over the first 12–24 hours and remain relatively constant for the remainder of the 72-hour application period, until patch removal. The magnitude of fentanyl serum concentration is proportional to the patch size. Steady-state serum concentration is achieved by the end of the second 72-hour application period and is maintained during subsequent applications of patches of the same size. Due to accumulation, the AUC and Cmax values during the dosing interval at steady state are approximately 40% higher than after a single dose. The achievement and maintenance of steady-state serum concentration depend on the individual patient's skin permeability and fentanyl clearance. High inter-subject variability in plasma fentanyl concentrations has been observed.
Pharmacokinetic modeling predicts that serum fentanyl concentration may increase by 14% (range: 0–26%) if a new patch is applied after 24 hours instead of the recommended 72 hours after application of the previous patch.
Elevated skin temperature may increase fentanyl absorption with transdermal administration (see section "Special precautions for use"). Skin temperature elevation due to the use of a low-temperature electric heating pad applied to the site of FENTANYL M SANDOZ*®* patch application 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 following intravenous administration in patients). Fentanyl accumulates in skeletal muscle and adipose tissue, from which it is slowly released back into the blood. In a study involving cancer patients receiving transdermal fentanyl, plasma protein binding averaged 95% (range: 77–100%). Fentanyl readily crosses the blood-brain barrier. It also crosses the placenta and is excreted into breast milk.
Metabolism.
Fentanyl has high clearance and is rapidly and extensively metabolized, primarily by CYP3A4 in the liver. The main metabolite, norfentanyl, and other metabolites are inactive. The skin does not participate in the metabolism of transdermally administered fentanyl. This was confirmed by analysis of human keratinocytes in clinical studies, where 92% of the dose delivered from the patch was found unchanged in the systemic circulation.
Elimination.
After 72-hour patch application, the mean elimination half-life of fentanyl ranges from 20 to 27 hours. Due to prolonged absorption of fentanyl from the skin after patch removal, the elimination half-life following transdermal administration is approximately 2–3 times longer than after intravenous administration. Following intravenous administration, the mean total clearance of fentanyl in studies ranged from 34 to 66 L/h. Over a 72-hour period, approximately 75% of the dose is excreted in urine and about 9% in feces. Fentanyl is excreted predominantly as metabolites, with less than 10% excreted unchanged.
Linearity/Non-linearity.
Serum fentanyl concentration is proportional to patch size. The pharmacokinetics of transdermal fentanyl do not change with repeated administration.
Pharmacokinetic/Pharmacodynamic relationship.
There is high inter-subject variability in fentanyl pharmacokinetics, the relationship between fentanyl concentration and therapeutic and adverse effects, and opioid tolerance. The minimum effective concentration of fentanyl depends on pain intensity and prior opioid exposure. Both the minimum effective concentration and toxic concentration increase with tolerance. Therefore, an optimal therapeutic concentration range for fentanyl cannot be established. Individual dose titration of fentanyl should be based on patient response and level of tolerance. The delayed onset of action, lasting 12 to 24 hours after application of the first patch or after dose escalation, should also be considered.
Special patient populations.
Elderly patients. Data from intravenous fentanyl studies suggest that elderly patients may have reduced clearance, prolonged elimination half-life, and increased sensitivity to the active substance compared to younger patients. Fentanyl pharmacokinetics in healthy elderly subjects differ only slightly from those in healthy young subjects, although peak serum concentrations were lower and mean elimination half-life was prolonged to approximately 34 hours. Elderly patients should be closely monitored for signs of fentanyl toxicity, and the dose should be reduced if necessary.
Patients with 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 excreted renally. However, since the effect of renal impairment on fentanyl pharmacokinetics has not been studied, caution is advised.
Patients with hepatic impairment. Patients with impaired liver function should be closely monitored for signs of fentanyl toxicity, and the dose should be reduced if necessary. Data from patients with liver cirrhosis and modeling data from patients with varying degrees of hepatic impairment receiving transdermal fentanyl indicate that fentanyl concentrations may be increased and fentanyl clearance reduced compared to patients with normal liver function. Modeling shows that the AUC at steady state in patients with Child–Pugh class B liver disease (Child–Pugh score = 8) is approximately 1.36 times higher than in patients with normal liver function (Child–Pugh score = 5.5). For patients with Child–Pugh class C liver disease (Child–Pugh score = 12.5), results indicate that fentanyl accumulates with each application, resulting in an AUC at steady state approximately 3.72 times higher.
Children. Fentanyl concentrations were measured in over 250 children aged 2 to 17 years who used fentanyl patches at doses ranging from 12.5 to 300 mcg/hour. When corrected for body weight, clearance (L/h/kg) was 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 pediatric dosing recommendations.
Preclinical safety data.
Preclinical data obtained from traditional repeat-dose toxicity studies revealed no specific risk for humans. Standard reproductive and developmental toxicity studies were conducted with parenteral administration of fentanyl. In rat studies, no effects on male fertility were observed. Some studies in female rats showed reduced fertility and embryonic lethality. The effects on the embryo were induced by maternal toxicity and not by a direct effect of the active substance on embryonic development. Studies in two animal species (rats and rabbits) did not demonstrate teratogenic effects. In pre- and postnatal studies, offspring survival was significantly reduced at doses causing slight maternal body weight reduction. These effects were likely due to altered maternal care or direct effects of fentanyl on offspring. No effects on physical development or behavior of offspring were observed. Mutagenicity studies in bacteria and rodents were negative. Fentanyl induced mutagenic effects in mammalian cell cultures in vitro, compared to other opioid analgesics. However, the mutagenic risk at therapeutic doses is unlikely, as effects occur only at high concentrations. Carcinogenicity studies (daily subcutaneous injections of fentanyl hydrochloride for 2 years in Sprague-Dawley rats) did not yield results indicating oncogenic potential.
Clinical characteristics.
Indications.
Treatment of severe chronic pain in adult patients requiring continuous long-term opioid therapy.
Long-term treatment of severe chronic pain in children aged 2 years and older who are already receiving opioid analgesic therapy.
Contraindications.
Known hypersensitivity to fentanyl or to any component of the patch.
Acute or postoperative pain, due to the inability to titrate the dose during short-term use and due to the risk of developing severe or life-threatening respiratory depression.
Severe respiratory depression.
Due to the risk of fatal respiratory depression, Fentanyl M SANDOZ® 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.
Interactions related to pharmacodynamics.
Central nervous system-acting agents and alcohol.
Concomitant use of other central nervous system (CNS)-depressant agents, including opioids, sedatives, benzodiazepines, hypnotics, general anesthetics, phenothiazines, tranquilizers, sedative antihistamines, alcoholic beverages, muscle relaxants, and gabapentinoids (gabapentin and pregabalin), may result in additive depressant effects; hypventilation, hypotension, excessive sedation, coma, and even death may occur. Concomitant use of any of these agents with Fentanyl M SANDOZ® requires close patient monitoring.
Monoamine oxidase inhibitors (MAOIs).
Transdermal fentanyl patches are not recommended for use in patients requiring concomitant administration of MAOIs. Serious and unpredictable interactions with MAOIs have been reported, including potentiation of opioid effects or enhanced serotonergic effects. Therefore, Fentanyl M SANDOZ® must not be used within 14 days following discontinuation of MAOIs.
Serotonergic medicinal products.
Concomitant use of transdermal fentanyl with 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.
Concomitant use of mixed opioid agonist/antagonists.
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 patients physically dependent on opioids.
Interactions related to pharmacokinetics.
Cytochrome P450 (CYP) 3A4 inhibitors.
Fentanyl is a drug with high extraction ratio that is rapidly and extensively metabolized, primarily by CYP3A4 enzymes.
Concomitant use of transdermal fentanyl with CYP3A4 inhibitors may lead to increased plasma concentrations of fentanyl. This may result in enhanced or prolonged therapeutic effects as well as adverse effects, including significant respiratory depression. Close monitoring is required in such cases. The extent 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 administration of CYP3A4 inhibitors and transdermal fentanyl is not recommended, except when close monitoring is ensured. Active substances such as amiodarone, cimetidine, clarithromycin, diltiazem, erythromycin, fluconazole, itraconazole, ketoconazole, nefazodone, ritonavir, verapamil, and voriconazole (this list is not exhaustive) may increase fentanyl concentrations. After short-term intravenous administration of fentanyl, coadministration with weak, moderate, or strong CYP3A4 inhibitors resulted in an overall reduction in fentanyl clearance of ≤25%; however, when coadministered with ritonavir (a strong CYP3A4 inhibitor), fentanyl clearance was reduced by an average of 67%. The extent of CYP3A4 inhibitor interaction during long-term transdermal fentanyl therapy is unknown but may be greater than with short-term intravenous administration.
CYP3A4 inducers. Concomitant use with CYP3A4 inducers may lead to decreased plasma concentrations of fentanyl and reduced therapeutic effect. Particular caution is required when using CYP3A4 inducers concomitantly with Fentanyl M SANDOZ®. The dose may need to be increased or a switch to another analgesic may be necessary. Prior to discontinuation of the CYP3A4 inducer, fentanyl dosage should be reduced and careful monitoring implemented. After stopping treatment with CYP3A4 inducers, their effects gradually diminish, potentially leading to increased fentanyl plasma concentrations and enhanced or prolonged therapeutic and adverse effects. Severe respiratory depression may occur. Careful patient monitoring should continue until a stable response to the drug is achieved. Active substances such as carbamazepine, phenobarbital, phenytoin, and rifampicin (this list is not exhaustive) may reduce fentanyl plasma concentrations.
Children. Interaction studies have been conducted only in adult patients.
Special precautions for use.
Patients who have experienced severe adverse effects should be closely monitored for at least 24 hours after removal of the Fentanyl M SANDOZ® patch, or longer depending on clinical symptoms, as plasma fentanyl concentrations decline gradually and reach 50% within 20–27 hours.
Patients and caregivers should be informed that Fentanyl M SANDOZ® contains an active substance in a concentration that could be fatal, especially to children. Therefore, the medicinal product must be stored out of reach of children both before and after use.
Patients who have not previously received opioid therapy and who are opioid-naïve. The use of Fentanyl M SANDOZ® in opioid-naïve patients is associated with very rare cases of significant respiratory depression and/or fatal events when fentanyl is used as initial opioid therapy, particularly in patients whose pain is not cancer-related. The potential for serious or life-threatening hypoventilation exists even with the lowest dose of transdermal fentanyl system at the beginning of therapy in opioid-naïve patients, especially in elderly patients or those with impaired renal or hepatic function. The tendency to develop tolerance varies among individual patients. Transdermal fentanyl patches are recommended for use only in patients who have demonstrated opioid tolerance.
Respiratory depression.
Significant respiratory depression may occur in some patients using the Fentanyl M SANDOZ® patch; patients should be monitored for such effects. Respiratory depression may persist even after removal of the transdermal patch. The incidence of respiratory depression increases with increasing fentanyl dose.
CNS-active substances may potentiate respiratory depression.
Chronic pulmonary diseases.
In patients with chronic obstructive or other lung diseases, the transdermal fentanyl patch may cause a number of serious adverse effects. In such patients, opioids may reduce the activity of the respiratory center and increase ventilatory resistance.
Prolonged treatment effect and tolerance.
Tolerance to analgesic effects, hyperalgesia, and physical and psychological dependence may develop in all patients with repeated use of opioids, while incomplete tolerance may develop to certain adverse reactions such as opioid-induced constipation. In particular, long-term opioid treatment in patients with chronic non-cancer-related pain may not lead to significant reduction in pain intensity. During therapy, physicians should maintain regular contact with the patient to assess the need for continued treatment (see section "Dosage and administration"). When it is decided that continued therapy provides no benefit, the dose should be gradually reduced to avoid withdrawal symptoms.
Do not abruptly discontinue Fentanyl M SANDOZ® in a patient physically dependent on opioids. Withdrawal syndrome may occur with abrupt discontinuation or dose reduction.
There have been reports that rapid dose reduction of Fentanyl M SANDOZ® in a patient physically dependent on opioids may lead to serious withdrawal symptoms and uncontrolled pain (see sections "Dosage and administration" and "Adverse reactions"). When a patient no longer requires therapy, gradual dose reduction is recommended to minimize withdrawal symptoms. Reduction of high doses may take weeks to months.
Opioid withdrawal syndrome is characterized by some or all of the following symptoms: restlessness, lacrimation, rhinorrhea, yawning, sweating, chills, myalgia, miosis, and tachycardia. Other symptoms may also develop, including irritability, agitation, anxiety, hyperkinesia, tremor, weakness, insomnia, anorexia, abdominal cramps, nausea, vomiting, diarrhea, elevated blood pressure, increased respiratory rate, or heart rate.
Opioid use disorder (dependence and abuse).
Repeated use of Fentanyl M SANDOZ® may lead to opioid use disorder (OUD). Higher doses and longer duration of opioid therapy may increase the risk of OUD. Abuse or misuse of Fentanyl M SANDOZ® may result in overdose and/or death. The risk of OUD is higher in patients with a personal or family history (in parents or siblings) of substance use disorders (including alcohol use disorders), in current tobacco users, or in patients with other psychiatric disorders (e.g., major depression, anxiety, or personality disorders).
Prior to initiating and during treatment with Fentanyl M SANDOZ®, the treatment goals and discontinuation plan 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. Patients should be advised to consult their physician if such signs appear.
Patients receiving opioids should be monitored for signs of addictive behavior, such as drug-seeking behavior (e.g., early requests for prescription renewal), especially those at increased risk. This includes reviewing concomitant opioid and psychoactive medication use (e.g., benzodiazepines). Patients showing signs and symptoms of OUD should be considered for consultation with an addiction specialist. If discontinuation of opioids is necessary, see section "Special precautions for use".
Risk associated with concomitant use of sedatives such as benzodiazepines or related medicinal products and alcohol.
Concomitant use of fentanyl and sedative medicinal products such as benzodiazepines increases the risk of sedation, respiratory depression, coma, and fatal outcomes due to CNS depressant effects. The dose and duration of use should be limited.
CNS disorders, including increased intracranial pressure.
Fentanyl M SANDOZ® should be used with caution in patients who may be particularly sensitive to increased CO₂ levels, i.e., patients with increased intracranial pressure, impaired consciousness, or coma. Fentanyl M SANDOZ® should be used with caution in patients with brain tumors.
Cardiac disorders.
Fentanyl may cause bradycardia and should therefore be administered cautiously to patients with bradyarrhythmias.
Arterial hypotension.
Opioids may cause hypotension, especially in patients with acute hypovolemia. Underlying symptomatic hypotension and/or hypovolemia should be corrected prior to initiating transdermal fentanyl patches.
Hepatic impairment.
Since fentanyl is metabolized to inactive metabolites in the liver, hepatic disease may lead to delayed elimination of the drug. Patients with hepatic insufficiency receiving Fentanyl M SANDOZ® should be closely monitored for signs of fentanyl toxicity, and the dose of Fentanyl M SANDOZ® should be reduced if necessary.
Renal impairment.
Although renal impairment is not expected to have a clinically significant impact on fentanyl elimination, caution should be exercised, as the pharmacokinetics of fentanyl have not been studied in this patient population. Patients with renal insufficiency receiving Fentanyl M SANDOZ® should be carefully monitored for signs of fentanyl toxicity, and the dose of Fentanyl M SANDOZ® should be reduced if necessary. Additional restrictions apply to patients with renal impairment who have not previously received opioids.
Fever/external heat sources.
Fentanyl concentrations may increase with elevated body temperature. Therefore, patients with fever should be monitored for opioid-related adverse effects, and the dose of the transdermal fentanyl patch should be adjusted if necessary. There is potential for temperature-dependent increases in fentanyl release from the system, which may lead to overdose and fatal outcomes. A clinical pharmacology study in healthy adult volunteers showed that application of heat to the patch site increased mean AUC of fentanyl by 120% and Cmax by 61%.
All patients are advised to avoid exposure to external heat sources such as electric heating pads, hot water bottles, electric blankets, heated waterbeds, heat lamps, sunbeds, prolonged hot baths, saunas, and hot tubs at the site of Fentanyl M SANDOZ® patch application, as temperature-dependent increases in fentanyl release from the patch are likely.
Serotonin syndrome.
Caution should be exercised when using transdermal fentanyl patches concomitantly with medicinal products affecting serotonergic neurotransmitter systems. Potentially life-threatening serotonin syndrome may occur when serotonergic agents such as selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs), or agents that negatively affect serotonin metabolism (particularly MAO inhibitors), are used concomitantly. This may occur even within the recommended dose range.
Serotonin syndrome may include mental status changes (e.g., agitation, hallucinations, coma), autonomic dysfunction (e.g., tachycardia, labile blood pressure, hyperthermia), neuromuscular abnormalities (e.g., hyperreflexia, incoordination, rigidity), and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea).
If serotonin syndrome is suspected, Fentanyl M SANDOZ® should be discontinued immediately.
Interactions with other medicinal products.
CYP3A4 inhibitors.
Concomitant use of the Fentanyl M SANDOZ® patch with cytochrome P450 3A4 (CYP3A4) inhibitors may increase plasma fentanyl concentrations, potentially enhancing or prolonging therapeutic and adverse effects and causing serious respiratory depression. Therefore, concomitant use of Fentanyl M SANDOZ® with CYP3A4 inhibitors is not recommended and should only be considered if the expected benefit outweighs the increased risk of adverse reactions. In general, the first fentanyl patch should be applied 2 days after discontinuation of CYP3A4 inhibitors. However, the duration of inhibition may vary, and for certain CYP3A4 inhibitors with long elimination half-lives, such as amiodarone, or those with time-dependent activity, such as erythromycin, idelalisib, nicardipine, and ritonavir, this period may be longer. Therefore, information regarding the CYP3A4 inhibitor, including the half-life of the active substance and duration of inhibitory effect, should be reviewed before first application of the fentanyl patch. For patients receiving Fentanyl M SANDOZ®, initiation of CYP3A4 inhibitors should occur 1 week after removal of the last patch. If concomitant use of fentanyl with CYP3A4 inhibitors cannot be avoided, careful monitoring for signs and symptoms of enhanced or prolonged fentanyl effects (particularly respiratory depression) is required. If necessary, the dose of Fentanyl M SANDOZ® should be reduced or treatment discontinued.
Accidental use of Fentanyl M SANDOZ® patch.
Accidental adhesion of the Fentanyl M SANDOZ® patch to another person’s skin (especially a child) during sleep or close physical contact with the patch wearer may lead to opioid overdose. The patch should be removed immediately if accidentally adhered to someone else’s skin.
Elderly patients.
Data from studies of intravenous fentanyl suggest that elderly patients may have reduced clearance, prolonged elimination half-life, and increased sensitivity to the active substance compared to younger patients. Elderly patients receiving Fentanyl M SANDOZ® should be closely monitored for signs of fentanyl toxicity, and the dose of Fentanyl M SANDOZ® should be reduced if necessary.
Effects on the gastrointestinal tract.
Opioids increase tone and reduce propulsive contractions of gastrointestinal smooth muscle. As a result, gastrointestinal transit time is prolonged, which may lead to constipation. Patients should be advised on preventive measures for constipation, and the use of prophylactic laxatives should be considered. Fentanyl M SANDOZ® should be used with extreme caution in patients with chronic constipation. Treatment with the Fentanyl M SANDOZ® patch should be discontinued if paralytic ileus is present or suspected.
Patients with myasthenia gravis.
Non-epileptic myoclonic reactions may occur. Caution should be exercised when treating patients with myasthenia gravis.
Concomitant use with mixed agonists/antagonists.
Concomitant use of buprenorphine, nalbuphine, or pentazocine is not recommended.
Children.
Fentanyl M SANDOZ® should not be used in children who have not previously received opioid therapy (see section "Dosage and administration"). The risk of severe or life-threatening hypoventilation exists regardless of the dose of the Fentanyl M SANDOZ® patch. Use of the Fentanyl M SANDOZ® patch has not been studied in children under 2 years of age. The Fentanyl M SANDOZ® patch may be used in patients aged 2 years and older only if they are opioid-tolerant.
To prevent accidental ingestion by children, the application site of the Fentanyl M SANDOZ® patch should be carefully selected and the correct application should be closely monitored.
Inappropriate use of fentanyl as a doping agent.
Fentanyl use may result in positive doping test results. Using Fentanyl M SANDOZ® as a doping agent may be harmful to health.
Removal of the transdermal patch. Used patches may still contain a significant amount of active substance. Used systems should be folded in half with the adhesive side inward so that the adhesive is not exposed, and then disposed of in a place inaccessible to children.
Fentanyl is indicated for patients requiring continuous long-term opioid therapy for the management of chronic cancer-related pain. Transmucosal fentanyl-containing medicinal products should only be used in patients already receiving other opioids for the treatment of chronic cancer-related pain.
Patients and their caregivers should be advised to store Fentanyl M SANDOZ® in a safe and secure place, inaccessible to others, due to risks including fatal outcomes associated with accidental ingestion, misuse, and abuse.
Use during pregnancy or breastfeeding.
Pregnancy. There are insufficient data on the use of the patch in pregnant women. Animal studies have shown some reproductive toxicity. The potential risk to humans is unknown; however, in other dosage forms, fentanyl, including intravenous formulations, has been shown to cross the placenta in early pregnancy. Neonatal withdrawal syndrome has been reported in newborns of mothers who chronically used transdermal fentanyl during pregnancy. Fentanyl M SANDOZ® should not be used during pregnancy unless clearly necessary.
Use of Fentanyl M SANDOZ® during labor is not recommended, as it is not intended for the management of acute or postoperative pain. Moreover, since fentanyl crosses the placenta, its use during labor may cause respiratory depression in the newborn.
Breastfeeding. Fentanyl passes into breast milk and may cause sedation and respiratory depression in the breastfed infant. Therefore, breastfeeding should be discontinued during treatment with Fentanyl M SANDOZ® and for at least 72 hours after patch removal.
Fertility. There are no clinical data on the effect of fentanyl on fertility. Some studies in rats have shown reduced fertility and increased embryonic lethality at maternally toxic doses.
Ability to affect reaction speed when driving or operating machinery.
Fentanyl M SANDOZ® may affect mental and psychomotor functions required for potentially hazardous activities such as driving a car or operating machinery.
Method of Administration and Dosage
Duration and Treatment Goals
Prior to initiating therapy with FENTANYL M SANDOZ®, a treatment strategy—including treatment duration, treatment goals, and a plan for discontinuation—should be agreed upon with the patient, in accordance with pain management guidelines. During therapy, the physician should maintain regular contact with the patient to assess the need for continued treatment, consider the possibility of treatment discontinuation, and, if necessary, adjust the dosage. In the absence of adequate pain control, consider the possibility of hyperalgesia, tolerance, and progression of the underlying disease (see section "Special Warnings and Precautions for Use").
FENTANYL M SANDOZ® is intended for transdermal administration. Dosage must be individually titrated according to the patient's condition and should be regularly evaluated after patch application. The lowest effective dose should be used. The patches are designed to release 25, 50, 75, and 100 mcg of fentanyl per hour into the systemic circulation, corresponding to approximately 0.6, 1.2, 1.8, and 2.4 mg per day, respectively.
Initial Dose
The initial dose of FENTANYL M SANDOZ® should be selected based on the patient's prior opioid regimen. FENTANYL M SANDOZ® is recommended for use in opioid-tolerant patients. Patient condition, body weight, age, degree of debilitation, and level of opioid tolerance should also be taken into account.
Adults
Opioid-Tolerant Patients
To determine the appropriate dose of FENTANYL M SANDOZ® when switching a patient from oral or intravenous opioids, refer to the Equianalgesic Dose Conversion Table provided below. Subsequently, the dose may be titrated upward or downward in 25 mcg/hour increments to achieve the lowest effective dose, depending on the patient's response to treatment and additional analgesic requirements.
Opioid-Naïve Patients
Transdermal fentanyl is generally not recommended for opioid-naïve patients. In such cases, alternative routes of administration (oral, parenteral) should be considered. To prevent overdose in opioid-naïve patients, it is recommended to initiate treatment with the lowest possible dose of an immediate-release opioid (morphine, hydromorphone, oxycodone, tramadol, or codeine) and titrate upward until reaching a dose equivalent to 25 mcg/hour of FENTANYL M SANDOZ®. The patient may then be transitioned to the FENTANYL M SANDOZ® patch at a dose of 25 mcg/hour.
If oral opioids cannot be used at the start of therapy and the FENTANYL M SANDOZ® patch is the only available option for opioid-naïve patients, the lowest available dose—25 mcg/hour—should be used. In such cases, the patient must be under close supervision. There is a risk of developing severe or life-threatening hypoventilation, even with the lowest dose of the drug during initial therapy.
Equianalgesic Dose Conversion
For patients currently receiving opioid analgesics, the initial dose of FENTANYL M SANDOZ® should take into account the prior daily opioid dose. To calculate the appropriate initial dose of FENTANYL M SANDOZ®, follow the instructions below:
- Calculate the current daily dose (mg/day) of the opioid being used.
- Convert this value to the equianalgesic daily dose of oral morphine using the multiplication factors in Table 1, according to the route of administration.
- To determine the corresponding dose of FENTANYL M SANDOZ® based on the calculated equianalgesic daily dose of morphine, use the dose conversion in Table 2 or 3 as follows:
a. Use Table 2 to determine the dose for adult patients requiring opioid rotation or who are less clinically stable (the conversion ratio of oral morphine to transdermal fentanyl is approximately 150:1).
b. Use Table 3 to determine the dose for adult patients on a stable and well-tolerated regimen (the conversion ratio of oral morphine to transdermal fentanyl is approximately 100:1).
Table 1
Conversion Table – Multiplication factors for converting prior daily opioid dose to equianalgesic daily dose of oral morphine
(dose in mg/day of prior opioid × factor = equianalgesic daily dose of oral morphine)
| 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 potency of oral/intramuscular morphine is based on clinical experience in patients with chronic pain.
b Based on study data of single-dose intramuscular administration of each listed active substance compared to morphine to determine relative potency. Recommended oral doses correspond to recommendations for switching from parenteral to oral administration.
Literature: Adapted from 1) Foley KM. The treatment of cancer pain. NEJM 1985; 313 (2):
84─95 and 2) McPherson ML. Introduction to opioid conversion calculations. In: Demystifying Opioid Conversion Calculations: A Guide for Effective Dosing. Bethesda, MD: American Society of Health-System Pharmacists; 2010:1─15.
Table 2.
Recommended initial dose of Fentanyl M SANDOZ® patch (based on daily oral morphine dose1) for patients requiring opioid rotation or who are less clinically stable: the conversion ratio of oral morphine to transdermal fentanyl is approximately 150:11
| Oral morphine daily dose (mg/day) |
Dose of Fentanyl M SANDOZ® patch (mcg/hour) |
| 90─134 |
25 |
| 180─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 Fentanyl M SANDOZ® transdermal patch.
Table 3.
Recommended initial dose of Fentanyl M SANDOZ® patch based on daily oral morphine dose1 (for patients on stable and well-tolerated opioid therapy: the conversion ratio of oral morphine to transdermal fentanyl is approximately 100:1):
| Oral morphine daily dose (mg/day) |
Fentanyl M SANDOZ® patch dose (mcg/hour) |
| 45─89 |
25 |
| 120─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 maximum analgesic effect of FENTANYL M SANDOZ® transdermal patch cannot be initially assessed until at least 24 hours after application, due to the gradual increase in serum fentanyl concentration over the first 24 hours following initial application.
To successfully switch from another analgesic to FENTANYL M SANDOZ®, prior pain medication should be gradually discontinued after the initial application of the transdermal patch.
Dose titration and maintenance therapy.
FENTANYL M SANDOZ® transdermal patch should be replaced every 72 hours.
The dose should be individually titrated based on daily use of supplemental analgesics until a balance between adequate pain control and treatment tolerability is achieved. The dose is typically increased by 25 mcg/hour increments; however, the patient's condition and need for additional analgesia should be taken into account (a daily oral morphine dose of 90 mg approximately corresponds to a FENTANYL M SANDOZ® dose of 25 mcg/hour). After a dose increase, up to 6 days may be required to reach steady-state at the new dosage level. Therefore, after increasing the dose, patients should use the patch with the increased dose for two consecutive 72-hour periods before any further dose escalation.
To achieve doses exceeding 100 mcg/hour, multiple patches may be used simultaneously. Patients may occasionally require additional doses of short-acting analgesics to manage breakthrough pain. Some patients may require additional or alternative analgesic therapies when doses of FENTANYL M SANDOZ® exceed 300 mcg/hour.
If adequate analgesia is not achieved after the initial dose 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 is necessary before 72 hours (e.g., due to poor adhesion), a new patch with the same delivery rate should be applied to a different skin site. This may result in increased fentanyl blood concentrations; therefore, patients should be closely monitored in such cases.
Discontinuation of FENTANYL M SANDOZ®.
When discontinuation of FENTANYL M SANDOZ® is required, switching to another opioid should be done gradually, starting with a low dose and slowly increasing. This approach is necessary because of the gradual decline in fentanyl concentration following patch removal; fentanyl serum concentrations decrease by 50% over 20 hours or longer. Opioid analgesia should always be discontinued gradually to prevent withdrawal syndrome.
Opioid withdrawal symptoms may occur in some patients after switching therapy or reducing the dose.
Tables 1, 2, and 3 should only be used to convert dosages when switching from other opioid analgesics to FENTANYL M SANDOZ®, and not when switching from FENTANYL M SANDOZ® to other opioid analgesics, to avoid incorrect dosage calculations and potential overdose.
Special patient groups.
Elderly patients.
Elderly patients receiving FENTANYL M SANDOZ® require careful monitoring, and dosage should be individually adjusted according to the patient's condition. Opioid-naïve elderly patients should not use FENTANYL M SANDOZ®, except when the expected benefit outweighs potential risks. In such cases, only the 12 mcg/hour dose should be considered for initial treatment.
Patients with renal or hepatic impairment.
Patients with renal or hepatic dysfunction require close monitoring, and dosage should be individually adjusted based on clinical status.
In opioid-naïve patients with renal or hepatic impairment, treatment with FENTANYL M SANDOZ® should only be considered if the anticipated benefit outweighs the risks. In such cases, only the 12 mcg/hour dose should be considered for initial therapy.
Children.
Children aged 16 years: dosing recommendations for adult patients should be followed.
Children aged 2 to 16 years: FENTANYL M SANDOZ® transdermal patch should only be used in patients who are already opioid-tolerant and who have been receiving opioid analgesics at a dose equivalent to at least 30 mg of oral morphine per day. For conversion from oral opioids to FENTANYL M SANDOZ® in pediatric patients, Table 1 should be used. Dose recommendations for FENTANYL M SANDOZ® based on daily oral morphine dose are provided in Table 4.
Table 4.
Recommended dose of FENTANYL M SANDOZ® transdermal patch (based on daily oral morphine dose2).
| Oral daily dose of morphine (mg/day) |
Dose of Fentanyl M SANDOZ® patch (mcg/hour) |
| For patients aged 2 to 16 years1 |
|
| 30─44 |
12.5 |
| 45─134 |
25 |
1 The conversion for doses exceeding 25 mcg/hour of Fentanyl M SANDOZ® corresponds to that for adult patients.
2 The daily oral morphine doses listed were used in clinical studies when switching to Fentanyl M SANDOZ® patch.
During pediatric studies, the required dose of transdermal fentanyl patch was conservatively calculated: 30 to 44 mg of oral morphine per day or an equivalent opioid dose was replaced with one Fentanyl M SANDOZ® patch at a dose of 12 mcg/hour. It should be noted that this conversion can only be used when switching patients from oral morphine (or equivalent agent) to the Fentanyl M SANDOZ® patch. This method must not be used to convert dosing when switching from transdermal fentanyl to other opioid analgesics due to the risk of overdose.
The analgesic effect of the first dose of Fentanyl M SANDOZ® patch will not be optimal during the first 24 hours. Therefore, during the first 12 hours after switching to the Fentanyl M SANDOZ® patch, the patient should continue to receive their previous usual analgesic dose. During the subsequent 12 hours, these analgesics may be administered as clinically needed.
Since peak fentanyl concentration is reached after 12–24 hours of treatment, it is recommended to monitor the patient for at least 48 hours after initiation of Fentanyl M SANDOZ® patch therapy or until dose adjustment, for the development of adverse reactions, which may include hypoventilation.
Fentanyl M SANDOZ® must not be used in children under 2 years of age, as safety and efficacy in this patient group have not been established.
Dose 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 until a balance between adequate analgesia and treatment tolerability is achieved. The dose should not be increased at intervals shorter than 72 hours. If the analgesic effect of Fentanyl M SANDOZ® is insufficient, supplemental analgesics such as morphine or another short-acting opioid should be administered. Depending on additional analgesic requirements and the child’s condition, a decision may be made to increase the dose. The dose should be increased by 12 mcg/hour.
Method of administration.
Fentanyl M SANDOZ® is intended for transdermal use.
The product should be applied to an intact, non-irradiated, flat area of skin on the trunk or upper arms.
For small children, the upper back should be selected for patch application to minimize the risk of the child removing the patch. The application site should have minimal hair. Before application, hair at the site should be clipped (not shaved). If the application site needs to be washed before patch application, it should be done using clean water only. Do not use soap, lotions, oils, or other products, as they may irritate the skin or alter its properties. The skin must be completely dry before application. The patch should be inspected before use. Do not use patches that are cut, torn, or otherwise damaged.
Fentanyl M SANDOZ® should be applied immediately after opening the sealed package.
The Fentanyl M SANDOZ® patch should be removed from its protective pouch by bending the pouch at the notch (located near the tip of the arrow on the pouch label) and then carefully tearing open the pouch material. The torn pouch should be opened like a book. The protective liner has a slit in the middle. The patch should be folded in half and each half of the protective liner removed, avoiding contact with the adhesive side of the patch using fingers. After removing both halves of the protective liner, the transdermal patch should be firmly pressed with the palm of the hand onto the application site for 30 seconds. Ensure that the system adheres tightly to the skin, especially at the edges. After completing the procedure, wash hands with clean water.
Fentanyl M SANDOZ® is designed for continuous use over 72 hours. A new patch should be applied to a different skin area after removal of the previous patch. The same skin area should not be used again until several days have passed.
Children.
Fentanyl M SANDOZ® must not be used in children under 2 years of age.
Use in children aged 2 years and older for long-term treatment of severe chronic pain who are already receiving therapy with opioid analgesics.
Overdose.
Symptoms. Overdose with fentanyl is manifested by an intensification of its pharmacological effects, the most serious of which is respiratory depression.
Treatment. Immediate safety measures for treating respiratory depression include rapid removal of the Fentanyl M SANDOZ® patch and physical and verbal stimulation of the patient. These measures may be supplemented by administration of a specific opioid antagonist—naloxone. Respiratory depression following overdose may last longer than the duration of action of the opioid antagonist. The interval between intravenous doses of the antagonist should be carefully selected; repeated administration or prolonged naloxone infusion may be necessary due to continued absorption of fentanyl from the skin after patch removal. The loss of analgesic effect may lead to the development of acute pain and catecholamine release.
Ensure airway patency and monitor respiratory support. Oxygen should be administered via an oral airway or endotracheal tube under continuous monitoring. Adequate body temperature and fluid administration should be maintained. If severe or persistent hypotension develops, hypovolemia should be considered. The condition should be managed by parenteral administration of appropriate fluids.
Symptoms and signs
Manifestations of fentanyl overdose include the continuation of its pharmacological effects, the most serious of which is respiratory depression. Toxic leukoencephalopathy has also been observed in cases of fentanyl overdose.
Side effects
The safety of the medicinal product was evaluated in 1565 adults and 289 children who participated in 11 clinical trials investigating the use of the product for the treatment of chronic pain, both related and unrelated to cancer. Each study subject received at least one dose of the medicinal product. Based on pooled safety data from these clinical trials, the most frequently observed adverse reactions (≥10% of cases) were: nausea (35.7%), vomiting (23.2%), constipation (23.1%), somnolence (15.0%), dizziness (13.1%), headache (11.8%), and insomnia (10.2%).
Adverse reactions reported during these clinical studies and during post-marketing surveillance are listed below.
Adverse effects are grouped by frequency:
Very common: ≥1/10. Common: ≥1/100 to <1/10.
Uncommon: ≥1/1000 to <1/100. Rare: ≥1/10,000 to <1/1000.
Very rare: <1/10,000. Not known (cannot be estimated from available data).
Immune system disorders.
Common: hypersensitivity.
Not known: anaphylactic shock, anaphylactic reaction, anaphylactoid reaction.
Metabolism and nutrition disorders.
Common: anorexia.
Psychiatric disorders.
Very common: somnolence, insomnia.
Common: depression, anxiety, confusion, hallucinations.
Uncommon: agitation, disorientation, euphoria.
Not known: tolerance, drug dependence.
Nervous system disorders.
Very common: dizziness, headache.
Common: tremor, paraesthesia.
Uncommon: hypaesthesia, convulsions (including clonic convulsions and grand mal seizures), amnesia, consciousness depression, loss of consciousness.
Not known: delirium.
Eye disorders.
Uncommon: blurred vision.
Rare: miosis.
Ear and labyrinth disorders.
Common: vertigo.
Cardiac disorders.
Common: palpitations, tachycardia.
Uncommon: bradycardia, cyanosis.
Rare: arrhythmia.
Vascular disorders.
Common: hypertension.
Uncommon: hypotension.
Respiratory, thoracic and mediastinal disorders.
Common: dyspnoea.
Uncommon: respiratory depression, respiratory distress syndrome, respiratory failure.
Rare: apnoea, hypoventilation.
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.
Endocrine disorders.
Not known: androgen deficiency.
General disorders and administration site conditions.
Common: fatigue, peripheral oedema, asthenia, malaise, feeling cold.
Uncommon: application site reaction, influenza-like illness, sensation of temperature change, hypersensitivity reaction at site of administration, withdrawal syndrome, pyrexia*.
Rare: application site dermatitis, application site eczema.
Not known: tolerance, drug dependence.
*The frequency category (uncommon) was determined based on frequency analysis including only adult and paediatric participants in clinical trials for non-cancer pain.
Adverse reactions in children.
The adverse reaction profile in children and adolescents treated with the medicinal product was similar to that observed in adults. No risk factors specific to the paediatric population were identified apart from those commonly observed with opioid use for pain relief associated with severe illness. No paediatric-specific risks associated with the use of fentanyl patches were identified when used in children aged 2 years and older as indicated. Very common adverse reactions observed during clinical trials in children were fever, vomiting, and nausea.
The safety of the medicinal product was evaluated in 289 paediatric patients (<18 years) 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 the medicinal product. Although inclusion criteria for paediatric trials were limited to age 2 years and older, two patients in these studies received their first dose at 23 months of age.
Based on pooled safety data from these 3 clinical trials, the most common adverse reactions in children (≥10% of cases) were: vomiting (33.9%), nausea (23.5%), headache (16.3%), constipation (13.5%), diarrhoea (12.8%), and pruritus (12.8%). These results were included in the overall safety data.
As with other opioid analgesics, repeated use of FENTANYL M SANDOZ® may lead to tolerance, physical dependence, and psychological dependence.
In some patients, symptoms of opioid withdrawal (such as nausea, vomiting, diarrhoea, anxiety, and tremor) may occur either after switching from a previous opioid analgesic to FENTANYL M SANDOZ® or upon abrupt discontinuation of treatment.
Neonatal withdrawal syndrome has been very rarely reported in newborns whose mothers had used the product regularly during pregnancy.
Cases of serotonin syndrome have been reported when fentanyl was used concomitantly with high doses of serotonergic agents.
In very rare cases, highly refined soybean oil may cause allergic reactions.
Tolerance
Tolerance may develop with repeated administration.
Drug dependence
Repeated use of FENTANYL M SANDOZ® may lead to drug dependence, even at therapeutic doses. The risk of developing drug dependence may vary depending on individual risk factors, dosage, and duration of opioid treatment (see section "Special precautions").
Shelf life. 2 years
Storage conditions.
Store at temperatures not exceeding 25 °C in the original packaging.
Keep out of the reach and sight of children.
Packaging. 1 patch per sachet; 5 sachets in a carton.
Prescription category. Prescription only.
Manufacturer. Hexal AG.
Manufacturer's address and place of business.
Industriestrasse 25, 83607 Holzkirchen, Germany.