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Patients who have experienced serious adverse events should be monitored for at least 24 hours after removal of fentanyl patch, or more, as clinical symptoms dictate, because serum fentanyl concentrations decline gradually and are reduced by about 50% 20 to 27 hours later.
Patients and their carers must be instructed that the fentanyl patch contains an active substance in an amount that can be fatal, especially to a child. Therefore, they must keep all patches out of the sight and reach of children, both before and after use.
Opioid-naïve and not opioid-tolerant states: Use of fentanyl patch in the opioid-naïve patient has been associated with very rare cases of significant respiratory depression and/or fatality when used as initial opioid therapy, especially in patients with non-cancer pain. The potential for serious or life-threatening hypoventilation exists even if the lowest dose of fentanyl patch is used in initiating therapy in opioid-naïve patients, especially in elderly or patients with hepatic or renal impairment. The tendency of tolerance development varies widely among individuals. It is recommended that fentanyl patch is used in patients who have demonstrated opioid tolerance (see Dosage & Administration).
Respiratory depression: Some patients may experience significant respiratory depression with fentanyl patch; patients must be observed for these effects. Respiratory depression may persist beyond the removal of the fentanyl patch. The incidence of respiratory depression increases as the fentanyl patch dose is increased (see Interactions).
Risk from concomitant use of sedative medicines such as benzodiazepines or related medicinal products and alcohol: Concomitant use of fentanyl and sedative medicines such as benzodiazepines or related medicinal products may result in sedation, respiratory depression, coma and death. Because of these risks, concomitant prescribing with these sedative medicines should be reserved for patients for whom alternative treatment options are not possible. If a decision is made to prescribe fentanyl concomitantly with sedative medicines, the lowest effective dose should be used, and the duration of treatment should be as short as possible.
The patients should be followed closely for signs and symptoms of respiratory depression and sedation. In this respect, it is strongly recommended to inform patients and their caregivers to be aware of these symptoms (see Interactions).
Chronic pulmonary disease: Fentanyl may have more severe adverse effects in patients with chronic obstructive, or other pulmonary disease. In such patients, opioids may decrease respiratory drive and increase airway resistance.
Drug dependence and potential for abuse: Tolerance, physical dependence, and psychological dependence may develop upon repeated administration of opioids.
Fentanyl can be abused in a manner similar to other opioid agonists. Abuse or intentional misuse of fentanyl patch may result in overdose and/or death. Patients with a prior history of drug dependence/alcohol abuse are more at risk to develop dependence and abuse in opioid treatment. Patients at increased risk of opioid abuse may still be appropriately treated with modified-release opioid formulations; however, these patients will require monitoring for signs of misuse, abuse, or addiction.
Central nervous system conditions including increased intracranial pressure: Fentanyl patch should be used with caution in patients who may be particularly susceptible to the intracranial effects of CO2 retention such as those with evidence of increased intracranial pressure, impaired consciousness, or coma. Fentanyl patch should be used with caution in patients with brain tumours.
Cardiac disease: Fentanyl may produce bradycardia and should therefore be administered with caution to patients with bradyarrhythmias.
Hypotension: Opioids may cause hypotension, especially in patients with acute hypovolaemia. Underlying, symptomatic hypotension and/or hypovolaemia should be corrected before treatment with fentanyl transdermal patches is initiated.
Hepatic impairment: Because fentanyl is metabolised to inactive metabolites in the liver, hepatic impairment might delay its elimination. If patients with hepatic impairment receive fentanyl patch, they should be observed carefully for signs of fentanyl toxicity and the dose of fentanyl patch reduced if necessary (see Pharmacology: Pharmacokinetics under Actions).
Renal impairment: Even though impairment of renal function is not expected to affect fentanyl elimination to a clinically relevant extent, caution is advised because fentanyl pharmacokinetics has not been evaluated in this patient population (see Pharmacology: Pharmacokinetics under Actions). If patients with renal impairment receive fentanyl patch, they should be observed carefully for signs of fentanyl toxicity and the dose reduced if necessary. Additional restrictions apply to opioid-naïve patients with renal impairment (see Dosage & Administration).
Fever/external heat application: Fentanyl concentrations may increase if the skin temperature increases (see Pharmacology: Pharmacokinetics under Actions). Therefore, patients with fever should be monitored for opioid undesirable effects and the fentanyl dose should be adjusted if necessary. There is a potential for temperature-dependent increases in fentanyl released from the system resulting in possible overdose and death.
All patients should be advised to avoid exposing the fentanyl patch application site to direct external heat sources such as heating pads, electric blankets, heated water beds, heat or tanning lamps, sunbathing, hot water bottles, prolonged hot baths, saunas and hot whirlpool spa baths.
Serotonin syndrome: Caution is advised when fentanyl is co-administered with medicinal products that affect the serotonergic neurotransmitter systems.
The development of a potentially life-threatening serotonin syndrome may occur with the concomitant use of serotonergic active substances such as selective serotonin re-uptake inhibitors (SSRIs) and serotonin norepinephrine re-uptake inhibitors (SNRIs), and with active substances which impair metabolism of serotonin (including monoamine oxidase inhibitors [MAOIs]). This may occur within the recommended dose.
Serotonin syndrome may include mental-status changes (e.g., agitation, hallucinations, coma), autonomic instability (e.g., tachycardia, labile blood pressure, hyperthermia), neuromuscular abnormalities (e.g., hyperreflexia, incoordination, rigidity), and / or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhoea).
If serotonin syndrome is suspected, treatment with fentanyl should be discontinued.
Interactions with other medicinal products CYP3A4 inhibitors: The concomitant use of fentanyl patch with cytochrome P450 3A4 (CYP3A4) inhibitors may result in an increase in fentanyl plasma concentrations, which could increase or prolong both the therapeutic and adverse effects, and may cause serious respiratory depression. Therefore, the concomitant use of fentanyl and CYP3A4 inhibitors is not recommended unless the benefits outweigh the increased risk of adverse effects. Generally, a patient should wait for 2 days after stopping treatment with a CYP3A4 inhibitor before applying the first fentanyl patch. However, the duration of inhibition varies and for some CYP3A4 inhibitors with a long elimination half-life, such as amiodarone, or for time-dependent inhibitors such as erythromycin, idelalisib, nicardipine and ritonavir, this period may need to be longer. Therefore, the product information of the CYP3A4 inhibitor must be consulted for the active substance's half-life and duration of the inhibitory effect before applying the first fentanyl patch. A patient who is treated with fentanyl patch should wait at least 1 week after removal of the last patch before initiating treatment with a CYP3A4 inhibitor. If concomitant use of fentanyl patch with a CYP3A4 inhibitor cannot be avoided, close monitoring for signs or symptoms of increased or prolonged therapeutic effects and adverse effects of fentanyl (in particular respiratory depression) is warranted, and the fentanyl dose must be reduced or interrupted as deemed necessary (see Interactions).
Accidental exposure by patch transfer: Accidental transfer of a fentanyl patch to the skin of a non-patch wearer (particularly a child), while sharing a bed or being in close physical contact with a patch wearer, may result in an opioid overdose for the non-patch wearer. Patients should be advised that if accidental patch transfer occurs, the transferred patch must be removed immediately from the skin of the non-patch wearer (see Overdosage).
Gastrointestinal tract: Opioids increase the tone and decrease the propulsive contractions of the smooth muscle of the gastrointestinal tract. The resultant prolongation in gastrointestinal transit time may be responsible for the constipating effect of fentanyl. Patients should be advised on measures to prevent constipation and prophylactic laxative use should be considered. Extra caution should be used in patients with chronic constipation. If paralytic ileus is present or suspected, treatment with fentanyl should be stopped.
Patients with myasthenia gravis: Non-epileptic (myo)clonic reactions can occur. Caution should be exercised when treating patients with myasthenia gravis.
Concomitant use of mixed opioid agonists/antagonists: The concomitant use of buprenorphine, nalbuphine or pentazocine is not recommended (see Interactions).
Effects on Ability to Drive and Use Machines: Fentanyl may impair mental and/or physical ability required for the performance of potentially hazardous tasks such as driving or operating machinery.
Use in Children: Fentanyl should not be administered to opioid-naïve paediatric patients (see Dosage & Administration). The potential for serious or life-threatening hypoventilation exists regardless of the dose of fentanyl transdermal system administered.
Fentanyl patch has not been studied in children under 2 years of age. Fentanyl patch should be administered only to opioid-tolerant children age 2 years or older (see Dosage & Administration).
To guard against accidental ingestion by children, use caution when choosing the application site for fentanyl patch (see Dosage & Administration and Instructions for use and handling under Cautions for Usage) and monitor adhesion of the patch closely.
Athletes must be aware that this medicine may cause a positive reaction to 'anti-doping' tests.
Use in the Elderly: Data from intravenous studies with fentanyl suggest that elderly patients may have reduced clearance, a prolonged half-life, and they may be more sensitive to the active substance than younger patients.
If elderly patients receive fentanyl patch, they should be observed carefully for signs of fentanyl toxicity and the dose reduced if necessary (see Pharmacology: Pharmacokinetics under Actions).
