Fenta

/ Rafa

This medicinal product should be applied to non-irritated and non-irradiated skin on a flat surface of the torso or upper arm. In young children, the upper back is the preferred location to apply the patch, to minimise the potential of the child removing the patch. A non-hairy area should be selected. If this is not possible, hair at the application site should be clipped (not shaved) prior to application. If the site of application requires to be cleansed prior to application of the patch, this should be done with water. Soaps, oils, lotions or any other agent that might irritate the skin or alter its characteristics should not be used. The skin should be completely dry before the patch is applied.
Following removal of both parts of the protective liner, the transdermal patch should be pressed firmly in place with the palm of the hand for approximately 30 seconds, making sure the contact is complete, especially around the edges. Then wash hands with clean water.
The patch should be worn continuously for 72 hours. A new patch should then be applied to a different skin site after removal of the previous transdermal patch. Several days should elapse before a new patch is applied to the same area of skin.
Initial dose selection: The appropriate initiating dose of Fenta should be based on the patient’s current opioid use. Fenta should be used in patients who have demonstrated opioid tolerance. Other factors to be considered are the current general condition and medical status of the patient, including body size, age, and extent of debilitation as well as degree of opioid tolerance.
Adults:
Opioid-tolerant patients: To convert opioid-tolerant patients from oral or parenteral opioids to Fenta refer to Equianalgesic potency conversion below. The dosage may subsequently be titrated upwards or downwards, if required, in increments of either 12.5 or 25 mcg/hr to achieve the lowest appropriate dose of Fenta depending on response and supplementary analgesic requirements.
Use in elderly patients: 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 drug than younger patients. Elderly, cachectic, or debilitated patients should be observed carefully for signs of fentanyl toxicity and the dose reduced if necessary.
Paediatric population
Children aged 16 years and above: follow adult dosage Children aged 2 to16 years old: Fenta should be administered only to opioid-tolerant paediatric patients (ages 2 to 16 years) who are already receiving at least 30 mg oral morphine equivalents per day.
Dose titration and maintenance:
If the analgesic effect is insufficient, supplementary morphine or another short-duration opioid should be administered. Depending on the additional analgesic needs and the pain status of the child, it may be decided to increase the dose. Dose adjustments should be done in 12.5 mcg/hr steps.
For full details see prescribing information.

Management of chronic and intractable pain requiring opioid analgesia in patients who are already receiving opioid therapy, who have demonstrated opioid tolerance.

– Hypersensitivity to the active substance or to any of the excipients.
– Acute or postoperative pain because there is no opportunity for dose titration during short-term use and because serious or life-threatening hypoventilation could result.
– Severe respiratory depression.

Patients who have experienced serious adverse events should be monitored for at least 24 hours after removal of the patch, or more, as clinical symptoms dictate, because serum fentanyl concentrations decline gradually and are reduced by about 50% 20 to 27 hours later.
Opioid-naive and not opioid-tolerant states: Use in the opioid-naive 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 is used in initiating therapy in opioid-naive patients, especially in elderly or patients with hepatic or renal impairment. The tendency of tolerance development varies widely among individuals. This medicinal product should only be used in patients who have demonstrated opioid tolerance.
Respiratory depression: Some patients may experience significant respiratory depression; patients must be observed for these effects. Respiratory depression may persist beyond the removal of the patch. The incidence of respiratory depression increases as the dose is increased.
Opioids can cause sleep-related breathing disorders including central sleep apnoea (CSA) and sleep-related hypoxia. Opioid use increases the risk of CSA in a dose-dependent fashion. In patients who present with CSA consider decreasing the total opioid dosage.
Risk from concomitant use of central nervous system (CNS) depressants, including sedative medicines such as benzodiazepines or related drugs, alcohol and CNS depressant narcotic drugs: Concomitant use with sedative medicines such as benzodiazepines or related drugs, alcohol, or CNS depressant narcotic drugs, may result in sedation, respiratory depression, coma and death. Because of these risks, concomitant prescribing with sedative medicines should be reserved for patients for whom alternative treatment options are not possible. If a decision is made to prescribe this medicinal product 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.
Chronic pulmonary disease: This medicinal product 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.
Long-term treatment effects and tolerance: In all patients, tolerance to the analgesic effects, hyperalgesia, physical dependence, and psychological dependence may develop upon repeated administration of opioids, whereas incomplete tolerance is developed for some side effects like opioid induced constipation. Particularly in patients with chronic non cancer pain, it has been reported that they may not experience a meaningful amelioration in pain intensity from continuous opioid treatment in the long term. When it is decided that there is no benefit for continuation, gradual down titration should be applied to address withdrawal symptoms.
Do not abruptly discontinue this drug in a patient physically dependent on opioids. There have been reports that rapid tapering of fentanyl transdermal patch in a patient physically dependent on opioids may lead to serious withdrawal symptoms and uncontrolled pain. When a patient no longer requires therapy, it is advisable to taper the dose gradually to minimise symptoms of withdrawal. Tapering from a high dose may take weeks to months.
Opioid use disorder (abuse and dependence): Repeated use may lead to Opioid use disorder (OUD). A higher dose and longer duration of opioid treatment can increase the risk of developing OUD. Abuse or intentional misuse may result in overdose and/or death. The risk of developing OUD is increased in patients with a personal or a family history (parents or siblings) of substance use disorders (including alcohol use disorder), in current tobacco users or in patients with a personal history of other mental health disorders (e.g. major depression, anxiety and personality disorders).
Central nervous system conditions including increased intracranial pressure: This medicinal product 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. This medicinal product 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.
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. Treatment should only be considered if the benefits outweigh the risks.
Fever/external heat application: Fentanyl concentrations may increase if the skin temperature increases. Therefore, patients with fever should be monitored for opioid undesirable effects and the 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 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 this drug 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 that impair metabolism of serotonin (including Monoamine Oxidase Inhibitors [MAOIs]). This may occur within the recommended dose. If serotonin syndrome is suspected, treatment with Fentanyl should be discontinued.
Interactions with other medicinal products:
CYP3A4 inhibitors: The concomitant use 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 with 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 transdermal 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 transdermal patch. A patient who is treated with Fentanyl TDP should wait at least 1 week after removal of the last patch before initiating treatment with a CYP3A4 inhibitor.
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.
Use in elderly patients: 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.
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 TDP 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.
Paediatric population: This medicinal product should not be administered to opioid-naive paediatric patients. The potential for serious or life-threatening hypoventilation exists regardless of the dose of Fentanyl TDP transdermal system administered.
This medicinal product should be administered only to opioid-tolerant children age 2 years or older.
To guard against accidental ingestion by children, use caution when choosing the application site and monitor adhesion of the patch closely.
Opioid induced hyperalgesia: Opioid induced hyperalgesia (OIH) is a paradoxical response to an opioid in which there is an increase in pain perception despite stable or increased opioid exposure. It differs from tolerance, in which higher opioid doses are required to achieve the same analgesic effect or treat recurring pain. OIH may manifest as increased levels of pain, more generalised pain (i.e., less focal), or pain from ordinary (i.e., non-painful) stimuli (allodynia) with no evidence of disease progression. When OIH is suspected, the dose of opioid should be reduced or tapered off, if possible.
Endocrine effects: Opioids such as fentanyl may influence the hypothalamic-pituitary-adrenal or – gonadal axes, especially after long-term use. Some changes that can be seen include an increase in serum prolactin, and decreases in plasma cortisol and testosterone. Clinical signs and symptoms may manifest from these hormonal changes. If an endocrine effect such as hyperprolactinaemia or adrenal insufficiency is suspected, appropriate laboratory testing is recommended and discontinuation of treatment with Fentanyl TDP should be considered.
See prescribing information for full details.

Very common: Somnolence, dizziness, headache, nausea, vomiting, constipation,
Common: Hypersensitivity, anorexia, insomnia, depression, anxiety, confusional state, hallucination, tremor, paraesthesia, vertigo, palpitations, tachycardia, hypertension, dyspnoea, diarrhoea, dry mouth, abdominal pain, abdominal pain upper, dyspepsia, hyperhidrosis, pruritus, rash, erythema, muscle spasms, urinary retention, fatigue, oedema peripheral, asthenia, malaise, feeling cold.
See prescribing information for full details.

The concomitant use of other Central Nervous System depressants, including opioids, sedatives, anxiolytics, hypnotics, general anaesthetics, phenothiazines, tranquilizers, antipsychotics, skeletal muscle relaxants, sedating antihistamines and alcoholic beverages may produce additive depressant effects; hypoventilation, hypotension and profound sedation, coma or death may occur. Therefore, the use of any of the above mentioned concomitant drugs requires special care and observation. Fentanyl, a high clearance drug, is rapidly and extensively metabolised mainly by CYP3A4. The concomitant use of transdermal fentanyl with cytochrome P450 3A4 (CYP3A4) inhibitors (e.g. ritonavir, ketoconazole, itraconazole, fluconazole, voriconazole, troleandomycin, clarithromycin, nelfinavir, nefazodone, verapamil, diltiazem, and amiodarone) 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. In this situation, special patient care and observation are appropriate. The concomitant use of CYP3A4 inhibitors and transdermal fentanyl is not recommended, unless the patient is closely monitored. The concomitant use with CYP3A4 inducers (e.g. rifampicin, carbamazepine, phenobarbital, phenytoin) could result in a decrease in fentanyl plasma concentrations and a decreased therapeutic effect. This may require a dose adjustment of transdermal fentanyl. After stopping the treatment of a CYP3A4 inducer, the effects of the inducer decline gradually and may result in a fentanyl plasma increase concentration which could increase or prolong both the therapeutic and adverse effects, and may cause serious respiratory depression. In this situation, careful monitoring and dose adjustment should be made if warranted.
Monoamine Oxidase Inhibitors (MAOI): Fenta is not recommended for use in patients who require the concomitant administration of an MAOI. Severe and unpredictable interactions with MAOIs, involving the potentiation of opiate effects or the potentiation of serotoninergic effects, have been reported. Therefore, Fenta should not be used within 14 days after discontinuation of treatment with MAOIs.
Serotonergic Drugs: Coadministration of transdermal fentanyl with a serotonergic agent, such as a Selective Serotonin Reuptake Inhibitor (SSRI) or a Serotonin Norepinephrine Re-uptake Inhibitor (SNRI) or a Monoamine Oxidase Inhibitor (MAOI), may increase the risk of serotonin syndrome, a potentially life-threatening condition.
Concomitant use of mixed agonists/antagonists: The concomitant use of buprenorphine, nalbuphine or pentazocine is not recommended. They have high affinity to opioid receptors with relatively low intrinsic activity and therefore partially antagonise the analgesic effect of fentanyl and may induce withdrawal symptoms in opioid dependent patients.
For full details see prescribing information.

Pregnancy: There are no adequate data from the use of fentanyl transdermal patch in pregnant women. The potential risk for humans is unknown, although fentanyl as an IV anaesthetic has been found to cross the placenta in human pregnancies. Neonatal withdrawal syndrome has been reported in newborn infants with chronic maternal use of fentanyl transdermal patch during pregnancy. This medicinal product should not be used during pregnancy unless clearly necessary.
Use during childbirth is not recommended because it should not be used in the management of acute or postoperative pain. Moreover, because fentanyl passes through the placenta, the use during childbirth might result in respiratory depression in the newborn infant.
Breastfeeding:
Fentanyl is excreted into human milk and may cause sedation/respiratory depression in a breastfed infant. Breastfeeding should therefore be discontinued during treatment and for at least 72 hours after removal of the patch.     

Symptoms and signs
The manifestations of fentanyl overdose are an extension of its pharmacologic actions, the most serious effect being respiratory depression. Toxic leukoencephalopathy has also been observed with fentanyl overdose.
Treatment
For management of respiratory depression, immediate countermeasures include removing the patch and physically or verbally stimulating the patient. These actions can be followed by administration of a specific opioid antagonist such as naloxone. Respiratory depression following an overdose may outlast the duration of action of the opioid antagonist. The interval between IV antagonist doses should be carefully chosen because of the possibility of re-narcotisation after the patch is removed; repeated administration or a continuous infusion of naloxone may be necessary. Reversal of the narcotic effect may result in acute onset of pain and release of catecholamines.
If the clinical situation warrants, a patent airway should be established and maintained, possibly with an oropharyngeal airway or endotracheal tube, and oxygen should be administered and respiration assisted or controlled, as appropriate. Adequate body temperature and fluid intake should be maintained.
If severe or persistent hypotension occurs, hypovolaemia should be considered, and the condition should be managed with appropriate parenteral fluid therapy.