Fendermal 25 μg/h, 50 μg/h, 75 μg/h, 100 μg/h Transdermal patches

The management of chronic intractable pain that requires opioid analgesia which cannot be managed by lesser means such as paracetamol- opioid combinations, non - steroidal analgesics or as required dosing with short acting opioids.

Posology
FENDERMAL doses should be individualised based upon the physical and opioid tolerance status of the patients and should be assessed at regular intervals after application. FENDERMAL should be applied on non -irritated and non- irradiated skin on a flat surface of the torso or upper arms. Hair at the application site (a non - hairy area is preferable) should be clipped (not shaved) prior to application. If the site of FENDERMAL application requires cleansing prior to application of the patch, this should be done with clear water. Soap, oils, lotion 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.

FENDERMAL should be applied immediately upon removal from the sealed package. The transdermal patch should be pressed firmly in place with the palm of the hand for 30 seconds, making sure the contact is complete, especially around the edges. FENDERMAL must be worn continuously for 72 hours. A new patch should be applied on 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.

Patients receiving opioid treatment for the first time:
Adults: In patients who have not previously received opioids (opioid nau00efve patients), the initial dosage should not exceed 25 u03bcg/h. To convert opioid u2013 tolerant patients from oral or parental opioids to FENDERMAL, refer to Equianalgesic potency conversion (Table 1), and recommended FENDERMAL dose based upon daily oral morphine dose (Table 2).

Switching from other opioids:
When changing over from oral or parenteral opioids to fentanyl treatment, the initial dosage should be calculated as follows:
1. Determine the quantity of analgesics required over the last 24 hours.
2. Convert the obtained sum to correspond to the oral morphine dosage using Table 1.
3. Determine the corresponding fentanyl dosage as follows:
a) Use Table 2 for patients who have a need for opioid rotation (conversion ratio of oral morphine to FENDERMAL equal to 150:1).
b) Use Table 3 for patients on stable and well tolerated opioid therapy (conversion ratio of oral morphine to FENDERMAL equal to 100:1).

• Hypersensitivity to fentanyl or to any of the excipients, listed in section 6.1.
• Acute or post- operative pain because there is no opportunity for dose titration during short term use and because serious or life- threatening hypoventilation could result.
• Mild or intermittent pain that can be managed with less potent analgesics or with as -needed administration of short- or intermediate- acting opioid analgesics.
• Acute or existing respiratory depression, comatose patients (see section 4.4).
• Bradycardiac dysrhythmias.
• Severely impaired central nervous system function.
• During labour and delivery (due to possible neonatal respiratory depression) (see section 4.6)
• Pregnancy and lactation (see section 4.4).
• Children less than 12 years of age.
• Potent cytochrome P450 3A4 inhibitors e.g. ritonavir (see section 4.4).
• Alcohol consumption (see section 4.4 and section 4.5).
• Concurrent use with MAO inhibitors (see section 4.5).
• Concurrent use with naltrexone (see section 4.5).
• Bronchial asthma, acute or severe (see section 4.4).

SHOULD NOT BE USED IN THE MANAGEMENT OF ACUTE OR POST - OPERATIVE PAIN SINCE SERIOUS LIFE - THREATENING HYPOVENTILATION COULD RESULT AND THERE IS NO OPPORTUNITY FOR DOSE TITRATION DURING SHORT TERM USE. PATIENTS WHO HAVE EXPERIENCED SERIOUS ADVERSE EVENTS SHOULD BE MONITORED FOR AT LEAST 24 HOURS AFTER FENDERMAL REMOVAL, OR MORE, AS CLINICAL SYMPTOMS DICTATE, BECAUSE SERUM FENTANYL CONCENTRATIONS DECLINE GRADUALLY AND ARE REDUCED BY 50 %, 20 TO 27 HOURS LATER. PATIENTS AND THEIR CARERS MUST BE INSTRUCTED THAT FENDERMAL 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. FENDERMAL SHOULD BE PRESCRIBED ONLY BY MEDICAL PRACTITIONERS EXPERIENCED IN THE CONTINUOUS ADMINISTRATION OF POTENT OPIOIDS; IN THE MANAGEMENT OF PATIENTS RECEIVING POTENT OPIOIDS FOR TREATMENT OF PAIN AND IN THE DETECTION AND MANAGEMENT OF HYPOVENTILATION INCLUDING THE USE OF OPIOID ANTAGONISTS.

CYP3A4 inhibitors
The concomitant use of FENDERMAL 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 FENDERMAL 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 FENDERMAL. 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 FENDERMAL. A patient who is treated with FENDERMAL should wait at least 1 week after removal of the last patch before initiating treatment with a CYP3A4 inhibitor. If concomitant use of FENDERMAL 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 FENDERMAL dosage must be reduced or interrupted as deemed necessary (see section 4.5).

Pregnancy
Safety during pregnancy and lactation has not been established. FENDERMAL should not be used during pregnancy. There are no adequate data from the use of FENDERMAL in pregnant women. Studies in animals have shown some reproductive toxicity (see section 5.3). 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 new - born infants with chronic maternal use of fentanyl during pregnancy. Use of FENDERMAL during labour and childbirth is not recommended (caesarean section included) because it should not be used in the management of acute or postoperative pain (see section 4.3). Moreover, because fentanyl passes through the placenta, the use of FENDERMAL during childbirth might result in respiratory depression in the new - born infant.

Lactation
Fentanyl is excreted into breast milk and may cause sedation and/or respiratory depression in a breastfed neonate/infant. Breastfeeding should therefore be discontinued during treatment with FENDERMAL and for at least 72 hours after removal of FENDERMAL.

Fertility
There are no clinical data on the effects of FENDERMAL on fertility. Some studies in rats have revealed reduced fertility and enhanced embryo mortality at maternally toxic doses (see section 5.3).

FENDERMAL may impair the mental and/or physical ability required for performing potentially hazardous tasks such as driving a car or operating machinery.

Immune system disorders
Frequent: Hypersensitivity
Frequency unknown: Anaphylactic shock, anaphylactic reaction, anaphylactoid reaction

Endocrine disorders
Frequency unknown: Androgen deficiency

Metabolism and nutrition disorders
Frequent: Anorexia

Psychiatric disorders
Frequent: Hallucination, sedation, nervousness, insomnia, depression, anxiety, confusional state
Less Frequent: Delusions, states of excitation, euphoric mood, agitation, disorientation
Frequency unknown: Delirium, dependence

Nervous system disorders
Frequent: Headache, dizziness, somnolence, tremor, paraesthesia
Less Frequent: Speech disorders, hypoesthesia, convulsion (including clonic convulsions and grand mal convulsions), paranoia, amnesia, depressed level of consciousness, loss of consciousness
Frequency unknown: Impaired coordination

Eye disorders
Less Frequent: Blurred vision, miosis
Frequency unknown: Amblyopia

Ear and labyrinth disorders
Frequent: Vertigo

Cardiac disorders
Frequent: Palpitations, tachycardia
Less Frequent: Bradycardia, cyanosis
Frequency unknown: Dysrhythmia

Vascular disorders
Frequent: Hypertension
Less Frequent: Hypotension, vasodilation

Respiratory, thoracic and mediastinal disorders
Frequent: Dyspnoea
Less Frequent: Respiratory problems, including asthma, respiratory depression, respiratory distress, apnoea, hypoventilation
Frequency unknown: Bradypnea

Gastrointestinal disorders
Frequent: Nausea, vomiting, constipation, diarrhoea, dry mouth, abdominal pain, abdominal pain upper, dyspepsia
Less frequent: Ileus, subileus
Frequency unknown: Hiccups, painful flatulence

Skin and subcutaneous tissue disorders
Frequent: Diaphoresis, hyperhidrosis, pruritus, rash, erythema
Less frequent: Exanthema, eczema, dermatitis allergic, skin disorder, dermatitis, dermatitis contact
Rash, erythema and pruritus will usually disappear within one day after the patch has been removed.

Musculoskeletal and connective tissue disorders
Frequent: Muscle spasms
Less frequent: Muscle twitching

Renal and urinary disorders
Frequent: Urinary retention
Frequency unknown: Cystalgia, oliguria

Reproductive system and breast disorders
Less frequent: Erectile dysfunction, sexual dysfunction

General disorders and administrative site conditions:
Frequent: Oedema peripheral, asthenia, feeling cold, fatigue, malaise
Less frequent: Medicine withdrawal syndrome, application site reaction (usually subside within 24 hours after removing the patch), influenza like illness, feeling of body temperature change, application site hypersensitivity, pyrexia*, application site dermatitis, application site eczema
* the assigned frequency is based on analyses of incidence including only adult and paediatric clinical study subjects with non - cancer pain.
Frequency unknown: drug tolerance

Symptoms: CNS depression which manifests as stupor, coma, respiratory depression including Cheyne - Stokes breathing and/or cyanosis. Hypothermia and/or clammy skin, flabby skeletal muscles, bradycardia as well as hypotension. Acute intoxication displays as profound sedation, ataxia, miosis, respiratory depression and cramps, with special emphasis on respiratory depression. Depending on the extent of respiratory depression, a further intensive care treatment may be necessary.

Treatment: For management of respiratory depression, immediate countermeasures include removing the FENDERMAL patch and verbally or physically 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 intravenous 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. Depending on the extent of respiratory depression, a further intensive care treatment may be necessary. 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. Atropine may be used to block the vagal effects such as bradycardia.