Osmach 75 Micrograms/H Transdermal Patch
SUMMARY OF PRODUCT CHARACTERISTICS
1 NAME OF THE MEDICINAL PRODUCT
Osmach 75 micrograms/h transdermal patch
2 QUALITATIVE AND QUANTITATIVE COMPOSITION
Each patch releases 75 micrograms fentanyl per hour. Each patch of 22.5 cm contains 12.375 mg fentanyl.
For the full list of excipients, see section 6.1.
3 PHARMACEUTICAL FORM
Transdermal patch
Transparent and colourless patch with blue imprint on the backing foil: “fentanyl 75 pg/h“
4 CLINICAL PARTICULARS
4.1 Therapeutic indications
Adults:
Osmach transdermal patch is indicated in severe chronic pain which can be adequately managed only with opioid analgesics.
Children:
Long term management of severe chronic pain in children receiving opioid therapy from 2 years of age.
4.2 Posology and method of administration
Posology
Adults
Initial dose selection
It is recommended that fentanyl be used in patients who have previously tolerated opioids. The initial fentanyl dose should be based on the patient’s opioid history, including the degree of opioid tolerance, if any, as well as on the current general condition and medical status of the patient.
In strong opioid-naive patients, fentanyl dose 12.5 pg/h, should be used as the initial dose.
Clinical experience with fentanyl is limited in opioid-naive patients. If therapy with fentanyl is considered appropriate in opioid-naive patients, it is recommended that these patients be titrated with low doses of short-acting opioids initially. Patients can then be converted to fentanyl 25 mcg/hr. The dose may subsequently be titrated upwards or downwards, if required, in increments of 12 or 25 mcg/hr to achieve the lowest appropriate dose of fentanyl depending on the response and supplementary analgesic requirements (see also section 4.4).
Switching from other opioids
When changing over from oral or parenteral opioids to fentanyl treatment, the initial dosage should be calculated as follows:
1. The quantity of analgesics required over the last 24 hours should be determined.
2. The obtained sum should be converted to correspond the oral morphine dosage using Table 1.
3. The corresponding fentanyl dosage should be determined as follows:
a) using Table 2 for patients who have a need for opioid rotation (conversion ratio of oral morphine to transdermal fentanyl equal to150:1)
b) using Table 3 for patients on stable and well tolerated opioid therapy (conversion ratio of oral morphine to transdermal fentanyl equal to 100:1)
All dosages given in the table are equivalent in analgesic effect to 10 mg parenteral morphine.
Table 1: Equianalgesic potency conversion
|
Equianalgesic doses (mg) | ||
|
Active substance |
Parenteral (im) |
Oral |
|
Morphine |
10 |
30-40 |
|
Hydromorphone |
1.5 |
7.5 |
|
Oxycodone |
10-15 |
20-30 |
|
Methadone |
10 |
20 |
|
Levorphanol |
2 |
4 |
|
Oxymorphine |
1 |
10 (rectal) |
|
Diamorphine |
5 |
60 |
|
Pethidine |
75 |
- |
|
Codeine |
- |
200 |
|
Buprenorphine |
0.4 |
0.8 (sublingual) |
|
Ketobemidone |
10 |
20-30 |
In opioid-tolerant patients, the initial dose of fentanyl should be based on the previous 24 hour opioid analgesic requirement. A recommended conversion scheme from oral morphine to fentanyl is given below in table 2:
Table 2: Recommended fentanyl dose based upon daily oral morphine dose (for patients who have a need for opioid rotation)1
|
Oral 24-hour morphine (mg/day) |
Fentanyl (yg/h) |
|
< 90 |
25 |
|
90 - 134 |
37 |
|
135 - 189 |
50 |
|
190 - 224 |
62 |
|
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 |
|
Oral morphine dose (mg/24 h) |
Transdermal fentanyl release (micrograms/h) |
|
< 44 |
12.5 |
|
45-134 |
25 |
|
135-224 |
50 |
|
225-314 |
75 |
|
315-404 |
100 |
|
405-494 |
125 |
|
495-584 |
150 |
|
585-674 |
175 |
|
675-764 |
200 |
|
765-854 |
225 |
|
855-944 |
250 |
|
945-1034 |
275 |
|
1035-1124 |
300 |
By combining several transdermal patches, a fentanyl release rate of over 100 micrograms/h can be achieved.
The initial evaluation of the maximum analgesic effect of Osmach transdermal patch should not be made before the patch has been worn for 24 hours. This is due to the gradual increase in serum fentanyl concentrations during the first 24 hours after application of the patch.
In the first 12 hours after changing to Osmach transdermal patch the patient continues to receive the previous analgesic at the previous dose; over the next 12 hours this analgesic is administered according to need.
Dose titration and maintenance therapy
The fentanyl patch should be replaced every 72 hours. The dose should be titrated individually until analgesic efficacy is attained. If analgesia is insufficient at the end of the initial application period, the dose may be increased. Dose adjustment, when necessary, should normally be performed in the following titration steps from 12.5 pg/h up to 75 pg/h: 12.5pg/h, 25 pg/h, 37 pg/h, 50 pg/h, 62 pg/h and 75 pg/h; thereafter dose adjustments should normally be performed in 25 pg/h increments, although the supplementary analgesic requirements (oral morphine 90 mg/day -fentanyl 25 pg/h) and pain status of the patient should be taken into account. More than one fentanyl patch may be used to achieve the desired dose. Patients may require periodic supplemental doses of a short-acting analgesic for ‘breakthrough’ pain. Additional or alternative methods of analgesia or alternative administration of opioids should be considered when the Osmach transdermal patch dose exceeds 300 micrograms/hour.
Withdrawal symptoms have been reported when changing from long-term treatment with morphine to transdermal fentanyl despite adequate analgesic efficacy. In case of withdrawal symptoms it is recommended to treat those with short-acting morphine in low doses.
Discontinuation of fentanyl
If discontinuation of the patch is necessary, any replacement with other opioids should be gradual, starting at a low dose and increasing slowly. This is because fentanyl levels fall gradually after the patch is removed.
After system removal, serum fentanyl concentrations decline gradually with mean terminal half-life ranging from 13-25 hours in adults and 22-25 hours in children ( see section 5.2). As a general rule, the discontinuation of opioid analgesia should be gradual, in order to prevent withdrawal symptoms Tables 2 and 3 should not be used to switch from transdermal fentanyl to a morphine treatment.
Opioid withdrawal symptoms (see section 4.8) are possible in some patients after conversion or dose adjustment.
Method of administration
As the transdermal patch is protected by an outer waterproof backing film, it can also be worn while showering.
Occasionally, additional adhesion of the patch may be required.
Fentanyl 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 fentanyl 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. Patches should be inspected prior to use. Patches that are cut, divided, or damaged in any way should not be used.
Fentanyl should be applied immediately after removal from the sealed pouch. Avoid touching the adhesive side of the patch. 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.
Fentanyl 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.
The need for continued treatment should be assessed at regular intervals.
Duration of administration
The patch should be changed after 72 hours. If an earlier change becomes necessary in individual cases, no change should be made before 48 hours have elapsed, otherwise a rise in mean fentanyl concentrations may occur. A new skin area must be selected for each application. A period of 7 days should be allowed to elapse before applying a new patch to the same area of skin. The analgesic effect may persist for some time after removal of the transdermal patch.
If traces of the transdermal patch remain on the skin after its removal, these can be cleaned off using copious amounts of soap and water. No alcohol or other solvents must be used for cleaning, as these may penetrate the skin due to the effect of the patch.
Paediatric population
Children aged 16 years and above: follow adult dosage Children aged 2 to 16 years old:
Osmach transdermal patches 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.
To convert paediatric patients from oral opioids to Osmach transdermal patches, refer to Table 4 “Recommended Osmach transdermal patch dose based upon daily oral morphine dose
Table 4: Recommended Osmach transdermal patch dose based upon daily oral morphine dose1_
|
Oral 24-Hour Morphine (mg/day) |
Osmach transdermal patch (pg/h) |
|
For paediatric patients2 | |
|
30 - 44 |
12.5 |
|
45-134 |
25 |
:In clinical trials these ranges of daily oral morphine doses were used as a basis for conversion to Osmach transdermal patch.
2
Conversion to Osmach transdermal patch doses greater than 25 pg /h is the same for adult and paediatric patients (see also table 2).
For children who receive more than 90 mg oral morphine a day, only limited information is currently available from clinical trials. In the paediatric studies, the required fentanyl transdermal patch dose was calculated conservatively: 30 mg to 44 mg oral morphine per day or its equivalent opioid dose was replaced by one Osmach 12pg/h patch. It should be noted that this conversion schedule for children only applies to the switch from oral morphine (or its equivalent) to Osmach transdermal patches. The conversion schedule should not be used to convert from Osmach transdermal patches into other opioids, as overdosing could then occur.
The analgesic effect of the first dose of Osmach transdermal patches will not be optimal within the first 24 hours. Therefore, during the first 12 hours after switching to Osmach transdermal patches, the patient should be given the previous regular dose of analgesics. In the next 12 hours, these analgesics should be provided based on clinical need.
Since peak fentanyl levels occur after 12 to 24 hours of treatment, monitoring of the patient for adverse events, which may include hypoventilation, is recommended for at least 48 hours after initiation of Osmach transdermal patch therapy or up-titration of the dose (see also section 4.4).
Dose titration and maintenance
If the analgesic effect of transdermal fentanyl 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 use more patches. Dose adjustments should be done in 12.5 pg /h steps.
Use in elderly patients
Elderly should be observed carefully and the dose reduced if necessary (see sections 4.4 and 5.2).
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. Studies of fentanyl in elderly patients demonstrated fentanyl pharmacokinetics which did not differ significantly from young patients although serum concentrations tended to be higher. Elderly, cachectic, or debilitated patients should be observed carefully for signs of fentanyl toxicity and the dose reduced if necessary.
Hepatic and renal impairment
Patients with hepatic or renal impairment should be observed carefully and the dose reduced if necessary (see section 4.4).
4.3 Contraindications
- Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
- Acute or postoperative pain, since dosage titration is not possible during short-term use.
- Severe impairment of the central nervous system.
- Severe respiratory depression
4.4 Special warnings and precautions for use
The product should be used only as part of an integrated treatment of pain in cases where the patient is adequately assessed medically, socially and psychologically.
Fentanyl patch should not be used in the management of acute or postoperative pain since there is no opportunity for dose titration during short-term use and because serious or life threatening hypoventilation could result.
Treatment with Osmach transdermal patch should only be initiated by an experienced physician familiar with the pharmacokinetics of Osmach transdermal patches and the risk for severe hypoventilation.
Patients who have experienced serious adverse events should be monitored for up to 24 hours after fentanyl patch removal since serum fentanyl concentrations decline gradually and are reduced by about 50% 17 (range 13-22) hours later.
Fentanyl patch should be kept out of reach of children before and after use.
In chronic non-cancer pain, it might be preferable to initiate the treatment with immediate-release strong opioids (e.g. morphine) and to prescribe Osmach transdermal patch after determination of the efficacy and the optimal dosage of the strong opioid.
Do not cut fentanyl patches. A patch that has been divided, cut, or damaged in any way should not be used.
If higher dosages than 500 mg morphine-equivalent are needed, a reassessment of opioid-therapy is recommended.
The most common adverse reactions following administration at usual doses are drowsiness, confusion, nausea, vomiting and constipation. The first of these are transient and their cause should be investigated if symptoms persist. Constipation, on the other hand, does not stop if treatment continues. All of these effects can be expected and should, therefore, be anticipated in order to optimise treatment, especially constipation. Corrective treatment may often be required (see section 4.8).
Breakthrough pain
Studies have shown that almost all patients, despite treatment with a fentanyl patch, require supplemental treatment with potent rapid-release medicinal products to arrest breakthrough pain.
Respiratory depression
As with all potent opioids some patients may experience significant respiratory depression with Osmach transdermal patch, and 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 fentanyl dose is increased (see section 4.9). CNS active drugs may increase the respiratory depression (see section 4.5).
In patients with existing respiratory depression, fentanyl should only be used with caution and at a lower dose.
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
Tolerance, physical and psychological dependence may develop upon repeated administration of opioids, but is rare in treatment of cancer related pain. Iatrogenic addiction following opioid administration is rare. 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. Fentanyl can be abused in a manner similar to other opioid agonists. Abuse or intentional misuse of Osmach transdermal patch may result in overdose and/or death.
Increased intracranial pressure
Osmach transdermal 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. Osmach transdermal 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.
Opioids may cause hypotension, especially in patients with acute hypovolemia. 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 Osmach transdermal patch, they should be observed carefully for signs of fentanyl toxicity and the dose reduced if necessary (see section 5.2).
Renal impairment
Less than 10 % of fentanyl is excreted unchanged by the kidney, and unlike morphine, there are no known active metabolites eliminated by the kidney. Data obtained with intravenous fentanyl in patients with renal failure suggest that the volume of distribution of fentanyl may be changed by dialysis. This may affect serum concentrations. If patients with renal impairment receive transdermal fentanyl they should be observed carefully for signs of fentanyl toxicity and the dose reduced if necessary (see section 5.2).
Fever/external heat application
A pharmacokinetic model suggests that serum fentanyl concentrations may increase by about one-third if the skin temperature increases to 40 °C. Therefore, patients with fever should be monitored for opioid side 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. A clinical pharmacology trial conducted in healthy adult subjects has shown that the application of heat over the patch increased mean fentanyl AUC values by 120 % and mean Cmax values by 61 %.
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, intensive sunbathing, hot water bottles, prolonged hot baths, saunas and hot whirlpool spa baths.
Hypersensitivity
Hypersensitivity (including anaphylaxis and anaphylactic shock) has been reported in association with the use of fentanyl.
Interactions with other medicinal products Interactions with CYP3A4 inhibitors:
The concomitant use of Osmach transdermal patch 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.
Therefore, the concomitant use of transdermal fentanyl and CYP3A4 inhibitors is not recommended unless the patient is closely monitored. Patients, especially those who are receiving fentanyl transdermal patch and CYP3A4 inhibitors, should be monitored for signs of respiratory depression and dosage adjustments should be made if warranted.
Serotonin syndrome
Caution is advised when fentanyl is coadministered with drugs that affect the serotoninergic neurotransmitter systems.
The development of a potentially life-threatening serotonin syndrome may occur with the concomitant use of serotonergic drugs such as Selective Serotonin Re-uptake Inhibitors (SSRIs) and Serotonin Norepinephrine Re-uptake Inhibitors (SNRIs), and with drugs 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.
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 section 4.9).
Use in elderly patients
Data from intravenous studies with fentanyl suggest that elderly patients may have reduced clearance and a prolonged half-life and they may be more sensitive to the active substance than younger patients. If elderly patients receive transdermal fentanyl, they should be observed carefully and the dose reduced if necessary.
Paediatric population
Transdermal fentanyl should not be administered to opioid naive paediatric patients (see section 4.2). The potential for serious or life-threatening hypoventilation exists regardless of the dose of transdermal fentanyl administered.
Transdermal fentanyl was not studied in children under 2 years of age. Transdermal fentanyl should be administered only to opioid-tolerant children aged 2 years or older (see section 4.2). Transdermal fentanyl should not be used in infants and toddlers under 2 years of age.
To guard against accidental ingestion by children, use caution when choosing the application site for Osmach transdermal patch (see section 4.2 and section 6.6) and monitor adhesion of the patch closely.
Lactation
As fentanyl is excreted into breast milk, breast-feeding should be discontinued during treatment with Osmach transdermal patch (see also section 4.6).
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 agonists/antagonists
The concomitant use of buprenorphine, nalbuphine or pentazocine is not recommended (see also section 4.5).
Doping
The use of Osmach transdermal patches may lead to a positive doping test.
The use of fentanyl patches as a doping agent may be hazardous to the health.
4.5 Interaction with other medicinal products and other forms of interaction
The concomitant use of other central nervous system depressants, including opioids, sedatives, hypnotics, general anaesthetics, phenothiazines, tranquilizers, 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 these drugs concomitantly with Osmach transdermal patch requires special patient care and observation.
Fentanyl, a high clearance active substance, 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 (see also section 4.4).
Monoamine Oxidase Inhibitors (MAOI)
Osmach transdermal patch 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, Osmach transdermal patch should not be used within 14 days after discontinuation of treatment with MAOIs.
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 (see also section 4.4).
Serotonergic Drugs
Coadministration of fentanyl with a serotonergic agent, such as a selective Serotonin Reuptake Inhibitor or a Serotonin Norepinephrine Reuptake Inhibitor, may increase the risk of serotonin syndrome, a potentially life-threatening condition.
4.6 Fertility, pregnancy and lactation
Pregnancy
There are no adequate data from the use of fentanyl patch 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 anesthetic has been found to cross the placenta in early human pregnancies. Neonatal withdrawal syndrome has been reported in newborn infants with chronic maternal use of fentanyl patch during pregnancy.Fentanyl patch should not be used during pregnancy unless clearly necessary.
Use of fentanyl patch during childbirth is not recommended 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 fentanyl patch during childbirth might result in respiratory depression in the newborn infant.
Breastfeeding
Fentanyl is excreted into breast milk and may cause sedation and respiratory depression in the breastfed infant. Breastfeeding should not be restarted until at least 6 days after the last administration of fentanyl.
4.7 Effects on ability to drive and use machines
Osmach transdermal patch may impair mental and/or physical ability required for the performance of potentially hazardous tasks such as driving a car or operating machinery. This has to be expected especially at the beginning of treatment, at any change of dosage as well as in connection with alcohol or tranquilizers. Patients stabilized on a specific dosage will not necessarily be restricted. Therefore, patients should consult their physician as to whether driving or use of machines is permitted.
4.8 Undesirable effects
The safety of Osmach transdermal patch was evaluated in 1854 subjects who participated in 11 clinical trials (double-blind fentanyl transdermal patch [placebo or active control] and/or open label Osmach transdermal patch [no control or active control]) used for the management of chronic malignant or non-malignant pain. These subjects took at least 1 dose of fentanyl transdermal patch and provided safety data. Based on pooled safety data from these clinical trials, the most commonly reported adverse drug reactions (ADRs) were (with % incidence): nausea (35.7 %), vomiting (23.2 %), constipation (23.1 %), somnolence (15.0 %), dizziness (13.1 %), and headache (11.8 %).
The ADRs reported with the use of fentanyl transdermal patch from these clinical trials, including the above-mentioned ADRs, and from post-marketing experiences are listed below.
The displayed frequency categories use the following convention: very common (>1/10); common (>1/100 to <1/10); uncommon (>1/1,000 to <1/100); rare (>1/10,000 to <1/1,000); very rare (<1/10,000); and not known (cannot be estimated from the available clinical trial data).
|
System Organ Class |
Adverse Drug Reactions | |||||
|
Frequency Category | ||||||
|
Very Common |
Common |
Uncommon |
Rare |
Very Rare |
Not Known | |
|
Immune System Disorders |
Hypersensitivi ty |
Anaphylactic shock, Anaphylactic reaction, Anaphylactoi d reaction | ||||
|
Metabolism and Nutrition Disorders |
Anorexia | |||||
|
Psychiatric Disorders |
Insomnia, Depression, Anxiety, Confusional state, Hallucination, Sedation, Nervousness |
Agitation, Disorientation , Euphoric mood |
Delusional ideas, States of excitement | |||
|
Nervous System Disorders |
Somnolence, Dizziness, Headache |
Tremor, Paraesthesia |
Hypoaesthesi a, Convulsion (including clonic convulsions and grand mal convulsion), Amnesia, Speech disorder |
Ataxia | ||
|
Eye Disorders |
Miosis |
Amblyopia | ||||
|
Ear and Labyrinth Disorders |
Vertigo | |||||
|
Cardiac Disorders |
Palpitations, Tachycardia |
Bradycardia, Cyanosis |
Arrhythmia | |||
|
Vascular Disorders |
Hypertension |
Hypotension |
Vasodilatatio n | |||
|
Respirator y, Thoracic and Mediastinal Disorders |
Dyspnoea |
Respiratory depression, Respiratory distress |
Apnoea, Hypoventilati on |
Bradypnoea | ||
|
Gastrointes tinal Disorders |
Nausea, Vomiting, Constipation |
Diarrhoea, Dry mouth, Abdominal pain, Abdominal pain upper, Dyspepsia |
Ileus |
Subileus, Hiccup |
Painful flatulence | |
|
System Organ Class |
Adverse Drug Reactions | |||||
|
Frequency Category | ||||||
|
Very Common |
Common |
Uncommon |
Rare |
Very Rare |
Not Known | |
|
Skin and Subcutaneo us Tissue Disorders |
Hyperhidrosis, Pruritus, Rash, Erythema *, Skin reactions on the application site |
Eczema, Dermatitis allergic, Skin disorder, Dermatitis, Dermatitis contact, Exanthema | ||||
|
Musculoske letal and Connective Tissue Disorders |
Muscle spasms |
Muscle twitching | ||||
|
Renal and Urinary Disorders |
Urinary retention |
Cystalgia, Oliguria | ||||
|
Reproducti ve System and Breast Disorders |
Erectile dysfunction, Sexual dysfunction | |||||
|
General Disorders and Administra tion Site Conditions |
Fatigue, Oedema peripheral, Asthenia, Malaise, Feeling cold |
Application site reaction, Influenza like illness, Feeling of body temperature change, Application site hypersensitivi ty, Drug withdrawal syndrome |
Application site dermatitis, Application site eczema | |||
* Rash, erythema and pruritus will usually disappear within one day after the patch has been removed.
As with other opioid analgesics, tolerance, physical dependence, and psychological dependence can develop on repeated use of Osmach transdermal patch (see section 4.4).
Opioid withdrawal symptoms (such as nausea, vomiting, diarrhoea, anxiety, and shivering) are possible in some patients after conversion from their previous opioid analgesic to Osmach transdermal patch or if therapy is stopped suddenly (see section 4.2). There have been very rare reports of newborn infants experiencing neonatal withdrawal syndrome when mothers chronically used Osmach transdermal patch during pregnancy (see section 4.6).
The adverse event profile in children and adolescents treated with transdermal fentanyl was similar to that observed in adults. No risk was identified in the paediatric population beyond that expected with the use of opioids for the relief of pain associated with serious illness and there does not appear to be any paediatric-specific risk associated with transdermal fentanyl use in children as young as 2 years old when used as directed. Very common adverse events reported in paediatric clinical trials were fever, vomiting, and nausea.
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard.
4.9 Overdose
Symptoms
The manifestations of fentanyl overdosage are an extension of its pharmacological actions, e.g. lethargy, coma, respiratory depression with Cheyne-Stokes respiration and/or cyanosis. Other symptoms may be hypothermia, decreased muscle tonus, bradycardia, hypotension. Signs of toxicity are deep sedation, ataxia, miosis, convulsions and respiratory depression, which is the main symptom.
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.
A starting dose of 0.4-2 mg naloxone hydrochloride i.v. is recommended for adults. If needed, a similar dose can be given every 2 or 3 minutes, or be administered as continued infusion as 2 mg in 500 ml sodium chloride 9 mg/ml (0.9%) solution for injection or glucose 50 mg/ml (5%) solution. The infusion rate should be adjusted according to previous bolus injections and the individual response of the patient. If intravenous administration is impossible, naloxone hydrochloride can also be given intramuscularly or subcutaneously. Following intramuscular or subcutaneous administration the onset of action will be slower compared with intravenous administration. Intramuscular administration will give a more prolonged effect than intravenous administration.
Respiratory depression following an overdose may outlast the duration of action of the opioid antagonist. The interval between i.v. antagonist doses should be carefully chosen because of the possibility of re-narcotization 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.
Intensive care unit treatment is important, if required by the patient’s clinical condition.
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, hypovolemia should be considered, and the condition should be managed with appropriate parenteral fluid therapy.
5 PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: opioids; Phenylpiperidine derivatives ATC code: N02AB03
Fentanyl is an opioid analgesic with affinity mainly to the p-receptor. Its principal therapeutic effects are analgesia and sedation. The serum concentrations of fentanyl that cause a minimal analgesic effect in opioid-naive patients fluctuate between 0.31.5 ng/ml; an increased incidence of adverse reactions is observed if serum levels exceed 2 ng/ml.
Both the lowest effective fentanyl concentration and the concentration causing adverse reactions will increase with the development of increasing tolerance. The tendency to develop tolerance varies considerably between individuals.
Paediatric population
The safety of Osmach transdermal patch was evaluated in three open-label trials in 293 paediatric patients with chronic pain, 2 years of age through to 18 years of age, of which 66 children were aged 2 to 6 years. In these studies, 30 mg to 45 mg oral morphine per day was replaced by one Osmach 12.5 micrograms/h transdermal patch. Starting doses of 25 micrograms/h and higher were used by 181 patients who had been on prior daily opioid doses of at least 45 mg of oral morphine.
5.2 Pharmacokinetic properties
Following administration of Osmach transdermal patch, fentanyl is continuously absorbed through the skin over a period of 72 hours. Due to the polymer matrix and the diffusion of fentanyl through the skin layers, the release rate remains relatively constant.
Absorption
After the first application of Osmach transdermal patch, serum fentanyl concentrations increase gradually, generally levelling off between 12 and 24 hours, and remaining relatively constant for the remainder of the 72-hour application period. The serum fentanyl concentrations attained are dependent on the Osmach transdermal patch size. By the second 72-hour application, a steady state serum concentration is reached and is maintained during subsequent applications of a patch of the same size.
Distribution
The plasma protein binding for fentanyl is 84 %.
Biotransformation
Fentanyl is metabolised primarily in the liver via CYP3A4. The major metabolite, norfentanyl, is inactive.
Elimination
When treatment with Osmach transdermal patch is withdrawn, serum fentanyl concentrations decline gradually, falling approximately 50 % in 13-22 hours in adults or 22-25 hours in children, respectively. Continued absorption of fentanyl from the skin accounts for a slower reduction in serum concentration than is seen after an intravenous infusion.
Around 75 % of fentanyl is excreted into the urine, mostly as metabolites, with less than 10 % as unchanged active substance. About 9 % of the dose is recovered in the faeces, primarily as metabolites.
Pharmacokinetics in special groups
Elderly and debilitated patients may have reduced clearance of fentanyl leading to prolonged terminal half life. In patients with renal or hepatic impairment, clearance of fentanyl may be altered because of changes of plasma proteins and metabolic clearance resulting in increased serum concentrations.
Paediatric population
Adjusting for body weight, clearance (l/h/kg) in paediatric patients, appears to be 82 % higher in children 2 to 5 years old and 25 % higher in children 6 to 10 years old when compared to children 11 to 16 years old, who are likely to have the same clearance as adults. These findings have been taken into consideration in determining the dosing recommendations for paediatric patients.
5.3 Preclinical safety data
Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity and genotoxicity.
Animal studies have shown reduced fertility and increased mortality in rat foetuses. Teratogenic effects have, however, not been demonstrated.
Long-term carcinogenicity studies have not been performed.
6 PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Adhesive layer
Backing film Polypropylene foil Blue printing ink
Release liner
Polyethylene terephthalate foil (siliconised)
6.2 Incompatibilities
Not applicable.
6.3 Shelf life
3 years
6.4 Special precautions for storage
This medicinal product does not require any special storage conditions.
6.5 Nature and contents of container
Each transdermal patch is packed in a separate sachet.
- Sachets made of composite foil containing the following layers from outside to inside:
coated Kraft paper, low density polyethylene foil, aluminium foil, Surlyn (thermoplastic ethylene-methacrylic acid copolymer).
Pack containing 3, 5, 10 or 20 transdermal patches
- Child resistant sachets made of composite foil containing the following layers from outside to inside:
PET foil, adhesive, aluminium foil, adhesive, Surlyn (ionomer-coex foil).
Pack containing 3, 5, 10 or 20 transdermal patches
- Child resistant sachets made of composite foil containing the following layers from outside to inside:
paper, adhesive, PET, Polymer, AL, Ionomer Pack containing 3, 5, 10 or 20 transdermal patches Not all pack sizes may be marketed.
6.6 Special precautions for disposal
High quantities of fentanyl remain in the transdermal patches even after use. Used patches should be folded so that the adhesive side of the patch adheres to itself and then they should be safely discarded. Unused patches should be returned to the (hospital) pharmacy.
7 MARKETING AUTHORISATION HOLDER
Ratiopharm GmbH Graf-Arco-Str.3 89079 Ulm Germany
8 MARKETING AUTHORISATION NUMBER(S)
PL 15773/0621
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
24/03/2011
10 DATE OF REVISION OF THE TEXT
24/03/2015
In clinical trials these ranges of daily oral morphine doses were used as a basis for conversion to fentanyl transdermal patches
Previous analgesic therapy should be phased out gradually from the time of the first patch application until analgesic efficacy with fentanyl is attained. For both strong opioid-naive and opioid tolerant patients, the initial evaluation of the analgesic effect of fentanyl should not be made until the patch has been worn for 24 hours due to the gradual increase in serum fentanyl concentrations up to this time.
Table 3: Recommended initial dose of transdermal fentanyl based on daily oral morphine dose (for patients who have a need for opioid rotation)