Zusammenfassung der Merkmale des Arzneimittels - Olmetec Plus 20 mg/25 mg
<Fentanyl Generic> 12 micrograms/hour transdermal patch
<Fentanyl Generic> 25 micrograms/hour transdermal patch
<Fentanyl Generic> 50 micrograms/hour transdermal patch
<Fentanyl Generic> 75 micrograms/hour transdermal patch
<Fentanyl Generic> 100 micrograms/hour transdermal patch
2. QUALITATIVE AND QUANTITATIVE COMPOSITION
<Fentanyl Generic> 12 micrograms/hour: 1 transdermal patch contains 2.55 mg fentanyl in a patch size of 4.25 cm2 and releases 12.5 micrograms fentanyl per hour
Excipient: soya oil
<Fentanyl Generic> 25 micrograms/hour: 1 transdermal patch contains 5.1 mg fentanyl in a patch size of 8.5 cm2 and releases 25 micrograms fentanyl per hour
Excipient: soya oil
<Fentanyl Generic> 50 micrograms/hour: 1 transdermal patch contains 10.2 mg fentanyl in a patch size of 17 cm2 and releases 50 micrograms fentanyl per hour
Excipient: soya oil
<Fentanyl Generic> 75 micrograms/hour: 1 transdermal patch contains 15.3 mg fentanyl in a patch size of 25.5 cm2 and releases 75 micrograms fentanyl per hour
Excipient: soya oil
<Fentanyl Generic> 100 micrograms/hour: 1 transdermal patch contains 20.4 mg fentanyl in a patch size of 34 cm2 and releases 100 micrograms fentanyl per hour
Excipient: soya oil
For a full list of excipients, see sectio
3. PHARMACEUTICAL FORM
Transdermal patch
Opaque, colourless, rectangular shaped patch with round corners and imprint on the backing foil: “fentanyl 12µg/h” in single sealed sachets.
Opaque, colourless, rectangular shaped patch with round corners and imprint on the backing foil: “fentanyl 25µg/h” in single sealed sachets.
Opaque, colourless, rectangular shaped patch with round corners and imprint on the backing foil: “fentanyl 50µg/h” in single sealed sachets.
Opaque, colourless, rectangular shaped patch with round corners and imprint on the backing foil: “fentanyl 75µg/h” in single sealed sachets.
Opaque, colourless, rectangular shaped patch with round corners and imprint on the backing foil: “fentanyl 100µg/h” in single sealed sachets.
4. CLINICAL PARTICULARS
4.1 Therapeutic indications
Chronic pains which can only be treated adequately and effectively with opioid-analgetics.
4.2 Posology and method of administration
<Fentanyl Generic> transdermal patches release fentanyl for a period of 72 hours
For the determination of the appropriate dose for the treatment of chronic pain, the analgetic which has been administered so far must be taken into consideration. The dose, effectiveness and possible tolerance development are adducted for the calculation of the quantity of fentanyl required.
Initial adjustment in opioid-naive patients
In the case of patients who have not received strongly active opioids so far, the therapy should commence with the lowest concentration of the active substance.
Changes from other intensively active 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 dosage given in the table are equivalent in analgesic effect to 10 mg parenteral morphine.
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 |
Tab. 2: Recommended initaial dose of transdermal fentanyl based on daily oral morphine dose (for patients who have a need for opioid rotation)
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 |
Tab. 3: Recommended initial dose of transdermal fentanyl based on daily oral morphine dose (for patients on stable and well tolerated opioid therapy)
| Oral morphine dose (mg/24 h) | → | Transdermal fentanyl release (micrograms/h) |
| < 60 | 12.5 | |
| 60–89 | 25 | |
| 90–149 | 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 |
Additional or alternative methods of analgesic treatment should be considered if the required dosage exceeds 300 microgram fentanyl per hour. For use in children fentanyl dosage finding is given in table 4.
In the case of inital adjustment and changing from other analgetics, the maximum analgetic effect can not be evaluated until ca. 24 hours have elapased, as the fentanyl level in the blood rises only gradually.
In the first 12 hours after the changing to the fentanyl transdermal patches the patient should still receive the same dose of the analgetic he has taken so far for the next 12 hours depending on requirements.
Dose adjustment in Fever:
Dosage adaptation may be required in these patients during feverish periods
Dose adjustment and long-term therapy:
After this period, only if necessary, a morphine solution or an equivalent short-term active opioid should only be administered in addition to the fentanyl transdermal patch (e.g. on the occurrence of severe pain).
As the dose calculation using the table above is intentionally done with a relatively low concentration of fentanyl, a supplementary intake of analgetics during the initial application period with fentanyl transdermal patches may be necessary. A subsequent increase of the dose of fentanyl (using a higher dosage or a supplementary transdermal patch) is possible without problems, but not earlier than 72 hours after the application of the fentanyl transdermal patch to prevent an unperceived accumulation of the activesubstance. The necessary transdermal patch strength is calculated using the regularly required quantity of analgetic in addition to the previously applied patch according to the table above.
The essential dose should be harmonized with the requirements of the patient and reviewed at regular intervals.
Change or termination of the therapy
In case of a long-term application it is expected that withdrawal symptoms may arise as a result of abrupt termination of the treatment or a sudden reduction in the dose.
If a change of therapy from fentanyl to another strongly active analgetic is intended, this product should be administered at half the dose specified in the table following the removal of the transdermal patch; the dose will then be adjusted appropriately according to the severity of pain experienced by the patient. If the treatment is terminated, the dose must be reduced gradually to prevent withdrawal symptoms.
Children
<Fentanyl Generic> 12 micrograms/h 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. 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 calculate conservatively: 30 mg to 45 mg oral morphine per day or its equivalent opioid dose was replaced by one fentanyl 12.5 micrograms/h patch. To convert paediatric patients from oral opioids to <Fentanyl Generic> 12 micrograms/h refer to Table 4 Recommended <Fentanyl Generic> 12 micrograms/h dose based upon daily oral morphine dose.
| Oral morphine (mg/24 hour) | Trans-dermal fentanyl Dose (mg/24 hour) | Transdermal fentanyl Release (µg/hour) | Transdermal fentanyl Absorption area (cm2) |
| 30–44 | 0.3 | 12,5 | 4.25 |
| 45–90 | 2×0,3 | 2× 12,5 | 2× 4.25 |
In young children, the upper back is the preferred location to apply the patch, to minimize the potential of the child removing the patch.
The analgesic effect of the first dose of fentanyl patches will not be optimal within the first 24 hours. Therefore, during the first 12 hours after switching to fentanyl, 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.
Conversion to Fentanyl doses greater than 25 μg/h is the same for adult and paediatric patients.
It should be noted that this conversion schedule for children only applies to the switch from oral morphine (or its equivalent) to Fentanyl transdermal patches. The conversion schedule should not be used to convert from Fentanyl into other opioids, as overdosing could then occur.
If the analgesic effect of <Fentanyl Generic> 12 micrograms/h 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 μg/hour steps.
The fentanyl transdermal patch should not be used for the treatment of children under 12 years of age unless the physician has explicitly prescibed the transdermal patch; as experience in the treatment of children is still very limited.
Because the dose is too high, the fentanyl transdermal patch is not recommended for use in children under the age of 12, unless the physician has explicity prescribed this particular transdermal patch.
Note
As the fentanyl serum level increases slowly, the initial adjustment or an increase of the dose should be carried out at a time which permits an extended vigilance control. If this cannot be guaranteed the initial dose adjustment should be carried out in a hospital to monitor the patients for adverse events, which may include hypoventilation, especially in children it is recommended for at least 48 hours after initiation of Fentanyl therapy or up-titration of the dose (see also section 4.4).
The recommended doses may be adjusted individually. The conversion tables are based upon the limited experience gained so far in clinical studies. In patients suffering from extreme pain higher doses may be used. In principle, the lowest dose necessary to maintain the required analgetic effect should be selected.
Method of administration
Immediately after the fentanyl transdermal patch has been removed from the package and the release film as well as both sections of the backing film have been detached, the transdermal patch is attached to a hairless part of the skin or a part from which the hair has been removed (with scissors, razors should not be used) of the upper body (chest, back, upper arm).
The skin should be cleaned carefully with clean water and thoroughly dried before the transdermal patch is attached (detergents or cleaning agents should not be used!). The transdermal patch is then adhered to the skin with the flat hand with a light pressure (for ca. 10–30 seceonds). It must be ensured that the application area does not show any microlesions (e.g. due to radiation or shaving) or irritation.
As the outside of the transdermal patch is protected by a waterproof foil, the transdermal patch needs not be removed to take a shower.
The transdermal patch should not be damaged, divided or cut up, as this may result in an uncontrolled release of fentanyl.
No creams, oils, lotions or powders should be applied to the application area as they may impair the effective adhesion of the of the transdermal patch to the skin.
Occasionally an additonal fixation of the transdermal patch may be required.
The required application area may limit a progressive increase of the dose.
Duration of use
The transdermal patch should be changed after a period of 72 hours. If necessary in individual cases, the transdermal patch may be changed earlier but not earlier than 48 hours after application, as the this could cause an increase in the mean serum concentration of fentanyl. A new skin area must be selected for every application. However, an area of skin can be used again to apply the transdermal patch, if 7 days have passed since the removal of the transdermal patch. The analgetic effect may persist for some time after the transdermal patch has been removed.
If residuals are found on the skin after the patch has been removed , they can be removed with lots of soap and water. The cleaning should not be performed using alcohol or other solvents, as these may penetrate the skin based on the specific effects of the transdermal patch.
4.3 Contraindications
Fentanyl must not be used in the case of:
– hypersensitivity to fentanyl, peanut or soya or to any of the excipients of the transdermal patch
– short term painful conditions, e.g. following surgery
– bradycardial arrhythmia
– seriously impaired CNS-function
4.4 Special warnings and precautions for use
As strongly active opioids can induce repiratory depression, fentanyl should be administered with caution and only at low doses to patients suffering from
– existing respiratory depression (e.g. as a result of other medical treatments, uremia or serious infections)
– chronic obstructive lung disease (e.g. chronic obstructive bronchitis, bronchial asthma and in general in patients suffering from significantly restricted respiratory reserve)
– impaired liver or kidney function.
The adminstration of opioids may increase the resistance in the respiratory tract in such patients.
A particularly careful medical supervison is essential in the case of
– patients who are particularly susceptible to CO2-retention (head injuries, brain tumours, with
– signs of of increased intracranial pressure, patients suffering from reduced consciousness
– or in coma). In such cases opioids may conceal the clinical course of head injuries.
– Patients suffering from drug or alcohol dependence.
The fentanyl transdermal patch should be used in the treatment of children under the age of 12 only following a stringent evaluation of the risk / benefit ratio due to the limited clinical experience in these children.
In elderly patients, the renal clearance is possibly reduced leading to a prolonged half-life, and these patients may react more sensitive to the substance than younger patients. In clinical trials with a fentanyl transdermal patch, the kinetic parameters of fentanyl did not differ significantly from those of younger patients although the serum concentrations tended to be higher in elederly patients.. Elderly patients should be closely observed for signs of over dose, and the dose should be reduced if necessary.
As fentanyl is metabolized in the liver, liver diseases may delay its excretion. Patients suffering from impairment of the liver or kidney function, weakened patients or patients with a low body weight should be closely monitored for signs of overdose, and the dose should be reduced, if necessary.
This medicinal product should only be used under the surveillance of physicians who are experienced in the field of pain therapy.
In case of a change of the fentanyl-containing system, additional medical supervison and information of the patient is advised to maintain continuous reduction of pain (if necessary in the same manner as in the initial adjustment).
If respiratory depression occurs during the treatment with fentanyl, the transdermal patch must be removed immediately and the patient must be kept awake and verbally encouraged to breathe until medical aid has arrived. As transdermally administered fentanyl has a half-life of 17 hours, the continuation or re-occurrence of a respiratory depression must be anticipated even after the transdermal patch has been removed. Patients suffering from severe undesirable effects, should be monitored carefully for at least 24 hours after the removal of the patch, whereby special attention must be paid to the respiration rate and the depth of sedation.
Respiratory depression may also persist after the removal of the transdermal patch. The probability of this undesirable effect increases with dose. Centrally depressant medicinal products may enhance this effect.
Fever/external heat application
In a pharmacokinetic model, evidence was seen that the blood concentration of fentanyl may possibly increase by one third, when the skin temperature rises to 40°C. For this reason febrile patients must be closely monitored for undesirable effects, and the dose of fentanyl must be adapted if necessary. It must be ensured that the application site is not exposed to sources of heat (the adherence may also be impaired). This includes heated cushions and electric blankets, heated water beds, radiant heaters, intensive sunbathing, saunas and hot (whirlpool) baths.
Use in paediatric patients
<Fentanyl Generic> 12 micrograms/h should not be administered to opioid naïve paediatric patients (see section 4.2). The potential for serious or life-threatening hypoventilation exists regardless of the dose of fentanyl transdermal patch administered (see table 4 in section 4.2).
Fentanyl transdermal patch has not been studied in children under 2 years of age and so should not be used in these children. <Fentanyl Generic> 12 micrograms/h should be administered only to opioidtolerant children age 2 years or older (see section 4.2).
To guard against accidental ingestion by children, use caution when choosing the application site for <Fentanyl Generic> 12 micrograms/h (see section 4.2) and monitor adhesion of the patch closely.
4.5 Interaction with other medicinal products and other forms of interaction
The following interactions of this medicinal product must be taken into account:
The sedating effect can be enhanced upon simultaneous adminstration of other central depressant medicinal products, such as opioids, sedatives or hypnotics, general anaesthetics and muscle relaxants, phenothiazines, tranquilizers, sedating antihistamines or alcohol. The occurrence of respiratory depression, changes in the blood pressure and deep sedation or coma is also possible. If a treatment with fentanyl in combination with one of the above listed medicinal products is taken into consideration, the dose of one or both of the medicinal products should be reduced.
Fentanyl, a substance with a high clearance, is rapidly and extensively metabolized mainly via Cytochrom-P450–3A4.
In case of simultaneous use with other active substances which inhibit this metabolic pathway such as erythromycin, itraconazol, ketoconazol, diltiazem, cimetidin, the duration of activity and the frequency of undesirable effects may be affected.
No significant effects on the pharmacokinetics of intravenously administered fentanyl were observed upon concurrent oral administration of itraconazol at 200 mg/d for 4 days.
A reduction of the clearance of intravenously administered fentanyl by two thirds has been observed upon concurrent oral administration of ritonavir, one of the strongest Cytochrom-P450–3A4 inhibitors. The plasma level of fentanyl may be so high that therapeutical effects and undesirable effects may be enhanced or prolonged. Severe respiratory depression may be the consequence. In this situation, special care and supervision of the patient is essential. The concurrent administration of ritonavir or other strong Cytochrom-P450–3A4 inhibitors and fentanyl is not recommended without close monitoring of the patient.
As pethidin and monoaminoxidase inhibitors (e.g. tranylcypromin) aggravate their toxic properties reciprocally, a similar interaction with fentanyl can be anticipated.
Although pentazocin and buprenorphin are analgetics, they also partially antagonise some of the effects of fentanyl (e.g. the analgesia) and may also trigger withdrawal symptoms in opiod dependent patients.
Patients, who are treated with fentanyl, should not drink any alcohol.
4.6 Pregnancy and lacation
The safety of fentanyl in pregnancy has not been established. Studies in animals have shown reproductive toxicity (see section 5.3). The potential risk for humans is unknown. Fentanyl should only be used during pregnancy when clearly necessary.
Long-term treatment during pregnancy may cause withdrawal symptoms in the infant. It is advised not to use fentanyl during labour and delivery (including caesarean section) since fentanyl passes the placenta and may cause respiratory depression in the new born infant.
Fentanyl is excreted into breast milk and may cause sedation and respiratory depression in the breastfed infant. Lactation should therefore be discontinued during treatment and for at least 72 hours after the removal of <Fentanyl Generic> (see also section 4.4)
4.7 Effects on ability to drive and use machines
<Fentanyl Generic> has no or negligible influence on the ability to drive and use machines. In patients with stable fentanyl dose adjustment, a significant impairment of the ability to drive and use machines is not expected. However at the onset of treatment, upon increase of dose or upon combination with other medicinal products, reactivity may be affected in individual cases, leading to impairment of the ability to drive or use machines. Such situations should be handled with caution.
4.8 Undesirable effects
The following defintions of frequency are employed for the evaluation of undesirable effects:
<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), not known (cannot be estimated from the available data)>
The most severe undesirable effect of fentanyl is constricted respiration.
The adverse event profile in children and adolescents treated with Fentanyl transdermal patch 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. There does not appear to be any paediatric-specific risk associated with Fentanyl transdermal patch 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.
Immune system disorders
Acute anaphylactic reactions may also occur.
Psychiatric disorders
Very common: somnolence.
Common: sedation, nervousness, lack of appetite.
Uncommon: euphoria, amnesia, insomnia, hallucinations, agitation.
Very rare: delusion, excitation, asthenia, depression, anxiety, confusion, disturbance of the
sexual functions, withdrawal symptoms.
Nervous system disorders
Very common: headache, dizziness.
Uncommon: tremors, paresthesia, speech impediments.
Very rare: impaired coordination, convulsion fits (including clonic and grand mal – fits).
Eye disorders
Very rare: amblyopia.
Cardiac disorders
Uncommon: tachycardia, bradycardia.
Rare: arrhythmia.
Vascular disorders
Uncommon: hypertension, hypotension.
Rare: vasodilatation.
Respiratory, thoracic and mediastinal disorders
Uncommon: dyspnea, hypoventilation.
Very rare: respiratory depression, apnoea.
Gastrointestinal disorders
Very common: nausea, vomiting, constipation.
Common: dryness of the mouth, dyspepsia.
Uncommon: diarrhoea.
Rare: hiccups.
Very rare: painful flatulence, ileus.
Skin and subcutaneous tissue disorders
Very common: sweating, pruritus.
Common: skin reactions at the application site (usually disappear within 24 hours after the
transdermal patch has been removed).
Uncommon: exanthema, erythema.
Renal and urinary disorders
Uncommon: urinary retention.
Very rare: urinary bladder pain, oliguria.
General disorders and administration site conditions
Rare: oedema, feeling of chill.
Individual undesirable effects may result from the original disease or may be caused by other therapies.
As is the case with other opioid analgetics, tolerance, psychological or physical dependence to fentanyl may develop upon repeated use.
Some patients may show withdrawal syptoms such as e.g. nausea, vomiting, diarrhoea, panic attacks or shivering when the therapy is changed from another strongly active opioid to Fentanyl or following an abrupt termination of the therapy.
4.9 Overdose
Signs of intoxication
An overdose of fentanyl may provoke CNS-depression, which is manifested in stupour, coma, and respiratory depression including Cheyne-Stokes-respiration and /or cyanosis.
Additonal symptoms comprise hypothermia and/or damp and cold skin, flaccid skeletal musculatur, bradykardia as well as hypotonia. The acute intoxication is characterized by pronounced sedation, ataxia, miosis, respiratory depression and convulsions, whereby the respiratory depression is the main symptom.
Therapy of intoxication
The fentanyl transdermal patch should be removed immediately and the patient should be encouraged to breathe using verbal or bodily stimulation. A specific antagonist such as Naloxon may then be administered, but the respiratory depression may persist longer than the effect of the antagonist. Repeated intravenous administration or continuous Naloxon infusion may be required. Sudden pain and the release of catecholamines may be the consequence of the antagonisation.
Further intensive medical care may be required depending on the extent of the respiratory depression. It must be ensured that the body temperature is normal and that sufficient fluid is taken in by the patient.
Hypovolemia may be the cause of a serious or persistent hypotension. This should be treated with an appropriate parenteral volume infusion.
5. PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: analgesics; opioids; phenylpiperidine derivatives
ATC-Code: N02AB03
Fentanyl is an opioid analgetic which interacts in particular with the µ-receptor. The most important therapeutic effects are analgesia and sedation. The serum concentration of fentanyl leading to a minimum analgetic effect in opioid-naive patients, ranges between 0.3–1.5 ng/ml; the frequency of undesirable effects increases above serum levels of 2 ng/ml.
The concentration leading to opioid-induced undesirable effects increases with duration of exposure of the patient to fentanyl. The predisposition to a development of tolerance varies considerably from individual to individual.
The safety of fentanyl was evaluated in three open-label trials in 293 paediatric patients with chronic pain, 2 years of age through 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 fentanyl 12 mcg/h patch. Starting dose of 25 mcg/h and higher were used by 181 patients who had been on prior daily opioid doses of at least 45 mg per dose of oral morphine.
5.2 Pharmacokinetic properties
Fentanyl is continously absorbed through the skin over a period of 72 hours following the application of the fentanyl transdermal patch. The rate of release is relatively constant due to the releasing polymer matrix and the diffusion of fentanyl through the layers of the skin. After the initial application, the serum concentration of fentanyl increases gradually reaching steady state between 12 and 24 hours after application and remaines relatively constant for the entire rest of a 72-hour period. The concentration in serum attained is proportioanl to the size of the fentanyl transdermal patch. Following repeated applications for 72 hours each, the concentration in serum reaches a steady state which is maintained at a constant level for subsequent applications of patches of the same size. After the removal of the fentanyl transdermal patch, the concentration of fentanyl in serum slowly declines complying with the half-life of ca. 21 ± 7. The continuous absorption of fentanyl from the skin depot leads to a slower elimination from the body as seen after an intravenous infusion. Elderly, cachectic or weakened patients may have a reduced clearance and consequently a prolonged terminal half-life of fentanyl. It is mainly metabolised in the liver. In the treatment of patients suffering from liver cirrhosis, no alteration in the pharmacokinetic parameters was exhibited following a single application of a fentanyl transdermal patch, although the serum concentration of fentanyl in these patients tended to be higher. Ca. 75 % of the absorbed substance was excreted via urine mainly as metabolites, while only less than 10 % was excreted in an unchanged form. Ca. 9 % of the dose is excreted via the faeces mainly in a metabolised form. An estimated fraction between 13 and 21 % of fentanyl is present in the plasma as free active substance.
Adjusting for body weight, clearance (L/hr/Kg) in paediatric patients, appears to be 82% higher in children 2 to 5 years old and 25% higher in children 6 to 1o 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.
The transdermal patch is an application form for the systemic adminstration of fentanyl, which ensures that an adequate serum level of Fentanyl will be maintained over a period of 72 hours with a constant rate of release.
The serum fentanyl concentrations attained are proportional to the patch size.
The relative bioavailability of fentanyl from the patch is 92%.
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.
No skin sensitisation was observed in guinea pigs. The use of <Fentanyl Generic> is not associated with a significant risk of phototoxic events according to UV/visible light absorption studies.
6. PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Matrix Components:
Aloe vera leaf extract oil (on the basis of soya oil)
Colophonium resin
Poly (2-ethylhexylacrylat,vinylacetat) (50:50)
Release liner:
Polyethylene terephtalat, polyester, siliconized
Backing foil with imprint:
Polyethylene terephthalat foil, printing ink
6.2 Incompatibilities
Not applicable
6.3 Shelf life
2 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 path is covered with a loose siliconised PETP foil cover sheet and is packed individually into a sealed sachet. The sachet is composed of different layers, paper, aluminium foil and polyethylene and is tightly sealed.
5 , 10, 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 transdermal patches should be folded with the adhesive surfaces inwards and discarded safely or whenever possible returned to the pharmacy. Patches which have not been used should be disposed after consultation with the pharmacist.
7. MARKETING AUTHORISATION HOLDER
[To be completed nationally]
8. MARKETING AUTHORISATION NUMBER(S)
[To be completed nationally]
9. DATE OF FIRST AUTHORISATION / RENEWAL OF THE AUTHORISATION
[To be completed nationally]