1. Name Of The Medicinal Product
Victanyl 75 micrograms/hour Transdermal Patch
fentanyl
2. Qualitative And Quantitative Composition
Each patch releases 75 micrograms fentanyl per hour. Each patch of 22.5 cm2 contains 12.375 mg fentanyl.
For a 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 µg/h“.
4. Clinical Particulars
4.1 Therapeutic Indications
The product is indicated in severe chronic pain which can be adequately managed only with opioid analgesics.
4.2 Posology And Method Of Administration
The dosing is individual and based on the patient's opioid history and takes into account:
• the possible development of tolerance,
• the current general condition, the medical status of the patient, and
• the degree of severity of the disorder.
The required fentanyl dosage is adjusted individually and should be assessed regularly after each administration.
Patients receiving opioid treatment for the first time
Patches with a release rate of 12.5 micrograms/hour are available and should be used for initial dosing. In very elderly or weak patients, it is not recommended to initiate an opioid treatment with Victanyl, due to their known susceptibility to opioid treatments. In these cases, it would be preferable to initiate a treatment with low doses of immediate release morphine and to prescribe Victanyl after determination of the optimal dosage.
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)
Table 1: Equianalgesic potency conversion
All dosages given in the table are equivalent in analgesic effect to 10 mg parenteral morphine.
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Table 2: Recommended initial dose of transdermal fentanyl based on daily oral morphine dose (for patients who have a need for opioid rotation)
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Table 3: Recommended initial dose of transdermal fentanyl based on daily oral morphine dose (for patients on stable and well tolerated opioid therapy)
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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 Fentanyl 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 Fentanyl 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 patch should be replaced every 72 hours. The dose should be titrated individually until analgesic efficacy is attained. In patients who experience a marked decrease in the period 48-72 hours after application, replacement of fentanyl after 48 hours may be necessary.
Patches with a release rate of 12.5 micrograms/hour are available and are appropriate for dose titration in the lower dosage area.. If analgesia is insufficient at the end of the initial application period, the dose may be increased after 3 days until the desired effect is obtained for each patient. Additional dose adjustment should normally be performed in 25 micrograms/hour increments, although the supplementary analgesic requirements and pain status of the patient should be taken into account. 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 Fentanyl 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.
Changing or ending therapy
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; it takes at least 17 hours for the fentanyl serum concentration to decrease by 50%. As a general rule, the discontinuation of opioid analgesia should be gradual, in order to prevent withdrawal symptoms (nausea, vomiting, diarrhoea, anxiety and muscular tremor). Tables 2 and 3 should not be used to switch from transdermal fentanyl to a morphine treatment.
Method of administration
Directly after removal from the pack and the release liner, Fentanyl transdermal patch is applied to a non-hairy area of skin on the upper body (chest, back, upper arm). To remove hair, scissors should be used instead of razors.
Prior to application, the skin should be carefully washed with clean water (no cleaning agents) and thoroughly dried. The transdermal patch is then applied using slight pressure with the palm of the hand for approximately 10-30 seconds. The skin area to which the patch is applied should be free of microlesions (e.g. due to irradiation or shaving) and skin irritation.
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.
If progressive dose increases are made, the active surface area required may reach a point where no further increase is possible.
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 may be used for cleaning, as these may penetrate the skin due to the effect of the patch.
Paediatric population
The experience in children under 12 years of age is limited. Victanyl should not be used in this population.
Use in elderly patients
Elderly should be observed carefully and the dose reduced if necessary (see sections 4.4 and 5.2).
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.
- Acute or postoperative pain, since dosage titration is not possible during short-term use.
- Severe impairment of the central nervous system.
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.
Treatment with Fentanyl transdermal patch should only be initiated by an experienced physician familiar with the pharmacokinetics of Fentanyl transdermal patches and the risk for severe hypoventilation.
After exhibiting a serious adverse reaction a patient should be monitored for 24 hours following removal of a transdermal patch due to the half life of fentanyl (see section 5.2).
In chronic non-cancer pain, it might be preferable to initiate the treatment with immediate-release strong opoids (e.g. morphine) and to prescribe fentanyl transdermal patch after determination of the efficacy and the optimal dosage of the strong opioid.
The transdermal patch should not be cut, since no information is available on the quality, efficacy and safety of such divided patches.
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).
The concomitant use of buprenorphine, nalbuphine or pentazocine is not recommended (see also section 4.5).
Breakthrough pain
Studies have shown that almost all patients, despite treatment with a fentanyl patch, require supplemental medication with potent rapid-release drugs to arrest breakthrough pain.
Respiratory depression
As with all potent opioids some patients may experience respiratory depression with the Fentanyl transdermal patch, and patients must be observed for this effect. Respiratory depression may persist beyond the removal of the patch. The incidence of respiratory depression increases as the fentanyl dose is increased. CNS active active substances may worsen the respiratory depression (see sections 4.5).
In patients with existing respiratory depression, fentanyl should only be used with caution and at a lower dose.
Chronic pulmonary disease
In patients with chronic obstructive or other pulmonary diseases fentanyl may have more severe adverse reactions, in such patients opioids may decrease respiratory drive and increase airway resistance.
Drug dependence
Tolerance and physical and psychological dependence may develop upon repeated administration of opioids, but is rare in treatment of cancer related pain.
Increased intracranial pressure
Fentanyl 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.
Cardiac disease
Opioids may cause hypotonia, especially in patients with hypovolemia. Caution should therefore be taken in treatment of patients with hypotonia and/or patients with hypovolemia. Fentanyl may produce bradycardia. Fentanyl transdermal patch should therefore not be administered to patients with bradyarrhythmias.
Impaired liver function
Fentanyl is metabolised to inactive metabolites in the liver, so patients with hepatic disease might have a delayed elimination. Patients with hepatic impairment should be observed carefully and the dose reduced if necessary.
Renal impairment
Less than 10 % of fentanyl is excreted unchanged by the kidneys, and unlike morphine, there are no known active metabolites eliminated by the kidneys. 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.
Patients with fever/external heat
Patients who develop fever should be monitored for opioid adverse reactions since significant increases in body temperature can potentially increase fentanyl absorption rate. The patch application site should not be exposed to heat from external heat sources, e.g. sauna.
Elderly patients
Data from intravenous studies with fentanyl suggest that the elderly patients may have reduced clearance, a prolonged half-life. Moreover elderly patients may be more sensitive to the active substance than younger patients. However, studies of Fentanyl transdermal patch in elderly patients demonstrated fentanyl pharmacokinetics which did not differ significantly from young patients although serum concentrations tended to be higher. Elderly or cachectic patients should be observed carefully and the dose reduced if necessary.
Paediatric patients
Due to limited experience in children under 12 years of age, Victanyl should be used in this age group only after careful consideration has been given to the benefit versus risk ratio.
Lactation
As fentanyl is excreted into breast milk, lactation should be discontinued under treatment with Victanyl (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.
Interactions
Combination with barbituric acid derivatives, buprenorphine, nalbuphine and pentazocine should in general be avoided (see section 4.5).
4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction
The concomitant use of barbituric acid derivatives should be avoided, since the respiratory depressing effect of fentanyl may be increased.
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 dependant patients (see also section 4.4).
The concomitant use of other CNS depressants, may produce additive depressant effects and hypoventilation, hypotension as well as profound sedation or coma may occur. The CNS depressants mentioned above include:
- opioids
- anxiolytics and tranquilizers
- hypnotics
- general anaesthetics
- phenothiazines
- skeletal muscle relaxants
- sedating antihistamines
- alcoholic beverages
Therefore, the use of any of the above mentioned concomitant medicinal products and active substances require observation of the patient.
MAO-inhibitors have been reported to increase the effect of narcotic analgesics, especially in patients with cardiac failure. Therefore, fentanyl should not be used within 14 days after discontinuation of treatment with MAO-inhibitors.
Fentanyl, a high clearance active substance, is rapidly and extensively metabolised mainly by CYP3A4.
Itraconazole (a potent CYP3A4 inhibitor) at 200 mg/day given orally for four days had no significant effect on the pharmacokinetics of intravenous fentanyl. Increased plasma concentrations were, however, observed in individual subjects. Oral administration of ritonavir (one of the most potent CYP3A4 inhibitors) reduced the clearance of intravenous fentanyl by two thirds and doubled the half-life. Concomitant use of potent CYP3A4-inhibitors (e.g. ritonavir) with transdermally administered fentanyl may result in increased plasma concentrations of fentanyl. This may increase or prolong both the therapeutic effects and the adverse reactions, which may cause severe respiratory depression. In such cases increased care and observation of the patient should be undertaken. Combined use of ritonavir or other potent CYP3A4-inhibitors with transdermal fentanyl is not recommended, unless the patient is carefully observed.
4.6 Pregnancy And Lactation
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 foetus or in the infant.
Fentanyl is excreted into breast milk and may cause sedation and respiratory depression in the breast-fed infant. Lactation should therefore be discontinued for at least 72 hours after the removal of Victanyl (see also section 4.4).
4.7 Effects On Ability To Drive And Use Machines
Victanyl has major influence on the ability to drive and use machines. 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 following frequencies are used for the description of the occurrence of adverse reactions:
Very common (
The most serious undesirable effect of fentanyl is respiratory depression.
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Other undesirable effects
Not known (cannot be estimated from the available data): Long-term use of fentanyl can lead to development of tolerance and physical and psychological dependence. After switching from previously prescribed opioid analgesics to Victanyl or after abrupt discontinuation of therapy patients may show opioid withdrawal symptoms (for instance: nausea, vomiting, diarrhoea, anxiety and shivering).
4.9 Overdose
Symptoms
The symptoms of fentanyl overdose 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, hypotonia. 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 should be started, including 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 due to overdose can persist longer than the effect of the opioid antagonist. Reversing the narcotic effect can give rise to acute pain and release of catecholamines. Intensive care unit treatment is important, if required by the patient's clinical condition. 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 which interacts predominantly with the μ-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 0.3–1.5 ng/ml; an increased incidence of adverse effects 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.
5.2 Pharmacokinetic Properties
Following administration of Fentanyl 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 Fentanyl 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 dependant on the Fentanyl transdermal patch size. For all practical purposes 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 metabolized primarily in the liver via CYP3A4. The major metabolite, norfentanyl, is inactive.
Elimination
When treatment with Fentanyl transdermal patches 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 drug. 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.
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
Polyacrylate adhesive layer
Backing film
Polypropylene foil
Blue printing ink
Release liner
Polyethylene terephthalate foil (siliconised)
6.2 Incompatibilities
Not applicable.
6.3 Shelf Life
36 months
6.4 Special Precautions For Storage
Do not store above 25 °C.
6.5 Nature And Contents Of Container
Each transdermal patch is packed in a separate sachet. The Composite foil containing the following layers from outside to inside: coated Kraft paper, low density polyethylene foil, aluminium foil, Surlyn
Pack containing 3 transdermal patches
Pack containing 4 transdermal patches
Pack containing 5 transdermal patches
Pack containing 8 transdermal patches
Pack containing 10 transdermal patches
Pack containing 16 transdermal patches
Pack containing 20 transdermal patches
Not all pack sizes may be marketed.
6.6 Special Precautions For Disposal And Other Handling
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 or whenever possible returned to the pharmacy. Any unused medicinal product should be discarded or returned to the pharmacy.
7. Marketing Authorisation Holder
Actavis Group PTC ehf
Reykjavikurvegur 76-78
220 IS Hafnarfjordur
Iceland
8. Marketing Authorisation Number(S)
PL 30306/0133
9. Date Of First Authorisation/Renewal Of The Authorisation
27/06/08
10. Date Of Revision Of The Text
10/02/10
11 DOSIMETRY (IF APPLICABLE)
Not applicable.
12 INSTRUCTIONS FOR PREPARATION OF RADIOPHARMACEUTICALS (IF APPLICABLE)
Not applicable.
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