Matrifen, 12 micrograms/hour Transdermal patch

Matrifen, 25 micrograms/hour Transdermal patch

Matrifen, 50 micrograms/hour Transdermal patch

Matrifen, 75 micrograms/hour Transdermal patch

Matrifen, 100 micrograms/hour Transdermal patch

Matrifen 12 micrograms/hour: Each transdermal patch contains 1.38 mg fentanyl in a patch of 4.2 cm² and releases fentanyl 12 micrograms/hour

Matrifen 25 micrograms/hour: Each transdermal patch contains 2.75 mg fentanyl in a patch of 8.4 cm² and releases fentanyl 25 micrograms/hour

Matrifen 50 micrograms/hour: Each transdermal patch contains 5.50 mg fentanyl in a patch of 16.8 cm² and releases fentanyl 50 micrograms/hour

Matrifen 75 micrograms/hour: Each transdermal patch contains 8.25 mg fentanyl in a patch of 25.2 cm² and releases fentanyl 75 micrograms/hour

Matrifen 100 micrograms/hour: Each transdermal patch contains 11.0 mg fentanyl in a patch of 33.6 cm² and releases fentanyl 100 micrograms/hour

For a full list of excipients, see section 6.1.

Transdermal patch.

Rectangular, translucent patch on a removable protective film. The protective film is larger than the patch.

The patches are equipped with a coloured imprint with trade name, active substance and strength:

Matrifen 12 micrograms/hour patch: brown imprint

Matrifen 25 micrograms/hour patch: red imprint

Matrifen 50 micrograms/hour patch: green imprint

Matrifen 75 micrograms/hour patch: light blue imprint

Matrifen 100 micrograms/hour patch: grey imprint

Severe chronic pain, which can be adequately managed only with opioid analgesics.

Fentanyl transdermal patches release the active substance over 72 hours. The fentanyl release rate is 12, 25, 50, 75 and 100 microgram/hour and the corresponding active surface area is 4.2, 8.4, 16.8, 25.2 and 33.6 cm².

The required fentanyl dosage is adjusted individually and should be assessed regularly after each administration.

Choice of initial dosage

The dosage level of fentanyl is based upon the previous use of opioids and takes into account the possible development of tolerance, concomitant medicinal treatment, the patient's general state of health and the degree of severity of the disorder.

The initial dosage should not exceed 25 micrograms/hour when the opioid response pattern for the pain condition is not fully known.

Changing from other opioid treatment

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 using Table 2.

Table 1: Equianalgesic efficacy of medicinal products

All i.m. and oral dosages given in the table are equivalent in analgesic effect to 10 mg morphine administered intramuscularly.

* Based on studies conducted with single doses, in which the i.m. dosage of each above-mentioned agent was compared with morphine in order to achieve an equivalent efficacy. Oral dosages are the recommended dosages when changing from parenteral to oral administration.

** The efficacy ratio of 3:1 for morphine i.m./oral dosages is based upon a study conducted in patients suffering from chronic pain.

Table 2: Recommended initial dose of Matrifen based upon daily oral morphine dose

Conversion schemes are based on clinical trials. Schemes based on other trials have been found useful in clinical practice and may be used.

The initial evaluation of the maximum analgesic effect of Matrifen 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. Previous treatment with opioids should therefore be phased out gradually from the time of the first patch application until analgesic efficacy with Matrifen is attained.

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. The dose 12 micrograms/hour is 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 12 micrograms/hour or 25 micrograms/hour increments, although the supplementary analgesic requirements and pain status of the patient should be taken into account. More than one patch may be used for dose adjustments and for doses greater than 100 micrograms/hour. 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 Matrifen 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 Matrifen

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% (see section 5.2). As a general rule, the discontinuation of opioid analgesia should be gradual, in order to prevent withdrawal symptoms (nausea, vomiting, diarrhea, anxiety and muscular tremor).

Use in elderly patients

Elderly or cachectic patients should be observed carefully and the dose reduced if necessary (see section 4.4).

Use in patients with hepatic or renal impairment

Patients with impaired hepatic or renal function should carefully be observed for symptoms of an overdosage and the dose should possibly be reduced (see section 4.4).

Use in febrile patients

Dose adjustment may be necessary in patients during episodes of fever (see section 4.4).

Method of administration

For transdermal use.

Fentanyl transdermal patch should be applied to non-irritated and non-irradiated skin on a flat surface of the torso or upper arm. Hair at the application site (hairless area is preferred) should be clipped (not shaved) prior to system application. If the site requires to be cleansed prior to application of the patch, this should be done with water. Soaps, oils, lotions, alcohol or any other agent that might irritate the skin or alter its characteristics should not be used. The skin should be completely dry before application of the patch.

Since the transdermal patch is protected outwardly by a waterproof covering foil, it may also be worn when taking a short shower.

Fentanyl transdermal patch is to be attached as soon as the pack has been opened. Following removal of the protective layer, 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. An additional fixing of the transdermal patch may be necessary. Fentanyl transdermal patch should be worn continuously for 72 hours after which the transdermal patch is replaced. A new transdermal patch should always be applied to a different site from the previous one. The same application site may be re-used only after an interval of at least 7 days.

The transdermal patch should not be divided or cut (see section 4.4)

For disposal instructions see section 6.6.

Use in children

Method of administration

In young children the upper back is the preferred location to apply the patch, to minimize the potential of the child removing the patch.

Posology

Matrifen should be administered only to opioid-tolerant paediatric patients (ages 2 to 16 years) who are already receiving at least 30 mg oral morphine equivalent per day. To convert paediatric patients from oral or parenteral opioids to Matrifen, refer to Equianalgesic potency conversion (Table 1), and Recommended initial Matrifen dose based upon daily oral morphine dose (Table 3).

Table 3: Recommended initial dose of Matrifen based upon daily oral morphine dose ¹

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 trandermal patch dose was calculated conservatively: 30 mg to 45 mg oral morphine per day or its equivalent opioid dose was replaced by one fentanyl 12 microgram/hour patch. It should be noted that this conversion schedule for children only applies to the switch from oral morphine (or its equivalent) to fentanyl patches. The conversion schedule could not be used to convert from fentanyl into other opioids, as overdose could then occur.

The analgesic effect of the first dose of Matrifen patches will not be optimal within the first 24 hours. Therefore during the first 12 hours after switching to Matrifen, the patients 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 Matrifen therapy or up-titration of the dose (see also section 4.4 Special warnings and precautions for use).

Dose titration and maintenance.

If the analgesic effect of Matrifen 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 micrograms/hour step.

Hypersensitivity to the active substance or to any of the excipients.

The product should not be used for treatment of acute or postoperative pain, because of the lack of opportunity for dose titration in the short term and the possibility of life-threatening respiratory depression.

Severe impairment of the central nervous system.

Concomitant use of MAO-inhibitors or within 14 days after discontinuation of MAO-inhibitors.

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.

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).

Both unused and used Fentanyl transdermal patches should be kept out of reach and sight of children.

The transdermal patch should not be divided or cut as the quality, efficacy and safety have not been established for divided patches.

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 drugs may worsen the respiratory depression (see section 4.5). Fentanyl should be used only with caution and at lower dose in patients with existing respiratory depression.

If a patient is to undergo measures that fully remove the sensation of pain (e.g. regional analgesia), it is advisable to prepare for the possibility of respiratory depression. Before such measures are carried out, the fentanyl dosage should be reduced or a changeover should be made to rapid- or short-acting opioid medication.

Chronic pulmonary disease

In patients with chronic obstructive or other pulmonary diseases fentanyl may have more severe adverse effects, 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

Matrifen 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. Fentanyl should be used with caution in patients in whom a cerebral tumour has been detected.

Cardiac disease

Fentanyl may produce bradycardia. Matrifen should therefore be administered with caution to patients with bradyarrhythmias.

Opioids may cause hypotonia, specially in patients with hypovolemia. Caution should therefore be taken in treatment of patients with hypotonia and/or patients with hypovolemia.

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 with fever should be monitored very closely for opioid side effects and if necessary the fentanyl dosage should be adjusted (see section 4.2). Patients should also be advised to avoid exposing the Fentanyl transdermal patch application site to direct external heat sources such as heating pads, hot water bottles, electric blankets, heat lamps or hot whirlpool spa baths while wearing the patch, since there is potential for temperature dependent increases in release of fentanyl from the patch.

The transdermal patch must always be removed before taking a sauna. Sauna bathing is possible only when replacing a transdermal patch (at intervals of 72 hours). A new transdermal patch is to be applied to cool, very dry skin.

Elderly Patients

Data from intravenous studies with fentanyl suggest that elderly patients may have reduced clearance, a prolonged half-life and they may be more sensitive to the drug than younger patients. Elderly, cachectic, or debilitated patients should be observed carefully for signs of fentanyl toxicity and the dose reduced if necessary.

Others

Non-epileptic (myo)clonic reactions can occur.

Caution should be exercised when treating patients with myasthenia gravis.

Children

Matrifen should not be administered to opioid naïve paediatric patients (see section 4.2 Posology and method of administration). The potential for serious or life-threatening hypoventilation exists regardless of the dose of Matrifen transdermal system administered (see Tables 1 and 3 in section 4.2 Posology and method of administration).

Fentanyl transdermal patch was not studied in children under 2 years of age. Matrifen should be administered only to opioid-tolerant children age 2 years or older (see section 4.2 Posology and method of administration). Matrifen should not be used in children under 2 years of age.

To guard against accidental ingestion by children, use caution when choosing the application site for Matrifen (see section 4.2 Posology and method of administration) and monitor adhesion of the patch closely.

Used transdermal patches

High quantities of fentanyl remain in the transdermal patches even after use. Due to safety and environmental reasons used transdermal patches, as well as any unused transdermal patches should be disposed of according to the instructions given in section 6.6.

The concomitant use of barbituric acid derivatives should be avoided, since the respiratory depressing effect of fentanyl may be increased.

The concomitant use of other CNS depressants, including opioids, anxiolytics and tranquilizers, hypnotics, general anaesthetics, phentiazines, skeletal muscle relaxants, sedating antihistamines and alcoholic beverages may produce additive depressant effects; hypoventilation, hypotonia and profound sedation or coma may occur. Therefore, the use of any of the above mentioned concomitant drugs requires observation of the patient.

MAO-inhibitors have been reported to increase the effect of narcotic analgesics, specially 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 drug, 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, ketoconazol, itraconazol, macrolide antibiotics) 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.

Although pentazocine or buprenorphine have an analgesic effect, they partially antagonize some effects of fentanyl (e.g. analgesia) and may induce withdrawal symptoms in opioids dependants.

The safety of fentanyl transdermal patches 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 newborn child. Fentanyl should not be used during labour and delivery (including caesarean section) since fentanyl passes the placenta and may cause respiratory depression in the foetus or in the newborn child.

Fentanyl is excreted into breast milk and may cause sedation and respiratory depression in the breast-fed child. Breast-feeding should therefore be discontinued for at least 72 hours after the last administration of Matrifen.

Fentanyl transdermal patches have 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.

The following frequencies are used for the description of the occurrence of adverse reactions:

Very common (>1/10), Common (>1/100, <1/10), Uncommon (>1/1000, <1/100), Rare (>1/10,000, <1/1000), Very rare (<1/10,000) including isolated reports.

The most serious adverse reaction of fentanyl is respiratory depression.

Psychiatric disorders

Very common: Somnolence

Common: Sedation, confusion, depression, anxiety, nervousness, hallucinations, lowered appetite

Uncommon: Euphoria, amnesia, sleeplessness, agitation

Very rare: Delusions, asthenia, disorder of sexual functions

Nervous system disorders

Very common: Drowsiness, headache

Uncommon: Tremor, paresthesia, speech disturbances

Very rare: Ataxia, non-epileptic myoclonial reactions

Eye disorders

Rare: Amblyopia

Cardiac disorders

Uncommon: Bradycardia, tachycardia, hypotonia, hypertonia

Rare: Arrhythmia, vasodilatation

Respiratory, thoracic and mediastinal disorders

Uncommon: Dyspnea, hypoventilation

Very rare: Respiratory depression, apnea, hemoptysis, lung obstruction, pharyngitis and laryngospasm

Gastrointestinal disorders

Very common: Nausea, vomiting, constipation

Common: Xerostomia, dyspepsia

Uncommon: Diarrhea

Rare: Hiccups

Very rare: Ileus, painful flatulence

Immune system disorders

Very rare: Anaphylaxis

Skin and subcutaneous tissue disorders

Very common: Sweating, pruritus

Common: Skin reaction at the application site

Uncommon: Rash, erythema

Rash erythema and pruritus will usually disappear within one day after the patch has been removed.

Renal and urinary disorders

Uncommon: Urinary retention

Very rare: Oliguria, pain in the bladder

General disorders

Rare: Oedema, feeling cold

Other adverse reactions

Tolerance, physical and psychological dependence can develop during long-term use of fentanyl. Opioid withdrawal symptoms (for instance: nausea, vomiting, diarrhea, anxiety and shivering) may occur in patients after switching from previously prescribed opioid analgesics to fentanyl transdermal patch.

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 and there does not appear to be any paediatric-specific risk associated with fentanyl trandermal 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.

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 isotonic sodium chloride solution (0.9 %) or 5% dextrose solution (0.004 mg/ml). 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.

Pharmacotherapeutic group: Analgesics, opioids

ATC code: N02AB03

Matrifen is a transdermal patch that provides continuous delivery of fentanyl. Fentanyl is an opioid analgesic with affinity mainly to the µ-receptor. The predominant pharmacological effects are pain relief and sedation. Patients not previously treated with opioids will have pain relief at a fentanyl concentration between 0.3 and 1.5 ng/ml. In this group of patients the frequency of adverse effects will increase at serum concentrations above 2 ng/ml. Both the lowest effective fentanyl concentration and the concentration causing adverse reactions will increase with the development of increasing tolerance. Development of tolerance varies considerably between individual subjects.

The fentanyl transdermal patch provides systemic delivery over the 72 hour administration period.

Absorption: After the first patch application 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. By the second 72-hour application, a steady- state serum concentration is reached and is maintained during subsequent applications of the patch of the same size. The absorption of fentanyl may differ somewhat between different application sites. A somewhat lower (approximately 25%) fentanyl absorption has been observed in studies with healthy volunteers after the patch has been applied on the chest compared with the upper arm and the back.

Distribution: The plasma protein binding for fentanyl is 84 %.

Biotransformation: Fentanyl shows linear kinetics and is metabolized primarily in the liver via CYP3A4. The major metabolite, norfentanyl, is inactive.

Elimination: After the fentanyl patch is removed, serum fentanyl concentrations decline gradually falling approximately 50% in 13-22 hours in adults or 22-25 hours in children. Continued absorption of fentanyl from the skin accounts for a slower disappearance of the drug from the serum 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

Impaired hepatic or renal function could cause increased serum concentrations. Elderly, cachectic or generally impaired patients may have a lower fentanyl clearance, which could cause a longer terminal half life for the compound (see section 4.2 and 4.4).

Children

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 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.

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.

Mutagenicity testing in bacteria and in rodents yielded negative results. As well as other opioids fentanyl showed mutagenic effects in vitro in mammalian cells. A mutagenic risk in therapeutic condition seems unlikely since effects were induced only in very high concentrations.

Long-term carcinogenicity studies have not been performed.

Dipropylene glycol

Hydroxypropyl cellulose

Dimeticone

Silicone adhesives (amine resistant)

Release membrane, ethylenvinylacetate (EVA)

Backing film, polyethylene terephthalate film (PET)

Removable protective film, fluoropolymercoated polyester film

Printing ink

Not applicable

2 years

This medicinal product does not require any special storage conditions.

Each patch is packed in a heat-sealed pouch made of paper, aluminium and polyacrylonitrile (PAN).

Pack sizes:

1, 2, 3, 4, 5, 8, 10, 16 and 20 patches

Not all pack sizes may be marketed

High quantities of fentanyl remain in the transdermal patches even after use. Used transdermal patches should be folded with the adhesive surfaces inwards, so the release membrane is not exposed, and due to safety and environmental reasons, discarded according to local requirements or returned to the pharmacy. Any unused medicinal product should be discarded according to local requirements or returned to the pharmacy.

There are no safety and pharmacokinetic data available for other application sites.

Nycomed UK Ltd

Three Globeside Business Park

Fieldhouse Lane

Marlow

Bucks

SL7 1HZ

UK

12 microgram/hour: PL 20810/0004

25 microgram/hour: PL 20810/0005

50 microgram/hour: PL 20810/0006

75 microgram/hour: PL 20810/0007

100 microgram/hour: PL 20810/0008

21/12/2006

10/11/2008

POM/CD2