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Drug Details

Matrifen

• Presentation
  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
• Description
  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
• Indications
  

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

• Adult Dosage
  

  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.

   

  Name of medicinal product	Equianalgesic dosage (mg)
  	i.m.*	Oral
  Morphine	10	30 (assuming repeated administration)**
  		60 (assuming a single dose or occasional doses)
  Hydromorphone	1.5	7.5
  Methadone	10	20
  Oxycodone	10-15	20-30
  Levorphanol	2	4
  Oxymorphine	1	10 (rectal)
  Diamorphine	5	60
  Pethidine	75	-
  Codeine	-	200
  Buprenorphine	0.4	0.8 (sublingual)
  Ketobemidone	10	30

  * 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

  Peroral morphine dose per 24-hours (mg/day)	Dose of Matrifen transdermal patch micrograms/hour_
  < 135	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

  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% . 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.

  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.

  Use in febrile patients

  Dose adjustment may be necessary in patients during episodes of fever.

  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

  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 

  Peroral morphine dose per 24-hours (mg/day)	Dose of Matrifen transdermal patch micrograms/hour
  For paediatric patients2 30-44	For paediatric patients2 12
  45-134	25
  1 Conversion schemes are based on clinical trials. 2 Conversion to Matrifen doses greater than 25 micrograms/hour is the same for adult and paediatric patients.

  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.

  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.

• Contra Indications
  

  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.

• Special Precautions
  

  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.

  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. 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. The potential for serious or life-threatening hypoventilation exists regardless of the dose of Matrifen transdermal system administered.

  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. 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 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 accordingly.

• Interactions
  

  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.

• Adverse Drug Reactions
  

  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.