Osmanil 75 micrograms/h transdermal patch

Transdermal patch

The product is indicated in severe chronic pain which can be adequately managed only with opioid analgesics.

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

For initial dosing patches with a release rate of 12.5 micrograms/hour should be used. In very elderly or weak patients, it is not recommended to initiate an opioid treatment with Osmanil, 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 Osmanil 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.

Table 2: Recommended initial dose of transdermal fentanyl based on daily oral morphine dose (for patients who have a need for opioid rotation)

Table 3: Recommended initial dose of transdermal fentanyl based on daily oral morphine dose (for patients on stable and well tolerated opioid therapy)

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 Osmanil 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 Osmanil 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. The dose 12.5 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 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 Osmanil 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, the 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 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 must be used for cleaning, as these may penetrate the skin due to the effect of the patch.

Paediatric population

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

Transdermal fentanyl should be administered only to opioid-tolerant paediatric patients (ages 2 to 16 years) who are already receiving at least 30 mg oral morphine equivalents per day.

To convert paediatric patients from oral or parenteral opioids to transdermal fentanyl, refer to “Equianalgesic potency conversion” (table 1), and “Recommended transdermal fentanyl dose based upon daily oral morphine dose (table 4).

Table 4: Recommended transdermal fentanyl dose based upon daily oral morphine dose¹

 ¹In clinical trials these ranges of daily oral morphine doses were used as a basis for conversion to transdermal fentanyl

²For conversion to Osmanil doses greater than 25 micrograms/h a conversion ratio of oral morphine to transdermal fentanyl of 150:1 is recommended (see table 2)

For children who receive more than 90 mg oral morphine a day, only limited information is currently available from clinical trials. In the paediatric studies, the required fentanyl transdermal patch dose was calculated conservatively: 30 mg to 45 mg oral morphine per day or its equivalent opioid dose was replaced by one Fentanyl 12 micrograms/hour transdermal patch. It should be noted that this conversion schedule for children only applies to the switch from oral morphine (or its equivalent) to transdermal fentanyl. The conversion schedule could not be used to convert from transdermal fentanyl into other opioids, as overdose could than occur.

The analgesic effect of the first dose of transdermal fentanyl will not be optimal within the first 24 hours. Therefore, during the first 12 hours after switching to transdermal 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.

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 transdermal fentanyl therapy or up-titration of the dose.

Dose titration and maintenance

If the analgesic effect of transdermal fentanyl is insufficient, supplementary morphine or another short-duration opioid should be administered. Depending on the additional analgesic needs and the pain status of the child, it may be decided to use more patches. Dose adjustments should be done in 12.5 micrograms/h steps.

Elderly should be observed carefully and the dose reduced if necessary.

Hepatic and renal impairment

Patients with hepatic or renal impairment should be observed carefully and the dose reduced if necessary.

• 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.

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 Osmanil 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.

In chronic non-cancer pain, it might be preferable to initiate the treatment with immediate-release strong opioids (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.

The concomitant use of barbituric acid derivatives, buprenorphine, nalbuphine or pentazocine is not recommended.

Breakthrough pain

Studies have shown that almost all patients, despite treatment with a fentanyl patch, require supplemental treatment with potent rapid-release medicinal products to arrest breakthrough pain.

Respiratory depression

As with all potent opioids some patients may experience respiratory depression with Osmanil, 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 substances may worsen the respiratory depression.

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

Osmanil 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 hypotension, especially in patients with hypovolemia. Caution should therefore be taken in treatment of patients with hypotension and/or patients with hypovolemia. Fentanyl may produce bradycardia. Osmanil should be administered with caution 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

Significant increases in body temperature can potentially increase fentanyl absorption rate. Therefore patients who develop fever should be monitored for opioid adverse reactions. 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 and 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

Transdermal fentanyl should not be administered to opioid naïve paediatric patients. The potential for serious or life-threatening hypoventilation exists regardless of the dose of transdermal fentanyl administered.

Transdermal fentanyl was not studied in infants and toddlers under 2 years of age. Transdermal fentanyl should be administered only to opioid-tolerant children aged 2 years or older. Transdermal fentanyl should not be used in infants and toddlers under 2 years of age.

To guard against accidental ingestion by children, use caution when choosing the application site for transdermal fentanyl patches and monitor adhesion of the patch closely. 

Lactation

As fentanyl is excreted into breast milk, lactation should be discontinued under treatment with Osmanil.

Patients with myasthenia gravis

Non-epileptic (myo)clonic reactions can occur. Caution should be exercised when treating patients with myasthenia gravis.

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.

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.

a) General Description:

External genital warts:

In the pivotal trials with 3 times a week dosing, the most frequently reported adverse drug reactions judged to be probably or possibly related to imiquimod cream treatment were application site reactions at the wart treatment site (33.7% of imiquimod treated patients). Some systemic adverse reactions, including headache (3.7%), influenza-like symptoms (1.1%), and myalgia (1.5%) were also reported.

Patient reported adverse reactions from 2292 patients treated with imiquimod cream in placebo controlled and open clinical studies are presented below. These adverse events are considered at least possibly causally related to treatment with imiquimod.

 Superficial basal cell carcinoma:

In trials with 5 times per week dosing 58% of patients experienced at least one adverse event. The most frequently reported adverse events from the trials judged probably or possibly related to imiquimod cream are application site disorders, with a frequency of 28.1%. Some systemic adverse reactions, including back pain (1.1%) and influenza-like symptoms (0.5%) were reported by imiquimod cream patients.

Patient reported adverse reactions from 185 patients treated with imiquimod cream in placebo controlled phase III clinical studies for superficial basal cell carcinoma are presented below. These adverse events are considered at least possibly causally related to treatment with imiquimod.

Actinic keratosis

In the pivotal trials with 3 times per week dosing for up to 2 courses each of 4 weeks, 56% of imiquimod patients reported at least one adverse event. The most frequently reported adverse event from these trials judged probably or possibly related to imiquimod cream was application site reactions (22% of imiquimod treated patients). Some systemic adverse reactions, including myalgia (2%) were reported by imiquimod treated patients.

Patient reported adverse reactions from 252 patients treated with imiquimod cream in vehicle controlled phase III clinical studies for actinic keratosis are presented below. These adverse events are considered at least possibly causally related to treatment with imiquimod.

b) Tabular Listing of adverse events:

Frequencies are defined as Very common (1/10), Common (1/100 to <1/10) and Uncommon (1/1,000 to <1/100). Lower frequencies from clinical trials are not reported here.

c) Frequently occurring adverse events:

External genital warts:

Investigators of placebo controlled trials were required to evaluate protocol mandated clinical signs (skin reactions). These protocol mandated clinical sign assessments indicate that local skin reactions including erythema (61%), erosion (30%), excoriation/flaking/scaling (23%) and oedema (14%) were common in these placebo controlled clinical trials with imiquimod cream applied three times weekly (see section 4.4). Local skin reactions, such as erythema, are probably an extension of the pharmacologic effects of imiquimod cream.

Remote site skin reactions, mainly erythema (44%), were also reported in the placebo controlled trials. These reactions were at non-wart sites which may have been in contact with imiquimod cream. Most skin reactions were mild to moderate in severity and resolved within 2 weeks of treatment discontinuation. However, in some cases these reactions have been severe, requiring treatment and/or causing incapacitation. In very rare cases, severe reactions at the urethral meatus have resulted in dysuria in women (see section 4.4).

 Superficial basal cell carcinoma:

Investigators of the placebo controlled clinical trials were required to evaluate protocol mandated clinical signs (skin reactions). These protocol mandated clinical sign assessments indicate that severe erythema (31%) severe erosions (13%) and severe scabbing and crusting (19%) were very common in these trials with imiquimod cream applied 5 times weekly. Local skin reactions, such as erythema, are probably an extension of the pharmacologic effect of imiquimod cream.

Skin infections during treatment with imiquimod have been observed. While serious sequelae have not resulted, the possibility of infection in broken skin should always be considered.

Actinic keratosis

In clinical trials of imiquimod cream 3 times weekly for 4 or 8 weeks the most frequently occurring application site reactions were itching at the target site (14%) and burning at the target site (5%). Severe erythema (24%) and severe scabbing and crusting (20%) were very common. Local skin reactions, such as erythema, are probably an extension of the pharmacologic effect of imiquimod cream. See 4.2 and 4.4 for information on rest periods.

Skin infections during treatment with imiquimod have been observed. While serious sequelae have not resulted, the possibility of infection in broken skin should always be considered.

d) Adverse events applicable to all indications:

Reports have been received of localised hypopigmentation and hyperpigmentation following imiquimod cream use. Follow-up information suggests that these skin colour changes may be permanent in some patients.

Clinical studies investigating the use of imiquimod for the treatment of actinic keratosis have detected a 0.4% (5/1214) frequency of alopecia at the treatment site or surrounding area. Postmarketing reports of suspected alopecia occurring during the treatment of sBCC and EGW have been received.

Reductions in haemoglobin, white blood cell count, absolute neutrophils and platelets have been observed in clinical trials. These reductions are not considered to be clinically significant in patients with normal haematologic reserve. Patients with reduced haematologic reserve have not been studied in clinical trials. Reductions in haematological parameters requiring clinical intervention have been reported from postmarketing experience. There have been postmarketing reports of elevated liver enzymes.

Rare reports have been received of exacerbation of autoimmune conditions.

Rare cases of remote site dermatologic drug reactions, including erythema multiforme, have been reported from clinical trials. Serious skin reactions reported from postmarketing experience include erythema multiforme, Stevens Johnson syndrome and cutaneous lupus erythematosus.

Winthrop Pharmaceuticals UK Limited

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