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

Patients receiving opioid treatment for the first time (opioid-naive patients)

Clinical experience with Victanyl is limited in opioid-naive patients. If therapy with Victanyl is considered appropriate in opioid-naive patients, it is recommended that these patients be titrated with low doses of short-acting opioids initially Patches with a release rate of 12.5 micrograms/hour are available and should be used for initial dosing.

Patients can then be converted to patches with 25 micrograms /hr. The dose may subsequently be titrated upwards or downwards, if required, in increments of 12 or 25 micrograms /hr to achieve the lowest appropriate dose of Victanyl depending on the response and supplementary analgesic requirements (see also section 4.4). 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.

In opioid-tolerant patients

The initial dose of Victanyl should be based on the previous 24 hour opioid analgesic requirement.

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 corresponding fentanyl dosage should be determined as follows:

a)    using Table 1 Conversion from oral morphine to fentanyl for patients where a conservative approach of opioid dosing is required (conversion ratio of oral morphine to transdermal fentanyl equal to150:1)

b)    using Table 2 for patients on stable and well tolerated opioid therapy (conversion ratio of oral morphine to transdermal fentanyl equal to 100:1)

c)    using Table 3 for paediatric patients. Conversion from oral morphine to fentanyl (conversion ratio of oral morphine to transdermal fentanyl equal to150:1)

Table 1: Recommended initial dose of transdermal fentanyl based on daily oral morphine dose (for patients where a conservative approach of opioid dosing is required)

Oral 24 hours morphine, (mg/day)	Transdermal Fentanyl dose (micrograms/h)
< 90	25
90 - 134	37
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

Table 2: Recommended initial dose of transdermal fentanyl based on daily oral morphine dose (for patients on stable and well tolerated opioid therapy)_

Oral morphine dose (mg/24 h)	Transdermal fentanyl release (micrograms/h)
< 60	12.5
60-89	25
90-149	50
150-209	75
210-269	100
270-329	125
330-389	150
390-449	175
450-509	200
510-569	225
570-629	250
630-689	275
690-749	300

By combining several transdermal patches, a fentanyl release rate of over 100 micrograms/h can be achieved .

Previous analgesic therapy should be phased out gradually from the time of the first patch application until analgesic efficacy with Victanyl is attained. For both strong opioid-naive and opioid tolerant patients, the initial evaluation of the analgesic effect of Victanyl should not be made until the patch has been worn for 24 hours due to the gradual increase in serum fentanyl concentrations up to this time.

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 of efficacy 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. Dose adjustment, when necessary, should normally be performed in the following titration steps from 25 micrograms /h up to 75 micrograms /h: 25 micrograms /h, 37 micrograms /h, 50 micrograms /h, 62 micrograms /h and 75 micrograms /h; thereafter dose adjustments should normally be performed in 25 micrograms /h increments, although the supplementary analgesic requirements (oral morphine 90 mg/day « Victanyl 25 micrograms /h) and pain status of the patient should be taken into account. More than one Victanyl may be used to achieve the desired dose.

Patients may require periodic supplemental doses of a short-acting analgesic for breakthrough pain. Additional or alternative methods of analgesia should be considered when the Fentanyl transdermalpatch dose exceeds 300 micrograms/hour.

Withdrawal symptoms (See section 4.8) 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 therapy

If discontinuation of Victanyl is necessary, any replacement with other opioids should be gradual, starting at a low dose and increasing slowly. This is because after system removal, serum fentanyl concentrations decline gradually with mean terminal half-life ranging from 13 to 25 hours. 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 1 and 2 should not be used to switch from transdermal fentanyl to a morphine treatment.

Use in 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. Studies of Victanyl in elderly patients demonstrated fentanyl pharmacokinetics which did not differ significantly from young patients although serum concentrations tended to be higher. Elderly, cachectic, or debilitated patients should be observed carefully for signs of fentanyl toxicity and the dose reduced if necessary.

In very elderly or weak patients, it is not recommended to initiate a 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.

Paediatric population Children aged 16 years and above:

Follow adult dosage.

Children aged 2 to 16 years old:

Victanyl 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 opioids to Victanyl refer to Table

3    Recommended Victanyl dose based upon daily oral morphine dose.

Table 3: Recommended initial dose of transdermal fentanyl based on daily oral morphine dose¹ (for Paediatric Patients²)_

Oral 24 hours morphine, (mg/day)	Transdermal Fentanyl dose (micrograms/h)
30 - 44	12
45 - 134	25

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

Fentanyl transdermal patches 2

Conversion to fentanyl transdermal patches doses greater than 25 micrograms /h 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 transdermal patch dose was calculated conservatively: 30 mg to 44 mg oral morphine per day or its equivalent opioid dose was replaced by one Victanyl 12 micrograms /h patch. It should be noted that this conversion schedule for children only applies to the switch from oral morphine (or its equivalent) to Victanyl patches. The conversion schedule should not be used to convert from Victanyl into other opioids, as overdosing could then occur.

The analgesic effect of the first dose of Victanyl patches will not be optimal within the first 24 hours. Therefore, during the first 12 hours after switching to Victanyl 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 Victanyl therapy or up-titration of the dose (see also section 4.4).

Dose titration and maintenance

If the analgesic effect of Victanyl is insufficient, supplementary morphine or another short-duration opioid should be administered. Depending on the additional analgesic needs and the pain status of the child, it may be decided to increase the dose.

Dose adjustments should be done in 12 microgram / hour steps.

Use in patients with hepatic or renal impairment

Patients with hepatic or renal impairment should be observed carefully and the dose reduced if necessary (see section 4.4).

Method of administration For transdermal use.

Victanyl should be applied to non-irritated and non-irradiated skin on a flat surface or the torso or upper arm.

For use in children:

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

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

All patients:

A non-hairy area should be selected. If this is not possible, hair at the application site should be clipped (not shaved) prior to application. If the site of Victanyl application requires to be cleansed prior to application of the patch, this should be done with water. Soaps, oils, lotions or any other agent that might irritate the skin or alter its characteristics should not be used. The skin should be completely dry before the patch is applied. Patches should be inspected prior to use. Patches that are cut, divided, or damaged in any way should not be used.

The Victanyl patch should be removed from the protective pouch by first folding the notch (located close to the tip of the arrow on the pouch label) and then carefully tearing the pouch material. If scissors are used to open the pouch, this should be done close to the sealed edge so as not to damage the patch inside.

Victanyl should be applied immediately after removal from the sealed pouch. Avoid touching the adhesive side of the patch. Following removal of both parts of the protective liner, 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. Then wash hands with clean water.

Victanyl should be worn continuously for 72 hours. A new patch should then be applied to a different skin site after removal of the previous transdermal patch. Several days should elapse before a new patch is applied to the same area of skin. The need for continued treatment should be assessed at regular intervals.

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.

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.

4.3 Contraindications

The use of this medicinal product is contraindicated in patients with known

hypersensitivity to the active substance rivastigmine, to other carbamate derivatives or to any of

the excipients listed in section 6.1 used in the formulation,

- Previous history of application site reactions suggestive of allergic contact dermatitis with rivastigmine patch (see section 4.4).

4.4 Special warnings and precautions for use Paediatric population

Victanyl should be kept out of sight and reach of children before and after 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 Victanyl should only be initiated by an experienced physician familiar with the pharmacokinetics of Fentanyl transdermal patches and the risk for severe hypoventilation.

The potential for serious or life-threatening hypoventilation exists even if the lowest dose of Victanyl is used in initiating therapy in opioid-naive patients.

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.

Do not cut the transdermal patch. A patch that has been divided, cut, or damaged in any way should not be used, 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.

Breakthrough pain

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

Respiratory depression

As with all potent opioids some patients may experience significant respiratory depression with Victanyl, and patients must be observed for these effects. Respiratory depression may persist beyond the removal of the patch. The incidence of respiratory depression increases as the fentanyl dose is increased (see Section 4.9, Overdose, concerning respiratory depression). CNS active active drugs may increase the respiratory depression (see sections 4.5).

Fentanyl should be used only with caution and at a lower dose in patients with existing respiratory depression.

Chronic pulmonary disease

Victanyl may have more severe adverse effects in patients with chronic obstructive or other pulmonary diseases. In such patients opioids may decrease respiratory drive and increase airway resistance.

Drug dependence and Potential for Abuse:

Tolerance and physical dependence and psychological dependence may develop upon repeated administration of opioids, but is rare in treatment of cancer related pain. Iatrogenic addiction following opioid administration is rare. Patients with a prior history of drug dependence/alcohol abuse are more at risk to develop dependence and abuse in opioid treatment. Patients at increased risk of opioid abuse may still be appropriately treated with modified-release opioid formulations; however, these patients will require monitoring for signs of misuse, abuse, or addiction. Fentanyl can be abused in a manner similar to other opioid agonists. Abuse or intentional misuse of Victanyl may result in overdose and/or death.

Increased intracranial pressure

Victanyl 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. Victanyl should be used with caution in patients with brain tumors.

Cardiac disease

Fentanyl may produce bradycardia and should therefore be administered with caution to patients with bradyarrhythmias. Opioids may cause hypotension, especially in patients with acute hypovolemia. Underlying, symptomatic hypotension and/ or hypovolaemia should be corrected before treatment with fentanyl transdermal patches is initiated.

Hepatic Impairment.

Because fentanyl is metabolized to inactive metabolites in the liver, hepatic impairment might delay its elimination. If patients with hepatic impairment receive Fentanyl transdermal patch, they should be observed carefully for signs of fentanyl toxicity and the dose of Fentanyl transdermal patch reduced if necessary (see Section 5.2).

Renal impairment

Less than 10 % of fentanyl is excreted unchanged by the kidney, 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 (see Section 5.2).

Fever/external heatapplication:

A pharmacokinetic model suggests that serum fentanyl concentrations may increase by about one-third if the skin temperature increases to 40° C. Therefore, patients with fever should be monitored for opioid side effects and the Fentanyl transdermalpatch dose should be adjusted if necessary. There is a potential for temperature-dependent increases in fentanyl released from the system resulting in possible overdose and death. A clinical pharmacology trial conducted in healthy adult subjects has shown that the application of heat over the Fentanyl transdermal patch system increased mean fentanyl AUC values by 120% and mean C_max values by 61%.

All patients should be advised to avoid exposing the Fentanyl transdermal patch application site to direct external heat sources such as heating pads, electric blankets, heated water beds, heat or tanning lamps, intensive sunbathing, hot water bottles, prolonged hot baths, saunas and hot whirlpool spa baths.

Interactions with other Medicinal Products:

Interactions with CYP3A4 Inhibitors:

The concomitant use of Fentanyl transdermal patch with cytochrome P450 3A4 (CYP3A4) inhibitors (e.g. ritonavir, ketoconazole, itraconazole, troleandomycin, clarithromycin, nelfinavir, nefazodone, verapamil, diltiazem, and amiodarone) may result in an increase in fentanyl plasma concentrations, which could increase or prolong both the therapeutic and adverse effects, and may cause serious respiratory depression. In this situation special patient care and observation are appropriate. Therefore, the concomitant use of transdermal fentanyl and CYP3A4 inhibitors is not recommended unless the patient is closely monitored. Patients, especially those who are receiving Fentanyl transdermal patch and CYP3A4 inhibitors, should be monitored for signs of respiratory depression and dosage adjustments should be made if warranted.

Use in Elderly patients

Data from intravenous studies with fentanyl suggest that the elderly patients may have reduced clearance, a prolonged half-life and they may be more sensitive to the drug 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. If elderly or cachectic patients receive Fentanyl transdermal patch, they should be observed carefully for signs of fentanyl toxicity and the dose reduced if necessary (see Section 5.2).

Use in paediatrics

Fentanyl transdermal patch should not be administered to opioid naive paediatric patients (see Section 4.2). The potential for serious or life-threatening hypoventilation exists regardless of the dose of Fentanyl transdermal patch system administered.

Fentanyl transdermal patch was not studied in children under 2 years of age. Fentanyl transdermal patch should be administered only to opioid-tolerant children age 2 years or older (see Section 4.2). Fentanyl transdermal patch 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 Victanyl (see Section 6.6) and monitor adhesion of the patch closely.

Lactation

As fentanyl is excreted into breast milk, breastfeeding should be discontinued during treatment with fentanyl (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.

Concomitant use of mixed agonists antagonists

The concomitant use of barbituric acid derivatives, buprenorphine, nalbuphine and pentazocine should in general be avoided (see section 4.5).

MRI scan

The fenanyl transdermal patch contains metal. The patch should be removed before MRI scan since it can overheat during an MRI scan and cause skin burns in the immediate area of the patch.

4.5 Interaction with other medicinal products and other forms of interaction

As a cholinesterase inhibitor, rivastigmine may exaggerate the effects of succinylcholine-type muscle relaxants during anaesthesia. Caution is recommended when selecting anaesthetic agents. Possible dose adjustments or temporarily stopping treatment can be considered if needed.

In view of its pharmacodynamic effects, rivastigmine should not be given concomitantly with other cholinomimetic substances and might interfere with the activity of anticholinergic medicinal products.

No pharmacokinetic interaction was observed between rivastigmine and digoxin, warfarin, diazepam or fluoxetine in studies in healthy volunteers. The increase in prothrombin time induced by warfarin is not affected by administration of rivastigmine. No untoward effects on cardiac conduction were observed following concomitant administration of digoxin and rivastigmine.

According to its metabolism, metabolic interactions with other medicinal products appear unlikely, although rivastigmine may inhibit the butyrylcholinesterase mediated metabolism of other substances.

4.6 Pregnancy and lactation

For rivastigmine no clinical data on exposed pregnancies are available. No effects on fertility or embryofoetal development were observed in rats and rabbits, except at doses related to maternal toxicity.

In peri/postnatal studies in rats, an increased gestation time was observed. Rivastigmine should not be used during pregnancy unless clearly necessary.

In animals, rivastigmine is excreted into milk. It is not known if rivastigmine is excreted into human milk. Therefore, women on rivastigmine should not breastfeed.

4.7 Effects on ability to drive and use machines

Alzheimer’s disease may cause gradual impairment of driving performance or compromise the ability to use machinery. Furthermore, rivastigmine can induce dizziness and somnolence, mainly when initiating treatment or increasing the dose. As a consequence, rivastigmine has minor or moderate influence on the ability to drive and use machines. Therefore, the ability of patients with dementia on rivastigmine to continue driving or operating complex machines should be routinely evaluated by the treating physician.

4.8 Undesirable effects

The safety of fentanyl was evaluated in 1854 subjects who participated in 11 clinical trials (double-blind fentanyl [placebo or active control] and/or open label fentanyl [no control or active control]) used for the management of chronic malignant or nonmalignant pain. These subjects took at least 1 dose of fentanyl and provided safety data. Based on pooled safety data from these clinical trials, the most commonly reported adverse drug reactions (ADRs) were (with % incidence): nausea (35.7%), vomiting (23.2%), constipation (23.1%), somnolence (15.0%), dizziness (13.1%), and headache (11.8%).

The ADRs reported with the use of fentanyl from these clinical trials, including the above-mentioned ADRs, and from post-marketing experiences are listed below.

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

Very common (>1/10)

Common (>1/100 to <1/10)

Uncommon (>1/1000 to <1/100)

Rare (>1/10,000 to <1/1000)

Very rare (<1/10,000) and not known (cannot be estimated from the available clinical trial data).

The most serious undesirable effect of fentanyl is respiratory depression.

System Organ Class	Adverse Drug Reactions
	Frequency Category
	Very Common	Common	Uncommon	Rare	Very Rare	Not Known
Immune System Disorders		Hypersensitivity			Anaphylaxi s	Anaphylactic shock, Anaphylactic reaction, Anaphylactoid reaction
Metabolism and Nutrition Disorders		Anorexia
Psychiatric Disorders		Insomnia, Depression, Anxiety, Confusional state, Hallucination Sedation, Nervousness	Agitation, Disorientation, Euphoric mood Amnesia,		Delusional ideas, States of excitement, Confusion,
Nervous System Disorders	Dizziness, Headache, Somnolence	Tremor, Paraesthesia,	Hypoaesthesia, Convulsion (including clonic convulsions and grand mal convulsion), Speech disorder.		Ataxia,
Eye Disorders				Miosis	Amblyopia.
Ear and Labyrinth Disorders		Vertigo
Cardiac Disorders		Palpitations, Tachycardia	Bradycardia, Cyanosis	Arrhythmia
Vascular Disorders		Hypertension	Hypotension	Vaso dilatation
Respiratory, Thoracic and Mediastinal Disorders		Dyspnoea	Respiratory depression, Respiratory distress	Apnoea, Hypo ventilation		Bradypnoea
Gastrointestinal Disorders	Nausea, Vomiting, Constipation	Diarrhoea, Dry mouth, Abdominal pain, Abdominal pain upper, Dyspepsia Xerostomia	Ileus	Subileus Hiccup	Painful flatulence

System Organ Class	Adverse Drug Reactions
	Frequency Category
	Very Common	Common	Uncommon	Rare	Very Rare	Not Known
Skin and Subcutaneous Tissue Disorders		Skin reaction on application site Hyperhidrosis, Pruritus, Rash Erythema	Eczema, Dermatitis allergic, Skin disorder, Dermatitis, Dermatitis contact Exanthema, Rash, erythema and pruritus will usually disappear within one day after the patch has been removed.
Musculoskelet al and Connective Tissue Disorders		Muscle spasms	Muscle twitching
Renal and Urinary Disorders		Urinary retention			Cystalgia, Oliguria.
Reproductive System and Breast Disorders			Erectile dysfunction, Sexual dysfunction
General Disorders and Administratio n Site Conditions		Fatigue, Oedema peripheral, Asthenia, Malaise Feeling cold	Application site reaction, Influenza like illness, Feeling of body temperature change, Application site hypersensitivity, Drug withdrawal syndrome	Application site dermatitis, Application site eczema

Other undesirable effects

As with other opioid analgesics, tolerance, physical dependence, and psychological dependence can develop on repeated use of Victanyl (see Section 4.4).

Opioid withdrawal symptoms (such as nausea, vomiting, diarrhoea, anxiety, and shivering) are possible in some patients after conversion from their previous opioid analgesic to Victanyl or if therapy is stopped suddenly (see Section 4.2).There have been very rare reports of newborn infants experiencing neonatal withdrawal syndrome when mothers chronically used Victanyl during pregnancy (see Section 4.6).

Paediatric population

The adverse event profile in children and adolescents treated with Victanyl 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 Victanyl 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.

4.9 Overdose

Symptoms

Most cases of accidental overdose have not been associated with any clinical signs or symptoms and almost all of the patients concerned continued rivastigmine treatment. Where symptoms have occurred, they have included nausea, vomiting and diarrhoea, hypertension or hallucinations. Due to the known vagotonic effect of cholinesterase inhibitors on heart rate, bradycardia and/or syncope may also occur.

Ingestion of 46 mg occurred in one case; following conservative management the patient fully recovered within 24 hours.

Treatment

As rivastigmine has a plasma half-life of about 1 hour and a duration of acetylcholinesterase inhibition of about 9 hours, it is recommended that in cases of asymptomatic overdose no further dose of rivastigmine should be administered for the next 24 hours. In overdose accompanied by severe nausea and vomiting, the use of antiemetics should be considered. Symptomatic treatment for other adverse reactions should be given as necessary.

In massive overdose, atropine can be used. An initial dose of 0.03 mg/kg intravenous atropine sulphate is recommended, with subsequent doses based on clinical response. Use of scopolamine as an antidote is not recommended.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: opioids; Phenylpiperidine derivatives ATC code: N02AB03

Fentanyl is an opioid analgesic with affinity mainly to the p-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.

Paediatric population

The safety of fentanyl transdermal patch was evaluated in three open-label trials in 293 paediatric patients with chronic pain, 2 years of age through to 18 years of age, of which 66 children were aged to 2 to 6 years. In these studies, 30 mg to 45 mg oral morphine per day was replaced by one Fentanyl 12 micrograms /h transdermal patch. Starting dose of 25 micrograms /h and higher were used by 181 patients who had been on prior daily opioid doses of at least 45 mg per dose of oral morphine.

5.2 Pharmacokinetic properties

Absorption

Rivastigmine is rapidly and completely absorbed. Peak plasma concentrations are reached in approximately 1 hour. As a consequence of rivastigmine’s interaction with its target enzyme, the increase in bioavailability is about 1.5-fold greater than that expected from the increase in dose. Absolute bioavailability after a 3 mg dose is about 36%±13%. Administration of rivastigmine with food delays absorption (tmax) by 90 min and lowers Cmax and increases AUC by approximately 30%.

Distribution

Protein binding of rivastigmine is approximately 40%. It readily crosses the blood brain barrier and has an apparent volume of distribution in the range of 1.8-2.7 l/kg.

Metabolism

Rivastigmine is rapidly and extensively metabolised (half-life in plasma approximately 1 hour), primarily via cholinesterase-mediated hydrolysis to the decarbamylated metabolite. In vitro, this metabolite shows minimal inhibition of acetylcholinesterase (<10%). Based on evidence from in vitro and animal studies the major cytochrome P450 isoenzymes are minimally involved in rivastigmine metabolism. Total plasma clearance of rivastigmine was approximately 130 l/h after a 0.2 mg intravenous dose and decreased to 70 l/h after a 2.7 mg intravenous dose.

Excretion

Unchanged rivastigmine is not found in the urine; renal excretion of the metabolites is the major route of elimination. Following administration of 14C-rivastigmine, renal elimination was rapid and essentially complete (>90%) within 24 hours. Less than 1% of the administered dose is excreted in the faeces. There is no accumulation of rivastigmine or the decarbamylated metabolite in patients with Alzheimer’s disease.

Elderly subjects

While bioavailability of rivastigmine is greater in elderly than in young healthy volunteers, studies in Alzheimer patients aged between 50 and 92 years showed no change in bioavailability with age.

Subjects with hepatic impairment

The Cmax of rivastigmine was approximately 60% higher and the AUC of rivastigmine was more than twice as high in subjects with mild to moderate hepatic impairment than in healthy subjects.

Subjects with renal impairment

Cmax and AUC of rivastigmine were more than twice as high in subjects with moderate renal impairment compared with healthy subjects; however there were no changes in Cmax and AUC of rivastigmine in subjects with severe renal impairment.

5.3 Preclinical safety data

Repeated-dose toxicity studies in rats, mice and dogs revealed only effects associated with an exaggerated pharmacological action. No target organ toxicity was observed. No safety margins to human exposure were achieved in the animal studies due to the sensitivity of the animal models used.

Rivastigmine was not mutagenic in a standard battery of in vitro and in vivo tests, except in a chromosomal aberration test in human peripheral lymphocytes at a dose 104 times the maximum clinical exposure. The in vivo micronucleus test was negative.

No evidence of carcinogenicity was found in studies in mice and rats at the maximum tolerated dose, although the exposure to rivastigmine and its metabolites was lower than the human exposure. When normalised to body surface area, the exposure to rivastigmine and its metabolites was approximately equivalent to the maximum recommended human dose of 12 mg/day(on mg/m² basis); however, when compared to the maximum human dose of 12mg/Kg , a multiple of approximately 6-fold was achieved in animals.

In animals, rivastigmine crosses the placenta and is excreted into milk. Oral studies in pregnant rats and rabbits gave no indication of teratogenic potential on the part of rivastigmine.

6.1    List of excipients

Granules:

Microcrystalline cellulose Hypromellose Silica, colloidal anhydrous Magnesium stearate

Body cap:

Gelatin

Titanium dioxide (E171)

Yellow iron oxide (E172)

Red iron oxide (E172)

6.2    Incompatibilities

Not applicable.

6.3    Shelf life

3 years

6.4    Special precautions for storage

Do not store above 30°C.

6.5    Nature and contents of container

- Blister of transparent PVC/PE/PVDC - Aluminium foil. Each box contains 28, 56 or 112 capsules.

Not all pack sizes may be marketed.

6.6    Special precautions for disposal and other handling

No special requirements.

7 MARKETING AUTHORISATION HOLDER

Pharmathen Pharmaceuticals S.A.

6 Dervenakion Street Pallini Attikis 15351 Greece

8    MARKETING AUTHORISATION NUMBER(S)

PL 17277/0062

9    DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

19/05/2010

10    DATE OF REVISION OF THE TEXT

06/03/2013