FENTA 25

Patient Leaflet According to the Pharmacists' Regulations (Preparations) - 1986

This medicine is sold with a doctor's prescription only

Fenta 12, Fenta 25, Fenta 50, Fenta 75, Fenta 100

Transdermal Patches

Active ingredient:

Each patch of Fenta 12 contains 2.063 mg Fentanyl and delivers 12.5 mcg/hr.

Each patch of Fenta 25 contains 4.125 mg Fentanyl and delivers 25 mcg/hr.

Each patch of Fenta 50 contains 8.25 mg Fentanyl and delivers 50 mcg/hr.

Each patch of Fenta 75 contains 12.375 mg Fentanyl and delivers 75 mcg/hr.

Each patch of Fenta 100 contains 16.5 mg Fentanyl and delivers 100 mcg/hr.

For a list of inactive ingredients, please see section 6.

Please read the entire leaflet carefully before using this medication.

This leaflet contains concise information about the medicine. If you have any further questions,

refer to the doctor or pharmacist.

This medicine has been prescribed for treating your condition. Do not pass it on to others. It may

harm them, even if it seems to you that their medical condition is similar to yours.

Medicines of the opioids group may cause addiction, especially with prolonged use and they

have a potential for misuse and overdose. A reaction to an overdose, may be manifested by slow

breathing and may even cause death. Make sure you know the name of the medicine, the

dosage that you take, how often you take it, the duration of treatment, potential side effects and

risks.

Additional information regarding the risk of dependence and addiction can be found at the

following link:

https://www.health.gov.il/UnitsOffice/HD/MTI/Drugs/risk/DocLib/opioids_en.pdf

Taking this medicine along with medicines from the benzodiazepines group, other medicines which

depress the central nervous system (including drugs) or alcohol may cause a feeling of profound

drowsiness, breathing difficulties (respiratory depression), coma and death.

1. What is the medicine intended for?

The medicine is intended for relief of strong chronic pain requiring opioid analgesia.

Fenta is indicated for patients who are already using opioid treatment.

Therapeutic Group

: Opioid analgesic

2. Before using the medicine

Do not use the medicine if:

You are sensitive (allergic) to the active ingredient or to any of the other ingredients this medicine contains

(for a list of inactive ingredients, please see section 6).

Do not use the medicine unless it was prescribed to you by the doctor for the treatment of pain.

Do not use if you have not used an opioid analgesic in the past.

Do not use for the relief of pain that is not chronic/persistent.

Do not use for the relief of mild or moderate pain.

Do not use for the relief of post-surgery pain.

Do not use Fenta if you are taking medicines of the monoamine oxidase inhibitor group (for the treatment of

depression), or if you took such a medicine within the last two weeks.

Do not use the medicine if you are breastfeeding.

Do not use in children under 2 years of age.

Special warnings concerning the use of the medicine:

Fenta patches contain fentanyl, an opioid substance, and are a potential for drug abuse.

Inform the doctor if you or one of your family members have ever developed dependence or abuse of

alcohol, prescription medicines or drugs.

Analgesics such as Fenta may cause dependence, however this is very rare if the medicine is used

according to the instructions.

After the dosage for use of Fenta has been determined, do not switch to a different dosage of Fenta

or to another patch that contains the active ingredient fentanyl or to a patch containing a different

narcotic substance, without consulting the doctor.

Prolonged use of this medicine may lead to the development of tolerance. After a certain period of

time your doctor may need to raise the dosage in order to maintain a suitable level of pain relief.

Stopping prolonged treatment with Fenta suddenly, may cause withdrawal symptoms to appear. See

'If you stop taking the medicine' paragraph. Therefore, do not stop the treatment with Fenta on your

own initiative, without explicit instructions from your doctor.

If your doctor decides to stop the treatment with this medicine, follow his/her instructions precisely.

Similar side effects may occur when switching from Fenta to other analgesics and vice versa. If you

experience these side effects, inform the doctor.

The use of opioid medicines, such as Fenta, may cause you unusual sleepiness and breathing

difficulties (e.g. slow and weak breathing). Very rarely, these breathing difficulties may be life-

threatening (particularly in patients who have not used opioid medicines in the past). If the patient's

breathing becomes slower and weaker, remove the patch and seek immediate medical

assistance or urgently call a doctor! Talk to the patient and even shake him/her in order to

ensure he/she stays awake until he/she receives medical assistance.

Elderly people, very thin people or very sick people might be more sensitive to the medicine's effects.

In cases of high fever, greater than desirable quantities of the active ingredient may be released and

absorbed into the body. Therefore, whenever you suffer from high fever, inform your doctor. The

doctor may adjust the dosage as necessary.

Release of greater than desirable quantities of the active ingredient and its absorption into the body

may also occur in cases of exposure to direct heat from an external source. Therefore, avoid staying

in saunas or in jacuzzis, prolonged stay in a hot bath, prolonged sun tanning, heat lamps or tanning

lamps, sunbaths, use of electric blankets and pillows, hot water bottles or heated water beds.

Make sure to use the Fenta patches appropriately and to dispose of them properly (please see

section 3).

When discarding the patch (used or unused), fold it in half, with the sticky side inward, and

dispose of it in a safe way immediately.

Never give Fenta to another person. Take all precautions in order to prevent the medicine from falling

into the hands of somebody who is not the patient.

Only the patient’s skin may come into contact with the Fenta patch.

A few cases are known in which similar patches were transferred from the patient to a person

sharing his/her bed. The patch may also stick to a child held by an adult who has a patch on

his/her body.

Keep the used and unused patches in a safe place and out of the reach and sight of children,

since accidental exposure of children to a new or used patch may cause life-threatening harm.

If the patch sticks to another person, remove it from him/her immediately, rinse the area

exposed to the patch with water only, and seek medical assistance immediately.

Do not put the patch in your mouth. Do not chew and/or swallow the patch.

If a child or any another person accidentally swallows the patch, proceed immediately to a doctor or a

hospital emergency room.

Do not cut the patch or separate its parts. Do not use a cut patch or a patch that seems damaged.

Do not apply the patch to skin that has small wounds, redness, burns or to skin that has undergone

radiation.

From time to time check (by sight or touch) the place where the patch has been applied, to verify that

it adheres properly, is not loose and has not fallen off. If the patch does not adhere properly, use a

plaster to stick the patch onto your skin. Do not try and remove the patch and stick it in another place!

If the patch fell off by itself, dispose of it safely and apply a new patch as soon as you notice this. The

new patch should be applied to a different place on the skin.

Before the treatment with Fenta tell the doctor:

If you are sensitive to any food or medicine.

If you suffer or have suffered in the past from impaired function of the: heart and/or blood vessels

(including blood pressure problems), liver, kidney/urinary system, lungs, respiratory system,

digestive system (e.g. intestinal obstruction, chronic constipation), pancreas, gallbladder.

If you suffer or have suffered in the past from myasthenia gravis, increased intracranial pressure,

head injury, brain damage, brain tumor, coma or impaired consciousness.

If you are taking or have recently taken any other medicines, including non-prescription

medicines and nutrition supplements, please tell your doctor or pharmacist. Especially

inform your doctor or pharmacist if you are taking the following medicines (it should be noted that

the following list mentions the active ingredients of the medicines. If you are unsure whether you

are using one of these medicines, please consult with your doctor or pharmacist):

Medicines that affect the central nervous system (e.g. sedatives such as medicines of the

benzodiazepine group, sleeping pills, medicines for treatment of mental problems, medicines for

treatment of epilepsy such as carbamazepine, phenobarbital, phenytoin).

Anesthetics for surgery, medicines for general anesthesia.

Medicines of the phenothiazine group (e.g. chlorpromazine, thioridazine and fluphenazine for the

treatment of schizophrenia).

Certain medicines for treatment of fungal infections (e.g. fluconazole, ketoconazole, voriconazole,

itraconazole).

Certain antibiotic preparations e.g. medicines containing troleandomycin, erythromycin or

clarithromycin.

Certain medicines for treatment of AIDS/HIV (such as medicines containing nelfinavir, amprenavir,

fosamprenavir or ritonavir).

Do not use ritonavir or nelfinavir (protease enzyme inhibitors for the treatment of AIDS/HIV) and

Fenta concomitantly, unless instructed by your doctor and with close medical supervision.

Muscle relaxants, antihistamines (for treatment of allergies) with a sedative effect.

Certain medicines for the heart and blood vessels (such as diltiazem and verapamil).

Certain medicines for the treatment of irregular heart rate (such as amiodarone).

Certain medicines for the treatment of depression (such as nefazodone, citalopram, duloxetine,

escitalopram, fluoxetine, fluvoxamine, paroxetine, sertraline, venlafaxine and other medicines from the

SSRIs group).

Aprepitant (for prevention of vomiting), rifampicin (for treatment of tuberculosis).

Other opioid analgesics (such as buprenorphine, nalbuphine or pentazocine).

Alcoholic beverages.

Do not use Fenta if you are taking medicines of the monoamine oxidase inhibitor group (for the

treatment of depression), or if you took such a medicine within the last two weeks.

Use of this medicine and alcohol consumption:

Do not drink wines or alcoholic beverages during the treatment with this medicine.

Pregnancy and breastfeeding:

Consult your doctor before using the medicine, if you are pregnant or planning to become

pregnant.

Do not breastfeed if you are using a patch. Do not breastfeed for at least 3 days after

removing the patch.

Do not use Fenta during childbirth.

Driving and use of machinery:

Use of this drug may reduce alertness and therefore caution should be exercised when driving a

vehicle, operating dangerous machinery or performing any other activity that requires special

vigilance.

Do not drive or use machinery unless you feel that the treatment does not impair your alertness

and in any case only after consulting your doctor, especially when starting treatment or when

there is a change in the dose you receive.

Use in children:

This medicine is usually not intended for infants and children, unless instructed by an

experienced doctor, and it is not intended for use by children under 2 years of age.

3. How to use this medicine?

Always use according to the doctor's instructions. Check with the doctor or pharmacist if you are

not sure.

The dosage and the manner of treatment will be determined by the doctor only.

The standard dosage is usually:

The dosage will be determined by the doctor only, taking into consideration the intensity of

the pain, your general condition, your age and the opioid treatment that you previously used.

Do not change the dosage without consulting your doctor.

Each patch is intended for 3 days of treatment (72 hours) only. Replace the patch every 72 hours,

unless otherwise instructed by your doctor.

Due to the slow absorption of the medicine into the skin, the effect may not be felt immediately with

the application of the first patch. Sometimes, the maximum effect is felt only after 24 hours from

application of the first patch. Therefore, you may need additional analgesics on the first day of

treatment.

Do not exceed the recommended dose.

If your pain returns, refer to your doctor, who may prescribe additional analgesics and change the

dosage of Fenta. Your doctor may instruct you to use a number of patches concomitantly.

Your doctor may prescribe you additional analgesics in order to relieve an outburst of incidental pain.

Carefully follow your doctor’s instructions.

Stopping prolonged treatment with Fenta suddenly, may cause withdrawal symptoms to appear (see

'If you stop taking the medicine' paragraph). Therefore, do not stop the treatment with Fenta on your

own initiative, without instructions from your doctor. If your doctor decides to stop the treatment with

this medicine, follow his/her instructions precisely.

Similar side effects may occur when switching from Fenta to other analgesics and vice versa.

Attention:

Do not swallow! This medicine is intended for external use only.

Do not put the patch in your mouth, do not chew and/or swallow the patch.

Do not cut the patch or separate its parts.

Do not use the patch if it is cut, damaged or seems damaged.

Do not apply the patch to skin that has small wounds, redness, burns or to skin that has undergone

radiation.

Do not stop using Fenta unless explicitly instructed to do so by the doctor. The doctor will instruct you

on the gradual manner to do so.

Directions for use:

Apply the Fenta patch immediately upon its removal from the aluminum sachet according to the

following instructions:

Apply the patch to a clean hairless area of the skin on the upper part of the arm or on the upper part

of the body (chest or back). Choose a place without scars, cuts or irritation. In patients who are

mentally/cognitively impaired and in children, the patch should preferably be applied to the upper

back in order to decrease the risk that they will remove the patch and put it in their mouth.

Cut off excess hair from the skin with scissors only (do not shave so as not to injure the skin).

Wash the skin (if necessary) in cold water only (without soap!). Dry the skin well and gently. Do not

use soap, lotion, oils or alcohol before applying the patch to the skin. Do not apply the patch

immediately after a hot shower or a hot bath. Wait until the skin is completely dry and cool.

Before applying a new patch, remove the previous patch. Open the aluminum sachet only right before

applying the patch.

Instructions for use (see illustrations).

Gently tear the aluminum sachet on the side and take out the patch.

Bend the patch along the “S” sign, until the protective cover is raised.

Remove half of the protective cover, stick the patch onto the skin (without

touching the sticky part) and remove the second half of the protective cover.

Press the patch to the skin for 30 seconds using your palm. Make sure

that the whole patch sticks well to the skin (particularly the patch edges).

After completing the application wash your hands with water only (without

soap).

5. Note the date of the patch application on the designated place on the

package (this will help you know when the 3 days of treatment have passed).

6. Leave the patch stuck to the skin for 3 days (72 hours) of treatment.

During these hours, you may bathe (shower or bath) and even swim with the

patch. Do not rub or soap the application area.

7. After 3 days, remove the patch by peeling it off the skin.

8. Fold the used patch in half, the sticky side inward, and dispose of it

immediately in a safe way.

9. Apply the next patch to another place on the skin. Do not apply a new

patch to the same area as the previous patch. You can apply the patch to the

same area again only after a few days.

Do not keep at home patches that remain after treatment with the medicine has ended.

If unnecessary patches remain, remove them from their aluminum sachets, remove the

protective cover, fold the patch in half (with the sticky side facing inwards) and

immediately dispose of it in a safe way.

If the patch fell off by itself, dispose of it and apply a new patch as soon as you notice this. The new

patch should be applied to a different place on the skin. Inform your doctor that the patch fell off. The

new patch should be replaced after 3 days (72 hours) or according to your doctor instructions.

If you have accidentally used a higher dosage: if you discovered that you accidentally used

more patches than recommended by the doctor or if the patch accidentally stuck to a child or to a

person who is not the patient, remove the patch immediately and proceed immediately to a

hospital emergency room and bring the package of the medicine along.

The most important sign indicating an overdose is breathing difficulties. If the patient suffers from

breathing difficulties (breathing too weakly or slowly), remove the patch immediately, and call the

doctor urgently! Talk to the patient and even shake him/her in order to ensure he/she stays awake

until he/she receives medical assistance. Additional signs include: tiredness, extreme sleepiness,

unclear thinking, inability to walk and/or to speak normally, fainting sensation, dizziness or confusion.

If you forgot to use the medicine and/or if you forgot to change the Fenta patch:

Change the patch as soon as you remember and write down the time and date. Change

the new patch after 3 days (72 hours) as usual.

If you are very late in relation to the time you were supposed to change your patch,

contact your doctor, since you might need additional analgesics. Do not use more

patches than instructed by the doctor.

Continue with the treatment as recommended by the doctor. Even if your state of health improves, do

not stop the treatment with this medicine without consulting your doctor

If you stop using the medicine:

Do not stop the treatment with Fenta on your own initiative,

without explicit instructions from your doctor.

Sudden discontinuation of prolonged treatment with Fenta may cause appearance of withdrawal

symptoms, such as: anxiety, tremor, nausea, vomiting, diarrhea, lack of appetite; change in heart

rate, blood pressure, and/or respiration; bristling hair, restlessness, weakness, yawning, muscle

pains, joint pains, back pain, abdominal pains, sweating, excessive nasal secretions, tearing,

dilated pupils, insomnia. Therefore, if your doctor decides to stop the treatment with this

medicine, follow his/her instructions precisely.

Do not take or use medicines in the dark! Check the label and the dose each time you use a

medicine. Wear glasses if you need them.

If you have further questions concerning the use of the medicine consult the doctor or pharmacist.

4. Side Effects

Like any medicine, the use of Fenta may cause side effects in some users. If the side effects persist

or they are bothersome or get worse, consult your doctor. Do not be alarmed while reading the list of

side effects. You may not suffer from any of them.

Upon the appearance of sleepiness, breathing difficulties (breathing too slowly or weakly),

shortness of breath, apnea, decrease in consciousness or loss of consciousness, contraction

of the pupils, severe allergic reaction manifested by swelling of the face or throat, skin irritation,

redness and appearance of skin blisters, and/or wheezing, difficulty breathing and very low

blood pressure which may be severe or life threatening: remove the patch and seek

immediate medical assistance or urgently call a doctor! Talk to the patient and even

shake him/her in order to make sure he/she stays awake until he/she receives medical

assistance.

Contact the doctor immediately if the following side effects appear: unusual thoughts,

hallucinations, supreme sense of happiness (euphoria), chest pain, coughing up blood,

urinating difficulties, fainting sensation, difficulties in walking or speaking, cold and humid skin.

Remove the patch and seek medical treatment if seizures occur.

Continue the treatment and refer to your doctor if skin reactions appear at the site of

application.

Additional side effects:

Very common side effects (appear in more than one user out of ten):

Headaches, dizziness, drowsiness, nausea, vomiting, constipation, difficulty falling asleep or staying

asleep.

Common side effects (appear in 1-10 users out of 100):

Loss of appetite; confusion; changes in vision, hearing, hallucinations (seeing, feeling, hearing things

that do not exist); anxiety, nervousness, feeling of great sadness or depression, tremor; tingling

sensation; awareness of heartbeat, rapid heartbeat, high blood pressure; dry mouth, indigestion,

abdominal pain, diarrhea; vertigo, hypersensitivity, allergic reaction which includes skin reaction

(urticaria); involuntary muscle movements including muscle spasms, tiredness, weakness, general

feeling of discomfort; cold sensation; swelling of the feet, ankles and hands; inability or difficulty to

urinate; shortness of breath.

Skin rash, itching, redness of the skin or excessive sweating. You may notice these symptoms also at

the application site. These symptoms are for the most part mild and disappear after removal of the

patch. If these symptoms do not disappear, or if the patch causes severe itching of your skin, inform

the doctor.

Uncommon side effects (appear in 1-10 users out of 1,000):

Supreme sense of happiness (euphoria), agitation, disorientation, decreased sensation (particularly in

the skin), blurred vision, memory loss, muscle twitching; slow heart rate, blue-tinted skin, low blood

pressure; difficulty or severe difficulty in breathing (respiratory depression); intestinal obstruction; skin

inflammation or skin allergy as a result of contact with something the user is allergic to; difficulty

during each stage of the normal sexual reaction (desire, arousal or orgasm), inability to obtain or

maintain an erection; skin reactions at the application site (including allergic reaction, eczema,

inflammation); cold or hot sensation or changes in body temperature; flu-like illness; unpleasant

symptoms that occur after discontinuation of the medicine or dosage lowering (withdrawal symptoms

such as nausea, vomiting, diarrhea, anxiety, tremor).

Rare side effects (appear in 1-10 users out of 10,000):

Contraction of the pupils; inability to breathe; partial intestinal obstruction, too little air entering the

lungs.

Very rare side effects (appear in less than 1 out of 10,000 users):

Severe allergic reaction causing wheezing, difficulty breathing and very low blood pressure that may

be severe or life threatening; very slow respiratory rate.

Side effects of unknown frequency (effects whose frequency has not yet been determined): shock or

anaphylactic reaction.

If you experience any side effects that are not mentioned in this leaflet or if there is any change in

your general feeling, consult the doctor immediately!

Side effects and drug interactions in children:

The following side effects were reported in clinical trials in children (up to 18 years of age):

Very common side effects (appear in more than one user out of ten): headache, nausea or vomiting,

constipation, diarrhea, itching.

Common side effects (appear in 1-10 users out of 100): Allergic reaction, loss of appetite, abdominal

pain, difficulty falling asleep or staying asleep, tiredness, weakness, drowsiness/sleepiness,

respiratory depression, feeling worried, anxiety or depression, hallucinations (seeing, feeling, hearing

things that do not exist), tremor, dizziness, decreased sensation or sensitivity (particularly in the skin),

dry mouth, rash, excessive sweating, redness of skin, muscle spasms, difficulty urinating; swelling

(edema) of the hands, ankles or feet; skin reactions at the application site.

Uncommon side effects (appear in 1-10 users out of 1,000): Confusion, sensation of pins and

needles, contraction of the pupils, sensation of dizziness (vertigo); blue-tinted skin, eczema,

inflammation and/or other skin reactions at the application site; withdrawal symptoms (e.g.: nausea,

vomiting, diarrhea, anxiety or tremor), flulike illness.

Parents must inform the doctor about any side effects, as well as any additional medicine given to the

child.

5. How to store the medicine?

Avoid poisoning! This medicine in particular, and any other medicine, should be stored in a

safe place out of the reach and sight of children and/or infants, to avoid poisoning, that might

cause life-threatening harm (see 'Special warnings concerning the use of the medicine' and 'If you

have accidentally used a higher dosage’ paragraphs).

Do not induce vomiting unless explicitly instructed to do so by the doctor.

Do not use the medicine after the expiry date (exp. date) stated on the package. The expiry date

refers to the last day of that month.

Storage conditions: Store below 25

C. Make sure the patches are kept in their original aluminum

sachet.

6. Additional information

In addition to the active ingredient, the patches also contain the following inactive

ingredient:

Polyacrylate adhesive layer.

What does the medicine look like and what does the package contain?

In each package there are 5 transparent transdermal patches. Each patch is packed in a separate

aluminum sachet.

Fenta 12: square patches of an area of 3.75 cm². On the back of the patch "fentanyl 12μg/h" is

printed in blue ink

Fenta 25: square patches of an area of 7.5 cm². On the back of the patch "fentanyl 25μg/h" is printed

in blue ink

Fenta 50: square patches of an area of 15 cm². On the back of the patch "fentanyl 50μg/h" is printed

in blue ink

Fenta 75: square patches of an area of 22.5 cm². On the back of the patch "fentanyl 75μg/h" is

printed in blue ink

Fenta 100: square patches of an area of 30 cm². On the back of the patch "fentanyl 100μg/h" is

printed in blue ink

Registration holder: Rafa Laboratories Ltd., P.O. Box 405, Jerusalem 9100301

Medicine registration number in the National Medicines Registry of the Ministry of Health:

Fenta 12: 1373931638, Fenta 25: 1363731287, Fenta 50: 1363831288, Fenta 75: 1363931289,

Fenta 100: 1364031290.

This leaflet was checked and approved by the Ministry of Health in January 2015.

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Fenta-DL-Jan 2015-May 2019_box_02

1. Name of the medicinal product

Fenta 12, Fenta 25, Fenta 50, Fenta 75, Fenta 100

2. Qualitative and quantitative composition

Fenta 12: Each patch releases 12.5 micrograms fentanyl per hour. Each patch of 3.75 cm

contains

2.063 mg fentanyl.

Fenta 25: Each patch releases 25 micrograms fentanyl per hour. Each patch of 7.5 cm

contains

4.125 mg fentanyl.

Fenta 50: Each patch releases 50 micrograms fentanyl per hour. Each patch of 15 cm

contains

8.25 mg fentanyl.

Fenta 75: Each patch releases 75 micrograms fentanyl per hour. Each patch of 22.5 cm

contains

12.375 mg fentanyl.

Fenta 100: Each patch releases 100 micrograms fentanyl per hour. Each patch of 30 cm

contains

16.5 mg fentanyl.

For a full list of excipients, see section 6.1.

3. Pharmaceutical form

Transdermal matrix patch.

Each patch is marked:

Fenta 12:Transparent and colourless patch with blue imprint on the backing foil: “fentanyl 12 µg/h“.

Fenta 25:Transparent and colourless patch with blue imprint on the backing foil: “fentanyl 25 µg/h“.

Fenta 50:Transparent and colourless patch with blue imprint on the backing foil: “fentanyl 50 µg/h“.

Fenta 75:Transparent and colourless patch with blue imprint on the backing foil: “fentanyl 75 µg/h“.

Fenta 100:Transparent and colourless patch with blue imprint on the backing foil: “fentanyl 100 µg/h“.

4. Clinical particulars

WARNING: RISKS FROM CONCOMITANT USE WITH BENZODIAZEPINES OR

OTHER CNS DEPRESSANTS

Concomitant use of opioids with benzodiazepines or other central nervous system

(CNS) depressants, including alcohol, may result in profound sedation, respiratory

depression, coma, and death [see section 4.5].

Reserve concomitant prescribing of these drugs for use in patients for whom

alternative treatment options are inadequate.

Limit dosages and durations to the minimum required.

Follow patients for signs and symptoms of respiratory depression and sedation.

4.1 Therapeutic indications

Management of chronic pain and intractable pain requiring opioid analgesia. Fenta should only be used

in patients who are already receiving opioid therapy who have demonstrated opioid tolerance.

4.2 Posology and method of administration

For transdermal use.

Fenta should be applied to non-irritated and non-irradiated skin on a flat surface of the torso or upper

arm. In young children, the upper back is the preferred location to apply the patch, to minimise the

potential of the child removing the patch. 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 Fenta 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.

Fenta 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.

Fenta 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.

Initial dose selection

The appropriate initiating dose of Fenta should be based on the patient's current opioid use. Fenta

should be used in patients who have demonstrated opioid tolerance. Other factors to be considered are

the current general condition and medical status of the patient, including body size, age, and extent of

debilitation as well as degree of opioid tolerance.

Adults:

Opioid-tolerant patients

To convert opioid-tolerant patients from oral or parenteral opioids to Fenta refer to Equianalgesic

potency conversion below. The dosage may subsequently be titrated upwards or downwards, if

required, in increments of either 12.5 or 25 mcg/hr to achieve the lowest appropriate dose of Fenta

depending on response and supplementary analgesic requirements.

Equianalgesic potency conversion

1. Calculate the previous 24-hour analgesic requirement.

2. Convert this amount to the equianalgesic oral morphine dose using Table 1. All IM and oral doses in

this chart are considered equivalent to 10 mg of IM morphine in analgesic effect.

3. To derive the dosage of Fenta corresponding to the calculated 24-hour, equianalgesic morphine

dosage, use the dosage-conversion Table 2 or Table 3 as follows:

Table 2 is for adult patients who have been stabilised on oral morphine or another immediate-release

opioid over several weeks and who need opioid rotation (conversion ratio of oral morphine to

transdermal fentanyl approximately equal to 150:1).

Table 3 is for highly opioid-tolerant adult patients who have been on a stable and well-tolerated opioid

regimen for a long period, and who need opioid rotation (conversion ratio of oral morphine to

transdermal fentanyl approximately equal to 100:1).

Tables 2 and 3 should not be used to switch from transdermal fentanyl to another opioid

treatment.

Table 1 Equianalgesic potency conversion

Drug name

Equianalgesic dose (mg)

IM*

Oral

morphine

10

30-40 (assuming repeated dosing)**

hydromorphone

1.5

7.5

methadone

10

20

oxycodone

15

30

levorphanol

2

4

oxymorphone

1

10 (rectal)

diamorphine

5

60

pethidine

75

—

codeine

130

200

buprenorphine

0.4

0.8 (sublingual)

* Based on single-dose studies in which an IM dose of each drug listed was compared with morphine to

establish the relative potency. Oral doses are those recommended when changing from a parenteral to

an oral route.

** The oral/IM potency for morphine is based on clinical experience in patients with chronic pain.

Reference: Adapted from Foley KM. The treatment of cancer pain. NEJM 1985; 313 (2): 84-95, with

updates.

Table 2: Recommended starting dosage of Fenta based upon daily oral morphine dosage

1

(for

patients stabilised on oral morphine or immediate release opioid for several weeks and who

need opioid rotation)

1

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

fentanyl transdermal patch.

Table 3: Recommended starting dosage of Fenta based upon daily oral morphine dosage (for

patients on stable and well tolerated opioid therapy for long periods and who need opioid

rotation)

Oral 24-hour morphine

(mg/day)

Fenta

Dosage

(mcg/hr)

≤ 44

12.5

45-89

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

Oral 24-hour morphine

(mg/day)

Fenta

Dosage

(mcg/hr)

<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

Previous analgesic therapy should be phased out gradually from the time of the first patch application

until analgesic efficacy with Fenta is attained. For opioid tolerant patients, the initial evaluation of the

analgesic effect of Fenta 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 Fenta patch should be replaced every 72 hours. The dose should be titrated individually until a

balance between analgesic efficacy and tolerability 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. If analgesia is insufficient at the end of the initial application period, the dose may be

increased. Dose adjustment, when necessary, should normally be performed in the following titration

steps from 25 mcg/hr up to 75 mcg/hr: 25 mcg/hr, 37 mcg/hr, 50 mcg/hr, 62 mcg/hr and 75 mcg/hr;

thereafter dose adjustments should normally be performed in 25 mcg/hr increments, although the

supplementary analgesic requirements (oral morphine 90 mg/day ≈ Fenta 25 mcg/hr) and pain status of

the patient should be taken into account. More than one Fenta patch 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

Fenta dose exceeds 300 mcg/hr.

Discontinuation of Fenta

If discontinuation of Fenta is necessary, any replacement with other opioids should be gradual, starting

at a low dose and increasing slowly. This is because fentanyl concentrations fall gradually after Fenta is

removed, it takes 17 hours or more for the fentanyl serum concentrations to decrease 50% (see Section

5.2, Pharmacokinetic Properties). As a general rule, the discontinuation of opioid analgesia should be

gradual, in order to prevent withdrawal symptoms.

Opioid withdrawal symptoms (See section 4.8, Undesirable effects) are possible in some patients after

conversion or dose adjustment.

Table 2 and Table 3 should not be used to convert from Fenta to other therapies to avoid overestimating

the new analgesic dose and potentially causing overdose.

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. Elderly, cachectic,

or debilitated patients should be observed carefully for signs of fentanyl toxicity and the dose reduced if

necessary (see section 5.2 Pharmacokinetic properties).

Paediatric population

Children aged 16 years and above: follow adult dosage

Children aged 2 to16 years old:

Fenta 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 Fenta refer to Table 4, Recommended Fenta dose based upon daily oral morphine

dose.

Table 4: Recommended Fenta dose based upon daily oral morphine dose

Oral 24-Hour Morphine (mg/day)

Fenta (mcg/hr)

For paediatric patients

30 - 44

12.5

.

45 - 134

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

fentanyl transdermal patch.

Conversion to Fenta doses greater than 25 mcg/hr 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 fentanyl transdermal patch of 12.5 mcg/hr. It should be noted that this conversion

schedule for children only applies to the switch from oral morphine (or its equivalent) to Fenta patches.

The conversion schedule should not be used to convert from Fenta into other opioids, as overdosing

could then occur.

The analgesic effect of the first dose of Fenta patches will not be optimal within the first 24 hours.

Therefore, during the first 12 hours after switching to Fenta, 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 Fenta

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 Fenta 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 12.5 mcg/hr steps.

4.3 Contraindications

Fenta is contraindicated in patients with known hypersensitivity to fentanyl or to the excipients present in

the patch.

Fenta is a sustained-release preparation indicated for the treatment of chronic intractable pain and is

contraindicated in acute or postoperative pain because there is no opportunity for dosage titration during

short term use and the possibility of serious or life-threatening respiratory depression.

Fenta is contraindicated in patients taking monoamine oxidase (MAO) inhibitors, or within 14 days of

such therapy.

4.4 Special warnings and precautions for use

PATIENTS WHO HAVE EXPERIENCED SERIOUS ADVERSE EVENTS SHOULD BE MONITORED

FOR AT LEAST 24 HOURS AFTER FENTA REMOVAL OR MORE AS CLINICAL SYMPTOMS

DICTATE BECAUSE SERUM FENTANYL CONCENTRATIONS DECLINE GRADUALLY AND ARE

REDUCED BY ABOUT 50% 17 (RANGE 13-22) HOURS LATER. (see section 5.2, Pharmacokinetic

Properties)

It is not possible to ensure the interchangeability of different makes of fentanyl transdermal patches in

individual patients. Therefore, it should be emphasised that patients should not be changed from one

make of fentanyl transdermal patches to another without specific counselling on the change from their

healthcare professionals.

Fenta should be kept out of reach and sight of children at all times before and after use.

Do not cut Fenta patches. A patch that has been divided, cut or damaged in any way should not be

used.

Use of fentanyl transdermal patch in opioid-naïve patients has been associated with very rare cases of

significant respiratory depression and/or fatality when used as initial opioid therapy. The potential for

serious or life-threatening hypoventilation exists even if the lowest dose of Fenta is used in initiating

therapy in opioid-naïve patients. Therefore, Fenta should only be used in patients who have

demonstrated opioid tolerance (See Section 4.2, Posology and method of administration).

When Fenta is administered for chronic intractable pain that will require prolonged treatment, it is

strongly recommended that the physician defines treatment outcomes with regards to pain relief and

functional improvement in accordance with locally defined pain management guidelines. Physician and

patient should agree to discontinue treatment if these objectives are not met.

Respiratory depression

As with all potent opioids, some patients may experience significant respiratory depression with Fenta;

patients must be observed for these effects. Respiratory depression may persist beyond the removal of

the Fenta patch. The incidence of respiratory depression increases as the Fenta dose is increased (see

Section 4.9, Overdose). CNS active drugs may increase the respiratory depression (see section 4.5,

Interaction with other medicinal products and other forms of interaction).

Serotonin Syndrome

Caution is advised when Fenta is coadministered with drugs that affect the serotonergic

neurotransmitter systems.

The development of a potentially life-threatening serotonin syndrome may occur with the concomitant

use of serotonergic drugs such as Selective Serotonin Re-uptake Inhibitors (SSRIs) and Serotonin

Norepinephrine Re-uptake Inhibitors (SNRIs), and with drugs which impair metabolism of serotonin

(including Monoamine Oxidase Inhibitors [MAOIs]). This may occur within the recommended dose.

Serotonin syndrome may include mental-status changes (e.g., agitation, hallucinations, coma),

autonomic instability (e.g, tachycardia, labile blood pressure, hyperthermia), neuromuscular

abnormalities (e.g. hyper-reflexia, incoordination, rigidity), and/or gastrointestinal symptoms (e.g,

nausea, vomiting, diarrhoea).

If serotonin syndrome is suspected, rapid discontinuation of Fenta should be considered.

Interactions with other Medicinal Products:

Interactions with CYP3A4 Inhibitors

The concomitant use of Fenta with cytochrome P450 3A4 inhibitors (e.g. ritonavir, ketoconazole,

itraconazole, troleandomycin, clarithromycin, erythromycin, 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 cytochrome P450 3A4 inhibitors is not recommended unless the patient is

closely monitored. Patients, especially those who are receiving Fenta and CYP3A4 inhibitors, should be

monitored for signs of respiratory depression and dosage adjustments should be made if warranted.

Concomitant use of mixed agonists/antagonists

The concomitant use of buprenorphine, nalbuphine or pentazocine is not recommended (see also

Section 4.5, Interaction with other medicinal products and other forms of interaction).

Chronic pulmonary disease

Fentanyl, like other opioids, may have more severe adverse effects in patients with chronic obstructive

or other pulmonary disease. In such patients, opioids may decrease respiratory drive and increase

airway resistance.

Drug dependence and potential for abuse

Tolerance, physical dependence and psychological dependence may develop upon repeated

administration of opioids such as fentanyl. 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 Fenta may result in overdose and/or death.

Increased intracranial pressure

Fenta should be used with caution in patients who may be particularly susceptible to the intracranial

effects of CO

retention such as those with evidence of increased intracranial pressure, impaired

consciousness or coma. Fenta should be used with caution in patients with brain tumours.

Cardiac disease

Fentanyl may produce bradycardia and Fenta should therefore be administered with caution to patients

with bradyarrhythmias.

Opioids may cause hypotension, especially in patients with acute hypovolaemia. Underlying,

symptomatic hypotension and/or hypovolaemia should be corrected before treatment with fentanyl

transdermal patches is initiated.

Hepatic impairment

Because fentanyl is metabolised to inactive metabolites in the liver, hepatic impairment might delay its

elimination. If patients with hepatic impairment receive Fenta, they should be observed carefully for

signs of fentanyl toxicity and the dose of Fenta reduced if necessary (see section 5.2 Pharmacokinetic

properties).

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 kidney. If patients with renal impairment receive Fenta, they

should be observed carefully for signs of fentanyl toxicity and the dose reduced if necessary (see

section 5.2 Pharmacokinetic properties).

Patients with fever/external heat

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 Fenta 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 Fenta transdermal system

increased mean fentanyl AUC values by 120% and mean Cmax values by 61%.

All patients should be advised to avoid exposing the Fenta application site to direct external heat

sources such as heating pads, hot water bottles, electric blankets, heated water beds, heat or tanning

lamps, intensive sun bathing, prolonged hot baths, saunas or hot whirlpool spa baths while wearing the

patch, since there is potential for temperature dependent increases in release of fentanyl from the patch.

Accidental Exposure by Patch Transfer

Accidental transfer of a fentanyl transdermal patch to the skin of a non- patch wearer (particularly a

child), while sharing a bed or being in close physical contact with a patch wearer, may result in an opioid

overdose for the non-patch wearer. Patients should be advised that if accidental patch transfer occurs,

the transferred patch must be removed immediately from the skin of the non-patch wearer. (See Section

4.9, Overdose).

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. If elderly patients

receive Fenta, they should be observed carefully for signs of fentanyl toxicity and the dose reduced if

necessary (see Section 5.2, Pharmacokinetic properties).

Gastrointestinal Tract

Opioids increase the tone and decrease the propulsive contractions of the smooth muscle of the

gastrointestinal tract. The resultant prolongation in gastrointestinal transit time may be responsible for

the constipating effect of fentanyl. Patients should be advised on measures to prevent constipation and

prophylactic laxative use should be considered. Extra caution should be used in patients with chronic

constipation. If paralytic ileus is present or suspected, treatment with Fenta should be stopped.

Use in paediatric patients

Fenta 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 Fenta administered (see Table 2 in section 4.2, Posology and method of administration).

Fentanyl transdermal patch has not been studied in children under 2 years of age and so should not be

used in these children. Fenta should be administered only to opioid-tolerant children age 2 years or

older (see section 4.2, Posology and method of administration).

To guard against accidental ingestion by children, use caution when choosing the application site for

Fenta (see section 4.2, Posology and method of administration) and monitor adhesion of the patch

closely.

Patch disposal

Used patches may contain significant residues of active substance. After removal, therefore, used

patches should be folded firmly in half, adhesive side inwards, so that the adhesive is not exposed, and

then discarded safely and out of the sight and reach of children according to the instructions in the pack.

Lactation

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

Fenta (see also Section 4.6, Pregnancy and lactation).

Patients with myasthenia gravis

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

myasthenia gravis.

4.5 Interaction with other medicinal products and other forms of interaction

The concomitant use of other Central Nervous System depressants, including opioids; sedatives,

anxiolytics or hypnotics (such as benzodiazepines), general anaesthetics, phenothiazines, tranquilizers,

antipsychotics, skeletal muscle relaxants, sedating antihistamines and alcoholic beverages may produce

additive depressant effects; hypoventilation, hypotension and profound sedation, coma or death may

occur. Therefore, the use of any of the above mentioned concomitant drugs requires special care and

observation.

Fentanyl, a high clearance drug, is rapidly and extensively metabolised mainly by CYP3A4.

The concomitant use of transdermal fentanyl with cytochrome P450 3A4 (CYP3A4) inhibitors (e.g.

ritonavir, ketoconazole, itraconazole, fluconazole, voriconazole, 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. The concomitant use of CYP3A4 inhibitors and transdermal fentanyl is not recommended,

unless the patient is closely monitored (see Section 4.4, Special Warnings and Precautions for Use).

The concomitant use with CYP3A4 inducers (e.g. rifampicin, carbamazepine, phenobarbital, phenytoin)

could result in a decrease in fentanyl plasma concentrations and a decreased therapeutic effect. This

may require a dose adjustment of transdermal fentanyl. After stopping the treatment of a CYP3A4

inducer, the effects of the inducer decline gradually and may result in a fentanyl plasma increase

concentration which could increase or prolong both the therapeutic and adverse effects, and may cause

serious respiratory depression. In this situation, careful monitoring and dose adjustment should be made

if warranted.

Monoamine Oxidase Inhibitors (MAOI)

Fenta is not recommended for use in patients who require the concomitant administration of an MAOI.

Severe and unpredictable interactions with MAOIs, involving the potentiation of opiate effects or the

potentiation of serotoninergic effects, have been reported. Therefore, Fenta should not be used within

14 days after discontinuation of treatment with MAOIs.

Serotonergic Drugs

Coadministration of transdermal fentanyl with a serotonergic agent, such as a Selective Serotonin Re-

uptake Inhibitor (SSRI) or a Serotonin Norepinephrine Re-uptake Inhibitor (SNRI) or a Monoamine

Oxidase Inhibitor (MAOI), may increase the risk of serotonin syndrome, a potentially life-threatening

condition.

Concomitant use of mixed agonists/antagonists

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 dependent patients (see also

Section 4.4, Special Warnings and Precautions for Use).

4.6 Pregnancy and lactation

There are no adequate data from the use of fentanyl transdermal patch in pregnant women. Studies in

animals have shown some reproductive toxicity (see section 5.3, Preclinical safety data). The potential

risk for humans is unknown, although in other formulations, fentanyl as an IV anaesthetic has been

found to cross the placenta in early human pregnancies. Neonatal withdrawal syndrome has been

reported in newborn infants with chronic maternal use of Fenta during pregnancy. Fenta should not be

used during pregnancy unless clearly necessary.

Use of Fenta during childbirth is not recommended because it should not be used in the management of

acute or postoperative pain (see section 4.3, Contraindications and 4.4, Special Warning and

Precautions). Moreover, because fentanyl passes through the placenta, the use of Fenta during

childbirth might result in respiratory depression in the newborn infant.

Fentanyl is excreted into breast milk and may cause sedation and respiratory depression in the

breastfed infant. Breastfeeding should therefore be discontinued during treatment with Fenta and for at

least 72 hours after removal of the patch.

4.7 Effects on ability to drive and use machines

Fenta may impair the mental and/or physical ability required to perform potentially hazardous tasks such

as driving a car or operating machinery.

This medicine can impair cognitive function and can affect a patient's ability to drive safely.

Patients should be told:

The medicine is likely to affect your ability to drive

Do not drive until you know how the medicine affects you

4.8 Undesirable effects

The safety of fentanyl transdermal patch was evaluated in 1854 adult and paediatric subjects who

participated in 11 clinical trials (double-blind fentanyl transdermal patch [placebo or active control]

and/or open label fentanyl transdermal patch [no control or active control]) used for the management of

chronic malignant or non-malignant pain. These subjects took at least one dose of fentanyl transdermal

patch and provided safety data. Based on pooled safety data from these clinical trials, the most

commonly reported (ie ≥10% incidence) Adverse Drug Reactions (ADRs) were (with % incidence):

nausea (35.7%), vomiting (23.2%), constipation (23.1%), somnolence (15.0%), dizziness (13.1%),

headache (11.8%) and insomnia (10.2%).

The ADRs reported with the use of fentanyl transdermal patch from these clinical trials, including the

above-mentioned ADRs, and from post-marketing experiences are listed below in Table A.

The displayed frequency categories use the following convention: very common (≥1/10); common

(≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000);

and not known (cannot be estimated from the available clinical trial data).

Table A: Adverse Drug Reactions in Adult and Paediatric Subjects

System Organ Class

Adverse Drug Reactions

Frequency Category

Very Common

(≥1/10)

Common

(≥1/100 to <1/10)

Uncommon

(≥1/1,000 to

<1/100)

Rare

(≥1/10,000 to

<1/1,000)

Not Known

Immune System

Disorders

Hypersensitivity

Anaphylactic

shock,

Anaphylactic

reaction,

Anaphylactoid

reaction

Metabolism and Nutrition

Disorders

Anorexia

Psychiatric Disorders

Insomnia,

Somnolence,

Depression,

Anxiety,

Confusional state,

Hallucination

Agitation,

Disorientation,

Euphoric mood

Nervous System

Disorders

Dizziness,

Headache

Tremor,

Paraesthesia

Hypoaesthesia,

Convulsion

(including clonic

convulsions and

grand mal

convulsion),

Amnesia,

Depressed level of

consciousness,

Loss of

consciousness

Eye Disorders

Vision blurred

Miosis

Ear and Labyrinth

Disorders

Vertigo

Cardiac Disorders

Palpitations,

Tachycardia

Bradycardia,

Cyanosis

Vascular Disorders

Hypertension

Hypotension

Respiratory, Thoracic

and Mediastinal

Disorders

Dyspnoea

Respiratory

depression,

Respiratory distress

Apnoea,

Hypoventilation

Bradypnoea

Gastrointestinal

Disorders

Nausea, Vomiting,

Constipation

Diarrhoea, Dry

mouth, Abdominal

pain, Upper

abdominal pain,

Dyspepsia

Ileus

Subileus

Skin and Subcutaneous

Tissue Disorders

Hyperhidrosis,

Pruritus, Rash,

Erythema

Eczema, Allergic

dermatitis, Skin

disorder,

Dermatitis, contact

dermatitis

Musculoskeletal and

Connective Tissue

Disorders

Muscle spasms

Muscle twitching

Renal and Urinary

Disorders

Urinary retention

Reproductive System and

Breast Disorders

Erectile

dysfunction, Sexual

dysfunction

General Disorders and

Administration Site

Conditions

Fatigue,

Peripheral,

oedema Asthenia,

Malaise, Feeling

cold

Application site

reaction, Influenza

like illness, Feeling

of body

temperature

change, Application

site

hypersensitivity,

Drug withdrawal

syndrome

Pyrexia

Application site

dermatitis,

Application site

eczema

Paediatric Subjects

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 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.

The safety of fentanyl transdermal patch was evaluated in 289 paediatric subjects (<18 years) who

participated in 3 clinical trials for the management of chronic or continuous pain of malignant or non-

malignant origin. These subjects took at least one dose of fentanyl transdermal patch and provided

safety data. Although the enrolment criteria for the paediatric studies restricted enrolment to subjects

who were a minimum of 2 years of age, 2 subjects in these studies received their first dose of fentanyl

transdermal patch at an age of 23 months.

Based on pooled safety data from these 3 clinical trials in paediatric subjects, the most commonly

reported (ie ≥10% incidence) Adverse Drug Reactions (ADRs) were (with % incidence): vomiting

(33.9%), nausea (23.5%), headache (16.3%), constipation (13.5%), diarrhoea (12.8%), and pruritus

(12.8%). Table B displays all ADRs reported in fentanyl transdermal patch -treated paediatric subjects in

the aforementioned clinical trials.

The ADRs for the paediatric population presented in Table B were assigned to frequency categories

using the same conventions as used for Table A.

Table B: Adverse Drug Reactions in Paediatric Subjects in clinical trials

System Organ Class

Adverse Drug Reactions

Frequency Category

Very Common

(≥1/10)

Common

(≥1/100 to <1/10)

Uncommon

(≥1/1,000 to <1/100)

Immune System Disorders

Hypersensitivity

Metabolism and Nutrition

Disorders

Anorexia

Psychiatric Disorders

Insomnia Somnolence, Anxiety,

Depression, Hallucination

Confusional state

Nervous System Disorders

Headache

Dizziness, Tremor,

Hypoaesthesia

Paraesthesia

Eye Disorders

Miosis

Ear and Labyrinth Disorders

Vertigo

Cardiac Disorders

Cyanosis

Respiratory, Thoracic and

Mediastinal Disorders

Respiratory depression

Gastrointestinal Disorders

Vomiting, Nausea,

Constipation, Diarrhoea

Abdominal pain, Upper

abdominal pain, Dry mouth

Skin and Subcutaneous

Tissue Disorders

Pruritus

Rash, Hyperhidrosis, Erythema Contact dermatitis,

Skin disorder,

Allergic dermatitis,

Eczema

Musculoskeletal and

Connective Tissue Disorders

Muscle spasms

Renal and Urinary Disorders

Urinary retention

General Disorders and

Administration Site

Conditions

Peripheral oedema Fatigue,

Application site reaction,

Asthenia

Drug withdrawal

syndrome, Influenza-

like illness

As with other opioid analgesics, tolerance, physical dependence, and psychological dependence can

develop on repeated use of Fenta (see Section 4.4, Special warnings and precautions for use).

Opioid withdrawal symptoms (such as nausea, vomiting, diarrhoea, anxiety, and shivering) are possible

in some patients after conversion from their previous opioid analgesic to Fenta or if therapy is stopped

suddenly (see Section 4.2, Posology and method of administration).

There have been reports of newborn infants experiencing neonatal withdrawal syndrome when mothers

chronically used fentanyl transdermal patch during pregnancy (see Section 4.6, Pregnancy and

lactation).

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows

continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are

asked to report any suspected adverse reactions

via the national reporting system at:

adr@MOH.HEALTH.GOV.IL

4.9 Overdose

Symptoms

The manifestations of fentanyl overdosage are an extension of its pharmacological actions, the most

serious effect being respiratory depression.

Treatment

For management of respiratory depression, immediate countermeasures include removing Fenta and

physically or verbally stimulating the patient. These actions can be followed by administration of a

specific opioid antagonist such as naloxone. Respiratory depression following an overdose may outlast

the duration of action of the opioid antagonist. The interval between IV antagonist doses should be

carefully chosen because of the possibility of re-narcotization after the patch is removed; repeated

administration or a continuous infusion of naloxone may be necessary. Reversal of the narcotic effect

may result in acute onset of pain and release of catecholamines.

If the clinical situation warrants, a patent airway should be established and maintained, possibly with an

oropharyngeal airway or endotracheal tube and oxygen should be administered and respiration assisted

or controlled, as appropriate. Adequate body temperature and fluid intake should be maintained.

If severe or persistent hypotension occurs, hypovolaemia should be considered, and the condition

should be managed with appropriate parenteral fluid therapy.

5. Pharmacological properties

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: opioids: phenylpiperidine derivatives

ATC code: N02A B03

Fentanyl is an opioid analgesic with a high affinity for the µ-opioid receptor.

Paediatric Patients

The safety of fentanyl transdermal patch was evaluated in three open-label trials in 289 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 44 mg oral morphine per day was replaced by one fentanyl

transdermal patch of 12.5 mcg/hr. Starting doses of 25 μg/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

Adults

Fenta provides continuous systemic delivery of fentanyl over the 72 hour administration period. Fentanyl

is released at a relatively constant rate. The concentration gradient existing between the matrix and the

lower concentration in the skin drives drug release. After the first Fenta 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. The serum fentanyl

concentrations attained are proportional to the Fenta patch size. By the second 72-hour application, a

steady state serum concentration is reached and is maintained during subsequent applications of a

patch of the same size.

A pharmacokinetic model has suggested that serum fentanyl concentrations may increase by 14%

(range 0- 26%) if a new patch is applied after 24 hours rather than the recommended 72-hour

application.

Distribution

The plasma-protein binding of fentanyl is about 84%.

Metabolism

Fentanyl is a high clearance drug and is rapidly and extensively metabolised primarily by CYP3A4 in the

liver. The major metabolite, norfentanyl, is inactive. Skin does not appear to metabolise fentanyl

delivered transdermally. This was determined in a human keratinocyte cell assay and in clinical studies

in which 92% of the dose delivered from the system was accounted for as unchanged fentanyl that

appeared in the systemic circulation.

Elimination

After Fenta is removed, serum fentanyl concentrations decline gradually, falling about 50% in about 17

(range 13-22) hours following a 24-hour application. Following a 72-hour application, the mean half-life

ranges from 20-27 hours. Continued absorption of fentanyl from the skin accounts for a slower

disappearance of the drug from the serum than is seen after an IV infusion, where the apparent half-life

is approximately 7 (range 3-12 hours). Fentanyl is metabolised primarily in the liver. Within 72 hours of

IV fentanyl administration, approximately 75% of the fentanyl dose 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. Mean values for unbound fractions of fentanyl in plasma are estimated to be

between 13 and 21%.

Special populations

Elderly

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. In a study

conducted with fentanyl transdermal patch, healthy elderly subjects had fentanyl pharmacokinetics

which did not differ significantly from healthy young subjects, although peak serum concentrations

tended to be lower and mean half-life values were prolonged to approximately 34 hours. Elderly patients

should be observed carefully for signs of fentanyl toxicity and the dose reduced if necessary (see

section 4.2 Posology and method of administration).

Paediatric Patients

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.

Hepatic impairment

In a study conducted with patients with hepatic cirrhosis, the pharmacokinetics of a single 50 μg/hr

application of fentanyl transdermal patch were assessed. Although t

and t

were not altered, the

mean plasma C

and AUC values increased by approximately 35% and 73%, respectively, in these

patients. Patients with hepatic impairment should be observed carefully for signs of fentanyl toxicity and

the dose of Fenta reduced if necessary (see section 4.4 Special warnings and precautions for use).

Renal impairment

Data obtained from a study administering IV fentanyl in patients undergoing renal transplantation

suggest that the clearance of fentanyl may be reduced in this patient population. If patients with renal

impairment receive Fenta, they should be observed carefully for signs of fentanyl toxicity and the dose

reduced if necessary (see section 4.4 Special warnings and precautions for use).

5.3 Preclinical safety data

In vitro fentanyl showed, like other opioid analgesics, mutagenic effects in a mammalian cell culture

assay, only at cytotoxic concentrations and along with metabolic activation. Fentanyl showed no

evidence of mutagenicity when tested in in vivo rodent studies and bacterial assays.

In a two-year carcinogenicity study conducted in rats, fentanyl was not associated with an increased

incidence of tumours at subcutaneous doses up to 33 µg/kg/day in males or 100 µg/kg/day in females.

The overall exposure (AUC

0-24 h

) achieved in this study was <40% of that likely to be achieved clinically

at the highest dose strength of fentanyl transdermal patch, 100 mcg/h, due to the maximum tolerated

plasma concentrations in rats.

Fentanyl was assessed for effects on fetal development in the rat and rabbit. Some tests on female rats

showed reduced fertility as well as embryo mortality and transient development delays. These findings

were related to maternal toxicity and not a direct effect of the drug on the developing embryo. These

changes were observed at steady-state plasma concentrations equivalent to (C

human

= 1.1)

and daily exposures slightly greater (AUC

0-24, rat

/ AUC

0-24, human

= 1.5) than those observed in the clinic

following use of the 100 mcg/h patch. No effects were observed in the rabbit, where a maximum plasma

concentration 6.6-fold the human steady-state fentanyl plasma concentration was achieved. The daily

exposure ratio (AUC

4-24, rabbit

/ AUC

0-24, human

= 1.1) was equivalent to those observed in the clinic

following use of the 100 mcg/h patch. There was no evidence of teratogenic effects.

6. Pharmaceutical particulars

6.1 List of excipients

Polyacrylate adhesive layer.

6.2 Incompatibilities

To prevent interference with the adhesive properties of Fenta, no creams, oils, lotions or powder should

be applied to the skin area when the Fenta transdermal patch is applied.

6.3 Special precautions for storage

This medicinal product does not require any special storage precautions.

6.4 Nature and contents of container

Each transdermal patch is packed in a separate sachet. The pack contains 5 transdermal patches

6.5 Special precautions for disposal and other handling

Please refer to section 4.2 for instructions on how to apply the patch. There are no safety and

pharmacokinetic data available for other application sites.

After removal, the used patch should be folded in half, adhesive side inwards so that the adhesive is not

exposed, placed in the original sachet and then discarded safely out of the sight and reach of children.

Unused patches should be returned to the pharmacy.

Wash hands with water only after applying or removing the patch.

7. Registration holder:

Rafa Laboratories Ltd., P.O.Box 405, Jerusalem 9100301.

Registration numbers:

Fenta 12: 1373931638

Fenta 25: 1363731287

Fenta 50: 1363831288

Fenta 75:

1363931289

Fenta 100: 1364031290

The format of this leaflet was determined by the Ministry of Health that checked and approved its

content in January 2015.