Actiq 600 micrograms compressed lozenge with integral oromucosal applicator

Ireland - English - HPRA (Health Products Regulatory Authority)

Buy It Now

Active ingredient:
Fentanyl
Available from:
Teva Pharma B.V.
ATC code:
N02AB; N02AB03
INN (International Name):
Fentanyl
Dosage:
600 microgram(s)
Pharmaceutical form:
Compressed lozenge
Prescription type:
Product subject to prescription which may not be renewed (A)
Therapeutic area:
Phenylpiperidine derivatives; fentanyl
Authorization status:
Marketed
Authorization number:
PA0749/195/003
Authorization date:
2002-01-23

PACKAGE LEAFLET

Package leaflet: Information for the user

ACTIQ 200 micrograms compressed lozenge with integral oromucosal applicator

ACTIQ 400 micrograms compressed lozenge with integral oromucosal applicator

ACTIQ 600 micrograms compressed lozenge with integral oromucosal applicator

ACTIQ 800 micrograms compressed lozenge with integral oromucosal applicator

ACTIQ 1,200 micrograms compressed lozenge with integral oromucosal applicator

ACTIQ 1,600 micrograms compressed lozenge with integral oromucosal applicator

Fentanyl

Read all of this leaflet carefully before you start using this medicine because it contains important

information for you.

Keep this leaflet. You may need to read it again.

If you have any further questions, ask your doctor or pharmacist.

This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, even if

their signs of illness are the same as yours.

If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects

not listed in this leaflet. See section 4.

What is in this leaflet

What ACTIQ is and what it is used for

What you need to know before you use ACTIQ

How to use ACTIQ

Possible side effects

How to store ACTIQ

Contents of the pack and other information

1.

What ACTIQ is and what it is used for

ACTIQ contains the active substance fentanyl which is a strong pain-relieving medicine known as an opioid.

The ACTIQ unit comes as a lozenge on a stick.

It is used to treat breakthrough pain in adults and adolescents aged 16 years and above with cancer

who are already taking other opioid pain medicines for their persistent (around-the-clock) cancer pain.

Breakthrough pain is additional sudden pain that occurs suddenly in spite of your having taken your

usual opioid pain-relieving medicines.

2.

What you need to know before you use ACTIQ

Do NOT use ACTIQ:

if you are not regularly using a prescribed opioid medicine (e.g. codeine, fentanyl, hydromorphone,

morphine, oxycodone, pethidine), every day on a regular schedule, for at least a week, to control your

persistent pain. If you have not been using these medicines you must not use ACTIQ, because it may

increase the risk that breathing could become dangerously slow and/or shallow, or even stop.

if you are allergic to fentanyl or any of the other ingredients of this medicine (listed in section 6).

if you are currently taking monoamine oxidase (MAO) inhibitors (medicines for severe depression) or

have taken them in the past 2 weeks (see section 2 under “Talk to your doctor or pharmacist BEFORE

using ACTIQ if:”).

if you have severe breathing problems or severe lung problems where you have an obstruction.

if you suffer from short-term pain (e. g. pain from injuries, surgery, headaches or migraines) other than

breakthrough pain.

Do NOT use ACTIQ if any of the above apply to you. If you are not sure, talk to your doctor or pharmacist

BEFORE using ACTIQ.

Warnings and precautions

Keep using the opioid pain medicine you take for your persistent (around-the-clock) cancer pain during your

ACTIQ treatment.

Talk to your doctor or pharmacist BEFORE using ACTIQ if:

Your other opioid pain medicine for your persistent (around-the-clock) cancer pain is not stabilised

yet.

You have any illness that affects your breathing (such as asthma, wheezing, or shortness of breath).

You have a head injury or have had any loss of consciousness.

You have problems with your heart especially slow heart rate.

You have liver or kidney problems - this will affect how your system breaks down the medicine.

You have low blood pressure due to a low amount of fluid in your circulation.

You have diabetes.

You are over 65 years old - you may need a lower dose and any dose increase will be reviewed very

carefully by your doctor.

You use benzodiazepines (see section 2 under ”Other medicines and ACTIQ”). Using benzodiazepines

can increase the chances of getting serious side effects including death.

You use antidepressants or antipsychotics (selective serotonin reuptake inhibitors [SSRIs], serotonin

norepinephrine reuptake inhibitors [SNRIs], monoamine oxidase (MAO) inhibitors; see section 2

under “Do not use ACTIQ” and “Other medicines and ACTIQ”). The use of these medicines with

ACTIQ can lead to a serotonin syndrome a potentially life-threatening condition (see section 2

under “Other medicines and ACTIQ”).

You have a history of alcoholism or any drug abuse or dependence.

You have ever developed adrenal insufficiency or lack of sex hormones (androgen deficiency) with

opioid use, a condition in which the adrenal glands do not produce enough hormones (see section 4

under “Serious side effects”).

You drink alcohol; please refer to section ACTIQ with food, drink and alcohol.

Consult your doctor WHILE using ACTIQ if:

You experience pain or increased sensitivity to pain (hyperalgesia) which does not respond to a higher

dosage of your medicine as prescribed by your doctor.

You exhibit signs of dental decay. ACTIQ contains approximately 2 grams of sugar; frequent use

exposes you to an increased risk of dental decay that may be serious. It is important to take good care

of your teeth during treatment with ACTIQ.

You experience a combination of the following symptoms: nausea, vomiting, anorexia, fatigue,

weakness, dizziness and low blood pressure. Together these symptoms may be a sign of a potentially

life-threatening condition called adrenal insufficiency, a condition in which the adrenal glands do not

produce enough hormones.

Seek URGENT medical advice if:

You experience symptoms such as difficulty in breathing or dizziness, swelling of the tongue, lip or

throat while using ACTIQ. These might be early symptoms of a serious allergic reaction (anaphylaxis,

hypersensitivity; see section 4 under “Serious side effects”)

Children and adolescents

ACTIQ is not recommended for children and adolescents below 16 years of age.

Other medicines and ACTIQ

Do not use this medicine and tell your doctor or pharmacist:

If you are taking other fentanyl treatments that have been prescribed for your breakthrough pain in the

past. If you still have some of these fentanyl treatments at home, check with your pharmacist how to

dispose of them.

If you are using monoamine oxidase (MAO) inhibitors (medicines for severe depression) or have

taken them in the past 2 weeks (see section 2 under “Do NOT use ACTIQ” and “Talk to your doctor

or pharmacist BEFORE using ACTIQ if:”).

Tell your doctor or pharmacist before using ACTIQ if you are taking or have recently taken or might take

any other medicines. This includes medicines obtained without a prescription, including herbal medicines. In

particular, tell your doctor or pharmacist if you are taking any of the following medicines:

Concomitant use of ACTIQ and sedative medicines such as benzodiazepines or related drugs increases

the risk of drowsiness, difficulties in breathing (respiratory depression), coma and may be life-

threatening. Because of this, concomitant use should only be considered when other treatment options

are not possible.

However if your doctor does prescribe ACTIQ together with sedative medicines the dose and duration

of concomitant treatment should be limited by your doctor.

Please tell your doctor about all sedative medicines you are taking (such as sleeping pills, medicines to

treat anxiety, some medicines to treat allergic reactions (antihistamines), or tranquillisers) and follow

your doctor’s dose recommendation closely. It could be helpful to inform friends or relatives to be

aware of the signs and symptoms stated above. Contact your doctor when experiencing such

symptoms.

Some muscle relaxants - such as baclofen, diazepam (see also section “Warnings and precautions”).

Any medicines that might affect how your body breaks down ACTIQ - such as ritonavir or other

medicines that help control HIV infection, other so-called ‘CYP3A4 inhibitors’ such as ketoconazole,

itraconazole, or fluconazole (used for fungal infections) and troleandomycin, clarithromycin, or

erythromycin (medicines for bacterial infections) and so-called ‘CYP3A4 inducers’ such as rifampin

or rifabutin (medicines for bacterial infections), carbamazepine, phenobarbital or phenytoin

(medicines used to treat convulsions/fits).

Certain types of strong pain killers, called partial agonist/antagonists e.g. buprenorphine, nalbuphine

and pentazocine (medicines for treatment of pain). You could experience symptoms of withdrawal

syndrome (nausea, vomiting, diarrhoea, anxiety, chills, tremor, and sweating) while using these

medicines.

Serotonergic medicinal products used to treat depression (antidepressants: such as selective serotonin

reuptake inhibitors [SSRIs] and serotonin norepinephrine reuptake inhibitors [SNRIs]) or

antipsychotics. The use of these medicines with ACTIQ can lead to serotonin syndrome a potentially

life-threatening condition (see section 2 under “Talk to your doctor or pharmacist BEFORE using

ACTIQ if:” and “Do NOT use ACTIQ:”). The symptoms of serotonin syndrome may include mental

status changes (e.g. agitation, hallucinations, coma), and other effects such as body temperature above

38 C, increase in heart rate, unstable blood pressure, and exaggeration of reflexes, muscular rigidity,

lack of coordination and/or gastrointestinal symptoms (e.g. nausea, vomiting, diarrhoea). Your doctor

will tell you whether ACTIQ is suitable for you.

If you are due to have surgery requiring a general anaesthetic speak with your doctor or nurse.

ACTIQ with food, drink and alcohol

ACTIQ may be used before or after meals. However do not use during meals.

You may drink some water before using ACTIQ to help moisten your mouth. However, do not drink

or eat anything while using ACTIQ.

Do not drink grapefruit juice while using ACTIQ. This is because it may affect the way your body

breaks down ACTIQ.

Do not drink alcohol while using ACTIQ. It can increase the chances of getting serious side effects

including death.

Pregnancy and breast-feeding

If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask your

doctor or pharmacist for advice before using this medicine.

Pregnancy

ACTIQ should not be used during pregnancy unless you have discussed this with your doctor.

If ACTIQ is used for a long time during pregnancy, there is a risk of the new-born child having withdrawal

symptoms which might be life-threatening if not recognized and treated by a doctor (see section 4 under

“Other side effects with frequency not known”).

You should not use ACTIQ during child-birth because fentanyl may cause breathing difficulties in the

new-born child.

Breast-feeding

Fentanyl can get into breast milk and may cause side effects in the breast-fed infant. Do not use ACTIQ if

you are breast-feeding. You should not start breast-feeding until at least 5 days after the last dose of ACTIQ.

Driving and using machines

This medicine may affect you being able to drive or use any tools or machines. Talk to your doctor about

whether it is safe for you to drive, or use any tools or machines in the first few hours after using ACTIQ.

Do not drive or use any tools or machines if you: feel sleepy or dizzy; have blurred or double vision; have

difficulty in concentrating. It is important you know how you react to ACTIQ before driving or using any

tools or machines.

ACTIQ contains glucose and sucrose (types of sugar)

If you have been told by your doctor that you cannot tolerate or digest some sugars, talk to your doctor

before using ACTIQ.

Each lozenge contains about 2 grams of glucose. If you have diabetes, you need to take this into

account.

The glucose in the lozenge may be harmful to the teeth. Always make sure you clean your teeth

regularly.

3.

How to use ACTIQ

Always use this medicine exactly as your doctor or pharmacist has told you. Check with your doctor or

pharmacist if you are not sure.

When you first start using ACTIQ, your doctor will work with you to find the dose that will relieve your

breakthrough pain. It is very important that you use ACTIQ exactly as the doctor tells you.

Do not change doses of ACTIQ or your other pain medicines on your own. Change in dose must be

prescribed and checked by your doctor.

If you are not sure about the right dose or if you have questions about using this medicine, talk to your

doctor.

How the medicine gets into your body

When you place the lozenge in your mouth:

The lozenge dissolves and the active substance is released. It takes around 15 minutes for this to

happen.

The active substance is absorbed through the lining of your mouth, into the blood system.

Using the medicine like this allows it to be absorbed quickly. This means that it relieves your breakthrough

pain quickly.

While the right dose is being found

You should start to feel some relief quickly while you are using ACTIQ. However, while you and the doctor

are finding out the dose that controls your breakthrough pain, you may not get enough pain relief 30 minutes

after starting to use one ACTIQ unit (15 minutes from when you finish using the ACTIQ unit). If this

happens, your doctor may allow you to use a second ACTIQ unit of the same strength for that same episode

of breakthrough pain. Do not use a second unit unless your doctor tells you to. Never use more than two

units to treat a single episode of breakthrough pain.

While the right dose is being found, you may need to have more than one strength of ACTIQ units at home.

However, keep only the strengths of ACTIQ units you need in the house. This is to stop possible confusion

or overdose. Talk to your pharmacist about how to dispose of any ACTIQ units you do not need.

How many units to use

Once the right dose has been found with your doctor, use 1 unit for an episode of breakthrough pain. Talk to

your doctor if your right dose of ACTIQ does not relieve your breakthrough pain for several episodes of

breakthrough pain in a row. Your doctor will decide if your dose needs to be changed.

You must let your doctor know immediately if you are using ACTIQ more than four times per day, as a

change may be required to your treatment regimen. Your doctor may change the treatment for your persistent

pain; when your persistent pain is controlled, your doctor may need to change the dose of ACTIQ. If your

doctor suspects ACTIQ-related increased sensitivity to pain (hyperalgesia), a reduction of your ACTIQ dose

may be considered (see section 2 under “Warnings and precautions”). For the most effective relief, let your

doctor know about your pain and how ACTIQ is working for you, so that the dose can be changed if needed.

How to use the medicine

Opening the pack – each ACTIQ unit is sealed in its own blister pack.

Open the pack when you are ready to use it. Do not open it in advance.

Hold the blister pack with the printed side away from you.

Hold the short tab end of the blister pack.

Put scissors close to the end of ACTIQ unit and cut the long tab end completely off (as shown).

Separate the printed backing from the blister pack and pull the printed backing completely off the

blister pack.

Remove the ACTIQ unit from the blister pack and put the lozenge in your mouth straight away.

Using the ACTIQ unit

Put the lozenge between your cheek and gum.

Using the handle, keep moving the lozenge round in your mouth, especially along your cheeks. Twirl

the handle often.

To get the most effective relief, finish the lozenge completely in 15 minutes. If you finish too quickly,

you will swallow more of the medicine and get less relief from your breakthrough pain.

Do not bite or chew the lozenge. This would mean lower blood levels and less pain relief than when

used as directed.

If for some reason you are not finishing the whole lozenge each time you have breakthrough pain, talk

to your doctor.

How often you should use ACTIQ

Once a dose is found that effectively controls your pain, do not use more than four ACTIQ units each day. If

you think you might need to use more than four ACTIQ units per day, talk to your doctor straight away.

How many ACTIQ units you should use

Do not use more than two units to treat any single episode of breakthrough pain.

If you use more ACTIQ than you should

The most common side effects of using too much are feeling sleepy, sick or dizzy.

If you begin to feel dizzy, sick, or very sleepy before the lozenge is completely dissolved, take it out of

your mouth and call another person in your house to help you.

A serious side effect of ACTIQ is slow and/or shallow breathing. This can occur if your dose of ACTIQ is

too high or if you take too much ACTIQ.

If this happens, get medical help straight away.

What to do if a child or adult accidentally takes ACTIQ

If you think someone has accidentally taken ACTIQ, get medical help straight away. Try to keep the person

awake (by calling their name and shaking their arm or shoulder) until emergency help arrives.

If you forget to use ACTIQ

If you still have the breakthrough pain, you may use ACTIQ as your doctor has told you. If the breakthrough

pain has stopped, do not use ACTIQ until the next breakthrough pain episode.

If you stop using ACTIQ

You should discontinue ACTIQ when you no longer have any breakthrough pain. You must however

continue to take your usual opioid pain relieving medicine to treat your persistent cancer pain as advised by

your doctor. You may experience withdrawal symptoms similar to the possible side effects of ACTIQ when

discontinuing ACTIQ. If you experience withdrawal symptoms or if you are concerned about your pain relief

you should contact your doctor. Your doctor will evaluate if you need medicine to reduce or eliminate the

withdrawal symptoms.

If you have any further questions on the use of this medicine, ask your doctor or pharmacist.

4.

Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody gets them. If you notice any

of these, contact your doctor.

Serious side effects

The most serious side effects are shallow breathing, low blood pressure and shock

You or your carer should REMOVE the ACTIQ unit from your mouth, contact your doctor

immediately and call for emergency help if you experience any of the following serious side

effects – you may need urgent medical attention:

Becoming very sleepy or having slow and/or shallow breathing.

Difficulty in breathing or dizziness, swelling of the tongue, lip or throat which may be early

signs of serious allergic reaction.

Note to Carers:

If you see that the patient using ACTIQ has slow and/or shallow breathing or if you have a hard time

waking the person up, take the following steps IMMEDIATELY:

Using the handle, remove the ACTIQ unit from the person’s mouth and keep it out of the reach

of children or pets until it is disposed of.

CALL FOR EMERGENCY HELP.

While waiting for emergency help, if the person seems to be breathing slowly, prompt them to

breathe every 5-10 seconds.

If you feel excessively dizzy, sleepy or otherwise ill while using ACTIQ, use the handle to remove the

lozenge and dispose of it according to the instructions given in this leaflet (see section 5). Then contact

your doctor for further directions on using ACTIQ.

Contact your doctor if you experience a combination of the following symptoms

Nausea, vomiting, loss of appetite, tiredness, weakness, dizziness and low blood pressure

Together these symptoms may be a sign of a potentially life-threatening condition called adrenal

insufficiency, a condition in which the adrenal glands do not produce enough hormones.

Prolonged treatment with fentanyl during pregnancy may cause withdrawal symptoms in the newborn

which can be life-threatening (see section 2 under “Pregnancy and breast-feeding”).

Other side effects

Very common: may affect more than 1 in 10 people

Vomiting, nausea/feeling sick, constipation, stomach (abdominal) pain

Asthenia (weakness), sleepiness, dizziness, headaches

Shortness of breath

Common: may affect up to 1 in 10 people

Confusion, anxiety, seeing or hearing things that are not there (hallucinations), depression, mood

swings

Feeling unwell

Muscle jerks, feeling of dizziness or "spinning", loss of consciousness, sedation, tingling or numbness,

difficulty coordinating movements, increased or altered sensitivity to touch, convulsions (fits)

Dry mouth, mouth inflammation, tongue problems (for example, burning sensation or ulcers), taste

alteration

Wind, abdominal bloating, indigestion, decreased appetite, weight loss

Blurred or double vision

Sweating, skin rash, itchy skin

Difficulty passing urine

Accidental injury (for example, falls)

Uncommon: may affect up to 1 in 100 people

Tooth decay, paralysis of the gut, mouth ulcers, gum bleeding

Coma, slurred speech

Abnormal dreams, feeling detached, abnormal thinking, excessive feeling of well being

Widening of blood vessels

Hives

Frequency not known

The following side effects have also been reported with the use of ACTIQ lozenge but it is not known how

often they may occur:

Receding gums, inflammation of the gum, tooth loss, severe breathing problems, flushing, feeling very

warm, diarrhoea, swelling of arms or legs, fatigue, insomnia, pyrexia, withdrawal syndrome (may

manifest by the occurrence of the following side effects nausea, vomiting, diarrhoea, anxiety, chills,

tremor, and sweating).

Lack of sex hormones (androgen deficiency)

Drug dependence (addiction)

Drug abuse

Delirium (symptoms may include a combination of agitation, restlessness, disorientation, confusion,

fear, seeing or hearing things that are not really there, sleep disturbance, nightmares).

Prolonged treatment with fentanyl during pregnancy may cause withdrawal symptoms in the newborn which

can be life-threatening (see section 2)

Whilst using ACTIQ you may experience irritation, pain and ulcer at the application site and gum bleeding.

Reporting of side effects

If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any

possible side effects not listed in this leaflet. You can also report side effects directly via HPRA

Pharmacovigilance, Earlsfort Terrace, IRL - Dublin 2; Tel: +353 1 6764971; Fax: +353 1 6762517. Website:

www.hpra.ie; E-mail: medsafety@hpra.ie.

By reporting side effects you can help provide more information on the safety of this medicine.

5.

How to store ACTIQ

The pain-relieving medicine in ACTIQ is very strong and could be life-threatening if taken

accidentally by a child. ACTIQ must be kept out of the sight and reach of children.

Do not use ACTIQ after the expiry date shown on the package label and the carton. The expiry date

refers to the last day of that month.

Do not store above 30 °C.

Always keep ACTIQ in its blister package until you are ready to use it. Do not use if the blister

package has been damaged or opened before you are ready to use it.

If you are no longer using ACTIQ, or if you have unused ACTIQ units in your home, return all unused

packs to your doctor or pharmacist.

How to dispose of ACTIQ after use

Partially used ACTIQ lozenge may contain enough medicine to be harmful or life-threatening to a child.

Even if there is a little or no medicine left on the handle, the handle itself must be properly disposed of as

follows:

If the medicine is totally gone, throw the handle away in a waste container that is out of reach of

children and pets.

If any medicine remains on the handle, place the lozenge under hot running water to dissolve the

remainder and then throw the handle away in a waste container that is out of the reach of children and

pets.

If you do not finish the entire lozenge and you cannot immediately dissolve the remaining medicine,

put the lozenge out of the reach of children and pets until such a time as you can dispose of the

partially used lozenge as instructed above.

Do not flush partially used lozenge, handles, or the blister packaging down the toilet.

6.

Contents of the pack and other information

What ACTIQ contains:

The active substance is fentanyl. Each individual lozenge contains either:

200 micrograms fentanyl (as citrate)

400 micrograms fentanyl (as citrate)

600 micrograms fentanyl (as citrate)

800 micrograms fentanyl (as citrate)

1,200 micrograms fentanyl (as citrate)

1,600 micrograms fentanyl (as citrate)

The other ingredients are:

Lozenge:

Dextrates hydrated (equivalent to approximately 2 grams of glucose).

Citric acid, disodium phosphate, artificial berry flavour (maltodextrin, propylene glycol, artificial

flavours, and triethylcitrate), magnesium stearate.

Edible glue used to attach the lozenge to the handle

Modified maize based food starch E 1450, confectioner’s sugar (as sucrose and maize starch), water.

Imprinting ink

Water, de-waxed white shellac, propylene glycol, blue synthetic coal tar dye (E 133), Ammonium

hydroxide (E 527) for pH adjustment

What ACTIQ looks like and contents of the pack

ACTIQ consists of a white to off-white solid lozenge attached to a handle for oromucosal application. The

lozenge may appear slightly mottled on storage. This is due to slight changes in the flavouring agent of the

product and does not affect how the product works in any way.

ACTIQ exists in 6 different strengths: 200, 400, 600, 800, 1,200 and 1,600 micrograms. The dosage strength

is marked on the white lozenge, on the handle, on the blister package and on the carton to ensure that you are

using the right medicine. Each strength is associated with a specific colour.

ACTIQ lozenges are supplied in individual blister packages.

Blister packages are supplied in cartons of 3, 6, 15 or 30 individual ACTIQ units.

Not all pack size may be marketed.

Marketing Authorisation Holder

Teva Pharma B.V.

Swensweg 5,

2031GA Haarlem,

The Netherlands

Manufacturer

Teva Pharmaceuticals Europe B.V.

Swensweg 5

2031 GA HAARLEM

Netherlands

This leaflet was last approved in July 2019.

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Summary of Product Characteristics

1 NAME OF THE MEDICINAL PRODUCT

Actiq 600 micrograms compressed lozenge with integral oromucosal applicator

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

One lozenge contains 600 micrograms fentanyl (as citrate).

Excipients(s) with known effect:

Each lozenge contains dextrates (equivalent to approximately 2 grams of glucose), sucrose (approximately 30 milligrams

confectioner’s sugar) and propylene glycol (part of the artificial berry flavour and imprinting ink) as excipients.

For the full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM

Compressed lozenge with integral oromucosal applicator.

Actiq is formulated as a white to off-white compressed powder medicinal product matrix attached using edible glue to a

fracture resistant radio opaque plastic applicator. The dosage strength is marked on the lozenge and on the plastic applicator.

4 CLINICAL PARTICULARS

4.1 Therapeutic Indications

Actiq is indicated for the management of breakthrough pain in patients already receiving maintenance opioid therapy for

chronic cancer pain. Breakthrough pain is a transitory exacerbation of pain that occurs on a background of otherwise

controlled persistent pain.

Patients receiving maintenance opioid therapy are those who are taking at least 60 mg of oral morphine daily, at least 25

micrograms of transdermal fentanyl per hour, at least 30 mg of oxycodone daily, at least 8 mg of oral hydromorphone daily or

an equianalgesic dose of another opioid for a week or longer.

4.2 Posology and method of administration

Posology

In order to minimise the risks of opioid‑related adverse reactions and to identify the successful dose, it is imperative that

patients be monitored closely by health professionals during the titration process.

ACTIQ is not interchangeable on a mcg to mcg basis with other short‑acting fentanyl products that are indicated for the use of

breakthrough cancer pain, as the pharmacokinetic profiles and/or dosing schedules of these products are significantly different.

Patients should be instructed not to use more than one short‑acting fentanyl product concurrently for the treatment of

breakthrough cancer pain, and to dispose of any fentanyl product prescribed for breakthrough pain (BTP) when switching to

ACTIQ. The number of ACTIQ strengths available to the patient at any time should be minimised to prevent confusion and

potential overdose.

Any unused ACTIQ units that the patient no longer requires must be disposed of properly. Patients must be reminded of the

requirements to keep ACTIQ stored in a location away from children.

Adults

Dose titration and maintenance therapy

ACTIQ should be individually titrated to a successful dose that provides adequate analgesia and minimises adverse reactions. In

clinical trials the successful dose of ACTIQ for breakthrough pain was not predicted from the daily maintenance dose of opioid.

a) Titration

Before patients are titrated with ACTIQ, it is expected that their background persistent pain will be controlled by use of opioid

therapy and that they are typically experiencing no more than 4 episodes of breakthrough pain per day.

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The initial dose of ACTIQ used should be 200 micrograms, titrating upwards as necessary through the range of available

dosage strengths (200, 400, 600, 800, 1,200 and 1,600 micrograms). Patients should be carefully monitored until a dose is

reached that provides adequate analgesia with acceptable adverse reactions using a single dosage unit per episode of

breakthrough pain. This is defined as the successful dose.

During titration, if adequate analgesia is not obtained within 30 minutes after starting the first unit (i.e. 15 minutes after the

patient completes consumption of a single ACTIQ unit), a second ACTIQ unit of the same strength may be consumed. No more

than two ACTIQ units should be used to treat any individual pain episode. At 1600 micrograms, a second dose is only likely to

be required by a minority of patients.

If treatment of consecutive breakthrough pain episodes requires more than one dosage unit per episode, an increase in dose

to the next higher available strength should be considered.

b) Maintenance

Once a successful dose has been established (i.e., on average, an episode is effectively treated with a single unit), patients

should be maintained on this dose and should limit consumption to a maximum of four ACTIQ units per day.

Patients should be monitored by a health professional to ensure that the maximum consumption of four units of ACTIQ per

day is not exceeded.

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Dose re‑ adjustment

The maintenance dose of ACTIQ should be increased when an episode is not effectively treated with a single unit for several

consecutive BTP episodes. For dose‑readjustment the same principles apply as outlined for dose titration (see above).

If more than four episodes of breakthrough pain are experienced per day the dose of the maintenance opioid therapy used for

persistent pain should be re‑evaluated. If the dose of the maintenance opioid therapy is increased, the dose of ACTIQ to treat

breakthrough pain may need to be reviewed.

In absence of adequate pain control, the possibility of hyperalgesia, tolerance and progression of underlying disease should be

considered (see section 4.4).

It is imperative that any dose re‑titration of any analgesic is monitored by a health professional.

Discontinuation of therapy

ACTIQ should be discontinued immediately if the patient no longer experiences breakthrough pain episodes. The treatment for

the persistent background pain should be kept as prescribed. If discontinuation of all opioid therapy is required, the patient

must be closely followed by the doctor as gradual downward opioid titration is necessary in order to avoid the possibility of

abrupt withdrawal effects.

Use in the elderly

Elderly patients have been shown to be more sensitive to the effects of fentanyl when administered intravenously. Therefore

dose titration needs to be approached with particular care. In the elderly, elimination of fentanyl is slower and the terminal

elimination half‑life is longer, which may result in accumulation of the active substance and to a greater risk of undesirable

effects.

Formal clinical trials with ACTIQ have not been conducted in the elderly. It has been observed, however, in clinical trials that

patients over 65 years of age required lower doses of ACTIQ for successful relief of breakthrough pain.

Use in patients with hepatic or renal impairment

Special care should be taken during the titration process in patients with kidney or liver dysfunction (see section 4.4).

Paediatric population

Adolescents aged 16 years and above:

Follow adult dosage.

Children and adolescents below 16 years:

Safety and efficacy in children and adolescents below 16 years have not been established. There is limited clinical trial

experience of the use of ACTIQ in paediatric patients already receiving maintenance opioid therapy (see sections 5.1 and 5.2).

Use in this patient population is therefore not recommended.

Method of administration

ACTIQ is intended for oromucosal administration, and therefore should be placed in the mouth against the cheek and should

be moved around the mouth using the applicator, with the aim of maximising the amount of mucosal exposure to the product.

The ACTIQ unit should be sucked, not chewed, as absorption of fentanyl via the buccal mucosa is rapid in comparison with

systemic absorption via the gastrointestinal tract. Water may be used to moisten the buccal mucosa in patients with a dry

mouth.

The ACTIQ unit should be consumed over a 15 minute period. If signs of excessive opioid effects appear before the ACTIQ unit

is fully consumed it should be immediately removed, and consideration given to decreasing future dosages.

4.3 Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

Patients without maintenance opioid therapy as there is an increased risk of respiratory depression.

Treatment of acute pain other than breakthrough pain.

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Simultaneous use of monoamine oxidase inhibitors (MAO inhibitors), or within 2 weeks after the cessation of the use of MAO

inhibitors (see sections 4.4 and 4.5).

Severe respiratory depression or severe obstructive lung conditions.

4.4 Special warnings and precautions for use

Accidental use in children

Patients and their carers must be instructed that ACTIQ contains an active substance in an amount that can be fatal to a child.

Death has been reported in children who have accidentally ingested ACTIQ.

Patients and their carers must be instructed to keep all units out of the sight and reach of children and to discard open and

unopened units appropriately. An evaluation of each out‑patient concerning possible accidental child exposures should be

undertaken.

Maintenance opioid therapy

The product must not be given to patients without maintenance opioid therapy as there is an increased risk of respiratory

depression and death. It is important that the maintenance opioid therapy used to treat the patient's persistent pain has been

stabilised before ACTIQ therapy begins and that the patient continues to be treated with the maintenance opioid therapy

whilst using ACTIQ.

Tolerance, dependence and abuse

Like for all opioids, tolerance, physical and/or psychological dependence and abuse of fentanyl may occur. However, iatrogenic

addiction following therapeutic use of opioids is known to occur. The risk is considered low in cancer patients with

breakthrough pain, but may be higher in those patients with a history of substance abuse and alcohol dependence.

All patients treated with opioids require careful monitoring for signs of abuse and addiction.

Hyperalgesia

As with other opioids, in case of insufficient pain control in response to an increased dose of fentanyl, the possibility of

opioid-induced hyperalgesia should be considered. A fentanyl dose reduction or discontinuation of fentanyl treatment or

treatment review may be indicated

Adrenal insufficiency

Cases of adrenal insufficiency have been reported with opioid use including fentanyl lozenges, more often following greater

than one month of use. Wean the patient off of the opioid to allow adrenal function to recover and continue corticosteroid

treatment until adrenal function recovers (see section 4.8).

Respiratory depression

As with all opioids, there is a risk of clinically significant respiratory depression associated with the use of ACTIQ, patients

should be monitored accordingly.

Particular caution should be used when titrating ACTIQ in patients with non‑severe chronic obstructive pulmonary disease or

other medical conditions predisposing them to respiratory depression, as even normally therapeutic doses of ACTIQ may

further decrease respiratory drive to the point of respiratory failure.

Alcohol

The concomitant use of alcohol with fentanyl can produce increased depressant effects which may result in a fatal outcome

(see section 4.5).

Risks of concomitant administration with benzodiazepines

Concomitant use of opioids, including ACTIQ, with benzodiazepines may result in profound sedation, respiratory depression,

coma, and death. Because of these risks, concomitant prescribing of opioids and benzodiazepines should be made only in

patients for whom alternative treatment options are inadequate.

If a decision is made to prescribe ACTIQ concomitantly with benzodiazepines, the lowest effective dosages and minimum

durations of concomitant use should be chosen. Patients should be closely monitored for signs and symptoms of respiratory

depression and sedation (see section 4.5).

Intracranial effects of CO

retention, impaired consciousness, head injury

ACTIQ should only be administered with extreme caution in patients who may be particularly susceptible to the intracranial

effects of CO

retention, such as those with evidence of increased intracranial pressure, or impaired consciousness. Opioids

may obscure the clinical course of a patient with a head injury and should be used only if clinically warranted.

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Bradyarrhythmias

Fentanyl may produce bradycardia. Fentanyl should be used with caution in patients with previous or pre‑existing

bradyarrhythmias.

Hepatic or renal impairment

In addition, ACTIQ should be administered with caution to patients with liver or kidney dysfunction. The influence of liver and

renal impairment on the pharmacokinetics of the medicinal product has not been evaluated, however, when administered

intravenously the clearance of fentanyl has been shown to be altered in hepatic and renal disease due to alterations in

metabolic clearance and plasma proteins. After administration of ACTIQ, impaired liver and renal function may both increase

the bioavailability of swallowed fentanyl and decrease its systemic clearance, which could lead to increased and prolonged

opioid effects. Therefore, special care should be taken during the titration process in patients with moderate or severe hepatic

or renal disease.

Hypovolaemia, hypotension

Careful consideration should be given to patients with hypovolaemia and hypotension.

Diabetic patients

Diabetic patients should be advised that the medicinal product contains dextrates (dextrates are composed of 93 % glucose

monohydrate and 7 % maltodextrin. The total glucose load per dosage unit is approximately 1.89 grams per dose).

Patients with rare hereditary problems of fructose intolerance, glucose‑galactose malabsorption or sucrase‑isomaltase

insufficiency should not use this medicinal product.

Dental decay

Normal oral hygiene is recommended to reduce any potential harm to the teeth. Because ACTIQ contains

approximately 2 grams of sugar, frequent consumption increases the risk of dental decay. The occurrence of dry mouth

associated with the use of opioid medicinal products may add to this risk.

Serotonin syndrome

Caution is advised when ACTIQ is co‑administered with medicinal products that affect the serotoninergic neurotransmitter

systems.

The development of a potentially life‑threatening serotonin syndrome may occur with the concomitant use of serotonergic

medicinal products such as selective serotonin reuptake inhibitors (SSRIs) and serotonin norepinephrine reuptake inhibitors

(SNRIs), and with medicinal products which impair metabolism of serotonin (including monoamine oxidase inhibitors [MAO

inhibitors]) (see section 4.3). 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., hyperreflexia, incoordination, rigidity),

and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhoea).

If serotonin syndrome is suspected, treatment with ACTIQ should be discontinued.

Anaphylaxis, hypersensitivity

Anaphylaxis and hypersensitivity have been reported in association with the use of oral transmucosal fentanyl products (see

section 4.8).

Paediatric population

ACTIQ is not recommended for use in children and adolescents below 16 years due to lack of data on safety and efficacy (see

sections 5.1 and 5.2).

4.5 Interaction with other medicinal products and other forms of interactions

Agents that affect CYP3A4 activity

CYP3A4 inhibitors

Fentanyl is metabolized by the CYP3A4 isoenzyme in the liver and intestinal mucosa. Potent inhibitors of CYP3A4 such as

macrolide antibiotics (e.g. erythromycin), azole antifungals (e.g. ketoconazole, itraconazole, and fluconazole) and certain

protease inhibitors (e.g. ritonavir), may increase the bioavailability of swallowed fentanyl and may also decrease its systemic

clearance which may result in increased or prolonged opioid effects. Similar effects could be seen after concurrent ingestion of

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grapefruit juice, which is known to inhibit CYP3A4. Hence caution is advised if fentanyl is given concomitantly with CYP3A4

inhibitors.

CYP3A4 inducers

Co-administration with agents that induce 3A4 activity may reduce the efficacy of ACTIQ.

Agents that can increase CNS depressant effects

Co-administration of fentanyl with other CNS depressants, including other opioids, sedatives or hypnotics (including

benzodiazepines), general anaesthetics, phenothiazines, tranquillisers, skeletal muscle relaxants, sedating antihistamines and

alcohol can produce additive depressant effects which may result in a fatal outcome (see section 4.4).

Sedative medicines such as benzodiazepines or related drugs

The concomitant use of opioids with sedative medicines such as benzodiazepines or related drugs increases the risk of

sedation, respiratory depression, coma and death because of additive CNS depressant effect. The dose and duration of

concomitant use should be limited (see section 4.4).

Partial opioid agonists/antagonists

The concomitant use of partial opioid agonists/antagonists (e.g. buprenorphine, nalbuphine, pentazocine) is not recommended.

They have high affinity to opioid receptors with relatively low intrinsic activity and therefore partially antagonise the analgesic

effect of fentanyl and may induce withdrawal symptoms in opioid dependant patients.

Serotonergic agents

Co-administration of fentanyl with a serotonergic agent, such as a selective serotonin reuptake inhibitor (SSRI) or a serotonin

norepinephrine reuptake inhibitor (SNRI) or a monoamine oxidase inhibitor (MAO inhibitor), may increase the risk of serotonin

syndrome, a potentially life‑threatening condition (see section 4.3).

4.6 Fertility, pregnancy and lactation

Pregnancy

There are no or limited amount of data from the use of fentanyl in pregnant women. Studies in animals have shown

reproductive toxicity (see section 5.3). Opioid analgesic agents can cause neonatal respiratory depression. With long‑term use

during pregnancy, there is a risk of neonatal opioid withdrawal syndromewhich may be life-threatening if not recognized and

treated, and requires management according to protocols developed by neonatology experts. ACTIQ should not be used in

pregnancy unless clearly necessary.

If opioid use is required for a prolonged period in a pregnant woman, advise the patient of the risk of neonatal opioid

withdrawal syndrome and ensure that appropriate treatment will be available (see section 4.8).

It is advised not to use fentanyl during labour and delivery (including caesarean section) because fentanyl passes through the

placenta and may cause respiratory depression in the fœtus. The placental transfer ratio is 0.44 (fœtal:maternal ratio 1.00:2.27).

Breastfeeding

Fentanyl passes into breast milk and may cause sedation and respiratory depression in the breastfed child. Fentanyl should not

be used by breastfeeding women and breast feeding should not be restarted until at least 5 days after the last administration

of fentanyl.

Fertility

There are no human data on fertility available. In animal studies, male fertility was impaired (see section 5.3).

4.7 Effects on ability to drive and use machines

No studies of the effects on the ability to drive and use machines have been performed. However, opioid analgesics may impair

the mental and/or physical ability required for the performance of potentially dangerous tasks (e.g., driving a car or operating

machinery). Patients should be advised not to drive or operate machinery if they experience somnolence, dizziness, blurred or

double vision while using ACTIQ.

4.8 Undesirable effects

Typical opioid adverse reactions are to be expected with ACTIQ. Frequently, these will cease or decrease in intensity with

continued use of the product, as the patient is titrated to the most appropriate dose. However, the most serious adverse events

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are respiratory depression (potentially leading to apnoea or respiratory arrest), circulatory depression, hypotension and shock

and all patients should be closely monitored for these.

Application site reactions, including gum bleeding, irritation, pain and ulcer have been reported in post‑marketing use.

Because the clinical trials of ACTIQ were designed to evaluate safety and efficacy in treating breakthrough pain, all patients

were also taking concomitant opioids, such as sustained‑release morphine or transdermal fentanyl, for their persistent pain.

Thus it is not possible to definitively separate the effects of ACTIQ alone.

The following adverse reactions have been reported with ACTIQ and/or other fentanyl‑containing compounds during clinical

studies and post marketing experience. Adverse reactions are listed below as MedDRA preferred term by system organ class

and frequency (frequencies are defined as: very common ≥ 1/10, common ≥ 1/100 to < 1/10, uncommon ≥ 1/1,000 to < 1/100,

not known (cannot be estimated from the available data):

System organ

class

Very common

common

uncommon

Not known

Immune system

disorders

anaphylactic

reaction,

tongue

oedema,

lip oedema

Endocrine

disorders

adrenal

insufficiency,

androgen

deficiency

Metabolism and

nutrition

disorders

anorexia

Psychiatric

disorders

confusion,

anxiety,

hallucinations,

depression,

emotional lability

abnormal dreams,

depersonalisation,

abnormal thinking,

euphoria

Insomnia,

drug

dependence

(addiction),

drug abuse,

delirium

Nervous system

disorders

somnolence,

dizziness,

headache

loss of consciousness,

convulsion,

vertigo,

myoclonus,

sedation,

paraesthesia (including hyperaesthesia/circumoral

paraesthesia),

abnormal gait/incoordination,

taste perversion

coma,

slurred speech

Eye disorders

abnormal vision (blurred, double vision)

Vascular

disorders

vasodilatation

flushing,

hot flush

Respiratory,

thoracic and

mediastinal

disorders

dyspnoea

pharyngeal

oedema,

respiratory

depression

Gastrointestinal

disorders

nausea, vomiting,

constipation,

abdominal pain

dry mouth,

dyspepsia,

stomatitis,

tongue disorder (for example, burning sensation,

ulcers),

flatulence,

abdomen enlarged

ileus,

mouth ulcers,

dental caries,

gingival bleeding

tooth loss,

gingival

recession,

gingivitis,

diarrhoea

Skin and

subcutaneous

pruritus,

sweating,

urticaria

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tissue disorders

rash

Renal and

urinary

disorders

urinary retention

General

disorders and

administration

site conditions

asthenia

application site reactions including irritation, pain

and ulcer,

malaise

fatigue,

peripheral

oedema,

pyrexia,

withdrawal

syndrome*,

neonatal

withdrawal

syndrome

(see section

4.6)

Investigations

weight decreased

Injury,

poisoning and

procedural

complications

accidental injury (for example, falls)

* opioid withdrawal symptoms such as nausea, vomiting, diarrhoea, anxiety, chills, tremor, and sweating have been observed

with transmucosal fentanyl.

Reporting of suspected adverse reactions

Reporting suspectedadverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring

of the benefit/risk balance of the medicinalproduct. Healthcare professionals are asked to report any suspected

adversereactions via HPRA Pharmacovigilance, Earlsfort Terrace, IRL - Dublin 2; Tel:+353 1 6764971; Fax: +353 1 6762517.

Website: www.hpra.ie; E-mail: medsafety@hpra.ie.

4.9 Overdose

Symptoms

The symptoms of fentanyl overdose are expected to be similar in nature to those of intravenous fentanyl and other opioids,

and are an extension of its pharmacological actions, with the most serious significant effects being altered mental status, loss

of consciousness, coma, cardiorespiratory arrest, respiratory depression, respiratory distress, and respiratory failure, which have

resulted in death.

Management

Immediate management of opioid overdose includes removal of the ACTIQ unit via the applicator, if still in the mouth,

ensuring a patent airway, physical and verbal stimulation of the patient, assessment of the level of consciousness, ventilatory

and circulatory status, and assisted ventilation (ventilatory support) if necessary.

Overdose (accidental ingestion) in the opioid naïve person

For treatment of overdose (accidental ingestion) in the opioid naïveperson, intravenous access should be obtained, and

naloxone or other opioid antagonists should be employed as clinically indicated. The duration of respiratory depression

following overdose may be longer than the effects of the opioid antagonist’s action (e.g., the half‑life of naloxone ranges from

30 to 81 minutes) and repeated administration may be necessary. Consult the Summary of Product Characteristics of the

individual opioid antagonist for details about such use.

Overdose in opioid‑maintained patients

For treatment of overdose in opioid‑maintained patients, intravenous access should be obtained. The judicious use of

naloxone or another opioid antagonist may be warranted in some instances, but it is associated with the risk of precipitating an

acute withdrawal syndrome.

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Although muscle rigidity interfering with respiration has not been seen following the use of ACTIQ, this is possible with

fentanyl and other opioids. If it occurs, it should be managed by the use of assisted ventilation, by an opioid antagonist, and as

a final alternative, by a neuromuscular blocking agent.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Opioid analgesic, phenylpiperidone derivative. ATC code: N02AB03.

Fentanyl, a pure opioid agonist, acts primarily through interaction with mu‑opioid receptors located in the brain, spinal cord

and smooth muscle. The primary site of therapeutic action is the CNS. The most clinically useful pharmacological effect of the

interaction of fentanyl with mu‑opioid receptors is analgesia. The analgesic effects of fentanyl are related to the blood level of

the active substance, if proper allowance is made for the delay into and out of the CNS (a process with a 3‑5 minute half‑life).

In opioid‑naïve individuals, analgesia occurs at blood levels of 1 to 2 ng/ml, while blood levels of 10‑20 ng/ml would produce

surgical anaesthesia and profound respiratory depression.

In patients with chronic cancer pain on stable doses of regularly scheduled opioids to control their persistent pain, ACTIQ

produced significantly more breakthrough pain relief compared with placebo at 15, 30, 45, and 60 minutes following

administration.

Secondary actions include increase in the tone and decrease in the contractions of the gastrointestinal smooth muscle, which

results in prolongation of gastrointestinal transit time and may be responsible for the constipatory effect of opioids.

While opioids generally increase the tone of urinary tract smooth muscle, the overall effect tends to vary, in some cases

producing urinary urgency, in others difficulty in urination.

All opioid mu‑receptor agonists, including fentanyl, produce dose dependent respiratory depression. The risk of respiratory

depression is less in patients with pain and those receiving chronic opioid therapy who develop tolerance to respiratory

depression and other opioid effects. In non‑tolerant subjects, typically peak respiratory effects are seen 15 to 30 minutes

following the administration of ACTIQ, and may persist for several hours.

Opioids may influence the hypothalamic-pituitary-adrenal or –gonadal axes. Some changes that can be seen include an

increase in serum prolactin, and decreases in plasma cortisol and testosterone. Clinical signs and symptoms may be manifest

from these hormonal changes (see also section 4.8).

Additional secondary pharmacological effect includes miosis.

Paediatric population

There is limited experience of the use of ACTIQ in paediatric patients, below the age of 16. In a clinical study, 15 (out of 38)

paediatric patients, ranging in age from 5 to 15 years, already receiving maintenance opioid therapy and with breakthrough

pain were treated with ACTIQ. The study was too small to allow conclusions on safety and efficacy in this patient population.

5.2 Pharmacokinetic properties

General introduction

Fentanyl is highly lipophilic and can be absorbed very rapidly through the oral mucosa and more slowly by the conventional

gastrointestinal route. It is subject to first-pass hepatic and intestinal metabolism and the metabolites do not contribute to

fentanyl’s therapeutic effects.

Absorption

The absorption pharmacokinetics of fentanyl from Actiq are a combination of rapid oromucosal absorption and slower

gastrointestinal absorption of swallowed fentanyl. Approximately 25% of the total dose of Actiq is rapidly absorbed from the

buccal mucosa. The remaining 75% of the dose is swallowed and slowly absorbed from the gastrointestinal tract. About 1/3 of

this amount (25% of the total dose) escapes hepatic and intestinal first-pass elimination and becomes systemically available.

Absolute bioavailability is about 50% compared to intravenous fentanyl, divided equally between rapid oromucosal and slower

gastrointestinal absorption. C

ranges from 0.39 to 2.51 ng/ml after consumption of Actiq (200 micrograms to 1600

micrograms). T

is around 20 to 40 minutes after consumption of an Actiq unit (range 20 – 480 minutes).

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Distribution

Animal data show that fentanyl is rapidly distributed to the brain, heart, lungs, kidneys and spleen followed by a slower

redistribution to muscles and fat. The plasma protein binding of fentanyl is 80-85%. The main binding protein is alpha-1-acid

glycoprotein, but both albumin and lipoproteins contribute to some extent. The free fraction of fentanyl increases with acidosis.

The mean volume of distribution at steady state (V

) is 4 l/kg.

Biotransformation

Fentanyl is metabolised in the liver and in the intestinal mucosa to norfentanyl by CYP3A4 isoform. Norfentanyl is not

pharmacologically active in animal studies. More than 90% of the administered dose of fentanyl is eliminated by

biotransformation to N-dealkylated and hydroxylated inactive metabolites.

Elimination

Less than 7% of the dose is excreted unchanged in the urine, and only about 1% is excreted unchanged in the faeces. The

metabolites are mainly excreted in the urine, while faecal excretion is less important. The total plasma clearance of fentanyl is

0.5 l/hr/kg (range 0.3-0.7 l/hr/kg). The terminal elimination half-life after Actiq administration is about 7 hours.

Linearity/non-linearity

Dose proportionality across the available range of dosages (200 micrograms to 1600 micrograms) of Actiq has been

demonstrated.

Paediatric population

In a clinical study, 15 paediatric patients, ranging in age from 5 to 15 years, already receiving maintenance opioid therapy and

with breakthrough pain were treated with ACTIQ at doses ranging from 200 micrograms to 600 micrograms. Area under the

curve values based on observed concentrations were 2-fold higher in younger children than adolescents (5.25 versus 2.65

ng.hr/mL, respectively) and 4-fold higher in the younger children as compared to adults (5.25 versus 1.20 ng.hr/mL). On a

weight-adjusted basis, clearance and volume of distribution values were similar across the age range.

5.3 Preclinical safety data

Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose

toxicity, genotoxicity and carcinogenicity.

Embryo-foetal developmental toxicity studies conducted in rats and rabbits revealed no compound-induced malformations or

developmental variations when administered during the period of organogenesis.

In a fertility and early embryonic development study in rats, a male-mediated effect was observed at high doses (300

microgram/kg/day, s.c.) and is consistent with the sedative effects of fentanyl in animal studies.

In studies on pre and postnatal development in rats the survival rate of offspring was significantly reduced at doses causing

severe maternal toxicity. Further findings at maternally toxic doses in F1 pups were delayed physical development, sensory

functions, reflexes and behaviour. These effects could either be indirect effects due to altered maternal care and/or decreased

lactation rate or a direct effect of fentanyl on the pups.

Carcinogenicity studies (26-week dermal alternative bioassay in Tg.AC transgenic mice; two-year subcutaneous carcinogenicity

study in rats) with fentanyl did not induce any findings indicative of oncogenic potential. Evaluation of brain slides from

carcinogenicity study in rats revealed brain lesions in animals administered high doses of fentanyl citrate. The relevance of

these findings to humans is unknown

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Lozenge:

Dextrates hydrated (containing glucose)

Citric acid

Disodium phosphate

Artificial berry flavour (maltodextrin, propylene glycol, artificial flavours and triethylcitrate)

Magnesium stearate

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Edible glue used to attach the lozenge to the handle:

Modified maize based food starch (E1450)

Confectioner’s sugar (sucrose and maize starch)

Water, purified

Imprinting ink:

De-ionised water

De-waxed white shellac

Acetone

Blue synthetic coal tar dye (E133)

Ammonium hydroxide (E527) for pH adjustment

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

3 years.

6.4 Special precautions for storage

Do not store above 30°C.

Store in protective blister until ready for use.

6.5 Nature and contents of container

Each Actiq dosage unit is contained in a heat sealed blister package consisting of a paper/foil laminated lid, and a PVC/Aclar

thermoformed blister, supplied in cartons of 3, 6, 15 or 30 individual units.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal of a used medicinal product or waste materials derived from such medicinal

product and other handling of the product

Lozenges with residual active substance should at no time be discarded or misplaced. Any used or unused but no longer

required product or waste material should be disposed of in accordance with local requirements.

7 MARKETING AUTHORISATION HOLDER

Teva Pharma B.V.

Swansweg 5

2031GA Haarlem

Netherlands

8 MARKETING AUTHORISATION NUMBER

PA0749/195/003

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 23

January 2002

Date of last renewal: 8

October 2010

10 DATE OF REVISION OF THE TEXT

July 2019

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