Actiq 1600 micrograms compressed lozenge with integral oromucosal applicator

Ireland - English - HPRA (Health Products Regulatory Authority)

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Active ingredient:
FENTANYL CITRATE
Available from:
Teva Pharma B.V.
ATC code:
N02AB; N02AB03
INN (International Name):
FENTANYL CITRATE
Dosage:
1600 microgram(s)
Pharmaceutical form:
Lozenge
Prescription type:
Product subject to prescription which may not be renewed (A)
Therapeutic area:
Phenylpiperidine derivatives; fentanyl
Authorization status:
Not marketed
Authorization number:
PA0749/195/006
Authorization date:
2002-01-23

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 pregnan

t 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

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

October 2018

Health Products Regulatory Authority

17 December 2018

CRN008KR0

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Summary of Product Characteristics

1 NAME OF THE MEDICINAL PRODUCT

Actiq 1600 micrograms compressed lozenge with integral oromucosal applicator.

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

One lozenge contains 1600 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

Health Products Regulatory Authority

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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.

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.

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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.

Health Products Regulatory Authority

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Page 4 of 19

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

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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.

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

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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

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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.

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.

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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).

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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 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

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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

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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 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,

depersonalisa

tion,

abnormal

thinking,

euphoria

Insomnia,

drug

dependence

(addiction),

drug abuse

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Nervous

system

disorders

somnolence,

dizziness,

headache

loss of

consciousness,

convulsion,

vertigo,

myoclonus,

sedation,

paraesthesia

(including

hyperaesthesia/circu

moral 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

Gastrointest

inal

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

subcutaneo

us tissue

disorders

pruritus,

sweating,

rash

urticaria

Renal and

urinary

disorders

urinary retention

General

disorders

and

administrati

on site

asthenia

application site

reactions including

irritation, pain and

ulcer,

malaise

fatigue,

peripheral

oedema,

pyrexia,

withdrawal

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conditions

syndrome*,

neonatal

withdrawal

syndrome

(see section

4.6)

Investigatio

ns

weight decreased

Injury,

poisoning

and

procedural

complicatio

ns

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 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 listed in Appendix V.

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

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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.

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.

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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.

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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).

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 mcg to 600 mcg. 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

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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 mcg/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

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

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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.

Swensweg 5

2031 GA Haarlem

The Netherlands

8 MARKETING AUTHORISATION NUMBER

PA0749/195/006

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9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 23 January 2002

Date of last renewal: 08 October 2010

10 DATE OF REVISION OF THE TEXT

December 2018

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