Consumer medicine information

Abstral

Fentanyl

BRAND INFORMATION

Brand name

Abstral

Active ingredient

Fentanyl

Schedule

S8

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Abstral.

SUMMARY CMI

ABSTRAL®

Consumer Medicine Information (CMI) summary

The full CMI on the next page has more details. If you are worried about using this medicine, speak to your doctor or pharmacist.

WARNING: Important safety information is provided in a boxed warning in the full CMI. Read before using this medicine.

1. Why am I taking ABSTRAL?

ABSTRAL contains the active ingredient fentanyl (as citrate). ABSTRAL is a strong pain medicine used to treat breakthrough cancer pain in adults who are already receiving an effective maintenance dose of opioid therapy for their underlying cancer pain. For more information, see Section 1. Why am I taking ABSTRAL? in the full CMI.

2. What should I know before I take ABSTRAL?

Do not take if you have ever had an allergic reaction to fentanyl or any of the ingredients listed at the end of the CMI. Talk to your doctor if you have any other medical conditions, take any other medicines, or are pregnant or plan to become pregnant or are breastfeeding. For more information, see Section 2. What should I know before I take ABSTRAL? in the full CMI.

3. What if I am taking other medicines?

Some medicines may interfere with ABSTRAL and affect how it works. A list of these medicines is in Section 3. What if I am taking other medicines? in the full CMI.

4. How do I take ABSTRAL?

  • ABSTRAL sublingual tablet is placed under your tongue until dissolved. Do not suck, chew or swallow the tablet
  • Do not eat or drink anything until the tablet is completely dissolved. If needed, you can moisten your mouth by rinsing it with water before placing the tablet under your tongue.

More instructions can be found in Section 4. How do I take ABSTRAL? in the full CMI.

5. What should I know while taking ABSTRAL?

Things you should do
  • Remind any doctor, dentist or pharmacist you visit that you are taking ABSTRAL
  • Carefully follow your doctor's instructions on how much ABSTRAL to take for each breakthrough pain episode, especially when you first start taking ABSTRAL or change the dose
  • Talk to your doctor or pharmacist if your pain does not improve.
Things you should not do
  • Do not take ABSTRAL for other types of pain (e.g. post-operative pain, headache, migraine)
  • Do not take ABSTRAL unless you have already been receiving opioid maintenance therapy for cancer-related pain for at least one week, because it may increase the risk of experiencing severe breathing difficulties
  • Do not take ABSTRAL if you have any lung conditions or breathing difficulties unless your doctor tells you to.
Driving or using machines
  • Do not drive or operate machinery while taking ABSTRAL as it can cause dizziness, drowsiness or blurred vision.
Drinking alcohol
  • Do not consume alcohol while taking ABSTRAL, as dizziness and drowsiness may become worse.
Looking after your medicine
  • Keep your medicine in a cool dry place below 25°C
  • Keep your medicine where children cannot reach it.

For more information, see Section 5. What should I know while taking ABSTRAL? in the full CMI.

6. Are there any side effects?

The most common side effects of ABSTRAL are nausea, drowsiness and vomiting. Tell your doctor or pharmacist immediately or go to Emergency Department at your nearest hospital if you experience shortness of breath, wheezing or difficulty breathing, fast or slow heartbeat, dizziness or light-headedness, unusual or extreme mood swings, blurred vision, swelling of the face, lips, tongue or other parts of the body, or skin rashes.

For more information, including what to do if you have any side effects, see Section 6. Are there any side effects? in the full CMI.

WARNING:

Limitations of use

ABSTRAL should only be taken when your doctor decides that other treatment options are not able to effectively manage your pain or you cannot tolerate them.

Hazardous and harmful use

ABSTRAL poses risks of abuse, misuse and addiction which can lead to overdose and death. Your doctor will monitor you regularly during treatment.

Life threatening respiratory depression

ABSTRAL can cause life-threatening or fatal breathing problems (slow, shallow, unusual or no breathing) even when taken as recommended. These problems can occur at any time during use, but the risk is higher when first starting ABSTRAL and after a dose increase, if you are older, or have an existing problem with your lungs. Your doctor will monitor you and change the dose as appropriate.

Use of other medicines or alcohol while taking ABSTRAL

Taking ABSTRAL with other medicines that can make you feel drowsy such as sleeping tablets (e.g. benzodiazepines), other pain relievers, antihistamines, antidepressants, antipsychotics, gabapentinoids (e.g. gabapentin and pregabalin), cannabis and alcohol may result in severe drowsiness, decreased awareness, breathing problems, coma and death. Your doctor will minimise the dose and duration of use, and monitor you for signs and symptoms of breathing difficulties and sedation. You must not drink alcohol while taking ABSTRAL.



FULL CMI

ABSTRAL®

Active ingredient: fentanyl (as citrate)

Consumer Medicine Information (CMI)

This leaflet provides important information about taking ABSTRAL.

You should also speak to your doctor or pharmacist if you would like further information or if you have any concerns or questions about taking ABSTRAL.

Where to find information in this leaflet:

1. Why am I taking ABSTRAL?
2. What should I know before I take ABSTRAL?
3. What if I am taking other medicines?
4. How do I take ABSTRAL?
5. What should I know while taking ABSTRAL?
6. Are there any side effects?
7. Product details

1. Why am I taking ABSTRAL?

ABSTRAL contains the active ingredient fentanyl (as citrate).

ABSTRAL belongs to a group of strong pain relieving medicines called opioid analgesics, and works by blocking the sensation of pain.

ABSTRAL is used to treat breakthrough pain in adults with cancer who are already receiving an effective maintenance dose of opioid therapy to control their persistent cancer pain. Breakthrough pain is a short episode of sudden intense pain despite well controlled persistent cancer pain.

2. What should I know before I take ABSTRAL?

Warnings

Opioids have a potential to cause addiction, even if taken exactly as prescribed. It is possible that ABSTRAL may become habit forming causing mental and physical dependence. If abused it may become less able to reduce pain.

Tolerance

As with all other opioid containing products, tolerance to ABSTRAL may develop, which means that you may need higher doses to control your breakthrough pain.

Dependence and Withdrawal

As with all other opioid containing products, your body may become used to you taking ABSTRAL. Taking it may result in physical dependence. Physical dependence means that you may experience withdrawal symptoms if you stop taking opioids suddenly, so it is important to take these exactly as directed by your doctor.

Continue taking your medicine for as long as you need it or your doctor tells you. If you stop taking ABSTRAL, you must continue to take your usual opioid pain relieving medicine to treat your persistent cancer pain as advised by your doctor. When you stop taking ABSTRAL there should be no noticeable effects but your pain may worsen and some people may experience some or all of the following withdrawal symptoms:

  • loss of appetite, nausea, vomiting or diarrhoea
  • nervousness, restlessness, agitation, trouble sleeping or anxiety
  • body aches, weakness or stomach cramps
  • increased heart rate, breathing rate or pupil size
  • watery eyes, runny nose, chills or yawning
  • increased sweating.

Do not take ABSTRAL:

  1. If you are allergic to fentanyl or any of the ingredients listed at the end of this leaflet. Always check the ingredients to make sure you can use this medicine
  2. If you are allergic to any other similar medicines (such as other opioid analgesics)
  3. For other types of short-term or acute pain (e.g. post-operative pain, headache, migraine)
  4. If you are not already receiving (and are not tolerant to) opioid maintenance therapy for cancer-related pain
  5. If you have any lung conditions or breathing difficulties.

Check with your doctor if you have or have had:

  • Difficulty breathing, wheezing, chronic cough, asthma or other breathing conditions such as chronic obstructive pulmonary disease (COPD),
  • Myasthenia gravis (immune disease that causes muscle weakness)
  • A brain tumour, increased pressure in your skull, reduced alertness, coma, or head injury
  • Heart problems
  • Liver or kidney problems
  • Low blood pressure
  • Mouth wounds or mucositis (inflammation and ulceration of the mouth or gut lining)

During treatment, you may be at risk of developing certain side effects. It is important you understand these risks and how to monitor for them. See additional information under Section 6. Are there any side effects?

Pregnancy and breastfeeding

Check with your doctor if you are pregnant or intend to become pregnant. Prolonged treatment with fentanyl during pregnancy or use during labour can cause breathing problems, signs of withdrawal, severe harm or life-threatening damage in the newborn.

Talk to your doctor if you are breastfeeding or intend to breastfeed. Fentanyl can get into breast milk and may cause side effects in the breast-fed infant. You should not start breastfeeding until at least 5 days after the last dose of ABSTRAL.

3. What if I am taking other medicines?

Tell your doctor or pharmacist if you are taking any other medicines, including any medicines, vitamins or supplements that you buy without a prescription from your pharmacy, supermarket or health food shop.

Some medicines may interfere with ABSTRAL and affect how it works. These include:

  • some antibiotics used to treat infections such as erythromycin, rifampicin or rifabutin
  • some medicines used to treat fungal infections such as ketoconazole and itraconazole
  • some medicines used to treat HIV infections such as ritonavir
  • some medicines used to treat convulsions/fits such as gabapentin, pregabalin, carbamazepine, phenobarbital or phenytoin
  • other medicines used to treat pain
  • cough suppressants
  • medicines used for surgery (anaesthetics) and muscle relaxants
  • some antihistamines
  • medicines used to help you relax, sleep, relieve anxiety, depression and mental disorders, such as barbiturates, benzodiazepines, cannabis
  • some antidepressants such as phenelzine and selegiline, as these may increase the risk of a potentially life-threatening condition called serotonin syndrome. Symptoms of serotonin syndrome include confusion, fast heartbeat, hallucinations, restlessness, shaking, shivering, sudden jerking of muscles, sweating)
  • alcohol
  • certain types of strong pain killers such as buprenorphine, nalbuphine and pentazocine. You could experience symptoms of withdrawal syndrome (nausea, vomiting, diarrhoea, anxiety, chills, tremor, and sweating) while using these medicines.

Check with your doctor or pharmacist if you are not sure whether the medicines, vitamins or supplements you are taking will affect ABSTRAL

4. How do I take ABSTRAL?

  • Follow all directions given to you by your doctor or pharmacist. They may differ from the information contained in this leaflet.
  • If you do not understand the instructions for use, ask your doctor or pharmacist for help.

How much to take

You must follow your doctor's instructions on how much ABSTRAL to take. Your dose is the dose that eases your breakthrough pain. This dose is determined by slowly increasing the ABSTRAL dose as explained below.

When starting ABSTRAL

Your persistent cancer pain must be well controlled on regular opioid pain medicines before you start ABSTRAL for the breakthrough pain. Do not stop your regular pain medicines.

  • You must start with 100 micrograms of ABSTRAL. If adequate pain relief is not achieved within 30 minutes, your doctor may recommend a supplemental (second) 100 microgram tablet.

Do not use more than two (2) doses of ABSTRAL for each episode of breakthrough cancer pain. Wait at least 2 hours before treating another episode of breakthrough pain with ABSTRAL.

  • If your pain is not relieved after the second supplemental dose, you cannot take another ABSTRAL tablet for at least 2 hours. Your doctor may recommend other pain medicines to relieve this episode of breakthrough pain
  • If adequate pain relief was not achieved for an earlier episode of breakthrough cancer pain, your doctor may slowly increase the dose for your next episode(s) of breakthrough cancer pain until you find a dose that gives you adequate relief and without severe side effects. This is because everyone's pain is different and finding the right dose for you is important.

After you have found the right ABSTRAL dose

  • After you and your doctor have found the dose of ABSTRAL that provides adequate breakthrough cancer pain relief for you, this is the ongoing dose that you should take for each episode of breakthrough cancer pain
  • DO NOT TAKE MORE THAN THE DOSE YOUR DOCTOR HAS RECOMMENDED FOR EACH EPISODE OF BREAKTHROUGH CANCER PAIN
  • You must tell your doctor immediately if you are using ABSTRAL more than four times per day, as your doctor may need to change your regular medicines for the persistent cancer pain
  • Your doctor may adjust your ABSTRAL dose whenever changes to your regular pain medications are made.
  • Once your persistent pain has been controlled, your doctor may need to change your dose of ABSTRAL further
  • Let your doctor know if your ABSTRAL dose is no longer providing pain relief. Your doctor will decide if your dose needs to be changed.
  • Do not change doses of ABSTRAL or your other pain medicines on your own.

When to take ABSTRAL

You can take ABSTRAL whenever you have an episode of breakthrough cancer pain; up to four (4) doses per day. You must wait for at least two (2) hours before treating another episode of breakthrough pain with ABSTRAL.

  • You can discontinue ABSTRAL when you no longer have any breakthrough cancer pain, but you must tell your doctor before you do so. You must also 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 ABSTRAL when discontinuing ABSTRAL. If you experience any withdrawal symptoms your doctor will evaluate if you need medicine to reduce or eliminate these.

How to take ABSTRAL

  • If your mouth is dry, take a sip of water to moisten it. Spit out or swallow the water before taking ABSTRAL.

STEP 1: Remove the tablet(s) from the blister pack immediately before use as follows:

  • Separate one of the blister squares from the pack by tearing along the dotted lines/perforations (keep the remaining blister squares together)
  • Peel back the edge of the foil as indicated by the arrow on the coloured strip, and gently remove the tablet.
  • Do not try to push ABSTRAL sublingual tablets through the foil top, as this will damage the tablet.

STEP 2: Place the tablet under your tongue as far back as you can, and let it dissolve completely.

  • ABSTRAL will dissolve rapidly under the tongue and be absorbed in order to provide pain relief. It is therefore important that you do not suck, chew or swallow the tablet.
  • You should not drink or eat anything until the tablet has completely dissolved under your tongue.

STEP 3: Dispose of the empty blister square.

If you take too much ABSTRAL

If you or someone else receives too much ABSTRAL (overdose) or experiences one or more of the symptoms below, immediately call triple zero (000) for an ambulance. Keep the person awake by talking to them or gently shaking them every now and then. You should follow the above steps even if someone other than you accidentally takes ABSTRAL that was prescribed for you. If someone takes an overdose they may experience one or more of the following symptoms:

  • Slow, unusual or difficult breathing
  • Drowsiness, dizziness or unconsciousness
  • Slow or weak heartbeat
  • Nausea or vomiting
  • Convulsions or fits.

If you think that you or someone else may have taken too much ABSTRAL, urgent medical attention may be needed.

You should immediately:

  • phone the Poisons Information Centre
    (by calling 13 11 26), or
  • contact your doctor, or
  • go to the Emergency Department at your nearest hospital.

You should do this even if there are no signs of discomfort or poisoning.

When seeking medical attention, take this leaflet and remaining medicine with you to show the doctor. Also tell them about any other medicines or alcohol which have been taken.

5. What should I know while taking ABSTRAL?

Things you should do

Keep all of your doctor's appointments so that your progress can be checked.

Tell your doctor or pharmacist if you do not feel well while you are taking ABSTRAL

Call your doctor straight away if:

  • You become pregnant while taking ABSTRAL
  • Your breakthrough cancer pain does not improve.

Remind any doctor, dentist or pharmacist you visit that you are taking ABSTRAL. If you are going to have surgery, tell the surgeon or anaesthetist that you are taking ABSTRAL.

Things you should not do

  • Do not take ABSTRAL to treat any other complaints unless your doctor or pharmacist tells you to
  • Do not give your medicine to anyone else, even if they have the same condition as you
  • Do not give ABSTRAL to anyone younger than 18 years of age
  • Do not switch from ABSTRAL to other medicines that contain fentanyl without your doctor's advice as it can result in a fatal overdose. ABSTRAL is NOT interchangeable with other fentanyl products. Your doctor will prescribe starting and maintenance doses of the new fentanyl medicine if you are switched
  • Do not substitute ABSTRAL for any other pain reliever. The use of ABSTRAL without dose titration or by individuals who have not already been taking regular opioid medication for at least one week may result in fatal overdose.
  • Do not take ABSTRAL for short-term pain that you would expect to go away in a few days, such as: pain from injuries, from doctors' or dentists' visits, surgery or headaches/migraines.
  • Do not drink grapefruit juice while you are prescribed ABSTRAL treatment as it may increase the side effects of ABSTRAL.

Things to be careful of

  • Do not take high doses of ABSTRAL for long periods of time unless your doctor tells you to
  • ABSTRAL may be habit forming.

The below medical emergencies can cause death. Get emergency medical help right away if:

  • A child accidentally takes ABSTRAL. ABSTRAL can cause an overdose and death in any child who takes it
  • An adult who has not been prescribed ABSTRAL takes it

Driving or using machines

Do not drive or operate machinery while taking ABSTRAL as ABSTRAL may cause dizziness, drowsiness or blurred vision in some people.

Drinking alcohol

Tell your doctor if you drink alcohol.

Do not consume alcohol while taking ABSTRAL, as dizziness and drowsiness may become worse. There is an increased risk of decreased awareness, breathing difficulties, coma and death if taken at the same time as alcohol.

Looking after your medicine

  • Keep your medicine where the temperature stays below 25°C
  • Keep your medicine in the original pack until it is time to take it.

Follow the instructions in the carton on how to take care of your medicine properly.

Store it in a cool dry place, away from moisture, heat or sunlight; for example, do not store it:

  • In the bathroom or near a sink, or
  • In the car or on window sills.

Do not use this medicine after the expiry date printed on the pack or if the packaging is torn or shows signs of tampering.

Keep it where young children cannot reach it.

A locked cupboard at least one-and-a-half metres above the ground is a good place to store medicines.

Getting rid of any unwanted medicine

If your doctor tells you to stop taking this medicine or it is out of date, take all unused medicine to any pharmacy for safe disposal.

6. Are there any side effects?

This medicine helps most people with breakthrough cancer pain, but it may have unwanted side effects in a few people. All medicines can have side effects. If you do experience any side effects, most of them are minor and temporary. However, some side effects may need medical attention.

See the information below and, if you need to, ask your doctor or pharmacist if you have any further questions about side effects. Do not be alarmed by the following list of side effects. You may not experience any of them.

Less serious side effects

Less serious side effectsWhat to do
General body-related:
  • headache, drowsiness, sleepiness, dizziness, tiredness
  • excessive sweating
  • dry mouth, sore mouth or mouth/gum/lip ulcers
  • blurred vision
  • low blood pressure
  • itchy skin rash, bruising
  • joint pain and stiffness
  • erectile dysfunction
Stomach and Bowel-related:
  • nausea
  • vomiting
  • constipation
  • loss of appetite, stomach pain, indigestion
  • tongue disorder
Speak to your doctor if you have any of these less-serious side effects and they worry you.

Serious side effects

Serious side effectsWhat to do
General body-related
  • unusual or extreme mood swings, anxiety, depression, change in mental status
Signs of taking too much ABSTRAL, or respiratory depression
  • trouble breathing
  • extreme drowsiness with slowed breathing
  • slow shallow breathing
  • feeling faint
  • dizziness
  • confusion
  • inability to think, talk, or walk normally
  • hallucinations
  • tremors
Allergic reaction-related:
  • sudden or rapidly developing rash, swelling, itchiness or hives on the skin
  • shortness of breath, wheezing or difficulty breathing or swallowing
  • swelling of face, lips, tongue, throat or other parts of the body
Heart-related:
  • fast or slow heart beat
Call your doctor straight away, or go straight to the Emergency Department at your nearest hospital if you notice any of these serious side effects.

Tell your doctor or pharmacist if you notice anything else that may be making you feel unwell.

Other side effects not listed here may occur in some people.

Reporting side effects

After you have received medical advice for any side effects you experience, you can report side effects to the Therapeutic Goods Administration online at www.tga.gov.au/reporting-problems. By reporting side effects, you can help provide more information on the safety of this medicine.

Always make sure you speak to your doctor or pharmacist before you decide to stop taking any of your medicines.

7. Product details

This medicine is only available with a doctor's prescription.

What ABSTRAL contains

Active ingredient
(main ingredient)		fentanyl (as citrate)
Other ingredients
(inactive ingredients)
  • mannitol
  • microcrystalline cellulose
  • colloidal anhydrous silica
  • croscarmellose sodium
  • magnesium stearate

Do not take ABSTRAL if you are allergic to any of these ingredients. This medicine does not contain lactose, sucrose, gluten, tartrazine or any other azo dyes.

What ABSTRAL looks like

ABSTRAL 100 microgram tablets are white, round and flat with bevelled edges (AUST R 193332)

ABSTRAL 200 microgram tablets are white, oval-shaped and flat with bevelled edges (AUST R 193335)

ABSTRAL 300 microgram tablets are white, arc triangle-shaped and flat with bevelled edges (AUST R 228199)

ABSTRAL 400 microgram tablets are white, diamond-shaped and flat with bevelled edges (AUST R 193336)

ABSTRAL 600 microgram tablets are white, "D"-shaped and flat with bevelled edges (AUST R 228208)

ABSTRAL 800 microgram tablets are white, caplet-shaped and flat with bevelled edges (AUST R 228209)

ABSTRAL is available in foil blister pack sizes of 10 or 30 tablets

Who distributes ABSTRAL

A. Menarini Australia Pty Ltd
Level 8, 67 Albert Ave, Chatswood NSW 2067
Medical Information: 1800 644 542

® = Registered Trademark

This leaflet was prepared in August 2020.

For the most up to date version of this leaflet, please go to www.menarini.com.au/cmi
[vA8-0]

Published by MIMS September 2020

BRAND INFORMATION

Brand name

Abstral

Active ingredient

Fentanyl

Schedule

S8

 

1 Name of Medicine

Fentanyl (as citrate).

2 Qualitative and Quantitative Composition

Each sublingual tablet contains 100, 200, 300, 400, 600, or 800 microgram of fentanyl (as citrate).
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Abstral fentanyl (as citrate) 100 microgram sublingual tablets (round-shaped, white, flat-faced, bevel-edged tablet).
Abstral fentanyl (as citrate) 200 microgram sublingual tablets (oval-shaped, white, flat-faced, bevel-edged tablet).
Abstral fentanyl (as citrate) 300 microgram sublingual tablets (triangle-shaped, white, flat-faced, bevel-edged tablet).
Abstral fentanyl (as citrate) 400 microgram sublingual tablets (diamond-shaped, white, flat-faced, bevel-edged tablet).
Abstral fentanyl (as citrate) 600 microgram sublingual tablets ("D"-shaped, white, flat-faced, bevel-edged tablet).
Abstral fentanyl (as citrate) 800 microgram sublingual tablets (caplet-shaped, white, flat-faced, bevel-edged tablet).

4 Clinical Particulars

4.1 Therapeutic Indications

Abstral is indicated for the management of breakthrough pain in adults with cancer who are already receiving maintenance opioid therapy for chronic pain. Breakthrough pain is a transient exacerbation of otherwise controlled chronic background pain.

4.2 Dose and Method of Administration

Abstral should only be administered to patients who are considered tolerant to their opioid therapy for persistent cancer pain. Patients can be considered opioid tolerant if they take at least 60 mg of oral morphine daily or an equianalgesic dose of another opioid for a week or longer.
Abstral sublingual tablets should be administered directly under the tongue at the deepest part. Abstral sublingual tablets should not be swallowed, but allowed to completely dissolve in the sublingual cavity without chewing or sucking. Patients should be advised not to eat or drink anything until the sublingual tablet is completely dissolved.
In patients who have a dry mouth, water may be used to moisten the buccal mucosa before taking Abstral.

Dose initiation, titration and maintenance.

Abstral dose must be individually upwardly titrated until the optimal maintenance dose for ongoing treatment of breakthrough cancer pain episodes is achieved.
The objective of dose titration is to identify an optimal maintenance dose for ongoing treatment of breakthrough cancer pain episodes. This optimal dose should provide adequate analgesia with an acceptable level of adverse reactions. Rescue medication can be used if adequate analgesia is not achieved after use of Abstral during the titration period.
The initial dose of Abstral used should be 100 microgram, titrating upwards as outlined below. Patients should be carefully monitored until an optimal dose is reached.
Abstral is not a generic of any other fentanyl product. Due to differences in the pharmacokinetic properties of different fentanyl products and the individual variability of patients, patients switching from other fentanyl containing products to Abstral must also start with the initial 100 microgram dose. Abstral is not equivalent on a microgram per microgram (1:1) basis with all other fentanyl products; therefore, do not switch patients on a microgram per microgram basis from any other fentanyl product. (See Titration in patients switching between immediate-release fentanyl-containing products).
The following steps are recommended for initiation and titration; although in all cases the physician should take into account the clinical need of the patient, age and concomitant illness.
Dose initiation and titration. No more than two (2) doses of Abstral, taken 30 minutes apart, should be administered for a single episode of breakthrough cancer pain during the titration phase. Wait 2 hours before treating another episode of breakthrough cancer pain.

Initiation.

All patients must initiate therapy with a single 100 microgram sublingual tablet. If adequate analgesia is achieved within 30 minutes of administration of a single dose, no titration is required and this dose should be used as the maintenance dose for the next breakthrough cancer pain episodes.
If adequate analgesia is not obtained within 30 minutes of administration, a supplemental (second) 100 microgram sublingual tablet may be administered (see Figure 1). As analgesia was inadequate from a single 100 microgram dose at initiation, upwards titration may be necessary (see Titration below). Allow for at least 2 hours before treating the next breakthrough cancer pain episode with Abstral.

Titration.

If analgesia was inadequate from a single 100 microgram dose at initiation, a 200 microgram dose should be administered for the next episode of breakthrough cancer pain (see Figure 1).
Similar to the initiation stage, if adequate analgesia is achieved within 30 minutes with the newly titrated dose, no further titration is required and this dose should be used as the maintenance dose for future breakthrough cancer pain episodes.
If adequate analgesia is not obtained within 30 minutes of administration of the 200 microgram dose, a supplemental (second) 100 microgram sublingual tablet may be administered for that breakthrough cancer pain episode (see Figure 1). As adequate analgesia was not obtained within 30 minutes of taking the newly titrated dose (200 microgram), an increase in dose to the next highest tablet strength should be considered for the next episode of breakthrough cancer pain (see Figure 1).
Dose escalation should continue in this stepwise manner for subsequent breakthrough cancer pain episodes until adequate analgesia with tolerable adverse reactions is achieved. For starting doses of 400 microgram and higher the supplemental (second) sublingual tablet should be 200 microgram (see Figure 1).
If adequate analgesia is achieved at the higher dose, but side effects are considered unacceptable, an intermediate dose (using the 100 microgram sublingual tablet where appropriate) may be administered for the next episode of breakthrough cancer pain.
The efficacy and safety of doses higher than 800 microgram have not been evaluated in clinical studies; therefore, doses higher than 800 microgram are not recommended.
During titration, patients can be instructed to use multiples of 100 microgram tablets and/or 200 microgram tablets for any single dose. No more than four (4) tablets should be used at any one time. In order to minimise the risk of opioid related adverse reactions and to identify the appropriate dose, it is imperative that patients be monitored closely by healthcare professionals during the titration process.
During titration patients should wait at least two (2) hours before treating another episode of breakthrough cancer pain with Abstral.
Maintenance therapy. Once an optimal dose has been established, which may be more than one tablet, patients should be maintained on this dose.
Patients should not take more than four (4) Abstral doses per day.
During the maintenance period patients should wait at least two (2) hours before treating another episode of breakthrough cancer pain with Abstral.

Dose readjustment.

If the response (analgesia or adverse reactions) to the titrated Abstral dose markedly changes, an adjustment of dose may be necessary to ensure that an optimal dose is maintained.
If more than four (4) episodes of breakthrough cancer pain are experienced per day over a period of more than four (4) consecutive days, re-evaluate the dose of the long acting opioid used for background, cancer related pain.
If the long acting opioid or dose of long acting opioid is changed, re-evaluate and retitrate the Abstral dose as necessary to ensure the patient is on an optimal dose.
It is imperative that any dose retitration of any analgesic is monitored by a healthcare professional.

Discontinuation of Abstral therapy.

Abstral should be discontinued immediately if the patient no longer experiences breakthrough cancer 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 in order to avoid the possibility of abrupt withdrawal effects (see Section 4.4 Special Warnings and Precautions for Use, Ceasing opioids).

Titration in patients switching between immediate-release fentanyl-containing products.

Fatal respiratory depression has occurred in patients treated with immediate-release transmucosal fentanyl, including following use in opioid non-tolerant patients and improper dosing.
The substitution of any one fentanyl product for any other fentanyl product may result in fatal overdose unless the new product is titrated from the recommended starting dose. When prescribing, do not convert patients on a microgram-per-microgram (1:1) basis from any other fentanyl products to Abstral.
Substantial differences may exist in the pharmacokinetic profile of immediate-release fentanyl products, which result in clinically important differences in the rate and extent of absorption of fentanyl. Therefore, when switching between fentanyl-containing products indicated for treatment of breakthrough cancer pain, including intranasal formulations, it is essential that patients are titrated with the new product, and not switched on a dose-for-dose (microgram-for-microgram) basis.

Use in children and adolescents.

Abstral must not be used in patients less than 18 years of age due to a lack of data on safety and efficacy.

Use in elderly patients.

Dose titration needs to be approached with particular care and patients observed carefully for signs of fentanyl toxicity (see Section 4.4 Special Warnings and Precautions for Use).

Use in patients with renal and hepatic impairment.

Patients with kidney or liver dysfunction should be carefully observed for signs of fentanyl toxicity during the Abstral titration phase (see Section 4.4 Special Warnings and Precautions for Use).

Special precautions for disposal.

Waste material should be disposed of safely. Patients/carers should be encouraged to return any unused product to the pharmacy, where it should be disposed of in accordance with national and local requirements.

4.3 Contraindications

Hypersensitivity to the active substance or to any of the excipients.
Non opioid-tolerant patients because of the risk of life-threatening respiratory depression.
Severe respiratory disease, severe obstructive lung conditions, acute respiratory disease and respiratory depression.
Use in patients not receiving opioid maintenance therapy for cancer-related pain.
Use in patients for non-breakthrough cancer pain.
Use in patients for acute and chronic non-cancer pain.

4.4 Special Warnings and Precautions for Use

Instructions to patients.

Patients and their carers must be instructed that Abstral contains an active substance in an amount that can be fatal to a child and, therefore, to keep all tablets out of the reach and sight of children.
Due to the potentially serious undesirable effects that can occur when taking an opioid such as Abstral, patients and their carers should be made fully aware of the importance of taking Abstral correctly and what action to take should symptoms of overdose occur.

Hazardous and harmful use.

Abstral contains the opioid fentanyl (as citrate) and is a potential drug of abuse, misuse and addiction. Addiction can occur in patients appropriately prescribed Abstral at recommended doses. Repeated use of Abstral may lead to opioid use disorder. Abuse or intentional misuse of ABSTRAL may result in overdose and/or death.
The risk of addiction is increased in patients with a personal or family history of substance abuse (including alcohol and prescription and illicit drugs) or mental illness. The risk also increases the longer the drug is used and with higher doses. Patients should be assessed for their risks for opioid abuse or addiction prior to being prescribed Abstral.
All patients receiving opioids should be routinely monitored for signs of misuse and abuse. Opioids are sought by people with addiction and may be subject to diversion. Strategies to reduce these risks include prescribing the drug in the smallest appropriate quantity and advising the patient on the safe storage and proper disposal of any unused drug (see Section 6.4 Special Precautions for Storage; Section 6.6 Special Precautions for Disposal). Caution patients that abuse of oral or transdermal forms of opioids by parenteral administration can result in serious adverse events, which may be fatal.
Patients should be advised not to share Abstral with anyone else.

Opioid-naive patients.

Abstral is contraindicated in non opioid-tolerant patients because of the risk of life threatening respiratory depression (see Section 4.3 Contraindications; Section 4.4 Special Warnings and Precautions for Use, Respiratory depression).

Stabilisation of chronic opioid therapy.

Before Abstral therapy is initiated, it is important that the patient's long-acting opioid treatment used to control their persistent pain has been stabilised.

Ceasing opioids.

For patients no longer requiring their chronic opioid therapy for the background cancer pain control, the Abstral dose should be taken into consideration, before the gradual downward titration of other opioids, to minimize possible withdrawal effects. In patients who continue to take their chronic opioid therapy for persistent pain but no longer require treatment for breakthrough pain, Abstral therapy can be discontinued immediately. The treatment by chronic opioids for the background cancer pain should be kept as prescribed. If discontinuation of all opioid therapy is required, the patient must be closely followed by the doctor.
Abrupt discontinuation or rapid decreasing of the dose in a person physically dependent on an opioid may result in serious withdrawal symptoms and uncontrolled pain (see Tolerance, dependence and withdrawal). Such symptoms may lead the patient to seek other sources of licit or illicit opioids. Opioids should not be ceased abruptly in a patient who is physically dependent but withdrawn by tapering the dose slowly. Factors to take into account when deciding how to discontinue or decrease therapy include the dose and duration of the opioid the patient has been taking, the type of pain being treated and the physical and psychological attributes of the patient. A multimodal approach to treatment should be in place before initiating an opioid analgesic taper. During tapering, patients require regular review and support to manage any increase in pain, psychological distress and withdrawal symptoms.
There are no standard tapering schedules suitable for all patients and an individualised plan is necessary. In general, tapering should involve a dose reduction of no more than 10 percent to 25 percent every 2 to 4 weeks. If the patient is experiencing increased pain or serious withdrawal symptoms, it may be necessary to go back to the previous dose until stable before proceeding with a more gradual taper.
When ceasing opioids in a patient who has a suspected opioid use disorder, the need for medication assisted treatment and/or referral to a specialist should be considered.

Hyperalgesia.

Hyperalgesia may occur with the use of opioids, particularly at high doses. Hyperalgesia may manifest as an unexplained increase in pain, increased levels of pain with increasing opioid dosages or diffuse sensitivity not associated with the original pain. Hyperalgesia should not be confused with tolerance (see Tolerance, dependence and withdrawal). If opioid induced hyperalgesia is suspected, the dose should be reduced and tapered off if possible. A change to a different opioid may be required.

Respiratory depression.

Serious, life-threatening or fatal respiratory depression can occur with the use of opioids even when used as recommended. It can occur at any time during the use of opioids but the risk is greatest during initiation of therapy, following an increase in dose, when used in high doses especially high potency and modified release formulations, or in opioid naïve patients. Patients should be monitored closely for respiratory depression at these times. Initiation of opioid treatment should be at the lower end of the dosage recommendations with careful titration of doses to achieve effective pain relief.
The risk of life-threatening respiratory depression is also higher in elderly, frail, or debilitated patients (see subsection on Special risk patients), and in patients with existing impairment of respiratory function (e.g. chronic obstructive pulmonary disease; asthma; other medical conditions predisposing them to respiratory depression such as myasthenia gravis) and in patients with hepatic or renal dysfunction (see subsection on Use in hepatic impairment and Use in renal impairment). Opioids should be used with caution and with close monitoring in these patients (see Section 4.2 Dose and Method of Administration). The use of opioids is contraindicated in patients with severe respiratory disease, acute respiratory disease and respiratory depression (see Section 4.3 Contraindications).
In general, careful calculation of analgesic doses is required when changing opioids or switching from immediate release to modified release formulations (see Section 4.2 Dose and Method of Administration), together with consideration of pharmacological differences between opioids. Consider starting the new opioid at a reduced dose to account for individual variation in response. It should be noted that Abstral is not interchangeable with other fentanyl products. When prescribing or dispensing, do not convert patients on a microgram-per-microgram (1:1) basis from any other fentanyl products to Abstral as this may lead to fatal overdose. If a change in opioid is required, it is essential that patients are again titrated with the new product (see Section 4.2 Dose and Method of Administration).

Tolerance, dependence and withdrawal.

Abstral is contraindicated for treatment of non-cancer pain, non-breakthrough cancer pain and in patients who are not receiving opioids as background maintenance therapy. Use in these patients carries a risk of dependence (in addition to the risk of life threatening respiratory depression). Careful record keeping of prescribing information, including quantity, frequency, and renewal requests is strongly advised.
Neuroadaptation of the opioid receptors to repeated administration of opioids, including fentanyl, can produce tolerance and physical and/or psychological dependence. Iatrogenic addiction following therapeutic use of opioids is known to occur. Tolerance is the need for increasing doses to maintain analgesia. Tolerance may occur to both the desired and undesired effects of the opioid.
Physical dependence, which can occur after several days to weeks of continued opioid usage, results in withdrawal symptoms if the opioid is ceased abruptly or the dose is significantly reduced. Withdrawal symptoms can also occur following the administration of an opioid antagonist (e.g. naloxone) or partial agonist (e.g. buprenorphine). Upon cessation of treatment with Abstral there should be no noticeable effects but drug withdrawal syndrome may occur, possible symptoms of which include: dysphoria, restlessness/agitation, tremor, lacrimation, rhinorrhoea, yawning, sweating, chills, paleness, myalgia, mydriasis, irritability, anxiety, increasing pain, backache, joint pain, weakness, abdominal cramps, insomnia, nausea, anorexia, vomiting, diarrhoea, increased blood pressure, increased respiratory rate and increased heart rate.
If discontinuation of all opioid therapy is required, Abstral may be immediately ceased while the background opioid should be gradually tapered. The patient must be closely monitored by the doctor in order to avoid the possibility of abrupt withdrawal effects (see section on Ceasing opioids).

Risks from concomitant use of benzodiazepines or other CNS depressants, including alcohol.

Concomitant use of opioids and benzodiazepines or other CNS depressants, including alcohol, may result in sedation, respiratory depression, hypotension, coma and death (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions). Because of these risks, concomitant prescribing of Abstral with CNS depressant medicines, such as other opioid analgesics, benzodiazepines, gabapentinoids, cannabis, sedatives, hypnotics, tricyclic antidepressants, antipsychotics, antihistamines, centrally-active anti-emetics and other CNS depressants, should be reserved for patients for whom other treatment options are not possible. If a decision is made to prescribe Abstral concomitantly with any of the medicines, the lowest effective dose should be used, and the duration of treatment should be as short as possible. Patients should be followed closely for signs and symptoms of respiratory depression and sedation. Patients and their caregivers should be made aware of these symptoms. Patients and their caregivers should also be informed of the potential harms of consuming alcohol while taking Abstral.

Accidental ingestion/exposure.

Accidental ingestion or exposure of Abstral, especially by children, can result in a fatal overdose of fentanyl. Patients and their caregivers should be given information on safe storage and disposal of unused Abstral (see Section 6.4 Special Precautions for Storage; Section 6.6 Special Precautions for Disposal).

Special risk patients.

Respiratory.

The use of opioids is contraindicated in patients with severe respiratory disease, severe obstructive lung conditions, acute respiratory disease and respiratory depression (see Section 4.3 Contraindications).
The risk of life-threatening respiratory depression is higher in elderly, frail or debilitated patients and in patients with existing impairment of respiratory function (e.g. chronic obstructive pulmonary disease; asthma; other medical conditions predisposing them to respiratory depression such as myasthenia gravis) and in patients with hepatic or renal dysfunction (see subsection on Use in hepatic impairment and Use in renal impairment). Abstral should be used with caution and with close monitoring in these patients, particularly during dose titration, because of the risk of further respiratory depression, which could lead to respiratory failure (see Section 4.2 Dose and Method of Administration).

Head injuries and raised intracranial pressure.

Abstral should only be administered with extreme caution in patients who may be particularly susceptible to the intracranial effects of hypercapnia, such as those showing evidence of raised intracranial pressure, reduced consciousness, coma, or brain tumours. In patients with head injuries, the clinical course may be masked by the use of opioids. In such a case, opioids should be used only if absolutely necessary.

Cardiovascular.

Intravenous fentanyl has been shown to cause bradycardia. Abstral should be used with caution in patients with previous or pre-existing bradyarrhythmias.

Hypovolaemia and hypotension.

Care should be taken in treating patients with hypovolaemia and hypotension.

Serotonin syndrome.

Caution is advised when Abstral is coadministered with drugs that affect the serotonergic neurotransmitter systems.
The development of a potentially life-threatening serotonin syndrome may occur with the concomitant use of serotonergic drugs such as Selective Serotonin Re-uptake Inhibitors (SSRIs) and Serotonin Noradrenalin Re-uptake Inhibitors (SNRIs), and with drugs which impair metabolism of serotonin (including Monoamine Oxidase Inhibitors [MAOIs]). This may occur within the recommended dose range.
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 Abstral should be discontinued.

Mucositis.

Abstral has not been studied in patients with mouth wounds or mucositis. There may be a risk of increased systemic drug exposure in such patients; therefore, extra caution is recommended during dose titration.

Use in hepatic impairment.

Abstral should be administered with caution to patients with liver dysfunction, especially during the titration phase. The use of Abstral in patients with hepatic impairment may increase the bioavailability of fentanyl and decrease its systemic clearance, which could lead to accumulation and increased and prolonged opioid effects.

Use in renal impairment.

Abstral should be administered with caution to patients with kidney dysfunction, especially during the titration phase. The use of Abstral in patients with renal impairment may increase the bioavailability of fentanyl and decrease its systemic clearance, which could lead to accumulation and increased and prolonged opioid effects.

Use in the elderly.

Data from intravenous studies with fentanyl suggest that elderly patients may have reduced clearance, a prolonged half-life and they may be more sensitive to the active substance than younger patients. Elderly, cachectic or frail, or debilitated patients should be observed carefully for signs of fentanyl toxicity and the dose reduced if necessary.

Paediatric use.

Abstral is not recommended for use in children and adolescents below 18 years since the appropriate posology and safety of Abstral have not been established in this population. The opioid maintenance dose, which constitutes adequate opioid tolerance for the use of Abstral, has not been investigated in children, nor has the adequate dosage been identified.

Effects on laboratory tests.

No data available.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Inducers and inhibitors of CYP3A4.

Fentanyl is metabolised by CYP3A4. Active substances that inhibit CYP3A4 activity such as macrolide antibiotics (e.g. erythromycin), azole antifungal agents (e.g. ketoconazole, itraconazole) or certain protease inhibitors (e.g. ritonavir) may increase the bioavailability of fentanyl by decreasing its systemic clearance, potentially enhancing or prolonging opioid effects. Grapefruit juice is also known to inhibit CYP3A4. Coadministration with agents that induce CYP3A4 activity may reduce the efficacy of fentanyl. Patients receiving fentanyl who stop therapy with, or decrease the dose of CYP3A4 inducers may be at risk of increased fentanyl activity or toxicity. Fentanyl should therefore be given with caution to patients if administered concomitantly with CYP3A4 inhibitors and/or inducers.
Use with potent cytochrome P450 3A4 inducers may decrease the effect of fentanyl.

CNS depressants.

Concomitant use of other CNS depressants, such as other morphine derivatives (analgesics and antitussives), general anaesthetics, skeletal muscle relaxants, sedative antidepressants, sedative H1 antihistamines, barbiturates, anxiolytics (i.e. benzodiazepines), hypnotics, antipsychotics, clonidine, centrally-active anti-emetics, gabapentinoids, cannabis and related substances may produce increased CNS depressant effects. Respiratory depression, hypotension, profound sedation, coma and death may occur.
Alcohol potentiates the sedative effects of morphine-based analgesics, therefore concomitant administration of alcoholic beverages or medicinal products containing alcohol with Abstral is not recommended.
(See Section 4.4 Special Warnings and Precautions for Use, Risks from concomitant use of benzodiazepines or other CNS depressants, including alcohol).

MAO inhibitors.

Abstral is not recommended for use in patients who have received monoamine oxidase (MAO) inhibitors within 14 days because severe and unpredictable potentiation by MAO inhibitors has been reported with opioid analgesics.

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 dependent patients.

Serotonergic drugs.

Coadministration of fentanyl with a serotonergic agent, such as a selective serotonin reuptake inhibitor (SSRI) or a serotonin noradrenaline reuptake inhibitor (SNRI) or a monoamine oxidase inhibitor (MAOI), may increase the risk of serotonin syndrome, a potentially life threatening condition.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

In humans, the prolonged use of opioid analgesics may result in sexual dysfunction, infertility or impairment of fertility in both sexes, and menstrual disturbance in women. Impairment of fertility has been observed in female rats given 160 microgram/kg/day subcutaneous fentanyl (no effect dose not established) or 400 microgram/kg/day intravenous fentanyl (no effect dose 100 microgram/kg/day). No effect was observed on the fertility of male rats given 400 microgram/kg/day intravenous fentanyl.
(Category C)
Fentanyl crosses the placenta in humans (fetal blood concentrations about 40% of maternal blood concentrations). There are no adequate and well controlled studies in pregnant women. Abstral should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. No epidemiological studies of congenital abnormalities in infants born to women treated with fentanyl during pregnancy have been reported. Chronic maternal treatment with fentanyl during pregnancy has been associated with transient respiratory depression, behavioural changes, or seizures in newborn infants characteristic of neonatal abstinence syndrome.
In pregnant rats, fentanyl is embryocidal as evidenced by increased resorption at doses of 30 microgram/kg/day intravenously or 160 microgram/kg/day or greater subcutaneously. Intravenous administration to rats at 30 microgram/kg/day during organogenesis was associated with prolonged delivery time and increased postnatal mortality of offsprings. There was no effect on embryofetal development when rats received fentanyl at subcutaneous doses up to 500 microgram/kg/day throughout gestation, and no evidence of teratogenicity in rabbits administered fentanyl at intravenous doses up to 400 microgram/kg/day during organogenesis. The significance of these findings for potential human risk is unknown.
 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 breastfeeding should not be restarted until at least 5 days after the last administration of fentanyl.

4.7 Effects on Ability to Drive and Use Machines

No studies on the effects on the ability to drive and use machines have been performed.
However, fentanyl may impair the mental or physical ability to perform potentially hazardous tasks such as driving or operating machinery. Patients should be advised not to drive or operate machinery if they become dizzy or drowsy or experience blurred or double vision while taking Abstral.

4.8 Adverse Effects (Undesirable Effects)

The safety assessment showed that the majority of patients in phase III studies (73.3%) experienced at least one treatment emergent adverse event (TEAE), which is to be expected considering the patient population and a long-term period of observation of up to 12 months. There was no evidence of any TEAEs becoming more prevalent or severe over time. 31.3% of patients experienced TEAEs that were considered product related by the investigator. The most common of these were nausea, somnolence and vomiting, all of which are known undesirable effects of opioids, and in keeping with the findings of previous clinical studies with Abstral. Serious TEAEs were experienced by 18.3% of patients; only one of these (affect lability) was considered related to study medication.
Undesirable effects typical of opioids are to be expected with Abstral; they tend to decrease in intensity with continued use. The most serious potential adverse reactions associated with opioid use are respiratory depression (which could lead to respiratory arrest), hypotension and shock.
The clinical trials of Abstral were designed to evaluate safety and efficacy in treating patients with breakthrough cancer pain; all patients were taking concomitant opioids, such as sustained release morphine, sustained release oxycodone or transdermal fentanyl, for their persistent pain. Therefore it is not possible to definitively separate the effects of Abstral alone.
The most frequently observed adverse reactions with Abstral include typical opioid adverse reactions, such as nausea, constipation, somnolence and headache.
The following adverse reactions have been reported with Abstral and/or other fentanyl containing compounds during clinical studies and from postmarketing experience. They are listed in Table 1 by system organ class and frequency (very common ≥ 1/10; common ≥ 1/100 to < 1/10; uncommon ≥ 1/1,000 to < 1/100; not known (cannot be estimated from available data)). Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

Reporting of suspected adverse reactions.

Reporting suspected adverse reactions after registration 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 at http://www.tga.gov.au/reporting-problems.

4.9 Overdose

For information on the management of overdose, contact the Poisons Information Centre on 13 11 26 (Australia).
The symptoms of fentanyl overdose are an extension of its pharmacological actions, the most serious effect being respiratory depression, which may lead to respiratory arrest. Coma is also known to occur.
Management of opioid overdose in the immediate term includes removal of any remaining Abstral sublingual tablets from the mouth, physical and verbal stimulation of the patient and an assessment of the level of consciousness. A patent airway should be established and maintained. If necessary an oropharyngeal airway or endotracheal tube should be inserted, oxygen administered and mechanical ventilation initiated, as appropriate. Adequate body temperature and parenteral fluid intake should be maintained.
For the treatment of accidental overdose in opioid naïve individuals, naloxone or other opioid antagonists should be used as clinically indicated and in accordance with their product information. Repeated administration of the opioid antagonist may be necessary if the duration of respiratory depression is prolonged.
Care should be taken when using naloxone or other opioid antagonists to treat overdose in opioid maintained patients, due to the risk of precipitating an acute withdrawal syndrome.
If severe or persistent hypotension occurs, hypovolaemia should be considered, and the condition should be managed with appropriate parenteral fluid therapy.
Muscle rigidity interfering with respiration has been reported with fentanyl and other opioids. In this situation, endotracheal intubation, assisted ventilation and administration of opioid antagonists as well as muscle relaxants may be requested.

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Fentanyl is a potent mu-opioid analgesic with rapid onset of analgesia and short duration of action. Fentanyl is approximately 100-fold more potent than morphine as an analgesic. Secondary effects of fentanyl on the central nervous system (CNS), respiratory and gastrointestinal function are typical of opioid analgesics and are considered to be class effects. These can include respiratory depression, bradycardia, hypothermia, constipation, miosis, physical dependence and euphoria.
The analgesic effects of fentanyl are related to the blood level of the active substance; in opioid naïve patients, minimum effective analgesic serum concentrations of fentanyl range from 0.3 to 1.2 nanogram/mL, while blood levels of 10 to 20 nanogram/mL produce surgical anaesthesia and profound respiratory depression.
Fentanyl, in common with all mu-opioid receptor agonists, produces dose dependent respiratory depression. This risk is higher in opioid naïve subjects than in patients experiencing severe pain or receiving chronic opioid therapy. Long-term treatment with opioids typically leads to development of tolerance to their secondary effects.
While opioids generally increase the tone of urinary tract smooth muscle, the net effect tends to be variable, in some cases producing urinary urgency, in others, difficulty in urination.
Opioids increase the tone and decrease the propulsive contractions of the smooth muscle of the gastrointestinal tract leading to a prolongation in gastrointestinal transit time, which may be responsible for the constipating effect of fentanyl.

Clinical trials.

Fentanyl citrate has been used extensively for pain relief, including cancer patients, and a significant body of research has been published in the scientific literature.
The efficacy of Abstral was investigated in study EN3267-005, a randomised, double blind, placebo controlled, multicenter phase III study in 131 opioid tolerant cancer patients with breakthrough pain. All patients (n = 131) were receiving a stable, fixed schedule oral opioid regimen equivalent to 60 to 1000 mg of oral morphine per day or transdermal fentanyl therapy equivalent to 50 to 300 microgram/h; were on a stable dose of opioid medication for relief of breakthrough pain; and were experiencing at least one but not more than 4 episodes of breakthrough pain per day. Pre-emptive use of Abstral for predictable pain episodes was not investigated in the clinical trials.
Patients were titrated to a single effective dose of Abstral for adequate treatment of their breakthrough cancer pain in an initial open label phase. Patients who were successfully titrated were then included in a double blind, randomised, placebo controlled phase of up to 2 weeks, during which 10 episodes of breakthrough cancer pain were treated with Abstral (7 doses) or placebo (3 doses). Patients who completed the double blind phase elected to continue in an open label extension phase using Abstral to treat breakthrough cancer pain episodes for up to 12 months.
Open label titration identified a successful dose of Abstral, within the range of 100 to 800 microgram. A "successful" dose was defined as the one, single dosage strength of Abstral that successfully treated all breakthrough cancer pain episodes that occurred for two consecutive days with tolerable side effects. Of the 131 patients enrolled, 53 (40.5%) discontinued during the titration period.
The final titrated dose of Abstral for breakthrough cancer pain was not predictable from the background opioid dose underlying the need for individual titration starting at 100 microgram.
The interim analysis of efficacy became the primary analysis because it lead to the double blind treatment phase of the study being terminated in accordance with the predefined stopping rules, after which patients proceeded directly from the titration period to the open label long-term extension.
The mean age of subjects in the intention-to-treat (ITT) population (n = 131) was 55.0 years (range 21 to 80 years) with 54.2% female and 45.8% male.
The primary efficacy endpoint was the Sum of Pain Intensity Difference (SPID) from baseline to 30 minutes after treating breakthrough cancer pain episodes with study medication. The secondary objectives were to compare the efficacy of Abstral with that of placebo in treating breakthrough cancer pain (BTcP) episodes in opioid tolerant cancer patients for 1) pain intensity difference (PID) and pain relief (PR) at time points 10, 15, 30 and 60 min; patient global evaluation of study medication, and the use of rescue medication; and 2) to evaluate the safety and tolerability of Abstral in treating BTcP episodes in opioid tolerant cancer patients, as measured by the occurrence of adverse events (AEs) and withdrawals because of AEs.
Abstral was found to be superior to placebo in treating breakthrough cancer pain as measured by SPID over the first 30 minutes of a breakthrough episode (49.3, 35.23 respectively, p = 0.0004). The difference of least squares mean between the treatments was 14.08 (95% CI: 6.515, 21.637).
The difference in SPID reached statistical significance (p = 0.006) as early as 10 minutes postdose and the difference continued to be statistically significant through all time points thereafter until the final assessment at 60 minutes postdose (Figure 2).
Abstral was also shown to provide improved reduction in Pain Intensity Difference (PID), a prespecified secondary endpoint, from the first measured time point (10 minutes) that was significantly different to placebo (1.16 vs. 0.88 respectively; p = 0.0055). The statistically significant difference was maintained to at least 60 minutes. (Figure 3).
Similarly, Abstral provided statistically significantly greater pain relief, compared with placebo, from 10 min postdose (prespecified secondary endpoint) and throughout the assessment period (p = 0.049; Figure 4). Clinically significant differences between Abstral and placebo were apparent approximately 30 minutes after dosing and were maintained for approximately 60 minutes after dosing.
The efficacy of Abstral compared with placebo was examined across gender, age, and dose subgroups, as well as by the type of opioid medication patients used for their fixed schedule analgesic treatment for chronic pain (Table 2).
Results of the subgroup analyses of the SPID for the ITT population consistently favoured the Abstral treatment group compared with the placebo treatment group regardless of gender or age. Higher mean SPIDs were found at 30 and 60 minutes after treatment with low (100 to 400 microgram) or high (600 to 800 microgram) doses, indicating that once titration to an appropriate dose was achieved, the response to Abstral was similar across dose groups. In addition, higher mean SPIDs were recorded at both 30 and 60 minutes after treatment with Abstral regardless of the type of background opioid medication used to treat chronic cancer pain.

5.2 Pharmacokinetic Properties

Absorption.

Fentanyl is a highly lipophilic drug absorbed very rapidly through the oral mucosa and more slowly through the gastrointestinal tract. Orally administered fentanyl undergoes pronounced hepatic and intestinal first pass effects.
Abstral is a quick dissolving sublingual tablet formulation. Rapid absorption of fentanyl occurs over about 30 minutes following administration of Abstral. The absolute bioavailability of Abstral has been calculated to be 54%. Mean maximal plasma concentrations of fentanyl range from 0.2 to 1.5 nanogram/mL (after administration of 100 to 800 microgram Abstral) and are reached within 22.5 to 240 minutes.

Distribution.

About 80-85% of fentanyl is bound by plasma proteins, mainly α1-glycoprotein and to a lesser extent albumin and lipoprotein. The volume of distribution of fentanyl at steady state is about 3-6 L/kg.

Metabolism.

Fentanyl is metabolised primarily via CYP3A4 to a number of pharmacologically inactive metabolites, including norfentanyl.

Excretion.

Within 72 hours of intravenous fentanyl administration around 75% of the dose is excreted into the urine, mostly as metabolites, with less than 10% as unchanged drug. About 9% of the dose is recovered in the faeces, primarily as metabolites. Total plasma clearance of fentanyl is about 0.5 L/h/kg. After Abstral administration, the mean elimination half-life of fentanyl is about 7 hours (range 3 to 12.5 hours) and the terminal half-life is about 20 hours (range 11.5 to 25 hours).
The pharmacokinetics of Abstral have been shown to be dose proportional over the dose range of 100 to 800 microgram. Pharmacokinetic studies have shown that multiple tablets are bioequivalent to single tablets of the equivalent dose.

Renal/hepatic impairment.

Impaired hepatic or renal function could cause increased serum concentrations. Elderly, cachectic or generally impaired patients may have a lower fentanyl clearance, which could cause a longer terminal half-life for the compound (see Section 4.4 Special Warnings and Precautions for Use; Section 4.2 Dose and Method of Administration).

5.3 Preclinical Safety Data

Genotoxicity.

Fentanyl showed no evidence of genotoxic potential in assays for gene mutations (Ames reverse mutation test, mouse lymphoma thymidine kinase assay), chromosomal damage (Chinese hamster ovary cells, mouse micronucleus test) and other genotoxic effects (unscheduled DNA synthesis in rat hepatocytes, mammalian cell transformation assay). The metabolite despropionylfentanyl was negative in assays for reverse mutation in bacteria and chromosomal damage in human lymphocytes. The genotoxic potential of fentanyl is considered to be low.

Carcinogenicity.

Carcinogenicity studies (26 week dermal alternative bioassay in Tg.AC transgenic mice; two year subcutaneous carcinogenicity study in rats) with fentanyl did not reveal any findings indicative of oncogenic potential. Evaluation of brain slides from the 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

Mannitol, microcrystalline cellulose, colloidal anhydrous silica, croscarmellose sodium, and magnesium stearate.

6.2 Incompatibilities

Incompatibilities were either not assessed or not identified as part of the registration of this medicine. See Section 4.5 Interactions with Other Medicines and Other Forms of Interactions.

6.3 Shelf Life

In Australia, information on the shelf life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG). The expiry date can be found on the packaging.

6.4 Special Precautions for Storage

Store below 25°C.
Store in the original blister package in order to protect from moisture.

6.5 Nature and Contents of Container

Abstral is supplied in child-resistant foil blister packs of 10 sublingual tablets.
Each blister pack is packaged in cartons of 10 or 30 sublingual tablets.
The packaging is colour-coded for each Abstral sublingual tablet strength.
Not all pack sizes may be marketed.

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of by taking to your local pharmacy.

6.7 Physicochemical Properties

Fentanyl citrate is a highly lipophilic white or almost white powder that is freely soluble in organic solvents (logPoctanol/water = 2.98) and soluble in water (1:40). The dissolution rate of fentanyl citrate is promoted by the use of a micronised grade.

Chemical structure.


Chemical name (IUPAC): N-phenyl-N-[1-(2-phenylethyl)piperidin- 4-yl]propanamide dihydrogen 2-hydroxypropane-1,2,3-tricarboxylate.

CAS number.

990-73-8.
Molecular formula: C22H28N2O.C6H8O7.
Molecular weight: 528.6 (free base 336.5).

Pharmacotherapeutic group.

Phenylpiperidine derivatives.

ATC code.

N02AB03.

7 Medicine Schedule (Poisons Standard)

Schedule 8 (controlled drug).

Summary Table of Changes