Consumer medicine information

Fentora

Fentanyl

BRAND INFORMATION

Brand name

Fentora

Active ingredient

Fentanyl

Schedule

S8

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Fentora.

What is in this leaflet

This leaflet answers some common questions about Fentora. It does not contain all of the available information. It does not take the place of talking to your doctor or pharmacist.

All medicines have risks and benefits. Your doctor has weighed the risks of your taking Fentora against the benefits they expect it will have for you.

If you have any concerns about taking Fentora, talk to your doctor or pharmacist.

Keep this leaflet with the medicine. You may want to read it again.

What Fentora is used for

Fentora contains a medicine called fentanyl citrate. It is a pain-relieving medicine known as an opioid, which is used to treat breakthrough pain in adult patients 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 in spite of you having taken your usual opioid pain-relieving medicines.

Opioid medicines are those that contain active ingredients such as morphine, fentanyl citrate, codeine, methadone, oxycodone, pethidine or buprenorphine.

Ask your doctor if you have any questions about why Fentora orally disintegrating tablets have been prescribed for you. Your doctor may have prescribed it for another use.

Fentora is only available on a doctor's prescription.

Before you take it

Fentora is not suitable for everyone.

When you must not take it

Do not take Fentora if:

  • you suffer from short-term pain or chronic pain other than breakthrough pain, such as pain from injuries or surgery, headaches or migraines.
  • you have not been prescribed opioid pain medicine ever.
  • you have not been prescribed opioid pain medicine every day on a regular schedule, for at least one week, to control your persistent pain. If you have not been using these medicines you must not use Fentora, because it may increase the risk that breathing could become dangerously slow and/or shallow, or even stop.
  • you are allergic (hypersensitive) to fentanyl, or any of the other ingredients of Fentora (see list at the end of this leaflet).
  • you suffer from severe breathing problems or severe obstructive lung conditions
  • you are also taking, or used in the last 2 weeks, medicines referred to as Monoamine Oxidase (MAO) Inhibitors.

Do not take Fentora after the expiry date shown on the blister package label and the carton.

Do not take Fentora if the packaging seems to have been opened or is damaged.

Things to be careful of

Addiction

You can become addicted to Fentora even if you take it exactly as prescribed. Fentora may become habit forming causing mental and physical dependence. If abused it may become less able to reduce pain.

Dependence

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

Tolerance

Tolerance to Fentora may develop, which means that the effect of the medicine may decrease. If this happens, more may be needed to maintain the same effect.

Continue taking your medicine for as long as your doctor tells you. If you stop having this medicine suddenly, your pain may worsen and you may experience some or all of the following withdrawal symptoms:

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

DO NOT use Fentora during labour and delivery.

It is important that you do not exceed your recommended dose.

Before you start to take it

Tell your doctor if:

  • you have any allergies
  • you are pregnant or intend to become pregnant
  • you are breast feeding or planning to breast feed
  • your other opioid pain medicine you take for your persistent (around-the-clock) cancer pain is not stabilized yet
  • you are suffering from any condition that has an effect on your breathing (such as asthma, wheezing, or shortness of breath).
  • You have a head injury
  • You have exceptionally slow heart rate or other heart problems
  • You have liver or kidney problems, as these organs have an effect on the way in which your system breaks down the medicine.
  • You have low amount of fluid in the circulation or low blood pressure
  • You have a history of addiction or substance abuse either personally or within your family
  • You experience an unexplained increase in pain.
  • You feel anxious, irritable or have sudden mood swings, these could be signs of addiction
  • You notice any changes in hormones such as prolactin, testosterone and cortisol from blood tests.

Your doctor should monitor you for these signs while on treatment. They may also conduct blood tests from time to time to ensure you are responding as expected to treatment.

These organs have an effect on the way in which your system breaks down the medicine.

Taking other medicines

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

Take special care with Fentora if:

  • you are taking any medicines which might normally have a sedative effect (make you sleepy), such as:
    - sleeping pills
    - medicines to treat anxiety
    - antihistamines
    - tranquillisers.
  • Other strong analgesics used to manage pain such as morphine, codeine, methadone, oxycodone, pethidine or buprenorphine.
  • you are taking any medicines or other substances that might have an effect on the way in which your body breaks down Fentora, such as:
    - medicines used to treat fungal infections, such as ketoconazole, itraconazole, and fluconazole
    - medicines that help control HIV infection, such as ritonavir, nelfinavir, amprenavir, and fosamprenavir
    - certain antibiotics such as clarithromycin and erythromycin
    - medicines used for severe nausea
    - medicines used to treat high blood pressure or heart disease, such as diltiazem and verapamil
    - medicines used for severe depression known as selective serotonin re-uptake inhibitors (SSRIs) or serotonin norepinephrine re-uptake inhibitors (SNRIs) or have done so in the past 2 weeks
    - muscle relaxants (such as cyclobenzaprine, metaxalone)
    - medicines used for severe depression called monoamine oxidase inhibitors (MAOIs) or have done so in the past 2 weeks

Using FENTORA with food or drink

  • Fentora may be used before or after, but not during, meals. You may drink some water before using Fentora to help moisten your mouth, but you should not drink or eat anything while taking the medicine.
  • You should not drink grapefruit juice while using Fentora because it may affect the way your body breaks down Fentora
  • Do not drink alcohol while using Fentora. It can increase the risk of experiencing dangerous side effects

Pregnancy and breast-feeding

Ask your doctor or pharmacist for advice before taking any medicine.

Fentora should not be used during pregnancy or breastfeeding. Breastfeeding should not be restarted until at least 6 days after the last administration of Fentora, unless you have discussed this with you doctor.

Driving and using machines

  • You should discuss with your doctor whether it is safe for you to drive, or operate machinery after taking Fentora.

Do not drive or operate machinery if you: are feeling sleepy or dizzy; have blurred or double vision; or have difficulty in concentrating. It is important you know how you react to Fentora before driving or operating machinery.

Important information about some of the ingredients of Fentora

Each tablet of Fentora 100 micrograms contains 10 mg of sodium. Each tablet of Fentora 200 micrograms, Fentora 400 micrograms, Fentora 600 micrograms and Fentora 800 micrograms contains 20 mg of sodium. You should take this into consideration and seek advice from your doctor.

How to take it

Do not take Fentora to treat any condition other than that directed by your doctor.

Fentora orally disintegrating tablets are for buccal use. When you place a tablet in your mouth, it dissolves and the medicine is absorbed through the lining of your mouth, into the blood system. Taking the medicine in this way allows it to be absorbed quickly to relieve your breakthrough pain.

How many to take

When you first start Fentora, your doctor will work with you to find the dose that will relieve your breakthrough pain. This process is called the titration process. Please refer to the titration flowchart in the Patient's guide for Fentora section of the leaflet for more information.

It is very important that you use Fentora exactly as the doctor tells you.

The initial dose is 100 micrograms. During determination of your right dose, your doctor may instruct you to take more than one tablet per episode. If your breakthrough pain is not relieved after 30 minutes, use only 1 more tablet of Fentora during the titration period.

Ask your doctor if you are not sure about the right dose or if you have any questions about taking Fentora.

You should start to feel some pain relief quickly while you are taking Fentora.

Contact your doctor if your right dose of Fentora does not relieve your breakthrough pain. Your doctor will decide if your dose needs to be changed.

It is recommended that you wait at least 4 hours before treating another episode of breakthrough pain with Fentora. The frequency may be increased if instructed by your doctor.

You must tell your doctor immediately if you are using Fentora more than four times per day, as the doctor may wish to change your medicine for your persistent pain. Once your persistent pain has been controlled, your doctor may need to change your dose of Fentora further.

For the most effective relief, let your doctor know about your pain and how Fentora is working for you so that the dose can be changed if needed.

Do not change doses of Fentora or your other pain medicines on your own. Any change in dosage must be prescribed and monitored by your doctor.

If you are not sure about the right dose, or if you have questions about taking this medicine, you should contact your doctor.

DO NOT TAKE MORE THAN THE DOSE YOUR DOCTOR HAS RECOMMENDED. Change in dosage must be directed and monitored by your doctor.

How to take it

  1. Open the blister only when you are ready to use the tablet.
    The tablet must be used immediately once removed from the blister.
    Separate one of the blister units from the blister card by tearing apart at the perforations.
    Bend the blister unit along the line where indicated.
    Peel the blister backing to expose the tablet. Do NOT attempt to push the tablet through the blister, because this can damage the tablet.
    Remove the tablet from the blister unit and immediately place the entire tablet near a molar tooth between the gum and the cheek (as shown in the picture).

Do not attempt to crush or split the tablet.
Sometimes your doctor may tell you to place the tablet under your tongue instead.

Do not bite, suck, chew, or swallow the tablet, as this will result in less pain relief than when taken as directed.

  • The tablet should be left between the cheek and gum until dissolved, which usually takes approximately 14 to 25 minutes.
  • You may feel a gentle bubbling sensation between your cheek and gum as the tablet dissolves.
  • In case of irritation, you may change the placement of the tablet on the gum.
  • After 30 minutes, if pieces of the tablet remain, they may be swallowed with a glass of water.

Always write the date and time each time you take Fentora tablet. A table called the 'Titration Dose Record' and 'Maintenance Dosing Record' in the leaflet located inside the box will help you record this information.

This will help you and your doctors monitor your pain level and if the dose is right for you.

Fentora contains no added flavours. You may sense a slight taste, or you may notice nothing at all.

How long to take it

You should not normally stop taking Fentora for breakthrough pain unless your doctor tells you to.

If you are taking high doses of Fentora and feel that the pain is getting worse with time please speak to your doctor.

Tell your doctor if you feel unwell during your course of treatment.

If you take too many Fentora units (overdose)

If you or someone else receive too much (overdose), and experience 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 has accidentally used Fentora 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 you or someone else may have used too much Fentora, you should immediately:

  • telephone your doctor, or
  • the Poisons Information Centre (telephone 13 11 26) or
  • go to Accident and Emergency at your nearest hospital

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.

The most common side effects are feeling sleepy, sick or dizzy. If you begin to feel very dizzy, or very sleepy before the tablet is completely dissolved, rinse your mouth with water and spit the remaining pieces of the tablet into a sink or toilet right away. Call another person to help you.

A serious side effect of Fentora is slow and/or shallow breathing. This can occur if your dose of this medicine is too high or if you take too much Fentora. You and your carer should discuss this side effect with your doctor immediately.

What to do if a child or adult accidentally takes Fentora

If you think someone has accidentally taken Fentora follow these steps:

  1. If the person is asleep, wake them up by calling their name and shaking their arm or shoulder.
  2. CALL FOR EMERGENCY HELP.
  3. While waiting for emergency help:
  • if the person seems to be breathing slowly, prompt them to breathe every 5-10 seconds
  • if the person has stopped breathing give mouth to mouth resuscitation until help arrives.

While you are taking it

Things you must do

Make sure that all of your doctors and pharmacists know about your use of Fentora. Remind them if any new medicines are about to be started, including any medicines that you may purchase without a prescription.

Things that you must not do

Do not use Fentora to treat any other complaints unless your doctor tells you to. It may not be safe to use Fentora for another complaint.

Do not give Fentora to someone else even if their symptoms are the same. Fentora should only be used by the person for whom it was prescribed. It may not be safe for another person to use Fentora.

Do not stop using Fentora unless your doctor advises you to do so. If you have been using Fentora for a long period of time but stop using it suddenly without your doctor's advice, you may experience withdrawal symptoms (such as nausea, vomiting, diarrhoea, anxiety and shivering). Seek your doctor's advice if you experience these symptoms.

If you become pregnant whilst taking Fentora, you should stop taking it and see your doctor immediately.

Side Effects

All medicines can have side effects. Sometimes they are serious, most of the time they are not. You may need medical treatment if you get some side effects. Do not be alarmed by this list of possible side effects. You may not experience any of them.

Ask your doctor or pharmacist to answer any questions you may have.

Tell your doctor if you experience any of the following:

  • headache
  • nausea/vomiting
  • feeling unwell
  • weakness, dizziness
  • sleepiness, sedation
  • constipation
  • anxiety.

If you feel excessively dizzy, sleepy or otherwise ill while taking Fentora, remove the Fentora unit and contact your doctor for further directions on using Fentora.

Tell your doctor immediately, or get someone to take you to Accident and Emergency at your nearest hospital if you notice any of the following:

  • becoming very sleepy
  • having slow or shallow breathing
  • sudden signs of allergy such as rash, itching or hives on the skin, swelling of the lips, tongue or throat, shortness of breath, wheezing or trouble breathing.

Opioids can cause sleep-related breathing disorders including central sleep apnoea (CSA) and sleep-related hypoxemia (insufficient oxygen intake).

Make sure that you are with someone who can keep you awake by talking to you or gently shaking you every now and then.

Whilst using the Fentora tablet you may experience irritation, pain, gum bleeding or an ulcer at the site of application.

Tell your doctor if you notice anything else that is making you feel unwell. Other side effects not listed in this leaflet may also occur in some patients.

After using it

Storage

Keep Fentora in the original package until it is time to take the dose. If you take Fentora out of its blister package, it may not keep as well.

Do not use it if the blister package has been damaged or opened before you are ready to use it.

Keep Fentora in a cool dry place where the temperature stays below 25°C.

Do not store it or any other medicine in the bathroom or near a sink. Do not leave it in the car on hot or cold days. Heat, cold and dampness can destroy some medicines.

Fentora orally disintegrating tablets must be kept out of the reach of children. The pain-relieving medicine in Fentora is very strong and could be life-threatening if taken accidentally by a child.

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

Disposal

If you no longer need to use this medicine or it is out of date, take it to any pharmacy for safe disposal.

Product description

What Fentora looks like

The orally disintegrating tablets are flat-faced, round, bevelled-edge tablets, embossed one side with a "C" and on the other side with "1" for FENTORA 100 micrograms, with "2" for FENTORA 200 micrograms, with "4" for FENTORA 400 micrograms, with "6" for FENTORA 600 micrograms, with "8" for FENTORA 800 micrograms.

FENTORA is supplied in individually sealed, child-resistant blister packs.

Ingredients

Active ingredient:

The active ingredient is fentanyl, present in the product as fentanyl citrate.

Inactive ingredients:

  • mannitol
  • sodium starch glycollate type A
  • sodium hydrogen carbonate
  • sodium carbonate
  • citric acid
  • magnesium stearate

Manufacturer/Supplier

Fentora is manufactured in the USA.

Supplied in Australia by:

Teva Pharma Australia Pty Ltd
Level 1, 37 Epping Rd
Macquarie Park
NSW 2113
Telephone: 1800 288 382

Australian Registration Numbers:

Fentora 100 micrograms:
AUST R 218435

Fentora 200 micrograms:
AUST R 218437

Fentora 400 micrograms:
AUST R 218433

Fentora 600 micrograms:
AUST R 218434

Fentora 800 micrograms:
AUST R 218436

Fentora is a registered trademark of Cima Labs Inc.

This leaflet was prepared in August 2021.

Published by MIMS October 2021

BRAND INFORMATION

Brand name

Fentora

Active ingredient

Fentanyl

Schedule

S8

 

1 Name of Medicine

Fentanyl citrate.

2 Qualitative and Quantitative Composition

Fentora (fentanyl citrate) is a synthetic opioid analgesic related to pethidine and with similar properties to morphine. Fentanyl citrate is a white, crystalline powder with a molecular weight of 528.6 and the molecular formula C22H28N2O,C6H8O7. Its chemical name is N-(1-Phenethyl-4-piperidyl) propionanilide dihydrogen citrate.
The citrate salt is sparingly soluble to soluble in water; sparingly soluble in alcohol; slightly soluble in chloroform; soluble to freely soluble in methyl alcohol.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Fentora orally disintegrating tablets are available in five unit strengths equivalent to 100, 200, 400, 600 and 800 micrograms of fentanyl base.

4 Clinical Particulars

4.1 Therapeutic Indications

Fentora is indicated for the treatment of breakthrough pain (BTP) in adults with cancer who are already receiving maintenance opioid therapy for chronic cancer pain.

4.2 Dose and Method of Administration

Treatment should be initiated by and remain under the guidance of a physician experienced in the management of opioid therapy in cancer patients. Physicians should keep in mind the potential of abuse of fentanyl. All patients treated with opioids require careful monitoring for signs of abuse and addiction.
Patients should be instructed not to use two different formulations of fentanyl concurrently for the treatment of breakthrough pain, and to dispose of any fentanyl product prescribed for BTP when switching to Fentora. The number of tablet strengths available to the patients at any time should be minimised to prevent confusion and potential overdose.

Dose titration.

Fentora should be individually titrated to an effective dose that provides adequate analgesia and minimises undesirable effects. In clinical studies, the effective dose of Fentora for BTP was not predictable from the daily maintenance dose of opioid. Patients should be carefully monitored until an effective dose is reached.

Titration in patients not switching from other fentanyl containing products.

The initial dose of Fentora should be 100 micrograms, titrating upwards as necessary through the range of available tablet strengths (100, 200, 400, 600, 800 micrograms).

Titration in patients switching from other fentanyl containing products.

Due to different absorption profiles, switching must not be done at a 1:1 ratio. If switching from another oral fentanyl citrate product, independent dose titration with Fentora is required as bioavailability between products differs significantly, especially when a different route of administration is used. However, in these patients, a starting dose higher than 100 micrograms may be considered.

Method of administration.

Fentora tablets once exposed to moisture utilises an effervescent reaction to deliver the active substance. Therefore patients should be instructed not to open the blister until ready to place the tablet in the buccal cavity.

Opening the blister package.

Patients should be instructed not to attempt to push the tablet through the blister because this could damage the orally disintegrating tablet. The correct method of releasing the tablet from the blister is by separating one blister unit from the blister card by tearing it apart at the perforations. The blister unit should then be flexed along the line printed on the backing foil where indicated. The backing foil should be peeled back to expose the tablet.
Patients should be instructed not to attempt to crush or split the tablet.
The tablet should not be stored once removed from the blister package as the tablet integrity cannot be guaranteed and a risk of accidental exposure to a tablet can occur.

Method of titration.

During titration, if adequate analgesia is not obtained within 30 minutes after the start of administration of a single tablet, a second Fentora tablet of the same strength may be used.
If treatment of a BTP episode requires more than one tablet, an increase in dose to the next higher available strength should be considered to treat the next BTP episode.
During titration, multiple tablets may be used: up to four 100 micrograms or up to four 200 micrograms tablets may be used to treat a single episode of BTP during dose titration according to the following schedule.
If the initial 100 micrograms tablet is not efficacious, the patient can be instructed to treat the next episode of BTP with two 100 micrograms tablets. It is recommended that one tablet should be placed in each side of the mouth. If this dose is considered to be the effective dose, treatment of successive episodes of BTP may be continued with a single 200 micrograms tablet of Fentora.
If a single 200 micrograms tablet of Fentora (or two 100 microgram tablets) is not considered to be efficacious the patient can be instructed to use two 200 micrograms tablets (or four 100 micrograms tablets) to treat the next episode of BTP. It is recommended that two tablets should be placed in each side of the mouth. If this dose is considered to be the effective dose, treatment of successive episodes of BTP may be continued with a single 400 micrograms tablet of Fentora.
For titration to 600 micrograms and 800 micrograms, tablets of 200 micrograms should be used.
Doses above 800 micrograms were not evaluated in clinical studies.
No more than two tablets should be used to treat any individual BTP episode, except when titrating using up to four tablets as described above.
Patients should wait at least 4 hours before treating another BTP episode with Fentora during titration. The frequency may be increased under clinical supervision.

Maintenance therapy.

Once an effective dose has been established during titration, patients should continue to take this dose as a single tablet of that given strength. Breakthrough pain episodes may vary in intensity and the required Fentora dose might increase over time due to progression of the underlying cancer disease. In these cases, a second tablet of the same strength may be used. If a second tablet of Fentora was required for several consecutive times, the usual maintenance dose is to be readjusted (see below).
Patients should wait at least 4 hours before treating another BTP episode with Fentora during maintenance therapy. The frequency may be increased under clinical supervision.

Dose readjustment.

The maintenance dose of Fentora should be increased when a patient requires more than one tablet per BTP episode for several consecutive BTP episodes. For dose readjustment the same principles apply as outlined for dose titration (see Figure 1).
Dose readjustment of the background opioid therapy may be required if patients consistently present with more than four BTP episodes per 24 hours. If the dose of background opioid therapy is increased, the dose of Fentora to treat BTP may need to be reviewed.
It is imperative that any dose retitration of any analgesic is monitored by a health professional.

Patients with xerostomia.

Patients experiencing xerostomia are advised to drink water to moisten the buccal cavity prior to administration of Fentora. If this recommendation does not result in an appropriate effervescence, then a switch of therapy may be advised.

Tablet administration.

Patients should remove the tablet from the blister unit and immediately place the entire Fentora tablet in the buccal cavity (near a molar between the cheek and gum). Alternatively, the tablet could be placed sublingually (under the tongue at the deepest part) (see Section 5.2 Pharmacokinetic Properties).
The Fentora tablet should not be sucked, chewed or swallowed, as this will result in lower plasma concentrations than when taken as directed.
Fentora should be placed and retained within the buccal cavity or sublingual cavity for a period sufficient to allow disintegration of the tablet which usually takes approximately 14-25 minutes.
After 30 minutes, if remnants from the Fentora tablet remain, they may be swallowed with a glass of water.
The length of time that the tablet takes to fully disintegrate following oromucosal administration does not appear to affect early systemic exposure to fentanyl.
Patients should not consume any food and drink when a tablet is in the buccal cavity. In case of buccal mucosa irritation, a change in tablet placement within the buccal cavity should be recommended.

Discontinuation of therapy.

Fentora therapy may usually be immediately discontinued if no longer required for BTP only, in patients who continue to take their chronic opioid therapy for persistent pain.
For patients requiring discontinuation of all opioid therapy, account should be taken of the Fentora dose in consideration of a gradual downward opioid titration to avoid the possibility of abrupt withdrawal effects.

4.3 Contraindications

Fentora is contraindicated in:
Hypersensitivity to the active substance or to any of the excipients (see Section 6.1 List of Excipients).
Patients without maintenance opioid therapy (see Section 5.1 Pharmacodynamic Properties, Clinical trials) as there is an increased risk of respiratory depression.
Severe respiratory disease, severe obstructive lung conditions, acute respiratory disease and respiratory depression.
Treatment of acute and chronic pain (e.g. postoperative pain, headache, migraine) other than breakthrough cancer pain.
Simultaneous use of monoamine-oxidase (MAO) inhibitors, or within 2 weeks after the cessation of the use of MAO inhibitors.
Product must not be used in opioid non-tolerant patients. Life-threatening respiratory depression could occur at any dose in patients not taking chronic opiates.

4.4 Special Warnings and Precautions for Use

Fentora is contraindicated for use in opioid non-tolerant patients. Life-threatening respiratory depression could occur at any dose in patients not taking chronic opiates (see Section 4.3 Contraindications; Section 4.4 Special Warnings and Precautions for Use, Respiratory depression). Deaths have occurred as a result of improper patient selection (e.g. use in opioid non-tolerant patients) and/or improper dosing.
In order to minimise the risks of opioid-related undesirable effects and to identify the effective dose, it is imperative that patients be monitored closely by health professionals during the titration process.
It is important that the long acting opioid treatment used to treat the patient's persistent pain has been stabilised before Fentora therapy begins and that the patient continues to be treated with the long acting opioid treatment whilst taking Fentora.
When switching from another oral fentanyl citrate product, independent dose titration is required as bioavailability between products differ significantly.

Hazardous and harmful use.

Fentora contains the opioid fentanyl citrate and is a potential drug of abuse, misuse and addiction. Addiction can occur in patients appropriately prescribed Fentora at recommended doses. However, iatrogenic addiction following therapeutic use of opioids is known to occur.
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 Fentora.
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 Fentora with anyone else.

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 Fentora but the risk is greatest during initiation of therapy or following an increase in dose. Patients should be monitored closely for respiratory depression at these times.
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). Titrate fentanyl citrate buccal tablets cautiously in patients with chronic obstructive pulmonary disease or pre-existing medical conditions predisposing them to respiratory depression.
The risk of life-threatening respiratory depression is also higher in elderly, frail, or debilitated patients and in patients with impaired hepatic, renal or respiratory function (e.g. chronic obstructive pulmonary disease; asthma). For further information, see Section 4.4 Special Warnings and Precautions for Use, Use in the elderly, Use in hepatic and 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 risk of respiratory depression is greater with the use of high doses of opioids, especially high potency and modified release formulations, and in opioid naïve patients. Initiation of opioid treatment should be at the lower end of the dosage recommendations with careful titration of doses to achieve effective pain relief. In general, careful calculation of equianalgesic doses is required when changing opioids or switching from immediate release to modified release formulations, together with consideration of pharmacological differences between opioids. Consider starting the new opioid at a reduced dose to account for individual variation in response. When prescribing or dispensing Fentora, do not convert patients on a microgram-per-microgram (1:1) basis from other fentanyl products to Fentora due to different absorption profiles (see Section 4.2 Dose and Method of Administration).

Respiratory disorders.

Opioids can cause sleep-related breathing disorders including central sleep apnoea (CSA) and sleep-related hypoxemia. Opioid use increases the risk of CSA in a dose-dependent fashion. In patients who present with CSA, consider decreasing the opioid dosage using best practices for opioid taper.

Risks from concomitant use of benzodiazepines or other CNS depressants, including alcohol and gabapentinoids (gabapentin or pregabalin).

Concomitant use of opioids and benzodiazepines or other CNS depressants, including alcohol and gabapentinoids (gabapentin or pregabalin), may result in sedation, respiratory depression, coma and death. Because of these risks, concomitant prescribing of Fentora 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 Fentora 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 Fentora.

Tolerance, dependence and withdrawal.

Neuroadaptation of the opioid receptors to repeated administration of opioids can produce tolerance and physical dependence. 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). The concomitant use of partial opioid agonists or opioid agonist-antagonists may partially antagonise the analgesic effect of fentanyl and may induce withdrawal symptoms in opioid dependent patients (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions, Partial opioid agonists or opioid agonist-antagonists). Withdrawal can result in some or all of the following symptoms: dysphoria, restlessness/agitation, lacrimation, rhinorrhoea, yawning, sweating, chills, 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, Fentora may be immediately ceased while the other maintenance opioid should be withdrawn by tapering the dose gradually (see Ceasing opioids and see Section 4.2 Dose and Method of Administration).

MAO inhibitors.

Fentanyl buccal tablets are not recommended for use in patients who have received monoamine oxidase (MAO) inhibitors within 14 days (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

Accidental ingestion/exposure.

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

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.

Ceasing opioids.

For patients no longer requiring their prolonged opioid therapy for the baseline cancer pain control, the Fentora 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, Fentora therapy can be discontinued immediately. The treatment by chronic opioids for the baseline 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 pain management 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 (see Section 4.2 Dose and Method of Administration). 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.

Chronic obstructive pulmonary disease.

Particular caution should be used when titrating Fentora in patients with nonsevere chronic obstructive pulmonary disease or other medical conditions predisposing them to respiratory depression, as even normally therapeutic doses of Fentora may further decrease respiratory drive to the point of respiratory failure.

Increased intracranial pressure, impaired consciousness.

Fentora should only be administered with extreme caution in patients who may be particularly susceptible to the intracranial effects of CO2 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.

Cardiac disease/ bradycardia.

Intravenous fentanyl may produce bradycardia. In clinical trials with Fentora, no clear evidence for bradycardia was observed. However, Fentora should be used with caution in patients with pre-existing bradyarrhythmias.
Careful consideration should be given to patients with hypovolaemia and hypotension.

Serotonin syndrome.

Caution is advised when fentanyl 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 reuptake inhibitors (SSRIs) and serotonin norepinephrine reuptake inhibitors (SNRIs), certain muscle relaxants (i.e. cyclobenzaprine, metaxalone) and with drugs which impair metabolism of serotonin (including monoamine oxidase inhibitors (MAOIs)). This may occur within the recommended dose.
Serotonin syndrome may include mental status changes (e.g. agitation, hallucinations, coma), autonomic instability (e.g. tachycardia, labile blood pressure, hyperthermia), neuromuscular abnormalities (e.g. hyper-reflexia, incoordination, rigidity), and/or gastrointestinal symptoms (e.g. nausea, vomiting, diarrhoea).
If serotonin syndrome is suspected, treatment with fentanyl should be discontinued.

Application site.

Application site reactions, including gum bleeding, irritation, pain and ulcer have been reported in postmarketing use. Therefore caution is advised for patients with mucositis and local tolerability issues.

Controlled sodium diet.

This medicinal product contains 10 mg sodium per 100 micrograms tablet, and 20 mg sodium per 400, 600 and 800 micrograms tablet. To be taken into consideration by patients on a controlled sodium diet.

Anaphylaxis and hypersensitivity.

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

Endocrine disorders and adrenal insufficiency.

Opioids may influence the hypothalamic-pituitary-adrenal or gonadal axes. Some changes that can be seen include an increase in serum prolactin and decrease in plasma cortisol and testosterone. Clinical signs and symptoms may manifest from these hormonal changes.
Cases of adrenal insufficiency have been reported with opioid use including fentanyl buccal tablets, 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.

Neonatal withdrawal syndrome.

Prolonged use of fentanyl buccal tablets during pregnancy can result in neonatal opioid withdrawal syndrome, which may be life-threatening if not recognized and treated (see Section 4.6 Fertility, Pregnancy and Lactation, Use in pregnancy).

Use in hepatic and renal impairment.

Fentora should be administered with caution to patients with hepatic or renal impairment because of the hepatic metabolism and renal excretion of fentanyl. When administered intravenously the clearance of fentanyl has been shown to be altered in hepatic and renal impairment due to alterations in metabolic clearance and plasma proteins. After administration of Fentora, impaired hepatic 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 impairment.

Use in the elderly.

In clinical studies patients older than 65 years tended to titrate to a lower effective dose than younger patients. It is recommended that increased caution should be exercised in titrating the dose of Fentora in elderly patients.

Paediatric use.

Fentora is not recommended for use in children and adolescents below 18 years due to a lack of data on safety and efficacy.

Effects on laboratory tests.

No data available.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Fentanyl is metabolised mainly via the human cytochrome P450 3A4 isoenzyme system (CYP3A4), therefore potential interactions may occur when Fentora is given concurrently with agents that affect CYP3A4 activity.
The concomitant use of Fentora with strong CYP3A4 inhibitors (e.g. ritonavir, ketoconazole, itraconazole, troleandomycin, clarithromycin, and nelfinavir) or moderate CYP3A4 inhibitors (e.g. amprenavir, aprepitant, diltiazem, erythromycin, fluconazole, fosamprenavir, grapefruit juice, and verapamil) may result in increased fentanyl plasma concentrations, potentially causing serious adverse drug reactions. These can include respiratory depression, hypotension and profound sedation (see Section 4.4 Special Warnings and Precautions for Use, Respiratory depression). Consider dosage adjustments if warranted. Patients receiving Fentora concomitantly with moderate or strong CYP3A4 inhibitors should be carefully monitored for an extended period of time. Dosage increase should be done with caution.
Coadministration with agents that induce 3A4 activity may reduce the efficacy of Fentora.
The concomitant use of other central nervous system depressants, including gabapentinoids (gabapentin and pregabalin) and other opioids, cannabis, tricyclic antidepressants, antipsychotics, centrally-active anti-emetics, sedatives (e.g. benzodiazepines) or hypnotics, general anaesthetics, phenothiazines, tranquillisers, skeletal muscle relaxants, antihistamines and alcohol may produce additive depressant effects. See Section 4.4 Special Warnings and Precautions for Use, Risks from concomitant use of benzodiazepines or other CNS depressants, including alcohol and gabapentinoids (gabapentin and pregabalin).
Fentora 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. See Section 4.3 Contraindications.

Partial opioid agonists or opioid agonist-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 norepinephrine 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.

When male rats treated with fentanyl for 28 days prior to and during mating were mated with untreated females, adverse effects on sperm parameters, which reduced fertility, were observed at a high subcutaneous dose of 300 microgram/kg/day that also resulted in mortalities. No effects on fertility were observed following administration of the same dose to females mated with untreated males. Estimated fentanyl exposure (plasma AUC) at this dose was about 10-fold that observed following a single dose of 800 microgram fentanyl in humans and about 2-fold that observed after four daily doses of 800 microgram fentanyl. Corresponding exposure ratios at the no observed effect level for fertility (100 microgram/kg/day) were 3 and 0.6.
(Category C)
Category C: Drugs which, owing to their pharmacological effects, have caused or may be suspected of causing, harmful effects on the human fetus or neonate without causing malformations. These effects may be reversible. Accompanying texts should be consulted for further details.
Fentanyl crosses the placenta in humans and has been found in fetal blood at concentrations about 40% of those found in maternal blood. Hence, do not use fentanyl buccal tablets during labour and delivery.
There are no adequate data from the use of fentanyl in pregnant women. In studies in which fentanyl was administered to rats and rabbits at respective subcutaneous doses of up to 100 and 250 microgram/kg/day during the period of organogenesis, no increased incidence of fetal malformations or variations was observed, but fetal weights were reduced in rats at the maternotoxic dose of 100 microgram/kg/day. Respective fentanyl exposures (plasma AUC) at these doses in rats and rabbits were about 3 and 5-fold that observed following a single dose of 800 microgram fentanyl in humans, and less than or equal to that observed in humans after four daily doses of 800 microgram fentanyl.
In a study in which rats received subcutaneous fentanyl from early gestation to weaning, reduced pup survival, growth and development were observed at clearly maternotoxic doses (100 and 400 microgram/kg/day). Fentanyl exposure (plasma AUC) at the no effect dose for pup developmental toxicity (50 microgram/kg/day) was similar to that observed following a single dose of 800 microgram fentanyl in humans and about 0.2-fold that observed after four daily doses of 800 microgram fentanyl.
Prolonged use of fentanyl buccal tablets during pregnancy can result in neonatal opioid withdrawal syndrome, which may be life threatening if not recognised and treated, and requires management according to protocols developed by neonatology experts. 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 4.4 Special Warnings and Precautions for Use).
Fentora should not be used in pregnancy unless clearly necessary.
 Following long-term treatment, fentanyl may cause withdrawal in the newborn infant.
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 6 days after the last administration of fentanyl.

4.7 Effects on Ability to Drive and Use Machines

As a class of medicines, opioid analgesics 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, or visual disturbance while taking Fentora and not to drive or operate machinery until they know how they react. The effects of this medicine on a person's ability to drive and use machines were not assessed as part of its registration.

4.8 Adverse Effects (Undesirable Effects)

The adverse events seen with Fentora are typical opioid side effects. Frequently, these will cease or decrease in intensity with continued use of the medicinal product, as the patient is titrated to the most appropriate dose. However, the most serious adverse reactions are respiratory depression (potentially leading to apnoea or respiratory arrest), circulatory depression, hypotension and shock. All patients should be closely monitored for these.
Because the clinical studies of Fentora were designed to evaluate safety and efficacy in treating BTP, 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 Fentora alone.
Table 1 summarises the adverse events occurring during the titration and post-titration periods in at least 5% of patients with cancer and breakthrough pain from three phase 3 studies in patients with cancer and BTP.
The following adverse reactions have been reported with Fentora during clinical studies and postmarketing experience. Adverse reactions are listed below 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, rare (≥ 1/10,000 to < 1/1,000), not known (cannot be estimated from the available data); within each frequency group, undesirable effects are presented in order of decreasing seriousness. See Table 2.
Tolerance, physical and/or psychological dependence may develop upon repeated administration of opioids such as fentanyl. Neonatal withdrawal syndrome may also develop (see Section 4.6 Fertility, Pregnancy and Lactation).
Opioid withdrawal symptoms such as nausea, vomiting, diarrhoea, anxiety and shivering have been observed in studies with Fentora.

Reporting suspected adverse effects.

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 www.tga.gov.au/reporting-problems.

4.9 Overdose

Clinical presentation.

The manifestations of fentanyl buccal tablets 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, hypotension, respiratory depression, respiratory distress, and respiratory failure, which have resulted in death.

Immediate management.

Immediate management of opioid overdose includes removal of the Fentora orally disintegrating tablet, 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.

Treatment of overdosage (accidental ingestion) in the opioid non-tolerant person.

For treatment of overdose (accidental ingestion) in the opioid naive person, 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 product information of the individual opioid antagonist for details about such use.

Treatment of overdose in opioid tolerant 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 Fentora, 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.
For information on the management of overdose, contact the Poisons Information Centre on 13 11 26 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Fentanyl is an opioid analgesic, interacting predominantly with the opioid mu-receptor. Its primary therapeutic actions are analgesia and sedation. Secondary pharmacological effects are respiratory depression, bradycardia, hypothermia, constipation, miosis, physical dependence and euphoria.
The analgesic effects of fentanyl are related to its plasma level. In general, the effective concentration and the concentration at which toxicity occurs increases with increasing tolerance to opioids. The rate of development of tolerance varies widely among individuals. As a result, the dose of Fentora should be individually titrated to achieve the desired effect (see Section 4.2 Dose and Method of Administration).
All opioid mu-receptor agonists, including fentanyl, produce dose dependent respiratory depression. The risk of respiratory depression is less in patients receiving chronic opioid therapy as these patients will develop tolerance to respiratory depressant effects.

Clinical trials.

The safety and efficacy of Fentora have been evaluated in patients taking the drug at the onset of the breakthrough pain episode. BTP is a transitory exacerbation of pain that occurs on a background of otherwise controlled persistent pain. Pre-emptive use of Fentora for predictable pain episodes was not investigated in the clinical trials.
Two double blind, randomized, placebo controlled crossover studies have been conducted involving a total of 248 patients with BTP and cancer who experienced on average 1 to 4 episodes of BTP per day while taking maintenance opioid therapy. Patients receiving maintenance opioid therapy are those who are taking at least 60 mg of oral morphine daily, at least 25 microgram 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.
During an initial open label phase, patients were titrated to an effective dose of Fentora. Patients who identified an effective dose entered the double blind phase of the study. The primary efficacy variable was the patient's assessment of pain intensity. Patients assessed pain intensity on a 11 point scale. For each BTP episode, pain intensity was assessed prior to and at several time points after treatment.
Sixty-seven percent of the patients were able to be titrated to an effective dose.
In the pivotal clinical study (study 1), the primary endpoint was the average sum of differences in pain intensity scores from dosing to 60 minutes, inclusive (SPID60), which was statistically significant compared to placebo (p < 0.0001). See Figure 2.
In the second pivotal study (study 2), the primary endpoint was SPID30, which was also statistically significant compared to placebo (p < 0.0001). See Figure 3.
Statistically significant improvement in pain intensity difference was seen with Fentora versus placebo as early as 10 minutes in study 1 and as early as 15 minutes (earliest time point measured) in study 2. These differences continued to be significant at each subsequent time point in each individual study.

5.2 Pharmacokinetic Properties

Absorption.

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.
Fentora employs a delivery technology which utilises an effervescent reaction which enhances the rate and extent of fentanyl absorbed through the buccal mucosa. Transient pH changes accompanying the effervescent reaction may optimise dissolution (at a lower pH) and membrane permeation (at a higher pH).
Dwell time (defined as the length of time that the tablet takes to fully disintegrate following buccal administration), does not affect early systemic exposure to fentanyl. In addition, a comparative study evaluating the absorption of one 400 microgram Fentora tablet administered either buccally (i.e. between the cheek and the gum) or sublingually met the criteria of bioequivalence.
Following oromucosal administration of Fentora, fentanyl is readily absorbed with an absolute bioavailability of 65%. The absorption profile of Fentora is largely the result of an initial rapid absorption from the buccal mucosa, with peak plasma concentrations following venous sampling generally attained within an hour after oromucosal administration. Approximately 50% of the total dose administered is rapidly absorbed transmucosally and becomes systemically available. The remaining half of the total dose is swallowed and slowly absorbed from the gastrointestinal tract where 30% of it becomes systemically available by bypassing hepatic and intestinal first pass elimination.
The main pharmacokinetic parameters are shown in Table 3.
In pharmacokinetic studies that compared the absolute and relative bioavailability of Fentora and oral transmucosal fentanyl citrate (OTFC), the rate and extent of fentanyl absorption in Fentora demonstrated exposure that was between 30% to 50% greater than that for oral transmucosal fentanyl citrate. If switching from another oral fentanyl citrate product, independent dose titration with Fentora is required as bioavailability between products differs significantly. However, in these patients, a starting dose higher than 100 micrograms may be considered. See Figure 4.
Differences in exposure with Fentora were observed in a clinical study with patients with grade 1 mucositis. Cmax and AUC0-8 were 1% and 25% higher in patients with mucositis compared to those without mucositis, respectively. The differences observed were not statistically or clinically significant.
Dose proportionality from 100 microgram to 1000 microgram of Fentora has been demonstrated.

Distribution.

Fentanyl is highly lipophilic and is well distributed beyond the vascular system, with a large apparent volume of distribution. After buccal administration of Fentora, fentanyl undergoes initial rapid distribution that represents an equilibration of fentanyl between plasma and the highly perfused tissues (brain, heart and lungs). Subsequently, fentanyl is redistributed between the deep tissue compartment (muscle and fat) and the plasma.
The plasma protein binding of fentanyl is 80% to 85%. The main binding protein is alpha1-acid glycoprotein, but both albumin and lipoproteins contribute to some extent. The free fraction of fentanyl increases with acidosis.

Metabolism.

The metabolic pathways following buccal administration of Fentora have not been characterised in clinical studies. 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.

Excretion.

Following the intravenous administration of fentanyl, less than 7% of the administered 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.
Following the administration of Fentora, the terminal elimination phase of fentanyl is the result of the redistribution between plasma and a deep tissue compartment. This phase of elimination is slow, resulting in a median terminal elimination half-life t1/2 of approximately 22 hours following buccal administration of the effervescent formulation and approximately 18 hours following intravenous administration. The total plasma clearance of fentanyl following intravenous administration is approximately 42 L/h.

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 genotoxic potential of fentanyl is considered to be low.

Carcinogenicity.

Carcinogenicity studies (26 week dermal bioassay in Tg.AC transgenic mice; two year subcutaneous study in rats) did not induce 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. At the highest doses tested in these studies (50 microgram/day in mice, 50 microgram/kg/day in male rats and 100 microgram/kg/day in female rats), systemic exposure (plasma Cmax in mice and AUC in rats) was about 3-fold (mice and female rats) and about 2-fold (male rats) that observed following a single dose of 800 microgram fentanyl in humans.

6 Pharmaceutical Particulars

6.1 List of Excipients

The excipients include mannitol, sodium starch glycollate type A, sodium hydrogen carbonate, sodium carbonate, citric acid and magnesium stearate.

6.2 Incompatibilities

Incompatibilities were either not assessed or not identified as part of the registration of this medicine.

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 package in order to protect from moisture.

6.5 Nature and Contents of Container

Fentora orally disintegrating tablets are available in five unit strengths equivalent to 100, 200, 400, 600 and 800 micrograms of fentanyl base. The orally disintegrating tablets are flat-faced, round, beveled-edge tablet, embossed one side with a "C" and on the other side with "1" for Fentora 100 micrograms, with "2" for Fentora 200 micrograms, with "4" for Fentora 400 micrograms, with "6" for Fentora 600 micrograms, or with "8" for Fentora 800 micrograms.
Fentora is supplied in aluminium laminated blister of PVC/aluminium foil/Polyamide/PVC with paper/polyester/aluminium foil lidding.
Blister packs are supplied in cartons of 4 or 28 tablets.

6.6 Special Precautions for Disposal

Patients and their carers must be instructed that Fentora contains an active substance in an amount that can be fatal, especially to a child. Therefore they must keep all tablets out of the reach and sight of children.
Patients and carers must be advised to dispose of any unopened tablets remaining from a prescription as soon as they are no longer needed.
Medicines should not be disposed of via wastewater or household waste. In Australia, any unused medicine or waste material should be disposed of by taking to your local pharmacy.

6.7 Physicochemical Properties

Chemical structure.


CAS number.

990-73-8.

7 Medicine Schedule (Poisons Standard)

Schedule 8.

Summary Table of Changes