Each sublingual tablet contains: 100 micrograms fentanyl (as citrate) 200 micrograms fentanyl (as citrate) 300 micrograms fentanyl (as citrate) 400 micrograms fentanyl (as citrate) 600 micrograms fentanyl (as citrate) 800 micrograms fentanyl (as citrate)

Sublingual tablet 100 microgram sublingual tablet is a white round tablet 200 microgram sublingual tablet is a white oval-shaped tablet 300 microgram sublingual tablets is a white triangle-shaped tablet 400 microgram sublingual tablets is a white diamond-shaped tablet 600 microgram sublingual tablet is a white “D”-shaped tablet 800 microgram sublingual tablet is a white capsule-shaped tablet

Management of breakthrough pain in adult patients using opioid therapy for chronic cancer pain. Breakthrough pain is a transient exacerbation of otherwise controlled chronic background pain.

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 oral morphine per day, 25 micrograms transdermal fentanyl per hour, 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 titration:

The optimal dose of Abstral will be determined by upward titration, on an individual patient basis. Several doses are available for use during the dose titration phase. The initial dose of Abstral used should be 100 micrograms, titrating upwards as necessary through the range of available dosage strengths.

Patients should be carefully monitored until an appropriate dose is reached, i.e. that provides adequate analgesia with acceptable adverse reactions for each episode of breakthrough pain.

Switching from other fentanyl containing products to Abstral must not occur at a 1:1 ratio because of different absorption profiles. If patients are switched from another fentanyl containing product, a new dose titration with Abstral is required.

The following dose regimen is recommended for titration, although in all cases the physician should take into account the clinical need of the patient, age and concomitant illness.

All patients must start therapy with a single 100 microgram sublingual tablet. If adequate analgesia is not obtained within 15-30 minutes of administration of a single sublingual tablet, a second 100 microgram sublingual tablet may be administered. If inadequate pain relief is obtained with 2 x 100 microgram sublingual tablets, an increase in dose to the next higher available strength for the next episode of breakthrough pain should be considered. Dose escalation should continue in a stepwise manner until adequate analgesia is achieved. This titration should follow the course of administering a single sublingual tablet, with administration of a supplemental second sublingual tablet after 1530 minutes, if inadequate pain relief is obtained. The dose strength for the supplemental sublingual tablet should be increased from 100 to 200 micrograms at doses of 400 micrograms and higher. This is illustrated in the schedule below. No more than two (2) sublingual tablets should be administered for a single episode of breakthrough pain during this titration phase.

If adequate analgesia is achieved at the higher dose, but undesirable effects are considered unacceptable, an intermediate dose (using the 50 microgram or 100 microgram sublingual tablet where appropriate) may be administered.

Doses higher than 800 micrograms have not been evaluated in clinical studies.

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 health professionals during the titration process.

Maintenance therapy:

Once an appropriate dose has been established, which may be more than one tablet, patients should be maintained on this dose and should limit consumption to a maximum of four Abstral doses per day.

Dose re-adjustment:

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 episodes of breakthrough pain are experienced per day over a period of more than four consecutive days, then the dose of the long acting opioid used for persistent pain should be re-evaluated. If the long acting opioid or dose of long acting opioid is changed the Abstral dose should be re-evaluated and re-titrated as necessary to ensure the patient is on an optimal dose.

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

Discontinuation of therapy:

For patients no longer requiring any opioid therapy, the Abstral dose should be taken into consideration before a gradual downward titration of opioids to minimise 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 may usually be discontinued immediately.

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

Dose titration needs to be approached with particular care and patients observed carefully for signs of fentanyl toxicity.

Hypersensitivity to the active substance or to any of the excipients.

Opioid-naïve patients because of the risk of life-threatening respiratory depression.

Severe respiratory depression or severe obstructive lung conditions

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 therapy 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.

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.

Upon repeated administration of opioids such as fentanyl, tolerance and physical and/or psychological dependence may develop. Iatrogenic addiction following therapeutic use of opioids is rare.

In common with all opioids, there is a risk of clinically significant respiratory depression associated with the use of Abstral. Particular caution should be exercised during dose titration with Abstral in patients with chronic obstructive pulmonary disease or other medical conditions predisposing them to respiratory depression (e.g. myasthenia gravis) because of the risk of further respiratory depression, which could lead to respiratory failure.

Abstral should only be administered with extreme caution in patients who may be particularly susceptible to the intracranial effects of hyperkapnia, 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.

Intravenous fentanyl has been shown to cause bradycardia. Abstral should be used with caution in patients with bradyarrhythmias.

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

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

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

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 and therefore extra caution is recommended during dose titration.

There should be no noticeable effects on cessation of treatment with Abstral, but possible symptoms of withdrawal are anxiety, tremor, sweating, paleness, nausea and vomiting

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. Fentanyl should therefore be given to patients with caution if administered concomitantly with CYP3A4 inhibitors.

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 (ie benzodiazepines), hypnotics, antipsychotics, clonidine and related substances may produce increased CNS depressant effects. Respiratory depression, hypotension and profound sedation 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.

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.

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.

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. Other very commonly reported adverse reactions include: nausea, vomiting, constipation, headache, somnolence/fatigue and dizziness.

Adverse reactions from clinical studies with Abstral in patients and volunteers, with a suspected relationship to treatment, are listed below by system organ class and frequency (very common  1/10; common  1/100 to < 1/10). Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

Nervous system disorders

Very common: Dizziness, somnolence, headache

Common: Vasovagal reaction, hypoaesthesia, paraesthesia, hyperacusis

Eye disorders

Common: Vision abnormal

Respiratory, thoracic and mediastinal disorders

Common: Respiratory depression, rhinitis, pharyngitis

Gastrointestinal disorders

Very common: Nausea

Common: Vomiting, abdominal pain, diarrhoea, constipation, stomach discomfort, dyspepsia, dry mouth

Skin and subcutaneous tissue disorders

Common: Rash, pruritus

Vascular disorders

Common: Orthostatic hypotension, flushing, hot flush

General disorders and administration site conditions

Very common: Fatigue

Common: Asthenia, application site irritation

Psychiatric disorders

Common: Depression, anorexia, concentration impaired, euphoria

All the above adverse reactions were reported in opioid naïve volunteers administered with Abstral. Patients (n=23) treated with Abstral only experienced dizziness, nausea and vomiting.

The following adverse reactions associated with other medicinal products containing fentanyl have also been reported (very common  1/10; common  1/100 to < 1/10; uncommon  1/1000 to < 1/100; rare  1/10,000 to < 1/1000; very rare < 1/10,000; not known (cannot be estimated from available data)):

Cardiac disorders

Uncommon: Bradycardia, tachycardia, hypertension

Very rare: Arrhythmias

Nervous system disorders

Common: Myoclonus, insomnia, taste disorders

Uncommon: Abnormal gait/coordination, vertigo, amnesia, speech disorders, tremor

Respiratory thoracic and mediastinal disorders

Uncommon: Hypoventilation, asthma, dyspnoea

Very rare: Apnoea, haemoptysis

Gastrointestinal disorders

Common: Gastro-intestinal occlusion, dysphagia, mouth ulcers/stomatitis, tongue disorder

Uncommon: Enlarged abdomen, flatulence, thirst

Rare: Hiccups

Renal and urinary disorders

Uncommon: Urinary retention, change in urinary frequency

Very rare: bladder spasm, oliguria

Skin and subcutaneous tissue disorders

Very common: Sweating

Injury, poisoning and procedural complications

Common: Accidental injuries

Vascular disorders

Common: Vasodilation

General disorders and administration site conditions

Uncommon: Malaise

Psychiatric disorders

Common: Hallucinations, confusion, anxiety, nervousness, abnormal thinking, abnormal dreams

Uncommon: Agitation, depersonalisation, emotional lability

ProStrakan Ltd

22 June 2009