Actiq

/ Abic

Method of administration: ACTIQ is intended for oromucosal administration, and therefore should be placed in the mouth against the cheek and should be moved around the mouth using the applicator, with the aim of maximising the amount of mucosal exposure to the product. The ACTIQ unit should be sucked, not chewed, as absorption of fentanyl via the buccal mucosa is rapid in comparison with systemic absorption via the gastrointestinal tract. Water may be used to moisten the buccal mucosa in patients with a dry mouth.
The ACTIQ unit should be consumed over a 15 minute period. If signs of excessive opioid effects appear before the ACTIQ unit is fully consumed it should be immediately removed, and consideration given to decreasing future dosages.
Dose titration and maintenance therapy
ACTIQ should be individually titrated to a “successful” dose that provides adequate analgesia and minimises side effects. In clinical trials the successful dose of ACTIQ for breakthrough pain was not predicted from the daily maintenance dose of opioid.
Titration: Before patients are titrated with ACTIQ, it is expected that their background persistent pain will be controlled by use of opioid therapy and that they are typically experiencing no more than 4 episodes of breakthrough pain per day.
The initial dose of ACTIQ used should be 200 micrograms, titrating upwards as necessary through the range of available dosage strengths (200, 400, 600, 800, 1200 and 1600 micrograms). Patients should be carefully monitored until a dose is reached that provides adequate analgesia with acceptable side effects using a single dosage unit per episode of breakthrough pain. This is defined as the successful dose.
During titration, if adequate analgesia is not obtained within 30 minutes after starting the first unit (i.e. 15 minutes after the patient completes consumption of a single ACTIQ unit), a second ACTIQ unit of the same strength may be consumed. No more than two ACTIQ units should be used to treat any individual pain episode. At 1600 mcg, a second dose is only likely to be required by a minority of patients.
If treatment of consecutive breakthrough pain episodes requires more than one dosage unit per episode, an increase in dose to the next higher available strength should be considered.
Maintenance: Once a successful dose has been established (i.e., on average, an episode is effectively treated with a single unit), patients should be maintained on this dose and should limit consumption to a maximum of four ACTIQ units per day.
Patients should be monitored by a health professional to ensure that the maximum consumption of four units of ACTIQ per day is not exceeded.
Dose re-adjustment: The maintenance dose of ACTIQ should be increased when an episode is not effectively treated with a single unit for several consecutive BTP episodes. For dose-readjustment the same principles apply as outlined for dose titration (see above).
If more than four episodes of breakthrough pain are experienced per day the dose of the long acting opioid used for persistent pain should be re-evaluated. If the dose of the long acting opioid is increased, the dose of ACTIQ to treat breakthrough pain may need to be reviewed It is imperative that any dose re-titration of any analgesic is monitored by a health professional.
Discontinuation of therapy: ACTIQ therapy may usually be immediately discontinued if no longer required for breakthrough pain, 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 ACTIQ dose in consideration of a gradual downward opioid titration to avoid the possibility of abrupt withdrawal effects.
Use in the elderly: Elderly patients have been shown to be more sensitive to the effects of fentanyl when administered intravenously. Therefore dose titration needs to be approached with particular care. In the elderly, elimination of fentanyl is slower and the terminal elimination half-life is longer, which may result in accumulation of the active substance and to a greater risk of undesirable effects.
Formal clinical trials with ACTIQ have not been conducted in the elderly. It has been observed, however, in clinical trials that patients over 65 years of age required lower doses of ACTIQ for successful relief of breakthrough pain.
Use in patients with hepatic or renal impairment: Special care should be taken during the titration process in patients with kidney or liver dysfunction.
Paediatric population
Children aged 16 years and above: follow adult dosage
Children aged 2 to 16 years old: There is limited clinical trial experience of the use of ACTIQ in paediatric patients already receiving maintenance opioid therapy. Safety and efficacy in paediatric patients below the age of 16 years have not been established; use in this patient population is therefore not recommended.

ACTIQ is indicated only for the management of breakthrough cancer pain in patients 16 and older with malignancies who are already receiving and who are tolerant to around the clock to opioid therapy for their underlying persistent cancer pain.
Patients considered opioid tolerant are those who are taking at least 60 mg morphine/day, at least 25 mcg transdermal fentanyl/hour, at least 30 mg of oxycodone daily, at least 8 mg oral hydromorphone daily or an equianalgesic dose of another opioid for a week or longer.

– Hypersensitivity to fentanyl or to any of the excipients.
– Patients without maintenance opioid therapy as there is an increased risk of respiratory depression.
– Treatment of acute pain other than breakthrough pain.
– Simultaneous use of monoamine-oxidase (MAO) inhibitors, or within 2 weeks after the cessation of the use of MAO inhibitors.
– Severe respiratory depression or severe obstructive lung conditions.

Patients and their caregivers must be instructed that ACTIQ contains an active substance in an amount that can be fatal to a child. Death has been reported in children who have accidentally ingested ACTIQ.
The product should not be given to patients without maintenance opioid therapy as there is an increased risk of respiratory depression and death.
Like for all opioids, tolerance, physical and/or psychological dependence and abuse of fentanyl may occur.
ACTIQ 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.
Fentanyl may produce bradycardia. Fentanyl should be used with caution in patients with previoius of pre-existing bradyarrhythmias.
ACTIQ should be administered with caution to patients with liver or kidney
dysfunction.
Careful consideration should be given to patients with hypovolaemia and hypotension.
Diabetic patients should be advised that the medicine product contains dextrates.
Patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption or sucrase-isomaltase insufficiency should not take this medicine.
Normal oral hygiene is recommended to reduce any potential harm to the teeth.
Caution is advised when ACTIQ is coadministered with drugs that affect the serotoninergic 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 Norepinephrine Re-uptake Inhibitors (SNRIs), and with drugs which impair metabolism of serotonin.
See prescribing information for full details.

The most serious adverse events are respiratory depression (potentially leading to apnoea or respiratory arrest), circulatory depression, hypotension and shock and all patients should be closely monitored for these.
Application site reactions, including gum bleeding, irritation, pain and ulcer have been reported in post-marketing use.
See prescribing information for full details.

Fentanyl is metabolized by the CYP3A4 isoenzyme in the liver and intestinal mucosa. Potent inhibitors of CYP3A4 such as macrolide antibiotics (e.g. erythromycin), azole antifungals (e.g. ketoconazole, itraconazole, and fluconazole) and certain protease inhibitors (e.g. ritonavir), may increase the bioavailability of swallowed fentanyl and may also decrease its systemic clearance which may result in increased or prolonged opioid effects. Similar effects could be seen after concurrent ingestion of grapefruit juice, which is known to inhibit CYP3A4. Hence caution is advised if fentanyl is given concomitantly with CYP3A4 inhibitors.
Coadministration with agents that induce 3A4 activity may reduce the efficacy of ACTIQ.
The concomitant use of other CNS depressants, including other opioids, sedatives or hypnotics, general anaesthetics, phenothiazines, tranquillisers, skeletal muscle relaxants, sedating antihistamines and alcohol may produce additive depressant effects.
Withdrawal symptoms may be precipitated through the administration of drugs with opioid antagonist activity, e.g., naloxone, or mixed agonist/antagonist analgesics (e.g., pentazocine, butorphanol, buprenorphine, nalbuphine).
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.

Pregnancy: There are no adequate data from the use of fentanyl in pregnant women. Studies in animals have shown reproductive toxicity. Opioid analgesic agents can cause neonatal respiratory depression. With long-term use during pregnancy, there is a risk of neonatal withdrawal symptoms. ACTIQ should not be used in pregnancy unless clearly necessary.
Lactation: Fentanyl passes into breast milk and may cause sedation and respiratory depression in the breastfed child. Fentanyl should not be used by breastfeeding women, and breast feeding should not be restarted until at least 48 hours after the last administration of fentanyl.

The symptoms of fentanyl overdosage are expected to be similar in nature to those of intravenous fentanyl and other opioids, and are an extension of its pharmacological actions, with the most serious significant effects being altered mental status, loss of consciousness, coma, cardiorespiratory arrest, respiratory depression, respiratory distress and respiratory failure, which have resulted in death.
Immediate management of opioid overdose includes removal of the ACTIQ unit via the applicator, if still in the mouth, ensuring a patent airway, physical and verbal stimulation of the patient, assessment of the level of consciousness, ventilatory and circulatory status, and assisted ventilation (ventilatory support) if necessary.
For treatment of overdosage (accidental ingestion) in the opioid naïve 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 Summary of Product Characteristics of the individual opioid antagonist for details about such use.
For treatment of overdose in opioid-maintained patients, intravenous access should be obtained. The judicious use of naloxone or another opioid antagonist may be warranted in some instances, but it is associated with the risk of precipitating an acute withdrawal syndrome.
Although muscle rigidity interfering with respiration has not been seen following the use of ACTIQ, this is possible with fentanyl and other opioids. If it occurs, it should be managed by the use of assisted ventilation, by an opioid antagonist, and as a final alternative, by a neuromuscular blocking agent.