ACTIQ

Posology In order to minimise the risks of opioid-related adverse reactions and to identify the “successful” dose, it is imperative that patients be monitored closely by health professionals during the titration process. ACTIQ is not interchangeable on a mcg to mcg basis with other short-acting fentanyl products that are indicated for the use of breakthrough cancer pain, as the pharmacokinetic profiles and/or dosing schedules of these products are significantly different.

Patients should be instructed not to use more than one short-acting fentanyl product concurrently for the treatment of breakthrough cancer pain, and to dispose of any fentanyl product prescribed for breakthrough pain (BTP) when switching to ACTIQ.

The number of ACTIQ strengths available to the patient at any time should be minimised to prevent confusion and potential overdose. Any unused ACTIQ units that the patient no longer requires must be disposed of properly. Patients must be reminded of the requirements to keep ACTIQ stored in a location away from children.

Adults Dose titration and maintenance therapy ACTIQ should be individually titrated to a “successful” dose that provides adequate analgesia and minimises adverse reactions. In clinical trials the successful dose of ACTIQ for breakthrough pain was not predicted from the daily maintenance dose of opioid.

a) Titration Before patients are titrated with ACTIQ, it is expected that their background persistent pain will be controlled by use of opioid therapy and that they are typically experiencing no more than 4 episodes of breakthrough pain per day.

The initial dose of ACTIQ used should be 200 micrograms, titrating upwards as necessary through the range of available dosage strengths (200, 400, 600, 800, 1,200 and 1,600 micrograms). Patients should be carefully monitored until a dose is reached that provides adequate analgesia with acceptable adverse reactions using a single dosage unit per episode of breakthrough pain.

This is defined as the successful dose. e. 15 minutes after the patient completes consumption of a single ACTIQ unit), a second ACTIQ unit of the same strength may be consumed. No more than two ACTIQ units should be used to treat any individual pain episode.

At 1600 micrograms, a second dose is only likely to be required by a minority of patients. 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.

, 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 maintenance opioid therapy used for persistent pain should be re-evaluated. If the dose of the maintenance opioid therapy is increased, the dose of ACTIQ to treat breakthrough pain may need to be reviewed.

4). It is imperative that any dose re-titration of any analgesic is monitored by a health professional. Treatment duration and goals Before initiating treatment with ACTIQ, a treatment strategy including treatment duration and treatment goals, and a plan for end of the treatment, should be agreed together with the patient, in accordance with pain management guidelines.

During treatment, there should be frequent contact between the physician and the patient to evaluate the need for continued treatment, consider discontinuation and to adjust dosages if needed. 4). ACTIQ should not be used longer than necessary.

Discontinuation of therapy ACTIQ should be discontinued immediately if the patient no longer experiences breakthrough pain episodes. The treatment for the persistent background pain should be kept as prescribed. If discontinuation of all opioid therapy is required, the patient must be closely followed by the doctor as gradual downward opioid titration is necessary in order to avoid the possibility of abrupt withdrawal effects.

Use in the elderly Elderly patients have been shown to be more sensitive to the effects of fentanyl when administered intravenously. Therefore dose titration needs to be approached with particular care. In the elderly, elimination of fentanyl is slower and the terminal elimination half-life is longer, which may result in accumulation of the active substance and to a greater risk of undesirable effects.

Formal clinical trials with ACTIQ have not been conducted in the elderly. It has been observed, however, in clinical trials that patients over 65 years of age required lower doses of ACTIQ for successful relief of breakthrough pain.

4).

Paediatric population Adolescents aged 16 years and above:

Follow adult dosage.

Children and adolescents below 16 years:

Safety and efficacy in children and adolescents below 16 years have not […]

Typical opioid adverse reactions are to be expected with ACTIQ. Frequently, these will cease or decrease in intensity with continued use of the product, as the patient is titrated to the most appropriate dose. However, the most serious adverse events are respiratory depression (potentially leading to apnoea or respiratory arrest), circulatory depression, hypotension and shock and all patients should be closely monitored for these.

Application site reactions, including gum bleeding, irritation, pain and ulcer have been reported in post-marketing use. Because the clinical trials of ACTIQ were designed to evaluate safety and efficacy in treating breakthrough pain, all patients were also taking concomitant opioids, such as sustained-release morphine or transdermal fentanyl, for their persistent pain.

Thus it is not possible to definitively separate the effects of ACTIQ alone. The following adverse reactions have been reported with ACTIQ and/or other fentanyl-containing compounds during clinical studies and post marketing experience.

6), drug tolerance, bleeding at the site of application Investigations weight decreased Injury, poisoning and procedural complications accidental injury (for example, falls) * opioid withdrawal symptoms such as nausea, vomiting, diarrhoea, anxiety, chills, tremor, and sweating have been observed with transmucosal fentanyl.

Description of selected adverse reactions Tolerance Tolerance can develop on repeated use. Drug dependence Repeated use of ACTIQ can lead to drug dependence, even at therapeutic doses. 4). Reporting of suspected adverse reactions Reporting suspected adverse reactions after authorisation of the medicinal product is important.

It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme. uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

Because of the risks, including fatal outcome, associated with accidental exposure, misuse, and abuse, patients and their carers must be advised to keep ACTIQ in a safe and secure place, not accessible by others. Accidental use in children Patients and their carers must be instructed that ACTIQ contains an active substance in an amount that can be fatal to a child.

Death has been reported in children who have accidentally ingested ACTIQ. Patients and their carers must be instructed to keep all units out of the sight and reach of children and to discard open and unopened units appropriately. An evaluation of each out-patient concerning possible accidental child exposures should be undertaken.

Maintenance opioid therapy The product must not be given to patients without maintenance opioid therapy as there is an increased risk of respiratory depression and death. It is important that the maintenance opioid therapy used to treat the patient’s persistent pain has been stabilised before ACTIQ therapy begins and that the patient continues to be treated with the maintenance opioid therapy whilst using ACTIQ.

Tolerance and opioid use disorder (abuse and dependence) Tolerance, physical dependence and psychological dependence may develop upon repeated administration of opioids. Fentanyl can be abused in a manner similar to other opioids and all patients treated with opioids require monitoring for signs of abuse and addiction.

Patients at increased risk of opioid abuse may still be appropriately treated with opioids; however, these patients will require additional monitoring for signs of misuse, abuse or addiction. Repeated use of ACTIQ may lead to Opioid Use Disorder (OUD).

A higher dose and longer duration of opioid treatment, can increase the risk of developing OUD. Abuse or intentional misuse of ACTIQ may result in overdose and/or death. g. major depression, anxiety and personality disorders). 2). Before and during treatment the patient should also be informed about the risks and signs of OUD.

Patients should be advised to contact their physician if these signs occur. g. too early requests for refills). This includes the review of concomitant opioids and psycho- active drugs (like benzodiazepines). For patients with signs and symptoms of OUD, consultation with an addiction specialist should be considered.

Hyperalgesia As with other opioids, in case of insufficient pain control in response to an increased dose of fentanyl, the possibility of opioid-induced hyperalgesia should be considered. A fentanyl dose reduction or discontinuation of fentanyl treatment or treatment review may be indicated Endocrine effects 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 lozenges, more often following greater than one month of use.

8). Respiratory depression As with all opioids, there is a risk of clinically significant respiratory depression associated with the use of ACTIQ, patients should be monitored accordingly. Particular caution should be used when titrating ACTIQ in patients with non-severe chronic obstructive pulmonary disease or other medical conditions predisposing them to respiratory depression, as even normally therapeutic doses of ACTIQ may further decrease respiratory drive to the point of respiratory failure.

Sleep-related breathing 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 total opioid dosage.

5). Risks of concomitant administration with benzodiazepines Concomitant use of opioids, including ACTIQ, with benzodiazepines may result in profound sedation, respiratory depression, coma, and death. Because of these risks, concomitant prescribing of opioids and benzodiazepines should be made only in patients for whom alternative treatment options are inadequate.

If a decision is made to prescribe ACTIQ concomitantly with benzodiazepines, the lowest effective dosages and minimum durations of concomitant use should be chosen. 5). Intracranial effects of CO2 retention, impaired consciousness, head injury ACTIQ should only be administered with extreme caution in patients who may be particularly susceptible to the intracranial effects of 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. Bradyarrhythmias Fentanyl may produce bradycardia. Fentanyl should be used with caution in patients with previous or pre-existing bradyarrhythmias.

Hepatic or renal impairment In addition, ACTIQ should be administered with caution to patients with […]

1. • Patients without maintenance opioid therapy as there is an increased risk of respiratory depression. • Treatment of acute pain other than breakthrough pain. 5). • Patients being treated with medicinal products containing sodium oxybate.

• Severe respiratory depression or severe obstructive lung conditions.