Special Warning : אזהרת שימוש

4.4   Special warnings and precautions for use
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. The risk of developing OUD is increased in patients with a personal or a family history (parents or siblings) of substance use disorders (including alcohol use disorder), in current tobacco users or in patients with a personal history of other mental health disorders (e.g. major depression, anxiety and personality disorders).

Before initiating treatment with ACTIQ and during the treatment, treatment goals and a discontinuation plan should be agreed with the patient (see section 4.2). 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.

Patients will require monitoring for signs of drug-seeking behaviour (e.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 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 (see section 4.8).

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.

Alcohol

The concomitant use of alcohol with fentanyl can produce increased depressant effects which may result in a fatal outcome (see section 4.5).

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. Patients should be closely monitored for signs and symptoms of respiratory depression and sedation (see section 4.5).

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 liver or kidney dysfunction. The influence of liver and renal impairment on the pharmacokinetics of the medicinal product has not been evaluated, however, when administered intravenously the clearance of fentanyl has been shown to be altered in hepatic and renal disease due to alterations in metabolic clearance and plasma proteins. After administration of ACTIQ, impaired liver 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 disease.

Hypovolaemia, hypotension

Careful consideration should be given to patients with hypovolaemia and hypotension.
Dental decay

Normal oral hygiene is recommended to reduce any potential harm to the teeth. Because ACTIQ contains approximately 2 grams of sugar, frequent consumption increases the risk of dental decay. The occurrence of dry mouth associated with the use of opioid medicinal products may add to this risk. During treatment with ACTIQ, regular dental visits are advised.

Serotonin syndrome

Caution is advised when ACTIQ is co-administered with medicinal products that affect the serotoninergic neurotransmitter systems.

The development of a potentially life-threatening serotonin syndrome may occur with the concomitant use of serotonergic medicinal products such as selective serotonin reuptake inhibitors (SSRIs) and serotonin norepinephrine reuptake inhibitors (SNRIs), and with medicinal products which impair metabolism of serotonin (including monoamine oxidase inhibitors [MAO inhibitors]) (see section 4.3). 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., hyperreflexia, incoordination, rigidity), and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhoea).

If serotonin syndrome is suspected, treatment with ACTIQ should be discontinued.

Anaphylaxis, hypersensitivity
Anaphylaxis and hypersensitivity have been reported in association with the use of oral transmucosal fentanyl products (see section 4.8).

Paediatric population

ACTIQ is not indicated for use in children and adolescents below 16 years due to lack of data on safety and efficacy.

Excipients

Glucose
Contains approximately 1.89 g glucose per dose. This should be taken into account in patients with diabetes mellitus.
Patients with rare glucose-galactose malabsorption should not take this medicinal product.
May be harmful to the teeth.


Sucrose
Patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption or sucrase- isomaltase insufficiency should not take this medicinal product.
May be harmful to the teeth.

Sodium
This medicine contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially ‘sodium-free’.

Effects on Driving

4.7    Effects on ability to drive and use machines

No studies of the effects on the ability to drive and use machines have been performed. However, opioid analgesics may 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, blurred or double vision while using ACTIQ.