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 Effentora in a safe and secure place, not accessible by others
Accidental use in children
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 sight and reach of children.

Monitoring
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.

Maintenance opioid treatment

It is important that the maintenance 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 maintenance opioid treatment whilst taking Fentora. The product must not be given to patients without maintenance opioid therapy as there is an increased risk of respiratory depression and death.

Respiratory depression
As with all opioids, there is a risk of clinically significant respiratory depression associated with the use of fentanyl. Improper patient selection (e.g., use in patients without maintenance opioid therapy) and/or improper dosing have resulted in fatal outcome with Fentora as well as with other fentanyl products.
Fentora should only be used for conditions specified in section 4.1.

Chronic obstructive pulmonary disease
Particular caution should be used when titrating Fentora in patients with non-severe 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.

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 or related drugs Concomitant use of opioids, including Fentora, with benzodiazepines or related drugs may result in profound sedation, respiratory depression, coma, and death. Because of these risks, concomitant prescribing of opioids and benzodiazepines or related drugs should be made only in patients for whom alternative treatment options are inadequate.
If a decision is made to prescribe Fentora concomitantly with benzodiazepines or related drugs, 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).

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.

Bradyarrhythmias
Fentanyl may produce bradycardia. Fentanyl should be used with caution in patients with previous or pre-existing bradyarrythmias.


Hepatic or renal impairment
In addition, Fentora should be administered with caution to patients with hepatic or renal impairment. The influence of hepatic 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 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.
Careful consideration should be given to patients with hypovolaemia and hypotension.
Serotonin Syndrome
Caution is advised when Fentora is co-administered 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 (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., hyperreflexia, incoordination, rigidity), and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhoea).

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

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 Fentora 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 Fentora 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).

Treatment duration and goals
Before initiating treatment with Fentora, 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. 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. 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. In absence of adequate pain control, the possibility of hyperalgesia, tolerance and progression of underlying disease should be considered (see section 4.4). Fentora should not be used longer than necessary.


Patients will require monitoring for signs of drug-seeking behavior (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.


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.


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.

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

Excipient(s)

Sodium
Fentora 100 micrograms buccal tablets
This medicinal product contains 10 mg sodium per buccal tablet, equivalent to 0.5 % of the WHO recommended maximum daily intake of 2 g sodium for an adult.

Fentora 200 micrograms buccal tablets
Fentora 400 micrograms buccal tablets
Fentora 600 micrograms buccal tablets
Fentora 800 micrograms buccal tablets
This medicinal product contains 20 mg sodium per per buccal tablet, equivalent to 1 % of the WHO recommended maximum daily intake of 2 g sodium for an adult.

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 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.