Fentora

/ Teva Israel LTD, Israel

Fentanyl should be individually titrated to an “effective” dose that provides adequate analgesia and minimises adverse reactions. In clinical studies, the effective dose of fentanyl for BTP was not predictable from the daily maintenance dose of opioid.
Patients should be carefully monitored until an effective dose is reached.
Titration in patients not switching from other fentanyl containing products
The initial dose of fentanyl should be 100 micrograms, titrating upwards as necessary through the range of available tablets strengths (100, 200, 400, 600, 800 micrograms).
Titration in patients switching from other fentanyl containing products
Due to different absorption profiles, switching must not be done at a 1:1 ratio. If switching from another oral fentanyl citrate product, independent dose titration with this medical product is required as bioavailability between products differs significantly. However, in these patients, a starting dose higher than 100 micrograms may be considered.
Method of titration
During titration, if adequate analgesia is not obtained within 30 minutes after the start of administration of a single tablet, a second tablet of the same strength may be used.
If treatment of a BTP episode requires more than one tablet, an increase in dose to the next higher available strength should be considered to treat the next BTP episode.
Maintenance therapy
Once an effective dose has been established during titration, patients should continue to take this dose as a single tablet of that given strength. Breakthrough pain episodes may vary in intensity and the required dose might increase over time due to progression of the underlying cancer disease. In these cases, a second tablet of the same strength may be used. If a second tablet of fentanyl was required for several consecutive times, the usual maintenance dose is to be readjusted.
Patients should wait at least 4 hours before treating another BTP episode with this medical product during maintenance therapy.
Dose readjustment
The maintenance dose of fentanyl should be increased when a patient requires more than one tablet per BTP episode for several consecutive BTP episodes. For dose-readjustment the same principles apply as outlined for dose titration.
Dose readjustment of the background opioid therapy may be required if patients consistently present with more than four BTP episodes per 24 hours.
Discontinuation of therapy
This medical product 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 in order to manage the risk of abrupt withdrawal effects.
For full details see prescribing information.

This medical product is indicated for the treatment of breakthrough pain (BTP) in adults with cancer who are already receiving maintenance opioid therapy for chronic cancer pain.
BTP is a transitory exacerbation of pain that occurs on a background of otherwise controlled
persistent pain.
Patients receiving maintenance opioid therapy are those who are taking at least 60 mg of oral morphine daily, at least 25 micrograms of transdermal fentanyl per hour, at least 30 mg of oxycodone daily, at least 8 mg of oral hydromorphone daily or an equianalgesic dose of another opioid for a week or longer.

* Hypersensitivity to the active substance or to any of the excipients
* Patients without maintenance opioid therapy as there is an increased risk of respiratory depression.
* Severe respiratory depression or severe obstructive lung conditions.
* Treatment of acute pain other than breakthrough pain.
* Concomitant treatment with medicinal products containing sodium oxybate.

Maintenance opioid treatment
It is important that the maintenance opioid treatment used to treat the patient’s persistent pain has been stabilised before therapy begins and that the patient continues to be treated with the maintenance opioid treatment whilst taking this medical product. 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 this medical product as well as with other fentanyl products.
Chronic obstructive pulmonary disease
Particular caution should be used when titrating in patients with non-severe chronic obstructive pulmonary disease or other medical conditions predisposing them to respiratory depression, as even normally therapeutic doses of fentanyl 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.
Risks of concomitant administration with benzodiazepines or related drugs
Concomitant use of opioids, including fentanyl, 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 fentanyl 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.
Increased intracranial pressure, impaired consciousness
Fentanyl 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, this medical product 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 this medical product, 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 fentanyl is co-administered with drugs that affect the serotoninergic neurotransmitter systems. If serotonin syndrome is suspected, treatment with fentanyl should be discontinued.
Tolerance and opioid use disorder (abuse and dependence)
Repeated administration of opioids can lead to tolerance, physical and psychological dependence. Fentanyl, like other opioids, carries a risk of misuse, abuse, and addiction; therefore, all patients should be monitored. Patients at higher risk may still receive opioid therapy but require closer monitoring. Repeated use of this medical product may result in Opioid Use Disorder (OUD), with risk increasing at higher doses, longer duration, or in those with personal or family history of substance use disorders, tobacco use, or mental health conditions.
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
For full details see prescribing information.

Very common: Dizziness, Headache, Nausea, Vomiting, Application site reactions including: bleeding, pain, ulcer, irritation, paraesthesia, anaesthesia, erythema, oedema, swelling and vesicles.
Common: Oral candidiasis, Anaemia, Neutropenia, Anorexia, Depression, Anxiety, Confusional state, Insomnia, Dysgeusia, Somnolence, Lethargy, Tremor, Sedation
Hypoaesthesia, Migraine, Tachycardia, Hypotension, Hypertension, Dyspnoea, Pharyngolaryn-geal pain, Constipation, Stomatitis, Dry mouth, Diarrhoea, Abdominal pain, Gastro-oesophageal reflux disease, Stomach discomfort, Dyspepsia Toothache,
Pruritus, Hyperhidrosis, Rash, Myalgia, Back pain, Peripheral oedema, Fatigue, Asthenia, Drug withdrawal syndrome, Chills, Weight decreased, Fall.
For full details see prescribing information.

Agents that affect CYP3A4 activity
Fentanyl is metabolised mainly via the human cytochrome P450 3A4 isoenzyme system (CYP3A4), therefore potential interactions may occur when fentanyl is given concurrently with agents that affect CYP3A4 activity.
CYP3A4 inhibitors
The concomitant use of fentanyl with strong CYP3A4 inhibitors (e.g., ritonavir, ketoconazole, itraconazole, troleandomycin, clarithromycin, and nelfinavir) or moderate CYP3A4 inhibitors (e.g., amprenavir, aprepitant, diltiazem, erythromycin, fluconazole, fosamprenavir, grapefruit juice, and verapamil) may result in increased fentanyl plasma concentrations, potentially causing serious adverse drug reactions including fatal respiratory depression. Patients receiving fentanyl concomitantly with moderate or strong CYP3A4 inhibitors should be carefully monitored for an extended period of time. Dosage increase should be done with caution.
Agents that can increase CNS depressant effects
Co-administration of fentanyl with other central nervous system depressants, including other opioids, sedatives or hypnotics, (including benzodiazepines), general anaesthetics, phenothiazines, tranquillisers, skeletal muscle relaxants, sedating antihistamines, gabapentinoids (gabapentin and pregabalin) and alcohol can produce additive depressant effects which may result in respiratory depression, hypotension, profound sedation, coma or a fatal outcome.
Partial opioid agonists/antagonists
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 dependant patients.
Serotoninergic agents
Co-administration of fentanyl with a serotoninergic agent, such as a Selective Serotonin Re-uptake Inhibitor (SSRI) or a Serotonin Norepinephrine Re-uptake Inhibitor (SNRI) or a Monoamine Oxidase Inhibitor (MAOI), may increase the risk of serotonin syndrome, a potentially life-threatening condition. Fentanyl is not recommended for use in patients who have received MAOIs within 14 days because severe and unpredictable potentiation by MAOIs has been reported with opioid analgesics.
Sodium oxybate
Concomitant use of medicinal products containing sodium oxybate and fentanyl is contraindicated (see section 4.3). The treatment with sodium oxybate should be discontinued before start of treatment.
For full details see prescribing information.

Pregnancy: There are no adequate data from the use of fentanyl in pregnant women. With long-term use of fentanyl during pregnancy, there is a risk of neonatal opioid withdrawal syndrome which may be life-threatening if not recognized and treated, and requires management. It is advised not to use fentanyl during labour and delivery (including caesarean section) because fentanyl passes through the placenta and may cause respiratory depression in the foetus. If fentanyl is administered, an antidote for the child should be readily available.
Lactation: Fentanyl passes into breast milk and may cause sedation and respiratory depression in the breast-fed child. Fentanyl should not be used by breastfeeding women and breastfeeding should not be restarted until at least 5 days after the last administration of fentanyl.
For full details see prescribing information.

The symptoms of fentanyl overdose 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, hypotension, respiratory depression, respiratory distress, and respiratory failure, which have resulted in death.
Cases of Cheyne Stokes respiration have been observed in case of fentanyl overdose, particularly in patients with history of heart failure.
Toxic leukoencephalopathy has also been observed with fentanyl overdose.
Management
Immediate management of opioid overdose includes removal of the fentanyl buccal tablet, 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.
Overdose (accidental ingestion) in the opioid-naive person
For treatment of overdose (accidental ingestion) in the opioid-naive 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.
Overdose in opioid-maintained patients
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.
For full details see prescribing information.