Source: European Medicines Agency (EU) Revision Year: 2019 Publisher: Kyowa Kirin Holdings B.V., Bloemlaan 2, 2132NP Hoofddorp, The Netherlands
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
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.
Patients and their carers must be instructed that PecFent contains an active substance in an amount that can be fatal to a child.
In order to minimise the risks of opioid-related adverse reactions and to identify the effective dose, it is imperative that patients be monitored closely by health professionals during the titration process.
It is important that the long acting opioid treatment used to treat the patient’s persistent pain has been stabilised before PecFent therapy begins.
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.
There is a risk of clinically significant respiratory depression associated with the use of fentanyl. Patients with pain who receive chronic opioid therapy develop tolerance to respiratory depression and hence the risk of respiratory depression in these patients is reduced. The use of concomitant central nervous system depressants may increase the risk of respiratory depression (see section 4.5).
In patients with chronic obstructive pulmonary diseases, fentanyl may cause more serious adverse reactions. In these patients, opioids may decrease respiratory drive and increase airway resistance.
PecFent 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 patients with a head injury and should be used only if clinically warranted.
Fentanyl may produce bradycardia. PecFent should, therefore, be used with caution in patients with previous or pre-existing bradyarrhythmias.
In addition, PecFent 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. 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.
Tolerance and physical and/or psychological dependence may develop upon repeated administration of opioids such as fentanyl. However, iatrogenic addiction following therapeutic use of opioids is known to occur.
Athletes should be informed that treatment with fentanyl could lead to positive doping tests.
Caution is advised when PecFent is coadministered 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 Re-uptake Inhibitors (SSRIs) and Serotonin Norepinephrine Re-uptake Inhibitors (SNRIs), and with medicinal products which impair metabolism of serotonin (including Monoamine Oxidase Inhibitors [MAOIs]). This may occur within the recommended dose (see section 4.5).
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 PecFent should be discontinued.
PecFent is only intended for nasal use, and must not be administered by any other route. Due to physico-chemical properties of excipients included in the formulation, intravenous or intra-arterial injection must be avoided in particular.
If the patient experiences recurrent episodes of epistaxis or nasal discomfort while taking PecFent, an alternative method of administration for treatment of breakthrough pain should be considered.
PecFent contains propylparahydroxybenzoate (E216). Propylparahydroxybenzoate may cause allergic reactions (possibly delayed) and, exceptionally, bronchospasm (if the medicinal product is not correctly administered).
Fentanyl is metabolised mainly via the human cytochrome P450 3A4 isoenzyme system (CYP3A4), therefore potential interactions may occur when PecFent is given concurrently with medicinal products that affect CYP3A4 activity. Coadministration with medicinal products that induce 3A4 activity may reduce the efficacy of PecFent. The concomitant use of PecFent 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 PecFent concomitantly with moderate or strong CYP3A4 inhibitors should be carefully monitored for an extended period of time. Dose increase should be undertaken with caution.
The concomitant use of other central nervous system depressants, including other opioids, sedatives or hypnotics, general anaesthetics, phenothiazines, tranquillisers, skeletal muscle relaxants, sedating antihistamines and alcohol may produce additive depressant effects.
Coadministration of fentanyl with a serotoninergic medicinal product, 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.
PecFent is not recommended for use in patients who have received monoamine oxidase (MAO) inhibitors within the previous 14 days because severe and unpredictable potentiation by MAO inhibitors has been reported with opioid analgesics.
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 dependent patients.
Concomitant use of nasally administered oxymetazoline has been shown to decrease the absorption of PecFent (see section 5.2). The concomitant use of nasally administered vasoconstrictive decongestants during titration is, therefore, not recommended as this may lead to patients titrating to a dose that is higher than required. PecFent maintenance treatment may also be less effective in patients with rhinitis when administered concomitantly with a nasal vasoconstrictive decongestant. If this occurs, patients should be advised to discontinue their decongestant.
Concomitant use of PecFent and other medicinal products (other than oxymetazoline) administered via the nose has not been evaluated in the clinical trials. Other nasally administered treatments should be avoided within 15 minutes of dosing with PecFent.
There are no adequate data from the use of fentanyl in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3). The potential risk for humans is unknown. PecFent should not be used during pregnancy unless clearly necessary.
Following long-term treatment, fentanyl may cause withdrawal in the new-born infant. 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 PecFent is administered, an antidote for the child should be readily available.
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 breast-feeding should not be restarted until at least 5 days after the last administration of fentanyl.
There are no clinical data on the effects of fentanyl on fertility.
Opioid analgesics may impair the mental and/or physical ability required for driving or operating machinery.
Patients should be advised not to drive or operate machinery if they experience somnolence, dizziness, or visual disturbance or other adverse reactions which can impair their ability to drive or operate machinery.
Typical opioid adverse reactions are to be expected with PecFent. Frequently, these will cease or decrease in intensity with continued use of the medicinal product, as the patient is titrated to the most appropriate dose. However, the most serious adverse reactions are respiratory depression (potentially leading to apnoea or respiratory arrest), circulatory depression, hypotension and shock and all patients should be monitored for these.
The clinical studies of PecFent were designed to evaluate safety and efficacy in treating BTP and all patients were also on background opioid therapies, such as sustained-release morphine or transdermal fentanyl, for their persistent pain. Therefore it is not possible to definitively separate the effects of PecFent alone.
The following adverse reactions have been reported with PecFent and/or other fentanyl-containing compounds during clinical studies and post marketing experience (frequencies defined as very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000); unknown (cannot be estimated from available data)).
Uncommon: Pneumonia, Nasopharyngitis, Pharyngitis, Rhinitis
Uncommon: Neutropenia
Uncommon: Hypersensitivity
Uncommon: Dehydration, Hyperglycaemia, Decreased appetite, Increased appetite
Common: Disorientation
Uncommon: Delirium, Hallucination, Confusional state, Depression, Attention deficit/hyperactivity disorder, Anxiety, Euphoric mood, Nervousness
Unknown: Insomnia, Drug dependence (addiction), Drug abuse
Common: Dysgeusia, Dizziness, Somnolence, Headache
Uncommon: Loss of consciousness, Depressed level of consciousness, Convulsion, Ageusia, Anosmia, Memory impairment, Parosmia, Speech disorder, Sedation, Lethargy, Tremor
Uncommon: Vertigo
Uncommon: Cyanosis
Uncommon: Cardiovascular insufficiency, Lymphoedema, Hypotension, Hot flush
Unknown: Flushing
Common: Epistaxis, Rhinorrhoea, Nasal discomfort
Uncommon: Upper airway obstruction, Pharyngolaryngeal pain Rhinalgia, Nasal mucosal disorder Cough, Dyspnoea, Sneezing, Upper respiratory tract congestion, Nasal congestion, Intranasal hypoaesthesia, Throat irritiation, Postnasal drip, Nasal dryness
Unknown: Respiratory depression
Common: Vomiting, Nausea, Constipation
Uncommon: Intestinal perforation, Peritonitis, Oral hypoaesthesia, Oral paraesthesia, Diarrhoea, Retching, Abdominal pain, Tongue disorder, Mouth ulceration, Dyspepsia, Dry mouth
Common: Pruritus
Uncommon: Hyperhydrosis, Urticaria
Uncommon: Arthralgia, Muscle twitching
Uncommon: Anuria, Dysuria, Proteinuria, Urinary hesitation
Uncommon: Vaginal haemorrhage
Uncommon: Non-cardiac chest pain, Asthenia, Chills, Face oedema, Peripheral oedema, Gait disturbance, Pyrexia, Fatigue, Malaise, Thirst
Unknown: Withdrawal syndrome*, Neonatal withdrawal syndrome
Uncommon: Platelet count decreased, Weight increased
Uncommon: Fall, Intentional drug misuse, Medication error
* See next section below
Opioid withdrawal symptoms such as nausea, vomiting, diarrhoea, anxiety, chills, tremor, and sweating have been observed with transmucosal fentanyl.
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 national reporting system listed in Appendix V.
Not applicable.
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