4.1. Therapeutic indications

PecFent is indicated for the management of breakthrough pain (BTP) in adults who are already receiving maintenance opioid therapy for chronic cancer pain. Breakthrough pain 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.

4.2. Posology and method of administration

Treatment should be initiated by and remain under the supervision of a physician experienced in the management of opioid therapy in cancer patients. Physicians should keep in mind the potential for abuse of fentanyl.

Posology

PecFent should be titrated to an “effective” dose that provides adequate analgesia and minimises adverse reactions without causing undue (or intolerable) adverse reactions, for two consecutively treated episodes of BTP. The efficacy of a given dose should be assessed over the ensuing 30 minute period.

Patients should be carefully monitored until an effective dose is reached.

PecFent is available in two strengths: 100 micrograms/spray and 400 micrograms/spray.

One dose of PecFent may include administration of 1 spray (100 microgram or 400 microgram doses) or 2 sprays (200 microgram or 800 microgram doses) of the same strength (either 100 microgram or 400 microgram strength).

Patients should not use more than 4 doses per day. Patients should wait at least 4 hours after a dose before treating another BTP episode with PecFent.

PecFent can deliver 100, 200, 400 and 800 microgram doses as follows:

Dose required (micrograms)

Product strength (micrograms)

Amount

100

100

One spray administered into one nostril

200

100

One spray administered into each nostril

400

400

One spray administered into one nostril

800

400

One spray administered into each nostril

Initial dose

• The initial dose of PecFent to treat episodes of BTP is always 100 micrograms (one spray), even in patients switching from other fentanyl containing products for their BTP.

• Patients must wait at least 4 hours before treating another episode of BTP with PecFent.

Method of titration

• Patients should be prescribed an initial titration supply of one bottle (2 sprays or 8 sprays) of PecFent 100 micrograms/spray.

• Patients whose initial dose is 100 micrograms and who need to titrate to a higher dose due to a lack of effect can be instructed to use two 100 microgram sprays (one in each nostril) for their next BTP episode. If this dose is not successful, the patient may be prescribed a bottle of PecFent 400 micrograms/spray and instructed to change to one 400 microgram spray for their next episode of pain. If this dose is not successful, the patient may be instructed to increase to two 400 microgram sprays (one in each nostril).

• From treatment initiation, patients should be closely followed and the dose titrated until an effective dose is reached and confirmed for two consecutively treated episodes of BTP.

Titration in patients switching between immediate-release fentanyl containing products

Substantial differences may exist in the pharmacokinetic profile of immediate-release fentanyl medicinal products, which result in clinically important differences in the rate and extent of absorption of fentanyl. Therefore, when switching between fentanyl containing medicinal products indicated for treatment of breakthrough pain, including intranasal formulations, it is essential that patients are again titrated with the new medicinal product, and not switched on a dose-for-dose (microgram-for-microgram) basis.

Maintenance therapy

Once an effective dose has been established during titration, patients should continue to take this dose up to a maximum of 4 doses per day.

Dose readjustment

Generally, the maintenance dose of PecFent should be increased only where the current dose fails to adequately treat the BTP for several consecutive episodes.

A review of the dose of the background opioid therapy may be required if patients consistently present with more than four BTP episodes per 24 hours.

In absence of adequate pain control, the possibility of hyperalgesia, tolerance and progression of underlying disease should be considered (see section 4.4).

If adverse reactions are intolerable or persistent, the dose should be reduced or treatment with PecFent replaced by another analgesic.

Treatment duration and goals

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

Discontinuation of therapy

PecFent should be discontinued immediately if the patient no longer experiences breakthrough pain episodes. The treatment for persistent backgound 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 therapy is necessary in order to avoid the possibility of abrupt withdrawal effects.

Special populations

Elderly (older than 65 years)

In the PecFent clinical trial programme, 104 (26.1%) of patients were over 60 years of age, 67 (16.8%) over 65 years and 15 (3.8%) over 75 years. There was no indication that older patients tended to titrate to lower doses or experience more adverse reactions. Nevertheless, in view of the importance of renal and hepatic function in the metabolism and clearance of fentanyl, additional care should be exercised in the use of PecFent in the elderly. No data on the pharmacokinetics of PecFent in elderly patients are available.

Hepatic or renal impairment

PecFent should be administered with caution to patients with moderate or severe hepatic or renal impairment (see section 4.4).

Paediatric population

The safety and efficacy of PecFent in children and adolescents aged below 18 years have not yet been established.

No data are available.

Method of administration

PecFent is for nasal use only.

The bottle should be removed from the child resistant container immediately prior to use and the protective cap removed. The bottle must be primed before first use by holding upright and simply pressing and releasing the finger grips either side of the nozzle until a green bar appears in the counting window (should occur after four sprays).

8 spray bottle:

If the product has not been used for 5 days, it should be re-primed by spraying once.

The patient should be advised to write the date of first use in the space provided on the label of the child resistant container.

To administer PecFent the nozzle is placed a short distance (about 1 cm) into the nostril and pointed slightly towards the bridge of the nose. A spray is then administered by pressing and releasing the finger grips either side of the nozzle. An audible click will be heard and the number displayed on the counter will advance by one.

Patients must be advised that they may not feel the spray being administered, and that they should, therefore, rely on the audible click and the number on the counter advancing to confirm that a spray has been delivered.

The PecFent spray droplets form a gel in the nose. Patients should be advised not to blow their nose immediately after PecFent administration.

The protective cap should be replaced after each use and the bottle returned to the child resistant container for safe storage.

4.3. Contraindications

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 being treated with medicinal products containing sodium oxybate.

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 PecFent in a safe and secure place, not accessible by others.

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.

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.

Respiratory depression

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).

Chronic pulmonary disease

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.

Increased intracranial pressure

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.

Cardiac disease

Fentanyl may produce bradycardia. PecFent should, therefore, be used with caution in patients with previous or pre-existing bradyarrhythmias.

Impaired hepatic or renal function

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 Opioid Use Disorder (abuse and dependence)

Tolerance and physical and/or psychological dependence may develop upon repeated administration of opioids such as fentanyl.

Repeated use of PecFent 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 PecFent 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 PecFent 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 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.

Athletes should be informed that treatment with fentanyl could lead to positive doping tests.

Serotonin Syndrome

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.

Route of administration

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.

Nasal conditions

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.

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.

Concomitant use with sedatives

Concomitant use of PecFent and sedative medicines such as benzodiazepines or related drugs may result in sedation, respiratory depression, coma and death. Because of these risks, concomitant prescribing with these sedative medicines should be reserved for patients for whom alternative treatment options are not possible. If a decision is made to prescribe PecFent concomitantly with sedative medicines, the lowest effective dose should be used, and the duration of treatment should be as short as possible.

The patients should be followed closely for signs and symptoms of respiratory depression and sedation.

In this respect, it is strongly recommended to inform patients and their caregivers to be aware of these symptoms (see section 4.5).

PecFent excipients

PecFent contains propylparahydroxybenzoate (E216). Propylparahydroxybenzoate may cause allergic reactions (possibly delayed) and, exceptionally, bronchospasm (if the medicinal product is not correctly administered).

4.5. Interaction with other medicinal products and other forms of interaction

Concomitant use of medicinal products containing sodium oxybate and fentanyl is contraindicated (see section 4.3). The treatment of sodium oxybate should be discontinued before start of treatment with PecFent.

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, gabapentinoids (gabapentin and pregabalin), sedating antihistamines and alcohol may produce additive depressant effects. Concomitant use of opioids with sedative medicines such as benzodiazepines or related drugs increases the risk of sedation, respiratory depression, coma and death because of additive CNS depressant effect. The lowest effective dose of sedative medicines should be used and duration of concomitant use should be limited (see section 4.4).

Serotoninergic medicinal products:

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.

Anticholinergics

Concomitant administration of PecFent with anticholinergics or medications with anticholinergic activity (e.g. tricyclic antidepressants, antihistamines, antipsychotics, muscle relaxants, anti-Parkinson drugs) may result in increased anticholinergic adverse effects.

4.6. Fertility, pregnancy and lactation

Pregnancy

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.

Breastfeeding

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.

Fertility

There are no clinical data on the effects of fentanyl on fertility.

4.7. Effects on ability to drive and use machines

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.

4.8. Undesirable effects

Summary of the safety profile

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.

Tabulated list of adverse reactions

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)).

Common

Uncommon

Unknown

Infections and infestations

Pneumonia

Nasopharyngitis

Pharyngitis

Rhinitis

Blood and lymphatic system disorders

Neutropenia

Immune system disorders

Hypersensitivity

Metabolism and nutrition disorders

Dehydration

Hyperglycaemia

Decreased appetite

Increased appetite

Psychiatric disorders

Disorientation

Delirium

Hallucination

Confusional state

Depression

Attention deficit/hyperactivity disorder

Anxiety

Euphoric mood

Nervousness

Insomnia

Drug dependence (addiction)

Drug abuse

Nervous system disorders

Dysgeusia

Dizziness

Somnolence

Headache

Loss of consciousness

Depressed level of consciousness

Convulsion

Ageusia

Anosmia

Memory impairment

Parosmia

Speech disorder

Sedation

Lethargy

Tremor

Ear and labyrinth disorders

Vertigo

Cardiac disorders

Cyanosis

Vascular disorders

Cardiovascular insufficiency

Lymphoedema

Hypotension

Hot flush

Flushing

Respiratory, thoracic and mediastinal disorders

Epistaxis

Rhinorrhoea

Nasal discomfort (such as “nasal burning”)

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

Respiratory depression

Gastrointestinal disorders

Vomiting

Nausea

Constipation

Intestinal perforation

Peritonitis

Oral hypoaesthesia

Oral paraesthesia

Diarrhoea

Retching

Abdominal pain

Tongue disorder

Mouth ulceration

Dyspepsia

Dry mouth

Skin and subcutaneous tissue disorders

Pruritus

Hyperhydrosis

Urticaria

Musculoskeletal and connective tissue disorders

Arthralgia

Muscle twitching

Renal and urinary disorders

Anuria

Dysuria

Proteinuria

Urinary hesitation

Reproductive system and breast disorders

Vaginal haemorrhage

General disorders and administration site conditions

Non-cardiac chest pain

Asthenia

Chills

Face oedema

Peripheral oedema

Gait disturbance

Pyrexia

Fatigue

Malaise

Thirst

Withdrawal syndrome*

Neonatal withdrawal syndrome

Drug tolerance

Investigations

Platelet count decreased

Weight increased

Injury, poisoning and procedural complications

Fall

Intentional drug misuse

Medication error

* 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 PecFent can lead to drug dependence, even at therapeutic doses. The risk of drug dependence may vary depending on a patient's individual risk factors, dosage, and duration of opioid treatment (see section 4.4).

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: Yellow Card Scheme

Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store

4.9. Overdose

The symptoms of fentanyl overdose via the nasal route 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 effect being respiratory depression. Coma is also known to occur.

Immediate management of opioid overdose includes 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.

Toxic leukoencephalopathy has also been observed with fentanyl overdose.

For treatment of overdose (accidental ingestion) in the opioid-naïve 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. For details about such use the Summary of Product Characteristics of the individual opioid antagonist should be consulted.

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.

It should be noted that although statistically significant increases in Cmax levels were seen following a second dose of PecFent given either one or two hours after the initial dose, this increase is not considered to be large enough to suggest that clinically concerning accumulation or over-exposure would occur, providing a wide safety margin for the recommended dose interval of four hours.

Although muscle rigidity interfering with respiration has not been seen following the use of PecFent, this is possible with fentanyl and other opioids. If it occurs, it should be managed by the use of assisted ventilation, by an opioid antagonist, and as a final alternative, by a neuromuscular blocking agent.

Cases of Cheyne Stokes respiration have been observed in case of fentanyl overdose, particularly in patients with history of heart failure.