PECFENT 100mcg 100mcg / spray nose spray solution medication leaflet

PecFent 100 micrograms/spray nasal spray, solution

PecFent 400 micrograms/spray nasal spray, solution

PecFent 100 micrograms/spray nasal spray, solution

Each ml of solution contains 1,000 micrograms fentanyl (as citrate)1 spray (100 microlitres) contains 100 micrograms fentanyl (as citrate)

Bottles contain:

0.95 ml (950 micrograms fentanyl) - 2 spray bottleor1.55 ml (1,550 micrograms fentanyl) - 8 spray bottle

PecFent 400 micrograms/spray nasal spray, solution

Each ml of solution contains 4,000 micrograms fentanyl (as citrate)1 spray (100 microlitres) contains 400 micrograms fentanyl (as citrate)

Each bottle contains 1.55 ml (6,200 micrograms fentanyl)

Each spray contains 0.02 mg propylparahydroxybenzoate (E216).

For the full list of excipients, see section 6.1.

Nasal spray, solution (nasal spray).

A clear to practically clear colourless aqueous solution.

PecFent is indicated for the management of breakthrough pain (BTP) in adults who are alreadyreceiving maintenance opioid therapy for chronic cancer pain. Breakthrough pain is a transitoryexacerbation 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 oralmorphine daily, at least 25 micrograms of transdermal fentanyl per hour, at least 30 mg of oxycodonedaily, at least 8 mg of oral hydromorphone daily or an equianalgesic dose of another opioid for a weekor longer.

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

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

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 or400 microgram strength).

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

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

Dose required Product strength Amount(micrograms) (micrograms)100 100 One spray administered into onenostril200 100 One spray administered into eachnostril400 400 One spray administered into onenostril800 400 One spray administered into eachnostril

Initial dose

* The initial dose of PecFent to treat episodes of BTP is always 100 micrograms (one spray), evenin 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 alack of effect can be instructed to use two 100 microgram sprays (one in each nostril) for theirnext 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 theirnext episode of pain. If this dose is not successful, the patient may be instructed to increase totwo 400 microgram sprays (one in each nostril).

* From treatment initiation, patients should be closely followed and the dose titrated until aneffective 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 fentanylmedicinal products, which result in clinically important differences in the rate and extent of absorptionof fentanyl. Therefore, when switching between fentanyl containing medicinal products indicated fortreatment of breakthrough pain, including intranasal formulations, it is essential that patients are againtitrated with the new medicinal product, and not switched on a dose-for-dose (microgram-for-microgram) basis.

Once an effective dose has been established during titration, patients should continue to take this doseup 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 toadequately treat the BTP for several consecutive episodes.

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

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

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

Treatment duration and goals

Before initiating treatment with PecFent, a treatment strategy including treatment duration and treatmentgoals, and a plan for end of the treatment, should be agreed together with the patient, in accordance withpain management guidelines. During treatment, there should be frequent contact between the physicianand the patient to evaluate the need for continued treatment, consider discontinuation and to adjustdosages if needed. In absence of adequate pain control, the possibility of hyperalgesia, tolerance andprogression of underlying disease should be considered (see section 4.4). PecFent should not be usedlonger than necessary.

Discontinuation of therapy

PecFent should be discontinued immediately if the patient no longer experiences breakthrough painepisodes. 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 doctoras gradual downward opioid titration therapy is necessary in order to avoid the possibility of abruptwithdrawal effects.

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 totitrate to lower doses or experience more adverse reactions. Nevertheless, in view of the importance ofrenal and hepatic function in the metabolism and clearance of fentanyl, additional care should beexercised in the use of PecFent in the elderly. No data on the pharmacokinetics of PecFent in elderlypatients are available.

Hepatic or renal impairment

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

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

No data are available.

PecFent is for nasal use only.

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

2 spray bottle:

The 2 spray bottle cannot be re-primed and once both doses are used, or if longer than 5 days sincepriming, the bottle and contents should be discarded as described in section 6.6.

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 thechild resistant container.

To administer PecFent the nozzle is placed a short distance (about 1 cm) into the nostril and pointedslightly towards the bridge of the nose. A spray is then administered by pressing and releasing thefinger grips either side of the nozzle. An audible click will be heard and the number displayed on thecounter 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 sprayhas been delivered.

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

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

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.

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 byothers.

Patients and their carers must be instructed that PecFent contains an active substance in an amount thatcan be fatal to a child.

In order to minimise the risks of opioid-related adverse reactions and to identify the effective dose, itis 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 beenstabilised 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 ordiscontinuation 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 andhence the risk of respiratory depression in these patients is reduced. The use of concomitant centralnervous 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 adversereactions. 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 particularlysusceptible to the intracranial effects of CO2 retention, such as those with evidence of increasedintracranial pressure or impaired consciousness. Opioids may obscure the clinical course of patientswith 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 withprevious 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 hasnot been evaluated; however, when administered intravenously the clearance of fentanyl has beenshown to be altered in hepatic and renal impairment due to alterations in metabolic clearance andplasma proteins. Therefore, special care should be taken during the titration process in patients withmoderate 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 administrationof opioids such as fentanyl.

Repeated use of PecFent may lead to Opioid Use Disorder (OUD). A higher dose and longer durationof opioid treatment, can increase the risk of developing OUD. Abuse or intentional misuse of PecFentmay result in overdose and/or death. The risk of developing OUD is increased in patients with apersonal or a family history (parents or siblings) of substance use disorders (including alcohol usedisorder), in current tobacco users or in patients with a personal history of other mental healthdisorders (e.g. major depression, anxiety and personality disorders).

Before initiating treatment with PecFent and during the treatment, treatment goals and a discontinuationplan should be agreed with the patient (see section 4.2). Before and during treatment the patient shouldalso be informed about the risks and signs of OUD. Patients should be advised to contact their physicianif 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). Forpatients with signs and symptoms of OUD, consultation with an addiction specialist should beconsidered.

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 theserotoninergic neurotransmitter systems.

The development of a potentially life-threatening serotonin syndrome may occur with the concomitantuse of serotonergic medicinal products such as Selective Serotonin Re-uptake Inhibitors (SSRIs) and

Serotonin Norepinephrine Re-uptake Inhibitors (SNRIs), and with medicinal products which impairmetabolism of serotonin (including Monoamine Oxidase Inhibitors [MAOIs]). This may occur withinthe 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), neuromuscularabnormalities (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 tophysico-chemical properties of excipients included in the formulation, intravenous or intra-arterialinjection must be avoided in particular.

Nasal conditions

If the patient experiences recurrent episodes of epistaxis or nasal discomfort while taking PecFent, analternative 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) andsleep-related hypoxemia. Opioid use increases the risk of CSA in a dose-dependent fashion. In patientswho 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 drugsmay result in sedation, respiratory depression, coma and death. Because of these risks, concomitantprescribing with these sedative medicines should be reserved for patients for whom alternativetreatment options are not possible. If a decision is made to prescribe PecFent concomitantlywith sedative medicines, the lowest effective dose should be used, and the duration of treatmentshould be as short as possible.

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

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

PecFent excipients

PecFent contains propylparahydroxybenzoate (E216). Propylparahydroxybenzoate may cause allergicreactions (possibly delayed) and, exceptionally, bronchospasm (if the medicinal product is notcorrectly administered).

Concomitant use of medicinal products containing sodium oxybate and fentanyl is contraindicated (seesection 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 medicinalproducts that affect CYP3A4 activity. Coadministration with medicinal products that induce 3A4activity may reduce the efficacy of PecFent. The concomitant use of PecFent with strong CYP3A4inhibitors (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 plasmaconcentrations, potentially causing serious adverse drug reactions including fatal respiratorydepression. Patients receiving PecFent concomitantly with moderate or strong CYP3A4 inhibitorsshould be carefully monitored for an extended period of time. Dose increase should be undertakenwith caution.

The concomitant use of other central nervous system depressants, including other opioids, sedatives orhypnotics, general anaesthetics, phenothiazines, tranquillisers, skeletal muscle relaxants,gabapentinoids (gabapentin and pregabalin) sedating antihistamines and alcohol may produce additivedepressant effects. Concomitant use of opioids with sedative medicines such as benzodiazepines orrelated 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 ofconcomitant 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 potentiallylife-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 MAOinhibitors 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 lowintrinsic activity and, therefore, partially antagonise the analgesic effect of fentanyl and may inducewithdrawal 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 decongestantsduring titration is, therefore, not recommended as this may lead to patients titrating to a dose that ishigher than required. PecFent maintenance treatment may also be less effective in patients with rhinitiswhen administered concomitantly with a nasal vasoconstrictive decongestant. If this occurs, patientsshould be advised to discontinue their decongestant.

Concomitant use of PecFent and other medicinal products (other than oxymetazoline) administered viathe nose has not been evaluated in the clinical trials. Other nasally administered treatments should beavoided within 15 minutes of dosing with PecFent.

There are no adequate data from the use of fentanyl in pregnant women. Studies in animals haveshown reproductive toxicity (see section 5.3). The potential risk for humans is unknown. PecFentshould not be used during pregnancy unless clearly necessary.

Following long-term treatment, fentanyl may cause withdrawal in the new-born infant. It is advisednot to use fentanyl during labour and delivery (including caesarean section) because fentanyl passesthrough the placenta and may cause respiratory depression in the foetus. If PecFent is administered, anantidote for the child should be readily available.

Fentanyl passes into breast milk and may cause sedation and respiratory depression in the breast-fedchild. Fentanyl should not be used by breastfeeding women and breast-feeding should not be restarteduntil 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 operatingmachinery.

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 operatemachinery.

Typical opioid adverse reactions are to be expected with PecFent. Frequently, these will cease ordecrease in intensity with continued use of the medicinal product, as the patient is titrated to the mostappropriate dose. However, the most serious adverse reactions are respiratory depression (potentiallyleading to apnoea or respiratory arrest), circulatory depression, hypotension and shock and all patientsshould be monitored for these.

The clinical studies of PecFent were designed to evaluate safety and efficacy in treating BTP and allpatients were also on background opioid therapies, such as sustained-release morphine or transdermalfentanyl, 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-containingcompounds during clinical studies and post marketing experience (frequencies defined as verycommon (≥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 Pneumoniainfestations Nasopharyngitis

Pharyngitis

Rhinitis

Blood and lymphatic Neutropeniasystem disorders

Immune system Hypersensitivitydisorders

Common Uncommon Unknown

Metabolism and Dehydrationnutrition disorders Hyperglycaemia

Decreased appetite

Increased appetite

Psychiatric disorders Disorientation Delirium Insomnia

Hallucination Drug dependence

Confusional state (addiction)

Depression Drug abuse

Attentiondeficit/hyperactivitydisorder

Anxiety

Euphoric mood

Nervousness

Nervous system Dysgeusia Loss of consciousnessdisorders Dizziness Depressed level of

Somnolence consciousness

Headache Convulsion

Ageusia

Anosmia

Memory impairment

Parosmia

Speech disorder

Sedation

Lethargy

Tremor

Ear and labyrinth Vertigodisorders

Cardiac disorders Cyanosis

Vascular disorders Cardiovascular Flushinginsufficiency

Lymphoedema

Hot flush

Respiratory, thoracic Epistaxis Upper airway Respiratory depressionand mediastinal Rhinorrhoea obstructiondisorders Nasal discomfort Pharyngolaryngeal pain(such as “nasal Rhinalgiaburning”) Nasal mucosal disorder

Cough

Sneezing

Upper respiratory tractcongestion

Nasal congestion

Intranasal hypoaesthesia

Throat irritiation

Postnasal drip

Nasal dryness

Common Uncommon Unknown

Gastrointestinal Vomiting Intestinal perforationdisorders Nausea Peritonitis

Constipation Oral hypoaesthesia

Oral paraesthesia

Retching

Abdominal pain

Tongue disorder

Mouth ulceration

Dyspepsia

Dry mouth

Skin and subcutaneous Pruritus Hyperhydrosistissue disorders Urticaria

Musculoskeletal and Arthralgiaconnective tissue Muscle twitchingdisorders

Renal and urinary Anuriadisorders Dysuria

Proteinuria

Urinary hesitation

Reproductive system Vaginal haemorrhageand breast disorders

General disorders and Non-cardiac chest pain Withdrawal syndrome*administration site Asthenia Neonatal withdrawalconditions Chills syndrome

Face oedema Drug tolerance

Peripheral oedema

Gait disturbance

Malaise

Thirst

Investigations Platelet count decreased

Weight increased

Injury, poisoning and Fallprocedural Intentional drug misusecomplications Medication error

* Opioid withdrawal symptoms such as nausea, vomiting, diarrhoea, anxiety, chills, tremor, andsweating have been observed with transmucosal fentanyl.

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 drugdependence may vary depending on a patient's individual risk factors, dosage, and duration of opioidtreatment (see section 4.4).

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

The symptoms of fentanyl overdose via the nasal route are expected to be similar in nature to those ofintravenous fentanyl and other opioids, and are an extension of its pharmacological actions, with themost serious significant effect being respiratory depression. Coma is also known to occur.

Immediate management of opioid overdose includes ensuring a patent airway, physical and verbalstimulation of the patient, assessment of the level of consciousness, ventilatory and circulatory status,and assisted ventilation (ventilatory support) if necessary. Toxic leukoencephalopathy has also beenobserved with fentanyl overdose.

For treatment of overdose (accidental ingestion) in the opioid-naïve person, intravenous access shouldbe obtained and naloxone or other opioid antagonists should be employed as clinically indicated. Theduration of respiratory depression following overdose may be longer than the effects of the opioidantagonist’s action (e.g. the half life of naloxone ranges from 30 to 81 minutes) and repeatedadministration may be necessary. For details about such use the Summary of Product Characteristicsof the individual opioid antagonist should be consulted.

For treatment of overdose in opioid-maintained patients, intravenous access should be obtained. Thejudicious use of naloxone or another opioid antagonist may be warranted in some instances, but it isassociated with the risk of precipitating an acute withdrawal syndrome.

It should be noted that although statistically significant increases in Cmax levels were seen following asecond dose of PecFent given either one or two hours after the initial dose, this increase is notconsidered to be large enough to suggest that clinically concerning accumulation or over-exposurewould 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 ofassisted ventilation, by an opioid antagonist, and as a final alternative, by a neuromuscular blockingagent.

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

Pharmacotherapeutic group: Analgesics; opioids; phenylpiperidine derivatives;

ATC code: N02AB03.

Fentanyl is an opioid analgesic, interacting predominantly with the opioid µ-receptor. Its primarytherapeutic actions are analgesia and sedation. Secondary pharmacological effects are respiratorydepression, bradycardia, hypothermia, constipation, miosis, physical dependence and euphoria.

Opioids may influence the hypothalamic-pituitary-adrenal or -gonadal axes. Some changes that can beseen include an increase in serum prolactin, and decreases in plasma cortisol and testosterone. Clinicalsigns and symptoms may be manifest from these hormonal changes.

A double-blind, randomised, placebo-controlled crossover study has been conducted in which 114patients who experienced on average 1 to 4 episodes of break through pain (BTP) per day while takingmaintenance opioid therapy were entered into an initial open-label titration phase in order to identifyan effective dose of PecFent (Study CP043). The patients entering the double-blind phase treated up to10 episodes of BTP with either PecFent (7 episodes) or placebo (3 episodes) in a random order.

Of the patients entering the titration phase, only 7 (6.1 %) were unable to be titrated to an effectivedose due to lack of efficacy and 6 (5.3 %) withdrew due to adverse events.

The primary endpoint was the comparison between the summed pain intensity difference at 30 minutesafter dosing (SPID30), which was 6.57 in the PecFent-treated episodes compared to 4.45 for placebo(p<0.0001 ). The SPID for PecFent-treated episodes was also significantly different to placebo at 1015, 45 and 60 minutes after administration.

The mean pain intensity scores (73 patients) for all PecFent-treated episodes (459 episodes) comparedto those treated with placebo (200 episodes) were significantly lower at 5, 10, 15, 30, 45 and60 minutes following administration (see Figure 1).

Figure 1: Mean (± SE) Pain Intensity Scores at Each Time Point (mITT Population)

PecFent

PecFent

PecFent

PecFent

The superior efficacy of PecFent over placebo was supported by data from secondary endpointsincluding the number of BTP episodes with clinically meaningful pain relief, defined as a reduction inpain intensity score of at least 2 (Figure 2).

Figure 2: Clinically Meaningful Pain Relief - PecFent vs placebo: % Patients’ Episodes With ≥2 Point

Reduction in Pain Intensity

In a double-blind, randomized comparator-controlled study (Study 044) of similar design to Study 043conducted in opioid-tolerant patients with breakthrough cancer pain on stable doses of regularlyscheduled opioids, PecFent was shown to be superior to immediate-release morphine sulfate (IRMS).

Superiority was demonstrated by the primary endpoint, Pain Intensity Difference within 15 minutes,which was 3.02 in patients treated with PecFent compared to 2.69 in patients treated with IRMS(p=0.0396).

In a long-term, open-label, safety study (Study 045), 355 patients entered the 16-week treatmentphase, during which 42,227 episodes of breakthrough cancer pain (BTP) were treated with PecFent.

One hundred of these patients continued treatment for up to 26 months in an extension phase. Of the355 patients treated in the open-label treatment phase, 90 % required no increase in dose.

In the randomised, placebo-controlled study (CP043) 9.4% of 459 PecFent-treated BTP episodes in 73patients required use of any further (rescue) medicinal products within 60 minutes of dosing. Duringthe longer-term, open-label study (CP045) this was 6.0 % of 42,227 episodes in 355 patients treatedwith PecFent during up to 159 days of treatment.

General introduction

Fentanyl is highly lipophilic and can be absorbed very rapidly through the nasal mucosa and moreslowly by the gastrointestinal route. It is subject to first pass hepatic and intestinal metabolism and themetabolites do not contribute to fentanyl’s therapeutic effects.

PecFent utilises the PecSys nasal drug delivery system to modulate the delivery and absorption offentanyl. The PecSys system allows the product to be sprayed into the front area of the nasal cavity asa fine mist of droplets, which gel on contact with the calcium ions present in the nasal mucosa.

Fentanyl diffuses from the gel and is absorbed through the nasal mucosa; this gel-modulatedabsorption of fentanyl restrains the peak in plasma concentration (Cmax) whilst allowing the attainmentof an early time to that peak (Tmax).

In a pharmacokinetic study comparing PecFent (100, 200, 400 and 800 micrograms) with oraltransmucosal fentanyl citrate (OTFC, 200 micrograms), fentanyl was shown to be rapidly absorbedfollowing single dose intranasal administration of PecFent, with median Tmax ranging from 15 to21 minutes (Tmax for OTFC was approximately 90 minutes). The variability of the pharmacokinetics offentanyl was considerable following treatment with both PecFent and OTFC. Relative bioavailabilityof fentanyl from the PecFent treatment compared to the 200 microgram OTFC was approximately120 %.

The main pharmacokinetic parameters are shown in the following table.

Pharmacokinetic parameters in adult subjects receiving PecFent and OTFC

Pharmacokinetic PecFent OTFCparameters 100 200 400 800 200(mean (%CV)) micrograms micrograms micrograms micrograms micrograms

Tmax (hours)* 0.33 (0.08- 0.25 (0.17- 0.35 (0.25- 0.34 (0.17- 1.50 (0.501.50) 1.60) 0.75) 3.00) -8.00)

Cmax (pg/ml) 351.5 (51.3) 780.8 (48.4) 1552.1 (26.2) 2844.0 (56.0) 317.4 (29.9)

AUC (pg.hour/ml) 2460.5 (17.9 4359.9 (29.8) 7513.4 (26.7) 17272 (48.9) 3735.0 (32.8)t1/2 (hour) 21.9 (13.6) 24.9 (51.3) 15.0 (24.7) 24.9 (92.5) 18.6 (31.4)

*Data for Tmax presented as median (range).

The curves for each dose level are similar in shape with increasing dose levels producing increasingplasma fentanyl levels. Dose-proportionality was demonstrated for Cmax and area under the curve(AUC) in the dose range 100 micrograms to 800 micrograms (see Figure 3). If switching to PecFentfrom another fentanyl product for BTP, independent dose titration with PecFent is required as thebioavailability between products differs significantly.

Figure 3: Mean plasma fentanyl concentrations following single doses of PecFent and OTFC inhealthy subjects3000 A. PecFent 100 µg dose B. PecFent 200 µg dose

C. PecFent 400 µg dose D. PecFent 800 µg dose

E. OTFC 200 µg dose0 0.5 1 1.5 2 2.5 3 3.5 4

Time (hours)

A pharmacokinetic study was conducted to evaluate the absorption and tolerability of a single dose of

PecFent in patients with pollen-induced seasonal allergic rhinitis, comparing the un-challenged,acutely challenged (rhinitic) and acutely challenged and then treated with oxymetazoline, states.

There was no clinically significant effect of acute rhinitis on Cmax, Tmax or overall exposure to fentanyl,comparing the unchallenged with the acutely challenged states. Following treatment of the acuterhinitic state with oxymetazoline, there were reductions in Cmax and exposure, and increases in Tmaxthat were statistically, and possibly clinically, significant.

Plasma Fentanyl (pg/ml)

Fentanyl is highly lipophilic and is well distributed beyond the vascular system, with a large apparentvolume of distribution. Animal data have shown that, following absorption, fentanyl is rapidlydistributed to the brain, heart, lungs, kidneys and spleen followed by a slower redistribution to musclesand fat.

The plasma protein binding of fentanyl is 80 - 85 %. The main binding protein is alpha-1-acidglycoprotein, but both albumin and lipoproteins contribute to some extent. The free fraction offentanyl increases with acidosis.

The metabolic pathways following nasal administration of PecFent have not been characterised inclinical studies. Fentanyl is metabolised in the liver to norfentanyl by cytochrome CYP3A4 isoform.

Norfentanyl is not pharmacologically active in animal studies. It is more than 90 % eliminated bybiotransformation to N-dealkylated and hydroxylated inactive metabolites.

Disposition of fentanyl following intranasal administration of PecFent has not been characterised in amass balance study. Less than 7 % of an administered dose of fentanyl is excreted unchanged in theurine and only about 1 % is excreted unchanged in the faeces. The metabolites are mainly excreted inthe urine, while faecal excretion is less important.

The total plasma clearance of fentanyl following intravenous administration is approximately 42 L/h.

Dose-proportionality was demonstrated for Cmax and AUC in the dose range 100 micrograms to800 micrograms.

The effect of renal or hepatic impairment on the pharmacokinetics of PecFent has not been studied.

Non-clinical data reveal no special hazard for humans based on conventional studies of safetypharmacology, repeated dose toxicity, genotoxicity and carcinogenicity.

Embryo-foetal developmental toxicity studies conducted in rats and rabbits revealed no compound-induced malformations or developmental variations when administered during the period oforganogenesis.

In a fertility and early embryonic development study in rats, a male-mediated effect was observed athigh doses (300 mcg/kg/day, s.c.) and is consistent with the sedative effects of fentanyl in animalstudies.

In studies on pre and postnatal development in rats the survival rate of offspring was significantlyreduced at doses causing severe maternal toxicity. Further findings at maternally toxic doses in F1pups were delayed physical development, sensory functions, reflexes and behaviour. These effectscould either be indirect effects due to altered maternal care and/or decreased lactation rate or a directeffect of fentanyl on the pups.

Carcinogenicity studies (26-week dermal alternative bioassay in Tg.AC transgenic mice; two-yearsubcutaneous carcinogenicity study in rats) with fentanyl did not induce any findings indicative ofoncogenic potential. Evaluation of brain slides from the carciogenicity study in rats revealed brainlesions in animals administered high doses of fentanyl citrate. The relevance of these findings tohumans is unknown.

Pectin (E440)

Mannitol (E421)

Phenylethyl alcohol

Propylparahydroxybenzoate (E216)

Sucrose

Hydrochloric acid (0.36%) or sodium hydroxide (for pH adjustment)

Purified water

Not applicable.

2 spray bottle:

18 months

After priming, use within 5 days.

8 spray bottle:

3 years

After first use: 60 days

Do not store above 25 °C.

Do not freeze.

Keep the bottle in the child resistant container in order to protect from light.

Store the bottle in the child resistant container at all times, even when finished.

Bottle (clear Type I glass) with an attached metering pump incorporating an audible dose counter anda protective cap (solid white cap for the 2 spray and translucent cap for the 8 spray). In each case theproduct is packed in a clam-shell-like child resistant container.

Bottles contain:

0.95 ml ensuring delivery of 2 full spraysor1.55 ml ensuring delivery of 8 full sprays.

Bottles in their child resistant containers are supplied in cartons containing:

For 2 spray bottle: 1 bottle.

For 8 spray bottle: 1, 4 or 12 bottles.

Not all presentations or pack sizes may be marketed.

Partially used PecFent bottles may contain enough medicine to be harmful or life-threatening to achild. Even if there is little or no medicine left in the bottle, PecFent must be disposed of properly,according to the following steps:

o Patients and caregivers must be instructed to properly dispose of all unused, partially used andused PecFent bottles. The patient should be instructed how to do this correctly.

o If there are any unwanted therapeutic sprays remaining in the bottle, the patient should beinstructed to expel these as follows:

2 spray bottle:

o Aim the spray away from themselves (and any other people) and expel remaining spray until thered number “2” appears in the counting window and there are no more full therapeutic spraysobtainable from the bottle.

o After the counter has advanced to “2”, the patient should continue to push down on the fingergrips (there will be some increased resistance) a total of four times in order to expel any residualmedicine from the bottle.

o After the 2 therapeutic sprays have been emitted, the patient will not hear a click and the counterwill not advance beyond “2”; further sprays emitted will not be full sprays and should not beused therapeutically.

8 spray bottle:

o Aim the spray away from themselves (and any other people) and expel remaining spray until thered number “8” appears in the counting window and there are no more full therapeutic spraysobtainable from the bottle.

o After the counter has advanced to “8”, the patient should continue to push down on the fingergrips (there will be some increased resistance) a total of four times in order to expel any residualmedicine from the bottle.

o After the 8 therapeutic sprays have been emitted, the patient will not hear a click and the counterwill not advance beyond “8”; further sprays emitted will not be full sprays and should not beused therapeutically.

As soon as PecFent is no longer needed, patients and members of their household must be advised tosystematically dispose of any bottles remaining from a prescription as soon as possible by returningthem to their child-resistant container and discarding them, according to local requirements or byreturning them to the pharmacy.

Grünenthal GmbH

Zieglerstraße 652078 Aachen

Germany

EU/1/10/644/007

EU/1/10/644/001

EU/1/10/644/002

EU/1/10/644/005

EU/1/10/644/003

EU/1/10/644/004

EU/1/10/644/006

Date of first authorisation: 31 August 2010

Date of latest renewal: 17 July 2015

Detailed information on this medicinal product is available on the website of the European Medicines

Agency http://www.ema.europa.eu/.