PecFent

1.

NAME OF THE MEDICINAL PRODUCT

PecFent 100 micrograms/spray nasal spray solution

2.

QUALITATIVE AND QUANTITATIVE COMPOSITION

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

1 spray (100 microliters) contains 100 micrograms fentanyl (as citrate)

Each bottle contains 1.55 ml (1.55 mg fentanyl) ensuring delivery of 8 sprays of 100 micrograms

Excipients

Each spray contains 0.02 mg propylhydroxybenzoate (E216).

For a full list of excipients, see section 6.1.

3.

PHARMACEUTICAL FORM

Nasal spray, solution (nasal spray)

A clear to practically clear colourless aqueous solution.

4.

CLINICAL PARTICULARS

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.

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 dose strength (either 100 microgram

or 400 microgram strength).

2

Patients should not take more than 4 doses per day. Patients should wait at least 4 hours after a dose

before treating another BTP episode with PecFent.

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 (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

products, which result in clinically important differences in the rate and extent of absorption of

fentanyl. Therefore, when switching between fentanyl containing products indicated for treatment of

breakthrough pain, including intranasal formulations, it is essential that patients are again titrated with

the new 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.

If adverse reactions are intolerable or persistent, the dose should be reduced or treatment with PecFent

replaced by another analgesic.

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.

Paediatric population

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

No data are available.

3

Use in the 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)

Method of administration

PecFent is for administration via the nasal route only.

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

Dose required

micrograms)

Product strength

(micrograms)

Amount

100

One spray administered into one

nostril

200

100

One spray administered into each

nostril

400

One spray administered into one

nostril

800

400

One spray administered into each

nostril

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).

If the product has not been used for more than 5 days or if it is more than 14 days since the product

was first used, the PecFent bottle should be discarded.

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 nasal spray pump permanently locks after the eighth spray has been administered.

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

4.3 Contraindications

Hypersensitivity to the active substance or to any of the excipients.

Use in opioid naïve patients.

Severe respiratory depression or severe obstructive lung conditions.

4.4 Special warnings and precautions for use

Patients and their carers must be instructed that PecFent contains an active substance in an amount that

can be fatal to a child, and therefore to keep PecFent out of the reach and sight of children.

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.

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 CO 2 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

Intravenous fentanyl may produce bradycardia. PecFent should therefore be used with caution in

patients with 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.

Abuse potential and tolerance

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 rare.

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

5

Route of administration

PecFent is only intended for intranasal administration, 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.

PecFent excipients

PecFent contains propylhydroxybenzoate (E216). In some patients this may cause allergic reactions

(possibly delayed) and, exceptionally, bronchospasm (if the product is not correctly administered).

4.5 Interaction with other medicinal products and other forms of interaction

Fentanyl is metabolised mainly via the human cytochrome P450 3A4 isoenzyme system (CYP3A4),

therefore potential interactions may occur when PecFent is given concurrently with agents that affect

CYP3A4 activity. Coadministration with agents 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.

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 dependant 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.

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.

6

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 48 hours 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

No studies on the effects on the ability to drive and use machines have been performed.

However, 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

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 adverse reactions considered to be at least possibly-related to treatment, from Phase II and III

clinical studies were as follows (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) within

each frequency grouping, adverse reactions are presented in order of decreasing seriousness).

Common

Uncommon

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

7

Common

Uncommon

Psychiatric disorders

Disorientation

Drug abuse

Delirium

Hallucination

Confusional state

Depression

Attention deficit/hyperactivity

disorder

Anxiety

Euphoric mood

Nervousness

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

Respiratory, thoracic and

mediastinal disorders

Epistaxis

Rhinorrhoea

Nasal discomfort

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

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

8

Common

Uncommon

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

Investigations

Platelet count decreased

Weight increased

Injury, poisoning and procedural

complications

Fall

Intentional drug misuse

Medication error

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.

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.

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. Consult the Summary of Product Characteristics of the individual

opioid antagonist for details about such use.

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 C max 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.

9

5.

PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Analgesics; phenylpiperidine derivatives; ATC code: N02A-B03.

Mechanism of action

Fentanyl is an opioid analgesic, interacting predominantly with the opioid µ-receptor. Its primary

therapeutic actions are analgesia and sedation. Secondary pharmacological effects are respiratory

depression, bradycardia, hypothermia, constipation, miosis, physical dependence and euphoria.

Pharmacodynamic effects

A double-blind, randomised, placebo-controlled crossover study has been conducted in which 114

patients who experienced on average 1 to 4 episodes of break through pain (BTP) per day while taking

maintenance opioid therapy were entered into an initial open-label titration phase in order to identify

an effective dose of PecFent (Study CP043). The patients entering the double-blind phase treated up to

10 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 effective

dose 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 minutes

after dosing (SPID 30 ), 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 10

15, 45 and 60 minutes after administration.

The mean pain intensity scores (73 patients) for all PecFent-treated episodes (459 episodes) compared

to those treated with placebo (200 episodes) were significantly lower at 5, 10, 15, 30, 45 and

60 minutes following administration (see Figure 1).

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

PecFent

10

The superior efficacy of PecFent over placebo was supported by data from secondary endpoints

including the number of BTP episodes with clinically meaningful pain relief, defined as a reduction in

pain 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 043

conducted in opioid-tolerant patients with breakthrough cancer pain on stable doses of regularly

scheduled 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 treatment

phase, 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 the

355 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 73

patients required use of any further (rescue) medicinal products within 60 minutes of dosing. During

the longer-term, open-label study (CP045) this was 6.0 % of 42,227 episodes in 355 patients treated

with PecFent during up to 159 days of treatment.

5.2 Pharmacokinetic properties

General introduction

Fentanyl is highly lipophilic and can be absorbed very rapidly through the nasal mucosa and more

slowly by the gastrointestinal route. It is subject to first pass hepatic and intestinal metabolism and the

metabolites do not contribute to fentanyl’s therapeutic effects.

PecFent utilises the PecSys nasal drug delivery system to modulate the delivery and absorption of

fentanyl. The PecSys system allows the product to be sprayed into the front area of the nasal cavity as

a 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-modulated

11

absorption of fentanyl restrains the peak in plasma concentration (C max ) whilst allowing the attainment

of an early time to that peak (T max ).

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

Absorption

In a pharmacokinetic study comparing PecFent (100, 200, 400 and 800 micrograms) with oral

transmucosal fentanyl citrate (OTFC, 200 micrograms), fentanyl was shown to be rapidly absorbed

following single dose intranasal administration of PecFent, with median T max ranging from 15 to

21 minutes (T max for OTFC was approximately 90 minutes). The variability of the pharmacokinetics of

fentanyl was considerable following treatment with both PecFent and OTFC. Relative bioavailability

of fentanyl from the PecFent treatment compared to the 200 microgram OTFC was approximately

120 %.

The main pharmacokinetic parameters are shown in the following table.

Pharmacokinetic parameters in adult subjects receiving PecFent and OTFC

Pharmacokinetic

parameters

(mean (%CV))

PecFent

OTFC

100

micrograms

200

micrograms

400

micrograms

800

micrograms

200

micrograms

1.50 (0.50

-8.00)

C max (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)

t 1/2 (hour) 21.9 (13.6) 24.9 (51.3) 15.0 (24.7) 24.9 (92.5) 18.6 (31.4)

*Data for T max presented as median (range).

0.33 (0.08-

1.50)

0.25 (0.17-

1.60)

0.35 (0.25-

0.75)

0.34 (0.17-

3.00)

The curves for each dose level are similar in shape with increasing dose levels producing increasing

plasma fentanyl levels. Dose-proportionality was demonstrated for C max and area under the curve

(AUC) in the dose range 100 micrograms to 800 micrograms (see Figure 3). If switching to PecFent

from another fentanyl product for BTP, independent dose titration with PecFent is required as the

bioavailability between products differs significantly.

Figure 3: Mean plasma fentanyl concentrations following single doses of PecFent and OTFC in

healthy subjects

4500

4000

3500

A. PecFent 100 µg dose

3000

B. PecFent 200 µg dose

2500

C. PecFent 400 µg dose

D. PecFent 800 µg dose

2000

1500

E. OTFC 200 µg dose

1000

500

0

0.5

1

1.5

2

2.5

3

3.5

4

Time (hours)

12

T max (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 C max , T max or overall exposure to fentanyl,

comparing the unchallenged with the acutely challenged states. Following treatment of the acute

rhinitic state with oxymetazoline, there were reductions in C max and exposure, and increases in T max

that were statistically, and possibly clinically, significant.

Distribution

Fentanyl is highly lipophilic and is well distributed beyond the vascular system, with a large apparent

volume of distribution. Animal data have shown that, following absorption, fentanyl is rapidly

distributed to the brain, heart, lungs, kidneys and spleen followed by a slower redistribution to muscles

and fat.

The plasma protein binding of fentanyl is 80 – 85 %. The main binding protein is alpha-1-acid

glycoprotein, but both albumin and lipoproteins contribute to some extent. The free fraction of

fentanyl increases with acidosis.

Biotransformation

The metabolic pathways following nasal administration of PecFent have not been characterised in

clinical 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 by

biotransformation to N-dealkylated and hydroxylated inactive metabolites.

Elimination

Disposition of fentanyl following intranasal administration of PecFent has not been characterised in a

mass balance study. Less than 7 % of an administered dose of fentanyl is excreted unchanged in the

urine and only about 1 % is excreted unchanged in the faeces. The metabolites are mainly excreted in

the urine, while faecal excretion is less important.

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

Linearity/non-linearity

Dose-proportionality was demonstrated for C max and AUC in the dose range 100 micrograms to

800 micrograms.

5.3 Preclinical safety data

Non-clinical data reveal no special hazard for humans based on conventional studies of safety

pharmacology, 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 of

organogenesis.

In a fertility and early embryonic development study in rats, a male-mediated effect was observed at

high doses (300 mcg/kg/day, s.c.) and is consistent with the sedative effects of fentanyl in animal

studies.

In studies on pre and postnatal development in rats the survival rate of offspring was significantly

reduced at doses causing severe maternal toxicity. Further findings at maternally toxic doses in F1

pups were delayed physical development, sensory functions, reflexes and behaviour. These effects

13

could either be indirect effects due to altered maternal care and/or decreased lactation rate or a direct

effect of fentanyl on the pups.

Carcinogenicity studies (26-week dermal alternative bioassay in Tg.AC transgenic mice; two-year

subcutaneous carcinogenicity study in rats) did not induce any findings indicative of oncogenic

potential.

6.

PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Pectin (E440)

Mannitol (E421)

Phenylethyl alcohol

Propyl hydroxybenzoate (E216)

Sucrose

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

Purified water

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

3 years

After first use: 14 days

After last actuation of the pump: 5 days

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

child resistant container

6.4 Special precautions for storage

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.

6.5 Nature and contents of container

Bottle (clear Type I glass) with an attached metering pump incorporating an audible dose counter and

lock, and a protective cap. Packed in a clam-shell-like child resistant container.

Each bottle contains 1.55 ml ensuring delivery of 8 sprays.

Bottles in their child resistant containers are supplied in cartons containing 1, 4 or 12 bottles.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal

As soon as PecFent is no longer needed, patients and members of their household must be advised to

systematically dispose of any bottles remaining from a prescription as soon as possible by returning

them to their child-resistant container and discarding them, according to local requirements or by

returning them to the pharmacy.

14

7.

MARKETING AUTHORISATION HOLDER

Archimedes Development Ltd

Nottingham

NG7 2TN

United Kingdom

8.

MARKETING AUTHORISATION NUMBER(S)

EU/1/10/644/001

EU/1/10/644/002

EU/1/10/644/005

9.

DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 31 August 2010

10. DATE OF REVISION OF THE TEXT

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

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

15

1.

NAME OF THE MEDICINAL PRODUCT

PecFent 400 micrograms/spray nasal spray solution

2.

QUALITATIVE AND QUANTITATIVE COMPOSITION

Each ml of solution contains 4,000 micrograms fentanyl (as citrate)

1 spray (100 microliters) contains 400 micrograms fentanyl (as citrate)

Each bottle contains 1.55 ml (6.20 mg fentanyl) ensuring delivery of 8 sprays of 400 micrograms

Excipients

Each spray contains 0.02 mg propylhydroxybenzoate (E216).

For a full list of excipients, see section 6.1.

3.

PHARMACEUTICAL FORM

Nasal spray, solution (nasal spray)

A clear to practically clear colourless aqueous solution.

4.

CLINICAL PARTICULARS

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.

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 dose strength (either 100 microgram

or 400 microgram strength).

16