Abstral 100 mikrogram Resoriblett, sublingual

Sverige - svenska - Läkemedelsverket (Medical Products Agency)

Produktens egenskaper Produktens egenskaper (SPC)

15-08-2019

Aktiva substanser:
fentanylcitrat
Tillgänglig från:
Orifarm AB
ATC-kod:
N02AB03
INN (International namn):
fentanyl citrate
Dos:
100 mikrogram
Läkemedelsform:
Resoriblett, sublingual
Sammansättning:
mannitol Hjälpämne; fentanylcitrat 157,1 mikrog Aktiv substans
Receptbelagda typ:
Receptbelagt
Bemyndigande status:
Avregistrerad
Godkännandenummer:
56731
Tillstånd datum:
2018-05-23

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SUMMARY OF PRODUCT CHARACTERISTICS

1.

NAME OF THE MEDICINAL PRODUCT

Abstral 100 microgram sublingual tablets

Abstral 200 microgram sublingual tablets

Abstral 300 microgram sublingual tablets

Abstral 400 microgram sublingual tablets

Abstral 600 microgram sublingual tablets

Abstral 800 microgram sublingual tablets

2.

QUALITATIVE AND QUANTITATIVE COMPOSITION

Each sublingual tablet contains:

100 micrograms fentanyl (as citrate)

200 micrograms fentanyl (as citrate)

300 micrograms fentanyl (as citrate)

400 micrograms fentanyl (as citrate)

600 micrograms fentanyl (as citrate)

800 micrograms fentanyl (as citrate)

For the full list of excipients, see section 6.1.

3.

PHARMACEUTICAL FORM

Sublingual tablet

100 microgram sublingual tablet is a white round tablet

200 microgram sublingual tablet is a white oval-shaped tablet

300 microgram sublingual tablet is a white triangle-shaped tablet

400 microgram sublingual tablet is a white diamond-shaped tablet

600 microgram sublingual tablet is a white “D”-shaped tablet

800 microgram sublingual tablet is a white capsule-shaped tablet

4.

CLINICAL PARTICULARS

4.1

Therapeutic indications

Management of breakthrough pain in adult patients using opioid therapy for chronic cancer pain.

Breakthrough pain is a transient exacerbation of otherwise controlled chronic background pain.

4.2

Posology and method of administration

Abstral should only be administered to patients who are considered tolerant to their opioid therapy for

persistent cancer pain. Patients can be considered opioid tolerant if they take 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.

Method of administration:

Abstral sublingual tablets should be administered directly under the tongue at the deepest part. Abstral

sublingual tablets should not be swallowed, but allowed to completely dissolve in the sublingual

cavity without chewing or sucking. Patients should be advised not to eat or drink anything until the

sublingual tablet is completely dissolved.

In patients who have a dry mouth water may be used to moisten the buccal mucosa before taking

Abstral.

Dose titration:

The object of dose titration is to identify an optimal maintenance dose for ongoing treatment of

breakthrough pain episodes. This optimal dose should provide adequate analgesia with an acceptable

level of adverse reactions.

The optimal dose of Abstral will be determined by upward titration, on an individual patient basis.

Several doses are available for use during the dose titration phase. The initial dose of Abstral used

should be 100 micrograms, titrating upwards as necessary through the range of available dosage

strengths.

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

Switching from other fentanyl containing products to Abstral must not occur at a 1:1 ratio because of

different absorption profiles. If patients are switched from another fentanyl containing product, a new

dose titration with Abstral is required.

The following dose regimen is recommended for titration, although in all cases the physician should

take into account the clinical need of the patient, age and concomitant illness.

All patients must start therapy with a single 100 microgram sublingual tablet. If adequate analgesia is

not obtained within 15-30 minutes of administration of a single sublingual tablet, a supplemental

(second) 100 microgram sublingual tablet may be administered. If adequate analgesia is not obtained

within 15-30 minutes of the first dose an increase in dose to the next highest tablet strength should be

considered for the next episode of breakthrough pain (Refer to figure below).

Dose escalation should continue in a stepwise manner until adequate analgesia with tolerable adverse

reactions is achieved. The dose strength for the supplemental (second) sublingual tablet should be

increased from 100 to 200 micrograms at doses of 400 micrograms and higher. This is illustrated in

the schedule below. No more than two (2) doses should be administered for a single episode of

breakthrough pain during this titration phase.

ABSTRAL TITRATION PROCESS

Strength (micrograms) of first sublingual

tablet per episode of breakthrough pain

Strength (micrograms) of supplemental

(second) sublingual tablet to be taken 15-30

minutes after first tablet, if required

If adequate analgesia is achieved at the higher dose, but undesirable effects are considered

unacceptable, an intermediate dose (using the 100 microgram sublingual tablet where appropriate)

may be administered.

During titration, patients can be instructed to use multiples of 100 microgram tablets and/or 200

microgram tablets for any single dose. No more than four (4) tablets should be used at any one time.

The efficacy and safety of doses higher than 800 micrograms have not been evaluated in clinical

studies in patients.

In order to minimise the risk of opioid–related adverse reactions and to identify the appropriate dose, it

is imperative that patients be monitored closely by health professionals during the titration process.

During titration patients should wait at least 2 hours before treating another episode of breakthrough

pain with Abstral.

Starting dose

100 µg

Adequate pain relief achieved within 15-30 minutes?

Yes

No

Take a second tablet

(See table to determine strength

of second tablet)

Increase first tablet to next

higher strength for next

breakthrough pain episode

Use this dose for

subsequent breakthrough

pain episodes

Maintenance therapy:

Once an appropriate dose has been established, which may be more than one tablet, patients should be

maintained on this dose and should limit consumption to a maximum of four Abstral doses per day.

During the maintenance period patients should wait at least 2 hours before treating another episode of

breakthrough pain with Abstral.

Dose re-adjustment:

If the response (analgesia or adverse reactions) to the titrated Abstral dose markedly changes, an

adjustment of dose may be necessary to ensure that an optimal dose is maintained.

If more than four episodes of breakthrough pain are experienced per day over a period of more than

four consecutive days, then the dose of the long acting opioid used for persistent pain should be re-

evaluated. If the long acting opioid or dose of long acting opioid is changed the Abstral dose should be

re-evaluated and re-titrated as necessary to ensure the patient is on an optimal dose.

It is imperative that any dose re-titration of any analgesic is monitored by a health professional.

In absence of adequate pain control, the possibility of hyperalgesia, tolerance and progression of

underlying disease should be considered (see section 4.4).

Discontinuation of therapy:

Abstral should be discontinued immediately if the patient no longer experiences breakthrough pain

episodes. The treatment for the persistent background pain should be kept as prescribed.

If discontinuation of all opioid therapy is required, the patient must be closely followed by the doctor

in order to avoid the possibility of abrupt withdrawal effects

.

Use in children and adolescents:

Abstral must not be used in patients less than 18 years of age due to a lack of data on safety and

efficacy.

Use in older people:

Dose titration needs to be approached with particular care and patients observed carefully for signs of

fentanyl toxicity (see section 4.4).

Use in patients with renal and hepatic impairment

Patients with kidney or liver dysfunction should be carefully observed for signs of fentanyl toxicity

during the Abstral titration phase (see section 4.4).

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

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

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

Due to the potentially serious undesirable effects that can occur when taking an opioid therapy such as

Abstral, patients and their carers should be made fully aware of the importance of taking Abstral

correctly and what action to take should symptoms of overdose occur.

Before Abstral therapy is initiated, it is important that the patient’s long-acting opioid treatment used

to control their persistent pain has been stabilised.

Opioid Use Disorder (abuse and dependence)

Tolerance and physical and/or psychological dependence may develop upon repeated administration

of opioids such as fentanyl. Iatrogenic addiction following therapeutic use of opioids is known to

occur.

Repeated use of Abstral may lead to Opioid Use Disorder (OUD). Abuse or intentional misuse of

Abstral 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).

Patients will require monitoring for signs of drug-seeking behaviour (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.

Respiratory Depression

In common with all opioids, there is a risk of clinically significant respiratory depression associated

with the use of Abstral. Particular caution should be exercised during dose titration with Abstral in

patients with chronic obstructive pulmonary disease or other medical conditions predisposing them to

respiratory depression (e.g. myasthenia gravis) because of the risk of further respiratory depression,

which could lead to respiratory failure.

Increased intracranial pressure

Abstral should only be administered with extreme caution in patients who may be particularly

susceptible to the intracranial effects of hyperkapnia, such as those showing evidence of raised

intracranial pressure, reduced consciousness, coma or brain tumours. In patients with head injuries, the

clinical course may be masked by the use of opioids. In such a case, opioids should be used only if

absolutely necessary.

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.

Cardiac disease

Fentanyl may produce bradycardia. Fentanyl should be used with caution in patients with previous or

pre-existing bradyarrhythmias.

Elderly, cachectic or debilitated population

Data from intravenous studies with fentanyl suggest that older patients may have reduced clearance, a

prolonged half-life and they may be more sensitive to the active substance than younger patients.

Older, cachectic, or debilitated patients should be observed carefully for signs of fentanyl toxicity and

the dose reduced if necessary.

Impaired hepatic or renal function

Abstral should be administered with caution to patients with liver or kidney dysfunction, especially

during the titration phase. The use of Abstral in patients with hepatic or renal impairment may increase

the bioavailability of fentanyl and decrease its systemic clearance, which could lead to accumulation

and increased and prolonged opioid effects.

Hypovolaemia and hypotension

Care should be taken in treating patients with hypovolaemia and hypotension.

Use in patients with mouth wounds or mucositis

Abstral has not been studied in patients with mouth wounds or mucositis. There may be a risk of

increased systemic drug exposure in such patients and therefore extra caution is recommended during

dose titration.

Abstral withdrawal

There should be no noticeable effects on cessation of treatment with Abstral, but possible symptoms of

withdrawal are anxiety, tremor, sweating, paleness, nausea and vomiting.

Serotonin Syndrome

Caution is advised when Abstral is co-administered with drugs that affect the serotoninergic

neurotransmitter systems.

The development of a potentially life-threatening serotonin syndrome may occur with the concomitant

use of serotonergic drugs such as Selective Serotonin Re-uptake Inhibitors (SSRIs) and Serotonin

Norepinephrine Re-uptake Inhibitors (SNRIs), and with drugs which impair metabolism of serotonin

(including Monoamine Oxidase Inhibitors [MAOIs]). This may occur within the recommended dose.

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 Abstral should be discontinued.

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.

Risk from concomitant use of sedative medicines such as benzodiazepines or related drugs

Concomitant use of Abstral 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 Abstral 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).

Abstral contains sodium

This medicine contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially ‘sodium-

free’.

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). Treatment with sodium oxybate should be discontinued before start of treatment with

Abstral.

Fentanyl is metabolised by CYP3A4. Active substances that inhibit CYP3A4 activity such as

macrolide antibiotics (e.g. erythromycin), azole antifungal agents (e.g. ketoconazole, itraconazole) or

certain protease inhibitors (e.g. ritonavir) may increase the bioavailability of fentanyl by decreasing its

systemic clearance, potentially enhancing or prolonging opioid effects. Grapefruit juice is also known

to inhibit CYP3A4. Coadministration with agents that induce CYP3A4 activity such as

antimycobacterials (e.g. rifampin, rifabutin), anticonvulsants (e.g. carbamazepine, phenytoin, and

phenobarbital), herbal products (e.g. St John’s wort (Hypericum perforatum)) may reduce the efficacy

of fentanyl. CYP3A4 inducers exert their effect in a time-dependent manner, and may take at least 2

weeks to reach maximal effect after introduction. Conversely, on discontinuation, CYP3A4 induction

may take at least 2 weeks to decline. Patients receiving fentanyl who stop therapy with, or decrease the

dose of CYP3A4 inducers, may be at risk of increased fentanyl activity or toxicity. Fentanyl should

therefore be given to patients with caution if administered concomitantly with CYP3A4 inhibitors

and/or inducers.

Concomitant use of other CNS depressants, such as other morphine derivatives (analgesics and

antitussives), general anaesthetics, skeletal muscle relaxants, sedative antidepressants, sedative H1

antihistamines, barbiturates, anxiolytics (i.e., benzodiazepines), hypnotics, antipsychotics, clonidine

and related substances may produce increased CNS depressant effects, increased risk of sedation,

respiratory depression, hypotension, coma and death because of additive CNS depressant effect. The

dose and duration of concomitant use should be limited (see section 4.4)..

Alcohol potentiates the sedative effects of morphine-based analgesics, therefore concomitant

administration of alcoholic beverages or medicinal products containing alcohol with Abstral is not

recommended.

Abstral is not recommended for use in patients who have received monoamine oxidase (MAO)

inhibitors within 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.

Serotoninergic Drugs

Co-administration of fentanyl with a serotoninergic agent, such as a Selective Serotonin Re-uptake

Inhibitor (SSRI) or a Serotonin Norepinephrine Re-uptake Inhibitor (SNRI) or a Monoamine Oxidase

Inhibitor (MAOI), may increase the risk of serotonin syndrome, a potentially life-threatening

condition.

4.6

Fertility, pregnancy and lactation

The safety of fentanyl in pregnancy has not been established. Studies in animals have shown

reproductive toxicity, with impaired fertility in rats (see section 5.3). The potential risk for humans is

unknown. Fentanyl should only be used during pregnancy when clearly necessary.

Long-term treatment during pregnancy may cause withdrawal symptoms in the new-born infant.

Fentanyl should not be used during labour and delivery (including caesarean section) since fentanyl

crosses the placenta and may cause respiratory depression in the foetus or in the new-born infant.

Breast-feeding

Fentanyl passes into breast milk and may cause sedation and respiratory depression in the breast-fed

child. Fentanyl should not be used by breastfeeding women and breastfeeding should not be restarted

until at least 5 days after the last administration of fentanyl.

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 with Abstral.

However, opioid analgesics are known to impair the mental or physical ability to perform potentially

hazardous tasks such as driving or operating machinery. Patients should be advised not to drive or

operate machinery if they become dizzy or drowsy or experience blurred or double vision while taking

Abstral.

4.8

Undesirable effects

Undesirable effects typical of opioids are to be expected with Abstral; they tend to decrease in

intensity with continued use. The most serious potential adverse reactions associated with opioid use

are respiratory depression (which could lead to respiratory arrest), hypotension and shock.

The clinical trials of Abstral were designed to evaluate safety and efficacy in treating patients with

breakthrough cancer pain; all patients were taking concomitant opioids, such as sustained-release

morphine, sustained-release oxycodone or transdermal fentanyl, for their persistent pain. Therefore, it

is not possible to definitively separate the effects of Abstral alone.

The most frequently observed adverse reactions with Abstral include typical opioid adverse reactions,

such as nausea, constipation, somnolence and headache.

Tabulated Summary of Adverse Reactions with Abstral and/or other fentanyl-containing compounds:

The following adverse reactions have been reported with Abstral

and/or other fentanyl-containing

compounds

during clinical studies and from post-marketing experience. They are listed below by

system organ class and frequency (very common

1/10; common

1/100 to < 1/10; uncommon

1/1,000 to <1/100; not known (cannot be estimated from available data)). Within each frequency

grouping, undesirable effects are presented in order of decreasing seriousness.

System Organ Class

Adverse Reaction by Frequency

Very common

1/10

Common

1/100 to < 1/10

Uncommon

1/1,000 to <1/100

Not known (cannot

be estimated from

available data)

Immune system

disorders

Hypersensitivity

Metabolism and

nutrition disorders

Anorexia

Decreased appetite

Psychiatric disorders

Depression

Paranoia

Confusional state

Disorientation

Mental status changes

Anxiety

Euphoric mood

Dysphoria

Emotional lability

Disturbance in attention

Insomnia

Hallucination

Drug dependence

(addiction)

Drug abuse

Delirium

System Organ Class

Adverse Reaction by Frequency

Very common

1/10

Common

1/100 to < 1/10

Uncommon

1/1,000 to <1/100

Not known (cannot

be estimated from

available data)

Nervous system

disorders

Dizziness

Headache

Somnolence

Amnesia

Parosmia

Dysgeusia

Tremor

Lethargy

Hypoaesthesia

Sleep disorder

Convulsion

Depressed level of

consciousness

Loss of

consciousness

Eye disorders

Vision blurred

Cardiac disorders

Tachycardia

Bradycardia

Vascular disorders

Hypotension

Respiratory,

thoracic and

mediastinal

disorders

Dyspnoea

Oropharyngeal pain

Throat tightness

Respiratory

depression

Gastrointestinal

disorders

Nausea

Stomatitis

Vomiting

Constipation

Dry mouth

Mouth ulceration

Gingival ulceration

Lip ulceration

Impaired gastric emptying

Abdominal pain

Dyspepsia

Stomach discomfort

Tongue disorder

Aphthous stomatitis

Swollen tongue

Diarrhoea

Skin and

subcutaneous tissue

disorders

Hyperhidrosis

Skin lesion

Rash

Pruritus allergic

Pruritus

Night sweats

Increased tendency to

bruise

Urticaria

Musculoskeletal and

connective tissue

disorders

Arthralgia

Musculoskeletal stiffness

Joint stiffness

Reproductive system

and breast disorders

Erectile dysfunction

General disorders

and administration

site conditions

Fatigue

*Drug withdrawal

syndrome

Asthenia

Malaise

Flushing

flush

Peripheral oedema

Pyrexia

Neonatal

withdrawal

syndrome

Injury, poisoning

and procedural

complications

Accidental overdose

Fall

opioid withdrawal symptoms such as nausea, vomiting, diarrhoea, anxiety, chills, tremor, and sweating have

been observed with transmucosal fentanyl

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 the national reporting system

listed below:

To be completed nationally

4.9

Overdose

The symptoms of fentanyl overdose are an extension of its pharmacological actions, the most serious

effect being respiratory depression, which may lead to respiratory arrest. Coma is also known to occur.

Management of opioid overdose in the immediate term includes removal of any remaining Abstral

sublingual tablets from the mouth, physical and verbal stimulation of the patient and an assessment of

the level of consciousness. A patent airway should be established and maintained. If necessary, an

oropharyngeal airway or endotracheal tube should be inserted, oxygen administered and mechanical

ventilation initiated, as appropriate. Adequate body temperature and parenteral fluid intake should be

maintained.

For the treatment of accidental overdose in opioid-naïve individuals, naloxone or other opioid

antagonists should be used as clinically indicated and in accordance with their Summary of Product

Characteristics. Repeated administration of the opioid antagonist may be necessary if the duration of

respiratory depression is prolonged.

Care should be taken when using naloxone or other opioid antagonists to treat overdose in opioid-

maintained patients, due to the risk of precipitating an acute withdrawal syndrome.

If severe or persistent hypotension occurs, hypovolaemia should be considered, and the condition

should be managed with appropriate parenteral fluid therapy.

Muscle rigidity interfering with respiration has been reported with fentanyl and other opioids. In this

situation, endotracheal intubation, assisted ventilation and administration of opioid antagonists as well

as muscle relaxants may be requested.

Cases of Cheyne Stokes respiration have been observed in case of fentanyl overdose, particularly in

patients with history of heart failure.

5.

PHARMACOLOGICAL PROPERTIES

5.1

Pharmacodynamic properties

Pharmacotherapeutic group: Analgesics; Opioids; Phenylpiperidine derivatives.

ATC code: N02AB03

Fentanyl is a potent µ-opioid analgesic with rapid onset of analgesia and short duration of action.

Fentanyl is approximately 100-fold more potent than morphine as an analgesic. Secondary effects of

fentanyl on central nervous system (CNS), respiratory and gastro-intestinal function are typical of

opioid analgesics and are considered to be class effects. These can include respiratory depression,

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

Opioids may influence the hypothalamic-pituitary-adrenal or –gonadal axes. Some changes that can be

seen include an increase in serum prolactin, and decreases in plasma cortisol and testosterone. Clinical

signs and symptoms may be manifest from these hormonal changes.

The analgesic effects of fentanyl are related to the blood level of the active substance; in opioid-naïve

patients, minimum effective analgesic serum concentrations of fentanyl range from 0.3-1.2 ng/ml,

while blood levels of 10-20 ng/ml produce surgical anaesthesia and profound respiratory depression.

In patients with chronic cancer pain on stable maintenance doses of opioids, statistically significant

improvement in pain intensity difference was seen with Abstral versus placebo from 10 minutes after

administration onwards (see figure 1 below) , with a significantly lower need for rescue analgesic

therapy.

Figure 1 Mean Pain Intensity Difference from baseline (± SE) for Abstral Compared with Placebo

(measured by a 0-10 Lickert scale)

The safety and efficacy of Abstral have been evaluated in patients taking the drug at the onset of the

breakthrough pain episode. Preemptive use of Abstral for predictable pain episodes was not

investigated in the clinical trials.

Fentanyl, in common with all µ-opioid receptor agonists, produces dose dependent respiratory

depression. This risk is higher in opioid-naïve subjects than in patients experiencing severe pain or

receiving chronic opioid therapy. Long-term treatment with opioids typically leads to development of

tolerance to their secondary effects.

While opioids generally increase the tone of urinary tract smooth muscle, the net effect tends to be

variable, in some cases producing urinary urgency, in others, difficulty in urination.

Opioids increase the tone and decrease the propulsive contractions of the smooth muscle of the

gastrointestinal tract leading to a prolongation in gastrointestinal transit time, which may be

responsible for the constipating effect of fentanyl.

5.2

Pharmacokinetic properties

Fentanyl is a highly lipophilic drug absorbed very rapidly through the oral mucosa and more slowly

through the gastrointestinal tract. Orally administered fentanyl undergoes pronounced hepatic and

intestinal first pass effects.

Abstral is a quick dissolving sublingual tablet formulation. Rapid absorption of fentanyl occurs over

about 30 minutes following administration of Abstral. The absolute bioavailability of Abstral has been

Mean Pain Intensity Difference

Time (min)

Placebo

Abstral

P=0.0004

P=0.0002

P=0.0011

P=0.0055

Mean Pain Intensity Difference

calculated to be 54 %. Mean maximal plasma concentrations of fentanyl range from 0.2 to 1.3 ng/ml

(after administration of 100 to 800 µg Abstral) and are reached within 22.5 to 240 minutes.

About 80-85% of fentanyl is bound by plasma proteins, mainly

1-glycoprotein and to a lesser extent

albumin and lipoprotein. The volume of distribution of fentanyl at steady state is about 3-6 l/kg.

Fentanyl is metabolised primarily via CYP3A4 to a number of pharmacologically inactive metabolites,

including norfentanyl. Within 72 hours of intravenous fentanyl administration around 75% of the dose

is excreted into the urine, mostly as metabolites, with less than 10% as unchanged drug. About 9% of

the dose is recovered in the faeces, primarily as metabolites. Total plasma clearance of fentanyl is

about 0.5 l/h/kg.

After Abstral administration, the main elimination half-life of fentanyl is about 7 hours (range 3-12.5

hours) and the terminal half-life is about 20 hours (range 11.5-25 hours).

The pharmacokinetics of Abstral have been shown to be dose proportional over the dose range of 100

to 800 µg. Pharmacokinetic studies have shown that multiple tablets are bioequivalent to single tablets

of the equivalent dose.

Renal/hepatic impairment

Impaired hepatic or renal function could cause increased serum concentrations. Older, cachectic or

generally impaired patients may have a lower fentanyl clearance, which could cause a longer terminal

half-life for the compound (see sections 4.2 and 4.4).

5.3

Preclinical safety data

Safety pharmacology and repeated dose toxicity data reveal no special hazard for humans that is not

already covered by other sections of this SPC. Animal studies have shown reduced fertility and

increased mortality in rat foetuses. Teratogenic effects have, however, not been demonstrated.

Mutagenicity testing in bacteria and in rodents yielded negative results. Like other opioids fentanyl

showed mutagenic effects

in vitro

in mammalian cells. A mutagenic risk with therapeutic use seems

unlikely since effects were induced only at very high concentrations.

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

subcutaneous carcinogenicity study in rats) with fentanyl did not reveal any findings indicative of

oncogenic potential. Evaluation of brain slides from the carcinogenicity study in rats revealed brain

lesions in animals administered high doses of fentanyl citrate. The relevance of these findings to

humans is unknown.

6.

PHARMACEUTICAL PARTICULARS

6.1

List of excipients

Mannitol (E421)

Silicified microcrystalline cellulose

Croscarmellose sodium

Magnesium stearate

6.2

Incompatibilities

Not applicable.

6.3

Shelf life

2 years

6.4

Special precautions for storage

Do not store above 25°C.

Store in the original blister package in order to protect from moisture.

6.5

Nature and contents of container

Abstral sublingual tablets are packaged in child resistant blisters of OPA/Aluminium/PVC pockets

with paper/polyester/Aluminium lidding contained in a cardboard outer carton. The packaging is

colour-coded for each Abstral sublingual tablet strength.

Pack size: Packs of 10 or 30 sublingual tablets. Not all pack sizes may be marketed.

6.6

Special precautions for disposal

Waste material should be disposed of safely. Patients/carers should be encouraged to return any

unused product to the Pharmacy, where it should be disposed of in accordance with national and local

requirements.

7.

MARKETING AUTHORISATION HOLDER

To be completed nationally

8.

MARKETING AUTHORISATION NUMBER(S)

To be completed nationally

9.

DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 29-02-2008

Date of latest renewal: 28-02-2013

10.

DATE OF REVISION OF THE TEXT

27 May 2021

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