Abstral 200 microgram sublingual tablets
Clinical detailsFour.1 Therapeutic symptoms
Management of breakthrough pain in adult patients the usage of opioid remedy for continual cancer pain. Breakthrough ache is a temporary exacerbation of otherwise managed continual history pain.
4.2 Posology and method of administration
Abstral should only be administered to patients who're considered tolerant to their opioid remedy for continual most cancers ache. Patients can be considered opioid tolerant in the event that they take at the least 60 mg of oral morphine daily, as a minimum 25 micrograms of transdermal fentanyl in step with hour, as a minimum 30 mg of oxycodone each day, at the least 8 mg of oral hydromorphone each day or an equianalgesic dose of every other opioid for every week or longer.
Method of administration:
Abstral sublingual capsules should be administered directly below the tongue on the private element. Abstral sublingual tablets ought to now not be swallowed, but allowed to absolutely dissolve in the sublingual hollow space without chewing or sucking. Patients must be suggested no longer to devour or drink something until the sublingual pill is absolutely dissolved.
In sufferers who've a dry mouth water can be used to moisten the buccal mucosa before taking Abstral.
Dose titration:
The object of dose titration is to perceive an optimal maintenance dose for ongoing treatment of leap forward pain episodes. This most suitable dose need to offer ok analgesia with a suitable degree of unfavourable reactions.
The top-rated dose of Abstral will be decided by way of upward titration, on an character patient foundation. Several doses are to be had for use during the dose titration segment. The initial dose of Abstral used have to be one hundred micrograms, titrating upwards as necessary through the variety of available dosage strengths.
Patients ought to be cautiously monitored until an surest dose is reached.
Switching from different fentanyl containing products to Abstral need to now not occur at a 1:1 ratio due to distinctive absorption profiles. If patients are switched from another fentanyl containing product, a new dose titration with Abstral is needed.
The following dose regimen is usually recommended for titration, despite the fact that in all instances the doctor should don't forget the scientific need of the patient, age and concomitant illness.
All patients should begin remedy with a unmarried one hundred microgram sublingual pill. If good enough analgesia is not received within 15-30 minutes of administration of a single sublingual tablet, a supplemental (second) 100 microgram sublingual tablet may be administered. If ok analgesia is not acquired within 15-30 minutes of the primary dose an boom in dose to the following maximum tablet electricity need to be taken into consideration for the subsequent episode of breakthrough ache (Refer to discern underneath).
Dose escalation have to maintain in a stepwise manner until good enough analgesia with tolerable detrimental reactions is accomplished. The dose electricity for the supplemental (second) sublingual pill need to be expanded from one hundred to 2 hundred micrograms at doses of four hundred micrograms and better. This is illustrated in the agenda below. No more than two (2) doses need to be administered for a unmarried episode of breakthrough ache for the duration of this titration phase.
Strength (micrograms) of first sublingual tablet in keeping with episode of step forward pain
Strength (micrograms) of supplemental (2nd) sublingual tablet to be taken 15-30 minutes after first pill, if required
A hundred
One hundred
200
One hundred
300
One hundred
Four hundred
2 hundred
Six hundred
2 hundred
800
-
If adequate analgesia is executed on the higher dose, but undesirable results are considered unacceptable, an intermediate dose (using the one hundred microgram sublingual tablet in which suitable) may be administered.
During titration, sufferers can be instructed to use multiples of one hundred microgram drugs and/or 200 microgram capsules for any single dose. No greater than four (4) tablets need to be used at any one time.
The efficacy and safety of doses better than 800 micrograms have not been evaluated in medical studies in sufferers.
In order to minimise the danger of opioid–associated unfavorable reactions and to discover an appropriate dose, it is imperative that sufferers be monitored carefully by health specialists during the titration system.
During titration sufferers should wait at the least 2 hours before treating every other episode of step forward pain with Abstral.
Maintenance therapy:
Once the ideal dose has been established, which may be more than one pill, sufferers ought to be maintained in this dose and should limit intake to a maximum of 4 Abstral doses per day.
During the preservation duration patients need to wait at least 2 hours before treating every other episode of leap forward pain with Abstral.
Dose re-adjustment:
If the reaction (analgesia or adverse reactions) to the titrated Abstral dose markedly adjustments, an adjustment of dose may be necessary to ensure that an highest quality dose is maintained.
If greater than four episodes of breakthrough pain are experienced in step with day over a period of extra than 4 consecutive days, then the dose of the long performing opioid used for continual pain need to be re-evaluated. If the lengthy appearing opioid or dose of lengthy performing opioid is modified the Abstral dose need to be re-evaluated and re-titrated as important to ensure the affected person is on an premiere dose.
It is imperative that any dose re-titration of any analgesic is monitored by way of a health expert.
In absence of adequate pain manipulate, the possibility of hyperalgesia, tolerance and progression of underlying disorder should be considered (see segment 4.4).
Discontinuation of therapy:
Abstral must be discontinued right away if the patient now not studies leap forward pain episodes. The remedy for the continual heritage pain should be kept as prescribed.
If discontinuation of all opioid therapy is required, the patient ought to be closely followed via the doctor for you to keep away from the opportunity of abrupt withdrawal consequences.
Use in children and youth:
Abstral need to not be utilized in sufferers much less than 18 years of age due to a loss of records on protection and efficacy.
Use in older people:
Dose titration needs to be approached with particular care and patients found carefully for signs of fentanyl toxicity (see section four.Four).
Use in sufferers with renal and hepatic impairment
Patients with kidney or liver disorder must be carefully located for symptoms of fentanyl toxicity in the course of the Abstral titration section (see section four.Four).
4.3 Contraindications
Hypersensitivity to the active substance or to any of the excipients listed in phase 6.1.
Patients without maintenance opioid therapy as there may be an increased threat of breathing melancholy.
Severe respiratory melancholy or intense obstructive lung conditions.
Treatment of acute pain aside from step forward ache.
Four.Four Special warnings and precautions for use
Patients and their carers need to be informed that Abstral includes an active substance in an amount that can be deadly to a toddler, and consequently to preserve all pills out of the reach and sight of children.
Due to the doubtlessly extreme undesirable outcomes that can arise whilst taking an opioid remedy including Abstral, sufferers and their carers must be made absolutely aware of the importance of taking Abstral efficaciously and what action to take need to signs of overdose occur.
Before Abstral therapy is initiated, it is crucial that the affected person's lengthy-performing opioid remedy used to govern their chronic ache has been stabilised.
Upon repeated management of opioids consisting of fentanyl, tolerance and bodily and/or mental dependence may expand. Iatrogenic addiction following therapeutic use of opioids is understood to arise.
In commonplace with all opioids, there is a chance of clinically good sized respiratory melancholy associated with the use of Abstral. Particular caution have to be exercised in the course of dose titration with Abstral in patients with persistent obstructive pulmonary disease or other medical situations predisposing them to respiration melancholy (e.G. Myasthenia gravis) because of the danger of in addition breathing despair, that could cause respiration failure.
Abstral must most effective be administered with excessive caution in patients who can be specifically prone to the intracranial effects of hyperkapnia, along with the ones displaying evidence of raised intracranial strain, decreased recognition, coma or brain tumours. In patients with head injuries, the scientific route can be masked by way of the use of opioids. In this kind of case, opioids ought to be used simplest if virtually essential.
As with other opioids, in case of insufficient pain manipulate in reaction to an elevated dose of fentanyl, the possibility of opioid-brought about hyperalgesia ought to be taken into consideration. A fentanyl dose reduction or discontinuation of fentanyl treatment or treatment assessment can be indicated.
Cardiac disorder
Fentanyl may also produce bradycardia. Fentanyl have to be used with caution in patients with preceding or pre-present bradyarrhythmias.
Data from intravenous studies with fentanyl suggest that older sufferers may have reduced clearance, a extended half-life and they may be extra touchy to the lively substance than younger patients. Older, cachectic, or debilitated sufferers have to be observed carefully for signs and symptoms of fentanyl toxicity and the dose reduced if vital.
Abstral ought to be administered with warning to patients with liver or kidney dysfunction, in particular throughout the titration section. The use of Abstral in sufferers with hepatic or renal impairment may additionally increase the bioavailability of fentanyl and decrease its systemic clearance, which could cause accumulation and improved and prolonged opioid outcomes.
Care have to be taken in treating sufferers with hypovolaemia and hypotension.
Abstral has now not been studied in sufferers with mouth wounds or mucositis. There may be a threat of expanded systemic drug publicity in such sufferers and therefore extra warning is usually recommended in the course of dose titration.
There should be no major outcomes on cessation of treatment with Abstral, however viable symptoms of withdrawal are anxiety, tremor, sweating, paleness, nausea and vomiting.
Serotonin Syndrome
• Caution is counseled whilst Abstral is co-administered with pills that have an effect on the serotoninergic neurotransmitter structures.
The improvement of a probably lifestyles-threatening serotonin syndrome can also occur with the concomitant use of serotonergic capsules inclusive of Selective Serotonin Re-uptake Inhibitors (SSRIs) and Serotonin Norepinephrine Re-uptake Inhibitors (SNRIs), and with capsules which impair metabolism of serotonin (inclusive of Monoamine Oxidase Inhibitors [MAOIs]). This may additionally arise in the endorsed dose.
Serotonin syndrome might also encompass mental-reputation changes (e.G., agitation, hallucinations, coma), autonomic instability (e.G., tachycardia, labile blood stress, hyperthermia), neuromuscular abnormalities (e.G., hyperreflexia, incoordination, stress), and/or gastrointestinal symptoms (e.G., nausea, vomiting, diarrhoea).
If serotonin syndrome is suspected, remedy with Abstral have to be discontinued.
4.Five Interaction with different medicinal products and different forms of interplay
Fentanyl is metabolised by CYP3A4. Active substances that inhibit CYP3A4 interest together with macrolide antibiotics (e.G. Erythromycin), azole antifungal marketers (e.G. Ketoconazole, itraconazole) or certain protease inhibitors (e.G. Ritonavir) may increase the bioavailability of fentanyl by using reducing its systemic clearance, probably enhancing or prolonging opioid effects. Grapefruit juice is also recognized to inhibit CYP3A4. Coadministration with sellers that induce CYP3A4 activity which includes antimycobacterials (e.G. Rifampin, rifabutin), anticonvulsants (e.G. Carbamazepine, phenytoin, and phenobarbital) natural merchandise (e.G. St John's wort, Hypericum perforatum) may reduce the efficacy of fentanyl. CYP3A4 inducers exert their effect in a time-structured manner, and may take at the least 2 weeks to attain maximal impact after introduction. Conversely, on discontinuation, CYP3A4 induction may additionally take at least 2 weeks to say no. Patients receiving fentanyl who prevent therapy with, or decrease the dose of CYP3A4 inducers may be prone to improved fentanyl pastime or toxicity. Fentanyl should therefore accept to sufferers with caution if administered concomitantly with CYP3A4 inhibitors and/or inducers.
Concomitant use of other CNS depressants, along with other morphine derivatives (analgesics and antitussives), trendy anaesthetics, skeletal muscle relaxants, sedative antidepressants, sedative H1 antihistamines, barbiturates, anxiolytics (ie benzodiazepines), hypnotics, antipsychotics, clonidine and associated materials may also produce multiplied CNS depressant consequences. Respiratory despair, hypotension and profound sedation may additionally arise.
Alcohol potentiates the sedative effects of morphine-based analgesics, therefore concomitant management of alcoholic drinks or medicinal products containing alcohol with Abstral is not endorsed.
Abstral is not recommended for use in patients who have acquired monoamine oxidase (MAO) inhibitors inside 14 days due to the fact excessive and unpredictable potentiation with the aid of MAO inhibitors has been said with opioid analgesics.
The concomitant use of partial opioid agonists/antagonists (e.G. Buprenorphine, nalbuphine, pentazocine) is not recommended. They have excessive affinity to opioid receptors with tremendously low intrinsic activity and therefore in part antagonise the analgesic impact of fentanyl and might result in withdrawal signs in opioid dependent patients.
Serotoninergic Drugs
Co-management 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 boom the threat of serotonin syndrome, a potentially lifestyles-threatening condition.
Four.6 Fertility, pregnancy and lactation
The safety of fentanyl in pregnancy has now not been mounted. Studies in animals have shown reproductive toxicity, with impaired fertility in rats (see section five.3). The potential danger for human beings is unknown. Fentanyl should only be used all through pregnancy whilst certainly vital.
Long-term remedy all through pregnancy might also reason withdrawal signs inside the new-born toddler.
Fentanyl must now not be used in the course of labour and delivery (along with caesarean section) because fentanyl crosses the placenta and can reason respiration melancholy inside the foetus or in the new-born infant.
Breast-feeding
Fentanyl passes into breast milk and can purpose sedation and respiratory melancholy inside the breast-fed baby. Fentanyl have to now not be used by breastfeeding ladies and breastfeeding ought to no longer be restarted till at least five days after the remaining management of fentanyl.
Four.7 Effects on ability to force and use machines
No studies at the results on the potential to force and use machines have been accomplished with Abstral.
However, opioid analgesics are recognised to impair the mental or bodily capability to carry out potentially hazardous tasks which include driving or operating equipment. Patients have to be recommended now not to force or operate equipment in the event that they become dizzy or drowsy or enjoy blurred or double vision even as taking Abstral.
This medication can impair cognitive function and can have an effect on a patient's capacity to force properly. This magnificence of medication is inside the listing of medicine covered in rules beneath 5a of the Road Traffic Act 1988. When prescribing this medication, sufferers need to be informed:
• The medicinal drug is likely to affect your ability to drive
• Do no longer drive until you understand how the drugs impacts you
• It is an offence to pressure at the same time as beneath the affect of this medicinal drug
• However, you would now not be committing an offence (referred to as 'statutory defence') if:
O The medicine has been prescribed to deal with a medical or dental hassle and
O You have taken it in keeping with the instructions given through the prescriber and inside the information provided with the medicine and
O It was now not affecting your potential to drive appropriately
4.Eight Undesirable results
Undesirable outcomes common of opioids are to be expected with Abstral; they tend to lower in depth with persisted use. The maximum extreme capacity negative reactions related to opioid use are respiratory depression (that may result in respiratory arrest), hypotension and shock.
The scientific trials of Abstral have been designed to evaluate safety and efficacy in treating sufferers with breakthrough cancer pain; all sufferers were taking concomitant opioids, consisting of sustained-launch morphine, sustained-launch oxycodone or transdermal fentanyl, for their continual ache. Therefore it is not viable to definitively separate the consequences of Abstral alone.
The maximum frequently found adverse reactions with Abstral include normal opioid unfavorable reactions, consisting of nausea, constipation, somnolence and headache.
Tabulated Summary of Adverse Reactions with Abstral and/or other fentanyl-containing compounds:
The following adverse reactions have been suggested with Abstral and/or different fentanyl-containing compounds at some stage in medical research and from submit-advertising and marketing experience. They are listed beneath by means of device organ elegance and frequency (very commonplace ≥ 1/10; commonplace ≥ 1/a hundred to < 1/10; unusual ≥1/1,000 to <1/a hundred; not recognised (can not be predicted from available records)). Within every frequency grouping, unwanted effects are presented so as of decreasing seriousness.
System Organ Class
Adverse Reaction by Frequency
Very not unusual
≥ 1/10
Common
≥ 1/one hundred to < 1/10
Uncommon
≥1/1,000 to <1/a hundred
Not recognised (can not be predicted from available data)
Immune gadget disorders
Hypersensitivity
Metabolism and nutrition problems
Anorexia
Decreased appetite
Psychiatric issues
Depression
Paranoia
Confusional state
Disorientation
Mental status changes
Anxiety
Euphoric mood
Dysphoria
Emotional lability
Disturbance in interest
Insomnia
Hallucination
Drug dependence (addiction)
Drug abuse
Nervous system disorders
Dizziness
Headache
Somnolence
Amnesia
Parosmia
Dysgeusia
Tremor
Lethargy
Hypoaesthesia
Sleep sickness
Convulsion
Depressed level of focus
Loss of cognizance
Eye problems
Vision blurred
Cardiac problems
Tachycardia
Bradycardia
Vascular issues
Hypotension
Respiratory, thoracic and mediastinal issues
Dyspnoea
Oropharyngeal ache
Throat tightness
Respiratory depression
Gastrointestinal issues
Nausea
Stomatitis
Vomiting
Constipation
Dry mouth
Mouth ulceration
Gingival ulceration
Lip ulceration
Impaired gastric emptying
Abdominal pain
Dyspepsia
Stomach soreness
Tongue disease
Aphthous stomatitis
Swollen tongue
Diarrhoea
Skin and subcutaneous tissue issues
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 gadget and breast issues
Erectile dysfunction
General issues and management website conditions
Fatigue
*Drug withdrawal syndrome
Asthenia
Malaise
Flushing and warm flush
Peripheral oedema
Pyrexia
Neonatal withdrawal syndrome
Injury, poisoning and procedural complications
Accidental overdose
Fall
* opioid withdrawal signs which include nausea, vomiting, diarrhoea, tension, chills, tremor, and sweating had been discovered with transmucosal fentanyl
Reporting of suspected adverse reactions
Reporting suspected damaging reactions after authorisation of the medicinal product is essential. It allows persevered monitoring of the benefit/hazard balance of the medicinal product. Healthcare professionals are requested to document any suspected damaging reactions thru Yellow Card Scheme: www.Mhra.Gov.Uk/yellowcard
4.Nine Overdose
The symptoms of fentanyl overdose are an extension of its pharmacological moves, the maximum severe impact being breathing depression, which might also result in breathing arrest. Coma is also known to arise.
Management of opioid overdose within the immediately term includes elimination of any closing Abstral sublingual tablets from the mouth, physical and verbal stimulation of the affected person and an evaluation of the extent of focus. A patent airway should be established and maintained. If important an oropharyngeal airway or endotracheal tube should be inserted, oxygen administered and mechanical air flow initiated, as suitable. Adequate body temperature and parenteral fluid intake should be maintained.
For the treatment of unintentional overdose in opioid-naïve people, naloxone or different opioid antagonists must be used as clinically indicated and according with their Summary of Product Characteristics. Repeated administration of the opioid antagonist may be important if the period of respiration depression is extended.
Care have to be taken while using naloxone or other opioid antagonists to treat overdose in opioid-maintained sufferers, due to the risk of precipitating an acute withdrawal syndrome.
If extreme or persistent hypotension occurs, hypovolaemia ought to be taken into consideration, and the situation must be managed with suitable parenteral fluid therapy.
Muscle stress interfering with breathing has been mentioned with fentanyl and other opioids. In this example, endotracheal intubation, assisted ventilation and management of opioid antagonists as well as muscle relaxants may be requested.
5. Pharmacological properties
Five.1 Pharmacodynamic properties
Pharmacotherapeutic institution: Analgesics; Opioids; Phenylpiperidine derivatives.
ATC code: N02AB03
Fentanyl is a potent µ-opioid analgesic with fast onset of analgesia and short duration of movement. Fentanyl is approximately one hundred-fold stronger than morphine as an analgesic. Secondary effects of fentanyl on central frightened device (CNS), respiratory and gastro-intestinal function are normal of opioid analgesics and are considered to be magnificence results. These can consist of respiratory depression, bradycardia, hypothermia, constipation, miosis, bodily dependence and euphoria.
Opioids can also influence the hypothalamic-pituitary-adrenal or –gonadal axes. Some adjustments that can be seen consist of an boom in serum prolactin, and decreases in plasma cortisol and testosterone. Clinical signs and symptoms may be show up from those hormonal adjustments.
The analgesic effects of fentanyl are associated with the blood stage of the lively substance; in opioid-naïve sufferers, minimum powerful analgesic serum concentrations of fentanyl range from zero.3-1.2 ng/ml, whilst blood levels of 10-20 ng/ml produce surgical anaesthesia and profound respiratory depression.
In sufferers with persistent most cancers pain on strong protection doses of opioids, statistically widespread improvement in pain depth difference became seen with Abstral as opposed to placebo from 10 minutes after management onwards (see figure 1 under), with a appreciably lower need for rescue analgesic therapy.
Figure 1 Mean Pain Intensity Difference from baseline (± SE) for Abstral Compared with Placebo (measured via a 0-10 Likert scale)
The protection and efficacy of Abstral were evaluated in patients taking the drug on the onset of the breakthrough ache episode. Pre-emptive use of Abstral for predictable pain episodes was now not investigated inside the clinical trials.
Fentanyl, in not unusual with all µ-opioid receptor agonists, produces dose based respiration melancholy. This chance is better in opioid-naïve subjects than in patients experiencing intense ache or receiving persistent opioid remedy. Long-time period remedy with opioids normally results in development of tolerance to their secondary effects.
While opioids typically growth the tone of urinary tract easy muscle, the internet effect has a tendency to be variable, in some instances producing urinary urgency, in others, trouble in urination.
Opioids boom the tone and decrease the propulsive contractions of the easy muscle of the gastrointestinal tract main to a prolongation in gastrointestinal transit time, which can be responsible for the constipating effect of fentanyl.
5.2 Pharmacokinetic homes
Fentanyl is a especially lipophilic drug absorbed very hastily via the oral mucosa and greater slowly via the gastrointestinal tract. Orally administered fentanyl undergoes suggested hepatic and intestinal first pass consequences.
Abstral is a brief dissolving sublingual pill components. Rapid absorption of fentanyl happens over about 30 minutes following management of Abstral. The absolute bioavailability of Abstral has been calculated to be fifty four %. Mean maximal plasma concentrations of fentanyl variety from zero.2 to one.Three ng/ml (after management of 100 to 800 µg Abstral) and are reached inside 22.Five to 240 mins.
About eighty-85% of fentanyl is certain by plasma proteins, mainly α1-glycoprotein and to a lesser quantity albumin and lipoprotein. The volume of distribution of fentanyl at constant state is set three-6 l/kg.
Fentanyl is metabolised in most cases via CYP3A4 to some of pharmacologically inactive metabolites, inclusive of norfentanyl. Within 72 hours of intravenous fentanyl administration around 75% of the dose is excreted into the urine, more often than not as metabolites, with much less than 10% as unchanged drug. About 9% of the dose is recovered within the faeces, generally as metabolites. Total plasma clearance of fentanyl is set zero.5 l/h/kg.
After Abstral administration, the main removal 1/2-existence of fentanyl is about 7 hours (range three-12.Five hours) and the terminal half-existence is ready 20 hours (variety 11.5-25 hours).
The pharmacokinetics of Abstral have been proven to be dose proportional over the dose range of one hundred to 800 µg. Pharmacokinetic studies have proven that multiple pills are bioequivalent to single pills of the equivalent dose.
Renal/hepatic impairment
Impaired hepatic or renal feature may want to cause accelerated serum concentrations. Older, cachectic or normally impaired patients may additionally have a lower fentanyl clearance, that may reason a longer terminal half-lifestyles for the compound (see sections 4.2 and 4.Four).
Five.3 Preclinical protection statistics
Safety pharmacology and repeated dose toxicity facts screen no unique chance for humans that isn't always already covered by using different sections of this SPC. Animal studies have proven reduced fertility and elevated mortality in rat foetuses. Teratogenic outcomes have, however, no longer been demonstrated.
Mutagenicity trying out in bacteria and in rodents yielded poor results. Like different opioids fentanyl showed mutagenic consequences in vitro in mammalian cells. A mutagenic risk with healing use seems not likely considering that consequences had been prompted only at very high concentrations.
Carcinogenicity studies (26-week dermal alternative bioassay in Tg.AC transgenic mice; -12 months subcutaneous carcinogenicity have a look at in rats) with fentanyl did not monitor any findings indicative of oncogenic capacity. Evaluation of mind slides from the carcinogenicity have a look at in rats discovered brain lesions in animals administered excessive doses of fentanyl citrate. The relevance of those findings to humans is unknown.
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