ACTIQ 1200 micro grams compressed lozenge with quintessential oromucosal applicator.

ACTIQ 1200 micro grams compressed lozenge with quintessential oromucosal applicator.

2. Qualitative and quantitative composition
One lozenge includes 1200 micrograms fentanyl (as citrate).

Excipient(s) with known impact:

Each lozenge contains dextrates (equivalent to about 2 grams of glucose), sucrose (approximately30 milligrams confectioner's sugar) and propylene glycol (a part of the artificial berry flavour and imprinting ink) as excipients.

For the entire list of excipients, see phase 6.1.

3. Pharmaceutical shape
Compressed lozenge with fundamental oromucosal applicator.

ACTIQ is formulated as a white to off-white compressed powder medicinal product matrix connected using safe to eat glue to a fracture resistant radio opaque plastic applicator. The dosage electricity is marked on the lozenge and on the plastic applicator.

4. Clinical particulars
4.1 Therapeutic symptoms
ACTIQ is indicated for the control of breakthrough ache in patients already receiving preservation opioid therapy for persistent most cancers ache. Breakthrough ache is a transitory exacerbation of ache that occurs on a background of in any other case managed persistent pain.

Patients receiving maintenance opioid therapy are those who are taking at least 60 mg of oral morphine each day, at least 25 micrograms of transdermal fentanyl in line with hour, at least 30 mg of oxycodone every day, at the least 8 mg of oral hydromorphone daily or an equianalgesic dose of every other opioid for a week or longer.

Four.2 Posology and technique of administration
Posology

In order to minimise the dangers of opioid-associated unfavourable reactions and to pick out the “a success” dose, it's far vital that patients be monitored intently by using health experts for the duration of the titration procedure.

ACTIQ isn't interchangeable on a mcg to mcg basis with different short-appearing fentanyl merchandise that are indicated for using step forward cancer pain, as the pharmacokinetic profiles and/or dosing schedules of those merchandise are drastically specific. Patients must be informed now not to use multiple short-appearing fentanyl product concurrently for the remedy of breakthrough cancer ache, and to dispose of any fentanyl product prescribed for step forward ache (BTP) when switching to ACTIQ. The range of ACTIQ strengths to be had to the patient at any time must be minimised to prevent confusion and capability overdose.

Any unused ACTIQ gadgets that the affected person now not requires have to be disposed of properly. Patients have to be reminded of the necessities to keep ACTIQ saved in a vicinity away from youngsters.

Adults

Dose titration and renovation remedy

ACTIQ need to be individually titrated to a “a hit” dose that provides good enough analgesia and minimises unfavorable reactions. In clinical trials the a success dose of ACTIQ for leap forward ache become not anticipated from the daily upkeep dose of opioid.

A) Titration

Before patients are titrated with ACTIQ, it is anticipated that their heritage continual ache could be managed by using use of opioid remedy and that they're normally experiencing no extra than four episodes of step forward ache in keeping with day.

The preliminary dose of ACTIQ used have to be 200 micrograms, titrating upwards as essential thru the range of to be had dosage strengths (two hundred, 400, six hundred, 800, 1,2 hundred and 1,six hundred micrograms). Patients have to be cautiously monitored till a dose is reached that offers adequate analgesia with applicable destructive reactions using a unmarried dosage unit in step with episode of step forward pain. This is defined because the a hit dose.

During titration, if ok analgesia isn't always acquired inside half-hour after beginning the first unit (i.E. 15 minutes after the patient completes consumption of a unmarried ACTIQ unit), a 2nd ACTIQ unit of the identical energy may be fed on. No greater than two ACTIQ devices ought to be used to treat any individual ache episode. At 1600 micrograms, a 2nd dose is handiest in all likelihood to be required by way of a minority of patients.

If remedy of consecutive breakthrough ache episodes requires more than one dosage unit in step with episode, an increase in dose to the following better available strength must be taken into consideration.



B) Maintenance

Once a successful dose has been mounted (i.E., on average, an episode is correctly dealt with with a single unit), sufferers must be maintained on this dose and ought to restriction intake to a maximum of 4 ACTIQ units per day.

Patients should be monitored by way of a health professional to make sure that the maximum consumption of four gadgets of ACTIQ consistent with day isn't handed.

Dose re-adjustment

The renovation dose of ACTIQ must be multiplied while an episode isn't always successfully treated with a single unit for several consecutive BTP episodes. For dose-readjustment the identical ideas follow as outlined for dose titration (see above).

If extra than four episodes of step forward ache are experienced per day the dose of the protection opioid therapy used for persistent pain have to be re-evaluated. If the dose of the preservation opioid remedy is multiplied, the dose of ACTIQ to deal with leap forward ache may additionally need to be reviewed.

In absence of adequate pain manipulate, the possibility of hyperalgesia, tolerance and development of underlying sickness should be taken into consideration (see phase 4.Four).

It is vital that any dose re-titration of any analgesic is monitored with the aid of a health professional.

Discontinuation of remedy

ACTIQ should be discontinued right now if the patient no longer reports step forward ache episodes. The treatment for the chronic historical past pain must be stored as prescribed. If discontinuation of all opioid remedy is needed, the affected person should be intently observed by using the doctor as sluggish downward opioid titration is important with a purpose to avoid the opportunity of abrupt withdrawal effects.

Use within the aged

Elderly sufferers have been proven to be extra touchy to the consequences of fentanyl while administered intravenously. Therefore dose titration desires to be approached with precise care. In the aged, elimination of fentanyl is slower and the terminal removal 1/2-life is longer, which might also result in accumulation of the lively substance and to a greater hazard of undesirable effects.

Formal medical trials with ACTIQ have not been carried out within the aged. It has been observed, however, in scientific trials that sufferers over 65 years of age required lower doses of ACTIQ for a success relief of step forward ache.

Use in patients with hepatic or renal impairment

Special care have to be taken in the course of the titration technique in sufferers with kidney or liver disorder (see section 4.4).

Paediatric population

Adolescents elderly 16 years and above:

Follow person dosage.

Children and adolescents under sixteen years:

Safety and efficacy in children and young people below 16 years have now not been mounted. There is restrained scientific trial experience of the usage of ACTIQ in paediatric sufferers already receiving upkeep opioid remedy (see sections five.1 and five.2). Use on this patient populace is consequently not endorsed.

Method of administration

ACTIQ is intended for oromucosal management, and therefore have to be placed within the mouth towards the cheek and have to be moved around the mouth the use of the applicator, with the goal of maximising the amount of mucosal publicity to the product. The ACTIQ unit must be sucked, no longer chewed, as absorption of fentanyl thru the buccal mucosa is rapid in comparison with systemic absorption via the gastrointestinal tract. Water may be used to moisten the buccal mucosa in sufferers with a dry mouth.

The ACTIQ unit must be fed on over a fifteen minute duration. If symptoms of immoderate opioid outcomes seem earlier than the ACTIQ unit is fully consumed it have to be at once removed, and consideration given to decreasing future dosages.

Four.Three Contraindications
• Hypersensitivity to the energetic substance or to any of the excipients indexed in phase 6.1.

• Patients with out renovation opioid remedy as there may be an elevated threat of respiration melancholy.

• Treatment of acute ache aside from breakthrough ache.

• Simultaneous use of monoamine oxidase inhibitors (MAO inhibitors), or within 2 weeks after the cessation of the usage of MAO inhibitors (see sections four.Four and four.5).

• Severe respiratory melancholy or extreme obstructive lung situations.

4.Four Special warnings and precautions for use
Accidental use in youngsters

Patients and their carers have to be advised that ACTIQ contains an energetic substance in an amount that may be fatal to a baby. Death has been said in youngsters who have by accident ingested ACTIQ.

Patients and their carers should be advised to hold all devices out of the sight and reach of youngsters and to discard open and unopened units as it should be. An assessment of every out-affected person concerning feasible unintended child exposures should be undertaken.

Maintenance opioid therapy

The product ought to no longer receive to sufferers with out maintenance opioid remedy as there may be an elevated threat of respiratory melancholy and death. It is critical that the renovation opioid therapy used to deal with the affected person's continual pain has been stabilised earlier than ACTIQ therapy starts and that the affected person is still treated with the upkeep opioid remedy whilst the usage of ACTIQ.

Tolerance, dependence and abuse

Like for all opioids, tolerance, physical and/or mental dependence and abuse of fentanyl can also occur. However, iatrogenic addiction following healing use of opioids is understood to arise. The danger is taken into consideration low in most cancers sufferers with step forward pain, however can be higher in the ones patients with a history of substance abuse and alcohol dependence.

All patients handled with opioids require careful tracking for signs of abuse and dependancy.

Hyperalgesia

As with other opioids, in case of inadequate ache manage in response to an accelerated dose of fentanyl, the possibility of opioid-prompted hyperalgesia have to be taken into consideration. A fentanyl dose discount or discontinuation of fentanyl remedy or treatment review can be indicated

Adrenal insufficiency

Cases of adrenal insufficiency have been mentioned with opioid use inclusive of fentanyl lozenges, extra often following extra than one month of use. Wean the patient off of the opioid to allow adrenal feature to get better and keep corticosteroid remedy till adrenal function recovers (see phase four.8).

Respiratory despair

As with all opioids, there's a chance of clinically sizable respiration despair associated with the use of ACTIQ, patients have to be monitored thus.

Particular caution ought to be used whilst titrating ACTIQ in sufferers with non-severe chronic obstructive pulmonary ailment or other clinical conditions predisposing them to respiration despair, as even usually therapeutic doses of ACTIQ may additionally similarly lower breathing pressure to the factor of breathing failure.

Alcohol

The concomitant use of alcohol with fentanyl can produce extended depressant consequences which might also result in a deadly outcome (see section 4.Five).

Risks of concomitant management with benzodiazepines

Concomitant use of opioids, which include ACTIQ, with benzodiazepines may bring about profound sedation, respiratory melancholy, coma, and demise. Because of those dangers, concomitant prescribing of opioids and benzodiazepines should be made only in sufferers for whom opportunity treatment alternatives are insufficient.

If a decision is made to prescribe ACTIQ concomitantly with benzodiazepines, the lowest effective dosages and minimal intervals of concomitant use must be selected. Patients ought to be carefully monitored for symptoms and signs of respiration depression and sedation (see segment 4.Five).

Intracranial outcomes of CO2 retention, impaired attention, head injury

ACTIQ ought to best be administered with intense warning in sufferers who can be specially at risk of the intracranial outcomes of CO2 retention, which include people with proof of increased intracranial pressure, or impaired recognition. Opioids may obscure the clinical path of a affected person with a head damage and have to be used simplest if clinically warranted.

Bradyarrhythmias

Fentanyl may also produce bradycardia. Fentanyl ought to be used with caution in sufferers with preceding or pre-current bradyarrhythmias.

Hepatic or renal impairment

In addition, ACTIQ should be administered with warning to sufferers with liver or kidney disorder. The affect of liver and renal impairment on the pharmacokinetics of the medicinal product has now not been evaluated, however, whilst administered intravenously the clearance of fentanyl has been proven to be altered in hepatic and renal disorder because of changes in metabolic clearance and plasma proteins. After administration of ACTIQ, impaired liver and renal feature may additionally both increase the bioavailability of swallowed fentanyl and decrease its systemic clearance, that may cause accelerated and prolonged opioid outcomes. Therefore, unique care have to be taken throughout the titration manner in patients with moderate or intense hepatic or renal disorder.

Hypovolaemia, hypotension

Careful consideration must accept to patients with hypovolaemia and hypotension.

Diabetic sufferers

Diabetic patients need to be suggested that the medicinal product consists of dextrates (dextrates are composed of ninety three % glucose monohydrate and 7 % maltodextrin. The total glucose load according to dosage unit is approximately 1.89 grams in step with dose).

Patients with rare hereditary troubles of fructose intolerance, glucose-galactose malabsorption or sucrase-isomaltase insufficiency should no longer use this medicinal product.

Dental decay

Normal oral hygiene is suggested to reduce any capacity damage to the teeth. Because ACTIQ incorporates approximately 2 grams of sugar, common consumption increases the risk of dental decay. The occurrence of dry mouth related to using opioid medicinal products might also add to this threat.

Serotonin syndrome

Caution is recommended while ACTIQ is co-administered with medicinal merchandise that affect the serotoninergic neurotransmitter systems.

The improvement of a probably life-threatening serotonin syndrome may additionally arise with the concomitant use of serotonergic medicinal merchandise consisting of selective serotonin reuptake inhibitors (SSRIs) and serotonin norepinephrine reuptake inhibitors (SNRIs), and with medicinal merchandise which impair metabolism of serotonin (such as monoamine oxidase inhibitors [MAO inhibitors]) (see segment 4.3). This might also occur within the advocated dose.

Serotonin syndrome may additionally encompass intellectual-reputation modifications (e.G., agitation, hallucinations, coma), autonomic instability (e.G., tachycardia, labile blood stress, hyperthermia), neuromuscular abnormalities (e.G., hyperreflexia, incoordination, pressure), and/or gastrointestinal symptoms (e.G., nausea, vomiting, diarrhoea).

If serotonin syndrome is suspected, remedy with ACTIQ must be discontinued.

Anaphylaxis, allergy

Anaphylaxis and allergic reaction had been said in association with the usage of oral transmucosal fentanyl merchandise (see segment 4.Eight).

Paediatric population

ACTIQ isn't encouraged to be used in youngsters and teenagers under sixteen years because of loss of information on protection and efficacy (see sections five.1 and five.2).

Four.Five Interaction with different medicinal products and different types of interaction
Agents that affect CYP3A4 hobby

CYP3A4 inhibitors

Fentanyl is metabolized by using the CYP3A4 isoenzyme in the liver and intestinal mucosa. Potent inhibitors of CYP3A4 inclusive of macrolide antibiotics (e.G. Erythromycin), azole antifungals (e.G. Ketoconazole, itraconazole, and fluconazole) and sure protease inhibitors (e.G. Ritonavir), can also growth the bioavailability of swallowed fentanyl and might also lower its systemic clearance which may also result in elevated or extended opioid effects. Similar effects can be seen after concurrent ingestion of grapefruit juice, which is thought to inhibit CYP3A4. Hence warning is advised if fentanyl is given concomitantly with CYP3A4 inhibitors.

CYP3A4 inducers

Co-administration with agents that set off 3A4 interest may also lessen the efficacy of ACTIQ.

Agents which could increase CNS depressant effects

Co-management of fentanyl with different CNS depressants, along with other opioids, sedatives or hypnotics (consisting of benzodiazepines), standard anaesthetics, phenothiazines, tranquillisers, skeletal muscle relaxants, sedating antihistamines and alcohol can produce additive depressant effects which can also bring about a fatal final results (see segment four.4).

Sedative medicines which includes benzodiazepines or related drugs

The concomitant use of opioids with sedative drugs consisting of benzodiazepines or associated tablets will increase the risk of sedation, respiration melancholy, coma and death because of additive CNS depressant effect. The dose and length of concomitant use should be limited (see phase four.Four).

Partial opioid agonists/antagonists

The concomitant use of partial opioid agonists/antagonists (e.G. Buprenorphine, nalbuphine, pentazocine) is not recommended. They have high affinity to opioid receptors with surprisingly low intrinsic pastime and therefore partially antagonise the analgesic impact of fentanyl and might result in withdrawal signs in opioid dependant patients.

Serotonergic dealers

Co-administration of fentanyl with a serotonergic agent, which includes a selective serotonin reuptake inhibitor (SSRI) or a serotonin norepinephrine reuptake inhibitor (SNRI) or a monoamine oxidase inhibitor (MAO inhibitor), can also increase the risk of serotonin syndrome, a probably life-threatening condition(see phase four.3).

Four.6 Fertility, pregnancy and lactation
Pregnancy

There are not any or restrained quantity of information from the use of fentanyl in pregnant ladies. Studies in animals have proven reproductive toxicity (see section 5.3). Opioid analgesic agents can motive neonatal respiration depression. With long-time period use at some stage in pregnancy, there's a threat of neonatal opioid withdrawal syndrome which may be existence-threatening if no longer recognized and dealt with, and requires control consistent with protocols developed through neonatology experts. ACTIQ need to now not be used in being pregnant unless truly vital.

If opioid use is required for a prolonged period in a pregnant girl, endorse the patient of the chance of neonatal opioid withdrawal syndrome and ensure that suitable remedy can be available (see segment 4.Eight).

It is suggested no longer to use fentanyl in the course of labour and transport (inclusive of caesarean segment) due to the fact fentanyl passes via the placenta and may reason breathing despair in the fœtus. The placental switch ratio is zero.44 (fœtal:maternal ratio 1.00:2.27).

Breastfeeding

Fentanyl passes into breast milk and may purpose sedation and respiratory depression inside the breastfed infant. Fentanyl ought to not be utilized by breastfeeding girls and breast feeding have to no longer be restarted until at the least 5 days after the closing administration of fentanyl.

Fertility

There are not any human information on fertility to be had. In animal research, male fertility become impaired (see segment five.Three).

Four.7 Effects on ability to pressure and use machines
No research of the results on the capacity to power and use machines were finished. However, opioid analgesics may also impair the intellectual and/or bodily capacity required for the performance of probably risky duties (e.G., driving a vehicle or working machinery). Patients need to be advised not to power or function machinery if they experience somnolence, dizziness, blurred or double vision while the use of ACTIQ.

This medicine can impair cognitive function and might affect a patient's potential to drive appropriately. This class of medicine is in the listing of medication included in policies beneath 5a of the Road Traffic Act 1988. When prescribing this medication, patients ought to be advised:

The remedy is probably to have an effect on your ability to force,

• Do now not drive until you know how the drugs impacts you

• It is an offence to power even as beneath the influence of this medicine

• However, you would not be committing an offence (called 'statutory defence') if:

O The medication has been prescribed to deal with a clinical or dental hassle and

O You have taken it consistent with the instructions given by the prescriber and in the information provided with the drugs and

O It become no longer affecting your ability to drive thoroughly.

Four.8 Undesirable results
Typical opioid damaging reactions are to be anticipated with ACTIQ. Frequently, these will end or lower in depth with persisted use of the product, as the patient is titrated to the most suitable dose. However, the most serious damaging activities are respiratory despair (potentially main to apnoea or respiratory arrest), circulatory despair, hypotension and shock and all sufferers should be intently monitored for those.

Application website online reactions, together with gum bleeding, infection, ache and ulcer have been stated in submit-advertising and marketing use.

Because the clinical trials of ACTIQ were designed to evaluate protection and efficacy in treating leap forward ache, all patients have been also taking concomitant opioids, including sustained-release morphine or transdermal fentanyl, for his or her chronic pain. Thus it is not possible to definitively separate the outcomes of ACTIQ on my own.

The following destructive reactions have been said with ACTIQ and/or different fentanyl-containing compounds during scientific research and put up advertising enjoy. Adverse reactions are listed under as MedDRA preferred time period with the aid of gadget organ magnificence and frequency (frequencies are defined as: very commonplace ≥ 1/10, not unusual ≥ 1/a hundred to < 1/10, uncommon ≥ 1/1,000 to < 1/one hundred, no longer recognised (can not be anticipated from the available statistics):

System organ class
Very commonplace
Common
Unusual
Not acknowledged
Immune machine issues
Anaphylactic response,
Tongue oedema,
Lip oedema
Endocrine problems
Adrenal insufficiency,
Androgen deficiency
Metabolism and vitamins issues
Anorexia
Psychiatric disorders
Confusion,
Anxiety,
Hallucinations,
Melancholy,
Emotional lability
Odd desires,
Depersonalisation,
Peculiar thinking,
Euphoria
Insomnia,
Drug dependence (dependancy),
Drug abuse
Nervous device issues
Somnolence,
Dizziness,
Headache
Loss of consciousness,
Convulsion,
Vertigo,
Myoclonus,
Sedation,
Paraesthesia (which include hyperaesthesia/circumoral paraesthesia),
Ordinary gait/incoordination,
Taste perversion
Coma,
Slurred speech
Eye issues
Peculiar vision (blurred, double imaginative and prescient)
Vascular problems
Vasodilatation
Flushing,
Hot flush
Respiratory, thoracic and mediastinal disorders
Dyspnoea
Pharyngeal oedema,
Respiration despair
Gastrointestinal problems
Nausea,
Vomiting,
Constipation,
Abdominal pain
Dry mouth,
Dyspepsia,
Stomatitis,
Tongue disorder (as an example, burning sensation, ulcers),
Flatulence,
Stomach enlarged
Ileus,
Mouth ulcers,
Dental caries,
Gingival bleeding
Teeth loss,
Gingival recession,
Gingivitis,
Diarrhoea
Skin and subcutaneous tissue disorders
Pruritus,
Sweating,
Rash
Urticaria
Renal and urinary problems
Urinary retention
General issues and management web site conditions
Asthenia
Utility web page reactions which include irritation, ache and ulcer,
Malaise
Fatigue,
Peripheral oedema,
Pyrexia,
Withdrawal syndrome*,
Neonatal withdrawal syndrome (see section four.6)
Investigations
Weight decreased
Injury, poisoning and procedural headaches
Accidental harm (for example, falls)
* opioid withdrawal signs along with nausea, vomiting, diarrhoea, anxiety, chills, tremor, and sweating have been observed with transmucosal fentanyl.

Reporting of suspected damaging reactions

Reporting suspected negative reactions after authorisation of the medicinal product is crucial. It permits persevered monitoring of the benefit/hazard stability of the medicinal product. Healthcare specialists are asked to record any suspected unfavourable reactions via the Yellow Card Scheme Website: www.Mhra.Gov.United kingdom/yellowcard or search for MHRA Yellow Card within the Google Play or Apple App Store

4.Nine Overdose
Symptoms

The symptoms of fentanyl overdose are expected to be comparable in nature to those of intravenous fentanyl and different opioids, and are an extension of its pharmacological moves, with the maximum serious good sized consequences being altered mental fame, loss of consciousness, coma, cardiorespiratory arrest, breathing depression, breathing misery, and respiratory failure, which have ended in loss of life.

Management

Immediate control of opioid overdose includes removal of the ACTIQ unit via the applicator, if nevertheless within the mouth, ensuring a patent airway, physical and verbal stimulation of the affected person, evaluation of the extent of recognition, ventilatory and circulatory status, and assisted ventilation (ventilatory assist) if important.

Overdose (unintentional ingestion) inside the opioid naive person

For remedy of overdose (unintentional ingestion) inside the opioid naive individual, intravenous access should be obtained, and naloxone or different opioid antagonists should be employed as clinically indicated. The length of breathing depression following overdose can be longer than the effects of the opioid antagonist's movement (e.G., the half-life of naloxone degrees from 30 to eighty one minutes) and repeated administration may be necessary. Consult the Summary of Product Characteristics of the person opioid antagonist for details about such use.

Overdose in opioid-maintained sufferers

For remedy of overdose in opioid-maintained patients, intravenous get entry to need to be obtained. The really apt use of naloxone or any other opioid antagonist can be warranted in a few times, however it is associated with the hazard of precipitating an acute withdrawal syndrome.

Although muscle stress interfering with respiration has no longer been seen following the usage of ACTIQ, this is feasible with fentanyl and different opioids. If it happens, it ought to be controlled by using using assisted air flow, by way of an opioid antagonist, and as a very last alternative, through a neuromuscular blocking agent.

Five. Pharmacological properties
Five.1 Pharmacodynamic houses
Pharmacotherapeutic institution: Opioid analgesic, phenylpiperidone spinoff. ATC code: N02AB03.

Fentanyl, a pure opioid agonist, acts typically via interplay with mu-opioid receptors located in the brain, spinal wire and easy muscle. The number one web site of therapeutic action is the CNS. The most clinically useful pharmacological effect of the interaction of fentanyl with mu-opioid receptors is analgesia. The analgesic consequences of fentanyl are related to the blood stage of the energetic substance, if right allowance is made for the postpone into and out of the CNS (a technique with a 3-five minute half of-existence). In opioid-naïve people, analgesia happens at blood degrees of 1 to 2 ng/ml, even as blood levels of 10-20 ng/ml might produce surgical anaesthesia and profound respiration depression.

In sufferers with persistent cancer ache on stable doses of frequently scheduled opioids to govern their persistent pain, ACTIQ produced extensively extra step forward pain comfort in comparison with placebo at 15, 30, forty five, and 60 mins following management.

Secondary actions include growth within the tone and decrease inside the contractions of the gastrointestinal easy muscle, which leads to prolongation of gastrointestinal transit time and may be liable for the constipatory effect of opioids.

While opioids normally increase the tone of urinary tract clean muscle, the general effect tends to differ, in a few cases producing urinary urgency, in others problem in urination.

All opioid mu-receptor agonists, which includes fentanyl, produce dose structured breathing melancholy. The threat of breathing depression is less in sufferers with pain and people receiving continual opioid remedy who develop tolerance to respiration despair and different opioid effects. In non-tolerant topics, commonly top breathing outcomes are seen 15 to half-hour following the administration of ACTIQ, and may persist for numerous hours.

Opioids may additionally have an effect on the hypothalamic-pituitary-adrenal or –gonadal axes. Some adjustments that may be seen consist of an boom in serum prolactin, and decreases in plasma cortisol and testosterone. Clinical symptoms and signs and symptoms may be show up from these hormonal modifications (see also segment 4.8).

Additional secondary pharmacological effect consists of miosis.

Paediatric population

There is restricted experience of the usage of ACTIQ in paediatric patients, beneath the age of sixteen. In a medical study, 15 (out of 38) paediatric sufferers, ranging in age from 5 to 15 years, already receiving renovation opioid remedy and with step forward ache were treated with ACTIQ. The have a look at turned into too small to allow conclusions on safety and efficacy in this affected person population.

5.2 Pharmacokinetic houses
General creation

Fentanyl is particularly lipophilic and can be absorbed very rapidly via the oral mucosa and extra slowly by the conventional gastrointestinal course. It is challenge to first-pass hepatic and intestinal metabolism and the metabolites do no longer make a contribution to fentanyl's healing effects.

Absorption

The absorption pharmacokinetics of fentanyl from ACTIQ are a mixture of speedy oromucosal absorption and slower gastrointestinal absorption of swallowed fentanyl. Approximately 25 % of the overall dose of ACTIQ is swiftly absorbed from the buccal mucosa. The closing seventy five % of the dose is swallowed and slowly absorbed from the gastrointestinal tract. About 1/3 of this quantity (25 % of the whole dose) escapes hepatic and intestinal first-pass elimination and turns into systemically to be had. Absolute bioavailability is about 50 % compared to intravenous fentanyl, divided similarly among fast oromucosal and slower gastrointestinal absorption. Cmax levels from 0.39 to two.51 ng/mL after consumption of ACTIQ (2 hundred micrograms to at least one,six hundred micrograms). Tmax is round 20 to 40 mins after intake of an ACTIQ unit (variety 20-480 minutes).

Distribution

Animal records display that fentanyl is hastily dispensed to the mind, coronary heart, lungs, kidneys and spleen accompanied with the aid of a slower redistribution to muscle tissues and fats. The plasma protein binding of fentanyl is 80-85 %. The primary binding protein is alpha-1-acid glycoprotein, but each albumin and lipoproteins make contributions to a degree. The loose fraction of fentanyl increases with acidosis. The imply volume of distribution at steady country (Vss) is four L/kg.

Biotransformation

Fentanyl is metabolised within the liver and inside the intestinal mucosa to norfentanyl by CYP3A4 isoform. Norfentanyl isn't always pharmacologically energetic in animal research. More than 90 % of the administered dose of fentanyl is removed by using biotransformation to N-dealkylated and hydroxylated inactive metabolites.

Elimination

Less than 7 % of the dose is excreted unchanged inside the urine, and only about 1 % is excreted unchanged in the faeces. The metabolites are in particular excreted in the urine, even as faecal excretion is less crucial. The general plasma clearance of fentanyl is 0.5 L/hr/kg (range 0.Three-zero.7 L/hr/kg). The terminal removal 1/2-life after ACTIQ management is ready 7 hours.

Linearity/non-linearity

Dose proportionality across the to be had range of dosages (200 micrograms to one,six hundred micrograms) of ACTIQ has been validated.

Paediatric population

In a scientific look at, 15 paediatric sufferers, ranging in age from five to 15 years, already receiving preservation opioid remedy and with step forward pain have been dealt with with ACTIQ at doses starting from two hundred mcg to 600 mcg. Area underneath the curve values primarily based on discovered concentrations had been 2-fold better in more youthful children than youth (five.25 as opposed to 2.Sixty five ng.Hr/mL, respectively) and four-fold better within the more youthful kids compared to adults (5.25 as opposed to 1.20 ng.Hr/mL). On a weight-adjusted foundation, clearance and volume of distribution values had been comparable across the age range.

Five.3 Preclinical protection statistics
Non-medical statistics screen no unique danger for people primarily based on conventional research of safety pharmacology, repeated dose toxicity, genotoxicity and carcinogenicity.

Embryo-foetal developmental toxicity research conducted in rats and rabbits found out no compound-brought about malformations or developmental versions whilst administered throughout the length of organogenesis.

In a fertility and early embryonic improvement study in rats, a male-mediated effect was found at high doses (three hundred mcg/kg/day, s.C.) and is consistent with the sedative results of fentanyl in animal research.

In research on pre and postnatal improvement in rats the survival fee of offspring became drastically decreased at doses causing severe maternal toxicity. Further findings at maternally toxic doses in F1 puppies have been behind schedule bodily improvement, sensory features, reflexes and behavior. These consequences ought to both be indirect effects because of altered maternal care and/or decreased lactation charge or an immediate effect of fentanyl on the pups.

Carcinogenicity research (26-week dermal opportunity bioassay in Tg.AC transgenic mice; -12 months subcutaneous carcinogenicity have a look at in rats) with fentanyl did no longer induce any findings indicative of oncogenic capacity. Evaluation of mind slides from carcinogenicity observe in rats discovered mind 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
Lozenge:

Dextrates hydrated (containing glucose)

Citric acid,

Disodium phosphate,

Artificial berry flavour (maltodextrin, propylene glycol, artificial flavours and triethylcitrate)

Magnesium stearate

Edible glue used to attach the lozenge to the manage:

Modified maize based food starch (E 1450)

Confectioner's sugar (sucrose and maize starch)

Water, purified

Imprinting ink:

De-ionised water

De-waxed white shellac

Propylene glycol

Blue artificial coal tar dye (E 133)

Ammonium hydroxide (E 527) for pH adjustment

6.2 Incompatibilities
Not applicable.

6.3 Shelf lifestyles
Three years

6.4 Special precautions for garage
Do now not store above 30 °C.

Store in shielding blister until equipped for use.

6.5 Nature and contents of container
Each ACTIQ dosage unit is contained in a warmness sealed blister bundle including a paper/foil laminated lid, and a PVC/Aclar thermoformed blister, furnished in cartons of 3, 6, 15 or 30 character units.

Not all percent sizes may be marketed.

6.6 Special precautions for disposal and different managing
Lozenges with residual energetic substance have to at no time be discarded or out of place. Any used or unused but now not required product or waste cloth need to be disposed of according with neighborhood requirements.



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