Actiq

Overdose

Symptoms

The symptoms of fentanyl overdose are expected to be similar in nature to those of intravenous fentanyl and other opioids, and are an extension of its pharmacological actions, with the most serious significant effects being altered mental status, loss of consciousness, coma, cardiorespiratory arrest, respiratory depression, respiratory distress, and respiratory failure, which have resulted in death.

Management

Immediate management of opioid overdose includes removal of the ACTIQ unit via the applicator, if still in the mouth, ensuring a patent airway, physical and verbal stimulation of the patient, assessment of the level of consciousness, ventilatory and circulatory status, and assisted ventilation (ventilatory support) if necessary.

Overdose (accidental ingestion) in the opioid naive person

For treatment of overdose (accidental ingestion) in the opioid naive person, intravenous access should be obtained, and naloxone or other opioid antagonists should be employed as clinically indicated. The duration of respiratory depression following overdose may be longer than the effects of the opioid antagonist's action (e.g., the half-life of naloxone ranges from 30 to 81 minutes) and repeated administration may be necessary. Consult the Summary of Product Characteristics of the individual opioid antagonist for details about such use.

Overdose in opioid-maintained patients

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

Although muscle rigidity interfering with respiration has not been seen following the use of ACTIQ, this is possible with fentanyl and other opioids. If it occurs, it should be managed by the use of assisted ventilation, by an opioid antagonist, and as a final alternative, by a neuromuscular blocking agent.

Shelf life

3 years

Incompatibilities

Not applicable.

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 handle:

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 synthetic coal tar dye (E 133)

Ammonium hydroxide (E 527) for pH adjustment

Undesirable effects

Typical opioid adverse reactions are to be expected with ACTIQ. Frequently, these will cease or decrease in intensity with continued use of the product, as the patient is titrated to the most appropriate dose. However, the most serious adverse events are respiratory depression (potentially leading to apnoea or respiratory arrest), circulatory depression, hypotension and shock and all patients should be closely monitored for these.

Application site reactions, including gum bleeding, irritation, pain and ulcer have been reported in post-marketing use.

Because the clinical trials of ACTIQ were designed to evaluate safety and efficacy in treating breakthrough pain, all patients were also taking concomitant opioids, such as sustained-release morphine or transdermal fentanyl, for their persistent pain. Thus it is not possible to definitively separate the effects of ACTIQ alone.

The following adverse reactions have been reported with ACTIQ and/or other fentanyl-containing compounds during clinical studies and post marketing experience. Adverse reactions are listed below as MedDRA preferred term by system organ class and frequency (frequencies are defined as: very common > 1/10, common > 1/100 to < 1/10, uncommon > 1/1,000 to < 1/100, not known (cannot be estimated from the available data):

* 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 Yellow Card Scheme at: www.mhra.gov.uk/yellowcard.

Preclinical safety data

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

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

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

In studies on pre and postnatal development in rats the survival rate of offspring was significantly reduced at doses causing severe maternal toxicity. Further findings at maternally toxic doses in F1 pups were delayed physical development, sensory functions, reflexes and behaviour. These effects could either be indirect effects due to altered maternal care and/or decreased lactation rate or a direct effect of fentanyl on the pups.

Carcinogenicity studies (26-week dermal alternative bioassay in Tg.AC transgenic mice; two-year subcutaneous carcinogenicity study in rats) with fentanyl did not induce any findings indicative of oncogenic potential. Evaluation of brain slides from carcinogenicity study in rats revealed brain lesions in animals administered high doses of fentanyl citrate. The relevance of these findings to humans is unknown

Pharmacotherapeutic group

Pharmacodynamic properties

Pharmacotherapeutic group: Opioid analgesic, phenylpiperidone derivative. ATC code: N02AB03.

Fentanyl, a pure opioid agonist, acts primarily through interaction with mu-opioid receptors located in the brain, spinal cord and smooth muscle. The primary site of therapeutic action is the central nervous system (CNS). The most clinically useful pharmacological effect of the interaction of fentanyl with mu-opioid receptors is analgesia. The analgesic effects of fentanyl are related to the blood level of the active substance, if proper allowance is made for the delay into and out of the CNS (a process with a 3-5 minute half-life). In opioid-naïve individuals, analgesia occurs at blood levels of 1 to 2 ng/ml, while blood levels of 10-20 ng/ml would produce surgical anaesthesia and profound respiratory depression.

In patients with chronic cancer pain on stable doses of regularly scheduled opioids to control their persistent pain, ACTIQ produced significantly more breakthrough pain relief compared with placebo at 15, 30, 45, and 60 minutes following administration.

Secondary actions include increase in the tone and decrease in the contractions of the gastrointestinal smooth muscle, which results in prolongation of gastrointestinal transit time and may be responsible for the constipatory effect of opioids.

While opioids generally increase the tone of urinary tract smooth muscle, the overall effect tends to vary, in some cases producing urinary urgency, in others difficulty in urination.

All opioid mu-receptor agonists, including fentanyl, produce dose dependent respiratory depression. The risk of respiratory depression is less in patients with pain and those receiving chronic opioid therapy who develop tolerance to respiratory depression and other opioid effects. In non-tolerant subjects, typically peak respiratory effects are seen 15 to 30 minutes following the administration of ACTIQ, and may persist for several hours.

Additional secondary pharmacological effect includes miosis.

Paediatric population

There is limited experience of the use of ACTIQ in paediatric patients, below the age of 16. In a clinical study, 15 (out of 38) paediatric patients, ranging in age from 5 to 15 years, already receiving maintenance opioid therapy and with breakthrough pain were treated with ACTIQ. The study was too small to allow conclusions on safety and efficacy in this patient population.

Pharmacokinetic properties

General introduction

Fentanyl is highly lipophilic and can be absorbed very rapidly through the oral mucosa and more slowly by the conventional gastrointestinal route. It is subject to first-pass hepatic and intestinal metabolism and the metabolites do not contribute to fentanyl's therapeutic effects.

Absorption

The absorption pharmacokinetics of fentanyl from ACTIQ are a combination of rapid oromucosal absorption and slower gastrointestinal absorption of swallowed fentanyl. Approximately 25 % of the total dose of ACTIQ is rapidly absorbed from the buccal mucosa. The remaining 75 % of the dose is swallowed and slowly absorbed from the gastrointestinal tract. About 1/3 of this amount (25 % of the total dose) escapes hepatic and intestinal first-pass elimination and becomes systemically available. Absolute bioavailability is about 50 % compared to intravenous fentanyl, divided equally between rapid oromucosal and slower gastrointestinal absorption. Cmax ranges from 0.39 to 2.51 ng/mL after consumption of ACTIQ (200 micrograms to 1,600 micrograms). Tmax is around 20 to 40 minutes after consumption of an ACTIQ unit (range 20-480 minutes).

Distribution

Animal data show that fentanyl is rapidly distributed to the brain, heart, lungs, kidneys and spleen followed by a slower redistribution to muscles and fat. The plasma protein binding of fentanyl is 80-85 %. The main binding protein is alpha-1-acid glycoprotein, but both albumin and lipoproteins contribute to some extent. The free fraction of fentanyl increases with acidosis. The mean volume of distribution at steady state (Vss) is 4 L/kg.

Biotransformation

Fentanyl is metabolised in the liver and in the intestinal mucosa to norfentanyl by CYP3A4 isoform. Norfentanyl is not pharmacologically active in animal studies. More than 90 % of the administered dose of fentanyl is eliminated by biotransformation to N-dealkylated and hydroxylated inactive metabolites.

Elimination

Less than 7 % of the dose is excreted unchanged in the urine, and only about 1 % is excreted unchanged in the faeces. The metabolites are mainly excreted in the urine, while faecal excretion is less important. The total plasma clearance of fentanyl is 0.5 L/hr/kg (range 0.3-0.7 L/hr/kg). The terminal elimination half-life after ACTIQ administration is about 7 hours.

Linearity/non-linearity

Dose proportionality across the available range of dosages (200 micrograms to 1,600 micrograms) of ACTIQ has been demonstrated.

Paediatric population

In a clinical study, 15 paediatric patients, ranging in age from 5 to 15 years, already receiving maintenance opioid therapy and with breakthrough pain were treated with ACTIQ at doses ranging from 200 mcg to 600 mcg. Area under the curve values based on observed concentrations were 2-fold higher in younger children than adolescents (5.25 versus 2.65 ng.hr/mL, respectively) and 4-fold higher in the younger children as compared to adults (5.25 versus 1.20 ng.hr/mL). On a weight-adjusted basis, clearance and volume of distribution values were similar across the age range.

Date of revision of the text

09/05/2017

Marketing authorisation holder

Teva Pharma B.V.

Swensweg 5

2031 GA Haarlem

The Netherlands

Special precautions for storage

Do not store above 30 °C.

Store in protective blister until ready for use.

Nature and contents of container

Each ACTIQ dosage unit is contained in a heat sealed blister package consisting of a paper/foil laminated lid, and a PVC/Aclar thermoformed blister, supplied in cartons of 3, 6, 15 or 30 individual units.

Not all pack sizes may be marketed.

Marketing authorisation number(s)

Actiq 1200 microgram compressed lozenge with integral oromucosal applicator

PL 14776/0096

Fertility, pregnancy and lactation

Pregnancy

There are no or limited amount of data from the use of fentanyl in pregnant women. Studies in animals have shown reproductive toxicity. Opioid analgesic agents can cause neonatal respiratory depression. With long-term use during pregnancy, there is a risk of neonatal opioid withdrawal syndrome which may be life-threatening if not recognized and treated, and requires management according to protocols developed by neonatology experts. ACTIQ should not be used in pregnancy unless clearly necessary.

If opioid use is required for a prolonged period in a pregnant woman, advise the patient of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available.

It is advised not to use fentanyl during labour and delivery (including caesarean section) because fentanyl passes through the placenta and may cause respiratory depression in the fœtus. The placental transfer ratio is 0.44 (fœtal:maternal ratio 1.00:2.27).

Breastfeeding

Fentanyl passes into breast milk and may cause sedation and respiratory depression in the breastfed child. Fentanyl should not be used by breastfeeding women and breast feeding should not be restarted until at least 5 days after the last administration of fentanyl.

Fertility

There are no human data on fertility available. In animal studies, male fertility was impaired.

Effects on ability to drive and use machines

No studies of the effects on the ability to drive and use machines have been performed. However, opioid analgesics may impair the mental and/or physical ability required for the performance of potentially dangerous tasks (e.g., driving a car or operating machinery). Patients should be advised not to drive or operate machinery if they experience somnolence, dizziness, blurred or double vision while using ACTIQ.

This medicine can impair cognitive function and can affect a patient's ability to drive safely. This class of medicine is in the list of drugs included in regulations under 5a of the Road Traffic Act 1988. When prescribing this medicine, patients should be told:

The medicine is likely to affect your ability to drive,

- Do not drive until you know how the medicine affects you

- It is an offence to drive while under the influence of this medicine

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

o The medicine has been prescribed to treat a medical or dental problem and

o You have taken it according to the instructions given by the prescriber and in the information provided with the medicine and

o It was not affecting your ability to drive safely.

Special precautions for disposal and other handling

Lozenges with residual active substance should at no time be discarded or misplaced. Any used or unused but no longer required product or waste material should be disposed of in accordance with local requirements.

Date of first authorisation/renewal of the authorisation

Date of first authorisation: 09 October 2000

Date of latest renewal: 08 October 2010

Interaction with other medicinal products and other forms of interaction

Agents that affect CYP3A4 activity

CYP3A4 inhibitors

Fentanyl is metabolized by the CYP3A4 isoenzyme in the liver and intestinal mucosa. Potent inhibitors of CYP3A4 such as macrolide antibiotics (e.g. erythromycin), azole antifungals (e.g. ketoconazole, itraconazole, and fluconazole) and certain protease inhibitors (e.g. ritonavir), may increase the bioavailability of swallowed fentanyl and may also decrease its systemic clearance which may result in increased or prolonged opioid effects. Similar effects could be seen after concurrent ingestion of grapefruit juice, which is known to inhibit CYP3A4. Hence caution is advised if fentanyl is given concomitantly with CYP3A4 inhibitors.

CYP3A4 inducers

Coadministration with agents that induce 3A4 activity may reduce the efficacy of ACTIQ.

Agents that can increase CNS depressant effects

Coadministration of fentanyl with other CNS depressants, including other opioids, sedatives or hypnotics, general anaesthetics, phenothiazines, tranquillisers, skeletal muscle relaxants, sedating antihistamines and alcohol can produce additive depressant effects which may result in a fatal outcome.

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 relatively low intrinsic activity and therefore partially antagonise the analgesic effect of fentanyl and may induce withdrawal symptoms in opioid dependant patients.

Serotonergic agents

Coadministration of fentanyl with a serotonergic agent, such as a selective serotonin reuptake inhibitor (SSRI) or a serotonin norepinephrine reuptake inhibitor (SNRI) or a monoamine oxidase inhibitor (MAO inhibitor), may increase the risk of serotonin syndrome, a potentially life-threatening condition. ACTIQ must not be used in patients who have received MAO inhibitors or within 2 weeks after the cessation of the use of MAO inhibitors.