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Drug Details

Effentora 100, 200, 400, 600 and 800 micrograms buccal tablets

• Drug Class Description
  Analgesics; opioids; phenylpiperidine derivatives
• Presentation
  Buccal tablet. Flat-faced, white, round bevelled-edge tablet, embossed on one side with a “C” and on the other side with “1” for 100 micrograms tablet, “2” for 200 micrograms tablet, “4” for 400 micrograms tablet, “6” for 600 micrograms tablet and “8” for 800 micrograms tablet.
• Description
  Each buccal tablet contains 100, 200, 400, 600 and 800 micrograms fentanyl (as citrate). Excipient(s): Each 100 micrograms tablet contains 8 mg of sodium. Each 200 micrograms tablet contains 16 mg of sodium. Each 400 micrograms tablet contains 16 mg of sodium. Each 600 micrograms tablet contains 16 mg of sodium. Each 800 micrograms tablet contains 16 mg of sodium.
• Indications
  

  Effentora is indicated for the treatment of breakthrough pain (BTP) in adults with cancer who are already receiving maintenance opioid therapy for chronic cancer pain. BTP is a transitory exacerbation of pain that occurs on a background of otherwise controlled persistent pain.

  Patients receiving maintenance opioid therapy are those who are taking at least 60 mg of oral morphine daily, at least 25 micrograms of transdermal fentanyl per hour, at least 30 mg of oxycodone daily, at least 8 mg of oral hydromorphone daily or an equianalgesic dose of another opioid for a week or longer.

• Adult Dosage
  

  Treatment should be initiated by and remain under the guidance of a physician experienced in the management of opioid therapy in cancer patients. Physicians should keep in mind the potential of abuse of fentanyl.

  Dose titration

  Effentora should be individually titrated to an “effective” dose that provides adequate analgesia and minimises undesirable effects. In clinical studies, the effective dose of Effentora for BTP was not predictable from the daily maintenance dose of opioid.

  Patients should be carefully monitored until an effective dose is reached.
  
  Titration in patients not switching from other fentanyl containing products

  The initial dose of Effentora should be 100 micrograms, titrating upwards as necessary through the range of available tablets strengths (100, 200, 400, 600, 800 micrograms).
  
  Titration in patients switching from other fentanyl containing products

  Due to different absorption profiles, switching must not be done at a 1:1 ratio. If switching from another oral fentanyl citrate product, independent dose titration with Effentora is required as bioavailability between products differs significantly. However, in these patients, a starting dose higher than 100 micrograms may be considered.

  Method of titration

  During titration, if adequate analgesia is not obtained within 30 minutes after the start of administration of a single tablet, a second Effentora tablet of the same strength may be used.

  If treatment of a BTP episode requires more than one tablet, an increase in dose to the next higher available strength should be considered to treat the next BTP episode.

  During titration, multiple tablets may be used: up to four 100 micrograms or up to four 200 micrograms tablets may be used to treat a single episode of BTP during dose titration according to the following schedule:

  • If the initial 100 micrograms tablet is not efficacious, the patient can be instructed to treat the next episode of BTP with two 100 micrograms tablets. It is recommended that one tablet should be placed in each side of the mouth. If this dose is considered to be the effective dose, treatment of successive episodes of BTP may be continued with a single 200 micrograms tablet of Effentora.
  • If a single 200 micrograms tablet of Effentora (or two 100 micrograms tablets) is not considered to be efficacious the patient can be instructed to use two 200 micrograms tablets (or four 100 micrograms tablets) to treat the next episode of BTP. It is recommended that two tablets should be placed in each side of the mouth. If this dose is considered to be the effective dose, treatment of successive episodes of BTP may be continued with a single 400 micrograms tablet of Effentora.
  • For titration to 600 micrograms and 800 micrograms, tablets of 200 micrograms should be used.

  Doses above 800 micrograms were not evaluated in clinical studies.

  No more than two tablets should be used to treat any individual BTP episode, except when titrating using up to four tablets as described above.

  Patients should wait at least 4 hours before treating another BTP episode with Effentora during titration.

  Maintenance therapy

  Once an effective dose has been established during titration, patients should continue to take this dose as a single tablet of that given strength.

  Patients should wait at least 4 hours before treating another BTP episode with Effentora during maintenance therapy.

  Dose readjustment

  Generally, the maintenance dose of Effentora should be increased when a patient requires more than one dose per BTP episode for several consecutive BTP episodes.

  Dose readjustment of Effentora and/or of the background opioid therapy may be required if patients consistently present with more than four BTP episodes per 24 hours.
  
  Discontinuation of therapy

  Effentora should be immediately discontinued if no longer required.

  Hepatic or renal impairment:

  Effentora should be administered with caution to patients with moderate or severe hepatic or renal impairment.

  Method of administration:

  Effentora tablet once exposed to moisture utilises an effervescent reaction to deliver the active substance. Therefore patients should be instructed not to open the blister until ready to place the tablet in the buccal cavity.

  Opening the blister package

  Patients should be instructed NOT to attempt to push the tablet through the blister because this could damage the buccal tablet. The correct method of releasing the tablet from the blister is:

  One of the blister units should be separated from the blister card by tearing it apart at the perforations. The blister unit should then be flexed along the line printed on the backing foil where indicated. The backing foil should be peeled back to expose the tablet.

  Patients should be instructed not to attempt to crush or split the tablet.

  The tablet should not be stored once removed from the blister package as the tablet integrity can not be guaranteed and a risk of accidental exposure to a tablet can occur.

  Tablet administration

  Patients should remove the tablet from the blister unit and immediately place the entire Effentora tablet in the upper portion of the buccal cavity (above an upper rear molar between the cheek and gum).

  Effentora should be placed and retained within the buccal cavity for a period sufficient to allow disintegration of the tablet which usually takes approximately 14-25 minutes.

  The Effentora tablet should not be sucked, chewed or swallowed, as this will result in lower plasma concentrations than when taken as directed.

  After 30 minutes, if remnants from the Effentora tablet remain, they may be swallowed with a glass of water.

  The length of time that the tablet takes to fully disintegrate following oromucosal administration does not appear to affect early systemic exposure to fentanyl.

  Patients should not consume any food and drink when a tablet is in the buccal cavity.

  In case of buccal mucosa irritation, a change in tablet placement within the buccal cavity should be recommended.

• Child Dosage
  

  Use in children and adolescents:

  Effentora is not recommended for use in children and adolescents below 18 years due to a lack of data on safety and efficacy.

   

• Elderly Dosage
  

  Use in the elderly (older than 65 years):

  In clinical studies patients older than 65 years tended to titrate to a lower effective dose than younger patients. It is recommended that increased caution should be exercised in titrating the dose of Effentora in elderly patients.

• Contra Indications
  

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

  Patients without maintenance opioid therapy as there is an increased risk of respiratory depression.

  Severe respiratory depression or severe obstructive lung conditions.

• Special Precautions
  

  Patients and their carers must be instructed that Effentora contains an active substance in an amount that can be fatal to a child, and therefore to keep all tablets out of the reach and sight of children.

  In order to minimise the risks of opioid-related undesirable effects and to identify the effective dose, it is imperative that patients be monitored closely by health professionals during the titration process.

  It is important that the long acting opioid treatment used to treat the patient's persistent pain has been stabilised before Effentora therapy begins.

  As with all opioids, there is a risk of clinically significant respiratory depression associated with the use of fentanyl. Particular caution should be used when titrating Effentora in patients with non-severe chronic obstructive pulmonary disease or other medical conditions predisposing them to respiratory depression, as even normally therapeutic doses of Effentora may further decrease respiratory drive to the point of respiratory failure.

  Effentora should only be administered with extreme caution in patients who may be particularly susceptible to the intracranial effects of CO2 retention, such as those with evidence of increased intracranial pressure or impaired consciousness. Opioids may obscure the clinical course of a patient with a head injury and should be used only if clinically warranted.

  Intravenous fentanyl may produce bradycardia. In clinical trials with Effentora, no clear evidence for bradycardia was observed. However, Effentora should be used with caution in patients with pre-existing bradyarrhythmias.

  In addition, Effentora should be administered with caution to patients with hepatic or renal impairment. The influence of hepatic and renal impairment on the pharmacokinetics of the medicinal product has not been evaluated, however, when administered intravenously the clearance of fentanyl has been shown to be altered in hepatic and renal impairment due to alterations in metabolic clearance and plasma proteins. After administration of Effentora, impaired hepatic and renal function may both increase the bioavailability of swallowed fentanyl and decrease its systemic clearance, which could lead to increased and prolonged opioid effects. Therefore, special care should be taken during the titration process in patients with moderate or severe hepatic or renal impairment.

  Careful consideration should be given to patients with hypovolaemia and hypotension.

  Tolerance and physical and/or psychological dependence may develop upon repeated administration of opioids such as fentanyl. However, iatrogenic addiction following therapeutic use of opioids is rare.

  This medicinal product contains:

  8 mg sodium per 100 micrograms tablet. 16 mg sodium per 200 micrograms tablet. 16 mg sodium per 400 micrograms tablet. 16 mg sodium per 600 micrograms tablet. 16 mg sodium per 800 micrograms tablet. To be taken into consideration by patients on a controlled sodium diet.

   

• Interactions
  

  Fentanyl is metabolised mainly via the human cytochrome P450 3A4 isoenzyme system (CYP3A4), therefore potential interactions may occur when Effentora is given concurrently with agents that affect CYP3A4 activity. Coadministration with agents that induce 3A4 activity may reduce the efficacy of Effentora. The concomitant use of Effentora with strong CYP3A4 inhibitors (e.g., ritonavir, ketoconazole, itraconazole, troleandomycin, clarithromycin, and nelfinavir) or moderate CYP3A4 inhibitors (e.g., amprenavir, aprepitant, diltiazem, erythromycin, fluconazole, fosamprenavir, grapefruit juice, and verapamil) may result in increased fentanyl plasma concentrations, potentially causing serious adverse drug reactions including fatal respiratory depression. Patients receiving Effentora concomitantly with moderate or strong CYP3A4 inhibitors should be carefully monitored for an extended period of time. Dosage increase should be done with caution.

  The concomitant use of other central nervous system depressants, including other opioids, sedatives or hypnotics, general anaesthetics, phenothiazines, tranquillisers, skeletal muscle relaxants, sedating antihistamines and alcohol may produce additive depressant effects.

  Effentora 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 dependant patients.

• Adverse Drug Reactions
  

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

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

  The adverse reactions considered to be at least possibly-related to treatment from clinical studies were as follows (frequencies defined as: very common 1/10, common 1/100 to <1/10, uncommon  1/1,000 to < 1/100; within each frequency grouping, undesirable effects are presented in order of decreasing seriousness):

  	Very common	Common	Uncommon
  Investigations			- Platelet count      decreased - Heart rate    increased - Haematocrit    decreased - Haemoglobin   decreased
  Cardiac disorders			- Tachycardia, - Bradycardia
  Blood and lymphatic system disorders			- Anaemia - Neutropenia - Thrombocytopenia
  Nervous system disorders	Dizziness	Dysgeusia Somnolence Lethargy Headache Tremor Sedation	- Depressed level  of consciousness - Disturbance in attention - Cognitive disorder - Hypoaesthesia - Balance disorder - Migraine - Motor dysfunction - Dysarthria
  Eye disorders			- Visual disturbance - Ocular hyperaemia - Abnormal sensation in eye - Photopsia - Blurred vision - Visual acuity reduced
  Ear and labyrinth disorders			- Vertigo - Tinnitus - Ear discomfort
  Respiratory, thoracic and mediastinal disorders			- Dyspnoea - Pharyngolaryngeal pain
  Gastrointestinal disorders	Nausea	Vomiting Constipation Stomatitis Dry mouth Diarrhoea	- Mouth ulceration - Oral hypoaesthesia - Oral discomfort - Oral mucosal blistering - Oral mucosal discolouration - Oral soft tissue disorder - Glossodynia - Tongue blistering - Gingival pain - Stomach discomfort - Tongue ulceration - Tongue disorder - Dyspepsia - Abdominal pain - Oesophagitis - Gastrooesophagal reflux disease - Chapped lips - Dry lip - Tooth disorder - Toothache
  Renal and urinary disorders			- Urinary retention
  Skin and subcutaneous tissue disorders		Pruritis Hyperhydrosis	- Cold sweat - Facial swelling - Rash - Generalised pruritus - Alopecia - Onychorrhexis
  Musculoskeletal and connective tissue disorders			- Myalgia - Muscle twitching - Muscular weakness - Back pain
  Metabolism and nutrition disorders			- Anorexia
  Infections and infestations			- Oral candidiasis - Pharyngitis - Oral pustule
  Injury, poisoning and procedural complications			- Fall
  Neoplasms benign, malignant and unspecified (including cysts and polyps)			- Multiple myeloma
  Vascular disorders			- Flushing - Hypertension - Hot flush
  General disorders and administration site conditions	Application site reactions including pain, ulcer, irritation, paraesthesia, anaesthesia, erythema, oedema, swelling and vesicles	Fatigue	- Asthenia - Malaise - Sluggishness - Chest discomfort - Feeling abnormal - Feeling jittery - Thirst - Feeling cold - Chills - Feeling hot - Drug withdrawal syndrome
  Psychiatric disorders		Disorientation Euphoric mood	- Anxiety - Nervousness - Hallucination - Visual hallucination - Insomnia - Confusional state