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Drug Details

ACTIQ

• Generic Name
  Fentanyl
• Presentation
  Actiq® 200 micrograms, 400 micrograms, 600 micrograms, 800 micrograms, 1200 micrograms, 1600 micrograms compressed lozenge with integral oromucosal applicator.
• Description
  One lozenge contains: 200 micrograms fentanyl (equivalent to 314.2 micrograms fentanyl citrate) 400 micrograms fentanyl (equivalent to 628.4 micrograms fentanyl citrate) 600 micrograms fentanyl (equivalent to 942.6 micrograms fentanyl citrate) 800 micrograms fentanyl (equivalent to 1256.8 micrograms fentanyl citrate) 1200 micrograms fentanyl (equivalent to 1885.2 micrograms fentanyl citrate) 1600 micrograms fentanyl (equivalent to 2513.6 micrograms fentanyl citrate) This product also contains dextrates (equivalent to approximately 2 grams of glucose), sucrose (approximately 30 milligrams confectioner's sugar), ethanol (part of the imprinting ink) and propylene glycol (part of the artificial berry flavour and imprinting ink) as excipients.
• Indications
  Actiq is indicated for the management of breakthrough pain in patients already receiving maintenance opioid therapy for chronic cancer pain. Breakthrough pain is a transitory exacerbation of pain that occurs on a background of otherwise controlled persistent pain.
• Adult Dosage
  

  In order to minimise the risks of opioid-related side-effects and to identify the “successful” dose, it is imperative that patients be monitored closely by health professionals during the titration process. Any unused Actiq units that the patient no longer requires must be disposed of properly. Patients must be reminded of the requirements to keep Actiq stored in a location away from children.

  Method of administration

  Actiq is intended for oromucosal administration, and therefore should be placed in the mouth against the cheek and should be moved around the mouth using the applicator, with the aim of maximising the amount of mucosal exposure to the product. The Actiq unit should be sucked, not chewed, as absorption of fentanyl via the buccal mucosa is rapid in comparison with systemic absorption via the gastrointestinal tract. Water may be used to moisten the buccal mucosa in patients with a dry mouth.

  The Actiq unit should be consumed over a 15 minute period. If signs of excessive opioid effects appear before the Actiq unit is fully consumed it should be immediately removed, and consideration given to decreasing future dosages.

  Dose titration and maintenance therapy

  Actiq should be individually titrated to a “successful” dose that provides adequate analgesia and minimises side effects. In clinical trials the successful dose of Actiq for breakthrough pain was not predicted from the daily maintenance dose of opioid.

  a) Titration

  Before patients are titrated with Actiq, it is expected that their background persistent pain will be controlled by use of opioid therapy and that they are typically experiencing no more than 4 episodes of breakthrough pain per day.

  The initial dose of Actiq used should be 200 micrograms, titrating upwards as necessary through the range of available dosage strengths (200, 400, 600, 800, 1200 and 1600 micrograms). Patients should be carefully monitored until a dose is reached that provides adequate analgesia with acceptable side effects using a single dosage unit per episode of breakthrough pain. This is defined as the successful dose.

  During titration, if adequate analgesia is not obtained within 15 minutes after the patient completes consumption of a single Actiq unit, a second Actiq unit of the same strength may be consumed. No more than two Actiq units should be used to treat any individual pain episode. At 1600 micrograms, a second dose is only likely to be required by a minority of patients.

  If treatment of consecutive breakthrough pain episodes requires more than one dosage unit per episode, an increase in dose to the next higher available strength should be considered.

  b) Maintenance

  Once a successful dose has been established (i.e., on average, an episode is effectively treated with a single unit), patients should be maintained on this dose and should limit consumption to a maximum of four Actiq units per day.

  Patients should be monitored by a health professional to ensure that the maximum consumption of four units of Actiq per day is not exceeded.

  c) Dose re-adjustment

  If more than four episodes of breakthrough pain are experienced per day, over a period of more than four consecutive days the dose of the long acting opioid used for persistent pain should be re-evaluated. If the dose of the long acting opioid is increased, the dose of Actiq to treat breakthrough pain may need to be reviewed.

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

  d) Discontinuation of therapy

  Actiq therapy may usually be immediately discontinued if no longer required for breakthrough pain only, in patients who continue to take their chronic opioid therapy for persistent pain.

  For patients requiring discontinuation of all opioid therapy, account should be taken of the Actiq dose in consideration of a gradual downward opioid titration to avoid the possibility of abrupt withdrawal effects. 

  Use in special patient populations

  Special care should be taken during the titration process in patients with kidney or liver dysfunction.

• Child Dosage
  

  The appropriate posology and safety of Actiq have not been established in children and adolescents.

• Elderly Dosage
  

  Elderly patients have been shown to be more sensitive to the effects of fentanyl when administered intravenously. Therefore dose titration needs to be approached with particular care. In the elderly, elimination of fentanyl is slower and the terminal elimination half-life is longer, which may result in accumulation of the active substance and to a greater risk of undesirable effects.

  Formal clinical trials with Actiq have not been conducted in the elderly. It has been observed, however, in clinical trials that patients over 65 years of age required lower doses of Actiq for successful relief of breakthrough pain.

• Contra Indications
  

  Hypersensitivity to fentanyl or to any of the excipients.

  Simultaneous use of monoamine-oxidase (MAO) inhibitors, or within 2 weeks after the cessation of the use of MAO inhibitors.

  Severe respiratory depression or severe obstructive lung conditions.

• Special Precautions
  

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

  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.

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

  The product should not be given to opioid-naïve patients as there is an increased risk of respiratory depression and the appropriate dose in this patient population has not yet been determined.

  Actiq 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. Therefore, Actiq should be used with caution in patients with bradyarrhythmias.

  In addition, Actiq should be administered with caution to patients with liver or kidney dysfunction. The influence of liver 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 disease due to alterations in metabolic clearance and plasma proteins. After administration of Actiq, impaired liver 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 disease.

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

  Diabetic patients should be advised that the medicine product contains dextrates (dextrates are composed of 93% dextrose monohydrate and 7% maltodextrin. The total glucose load per dosage unit is approximately 1.89 grams per dose).

  Patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption or sucrase-isomaltase insufficiency should not take this medicine.

  Normal oral hygiene is recommended to avoid any potential harm to the teeth.

  An evaluation of each out-patient concerning possible accidental child exposures should be undertaken.

  Lozenges must be kept out of reach and sight of children and non-patients at all times before and after use. For instructions on handling and disposal.

• Interactions
  

  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.

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

  Withdrawal symptoms may be precipitated through the administration of drugs with opioid antagonist activity, e.g., naloxone, or mixed agonist/antagonist analgesics (e.g., pentazocine, butorphanol, buprenorphine, nalbuphine).

• Adverse Drug Reactions
  

  Typical opioid side effects 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 and irritation, 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 adverse events considered to be at least possibly-related to treatment, from clinical trials were as follows (very common >10%, common >1 - 10%, uncommon >0.1 - 1%):

  Metabolism and nutrition disorders
  Uncommon : anorexia

  Psychiatric disorders
  Common: confusion, anxiety, hallucinations, abnormal thinking
  Uncommon: abnormal dreams, depersonalisation, depression, emotional lability, euphoria

  Nervous system disorders
  Very common: somnolence, dizziness
  Common: headache, myoclonus, taste perversion
  Uncommon: paraesthesia (including hyperaesthesia/circumoral paraesthesia) abnormal gait/incoordination

  Eye disorders
  Uncommon:  Abnormal vision (blurred, double vision)
   
  Vascular disorders 
  Common: vasodilatation
    
  Respiratory, thoracic and mediastinal disorders
  Uncommon: dyspnoea 

  Gastrointestinal disorders
  Very common:  nausea, constipation
  Common:  vomiting, dry mouth, abdominal pain, dyspepsia, mouth ulcers/stomatitis, tongue disorder (for example, burning sensation, ulcers)
  Uncommon:  flatulence, abdomen enlarged
    
  Skin and subcutaneous tissue disorders
  Common:  pruritus, sweating
  Uncommon:  Rash
    
  Renal and urinary disorders 
  Uncommon: urinary retention
   
  General disorders and administration site conditions  
  Common:  asthenia
  Uncommon: malaise
   
  Injury, poisoning and procedural complications
  Common: accidental injury (for example, falls)