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Drug Details

PecFent

• Presentation
  Nasal spray, solution (nasal spray) A clear to practically clear colourless aqueous solution.
• Description
  Each ml of solution contains 1,000 micrograms fentanyl (as citrate) 1 spray (100 microliters) contains 100 micrograms fentanyl (as citrate) Each bottle contains 1.55 ml (1.55 mg fentanyl) ensuring delivery of 8 sprays of 100 micrograms Excipients Each spray contains 0.02 mg propylhydroxybenzoate (E216).
• Indications
  

  PecFent is indicated for the management of breakthrough pain (BTP) in adults who are 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.

  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 supervision of a physician experienced in the management of opioid therapy in cancer patients. Physicians should keep in mind the potential for abuse of fentanyl.

  Posology
  PecFent should be titrated to an “effective” dose that provides adequate analgesia and minimises adverse reactions without causing undue (or intolerable) adverse reactions, for two consecutively treated episodes of BTP. The efficacy of a given dose should be assessed over the ensuing 30 minute period.

  Patients should be carefully monitored until an effective dose is reached.
  One dose of PecFent may include administration of 1 spray (100 microgram or 400 microgram doses) or 2 sprays (200 microgram or 800 microgram doses) of the same dose strength (either 100 microgram or 400 microgram strength).

  Patients should not take more than 4 doses per day. Patients should wait at least 4 hours after a dose before treating another BTP episode with PecFent.

  Initial dose

  • The initial dose of PecFent to treat episodes of BTP is always 100 micrograms (one spray), even in patients switching from other fentanyl containing products for their BTP.
  • Patients must wait at least 4 hours before treating another episode of BTP with PecFent.

  Method of titration
  • Patients should be prescribed an initial titration supply of one bottle (8 sprays) of PecFent 100 micrograms/spray.
  • Patients whose initial dose is 100 micrograms and who need to titrate to a higher dose due to a lack of effect can be instructed to use two 100 microgram sprays (one in each nostril) for their next BTP episode. If this dose is not successful, the patient may be prescribed a bottle of PecFent 400 micrograms/spray and instructed to change to one 400 microgram spray for their next episode of pain. If this dose is not successful, the patient may be instructed to increase to two 400 microgram sprays (one in each nostril).
  • From treatment initiation, patients should be closely followed and the dose titrated until an effective dose is reached and confirmed for two consecutively treated episodes of BTP.

  Titration in patients switching between immediate-release fentanyl containing products
  Substantial differences may exist in the pharmacokinetic profile of immediate-release fentanyl products, which result in clinically important differences in the rate and extent of absorption of fentanyl. Therefore, when switching between fentanyl containing products indicated for treatment of breakthrough pain, including intranasal formulations, it is essential that patients are again titrated with the new product, and not switched on a dose-for-dose (microgram-for-microgram) basis.

  Maintenance therapy
  Once an effective dose has been established during titration, patients should continue to take this dose up to a maximum of 4 doses per day.

  Dose readjustment
  Generally, the maintenance dose of PecFent should be increased only where the current dose fails to adequately treat the BTP for several consecutive episodes.

  A review of the dose of the background opioid therapy may be required if patients consistently present with more than four BTP episodes per 24 hours.

  If adverse reactions are intolerable or persistent, the dose should be reduced or treatment with PecFent replaced by another analgesic.

  Discontinuation of therapy
  PecFent should be discontinued immediately if the patient no longer experiences breakthrough pain episodes. The treatment for persistent backgound pain should be kept as prescribed. If discontinuation of all opioid therapy is required, the patient must be closely followed by the doctor
  as gradual downward opioid titration therapy is necessary in order to avoid the possibility of abrupt withdrawal effects.

  Paediatric population
  The safety and efficacy of PecFent in children aged below 18 years have not yet been established. No data are available.

  Use in the elderly (older than 65 years)
  In the PecFent clinical trial programme, 104 (26.1%) of patients were over 60 years of age, 67 (16.8%) over 65 years and 15 (3.8%) over 75 years. There was no indication that older patients tended to titrate to lower doses or experience more adverse reactions. Nevertheless, in view of the importance of renal and hepatic function in the metabolism and clearance of fentanyl, additional care should be exercised in the use of PecFent in the elderly. No data on the pharmacokinetics of PecFent in elderly patients are available.

  Hepatic or renal impairment
  PecFent should be administered with caution to patients with moderate or severe hepatic or renal impairment

  Method of administration
  PecFent is for administration via the nasal route only.
  PecFent can deliver 100, 200, 400 and 800 microgram doses as follows:

  Dose required micrograms)	Product strength (micrograms)	Amount
  100	100	One spray administered into one nostril
  200	100	One spray administered into each nostril
  400	400	One spray administered into one nostril
  800	400	One spray administered into each nostril

  The bottle should be removed from the child resistant container immediately prior to use and the protective cap removed. The bottle must be primed before first use by holding upright and simply pressing and releasing the finger grips either side of the nozzle until a green bar appears in the counting window (should occur after four sprays).

  If the product has not been used for more than 5 days or if it is more than 14 days since the product was first used, the PecFent bottle should be discarded.

  To administer PecFent the nozzle is placed a short distance (about 1 cm) into the nostril and pointed slightly towards the bridge of the nose. A spray is then administered by pressing and releasing the finger grips either side of the nozzle. An audible click will be heard and the number displayed on the
  counter will advance by one.

  Patients must be advised that they may not feel the spray being administered, and that they should therefore rely on the audible click and the number on the counter advancing to confirm that a spray has been delivered. The nasal spray pump permanently locks after the eighth spray has been administered.

  The PecFent spray droplets form a gel in the nose. Patients should be advised not to blow their nose immediately after PecFent administration.
  The protective cap should be replaced after each use and the bottle returned to the child resistant container for safe storage.

• Contra Indications
  

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

  Use in opioid naïve patients.

  Severe respiratory depression or severe obstructive lung conditions.

• Special Precautions
  

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

  In order to minimise the risks of opioid-related adverse reactions 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 PecFent therapy begins.

  Respiratory depression
  There is a risk of clinically significant respiratory depression associated with the use of fentanyl.

  Patients with pain who receive chronic opioid therapy develop tolerance to respiratory depression and hence the risk of respiratory depression in these patients is reduced. The use of concomitant central nervous system depressants may increase the risk of respiratory depression.

  Chronic pulmonary disease
  In patients with chronic obstructive pulmonary diseases, fentanyl may cause more serious adverse reactions. In these patients, opioids may decrease respiratory drive and increase airway resistance.

  Increased intracranial pressure
  PecFent 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 patients
  with a head injury and should be used only if clinically warranted.

  Cardiac disease
  Intravenous fentanyl may produce bradycardia. PecFent should therefore be used with caution in patients with pre-existing bradyarrhythmias.

  Impaired hepatic or renal function
  In addition, PecFent 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. 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.

  Abuse potential and tolerance
  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.

  Athletes should be informed that treatment with fentanyl could lead to positive doping tests.
  
  Route of administration
  PecFent is only intended for intranasal administration, and must not be administered by any other route. Due to physico-chemical properties of excipients included in the formulation, intravenous or intra-arterial injection must be avoided in particular.

  Nasal conditions
  If the patient experiences recurrent episodes of epistaxis or nasal discomfort while taking PecFent, an alternative method of administration for treatment of breakthrough pain should be considered.

  PecFent excipients
  PecFent contains propylhydroxybenzoate (E216). In some patients this may cause allergic reactions (possibly delayed) and, exceptionally, bronchospasm (if the product is not correctly administered).

• Interactions
  

  therefore potential interactions may occur when PecFent is given concurrently with agents that affect CYP3A4 activity. Coadministration with agents that induce 3A4 activity may reduce the efficacy of PecFent. The concomitant use of PecFent 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 PecFent concomitantly with moderate or strong CYP3A4 inhibitors should be carefully monitored for an extended period of time.

  Dose increase should be undertaken 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.

  PecFent is not recommended for use in patients who have received monoamine oxidase (MAO) inhibitors within the previous 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.

  Concomitant use of nasally administered oxymetazoline has been shown to decrease the absorption of PecFent (see section 5.2). The concomitant use of nasally administered vasoconstrictive decongestants during titration is therefore not recommended as this may lead to patients titrating to a dose that is higher than required. PecFent maintenance treatment may also be less effective in patients with rhinitis when administered concomitantly with a nasal vasoconstrictive decongestant. If this occurs, patients should be advised to discontinue their decongestant.

  Concomitant use of PecFent and other medicinal products (other than oxymetazoline) administered via the nose has not been evaluated in the clinical trials. Other nasally administered treatments should be avoided within 15 minutes of dosing with PecFent.

• Adverse Drug Reactions
  

  Typical opioid adverse reactions are to be expected with PecFent. 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 monitored for these.

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

  The adverse reactions considered to be at least possibly-related to treatment, from Phase II and III 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); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000) within each frequency grouping, adverse reactions are presented in order of decreasing seriousness).

  	Common	Uncommon
  Infections and infestations		Pneumonia Nasopharyngitis Pharyngitis Rhinitis
  Blood and lymphatic system disorders		Neutropenia
  Immune system disorders		Hypersensitivity
  Metabolism and nutrition disorders		Dehydration Hyperglycaemia Decreased appetite Increased appetite
  Psychiatric disorders	Disorientation	Drug abuse Delirium Hallucination Confusional state Depression Attention deficit/hyperactivity disorder Anxiety Euphoric mood Nervousness
  Nervous system disorders	Dysgeusia Dizziness Somnolence Headache	Loss of consciousness Depressed level of consciousness Convulsion Ageusia Anosmia Memory impairment Parosmia Speech disorder Sedation Lethargy Tremor
  Ear and labyrinth disorders		Vertigo
  Cardiac disorders		Cyanosis
  Vascular disorders		Cardiovascular insufficiency Lymphoedema Hypotension Hot flush
  Respiratory, thoracic and mediastinal disorders	Epistaxis Rhinorrhoea Nasal discomfort	Upper airway obstruction Pharyngolaryngeal pain Rhinalgia Nasal mucosal disorder Cough Dyspnoea Sneezing Upper respiratory tract congestion Nasal congestion Intranasal hypoaesthesia Throat irritiation Postnasal drip Nasal dryness
  Gastrointestinal disorders	Vomiting Nausea Constipation	Intestinal perforation Peritonitis Oral hypoaesthesia Oral paraesthesia Diarrhoea Retching Abdominal pain Tongue disorder Mouth ulceration Dyspepsia Dry mouth
  Skin and subcutaneous tissue disorders	Pruritus	Hyperhydrosis Urticaria
  Musculoskeletal and connective tissue disorders		Arthralgia Muscle twitching
  Renal and urinary disorders		Anuria Dysuria Proteinuria Urinary hesitation
  Reproductive system and breast disorders		Vaginal haemorrhage
  General disorders and administration site conditions		Non-cardiac chest pain Asthenia Chills Face oedema Peripheral oedema Gait disturbance Pyrexia Fatigue Malaise Thirst
  Investigations		Platelet count decreased Weight increased
  Injury, poisoning and procedural complications		Fall Intentional drug misuse Medication error