PosologyPatients should be individually titrated to the dose that provides adequate analgesia with tolerable adverse drug reactions. Patients must be carefully monitored during the titration process. Titration to a higher dose necessitates contact with the health care professional.The dose of Instanyl for treatment of breakthrough pain was independent of the daily maintenance dose of opioid in the clinical studies (see section 5.1). Maximum daily dose: Treatment of up to four breakthrough pain episodes, each with no more than two doses separated by at least 10 minutes.Patients should wait at least 4 hours before treating another breakthrough pain episode with Instanyl during both titration and maintenance therapy.
Dose titrationBefore patients are titrated with Instanyl, it is expected that their background persistent pain is controlled by use of chronic opioid therapy and that they are experiencing no more than four episodes of breakthrough pain per day.
Method of titrationThe initial strength should be one dose of 50 micrograms in one nostril, titrating upwards as necessary through the range of available strengths (50, 100, and 200 micrograms). If adequate analgesia is not obtained redosing of the same strength may be administered at the earliest after 10 minutes. Each titration step (dose strength) should be evaluated in several episodes.
Maintenance therapyOnce the dose has been established according to the steps described above, the patient should be maintained on this strength of Instanyl. If the patient has insufficient pain relief, redosing with same strength can be done at the earliest after 10 minutes.
Dose adjustmentGenerally, the maintenance strength of Instanyl should be increased when a patient requires more than one dose per breakthrough pain episode for several consecutive episodes.Dose adjustment of the background opioid therapy may be required if the patient consistently presents with more than four breakthrough pain episodes per 24 hours. If adverse reactions are intolerable or persistent, the strength should be reduced or treatment with Instanyl be replaced by other analgesics.
Discontinuation of therapyInstanyl should be discontinued immediately if the patient no longer experiences breakthrough pain episodes. The treatment for the persistent background 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 is necessary in order to avoid the possibility of abrupt withdrawal effects.
ElderlyLimited data on pharmacokinetics, efficacy and safety are available for the use of Instanyl in patients above >65 years of age. Elderly patients may have a reduced clearance, a prolonged half-life and higher sensitivity to fentanyl than younger patients. Caution should therefore be taken in treatment of elderly, cachectic or debilitated patients.In clinical trials elderly patients tend to titrate to a lower effective strength than patients less than 65 years of age. Particular caution should be exercised when titrating Instanyl in elderly patients.
Hepatic impairmentInstanyl should be administered with caution to patients with moderate to severe hepatic impairment (see section 4.4).
Renal impairmentInstanyl should be administered with caution to patients with moderate to severe renal impairment (see section 4.4).
Paediatric populationThe safety and efficacy of Instanyl in children aged below 18 years have not yet been established.No data are available.
Method of administrationInstanyl is intended for nasal use.It is recommended that the patient sit or stand in upright position when administrating Instanyl. Cleaning of the nasal spray tip is required after each use.
Precautions to be taken before handling or administering the medicinal productBefore using Instanyl for the first time, the nasal spray must be primed until a fine mist appears; 3 to 4 actuations of the nasal spray are usually required. If the product has not been used for a period of more than seven days, the nasal spray must be primed again by actuating once before the next dose is taken.During the priming process product will be expelled. Therefore, the patient must be instructed that the priming should be conducted in a well ventilated area, pointing away from the patient and other people, and away from surfaces and objects that could come into contact with other people, particularly children.
Respiratory depressionClinical significant respiratory depression may occur with fentanyl, and patients must be observed for these effects. 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 (see section 4.5).
Chronic pulmonary diseaseIn patients with chronic obstructive pulmonary diseases, fentanyl may have more severe adverse reactions. In these patients, opioids may decrease respiratory drive and increase airway resistance.
Impaired renal or hepatic functionFentanyl should be administered with caution to patients with moderate to severe hepatic or renal impairment. The influence of hepatic and renal impairment on the pharmacokinetics of Instanyl have not been evaluated; however, when administered intravenously the clearance of fentanyl has shown to be altered due to hepatic and renal impairment caused by alterations in metabolic clearance and plasma proteins.
Increased intracranial pressureFentanyl should be used with caution in patients with evidence of increased intracranial pressure, impaired consciousness or coma. Instanyl should be used with caution in patients with cerebral tumour or head injury.
Cardiac diseaseFentanyl may produce bradycardia. Fentanyl should therefore be used with caution in patients with previous or pre-existing bradyarrhythmias. Opioids may cause hypotension, especially in patients with hypovolaemia. Instanyl should therefore be used with caution in patients with hypotension and/or hypovolaemia.
Serotonin SyndromeCaution is advised when Instanyl is coadministered with drugs that affect the serotoninergic neurotransmitter systems.The development of a potentially life-threatening serotonin syndrome may occur with the concomitant use of serotonergic drugs such as Selective Serotonin Re-uptake Inhibitors (SSRIs) and Serotonin Norepinephrine Re-uptake Inhibitors (SNRIs), and with drugs which impair metabolism of serotonin (including Monoamine Oxidase Inhibitors [MAOIs]). This may occur within the recommended dose.Serotonin syndrome may include mental-status changes (e.g., agitation, hallucinations, coma), autonomic instability (e.g., tachycardia, labile blood pressure, hyperthermia), neuromuscular abnormalities (e.g., hyperreflexia, incoordination, rigidity), and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhoea).If serotonin syndrome is suspected, treatment with Instanyl should be discontinued.
Nasal conditionsIf the patient experiences recurrent episodes of epistaxis or nasal discomfort while taking Instanyl, an alternative administration form for treatment of breakthrough pain should be considered.
Common coldThe overall extent of fentanyl exposure in subjects with common cold without prior treatment with nasal vasoconstrictor is comparable to that in healthy subjects. For concomitant use of nasal vasoconstrictor see section 4.5.
Abuse potential and dependenceTolerance 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 in the treatment of cancer related pain.
Withdrawal symptomsWithdrawal symptoms may be precipitated through the administration of substances with opioid antagonist activity, e.g. naloxone, or mixed agonist/antagonist analgesic (e.g. pentazocine, butorphanol, buprenorphine, nalbuphine).
PregnancyThere are no adequate data from the use of fentanyl in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3). The potential risk for humans is unknown. Instanyl should not be used in pregnancy unless clearly necessary.Following long-term treatment, fentanyl may cause withdrawal in the new-born infant. 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 foetus. If Instanyl is administered, an antidote for the child should be readily available.
Breast-feedingFentanyl passes into breast milk and may cause sedation and respiratory depression in the breast-fed child. Fentanyl should not be used by breastfeeding women and breastfeeding should not be restarted until at least 5 days after the last administration of fentanyl.
FertilityThere are no human data on fertility available. In animal studies, male and female fertility was impaired at sedative doses (see section 5.3).
Summary of the safety profileTypical opioid adverse reactions are to be expected with Instanyl. Frequently, most of these will cease or decrease in intensity with continued use of the medicinal product. 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 trials of Instanyl 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 Instanyl alone. The adverse reactions considered to be at least possibly related to treatment in the clinical trials of Instanyl are included in the table below.
Tabulated list of adverse reactionsThe following categories are used to rank the undesirable effects by frequency of occurrence: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1000 to <1/100); rare (≥1/10,000 to <1/1000); and very rare (<1/10,000), not known (cannot be estimated from the available data). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.The following adverse reactions have been reported with Instanyl and/or other fentanyl-containing compounds during clinical studies and post marketing experience:
|System organ class||Common||Uncommon||Not known|
|Psychiatric disorders||Dependence, insomnia||Hallucination|
|Nervous system disorders||Somnolence, dizziness, headache||Sedation, myoclonus, paraesthesia, dysaesthesia, dysgeusia||Convulsion|
|Ear and Labyrinth disorders||Vertigo||Motion sickness|
|Vascular disorders||Flushing, hot flush|
|Respiratory, thoracic and mediastinal disorders||Throat irritation||Respiratory depression, epistaxis, nasal ulcer, rhinorrhea||Nasal septum perforation|
|Gastrointestinal disorders||Nausea, vomiting||Constipation, stomatitis, dry mouth||Diarrhoea|
|Skin and subcutaneous tissue disorders||Hyperhidrosis||Pain of skin, pruritus|
|General disorders and administration site conditions||Pyrexia||Fatigue, malaise peripheral oedema, withdrawal syndrome*|
|Injury, poisoning and procedural complications||Fall|
Reporting of suspected adverse reactionsReporting suspected adverse reactions is an important way to gather more information to continuously monitor 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.
SymptomsThe symptoms of fentanyl overdose are expected to be an extension of its pharmacological actions e.g. lethargy, coma and severe respiratory depression. Other symptoms may be hypothermia, decreased muscle tonus, bradycardia and hypotension. Signs of toxicity are deep sedation, ataxia, miosis, convulsions and respiratory depression which is the main symptom.
TreatmentFor management of respiratory depression immediate countermeasures should be started including physical or verbal stimulation of the patient. These actions can be followed by administration of a specific opioid antagonist such as naloxone. Respiratory depression following an overdose may outlast the duration of action of the opioid antagonist. The half-life of the antagonist may be short, therefore repeated administration or continuous infusion may be necessary. Reversal of the narcotic effect may result in acute onset of pain and release of catecholamines.If the clinical situation warrants, a patent airway should be established and maintained, possibly with an oropharyngeal airway or endotracheal tube and oxygen should be administered and respiration assisted or controlled, as appropriate. Adequate body temperature and fluid intake should be maintained.If severe or persistent hypotension occurs, hypovolemia should be considered and the condition should be managed with appropiate parenteral fluid therapy.
Mechanism of actionFentanyl is an opioid analgesic interacting primarily with the opioid μ-receptor as a pure agonist with low affinity for the δ- and κ-opioid receptors. The primary therapeutic action is analgesia. The secondary pharmacological effects are respiratory depression, bradycardia, hypothermia, constipation, miosis, physical dependence and euphoria.
Clinical safety and efficacyThe efficacy and safety of Instanyl (50, 100 and 200 micrograms) have been assessed in two randomised, double-blind, cross-over, placebo-controlled pivotal studies in 279 opioid-tolerant adult cancer patients (age 32-86 years) with breakthrough pain (BTP). The patients had an average of 1 to 4 episodes per day while taking maintenance opioid therapy. Patients in the second pivotal study had earlier participated in the Instanyl pharmacokinetic study or in the first pivotal study.The clinical studies demonstrated the efficacy and safety of Instanyl. No distinct correlation between the maintenance opioid dose and Instanyl doses have been established, however in the second pivotal study patients with low maintenance opioid dose tended to achieve effective pain relief with a correspondingly lower strength of Instanyl compared to patients taking higher levels of maintenance opioid dose. This was most distinct for patients ending on Instanyl 50 micrograms.In the clinical studies in cancer patients, the most frequent strengths used were 100 and 200 micrograms.All three strengths of Instanyl showed statistically significant (p<0.001) higher pain intensity difference at 10 minutes (PID10) compared with placebo. Furthermore, Instanyl was significantly superior to placebo in BTP relief at 10, 20, 40, and 60 minutes following administration. The results of summary of PID at 60 minutes (SPID0-60) showed that all strengths of Instanyl had significantly higher mean SPID0-60 scores compared with placebo (p<0.001) demonstrating better pain relief of Instanyl compared to placebo during 60 minutes.The safety and efficacy of Instanyl have been evaluated in patients taking the medicinal product at the onset of a breakthrough pain episode. Instanyl should not be used pre-emptively.The clinical experience with Instanyl in patients with background opioid treatment equivalent to ≥ 500 mg/day morphine or ≥ 200 micrograms/hour transdermal fentanyl is limited.Instanyl in doses above 400 micrograms have not been evaluated in clinical trials.
AbsorptionFentanyl is highly lipophilic. Fentanyl exhibits three compartment distribution kinetics. Animal data shows that following absorption, 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 approximately 80%. The absolute bioavailability of Instanyl is about 89%. Clinical data show that fentanyl is absorbed very rapidly through the nasal mucosa. Administration of Instanyl in single doses ranging from 50 to 200 micrograms fentanyl per dose in opioid tolerant cancer patients produces a rapid Cmax level of 0.35 to 1.2 ng/ml. The corresponding median Tmax are 12-15 minutes. However, higher values for Tmax were observed in a dose-proportionality study in healthy volunteers.
DistributionAfter intravenous administration of fentanyl the initial distribution half-life is approximately 6 minutes and a similar half-life is seen after the nasal administration of Instanyl. The elimination half-life is approximately 3-4 hours for Instanyl in cancer patients.
BiotransformationFentanyl is metabolised primarily in the liver via CYP3A4. The major metabolite, norfentanyl is inactive.
EliminationAbout 75% of fentanyl is excreted into the urine, mostly as inactive metabolites, with less than 10% as unchanged active substance. About 9% of the dose is recovered in the faeces primarily as metabolites.
LinearityInstanyl shows linear kinetics. Dose linearity from 50 micrograms to 400 micrograms of Instanyl has been demonstrated in healthy subjects.A drug-drug-interaction study was performed with a nasal vasoconstrictor (oxymetazoline). Subjects with allergic rhinitis received oxymetazoline nasal spray one hour prior to Instanyl. Comparable bioavailability (AUC) of fentanyl was achieved with and without oxymetazoline, while fentanyl Cmax decreased and Tmax increased by a factor two when oxymetazoline was administered. The overall extent of fentanyl exposure in subjects with allergic rhinitis without prior treatment with nasal vasoconstrictor is comparable to that in healthy subjects. Concomitant use of nasal vasoconstrictor should be avoided (see section 4.5).
BioequivalenceA pharmacokinetic study has shown that Instanyl single-dose and multi-dose nasal spray are bioequivalent.
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