Chemical formula: C₂₂H₂₈N₂O Molecular mass: 336.471 g/mol PubChem compound: 3345
Fentanyl interacts in the following cases:
Fentanyl is not recommended for use in patients who require the concomitant administration of an MAOI. Severe and unpredictable interactions with MAOIs, involving the potentiation of opiate effects or the potentiation of serotoninergic effects, have been reported. Therefore, Fentanyl should not be used within 14 days after discontinuation of treatment with MAOIs.
The concomitant use of transdermal fentanyl with CYP3A4 inducers may result in a decrease in fentanyl plasma concentrations and a decreased therapeutic effect. Caution is advised upon concomitant use of CYP3A4 inducers and fentanyl. The dose of fentanyl may need to be increased or a switch to another analgesic active substance may be needed. A fentanyl dose decrease and careful monitoring is warranted in anticipation of stopping concomitant treatment with a CYP3A4 inducer. The effects of the inducer decline gradually and may result in increased fentanyl plasma concentrations, which could increase or prolong both the therapeutic and adverse effects, and may cause serious respiratory depression. Careful monitoring should be continued until stable drug effects are achieved. Examples of active substance that may decrease fentanyl plasma concentrations include: carbamazepine, phenobarbital, phenytoin and rifampicin (this list is not exhaustive).
Fentanyl, a high clearance active substance, is rapidly and extensively metabolised mainly by CYP3A4.
The concomitant use of Matrifen with cytochrome P450 3A4 (CYP3A4) inhibitors may result in an increase in fentanyl plasma concentrations, which could increase or prolong both the therapeutic and adverse effects, and may cause serious respiratory depression. The extent of interaction with strong CYP3A4 inhibitors is expected to be greater than with weak or moderate CYP3A4 inhibitors. Cases of serious respiratory depression after coadministration of CYP3A4 inhibitors with transdermal fentanyl have been reported, including a fatal case after coadministration with a moderate CYP3A4 inhibitor. The concomitant use of CYP3A4 inhibitors and Matrifen is not recommended, unless the patient is closely monitored. Examples of active substances that may increase fentanyl concentrations include: amiodarone, cimetidine, clarithromycin, diltiazem, erythromycin, fluconazole, itraconazole, ketoconazole, nefazodone, ritonavir, verapamil and voriconazole (this list is not exhaustive). After coadministration of weak, moderate or strong CYP3A4 inhibitors with short-term intravenous fentanyl administration, decreases in fentanyl clearance were generally <25%, however with ritonavir (a strong CYP3A4 inhibitor), fentanyl clearance decreased on average 67%. The extent of the interactions of CYP3A4 inhibitors with long-term transdermal fentanyl administration is not known, but may be greater than with shortterm intravenous administration.
Because fentanyl is metabolised to inactive metabolites in the liver, hepatic impairment might delay its elimination. If patients with hepatic impairment receive fentanyl, they should be observed carefully for signs of fentanyl toxicity and the dose of fentanyl reduced if necessary.
Even though impairment of renal function is not expected to affect fentanyl elimination to a clinically relevant extent, caution is advised because fentanyl pharmacokinetics has not been evaluated in this patient population. If patients with renal impairment receive fentanyl they should be observed carefully for signs of fentanyl toxicity and the dose reduced if necessary. Additional restrictions apply to opioid-naïve patients with renal impairment.
Co-administration of fentanyl with a serotonergic medicinal products, such as a Selective Serotonin Re-uptake Inhibitor (SSRI) or a Serotonin Norepinephrine Re-uptake Inhibitor (SNRI) or a Monoamine Oxidase Inhibitor (MAOI), may increase the risk of serotonin syndrome, a potentially life threatening condition.
Caution is advised when fentanyl is co-administered with medicinal products that affect the serotonergic neurotransmitter systems.
The development of a potentially life-threatening serotonin syndrome may occur with the concomitant use of serotonergic active substances such as Selective Serotonin Re-uptake Inhibitors (SSRIs) and Serotonin Norepinephrine Re-uptake Inhibitors (SNRIs), and with active substances 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 fentanyl should be discontinued.
The concomitant use of other central nervous system depressants, (including opioids, sedatives such as benzodiazepines or related drugs, hypnotics, general anaesthetics, phenothiazines, tranquilizers, sedating antihistamines, and alcoholic beverages) and skeletal muscle relaxants, may produce additive CNS depressant effects; hypotension, profound sedation, hypoventilation, respiratory depression, coma or death may occur. Therefore, the use of any of these medicinal products concomitantly with Matrifen requires special patient care and observation. The dose and duration of concomitant use should be limited.
There are no clinical data on the effects of fentanyl on fertility. Some studies in rats have revealed reduced fertility and enhanced embryo mortality at maternally toxic doses.
The effects of fentanyl are enhanced and prolonged when combined with baclofen.
The concomitant use of buprenorphine, nalbuphine or 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 dependent patients.
Pretreatment with, or concurrent administration of, cimetidine may increase plasma levels of fentanyl, when repeated doses of both drugs are used.
Co-administration of clonidine can enhance the effects of fentanyl and, in particular, prolong the respiratory depression caused by it.
Concomitant use of fentanyl and droperidol can result in higher incidence of hypotension.
Plasma concentration of etomidate increased considerably (by a factor 2 to 3) when combined with fentanyl. The total plasma clearance and volume of distribution of etomidate are decreased by a factor 2 to 3 without a change in half-life when administered with fentanyl.
Co-administration of fluconazole or voriconazole and fentanyl may result in an increased exposure to fentanyl.
Simultaneous administration of fentanyl and intravenous midazolam results in an increase in the terminal plasma half-life and a reduction in the plasma clearance of midazolam. When these drugs are co-administered with fentanyl their dose may need to be reduced.
Vecuronium may cause hemodynamic depression if combined with fentanyl.
Opioids increase the tone and decrease the propulsive contractions of the smooth muscle of the gastrointestinal tract. The resultant prolongation in gastrointestinal transit time may be responsible for the constipating effect of fentanyl. Patients should be advised on measures to prevent constipation and prophylactic laxative use should be considered. Extra caution should be used in patients with chronic constipation. If paralytic ileus is present or suspected, treatment with fentanyl should be stopped.
Fentanyl may have more severe adverse effects in patients with chronic obstructive or other pulmonary disease. In such patients, opioids may decrease respiratory drive and increase airway resistance.
Fentanyl concentrations may increase if the skin temperature increases. Therefore, patients with fever should be monitored for opioid undesirable effects and the fentanyl dose should be adjusted if necessary. There is a potential for temperature-dependent increases in fentanyl released from the system resulting in possible overdose and death.
All patients should be advised to avoid exposing the fentanyl application site to direct external heat sources such as heating pads, electric blankets, heated water beds, heat or tanning lamps, sunbathing, hot water bottles, prolonged hot baths, saunas and hot whirlpool spa baths.
Fentanyl should be used with caution in patients who may be particularly susceptible to the intracranial effects of CO2 retention such as those with evidence of increased intracranial pressure, impaired consciousness, or coma. Fentanyl should be used with caution in patients with brain tumors.
Fentanyl may produce bradycardia and should therefore be administered with caution to patients with bradyarrhythmias.
Non-epileptic (myo)clonic reactions can occur. Caution should be exercised when treating patients with myasthenia gravis.
There are no adequate data from the use of fentanyl in pregnant women. Fentanyl can cross the placenta in early pregnancy. Studies in animals have shown reproductive toxicity, with impaired fertility in rats. The potential risk for humans is unknown. Fentanyl should only be used during pregnancy when clearly necessary.
Long-term treatment during pregnancy may cause withdrawal symptoms in the new-born infant. I.M. or I.V. administration during childbirth, (including caesarean section) is not recommended because Fentanyl crosses the placenta and because the foetal respiratory centre is particularly sensitive to opiates. If fentanyl is nevertheless administered, an antidote for the child should always be at hand.
Fentanyl should not be used during labour and delivery (including caesarean section) since fentanyl crosses the placenta and may cause respiratory depression in the foetus or in the new-born infant.
Fentanyl 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 buccal ore nasal administration of fentanyl and 24 hours of IV administration.
Breastfeeding should be discontinued during treatment with transdermal patches and for at least 72 hours after removal of the patch.
There are no clinical data on the effects of fentanyl on fertility. Some studies in rats have revealed reduced fertility and enhanced embryo mortality at maternally toxic doses.
No studies on the effects on the ability to drive and use machines have been performed with Abstral.
However, opioid analgesics are known to impair the mental or physical ability to perform potentially hazardous tasks such as driving or operating machinery. Patients should be advised not to drive or operate machinery if they become dizzy or drowsy or experience blurred or double vision while taking Abstral.
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:
Opioid analgesics may impair the mental and/or physical ability required for driving or operating machinery.
Patients should be advised not to drive or operate machinery if they experience somnolence, dizziness, or visual disturbance or other adverse reactions which can impair their ability to drive or operate machinery.
Undesirable effects typical of opioids are to be expected with fentanyl; they tend to decrease in intensity with continued use. The most serious potential adverse reactions associated with opioid use are respiratory depression (which could lead to respiratory arrest), hypotension and shock.
The clinical trials of fentanyl were designed to evaluate safety and efficacy in treating patients with breakthrough cancer pain; all patients were taking concomitant opioids, such as sustained-release morphine, sustained-release oxycodone or transdermal fentanyl, for their persistent pain. Therefore it is not possible to definitively separate the effects of fentanyl alone.
The most frequently observed adverse reactions with fentanyl include typical opioid adverse reactions, such as nausea, constipation, somnolence and headache.
The following adverse reactions have been reported with fentanyl and/or other fentanyl-containing compounds during clinical studies and from post-marketing experience. They are listed below by system organ class and frequency (very common ≥1/10; common ≥1/100 to <1/10; uncommon ≥1/1,000 to <1/100; not known (cannot be estimated from available data)). Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.
Uncommon: Hypersensitivity
Uncommon: Anorexia, Decreased appetite
Uncommon: Depression, Paranoia, Confusional state, Disorientation, Mental status changes, Anxiety, Euphoric mood, Dysphoria, Emotional lability, Disturbance in attention, Insomnia
Not known: Hallucination, Drug dependence (addiction), Drug abuse
Common: Dizziness, Headache, Somnolence
Uncommon: Amnesia, Parosmia, Dysgeusia, Tremor, Lethargy, Hypoaesthesia, Sleep disorder
Not known: Convulsion, Depressed level of consciousness, Loss of consciousness
Uncommon: Vision blurred
Uncommon: Tachycardia, Bradycardia
Uncommon: Hypotension
Common: Dyspnoea
Uncommon: Oropharyngeal pain, Throat tightness
Not known: Respiratory depression
Very common: Nausea
Common: Stomatitis, Vomiting, Constipation, Dry mouth
Uncommon: Mouth ulceration, Gingival ulceration, Lip ulceration, Impaired gastric emptying, Abdominal pain, Dyspepsia, Stomach discomfort, Tongue disorder, Aphthous stomatitis
Not known: Swollen tongue, Diarrhoea
Common: Hyperhidrosis
Uncommon: Skin lesion, Rash, Pruritus allergic, Pruritus, Night sweats, Increased tendency to bruise
Not known: Urticaria
Uncommon: Arthralgia, Musculoskeletal stiffness, Joint stiffness
Uncommon: Erectile dysfunction
Common: Fatigue
Uncommon: *Drug withdrawal syndrome, Asthenia, Malaise
Not known: Flushing and hot flush, Peripheral oedema, Pyrexia, Neonatal withdrawal syndrome
Uncommon: Accidental overdose
Not known: Fall
* opioid withdrawal symptoms such as nausea, vomiting, diarrhoea, anxiety, chills, tremor, and sweating have been observed with transmucosal fentanyl
The safety of fentanyl IV was evaluated in 376 subjects who participated in 20 clinical trials evaluating fentanyl IV as an anesthetic. These subjects took at least 1 dose of fentanyl IV and provided safety data. Based on pooled safety data from these clinical trials, the most commonly reported (≥5% incidence) Adverse Drug Reactions (ADRs) were (with % incidence): Nausea (26.1); Vomiting (18.6); Muscle Rigidity (10.4); Hypotension (8.8); Hypertension (8.8); Bradycardia (6.1); and Sedation (5.3).
Including the above-mentioned ADRs, the following list displays ADRs that have been reported with the use of fentanyl IV from either clinical trials or postmarketing experiences.
The displayed frequency categories use the following convention: 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); and not known (cannot be estimated from the available clinical trial data).
Adverse Drug Reactions:
Not Known: Hypersensitivity (such as anaphylactic shock, anaphylactic reaction, urticaria)
Uncommon: Euphoric mood
Not Known: Delirium
Common: Dyskinesia; Sedation; Dizziness
Uncommon: Headache
Not Known: Convulsions; Loss of consciousness; Myoclonus; Hyperalgesia
Common: Visual disturbance
Common: Bradycardia; Tachycardia; Arrhythmia
Cardiac arrest
Common: Hypotension; Hypertension; Vein pain
Uncommon: Phlebitis; Blood pressure fluctuation
Common: Laryngospasm; Bronchospasm; Apnoea
Uncommon: Hyperventilation; Hiccups
Not Known: Respiratory depression; Cough
Very Common: Nausea; Vomiting
Not Known: Constipation
Common: Dermatitis allergic
Not Known: Pruritus
Very Common: Muscle Rigidity (which may also involve the thoracic muscles)
Uncommon: Chills; Hypothermia
Not Known: Drug withdrawal syndrome
Common: Confusion postoperative
Uncommon: Airway complication of anaesthesia; Agitation postoperative
When a neuroleptic is used with fentanyl, the following adverse reactions may be observed: chills and/or shivering, restlessness, postoperative hallucinatory episodes and extrapyramidal symptoms.
The safety of transdermal fentanyl was evaluated in 1565 adult and 289 paediatric subjects who participated in 11 clinical trials (1 double-blind, placebo-controlled; 7 open-label, active-controlled; 3 open-label, uncontrolled) used for the management of chronic malignant or non-malignant pain. These subjects received at least one dose of transdermal fentanyl and provided safety data. Based on pooled safety data from these clinical trials, the most commonly reported (i.e. ≥10% incidence) adverse drug reactions (ADRs) were: nausea (35.7%), vomiting (23.2%), constipation (23.1%), somnolence (15.0%), dizziness (13.1%), and headache (11.8%).
The adverse reactions reported with the use of transdermal fentanyl from these clinical studies, including the above-mentioned adverse reactions, and from post-marketing experiences are listed below.
The displayed frequency categories use the following convention: 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); and not known (cannot be estimated from the available clinical trial data). The adverse reactions are presented by System Organ Class and in order of decreasing seriousness within each frequency category.
Adverse Drug Reactions in Adult and Paediatric Subjects
Common: Hypersensitivity
Not Known: Anaphylactic shock, Anaphylactic reaction, Anaphylactoid reaction
Common: Anorexia
Common: Insomnia, Depression, Anxiety, Confusional state, Hallucination
Uncommon: Agitation, Disorientation, Euphoric mood
Very Common: Somnolence, Dizziness, Headache
Common: Tremor, Paraesthesia
Uncommon: Hypoaesthesia, Convulsion (including clonic convulsions and grand mal convulsion), Amnesia, Depressed level of consciousness, Loss of consciousness
Uncommon: Vision blurred
Rare: Miosis
Common: Vertigo
Cardiac Disorders
Common: Palpitations, Tachycardia
Uncommon: Bradycardia, Cyanosis
Common: Hypertension
Uncommon: Hypotension
Common: Dyspnoea
Uncommon: Respiratory depression, Respiratory distress
Rare: Apnoea, Hypoventilation
Not Known: Bradypnoea
Very Common: Nausea, Vomiting, Constipation
Common: Diarrhoea, Dry mouth, Abdominal pain, Abdominal pain upper, Dyspepsia
Uncommon: Ileus
Rare: Subileus
Common: Hyperhidrosis, Pruritus, Rash, Erythema
Uncommon: Eczema, Dermatitis allergic, Skin disorder, Dermatitis, Dermatitis contact
Common: Muscle spasms
Uncommon: Muscle twitching
Common: Urinary retention
Uncommon: Erectile dysfunction, Sexual dysfunction
General Disorders and Administration Site Conditions
Common: Fatigue, Oedema peripheral, Asthenia, Malaise, Feeling cold
Uncommon: Application site reaction, Influenza like illness, Feeling of body temperature change, Application site hypersensitivity, Drug withdrawal syndrome, Pyrexia*
Rare: Application site dermatitis, Application site eczema
* the assigned frequency (uncommon) is based on analyses of incidence including only adult and paediatric clinical study subjects with non-cancer pain.
The safety of fentanyl transdermal patch was evaluated in 289 paediatric subjects (<18 years) who participated in 3 clinical studies for the management of chronic or continuous pain of malignant or non-malignant origin. These subjects received at least one dose of fentanyl transdermal patch and provided safety data.
The safety profile in children and adolescents treated with fentanyl transdermal patch was similar to that observed in adults. No risk was identified in the paediatric population beyond that expected with the use of opioids for the relief of pain associated with serious illness and there does not appear to be any paediatric-specific risk associated with fentanyl transdermal patch use in children as young as 2 years old when used as directed.
Based on pooled safety data from these 3 clinical trials in paediatric subjects, the most commonly reported (i.e. ≥10% incidence) adverse reactions were vomiting (33.9%), nausea (23.5%), headache (16.3%), constipation (13.5%), diarrhoea (12.8%), and pruritus (12.8%).
Tolerance, physical dependence, and psychological dependence can develop on repeated use of fentanyl.
Opioid withdrawal symptoms (such as nausea, vomiting, diarrhoea, anxiety, and shivering) are possible in some patients after conversion from their previous opioid analgesic to fentanyl transdermal patch or if therapy is stopped suddenly.
There have been very rare reports of newborn infants experiencing neonatal withdrawal syndrome when mothers chronically used transdermal fentanyl during pregnancy.
Cases of serotonin syndrome have been reported when fentanyl was administered concomitantly with highly serotonergic drugs.
Typical opioid adverse reactions are to be expected with fentanyl nasal spray. 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 fentanyl nasal spray 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 fentanyl nasal spray alone.
The following adverse reactions have been reported with PecFent and/or other fentanyl-containing compounds during clinical studies and post marketing experience (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); unknown (cannot be estimated from available data)).
Uncommon: Pneumonia, Nasopharyngitis, Pharyngitis, Rhinitis
Uncommon: Neutropenia
Uncommon: Hypersensitivity
Uncommon: Dehydration, Hyperglycaemia, Decreased appetite, Increased appetite
Common: Disorientation
Uncommon: Delirium, Hallucination, Confusional state, Depression, Attention deficit/hyperactivity disorder, Anxiety, Euphoric mood, Nervousness
Unknown: Insomnia, Drug dependence (addiction), Drug abuse
Common: Dysgeusia, Dizziness, Somnolence, Headache
Uncommon: Loss of consciousness, Depressed level of consciousness, Convulsion, Ageusia, Anosmia, Memory impairment, Parosmia, Speech disorder, Sedation, Lethargy, Tremor
Uncommon: Vertigo
Uncommon: Cyanosis
Uncommon: Cardiovascular insufficiency, Lymphoedema, Hypotension, Hot flush
Unknown: Flushing
Common: Epistaxis, Rhinorrhoea, Nasal discomfort
Uncommon: 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
Unknown: Respiratory depression
Common: Vomiting, Nausea, Constipation
Uncommon: Intestinal perforation, Peritonitis, Oral hypoaesthesia, Oral paraesthesia, Diarrhoea, Retching, Abdominal pain, Tongue disorder, Mouth ulceration, Dyspepsia, Dry mouth
Common: Pruritus
Uncommon: Hyperhydrosis, Urticaria
Uncommon: Arthralgia, Muscle twitching
Uncommon: Anuria, Dysuria, Proteinuria, Urinary hesitation
Uncommon: Vaginal haemorrhage
Uncommon: Non-cardiac chest pain, Asthenia, Chills, Face oedema, Peripheral oedema, Gait disturbance, Pyrexia, Fatigue, Malaise, Thirst
Unknown: Withdrawal syndrome*, Neonatal withdrawal syndrome
Uncommon: Platelet count decreased, Weight increased
Uncommon: Fall, Intentional drug misuse, Medication error
* See next section below
Opioid withdrawal symptoms such as nausea, vomiting, diarrhoea, anxiety, chills, tremor, and sweating have been observed with transmucosal fentanyl.
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