Fentanyl

Registered South African indications:

• Breakthrough pain in cancer

Contraindications

South African manufacturer recommendations

• Hypersensitivity to the active ingredient or any of its excipients
• Breastfeeding
• Patients without maintenance opioid therapy
• Severe respiratory depression or severe obstructive lung conditions
• Treatment of acute pain other than breakthrough pain
• Coadministration with medicinal agents containing sodium oxybate

Recommendations in other jurisdictions

• Hypersensitivity to the active ingredient or any of its excipients
• Patients without maintenance opioid therapy
• Severe respiratory depression or severe obstructive lung conditions
• Treatment of acute pain other than breakthrough pain
• Coadministration with medicinal agents containing sodium oxybate

Cautions

South African manufacturer recommendations

• Pregnancy
• Labour and delivery (including caesarean section)
• Moderate to severe renal impairment
• Moderate to severe hepatic impairment
• Elderly
• Xerostomia
• Accidental use in children
• Titration process and improper dosing
• Patients without maintenance opioid therapy
• Non-severe chronic obstructive pulmonary disease or other medical conditions predisposing to respiratory depression
• Patients who may be particularly susceptible to the intracranial effects of CO₂ retention e.g. those with evidence of increased intracranial pressure or impaired consciousness
• Previous or pre-existing bradydysrythmias
• Hypovolaemia
• Hypotension
• Repeated adminstration
• High doses
• Coadministration with serotoninergic agents
• Coadministration with agents which impair metabolism of serotonin e.g. monoamine oxidase inhibitors (MAOIs)
• Sodium-controlled diet 
• May impair ability to drive and operate machinery 

Recommendations in other jurisdictions

• Pregnancy
• Breastfeeding
• Labour and delivery (including caesarean section)
• Moderate to severe renal impairment
• Moderate to severe hepatic impairment
• Elderly
• Xerostomia
• Accidental use in children
• Titration process and improper dosing
• Patients without maintenance opioid therapy
• Non-severe chronic obstructive pulmonary disease or other medical conditions predisposing to respiratory depression
• Central sleep apnoea
• Patients who may be particularly susceptible to the intracranial effects of CO₂ retention e.g. those with evidence of increased intracranial pressure or impaired consciousness
• Previous or pre-existing bradydysrythmias
• Hypovolaemia
• Hypotension
• Repeated administration
• Patients at increased risk of opioid abuse
• Risk factors for opioid use disorder (OUD)
  - Personal or family history (parents or siblings) of substance use disorders (including alcohol use disorder)
  - Current tobacco users
  - Personal history of other mental health disorders e.g. major depression, anxiety and personality disorders
• High doses
• Coadministration with serotoninergic agents
• Coadministration with agents which impair metabolism of serotonin e.g. monoamine oxidase inhibitors (MAOIs)
• Sodium-controlled diet
• May impair ability to drive and operate machinery 

Forms avail. in SA and covered in this monograph: eft

Dosages below are applicable to:

• South African registered indications and dosages
• Indications and dosages registered in other jurisdictions

Treatment should be initiated by and remain under the guidance of a medical practitioner experienced in the management of opioid therapy in cancer patients

Breakthrough pain ((BTP) in cancer
- In patients already receiving maintenance opioid therapy* for chronic cancer pain

Titration in patients not switching from other fentanyl-containing products

• Oral (eft): Initial: 100μg; Titrate upwards as necessary through the range of available strengths to provide adequate analgesia; Maintenance: Effective dose established during titration or increased when a patient requires more than one tablet per BTP episode for several consecutive BTP episodes; Max: 800mg/dose

Titration in patients switching from other fentanyl-containing products

• Oral (eft): Initial: 100μg or higher if necessary; Titrate upwards as necessary through the range of available strengths to provide adequate analgesia; Maintenance: Effective dose established during titration or increased when a patient requires more than one tablet per BTP episode for several consecutive BTP episodes; Max: 800mg/dose

---

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

---

See additional prescribing points for method of titration, maintenance therapy, dose readjustment, discontinuation of therapy and method of administration

---

Medical practitioners should keep in mind the potential of abuse of fentanyl

---

Patients should be instructed not to use two different formulations of fentanyl concurrently for the treatment of breakthrough pain (BTP), and to dispose of any fentanyl product prescribed for BTP when switching to fentanyl effervescent buccal tablets. The number of tablet strengths available to the patients at any time should be minimised to prevent confusion and potential overdose

---

Fentanyl effervescent buccal tablets should be individually titrated to an “effective” dose that provides adequate analgesia and minimises adverse reactions. In clinical studies, the effective dose for BTP was not predictable from the daily maintenance dose of opioid. Patients should be carefully monitored until an effective dose is reached

---

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

Not established for use in children below 18 years

Pregnancy 

South African manufacturer recommendations

• Caution; positive evidence of risk in animal studies 
• There are no adequate data from the use of fentanyl in pregnant women. Studies in animals have shown some reproductive toxicity. The potential risk for humans is unknown
• With long-term use of fentanyl during pregnancy, there is a risk of neonatal opioid withdrawal syndrome which may be life-threatening if not recognised and treated, and requires management according to protocols developed by neonatology experts. If opioid use is required for a prolonged period in a pregnant woman, advise the patient of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available
• 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 fentanyl effervescent buccal tablets are administered, an antidote for the child should be readily available

Recommendations in other jurisdictions

• Caution; positive evidence of risk in animal studies 
• There are no adequate data from the use of fentanyl in pregnant women. Studies in animals have shown some reproductive toxicity. The potential risk for humans is unknown. Fentanyl effervescent buccal tablets should not be used in pregnancy unless clearly necessary
• With long-term use of fentanyl during pregnancy, there is a risk of neonatal opioid withdrawal syndrome which may be life-threatening if not recognised and treated, and requires management according to protocols developed by neonatology experts. If opioid use is required for a prolonged period in a pregnant woman, advise the patient of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available
• 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 fentanyl effervescent buccal tablets are administered, an antidote for the child should be readily available

Breastfeeding

South African manufacturer recommendations

• Contraindicated 
• Fentanyl effervescent buccal tablets pass into breast milk and may cause sedation and respiratory depression in the breastfed child. Fentanyl effervescent buccal tablets should not be used by breastfeeding women and breastfeeding should not be restarted until at least 5 days after the last administration of  fentanyl effervescent buccal tablets

Recommendations in other jurisdictions

• Caution; not recommended 
• Fentanyl passes into breast milk and may cause sedation and respiratory depression in the breastfed 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

Fertility

• There are no human data on fertility available. In animal studies, male fertility was impaired

Renal Impairment

• Mild: No dose adjustment recommended
• Moderate to severe: Caution; no dose adjustment recommended

Hepatic Impairment

• Mild: No dose adjustment recommended
• Moderate to severe: Caution; no dose adjustment recommended

Elderly 

• Caution; dose adjustment recommended
  In clinical studies patients older than 65 years tended to titrate to a lower effective dose than younger patients. Increased caution should be exercised in titrating the dose in elderly patients

Porphyria Information

• Probably not porphyrinogenic (PNP) 

Drugs in Sport

• Prohibited - In competition 

Central Nervous System Disorders

• Insomnia
• Depression
• Anxiety
• Confusional state
• Hallucination
  - Visual hallucination
• Euphoric mood
• Nervousness
• Mental status changes
• Disorientation
• Drug dependence (addiction)
• Drug abuse
• Delirium
• Dizziness
• Headache
• Somnolence
• Lethargy
• Depressed level of consciousness
• Loss of consciousness (in the context of overdose)
• Disturbance in attention
• Cognitive disorder
• Motor dysfunction
• Seizures
• Tremor
• Sedation
• Hypoaesthesia
• Migraine
• Balance disorder
• Dysarthria
• Asthenia
• Drug withdrawal syndrome
  - Nausea and vomiting
  - Diarrhoea
  - Anxiety
  - Chills
  - Tremor
  - Sweating
• Sluggishness
• Neonatal withdrawal syndrome
• Fall

Cardiovascular Disorders

• Tachycardia
• Bradycardia
• Hypertension
• Hypotension
• Flushing
• Hot flush
• Chest discomfort
• Increased heart rate

Respiratory Disorders

• Pharyngitis
• Dyspnoea
• Pharyngolaryngeal pain
• Respiratory depression
• Sleep apnoea syndrome
• Respiratory arrest (in the context of overdose)

Gastrointestinal Disorders

• Oral candidiasis
• Oral pustule
• Nausea and vomiting
• Constipation
• Stomatitis
• Diarrhoea
• Dry mouth
• Abdominal pain
• Gastro-oesophageal reflux disease
• Stomach discomfort
• Dyspepsia
• Toothache
• Ileus
• Mouth ulceration
• Oral hypoaesthesia
• Oral discomfort
• Oral mucosal discolouration
• Oral soft tissue disorder
• Glossodynia
• Tongue blistering
• Gingival pain
• Tongue ulceration
• Tongue disorder
• Oesophagitis
• Chapped lips
• Tooth disorder
• Oral mucosal blistering
• Dry lip

Hepatobiliary Disorders

• Biliary dilatation

Genitourinary Disorders

• Urinary retention

Endocrine and Metabolic Disorders

• Anorexia 
• Adrenal insufficiency
• Androgen deficiency
• Decreased weight
• Thirst 
• Hypogonadism 

Musculoskeletal Disorders

• Myalgia
• Back pain
• Muscle twitching 
• Muscular weakness

Skin and Subcutaneous Tissue Disorders

• Hyperhidrosis
• Pruritus
• Rash
• Cold sweat
• Facial swelling
• Generalised pruritus
• Alopecia
• Onychorrhexis
• Application site reactions
  - Bleeding
  - Pain
  - Ulcer
  - Irritation
  - Paraesthesia
  - Anaesthesia
  - Erythema
  - Oedema
  - Swelling
  - Vesicles

Immune, Blood and Lymphatic System Disorders

• Anaemia
• Neutropenia
• Thrombocytopenia
• Hypersensitivity
  - Rash
  - Erythema
  - Lip and face swelling
  - Urticaria
• Peripheral oedema
• Chills
• Feeling hot
• Feeling cold 
• Pyrexia 
• Decreased platelet count
• Decreased haematocrit
• Decreased haemoglobin 

Sensory Disorders

• Visual disturbance
• Ocular hyperaemia
• Blurred vision
• Reduced visual acuity 
• Abnormal sensation in eye
• Photopsia
• Dysgeusia
• Vertigo
• Tinnitus
• Ear discomfort

Others

• Feeling abnormal
• Feeling jittery

• CYP3A4 inducers
• Moderate or strong CYP3A4 inhibitors
• Ritonavir
• Ketoconazole
• Itraconazole
• Troleandomycin
• Clarithromycin
• Nelfinavir
• Amprenavir
• Aprepitant
• Diltiazem
• Erythromycin
• Fluconazole
• Fosamprenavir
• Verapamil
• Central nervous system depressants
• Opioids
• Sedatives
• Hypnotics
• Benzodiazepines
• General anaesthetics
• Phenothiazines
• Tranquillisers
• Skeletal muscle relaxants
• Sedating antihistamines
• Gabapentinoids
• Gabapentin
• Pregabalin
• Partial opioid agonists
• Partial opioid antagonists
• Buprenorphine
• Nalbuphine
• Pentazocine
• Serotoninergic agents 
• Selective serotonin reuptake inhibitors (SSRI)
• Serotonin norepinephrine reuptake inhibitors (SNRI)
• Monoamine oxidase inhibitors (MAOI)
• Sodium oxybate

Other interactions

• Grapefruit juice
• Alcohol

• Blood pressure (BP)
• Heart rate

Additional observations

• Pain relief
• Respiratory and mental status/alertness
• Signs of misuse, abuse, or addiction
• Symptoms of serotonin syndrome such as mental status changes (e.g. agitation, hallucinations, coma), autonomic instability (e.g. tachycardia, labile BP, hyperthermia), neuromuscular changes (e.g. hyperreflexia, incoordination), and/or gastrointestinal symptoms (eg, nausea, vomiting, diarrhoea)
• Symptoms of neonatal withdrawal syndrome in babies born to mothers using opioids during pregnancy, including irritability, hyperactivity and abnormal sleep pattern, high-pitched cry, tremor, vomiting, diarrhoea, and failure to gain weight
• During discontinuation
  - Pain control 
  - Withdrawal symptoms
  - Mood changes
  - Suicidal ideation
  - Use of other substances
• Signs or symptoms of hypogonadism or hypoadrenalism 

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 tablet of the same strength may be used
• If treatment of a breakthrough pain (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 100μg or up to four 200μg tablets may be used to treat a single episode of BTP during dose titration according to the following schedule:
  
  - If the initial 100μg tablet is not efficacious, the patient can be instructed to treat the next episode of BTP with two 100μg 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 200μg tablet
  - If a single 200μg tablet (or two 100μg tablets) is not considered to be efficacious the patient can be instructed to use two 200μg tablets (or four 100μg 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 400μg
  - For titration to 600μg and 800μg, tablets of 200μg should be used. Doses above 800μg 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 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. BTP episodes may vary in intensity and the required dose might increase over time due to progression of the underlying cancer disease. In these cases, a second tablet of the same strength may be used. If a second tablet was required for several consecutive times, the usual maintenance dose is to be readjusted
• Patients should wait at least 4 hours before treating another BTP episode during maintenance therapy

Dose readjustment

• The maintenance dose should be increased when a patient requires more than one tablet per BTP episode for several consecutive BTP episodes. For dose-readjustment the same principles apply as outlined for dose titration above 
• Dose readjustment of the background opioid therapy may be required if patients consistently present with more than four BTP episodes per 24 hours
• In absence of adequate pain control, the possibility of hyperalgesia, tolerance and progression of underlying disease should be considered 

Discontinuation of therapy

• Fentanyl effervescent buccal tablets should be discontinued immediately if the patient no longer experiences BTP 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 in order to manage the risk of abrupt withdrawal effects

Method of administration

• Fentanyl effervescent buccal tablets 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
• Patients should be instructed not to attempt to push the tablet through the blister because this could damage the buccal tablet
• Patients should remove the tablet from the blister unit and immediately place the entire tablet in the buccal cavity (near a molar between the cheek and gum)
• The tablet should not be sucked, chewed or swallowed, as this will result in lower plasma concentrations than when taken as directed
• Tablet(s) 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. Alternatively, the tablet could be placed sublingually
• After 30 minutes, if remnants from the tablet remain, they may be swallowed with a glass of water
• 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

Fentanyl is an opioid analgesic, interacting predominantly with the opioid μ-receptor. Its primary therapeutic actions are analgesia and sedation. Secondary pharmacological effects are respiratory depression, bradycardia, hypothermia, constipation, miosis, physical dependence and euphoria. The analgesic effects of fentanyl are related to its plasma level. In general, the effective concentration and the concentration at which toxicity occurs increase with increasing tolerance to opioids. The rate of development of tolerance varies widely among individuals. As a result, the dose of fentanyl effervescent buccal tablets should be individually titrated to achieve the desired effect.  

Effervescent tablet 100µg

• Effentora 100 (Teva Pharmaceuticals) originator

Effervescent tablet 200µg

• Effentora 200 (Teva Pharmaceuticals) originator

Effervescent tablet 400µg

• Effentora 400 (Teva Pharmaceuticals) originator