Section

Changes

4.8          Undesirable effects

Added

Respiratory, thoracic and mediastinal disorders

dyspnoea

10.          DATE OF REVISION OF THE TEXT

10 October 2019

Section

Update

4.2 - Posology and method of administration

Updated text in red:

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 of abuse, misuse, addiction and overdose of fentanyl.

…

Elderly and Cachectic population

Limited 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. Limited data on pharmacokinetics are available for the use of fentanyl in cachectic (debilitated) patients. Cachectic patients may have reduced clearance of fentanyl. Caution should therefore be taken in treatment of elderly, cachectic or debilitated patients.

4.4 - Special warnings and precautions for use

Cardiac disease

Fentanyl use may be associated with bradycardia.

4.6 - Fertility, pregnancy and lactation

Pregnancy

There 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 and if the benefits outweigh the risks.

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 newborn (neonate). If Instanyl has been administered, an antidote for the child should be readily available.

4.7 - Effects on ability to drive and use machines

No studies of the effects on the ability to drive and use machines have been performed. However, opioid analgesics are known to impair the mental and/or physical ability required for driving or operating machinery. Patients undergoing treatment with Instanyl should be advised not to drive or operate machinery. Instanyl can cause somnolence, dizziness, visual disturbances or other adverse reactions which may affect their ability to drive or operate machinery.

4.8 - Undesirable effects

Deleted text:

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.

4.9 - Overdose

The signs and symptoms of fentanyl overdose are expected to be an extension of its pharmacological actions e.g. lethargy, coma and severe respiratory depression. Other signs 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.

5.1 - Pharmacodynamic properties

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 receiving low maintenance opioid dose tended to achieve effective pain relief with a lower strength of Instanyl compared to patients taking higher levels of maintenance opioid dose. This observation was most distinct for patients receiving Instanyl 50 micrograms.

5.2 - Pharmacokinetic properties

The plasma protein binding of fentanyl is approximately 80%. The absolute bioavailability of Instanyl is approximately 89%.

10 – Date of Revision of the text

01 July 2019

Section

Changes

4.3          Contraindications

Added:

Patients being treated with medicinal products containing sodium oxybate.

4.4          Special warnings and precautions for use

Respiratory depression

Clinically 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 may be reduced. The use of concomitant central nervous system depressants may increase the risk of respiratory depression (see section 4.5).

Chronic pulmonary disease

In 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.

4.5          Interaction with other medicinal products and other forms of interaction

Added

Concomitant use of medicinal products containing sodium oxybate and fentanyl is contraindicated (see section 4.3).

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) and skeletal muscle relaxants, may produce additive depressant effects: hypoventilation, hypotension, profound sedation, coma or death may occur. Therefore, the use of any of these medicinal products concomitantly with Instanyl requires special patient care and observation.

4.8          Undesirable effects

Added/ updated:

Nervous system disorders: Convulsions, loss of consciousness

Pregnancy, puerperium and perinatal conditions: Neonatal withdrawal syndrome

Injury, poisoning and procedural complications: Fatigue, malaise peripheral oedema, withdrawal syndrome*, neonatal withdrawal syndrome

10. Date of Revision of the text

5 March 2019

Change to section

Details of change

4.2 Posology and method of administration

Text in blue removed and text in red added:

Posology

Patients 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. On exceptional occasions where a new episode occurs earlier, patients can use Instanyl to treat it but they must wait at least 2 hours before doing so. Dose adjustment of the background opioid therapy following pain reassessment should be considered if the patient frequently presents with breakthrough pain episodes that are less than 4 hours apart or with more than four breakthrough pain episodes per 24 hours.

...

…

Dose adjustment

Generally, 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 following pain reassessment should be considered may be required if the patient frequently consistently presents with breakthrough pain episodes that are less than 4 hours apart or 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.

…

5.1 Pharmacological Properties

Text in blue removed and text in red added:

…

Clinical safety and efficacy

The 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; however, patients should be titrated to the optimal dose of Instanyl for treating BTP in cancer (see section 4.2).

 …

10. Date of revision of the text

Updated text in red:

7^th March 2017

Change to section

Details of change

6.1 List of excipients

Text in blue removed and text in red added:

Sodium dihydrogen phosphate dihydrate

Disodium phosphate dihydrate

Purified water Water for injections

10. Date of revision of the text

Updated text in red:

22^nd September 2016

Change to section

Details of change

6.4 Special precautions for storage

Added:

Keep the blister in the outer carton. Keep stored upright.

10. DATE OF REVISION OF THE TEXT

Changed to:

17^th September 2015

Change to section

Details of change

4.6. Fertility, pregnancy and lactation

Changed:

Breast-feeding

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 48 hours 5 days after the last administration of fentanyl.

4.8. Undesirable Effects

 Added:

Fatigue, malaise peripheral oedema, withdrawal syndrome*

*opioid withdrawal symptoms such as nausea, vomiting, diarrhoea, anxiety, chills, tremor, and sweating have been observed with transmucosal fentanyl

10. DATE OF REVISION OF THE TEXT

Changed to:

05^th March 2015

Change to section

Details of change

4.3. Contradictions

Added:

‘‘Patients without maintenance opioid therapy as there is an increased risk of respiratory depression’’

‘’Treatment of acute pain other than breakthrough pain’’

4.4. Special warnings and precautions for use

Changed/Added:

Fentanyl may produce bradycardia. Fentanyl should therefore be administered used with caution to in patients with previous or pre-existing bradyarrhythmias

Added:

Serotonin Syndrome

Caution 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’’

4.5. Interaction with other medicinal products and other forms of interaction

Added:

‘’Coadministration of fentanyl with a serotoninergic agent, 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’’

Changed:

‘’Monoamine Oxidase MAO’’ to ‘’ a Monoamine Oxidase Inhibitor MAOI’’

4.6  Fertility, pregnancy and lactation

Changed:

“Breastfeeding

Fentanyl is excreted into human milk and may cause sedation and respiratory depression in the breast-fed infant. Fentanyl should only be used by breastfeeding women if the benefits outweigh the potential risks for both mother and child” to

‘’Breast-feeding

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 48 hours after the last administration of fentanyl’’

4.8. Undesirable effects

 
Tabular list of adverse reactions

4.8. Undesirable effects- how to report a side  

Added:

‘’Tabular list of adverse reactions’’

‘’The following adverse reactions have been reported with Instanyl and/or other fentanyl-containing compounds during clinical studies and post marketing experience’’

‘’Injury, poisoning and procedural complications’’

Not known: Fall

General disorders and administration site conditions:

Not known: ‘’Fatigue, malaise peripheral oedema’’

Gastrointestinal disorders

Not known: ‘’ Diarrhoea’’

Nervous system disorders:

Not known: ‘’ Convulsion’’

Reporting of suspected adverse reactions:

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions to Pharmacovigilance Section, Irish Medicines Board, Kevin O'Malley House, Earlsfort Centre, Earlsfort Terrace, IRL – Dublin 2. Tel: +353 1 6764971, Fax: +353 1 6767836, Website: www.imb.ie. e-mail:imbpharmacovigilance@imb.ie. 

10. DATE OF REVISION OF THE TEXT

Changed to:

28^th February 2014