Instanyl

1

ANNEX I

SUMMARY OF PRODUCT CHARACTERISTICS



2

1. NAME OF THE MEDICINAL PRODUCT

Instanyl 50 micrograms/dose nasal spray, solution
Instanyl 100 micrograms/dose nasal spray, solution
Instanyl 200 micrograms/dose nasal spray, solution

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Instanyl 50 micrograms/dose nasal spray, solution
Each ml of solution contains fentanyl citrate equivalent to 500 micrograms fentanyl.
1 dose (100 microlitres) contains 50 micrograms fentanyl.

Instanyl 100 micrograms/dose nasal spray, solution
Each ml of solution contains fentanyl citrate equivalent to 1,000 micrograms fentanyl.
1 dose (100 microlitres) contains 100 micrograms fentanyl.

Instanyl 200 micrograms/dose nasal spray, solution
Each ml of solution contains fentanyl citrate equivalent to 2,000 micrograms fentanyl.
1 dose (100 microlitres) contains 200 micrograms fentanyl.

For the full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Nasal spray, solution (nasal spray)
Clear, colourless solution.

4. CLINICAL PARTICULARS

4.1 Therapeutic indications

Instanyl is indicated for the management of breakthrough pain in adults 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 oxycodone 
daily, at least 8 mg of oral hydromorphone daily or an equianalgesic dose of another opioid for a week 
or longer.

4.2 Posology and method of administration

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.

Posology

Patients should be individually titrated to a 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. In absence of adequate 
pain control, the possibility of hyperalgesia, tolerance and progression of underlying disease should be 
considered (see section 4.4).



3

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 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 titration
Before 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 titration
The 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 
achieved, 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 therapy
Once 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 undertaken at the earliest after 10 minutes.

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
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.

Start at 50 micrograms

- Use one dose of Instanyl
- Wait 10 minutes

Dose obtained

Adequate pain relief with one dose of Instanyl

Yes No

Redose with same 
strength. 
Consider next higher 
strength for next episode



4

If adverse reactions are intolerable or persistent, the strength should be reduced or treatment with 
Instanyl be replaced by other analgesics.

Discontinuation of therapy
Instanyl 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 
physician as gradual downward opioid titration is necessary in order to avoid the possibility of abrupt 
withdrawal effects.

Special populations

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.
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 impairment
Instanyl should be administered with caution to patients with moderate to severe hepatic impairment 
(see section 4.4).

Renal impairment
Instanyl should be administered with caution to patients with moderate to severe renal impairment (see 
section 4.4).

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

Method of administration

Instanyl is intended for nasal use only.
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 product
Before 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 7 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.

4.3 Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
Patients without maintenance opioid therapy as there is an increased risk of respiratory depression.
Treatment of acute pain other than breakthrough pain.
Patients being treated with medicinal products containing sodium oxybate.



5

Severe respiratory depression or severe obstructive lung conditions.
Previous facial radiotherapy.
Recurrent episodes of epistaxis (see section 4.4).

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 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.

Impaired renal or hepatic function

Fentanyl 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 pressure

Fentanyl 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 disease

Fentanyl use may be associated with 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 syndrome

Caution is advised when Instanyl is coadministered with medicinal products that affect the 
serotoninergic neurotransmitter systems.

The development of a potentially life-threatening serotonin syndrome may occur with the concomitant 
use of serotonergic medicinal products such as Selective Serotonin Re-uptake Inhibitors (SSRIs) and 
Serotonin Norepinephrine Re-uptake Inhibitors (SNRIs), and with medicinal products 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.



6

Hyperalgesia

As with other opioids, in case of insufficient pain control in response to an increased dose of fentanyl, 
the possibility of opioid-induced hyperalgesia should be considered. A fentanyl dose reduction or 
discontinuation of fentanyl treatment or treatment review may be indicated.

Nasal conditions

If 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 cold

The 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 dependence

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 
known to occur in the treatment of cancer related pain.

Withdrawal symptoms

Withdrawal 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).

4.5 Interaction with other medicinal products and other forms of interaction

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

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.

Instanyl is not recommended for use in patients who have received Monoamine Oxidase Inhibitors 
(MAOIs) within 14 days because severe and unpredictable potentiation by MAOIs inhibitors has been 
reported with opioid analgesics.

Fentanyl is metabolised mainly via the human cytochrome P450 3A4 isoenzyme system (CYP3A4), 
therefore potential interactions may occur when Instanyl is given concurrently with medicinal products 
that affect CYP3A4 activity. Coadministration with medicinal products that induce 3A4 activity may 
reduce the efficacy of Instanyl. The concomitant use of Instanyl 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, 
and verapamil) may result in increased fentanyl plasma concentrations, potentially causing serious 
adverse drug reactions including fatal respiratory depression.
Patients receiving Instanyl concomitantly with moderate or strong CYP3A4 inhibitors should be 
carefully monitored for an extended period of time. Dose increase should be done with caution.

In a pharmacokinetic interaction study it was found that the maximum plasma concentration of nasally 
applied fentanyl was reduced about 50% by the concomitant use of oxymetazoline, while the time to 



7

reach Cmax (Tmax) was doubled. This may reduce the efficacy of Instanyl. It is recommended that 
concomitant use of nasal decongestants is avoided (see section 5.2).

The concomitant use of other central nervous system depressants (including opioids, sedatives, 
hypnotics, general anaesthetics, phenothiazines, tranquillisers, 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.

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 dependent patients.

Concomitant use of Instanyl with other medicinal products (other than oxymetazoline) administered 
via the nose has not been evaluated in the clinical trials. It is recommended that alternative 
administration forms should be considered for concomitant treatment of concurrent diseases that can 
be treated via nasal administration.

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.

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 5 days after the last administration of fentanyl.

Fertility

There are no human data on fertility available. In animal studies, male and female fertility was 
impaired at sedative doses (see section 5.3).

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

Summary of the safety profile

Typical 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 



8

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 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 reactions

The 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 Insomnia Hallucination, drug 

dependence 
(addiction), drug 
abuse

Nervous system disorders Somnolence, 
dizziness, headache

Sedation, 
myoclonus, 
paraesthesia, 
dysaesthesia, 
dysgeusia

Convulsions, loss of 
consciousness

Ear and Labyrinth disorders Vertigo Motion sickness
Cardiac disorders Hypotension
Vascular disorders Flushing, hot flush
Respiratory, thoracic and 
mediastinal disorders

Throat irritation Respiratory 
depression, 
epistaxis, nasal 
ulcer, rhinorrhea

Nasal septum 
perforation, 
dyspnoea

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*, neonatal 
withdrawal 
syndrome

Injury, poisoning and 
procedural complications 

Fall

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

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 via the national reporting system 
listed in Appendix V.



9

4.9 Overdose

Symptoms

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.

Treatment

For 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.

5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Analgesics, opioids, ATC code: N02AB03

Mechanism of action

Fentanyl is an opioid analgesic interacting primarily with the opioid μ-receptor as a pure agonist with 
low affinity for the - 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 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 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.
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

All three strengths of Instanyl demonstrated 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.

Opioids may influence the hypothalamic-pituitary-adrenal or –gonadal axes. Some changes that can be 
seen include an increase in serum prolactin, and decreases in plasma cortisol and testosterone. Clinical 
signs and symptoms may be manifest from these hormonal changes.

5.2 Pharmacokinetic properties

Absorption

Fentanyl 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 approximately 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.

Distribution

After 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.

Biotransformation

Fentanyl is metabolised primarily in the liver via CYP3A4. The major metabolite, norfentanyl is 
inactive. 

Elimination

About 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.

Linearity

Instanyl 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 



11

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).

Bioequivalence

A pharmacokinetic study has shown that Instanyl single-dose and multi-dose nasal spray are 
bioequivalent.

5.3 Preclinical safety data

Non-clinical data reveal no special hazard for humans based on conventional studies of safety 
pharmacology, repeated dose toxicity,genotoxicity and carcinogenicity.

In a fertility and early embryonic development study in rats, a male-mediated effect was observed at 
high doses (300 µg/kg/day, s.c.) and is consistent with the sedative effects of fentanyl in animal 
studies. Furthermore, studies in female rats revealed reduced fertility and enhanced embryonal 
mortality. More recent studies showed that effects on the embryo were due to maternal toxicity and 
not to direct effects of the substances on the developing embryo. In a study on pre- and postnatal 
development the survival rate of offspring was significantly reduced at doses which slightly reduced 
maternal weight. This effect could either be due to altered maternal care or a direct effect of fentanyl 
on the pups. Effects on somatic development and behaviour of the offspring were not observed. 
Teratogenic effects have not been demonstrated.

Local tolerance studies with Instanyl in mini-pigs demonstrated that Instanyl administration was well 
tolerated.

Carcinogenicity studies (26-week dermal alternative bioassay in Tg.AC transgenic mice; two-year 
subcutaneous carcinogenicity study in rats) with fentanyl did not reveal any findings indicative of 
oncogenic potential. Evaluation of brain slides from the carcinogenicity study in rats revealed brain 
lesions in animals administered high doses of fentanyl citrate. The relevance of these findings to 
humans is unknown.

6. PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Sodium dihydrogen phosphate dihydrate
Disodium phosphate dihydrate
Purified water

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

3 years

6.4 Special precautions for storage

Store below 30 C.
Do not freeze.
Keep the bottle stored upright.



12

6.5 Nature and contents of container

Bottle (brown Type 1 glass) with metering pump and dust cap packed in a child-resistant outer box.

Available in the following presentations:

Instanyl 50 micrograms/dose nasal spray, solution
1.8 ml containing 0.90 mg fentanyl ensuring the delivery of 10 doses of 50 micrograms
2.9 ml containing 1.45 mg fentanyl ensuring the delivery of 20 doses of 50 micrograms
5.0 ml containing 2.50 mg fentanyl ensuring the delivery of 40 doses of 50 micrograms

Instanyl 100 micrograms/dose nasal spray, solution
1.8 ml containing 1.80 mg fentanyl ensuring the delivery of 10 doses of 100 micrograms
2.9 ml containing 2.90 mg fentanyl ensuring the delivery of 20 doses of 100 micrograms
5.0 ml containing 5.00 mg fentanyl ensuring the delivery of 40 doses of 100 micrograms

Instanyl 200 micrograms/dose nasal spray, solution
1.8 ml containing 3.60 mg fentanyl ensuring the delivery of 10 doses of 200 micrograms
2.9 ml containing 5.80 mg fentanyl ensuring the delivery of 20 doses of 200 micrograms
5.0 ml containing 10.00 mg fentanyl ensuring the delivery of 40 doses of 200 micrograms

Not all pack sizes may be marketed.

6.6 Special precautions for disposal

Because of the possible misuse of fentanyl and the possible amount of the solution left, the used and 
unused nasal spray solutions must be returned systematically and suitably in the child-resistant outer 
box and disposed of in accordance with local requirements or returned to the pharmacy.

7. MARKETING AUTHORISATION HOLDER

Takeda Pharma A/S
Dybendal Alle 10
DK-2630 Taastrup
Denmark 

8. MARKETING AUTHORISATION NUMBER(S) 

Instanyl 50 micrograms/dose nasal spray, solution
EU/1/09/531/001-003

Instanyl 100 micrograms/dose nasal spray, solution
EU/1/09/531/004-006

Instanyl 200 micrograms/dose nasal spray, solution
EU/1/09/531/007-009

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 20 July 2009
Date of latest renewal: 01 July 2019



13

10. DATE OF REVISION OF THE TEXT

Detailed information on this medicinal product is available on the website of the European Medicines 
Agency http://www.ema.europa.eu.



14

1. NAME OF THE MEDICINAL PRODUCT

Instanyl 50 micrograms nasal spray, solution in single-dose container
Instanyl 100 micrograms nasal spray, solution in single-dose container
Instanyl 200 micrograms nasal spray, solution in single-dose container

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Instanyl 50 micrograms nasal spray, solution in single-dose container
Each single-dose container contains one dose (100 microlitres) of fentanyl citrate equivalent to 
50 micrograms fentanyl.

Instanyl 100 micrograms nasal spray, solution in single-dose container
Each single-dose container contains one dose (100 microlitres) of fentanyl citrate equivalent to 
100 micrograms fentanyl.

Instanyl 200 micrograms nasal spray, solution in single-dose container
Each single-dose container contains one dose (100 microlitres) of fentanyl citrate equivalent to 
200 micrograms fentanyl.

For the full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Nasal spray, solution (nasal spray)
Clear, colourless solution.

4. CLINICAL PARTICULARS

4.1 Therapeutic indications

Instanyl is indicated for the management of breakthrough pain in adults 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 oxycodone 
daily, at least 8 mg of oral hydromorphone daily or an equianalgesic dose of another opioid for a week 
or longer.

4.2 Posology and method of administration

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.

Posology

Patients should be individually titrated to a 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. In absence of adequate 
pain control, the possibility of hyperalgesia, tolerance and progression of underlying disease should be 
considered (see section 4.4).



15

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 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 titration
Before 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 titration
The 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 
achieved, 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 therapy
Once 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 undertaken at the earliest after 10 minutes.

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
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.

Start at 50 micrograms

- Use one dose of Instanyl
- Wait 10 minutes

Dose obtained

Adequate pain relief with one dose of Instanyl

Yes No

Redose with same 
strength. 
Consider next higher 
strength for next episode



16

If adverse reactions are intolerable or persistent, the strength should be reduced or treatment with 
Instanyl be replaced by other analgesics.

Discontinuation of therapy
Instanyl 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 
physician as gradual downward opioid titration is necessary in order to avoid the possibility of abrupt 
withdrawal effects.

Special populations

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.
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 impairment
Instanyl should be administered with caution to patients with moderate to severe hepatic impairment
(see section 4.4).

Renal impairment
Instanyl should be administered with caution to patients with moderate to severe renal impairment (see 
section 4.4).

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

Method of administration

Instanyl is intended for nasal use only.
It is recommended that the patient’s head is in upright position when administrating Instanyl.

4.3 Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
Patients without maintenance opioid therapy as there is an increased risk of respiratory depression. 
Treatment of acute pain other than breakthrough pain.
Patients being treated with medicinal products containing sodium oxybate.
Severe respiratory depression or severe obstructive lung conditions.
Previous facial radiotherapy.
Recurrent episodes of epistaxis (see section 4.4).

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



17

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.

Impaired renal or hepatic function

Fentanyl 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 pressure

Fentanyl 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 disease

Fentanyl use may be associated with 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 syndrome

Caution is advised when Instanyl is coadministered with medicinal products that affect the 
serotoninergic neurotransmitter systems.

The development of a potentially life-threatening serotonin syndrome may occur with the concomitant 
use of serotonergic medicinal products such as Selective Serotonin Re-uptake Inhibitors (SSRIs) and 
Serotonin Norepinephrine Re-uptake Inhibitors (SNRIs), and with medicinal products 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.

Hyperalgesia

As with other opioids, in case of insufficient pain control in response to an increased dose of fentanyl, 
the possibility of opioid-induced hyperalgesia should be considered. A fentanyl dose reduction or 
discontinuation of fentanyl treatment or treatment review may be indicated.

Nasal conditions

If 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.



18

Common cold

The 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 dependence

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 
known to occur in the treatment of cancer related pain.

Withdrawal symptoms

Withdrawal 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).

4.5 Interaction with other medicinal products and other forms of interaction

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

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.

Instanyl is not recommended for use in patients who have received Monoamine Oxidase Inhibitors 
(MAOIs) within 14 days because severe and unpredictable potentiation by MAOIs inhibitors has been 
reported with opioid analgesics.

Fentanyl is metabolised mainly via the human cytochrome P450 3A4 isoenzyme system (CYP3A4), 
therefore potential interactions may occur when Instanyl is given concurrently with medicinal products 
that affect CYP3A4 activity. Coadministration with medicinal products that induce 3A4 activity may 
reduce the efficacy of Instanyl. The concomitant use of Instanyl 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, 
and verapamil) may result in increased fentanyl plasma concentrations, potentially causing serious 
adverse drug reactions including fatal respiratory depression.
Patients receiving Instanyl concomitantly with moderate or strong CYP3A4 inhibitors should be 
carefully monitored for an extended period of time. Dose increase should be done with caution.

In a pharmacokinetic interaction study it was found that the maximum plasma concentration of nasally 
applied fentanyl was reduced about 50% by the concomitant use of oxymetazoline, while the time to 
reach Cmax (Tmax) was doubled. This may reduce the efficacy of Instanyl. It is recommended that 
concomitant use of nasal decongestants is avoided (see section 5.2).

The concomitant use of other central nervous system depressants (including opioids, sedatives, 
hypnotics, general anaesthetics, phenothiazines, tranquillisers, 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.

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 



19

intrinsic activity and therefore partially antagonise the analgesic effect of fentanyl and may induce 
withdrawal symptoms in opioid dependent patients.

Concomitant use of Instanyl with other medicinal products (other than oxymetazoline) administered 
via the nose has not been evaluated in the clinical trials. It is recommended that alternative 
administration forms should be considered for concomitant treatment of concurrent diseases that can 
be treated via nasal administration.

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.

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 5 days after the last administration of fentanyl.

Fertility

There are no human data on fertility available. In animal studies, male and female fertility was 
impaired at sedative doses (see section 5.3).

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

Summary of the safety profile

Typical 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 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 reactions

The 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).



20

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 Insomnia Hallucination, drug 

dependence 
(addiction), drug 
abuse

Nervous system disorders Somnolence, 
dizziness, headache

Sedation, myoclonus, 
paraesthesia, 
dysaesthesia, 
dysgeusia

Convulsions, loss of 
consciousness

Ear and Labyrinth disorders Vertigo Motion sickness
Cardiac disorders Hypotension
Vascular disorders Flushing, hot flush
Respiratory, thoracic and 
mediastinal disorders

Throat irritation Respiratory 
depression, epistaxis, 
nasal ulcer, rhinorrhea

Nasal septum 
perforation, 
dyspnoea

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*, neonatal 
withdrawal 
syndrome

Injury, poisoning and 
procedural complications 

Fall

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

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 via the national reporting system 
listed in Appendix V.

4.9 Overdose

Symptoms

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.

Treatment

For 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 



21

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.

5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Analgesics, opioids, ATC code: N02AB03

Mechanism of action

Fentanyl is an opioid analgesic interacting primarily with the opioid μ-receptor as a pure agonist with 
low affinity for the - 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 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 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.
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).

All three strengths of Instanyl demonstrated 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.



22

Opioids may influence the hypothalamic-pituitary-adrenal or –gonadal axes. Some changes that can be 
seen include an increase in serum prolactin, and decreases in plasma cortisol and testosterone. Clinical 
signs and symptoms may be manifest from these hormonal changes.

5.2 Pharmacokinetic properties

Absorption

Fentanyl 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 approximately 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.

Distribution

After 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.

Biotransformation

Fentanyl is metabolised primarily in the liver via CYP3A4. The major metabolite, norfentanyl is 
inactive. 

Elimination

About 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.

Linearity

Instanyl 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).

Bioequivalence

A pharmacokinetic study has shown that Instanyl single-dose and multi-dose nasal spray are 
bioequivalent.

5.3 Preclinical safety data

Non-clinical data reveal no special hazard for humans based on conventional studies of safety 
pharmacology, repeated dose toxicity,genotoxicity and carcinogenicity.



23

In a fertility and early embryonic development study in rats, a male-mediated effect was observed at 
high doses (300 µg/kg/day, s.c.) and is consistent with the sedative effects of fentanyl in animal 
studies. Furthermore, studies in female rats revealed reduced fertility and enhanced embryonal 
mortality. More recent studies showed that effects on the embryo were due to maternal toxicity and 
not to direct effects of the substances on the developing embryo. In a study on pre- and postnatal 
development the survival rate of offspring was significantly reduced at doses which slightly reduced 
maternal weight. This effect could either be due to altered maternal care or a direct effect of fentanyl 
on the pups. Effects on somatic development and behaviour of the offspring were not observed. 
Teratogenic effects have not been demonstrated.

Local tolerance studies with Instanyl in mini-pigs demonstrated that Instanyl administration was well 
tolerated.

Carcinogenicity studies (26-week dermal alternative bioassay in Tg.AC transgenic mice; two-year 
subcutaneous carcinogenicity study in rats) with fentanyl did not reveal any findings indicative of 
oncogenic potential. Evaluation of brain slides from the carcinogenicity study in rats revealed brain 
lesions in animals administered high doses of fentanyl citrate. The relevance of these findings to 
humans is unknown.

6. PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Sodium dihydrogen phosphate dihydrate
Disodium phosphate dihydrate
Water for injections

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

Instanyl 50 micrograms nasal spray, solution in single-dose container
23 months

Instanyl 100 micrograms nasal spray, solution in single-dose container
3 years

Instanyl 200 micrograms nasal spray, solution in single-dose container
42 months

6.4 Special precautions for storage

Store below 30 C.
Keep the blister in the outer carton. Keep stored upright. 

6.5 Nature and contents of container

Single-dose container consisting of a vial (clear type I glass) integrated in a polypropylene spray 
container, packed in child-resistant blister.

Pack sizes: 2, 6, 8 and 10 single-dose containers.

Not all pack sizes may be marketed.



24

6.6 Special precautions for disposal 

Each single-dose container contains only one dose. The single-dose container should not be tested 
before use.

Because of the possible misuse of fentanyl unused nasal spray single-dose containers must be returned 
systematically and suitably in the child-resistant blister and disposed of in accordance with local 
requirements or returned to the pharmacy.

7. MARKETING AUTHORISATION HOLDER

Takeda Pharma A/S
Dybendal Alle 10
DK-2630 Taastrup
Denmark 

8. MARKETING AUTHORISATION NUMBER(S)

Instanyl 50 micrograms nasal spray, solution in single-dose container
EU/1/09/531/010-013

Instanyl 100 micrograms nasal spray, solution in single-dose container
EU/1/09/531/014-017

Instanyl 200 micrograms nasal spray, solution in single-dose container
EU/1/09/531/018-021

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 20 July 2009
Date of latest renewal: 01 July 2019

10. DATE OF REVISION OF THE TEXT

Detailed information on this medicinal product is available on the website of the European Medicines 
Agency http://www.ema.europa.eu.



25

1. NAME OF THE MEDICINAL PRODUCT

Instanyl 50 micrograms/dose nasal spray, solution
Instanyl 100 micrograms/dose nasal spray, solution
Instanyl 200 micrograms/dose nasal spray, solution

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Instanyl 50 micrograms/dose nasal spray, solution
Each ml of solution contains fentanyl citrate equivalent to 500 micrograms fentanyl.
1 dose (100 microlitres) contains 50 micrograms fentanyl.

Instanyl 100 micrograms/dose nasal spray, solution
Each ml of solution contains fentanyl citrate equivalent to 1,000 micrograms fentanyl.
1 dose (100 microlitres) contains 100 micrograms fentanyl.

Instanyl 200 micrograms/dose nasal spray, solution
Each ml of solution contains fentanyl citrate equivalent to 2,000 micrograms fentanyl.
1 dose (100 microlitres) contains 200 micrograms fentanyl.

For the full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Nasal spray, solution (nasal spray). DoseGuard
Clear, colourless solution.

4. CLINICAL PARTICULARS

4.1 Therapeutic indications

Instanyl is indicated for the management of breakthrough pain in adults 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 oxycodone 
daily, at least 8 mg of oral hydromorphone daily or an equianalgesic dose of another opioid for a week 
or longer.

4.2 Posology and method of administration

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.

Posology

Patients should be individually titrated to a 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. In absence of adequate 
pain control, the possibility of hyperalgesia, tolerance and progression of underlying disease should be 
considered (see section 4.4).



26

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 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 titration
Before 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 titration
The 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 
achieved, 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 therapy
Once 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 the 
same strength can be undertaken at the earliest after 10 minutes.

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
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.

Start at 50 micrograms

- Use one dose of Instanyl
- Wait 10 minutes

Dose obtained

Adequate pain relief with one dose of Instanyl

Yes No

Redose with same 
strength. 
Consider next higher 
strength for next episode



27

If adverse reactions are intolerable or persistent, the strength should be reduced or treatment with 
Instanyl be replaced by other analgesics. 

Discontinuation of therapy
Instanyl 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 
physician as gradual downward opioid titration is necessary in order to avoid the possibility of abrupt 
withdrawal effects.

Special populations

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.
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 impairment
Instanyl should be administered with caution to patients with moderate to severe hepatic impairment 
(see section 4.4).

Renal impairment
Instanyl should be administered with caution to patients with moderate to severe renal impairment (see 
section 4.4).

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

Method of administration

Instanyl is intended for nasal use only.
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.

Instanyl incorporates an electronic dose counter, and a lock out period between doses to minimise the 
risk of accidental overdose, misuse and abuse and to provide some reassurance to patients regarding 
these risks. Following administration of two doses within 60 minutes, Instanyl will lock for a period of 
2 hours, from the first dose taken, before another dose can be administered.

Precautions to be taken before handling or administering the medicinal product
Before using Instanyl for the first time, the nasal spray must be primed. A priming sequence of 5 
actuations of the nasal spray container is required, indicated by ‘P5’, ‘P4’, ‘P3’, ‘P2’ and ‘P1’ in the 
display. 

If the product has not been used for a period of more than 7 days, the nasal spray must be primed again, 
by actuating once before the next dose is taken, this is indicated by ‘P’ in the display.

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.



28

4.3 Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
Patients without maintenance opioid therapy as there is an increased risk of respiratory depression.
Treatment of acute pain other than breakthrough pain.
Patients being treated with medicinal products containing sodium oxybate.
Severe respiratory depression or severe obstructive lung conditions.
Previous facial radiotherapy.
Recurrent episodes of epistaxis (see section 4.4).

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 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.

Impaired renal or hepatic function

Fentanyl 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 pressure

Fentanyl 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 disease

Fentanyl use may be associated with 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 syndrome

Caution is advised when Instanyl is coadministered with medicinal products that affect the 
serotoninergic neurotransmitter systems.

The development of a potentially life-threatening serotonin syndrome may occur with the concomitant 
use of serotonergic medicinal products such as Selective Serotonin Re-uptake Inhibitors (SSRIs) and 
Serotonin Norepinephrine Re-uptake Inhibitors (SNRIs), and with medicinal products which impair 
metabolism of serotonin (including Monoamine Oxidase Inhibitors [MAOIs]). This may occur within 
the recommended dose.



29

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.

Hyperalgesia

As with other opioids, in case of insufficient pain control in response to an increased dose of fentanyl, 
the possibility of opioid-induced hyperalgesia should be considered. A fentanyl dose reduction or 
discontinuation of fentanyl treatment or treatment review may be indicated.

Nasal conditions

If 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 cold

The 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 dependence

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 
known to occur in the treatment of cancer related pain.

Withdrawal symptoms

Withdrawal 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).

4.5 Interaction with other medicinal products and other forms of interaction

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

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.

Instanyl is not recommended for use in patients who have received Monoamine Oxidase Inhibitors 
(MAOIs) within 14 days because severe and unpredictable potentiation by MAOIs inhibitors has been 
reported with opioid analgesics.

Fentanyl is metabolised mainly via the human cytochrome P450 3A4 isoenzyme system (CYP3A4), 
therefore potential interactions may occur when Instanyl is given concurrently with medicinal products 
that affect CYP3A4 activity. Coadministration with medicinal products that induce 3A4 activity may 
reduce the efficacy of Instanyl. The concomitant use of Instanyl 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, 



30

and verapamil) may result in increased fentanyl plasma concentrations, potentially causing serious 
adverse drug reactions including fatal respiratory depression.
Patients receiving Instanyl concomitantly with moderate or strong CYP3A4 inhibitors should be 
carefully monitored for an extended period of time. Dose increase should be done with caution.

In a pharmacokinetic interaction study it was found that the maximum plasma concentration of nasally 
applied fentanyl was reduced about 50% by the concomitant use of oxymetazoline, while the time to 
reach Cmax (Tmax) was doubled. This may reduce the efficacy of Instanyl. It is recommended that 
concomitant use of nasal decongestants is avoided (see section 5.2).

The concomitant use of other central nervous system depressants, (including opioids, sedatives,
hypnotics, general anaesthetics, phenothiazines, tranquillisers, 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.

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 dependent patients.

Concomitant use of Instanyl with other medicinal products (other than oxymetazoline) administered 
via the nose has not been evaluated in the clinical trials. It is recommended that alternative 
administration forms should be considered for concomitant treatment of concurrent diseases that can 
be treated via nasal administration.

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.

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 5 days after the last administration of fentanyl.

Fertility

There are no human data on fertility available. In animal studies, male and female fertility was 
impaired at sedative doses (see section 5.3).

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.



31

4.8 Undesirable effects

Summary of the safety profile

Typical 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 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 reactions

The 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 Insomnia Hallucination, drug 

dependence 
(addiction), drug 
abuse

Nervous system disorders Somnolence, 
dizziness, headache

Sedation, 
myoclonus, 
paraesthesia, 
dysaesthesia, 
dysgeusia

Convulsions, loss of 
consciousness

Ear and Labyrinth disorders Vertigo Motion sickness
Cardiac disorders Hypotension
Vascular disorders Flushing, hot flush
Respiratory, thoracic and 
mediastinal disorders

Throat irritation Respiratory 
depression, 
epistaxis, nasal 
ulcer, rhinorrhea

Nasal septum 
perforation, 
dyspnoea

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*, neonatal 
withdrawal 
syndrome

Injury, poisoning and 
procedural complications 

Fall

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



32

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 via the national reporting system 
listed in Appendix V.

4.9 Overdose

Symptoms

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.

Treatment

For 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.

5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Analgesics, opioids, ATC code: N02AB03

Mechanism of action

Fentanyl is an opioid analgesic interacting primarily with the opioid μ-receptor as a pure agonist with 
low affinity for the - 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 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 



33

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.
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).

All three strengths of Instanyl demonstrated 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.

Opioids may influence the hypothalamic-pituitary-adrenal or –gonadal axes. Some changes that can be 
seen include an increase in serum prolactin, and decreases in plasma cortisol and testosterone. Clinical 
signs and symptoms may be manifest from these hormonal changes.

5.2 Pharmacokinetic properties

Absorption

Fentanyl 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 approximately 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.

Distribution

After 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.

Biotransformation

Fentanyl is metabolised primarily in the liver via CYP3A4. The major metabolite, norfentanyl is 
inactive. 

Elimination

About 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.



34

Linearity

Instanyl 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).

Bioequivalence

A pharmacokinetic study has shown that Instanyl single-dose and multi-dose nasal spray are 
bioequivalent.

5.3 Preclinical safety data

Non-clinical data reveal no special hazard for humans based on conventional studies of safety 
pharmacology, repeated dose toxicity,genotoxicity and carcinogenicity.

In a fertility and early embryonic development study in rats, a male-mediated effect was observed at 
high doses (300 µg/kg/day, s.c.) and is consistent with the sedative effects of fentanyl in animal 
studies. Furthermore, studies in female rats revealed reduced fertility and enhanced embryonal 
mortality. More recent studies showed that effects on the embryo were due to maternal toxicity and 
not to direct effects of the substances on the developing embryo. In a study on pre- and postnatal 
development the survival rate of offspring was significantly reduced at doses which slightly reduced 
maternal weight. This effect could either be due to altered maternal care or a direct effect of fentanyl 
on the pups. Effects on somatic development and behaviour of the offspring were not observed. 
Teratogenic effects have not been demonstrated.

Local tolerance studies with Instanyl in mini-pigs demonstrated that Instanyl administration was well 
tolerated.

Carcinogenicity studies (26-week dermal alternative bioassay in Tg.AC transgenic mice; two-year 
subcutaneous carcinogenicity study in rats) with fentanyl did not reveal any findings indicative of 
oncogenic potential. Evaluation of brain slides from the carcinogenicity study in rats revealed brain 
lesions in animals administered high doses of fentanyl citrate. The relevance of these findings to 
humans is unknown.

6. PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Sodium dihydrogen phosphate dihydrate
Disodium phosphate dihydrate
Purified water

6.2 Incompatibilities

Not applicable.



35

6.3 Shelf life

Instanyl 50 micrograms/dose nasal spray, solution.
Instanyl 100 micrograms/dose nasal spray, solution.
Instanyl 200 micrograms/dose nasal spray, solution. 
18 months

6.4 Special precautions for storage

Store below 30 C. 
Do not freeze.

6.5 Nature and contents of container

A polypropylene (PP) nasal spray container consisting of a glass bottle (brown Type 1 glass) with 
metering pump. The nasal spray container has an electronic display, a dose counter, a lock-out 
mechanism and a child-resistant cap.

Available in the following presentations:

Instanyl 50 micrograms/dose nasal spray, solution. DoseGuard
2.0 ml containing 1.00 mg fentanyl ensuring the delivery of 10 doses of 50 micrograms
3.2 ml containing 1.60 mg fentanyl ensuring the delivery of 20 doses of 50 micrograms
4.3 ml containing 2.15 mg fentanyl ensuring the delivery of 30 doses of 50 micrograms
5.3 ml containing 2.65 mg fentanyl ensuring the delivery of 40 doses of 50 micrograms

Instanyl 100 micrograms/dose nasal spray, solution. DoseGuard
2.0 ml containing 2.00 mg fentanyl ensuring the delivery of 10 doses of 100 micrograms
3.2 ml containing 3.20 mg fentanyl ensuring the delivery of 20 doses of 100 micrograms
4.3 ml containing 4.30 mg fentanyl ensuring the delivery of 30 doses of 100 micrograms
5.3 ml containing 5.30 mg fentanyl ensuring the delivery of 40 doses of 100 micrograms

Instanyl 200 micrograms/dose nasal spray, solution. DoseGuard
2.0 ml containing 4.00 mg fentanyl ensuring the delivery of 10 doses of 200 micrograms
3.2 ml containing 6.40 mg fentanyl ensuring the delivery of 20 doses of 200 micrograms
4.3 ml containing 8.60 mg fentanyl ensuring the delivery of 30 doses of 200 micrograms
5.3 ml containing 10.60 mg fentanyl ensuring the delivery of 40 doses of 200 micrograms

Not all pack sizes may be marketed. 

6.6 Special precautions for disposal 

Because of the possible misuse of fentanyl and the possible amount of the solution left, any used and 
unused nasal spray must be returned systematically and appropriately disposed of in accordance with 
local requirements or returned to the pharmacy. 

The nasal spray container contains batteries. The batteries cannot be replaced.

7. MARKETING AUTHORISATION HOLDER

Takeda Pharma A/S
Dybendal Alle 10
DK-2630 Taastrup
Denmark 



36

8. MARKETING AUTHORISATION NUMBER(S)

Instanyl 50 micrograms/dose nasal spray, solution
EU/1/09/531/022-025

Instanyl 100 micrograms/dose nasal spray, solution
EU/1/09/531/026-029

Instanyl 200 micrograms/dose nasal spray, solution
EU/1/09/531/030-033

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 20 July 2009

Date of latest renewal: 01 July 2019

10. DATE OF REVISION OF THE TEXT

Detailed information on this medicinal product is available on the website of the European Medicines 
Agency http://www.ema.europa.eu.



37

ANNEX II

A. MANUFACTURERS RESPONSIBLE FOR BATCH 
RELEASE

B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY 
AND USE

C. OTHER CONDITIONS AND REQUIREMENTS OF THE 
MARKETING AUTHORISATION

D. CONDITIONS OR RESTRICTIONS WITH REGARD TO 
THE SAFE AND EFFECTIVE USE OF THE MEDICINAL 
PRODUCT



38

A. MANUFACTURERS RESPONSIBLE FOR BATCH RELEASE

Name and address of the manufacturer responsible for batch release for multi-dose nasal spray

Takeda GmbH
Robert-Bosch-Strasse 8
D – 78224 Singen
Germany

Name and address of the manufacturers responsible for batch release for single-dose nasal spray

Takeda Pharma A/S
Dybendal Alle 10
DK-2630 Taastrup
Denmark

Takeda GmbH
Robert-Bosch-Strasse 8
D – 78224 Singen
Germany

Curida AS
Solbærvegen 5
NO-2409 Elverum
Norway

Name and address of the manufacturer responsible for batch release for multi-dose nasal spray 
DoseGuard

Takeda GmbH
Robert-Bosch-Strasse 8
D – 78224 Singen
Germany

The printed package leaflet of the medicinal product must state the name and address of the 
manufacturer responsible for the release of the concerned batch.

B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE 

Medicinal product subject to special and restricted medical prescription (See Annex I: Summary of 
Product Characteristics, section 4.2).

C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING 
AUTHORISATION

 Periodic safety update reports (PSURs)

The requirements for submission of PSURs for this medicinal product are set out in the list of Union 
reference dates (EURD list) provided for under Article 107c(7) of Directive 2001/83/EC and any 
subsequent updates published on the European medicines web-portal.



39

D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND 
EFFECTIVE USE OF THE MEDICINAL PRODUCT

 Risk management plan (RMP)

The marketing authorisation holder (MAH) shall perform the required pharmacovigilance 
activities and interventions detailed in the agreed RMP presented in Module 1.8.2 of the 
marketing authorisation and any agreed subsequent updates of the RMP.

An updated RMP should be submitted:
 At the request of the European Medicines Agency;
 Whenever the risk management system is modified, especially as the result of new information 

being received that may lead to a significant change to the benefit/risk profile or as the result of 
an important (pharmacovigilance or risk minimisation) milestone being reached.

 Additional risk minimisation measures

Prior to launch of the multi-dose and single-dose product in each Member State the MAH shall agree 
the final educational material with the National Competent Authority.

The MAH shall ensure that, all physicians, pharmacists and patients expected to 
prescribe/dispense/use Instanyl are provided with educational material regarding the correct and safe 
use of the product.

Educational material for the patients will contain the following:

 Patient information leaflet
 A patient/carer guide
 Enhanced digital access information

Patient/carer guide
 Instanyl to be used only if patients/carers have received the proper information regarding the 

use of the device and the safety precautions.
 Explanation of the indication.
 Explanation of Breakthrough Pain, Patients perception of pain and its treatment.
 Explanation of off label use, misuse, abuse, medication error, overdose, death and addiction.
 Definition of a patient at risk of overdose, abuse, misuse, dependence and addiction in order to 

inform prescribers/ pharmacists.
 Not to use Instanyl to treat any other short-term pain or pain status and/or for treatment of more 

than 4 breakthrough cancer pain episodes a day (section 3 PIL).
 Formulations are not interchangeable.
 Need for reference to prescriber/ pharmacists in case of any question.

How to use Instanyl 
 Instructions for use of the nasal spray device.
 Instructions for opening and closing of the child-resistant box (for the multi-dose nasal spray), 

the child resistant cap (for the multi-dose nasal spray DoseGuard) or blister (for the single-dose 
nasal spray).

 For the multi-dose nasal spray and the multi-dose nasal spray DoseGuard: information about the 
dose counting scheme.

 For the multi-dose nasal spray or the multi-dose nasal spray DoseGuard, all unused devices or 
empty containers should be returned systematically according to the local regulation.

 For the single-dose nasal spray all unused devices should be returned systematically according 
to the local regulation.

 Advice on how to find digital information and instructional videos.



40

Educational material for the physicians will contain the following:

 The Summary of Product Characteristics and Package leaflet
 Guide for Physicians
 Prescribing checklist
 Enhanced digital access information

Guide for Physicians
 Treatment to be initiated/supervised by a physician experienced in the management of opioid 

therapy in cancer patients, in particularly regarding transition from hospital to home.
 Explanation of off label uses (i.e: indication, age) and the serious risks of misuse, abuse, 

medication error, overdose, death and addiction.
 Need for communication to patients/carers: 

o Treatment management and risks of abuse and dependence.
o Need of periodic review by prescribers.
o Encouragement for reporting of any issue with the management of the treatment.

 Identification and monitoring of patients at risk of abuse and misuse before and during the 
treatment to identify the key features of opioid use disorder (OUD): distinguishing features of 
opioid related side effects and opioid use disorder.

 Importance of reporting off-label use, misuse, abuse, addiction and overdose.
 Need for tailoring therapy if OUD is recognized.

The prescribers of Instanyl nasal spray must critically select the patients and counsel them on:
 Instructions for use of the nasal spray device.
 Instructions for opening and closing of the child-resistant box (for the multi-dose nasal spray), 

the child resistant cap (for the multi-dose nasal spray DoseGuard) or blister (for the single-dose 
nasal spray).

 Information about the dose counting scheme included in the labelling and the educational 
material for the multi-dose nasal spray.

 That for the multi-dose nasal spray and multi-dose nasal spray (DoseGuard) all unused devices 
or empty containers should be returned systematically according to the local regulation.

 That for the single-dose nasal spray all unused devices should be returned systematically 
according to the local regulation.

 Never sharing their medication or diverting the purpose of its use.
 Updated label information including hyperalgesia, use in pregnancy, drug interactions such as 

with benzodiazepines, iatrogenic addiction, withdrawal and dependence.
 The prescriber must make use of the checklist for prescribers.

Prescribing checklist
Required actions before prescribing Instanyl. Please complete all of the following before prescribing 
Instanyl single-dose or multi-dose nasal spray or multi-dose nasal spray DoseGuard:
 Ensure that all elements of the approved indication are fulfilled.
 Provide instructions for using the nasal spray to patient and/or carer.
 For single-dose nasal spray only: Advise the patient on the single use nature of the nasal spray 

(each nasal spray contains only one dose and the plunger should only be pressed once the spray 
tip is inserted into the nose, it should not be tested before use).

 Ensure the patient reads the package leaflet inside the Instanyl box.
 Supply the patient with the Instanyl patient brochure provided covering the below:

o Cancer and Pain.
o Instanyl. What is it? How do I use it?
o Instanyl. Risks of misuse.

 Advise patient on how to open the child-resistant blister (for single-use Instanyl), the 
child-resistant box (for multi-dose Instanyl) or the child resistant cap (for multi-dose Instanyl 
DoseGuard) as described in the patient brochure ‘Instanyl. What is it? How do I use it?’

 Explain the risks of using more than the recommended amount of Instanyl.



41

 Explain the use of the dose monitoring cards.
 Advise the patient on the signs of fentanyl overdose and the need for immediate medical 

assistance.
 Explain secure storage and the need to keep out of the reach and sight of children.
 Explain correct disposal of Instanyl single-dose or multi-dose nasal spray or multi-dose nasal 

spray DoseGuard.
 Remind the patient and/or caregiver that they should ask their doctor if they have any questions 

or concerns about how to use Instanyl or about the associated risks of misuse and abuse.

Educational material for the pharmacists will contain the following:

 The Summary of Product Characteristics and Package Leaflet
 Guide for Pharmacists
 Dispensing checklist
 Enhanced digital access information

Guide for Pharmacists 
 Treatment to be initiated/supervised by a physician experienced in the management of opioid 

therapy in cancer patients, in particularly regarding transition from hospital to home.
 Explanation of off label uses (i.e: indication, age) and the serious risks of misuse, abuse, 

medication error, overdose, death and addiction.
 Need for communication to patients/carers: 

o Treatment management and risks of abuse and dependence.
o Need of periodic review by prescribers.
o Encouragement for reporting of any issue with the management of the treatment.

 Monitoring of patients at risk of abuse and misuse during the treatment to identify the key 
features of opioid use disorder (OUD): distinguishing features of opioid related side effects and 
opioid use disorder.

 Importance of reporting off-label use, misuse, abuse, addiction and overdose.
 Physician should be contacted if OUD recognized.
 Pharmacist must be familiar with the educational materials before is given to the patient.
 Instanyl nasal spray not interchangeable with other Fentanyl products.

The pharmacists dispensing Instanyl nasal spray must counsel the patients on:
 Instructions for use of the nasal spray device.
 Instructions for opening and closing of the child-resistant box (for the multi-dose nasal spray), 

the child resistant cap (for the multi-dose nasal spray DoseGuard) or blister (for the single-dose 
nasal spray).

 Information about dose counting scheme included in the labelling and the educational material 
for the multi-dose nasal spray or multi-dose nasal spray DoseGuard.

 The pharmacist must inform the patients that in order to prevent theft and misuse of Instanyl 
nasal spray they have to keep it in a safe place to avoid misuse and diversion.

 For the multi-dose nasal spray or multi-dose nasal spray DoseGuard, all unused devices or 
empty containers should be returned systematically according to the local regulation.

 For the single-dose nasal spray all unused devices should be returned systematically according 
to the local regulation.

 The pharmacist must make use of the checklist for pharmacists.

Dispensing checklist
Required actions before supplying Instanyl. Please complete the following before Instanyl single-dose, 
multi-dose nasal spray or multi-dose nasal spray DoseGuard is supplied:
 Ensure that all elements of the approved indication are fulfilled.
 Provide instructions for using the nasal spray to patient and/or carer.



42

 For single-dose nasal spray only: Advise the patient on the single use nature of the nasal spray 
(each nasal spray contains only one dose and the plunger should only be pressed once the spray 
tip is inserted into the nose, it should not be tested before use).

 Ensure the patient reads the package leaflet inside the Instanyl single-dose, multi-dose or 
multi-dose DoseGuard carton box.

 Supply the patient with the Instanyl patient brochure provided covering the below:
o Cancer and Pain.
o Instanyl. What is it? How do I use it?
o Instanyl. Risks of misuse.

 Advise patient on how to open the child-resistant blister (for single-use Instanyl), the 
child-resistant box (for multi-dose Instanyl) or the child resistant cap (for multi-dose Instanyl 
DoseGuard) as described in the patient brochure ‘Instanyl. What is it? How do I use it?

 Explain the risks of using more than the recommended amount of Instanyl.
 Explain the use of the dose monitoring cards.
 Advise the patient on the signs of fentanyl overdose and the need for immediate medical 

assistance.
 Explain secure storage and the need to keep out of the reach and sight of children.
 Explain correct disposal of Instanyl single-dose or multi-dose nasal spray or multi-dose nasal 

spray DoseGuard.

Digital access to educational material

Digital access to all education material updates will be enhanced. Prescriber (physician), pharmacist 
and patient educational materials will be accessible via a website, and will be available for download. 
Instructional videos on use of the product will be also be accessible via a website. Details of enhanced 
digital accessibility will be discussed with National Competent Authorities and EMA upon approval of 
this RMP, as appropriate.



43

ANNEX III

LABELLING AND PACKAGE LEAFLET



44

A. LABELLING



45

PARTICULARS TO APPEAR ON THE OUTER PACKAGING

CHILD-RESISTANT OUTER BOX (Multi dose)

1. NAME OF THE MEDICINAL PRODUCT

Instanyl 50 micrograms/dose nasal spray, solution
fentanyl

2. STATEMENT OF ACTIVE SUBSTANCE(S)

1 ml contains fentanyl citrate equivalent to 500 micrograms fentanyl. 1 dose of 100 microlitres equals 
50 micrograms fentanyl.

3. LIST OF EXCIPIENTS

Also contains: sodium dihydrogen phosphate dihydrate, disodium phosphate dihydrate, purified water

4. PHARMACEUTICAL FORM AND CONTENTS

Nasal spray, solution 1.8 ml
Nasal spray, solution 2.9 ml
Nasal spray, solution 5.0 ml

1.8 ml - 10 doses
2.9 ml - 20 doses
5.0 ml - 40 doses

5. METHOD AND ROUTE(S) OF ADMINISTRATION

Read the package leaflet before use.
For nasal use

Instruction for opening and closing the box: 
- Pick up the box

- Remove the tamper evidence the first time the box is opened
- Place a thumb and a middle finger on the side tabs



46

- Press side tabs inwards using your thumb and middle finger
- At the same time, place your other thumb on the front pressure pad and also press inwards
- Continue to apply pressure on all three points

- Pull lid to open
- After use of Instanyl the nasal spray must be placed in the inner tray again and the box closed 

- When closing the box, make sure that the side tabs locate back into the slots
- Press down firmly until the side tabs click into position

Tick off one box after each dose 
[Tick boxes of 10, 20 or 40 tick boxes]

Always place the nasal spray in the child-resistant box after use.

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 
OF THE SIGHT AND REACH OF CHILDREN

Keep out of the sight and reach of children.

7. OTHER SPECIAL WARNING(S), IF NECESSARY



47

8. EXPIRY DATE

EXP

9. SPECIAL STORAGE CONDITIONS

Store below 30C. 
Keep the bottle stored upright.
Do not freeze.

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE

Refer to the package leaflet for information on disposal

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER

Takeda Pharma A/S
Dybendal Alle 10
DK-2630 Taastrup
Denmark 

12. MARKETING AUTHORISATION NUMBER(S) 

EU/1/09/531/001
EU/1/09/531/002
EU/1/09/531/003

13. BATCH NUMBER

Lot

14. GENERAL CLASSIFICATION FOR SUPPLY

15. INSTRUCTIONS ON USE

16. INFORMATION IN BRAILLE

Instanyl 50

17. UNIQUE IDENTIFIER – 2D BARCODE

2D barcode carrying the unique identifier included.



48

18. UNIQUE IDENTIFIER – HUMAN READABLE DATA

PC
SN
NN



49

MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS

LABEL / BOTTLE (Multi dose)

1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION

Instanyl 50 micrograms/dose nasal spray 
fentanyl 
Nasal use

2. METHOD OF ADMINISTRATION

3. EXPIRY DATE

EXP

4. BATCH NUMBER

Lot

5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT

1.8 ml - 10 doses
2.9 ml - 20 doses
5.0 ml - 40 doses

6. OTHER



50

PARTICULARS TO APPEAR ON THE OUTER PACKAGING

CHILD-RESISTANT OUTER BOX (Multi dose)

1. NAME OF THE MEDICINAL PRODUCT

Instanyl 100 micrograms/dose nasal spray, solution
fentanyl

2. STATEMENT OF ACTIVE SUBSTANCE(S)

1 ml contains fentanyl citrate equivalent to 1,000 micrograms fentanyl. 1 dose of 100 microlitres 
equals 100 micrograms fentanyl.

3. LIST OF EXCIPIENTS

Also contains: sodium dihydrogen phosphate dihydrate, disodium phosphate dihydrate, purified water

4. PHARMACEUTICAL FORM AND CONTENTS

Nasal spray, solution 1.8 ml
Nasal spray, solution 2.9 ml
Nasal spray, solution 5.0 ml

1.8 ml - 10 doses
2.9 ml - 20 doses
5.0 ml - 40 doses

5. METHOD AND ROUTE(S) OF ADMINISTRATION

Read the package leaflet before use.
For nasal use

Instruction for opening and closing the box:
- Pick up the box

- Remove the tamper evidence the first time the box is opened
- Place a thumb and a middle finger on the side tabs



51

- Press side tabs inwards using your thumb and middle finger
- At the same time, place your other thumb on the front pressure pad and also press inwards
- Continue to apply pressure on all three points

- Pull lid to open
- After use of Instanyl the nasal spray must be placed in the inner tray again and the box closed 

- When closing the box, make sure that the side tabs locate back into the slots
- Press down firmly until the side tabs click into position

Tick off one box after each dose 
[Tick boxes of 10, 20 or 40 tick boxes]

Always place the nasal spray in the child-resistant box after use.

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 
OF THE SIGHT AND REACH OF CHILDREN

Keep out of the sight and reach of children.

7. OTHER SPECIAL WARNING(S), IF NECESSARY



52

8. EXPIRY DATE

EXP

9. SPECIAL STORAGE CONDITIONS

Store below 30C. 
Keep the bottle stored upright.
Do not freeze.

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE

Refer to the package leaflet for information on disposal

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER

Takeda Pharma A/S
Dybendal Alle 10
DK-2630 Taastrup
Denmark

12. MARKETING AUTHORISATION NUMBER(S) 

EU/1/09/531/004
EU/1/09/531/005
EU/1/09/531/006

13. BATCH NUMBER

Lot

14. GENERAL CLASSIFICATION FOR SUPPLY

15. INSTRUCTIONS ON USE

16. INFORMATION IN BRAILLE

Instanyl 100

17. UNIQUE IDENTIFIER – 2D BARCODE

2D barcode carrying the unique identifier included.



53

18. UNIQUE IDENTIFIER – HUMAN READABLE DATA

PC
SN
NN



54

MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS

LABEL / BOTTLE (Multi dose)

1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION

Instanyl 100 micrograms/dose nasal spray
fentanyl 
Nasal use

2. METHOD OF ADMINISTRATION

3. EXPIRY DATE

EXP

4. BATCH NUMBER

Lot

5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT

1.8 ml - 10 doses
2.9 ml - 20 doses
5.0 ml - 40 doses

6. OTHER



55

PARTICULARS TO APPEAR ON THE OUTER PACKAGING

CHILD-RESISTANT OUTER BOX (Multi dose)

1. NAME OF THE MEDICINAL PRODUCT

Instanyl 200 micrograms/dose nasal spray, solution
fentanyl

2. STATEMENT OF ACTIVE SUBSTANCE(S)

1 ml contains fentanyl citrate equivalent to 2,000 micrograms fentanyl. 1 dose of 100 microlitres 
equals 200 micrograms fentanyl.

3. LIST OF EXCIPIENTS

Also contains: sodium dihydrogen phosphate dihydrate, disodium phosphate dihydrate, purified water

4. PHARMACEUTICAL FORM AND CONTENTS

Nasal spray, solution 1.8 ml
Nasal spray, solution 2.9 ml
Nasal spray, solution 5.0 ml

1.8 ml - 10 doses
2.9 ml - 20 doses
5.0 ml - 40 doses

5. METHOD AND ROUTE(S) OF ADMINISTRATION

Read the package leaflet before use.
For nasal use

Instruction for opening and closing the box:
- Pick up the box

- Remove the tamper evidence the first time the box is opened
- Place a thumb and a middle finger on the side tabs



56

- Press side tabs inwards using your thumb and middle finger
- At the same time, place your other thumb on the front pressure pad and also press inwards
- Continue to apply pressure on all three points

- Pull lid to open
- After use of Instanyl the nasal spray must be placed in the inner tray again and the box closed 

- When closing the box, make sure that the side tabs locate back into the slots
- Press down firmly until the side tabs click into position

Tick off one box after each dose 
[Tick boxes of 10, 20 or 40 tick boxes]

Always place the nasal spray in the child-resistant box after use.

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 
OF THE SIGHT AND REACH OF CHILDREN

Keep out of the sight and reach of children.

7. OTHER SPECIAL WARNING(S), IF NECESSARY



57

8. EXPIRY DATE

EXP

9. SPECIAL STORAGE CONDITIONS

Store below 30C. 
Keep the bottle stored upright.
Do not freeze.

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE

Refer to the package leaflet for information on disposal

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER

Takeda Pharma A/S
Dybendal Alle 10
DK-2630 Taastrup
Denmark 

12. MARKETING AUTHORISATION NUMBER(S) 

EU/1/09/531/007
EU/1/09/531/008
EU/1/09/531/009

13. BATCH NUMBER

Lot

14. GENERAL CLASSIFICATION FOR SUPPLY

15. INSTRUCTIONS ON USE

16. INFORMATION IN BRAILLE

Instanyl 200

17. UNIQUE IDENTIFIER – 2D BARCODE

2D barcode carrying the unique identifier included.



58

18. UNIQUE IDENTIFIER – HUMAN READABLE DATA

PC
SN
NN



59

MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS

LABEL / BOTTLE (Multi-dose)

1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION

Instanyl 200 micrograms/dose nasal spray 
fentanyl 
Nasal use

2. METHOD OF ADMINISTRATION

3. EXPIRY DATE

EXP

4. BATCH NUMBER

Lot

5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT

1.8 ml - 10 doses
2.9 ml - 20 doses
5.0 ml - 40 doses

6. OTHER



60

PARTICULARS TO APPEAR ON THE OUTER PACKAGING

OUTER BOX - CARTON (Single Dose) 

1. NAME OF THE MEDICINAL PRODUCT

Instanyl 50 micrograms nasal spray, solution in single-dose container
fentanyl

2. STATEMENT OF ACTIVE SUBSTANCE(S)

1 dose (100 microlitres) contains fentanyl citrate equivalent to 50 micrograms (mcg) fentanyl 

3. LIST OF EXCIPIENTS

Also contains: sodium dihydrogen phosphate dihydrate, disodium phosphate dihydrate, water for 
injections

4. PHARMACEUTICAL FORM AND CONTENTS

Nasal spray, solution 

2 single-dose containers
6 single-dose containers
8 single-dose containers
10 single-dose containers

5. METHOD AND ROUTE(S) OF ADMINISTRATION

Read the package leaflet before use.
For nasal use
The spray container contains only one dose. Do not test before use.

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 
OF THE SIGHT AND REACH OF CHILDREN

Keep out of the sight and reach of children.

7. OTHER SPECIAL WARNING(S), IF NECESSARY

8. EXPIRY DATE

EXP



61

9. SPECIAL STORAGE CONDITIONS

Store below 30C. 
Keep the blister in the outer carton. Keep stored upright.

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE

Refer to the package leaflet for information on disposal

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER

Takeda Pharma A/S
Dybendal Alle 10
DK-2630 Taastrup
Denmark

12. MARKETING AUTHORISATION NUMBER(S) 

EU/1/09/531/010
EU/1/09/531/011
EU/1/09/531/012
EU/1/09/531/013

13. BATCH NUMBER

Lot

14. GENERAL CLASSIFICATION FOR SUPPLY

15. INSTRUCTIONS ON USE

16. INFORMATION IN BRAILLE

Instanyl 50, single-dose

17. UNIQUE IDENTIFIER – 2D BARCODE

2D barcode carrying the unique identifier included.

18. UNIQUE IDENTIFIER – HUMAN READABLE DATA

PC
SN
NN



62

MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS

INTERMEDIATE CHILD-RESISTANT BLISTER (Single dose) 

1. NAME OF THE MEDICINAL PRODUCT

Instanyl 50 micrograms nasal spray
fentanyl 

2. NAME OF THE MARKETING AUTHORISATION HOLDER

Takeda Pharma A/S

3. EXPIRY DATE

EXP

4. BATCH NUMBER

Lot

5. OTHER

Nasal use
1 dose
Keep out of the sight and reach of children.



63

MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS

LABEL / SINGLE-DOSE NASAL SPRAY

1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION

Instanyl 50 mcg nasal spray
fentanyl 
Nasal use

2. METHOD OF ADMINISTRATION

3. EXPIRY DATE

EXP

4. BATCH NUMBER

Lot

5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT

1 dose

6. OTHER



64

PARTICULARS TO APPEAR ON THE OUTER PACKAGING

OUTER BOX - CARTON (Single dose)

1. NAME OF THE MEDICINAL PRODUCT

Instanyl 100 micrograms nasal spray, solution in single-dose container
fentanyl

2. STATEMENT OF ACTIVE SUBSTANCE(S)

1 dose (100 microlitres) contains fentanyl citrate equivalent to 100 micrograms (mcg) fentanyl 

3. LIST OF EXCIPIENTS

Also contains: sodium dihydrogen phosphate dihydrate, disodium phosphate dihydrate, water for 
injections

4. PHARMACEUTICAL FORM AND CONTENTS

Nasal spray, solution 

2 single-dose containers
6 single-dose containers
8 single-dose containers
10 single-dose containers

5. METHOD AND ROUTE(S) OF ADMINISTRATION

Read the package leaflet before use.
For nasal use
The spray container contains only one dose. Do not test before use.

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 
OF THE SIGHT AND REACH OF CHILDREN

Keep out of the sight and reach of children.

7. OTHER SPECIAL WARNING(S), IF NECESSARY

8. EXPIRY DATE

EXP



65

9. SPECIAL STORAGE CONDITIONS

Store below 30C. 
Keep the blister in the outer carton. Keep stored upright.

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE

Refer to the package leaflet for information on disposal

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER

Takeda Pharma A/S
Dybendal Alle 10
DK-2630 Taastrup
Denmark

12. MARKETING AUTHORISATION NUMBER(S) 

EU/1/09/531/014
EU/1/09/531/015
EU/1/09/531/016
EU/1/09/531/017

13. BATCH NUMBER

Lot

14. GENERAL CLASSIFICATION FOR SUPPLY

15. INSTRUCTIONS ON USE

16. INFORMATION IN BRAILLE

Instanyl 100, single-dose

17. UNIQUE IDENTIFIER – 2D BARCODE

2D barcode carrying the unique identifier included.

18. UNIQUE IDENTIFIER – HUMAN READABLE DATA

PC
SN



66

NN



67

MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS

INTERMEDIATE CHILD-RESISTANT BLISTER (Single dose)

1. NAME OF THE MEDICINAL PRODUCT

Instanyl 100 micrograms nasal spray
fentanyl 

2. NAME OF THE MARKETING AUTHORISATION HOLDER

Takeda Pharma A/S

3. EXPIRY DATE

EXP

4. BATCH NUMBER

Lot

5. OTHER

Nasal use
1 dose
Keep out of the sight and reach of children.



68

MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS

LABEL / SINGLE-DOSE NASAL SPRAY

1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION

Instanyl 100 mcg nasal spray
fentanyl 
Nasal use

2. METHOD OF ADMINISTRATION

3. EXPIRY DATE

EXP

4. BATCH NUMBER

Lot

5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT

1 dose

6. OTHER



69

PARTICULARS TO APPEAR ON THE OUTER PACKAGING

OUTER BOX - CARTON (Single dose)

1. NAME OF THE MEDICINAL PRODUCT

Instanyl 200 micrograms nasal spray, solution in single-dose container
fentanyl

2. STATEMENT OF ACTIVE SUBSTANCE(S)

1 dose (100 microlitres) contains fentanyl citrate equivalent to 200 micrograms (mcg) fentanyl 

3. LIST OF EXCIPIENTS

Also contains: sodium dihydrogen phosphate dihydrate, disodium phosphate dihydrate, water for 
injections

4. PHARMACEUTICAL FORM AND CONTENTS

Nasal spray, solution 

2 single-dose containers
6 single-dose containers
8 single-dose containers
10 single-dose containers

5. METHOD AND ROUTE(S) OF ADMINISTRATION

Read the package leaflet before use.
For nasal use
The spray container contains only one dose. Do not test before use.

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 
OF THE SIGHT AND REACH OF CHILDREN

Keep out of the sight and reach of children.

7. OTHER SPECIAL WARNING(S), IF NECESSARY

8. EXPIRY DATE

EXP



70

9. SPECIAL STORAGE CONDITIONS

Store below 30C. 
Keep the blister in the outer carton. Keep stored upright.

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE

Refer to the package leaflet for information on disposal

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER

Takeda Pharma A/S
Dybendal Alle 10
DK-2630 Taastrup
Denmark

12. MARKETING AUTHORISATION NUMBER(S) 

EU/1/09/531/018
EU/1/09/531/019
EU/1/09/531/020
EU/1/09/531/021

13. BATCH NUMBER

Lot

14. GENERAL CLASSIFICATION FOR SUPPLY

15. INSTRUCTIONS ON USE

16. INFORMATION IN BRAILLE

Instanyl 200, single-dose

17. UNIQUE IDENTIFIER – 2D BARCODE

2D barcode carrying the unique identifier included.

18. UNIQUE IDENTIFIER – HUMAN READABLE DATA

PC
SN
NN



71

MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS

INTERMEDIATE CHILD-RESISTANT BLISTER PACK (Single dose)

1. NAME OF THE MEDICINAL PRODUCT

Instanyl 200 micrograms nasal spray
fentanyl 

2. NAME OF THE MARKETING AUTHORISATION HOLDER

Takeda Pharma A/S

3. EXPIRY DATE

EXP

4. BATCH NUMBER

Lot

5. OTHER

Nasal use
1 dose
Keep out of the sight and reach of children.



72

MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS

LABEL / SINGLE-DOSE NASAL SPRAY

1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION

Instanyl 200 mcg nasal spray
fentanyl 
Nasal use

2. METHOD OF ADMINISTRATION

3. EXPIRY DATE

EXP

4. BATCH NUMBER

Lot

5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT

1 dose

6. OTHER



73

PARTICULARS TO APPEAR ON THE OUTER PACKAGING

OUTER BOX – CARTON: DoseGuard

1. NAME OF THE MEDICINAL PRODUCT

Instanyl 50 micrograms/dose nasal spray, solution
fentanyl

2. STATEMENT OF ACTIVE SUBSTANCE(S)

1 ml contains fentanyl citrate equivalent to 500 micrograms fentanyl. 1 dose of 100 microlitres equals 
50 micrograms fentanyl.

3. LIST OF EXCIPIENTS

Also contains: sodium dihydrogen phosphate dihydrate, disodium phosphate dihydrate, purified water

4. PHARMACEUTICAL FORM AND CONTENTS

DoseGuard
Nasal spray, solution 2.0 ml.
Nasal spray, solution 3.2 ml
Nasal spray, solution 4.3 ml
Nasal spray, solution 5.3 ml

10 doses (2.0 ml)
20 doses (3.2 ml)
30 doses (4.3 ml)
40 doses (5.3 ml)

5. METHOD AND ROUTE(S) OF ADMINISTRATION

Read the package leaflet before use.
For nasal use

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 
OF THE SIGHT AND REACH OF CHILDREN

Keep out of the sight and reach of children.
Always close after use by putting the child-resistant cap back on to the nasal spray.

7. OTHER SPECIAL WARNING(S), IF NECESSARY



74

8. EXPIRY DATE

EXP

9. SPECIAL STORAGE CONDITIONS

Store below 30C. 
Do not freeze.

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE

Refer to the package leaflet for information on disposal

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER

Takeda Pharma A/S
Dybendal Alle 10
DK-2630 Taastrup
Denmark

12. MARKETING AUTHORISATION NUMBER(S) 

EU/1/09/531/022
EU/1/09/531/023
EU/1/09/531/024
EU/1/09/531/025

13. BATCH NUMBER

Lot

14. GENERAL CLASSIFICATION FOR SUPPLY

15. INSTRUCTIONS ON USE

16. INFORMATION IN BRAILLE

Instanyl 50

17. UNIQUE IDENTIFIER – 2D BARCODE

2D barcode carrying the unique identifier included.



75

18. UNIQUE IDENTIFIER – HUMAN READABLE DATA

PC
SN
NN



76

MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS

LABEL / NASAL SPRAY DoseGuard

1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION

Instanyl 50 micrograms/dose nasal spray 
fentanyl 
Nasal use

2. METHOD OF ADMINISTRATION

3. EXPIRY DATE

EXP

4. BATCH NUMBER

Lot

5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT

10 doses (2.0 ml)
20 doses (3.2 ml)
30 doses (4.3 ml)
40 doses (5.3 ml)

6. OTHER

Keep out of the sight and reach of children
Always close after use by putting the child-resistant cap back on to the nasal spray.



77

PARTICULARS TO APPEAR ON THE OUTER PACKAGING

OUTER BOX – CARTON DoseGuard

1. NAME OF THE MEDICINAL PRODUCT

Instanyl 100 micrograms/dose nasal spray, solution
fentanyl

2. STATEMENT OF ACTIVE SUBSTANCE(S)

1 ml contains fentanyl citrate equivalent to 1,000 micrograms fentanyl. 1 dose of 100 microlitres 
equals 100 micrograms fentanyl.

3. LIST OF EXCIPIENTS

Also contains: sodium dihydrogen phosphate dihydrate, disodium phosphate dihydrate, purified water

4. PHARMACEUTICAL FORM AND CONTENTS

DoseGuard
Nasal spray, solution 2.0 ml
Nasal spray, solution 3.2 ml
Nasal spray, solution 4.3 ml
Nasal spray, solution 5.3 ml

10 doses (2.0 ml)
20 doses (3.2 ml)
30 doses (4.3 ml)
40 doses (5.3 ml)

5. METHOD AND ROUTE(S) OF ADMINISTRATION

Read the package leaflet before use.
For nasal use

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 
OF THE SIGHT AND REACH OF CHILDREN

Keep out of the sight and reach of children.
Always close after use by putting the child-resistant cap back on to the nasal spray.

7. OTHER SPECIAL WARNING(S), IF NECESSARY



78

8. EXPIRY DATE

EXP

9. SPECIAL STORAGE CONDITIONS

Store below 30C. 
Do not freeze.

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE

Refer to the package leaflet for information on disposal

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER

Takeda Pharma A/S
Dybendal Alle 10
DK-2630 Taastrup
Denmark

12. MARKETING AUTHORISATION NUMBER(S) 

EU/1/09/531/026
EU/1/09/531/027
EU/1/09/531/028
EU/1/09/531/029

13. BATCH NUMBER

Lot

14. GENERAL CLASSIFICATION FOR SUPPLY

15. INSTRUCTIONS ON USE

16. INFORMATION IN BRAILLE

Instanyl 100 

17. UNIQUE IDENTIFIER – 2D BARCODE

2D barcode carrying the unique identifier included.



79

18. UNIQUE IDENTIFIER – HUMAN READABLE DATA

PC
SN
NN



80

MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS

LABEL / NASAL SPRAY DoseGuard

1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION

Instanyl 100 micrograms/dose nasal spray 
fentanyl 
Nasal use

2. METHOD OF ADMINISTRATION

3. EXPIRY DATE

EXP

4. BATCH NUMBER

Lot

5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT

10 doses (2.0 ml)
20 doses (3.2 ml)
30 doses (4.3 ml)
40 doses (5.3 ml)

6. OTHER

Keep out of the sight and reach of children
Always close after use by putting the child-resistant cap back on to the nasal spray.



81

PARTICULARS TO APPEAR ON THE OUTER PACKAGING

OUTER BOX - CARTON DoseGuard

1. NAME OF THE MEDICINAL PRODUCT

Instanyl 200 micrograms/dose nasal spray, solution
fentanyl

2. STATEMENT OF ACTIVE SUBSTANCE(S)

1 ml contains fentanyl citrate equivalent to 2,000 micrograms fentanyl. 1 dose of 100 microlitres 
equals 200 micrograms fentanyl.

3. LIST OF EXCIPIENTS

Also contains: sodium dihydrogen phosphate dihydrate, disodium phosphate dihydrate, purified water

4. PHARMACEUTICAL FORM AND CONTENTS

DoseGuard
Nasal spray, solution 2.0 ml
Nasal spray, solution 3.2 ml
Nasal spray, solution 4.3 ml
Nasal spray, solution 5.3 ml

10 doses (2.0 ml)
20 doses (3.2 ml)
30 doses (4.3 ml)
40 doses (5.3 ml)

5. METHOD AND ROUTE(S) OF ADMINISTRATION

Read the package leaflet before use.
For nasal use

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 
OF THE SIGHT AND REACH OF CHILDREN

Keep out of the sight and reach of children.
Always close after use by putting the child-resistant cap back on to the nasal spray.

7. OTHER SPECIAL WARNING(S), IF NECESSARY



82

8. EXPIRY DATE

EXP

9. SPECIAL STORAGE CONDITIONS

Store below 30C. 
Do not freeze.

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE

Refer to the package leaflet for information on disposal

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER

Takeda Pharma A/S
Dybendal Alle 10
DK-2630 Taastrup
Denmark

12. MARKETING AUTHORISATION NUMBER(S) 

EU/1/09/531/030
EU/1/09/531/031
EU/1/09/531/032
EU/1/09/531/033

13. BATCH NUMBER

Lot

14. GENERAL CLASSIFICATION FOR SUPPLY

15. INSTRUCTIONS ON USE

16. INFORMATION IN BRAILLE

Instanyl 200



83

17. UNIQUE IDENTIFIER – 2D BARCODE

2D barcode carrying the unique identifier included.

18. UNIQUE IDENTIFIER – HUMAN READABLE DATA

PC
SN
NN



84

MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS

LABEL / NASAL SPRAY DoseGuard

1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION

Instanyl 200 micrograms/dose nasal spray 
fentanyl 
Nasal use

2. METHOD OF ADMINISTRATION

3. EXPIRY DATE

EXP

4. BATCH NUMBER

Lot

5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT

10 doses (2.0 ml)
20 doses (3.2 ml)
30 doses (4.3 ml)
40 doses (5.3 ml)

6. OTHER

Keep out of the sight and reach of children
Always close after use by putting the child-resistant cap back on to the nasal spray.



85

B. PACKAGE LEAFLET



86

Package leaflet: Information for the user

Instanyl 50 micrograms/dose nasal spray, solution
Instanyl 100 micrograms/dose nasal spray, solution
Instanyl 200 micrograms/dose nasal spray, solution

fentanyl

Read all of this leaflet carefully before you start using this medicine because it contains 
important information for you.
- Keep this leaflet. You may need to read it again.
- If you have any further questions, ask your doctor or pharmacist.
- This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, 

even if their signs of illness are the same as yours.
- If you get any side effects, talk to your doctor, nurse or pharmacist. This includes any possible 

side effects not listed in this leaflet. See section 4.

What is in this leaflet

1. What Instanyl is and what it is used for
2. What you need to know before you use Instanyl
3. How to use Instanyl
4. Possible side effects
5. How to store Instanyl
6. Contents of the pack and other information

1. What Instanyl is and what it is used for

Instanyl contains the active substance fentanyl and belongs to a group of strong painkillers called 
opioids. Opioids act by blocking the pain signals to the brain. 
Instanyl acts rapidly and is used for relieving breakthrough pain in adult cancer patients already treated 
with opioids for their usual pain. Breakthrough pain is an additional sudden pain that occurs despite 
you having taken your usual opioid pain relieving medicines.

2. What you need to know before you use Instanyl

Do not use Instanyl
- if you are allergic to fentanyl or any of the other ingredients of this medicine (listed in 

section 6).
- if you are not regularly using a prescribed opioid medicine (e.g codeine, fentanyl, 

hydromorphone, morphine, oxycodone, pethidine), every day on a regular schedule, for at least 
a week, to control your persistent pain. If you have not been using these medicines you must not 
use Instanyl, because it may increase the risk that breathing could become dangerously slow 
and/or shallow, or even stop.

- If you are taking a medicine which contains sodium oxybate.
- if you suffer from short-term pain other than breakthrough pain.
- if you have serious difficulties breathing or suffer from a serious obstructive lung disease.
- if you have previously received facial radiotherapy.
- if you suffer from recurrent episodes of nose bleeding.

Warnings and precautions
Talk to your doctor before using Instanyl, especially:
- if you suffer from a long-term obstructive lung disease, your breathing may be impaired by 

Instanyl.



87

- if you have problems with your heart especially slow heart rate, low blood pressure or low 
blood volume.

- if you have problems with your liver or kidneys.
- if you have problems with your brain function, e.g. due to a brain tumour, a head injury or 

increased intracranial pressure.
- if you have ever developed adrenal insufficiency or lack of sex hormones (androgen deficiency) 

with opioid use.
- if you take antidepressants or antipsychotics, please refer to the section ‘Other medicines and 

Instanyl’.
- if you take medicines called partial agonist/antagonists e.g. buprenorphine, nalbuphine and 

pentazocine (medicines for treatment of pain) as you may experience symptoms of withdrawal 
syndrome. Please refer to the section Other medicines and Instanyl for more information.

- if you use other nasal spray products, e.g. for common cold or allergy.

If you experience difficulties breathing while being treated with Instanyl, it is very important 
that you contact your doctor or hospital immediately.

Consult your doctor while using Instanyl, if:
- you experience pain or increased sensitivity to pain (hyperalgesia) which does not respond to a

higher dosage of your medicine as prescribed by your doctor.
- you experience a combination of the following symptoms: nausea, vomiting, anorexia, fatigue, 

weakness, dizziness and low blood pressure. Together these symptoms may be a sign of a 
potentially life-threatening condition called adrenal insufficiency, a condition in which the 
adrenal glands do not produce enough hormones.

If you experience recurrent nose bleeding or nasal discomfort whilst being treated with Instanyl, you 
must contact your doctor, who will consider alternative treatment for your breakthrough pain.

If you think you are becoming dependent on Instanyl, it is important that you inform you doctor.

Children and adolescents
Instanyl should not be used in children and adolescents under 18 years of age.

Other medicines and Instanyl
Tell your doctor or pharmacist if you are taking, have recently taken or might take any other 
medicines, including medicines obtained without a prescription.

Instanyl may affect or be affected by other medicines.
Special care should be taken if you are treated with any of the following medicines:
- any medicines which might normally make you sleepy (have a sedative effect) such as sleeping 

pills, medicines to treat anxiety, antihistamines, or tranquillisers. The use of such other drugs at 
the same time as Instanyl, may cause deep sedation and affect your ability to breath, which may 
lead to coma and be life-threatening.

- any medicines that might have an effect on the way in which your body breaks down Instanyl, 
such as:
 ritonavir, nelfinavir, amprenavir, and fosamprenavir (medicines that help control HIV 

infection);
 CYP3A4 inhibitors such as ketoconazole, itraconazole, or fluconazole (used for treatment 

of fungal infections);
 troleandomycin, clarithromycin, or erythromycin (medicines for treatment of bacterial 

infections);
 aprepitant (used to treat severe nausea);
 diltiazem and verapamil (medicines for treatment of high blood pressure or heart 

diseases).
- medicines called Monoamine Oxidase Inhibitors (MAOI) used for severe depression, even if 

you have been treated with one in the past 2 weeks.



88

- The risk of side effects increases if you are taking medicines such as certain antidepressants or 
antipsychotics. Instanyl may interact with these medicines and you may experience mental 
status changes (e.g. agitation, hallucinations, coma), and other effects such as body temperature 
above 38 °C, increase in heart rate, unstable blood pressure, and exaggeration of reflexes, 
muscular rigidity, lack of coordination and/or gastrointestinal symptoms (e.g. nausea, vomiting, 
diarrhoea). Your doctor will tell you whether Instanyl is suitable for you.

- medicines called partial agonist/antagonists e.g. buprenorphine, nalbuphine and pentazocine 
(medicines for treatment of pain). You could experience symptoms of withdrawal syndrome
(nausea, vomiting, diarrhoea, anxiety, chills, tremor, and sweating).

- other medicines taken via the nose, especially oxymetazoline, xylometazoline and similar 
medicines, which are used for relief of nose congestions.

Instanyl with food, drink and alcohol
Do not drink alcohol whilst being treated with Instanyl, as it can increase the risk of experiencing 
dangerous side effects.

Pregnancy and breast-feeding
If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby ask 
your doctor or pharmacist for advice before taking any medicine.

Instanyl should not be used during pregnancy unless you have discussed this with your doctor.

Instanyl should not be used during childbirth because fentanyl may cause serious breathing problems 
in the new-born child.

Fentanyl can get into breast milk and may cause side effects in the breast-fed infant. Do not use
Instanyl if you are breast-feeding. You should not start breast-feeding until at least 5 days after the 
last dose of Instanyl.

Driving and using machines
You should not drive or use machinery whilst being treated with Instanyl. Instanyl can cause 
dizziness, drowsiness and visual disturbances, which may affect your ability to drive or use machines.

3. How to use Instanyl

Always use this medicine exactly as your doctor has told you. Check with your doctor or pharmacist if 
you are not sure. 

The dose of Instanyl is independent of your usual cancer pain treatment.

When you first start using Instanyl, your doctor will work with you to find the dose that will relieve 
your breakthrough pain.
The initial dose is one puff of 50 micrograms in one nostril each time you have an episode of 
breakthrough pain. During the determination of your right dose, your doctor may instruct you to 
change to a higher dose. 

If your breakthrough pain is not relieved after 10 minutes, you may use only one puff more for this 
episode.
Generally you should wait 4 hours before treating another episode of breakthrough pain. On 
exceptional occasions where a new episode occurs earlier, you can use Instanyl to treat it but you must 
wait at least 2 hours before doing so. If you regularly have breakthrough pain episodes that are less 
than 4 hours apart, contact your doctor as your usual cancer pain treatment may have to be changed.

You can use Instanyl to treat up to four episodes of breakthrough pain per day.



89

If you experience more than four episodes of breakthrough pain per day, contact your doctor, as your 
usual cancer pain treatment may have to be changed.

In order to keep track of the number of doses of Instanyl used, you should use the tick-boxes in the 
booklet placed on top of the child-resistant outer box.

Do not change the dose of Instanyl or your other pain medicines on your own. Change in dose must be 
done together with your doctor.

Instanyl is for nasal use.

Please read the instruction for use at the end of this leaflet to learn how to use Instanyl.

If you use more Instanyl than you should or if you think someone has accidentally used Instanyl
You should contact your doctor, hospital or emergency room for assessment of the risk and for advice 
if you have taken more Instanyl than you should.

Symptoms of overdose are:
Sleepiness, drowiness, dizziness, reduced body temperature, slow heart beat, difficulties coordinating 
arms and legs.
In serious cases taking too much Instanyl may cause coma, sedation, convulsions or severe breathing 
difficulties (very slow or shallow breathing).
If you feel any of the above symptoms you should seek immediate medical assistance.

Note to carers
If you see the person taking Instanyl suddenly acting slowly, having difficulties breathing or if you 
have difficulties waking the person up:
- you should immediately call for emergency help.
- while waiting for the emergency help, you must try to keep the person awake by talking to or 

gently shaking the person every now and then.
- if the person has difficulty breathing, you should prompt the person to breathe in every 

5-10 seconds.
- if the person has stopped breathing, you should attempt to resuscitate her/him until emergency 

help arrives.

If you think someone has accidentally taken Instanyl, please seek immediate medical assistance. Try to 
keep the person awake until emergency help arrives.
If someone has accidentally taken Instanyl, they may have the same symptoms as described above for 
overdose.

If you forget to use Instanyl
If the breakthrough pain is still ongoing, you may take Instanyl as prescribed by your doctor. If the 
breakthrough pain has stopped, do not take Instanyl until the next episode of breakthrough pain occurs.

If you stop using Instanyl
You should discontinue Instanyl when you no longer have any breakthrough pain. You should 
however continue to take your usual pain relieving medicine to treat your cancer pain. Contact your 
doctor to confirm the correct dose of your usual medicine if you are not sure.
You may experience withdrawal symptoms similar to the possible side effects of Instanyl when 
discontinuing Instanyl. If you experience withdrawal symptoms, you should contact your doctor. Your 
doctor will evaluate if you need medicine to reduce or eliminate the withdrawal symptoms.

If you have any further questions on the use of this product, ask your doctor or pharmacist.



90

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody gets them.
The side effects will often stop or reduce in intensity with continued use of the product.

Discontinue the treatment and contact your doctor, hospital or emergency room immediately, if 
you:
- experience severe breathing difficulties.
- have a rattling sound when you breathe in.
- have convulsive pain.
- experience extreme dizziness.
These side effects can be very serious.

Other side effects reported after use of Instanyl:

Common (may affect up to 1 in 10 people):
Sleepiness, dizziness even with difficulties keeping balance, headache, irritation of the throat, nausea, 
vomiting, flushing, feeling very warm, excessive sweating.

Uncommon (may affect up to 1 in 100 people):
Sleeplessness, drowsiness, convulsive muscle contractions, abnormal sensation of the skin even 
unpleasant, change of taste, motion sickness, low blood pressure, severe breathing problems, nose 
bleeds, nasal ulcer, runny nose, constipation, inflammation of the mouth, dry mouth, skin pain, itching 
of the skin, fever.

Not known (frequency cannot be estimated from the available data):
Fall, diarrhoea, convulsions (fits), loss of consciousness, swelling of arms or legs, seeing or hearing 
things that are not really there (hallucinations), drug dependence (addiction), drug abuse, fatigue, 
malaise, withdrawal syndrome (may manifest by the occurrence of the following side effects nausea, 
vomiting, diarrhoea, anxiety, chills, tremor, and sweating), shortness of breath.

There have also been reports of patients developing a hole in the septum of the nose – the structure, 
which separates the nostrils.

Prolonged treatment with fentanyl during pregnancy may cause withdrawal symptoms in the newborn 
which can be life-threatening (see section 2)

You should tell your doctor if you experience recurrent episodes of nose bleeding or nasal discomfort.

Reporting of side effects
If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects 
not listed in this leaflet. You can also report side effects directly via the national reporting system 
listed in Appendix V. By reporting side effects you can help provide more information on the safety of 
this medicine.

5. How to store Instanyl

The pain-relieving medicine in Instanyl is very strong and can be life-threatening to children. 
Instanyl must be kept out of the sight and reach of children. Always place the nasal spray in the 
child-resistant box after use.
Do not use Instanyl after the expiry date which is stated on the bottle after EXP. The expiry date refers 
to the last day of the month.
Store below 30C. Keep the nasal spray stored upright. Do not freeze. If Instanyl nasal spray is frozen 
the spray pump may crack. If uncertain of how the pump has been stored, you should check the spray 
pump before use. 



91

Instanyl that has passed the expiry date or is no longer required, may still contain enough medicine to 
be harmful to other people, especially children. Do not throw away any medicines via wastewater or 
household waste. Any used or unused nasal spray should be returned systematically and suitably in the 
child-resistant outer box and discarded according to local requirements or returned to the pharmacy. 
Ask your pharmacist how to dispose of medicines you no longer use. These measures will help to 
protect the environment.

6. Contents of the pack and other information

What Instanyl contains
The active substance is fentanyl. The content is:
50 micrograms/dose: 1 ml contains fentanyl citrate equivalent to 500 micrograms fentanyl. 1 puff 
(100 microlitres) contains 50 micrograms fentanyl.
100 micrograms/dose: 1 ml contains fentanyl citrate equivalent to 1,000 micrograms fentanyl. 1 puff 
(100 microlitres) contains 100 micrograms fentanyl.
200 micrograms/dose: 1 ml contains fentanyl citrate equivalent to 2,000 micrograms fentanyl. 1 puff 
(100 microlitres) contains 200 micrograms fentanyl.

The other ingredients are sodium dihydrogen phosphate dihydrate, disodium phosphate dihydrate, and 
purified water.

What Instanyl looks like and contents of the pack
Instanyl is a nasal spray, solution. The solution is clear and colourless. It is contained in a brown glass 
bottle with a metering pump. 
The nasal spray is supplied in a child-resistant outer box and comes in three different pack sizes: 
1.8 ml (equal to 10 doses), 2.9 ml (equal to 20 doses) and 5.0 ml (equal to 40 doses).
Not all pack sizes may be marketed.

The labelling of the three Instanyl strengths is differentiated by colour: 
50 micrograms/dose labelling is orange.
100 micrograms/dose labelling is purple.
200 micrograms/dose labelling is greenish-blue.

Marketing Authorisation Holder 
Takeda Pharma A/S
Dybendal Alle 10
DK-2630 Taastrup
Denmark 

Manufacturer
Takeda GmbH
Robert-Bosch-Strasse 8
D – 78224 Singen
Germany

For any information about this medicine, please contact the local representative of the Marketing 
Authorisation Holder.

België/Belgique/Belgien/Luxembourg/
Luxemburg
Takeda Belgium
Tél/Tel: +32 2 464 06 11
takeda-belgium@takeda.com

Lietuva
Takeda, UAB
Tel: +370 521 09 070



92

България
Такеда България
Тел.: + 359 2 958 27 36

Magyarország 
Takeda Pharma Kft.
Tel.: +361 2707030 

Česká republika
Takeda Pharmaceuticals Czech Republic s.r.o.
Tel: + 420 234 722 722

Malta / Κύπρος
Takeda Pharma A/S
Tel/Τηλ: +45 46 77 11 11

Danmark
Takeda Pharma A/S
Tlf: +45 46 77 11 11

Nederland
Takeda Nederland bv
Tel: +31 23 56 68 777

Deutschland
Takeda GmbH
Tel: +49 (0) 800 825 3325
medinfo@takeda.de

Norge
Takeda AS
Tlf: +47 6676 3030
infonorge@takeda.com

Eesti
Takeda Pharma AS
Tel: +372 6177 669
info@takeda.ee

Österreich
Takeda Pharma Ges.m.b.H. 
Tel: +43 (0) 800 20 80 50 

Ελλάδα
TAKEDA ΕΛΛΑΣ Α.Ε.
Τηλ: +30 210 6387800
gr.info@takeda.com

Polska
Takeda Pharma sp. z o.o.
Tel.: +48 22 608 13 00

España
Takeda Farmacéutica España S.A.
Tel: +34 917 90 42 22
spain@takeda.com

Portugal
Takeda Farmacêuticos Portugal, Lda.
Tel: + 351 21 120 1457

France
Takeda France S.A.S
Tél: +33 1 46 25 16 16 

România 
Takeda Pharmaceuticals SRL
Tel: +40 21 335 03 91

Hrvatska
Takeda Pharmaceuticals Croatia d.o.o
Tel: +385 1 377 88 96

Slovenija
Takeda GmbH Podružnica Slovenija
Tel: +386 (0) 59 082 480

Ireland
Takeda Products Ireland Ltd.
Tel: +353 (0) 1 6420021

Slovenská republika
Takeda Pharmaceuticals Slovakia s.r.o.
Tel: +421 (2) 20 602 600

Ísland
Vistor hf.
Sími: +354 535 7000
vistor@vistor.is

Suomi/Finland
Takeda Oy
Puh/Tel: +358 20 746 5000
infoposti@takeda.com

Italia
Takeda Italia S.p.A.
Tel: +39 06 502601

Sverige
Takeda Pharma AB
Tel: +46 8 731 28 00
infosweden@takeda.com



93

Κύπρος
Takeda Pharma A/S
Τηλ: +45 46 77 11 11

Latvija
Takeda Latvia SIA
Tel: +371 67840082

United Kingdom
Takeda UK Ltd
Tel: +44 (0)1628 537 900

This leaflet was last revised in {MM/YYYY}.

Detailed information on this medicine is available on the European Medicines Agency web site: 
http://www.ema.europa.eu.



94

INSTRUCTIONS FOR USE OF INSTANYL NASAL SPRAY

Please read the following instructions carefully to learn how to use Instanyl nasal spray:

Preparing Instanyl nasal spray for use:
- Before using the nasal spray for the first time:

 It must be pumped 3 or 4 times (primed) until a fine mist appears.
- During this priming process medicine will be expelled. Therefore:

 Priming should be performed in a well ventilated area.
 Do not point the nasal spray in the direction of yourself and other people.
 Do not point in the direction of surfaces and objects that could come into contact 

with other people, particularly children.
- If you have not used Instanyl for more than 7 days the pump must be primed again by spraying 

once before the next dose is taken.

Instanyl nasal spray should be used in the following way:
1. Blow your nose if it feels blocked or you have a cold.
2. You should sit or stand in upright position.
3. Remove the protective cap from the spray.

4. Hold the nasal spray upright.
5. Bend your head slightly forward.
6. Close one nostril by placing your finger against the side of your nose and insert the spray tip into 

the other nostril (approximately 1 cm). It does not matter which nostril you use. If you have to 
take a second dose after 10 minutes to get sufficient pain relief, this dose should be taken in the 
other nostril.

7. Press the pump down quickly and completely with two fingers, once, while breathing in through 
your nose. You must make sure the pump is pressed all the way down. You may not feel the dose
in your nose, but you have received it when you have pressed the pump.

8. Clean the nasal spray tip after use with a clean tissue, and then throw away the tissue afterwards.



95

If after 10 minutes you need a second dose of Instanyl to relieve your pain, repeat steps 1 to 8 in the 
other nostril.

Always place Instanyl in the child-resistant box after use. Keep out of the sight and reach of 
children.

Keep track of how many doses you have used and how many you have left in your nasal spray by 
using the dose-counting card provided with Instanyl nasal spray. Every time you use Instanyl nasal 
spray, make sure you or your carer fills in the information on the card.

If Instanyl nasal spray is blocked or does not spray properly:
 If it is blocked, aim the nasal spray away from you (and any other people) and push firmly down 

on the pump. This should clear any blockage. 
 If your nasal spray is still not working properly, talk to your pharmacist. Never try to fix the 

nasal spray yourself or take it apart. This is because it may then give you the wrong dose. 



96

Package leaflet: Information for the user

Instanyl 50 micrograms nasal spray, solution in single-dose container
Instanyl 100 micrograms nasal spray, solution in single-dose container
Instanyl 200 micrograms nasal spray, solution in single-dose container

fentanyl

Read all of this leaflet carefully before you start using this medicine because it contains 
important information for you.
- Keep this leaflet. You may need to read it again.
- If you have any further questions, ask your doctor or pharmacist.
- This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, 

even if their signs of illness are the same as yours.
- If you get any side effects, talk to your doctor, nurse or pharmacist. This includes any possible 

side effects not listed in this leaflet. See section 4.

What is in this leaflet

1. What Instanyl is and what it is used for
2. What you need to know before you use Instanyl
3. How to use Instanyl
4. Possible side effects
5. How to store Instanyl
6. Contents of the pack and other information

1. What Instanyl is and what it is used for

Instanyl contains the active substance fentanyl and belongs to a group of strong painkillers called 
opioids. Opioids act by blocking the pain signals to the brain. 
Instanyl acts rapidly and is used for relieving breakthrough pain in adult cancer patients already treated 
with opioids for their usual pain. Breakthrough pain is an additional sudden pain that occurs despite 
you having taken your usual opioid pain relieving medicines.

2. What you need to know before you use Instanyl

Do not use Instanyl
- if you are allergic to fentanyl or any of the other ingredients of this medicine (listed in 

section 6).
- if you are not regularly using a prescribed opioid medicine (e.g codeine, fentanyl, 

hydromorphone, morphine, oxycodone, pethidine), every day on a regular schedule, for at least 
a week, to control your persistent pain. If you have not been using these medicines you must not 
use Instanyl, because it may increase the risk that breathing could become dangerously slow 
and/or shallow, or even stop.

- if you are taking a medicine which contains sodium oxybate.
- if you suffer from short-term pain other than breakthrough pain.
- if you have serious difficulties breathing or suffer from a serious obstructive lung disease.
- if you have previously received facial radiotherapy.
- if you suffer from recurrent episodes of nose bleeding.

Warnings and precautions
Talk to your doctor before using Instanyl, especially:
- if you suffer from a long-term obstructive lung disease, your breathing may be impaired by 

Instanyl.
- if you have problems with your heart especially slow heart rate, low blood pressure or low 

blood volume.



97

- if you have problems with your liver or kidneys.
- if you have problems with your brain function, e.g. due to a brain tumour, a head injury or 

increased intracranial pressure.
- if you have ever developed adrenal insufficiency or lack of sex hormones (androgen deficiency) 

with opioid use.
- if you take antidepressants or antipsychotics, please refer to the section ‘Other medicines and 

Instanyl’.
- if you take medicines called partial agonist/antagonists e.g. buprenorphine, nalbuphine and 

pentazocine (medicines for treatment of pain) as you may experience symptoms of withdrawal 
syndrome. Please refer to the section Other medicines and Instanyl for more information.

- if you use other nasal spray products, e.g. for common cold or allergy.

If you experience difficulties breathing while being treated with Instanyl, it is very important 
that you contact your doctor or hospital immediately.

Consult your doctor while using Instanyl, if:
- you experience pain or increased sensitivity to pain (hyperalgesia) which does not respond to a 

higher dosage of your medicine as prescribed by your doctor.
- you experience a combination of the following symptoms: nausea, vomiting, anorexia, fatigue, 

weakness, dizziness and low blood pressure. Together these symptoms may be a sign of a 
potentially life-threatening condition called adrenal insufficiency, a condition in which the 
adrenal glands do not produce enough hormones.

If you experience recurrent nose bleeding or nasal discomfort whilst being treated with Instanyl, you 
must contact your doctor, who will consider alternative treatment for your breakthrough pain.

If you think you are becoming dependent on Instanyl, it is important that you inform you doctor.

Children and adolescents
Instanyl should not be used in children and adolescents under 18 years of age.

Other medicines and Instanyl
Tell your doctor or pharmacist if you are taking, have recently taken or might take any other 
medicines, including medicines obtained without a prescription.

Instanyl may affect or be affected by other medicines.
Special care should be taken if you are treated with any of the following medicines: 
- any medicines which might normally make you sleepy (have a sedative effect) such as sleeping 

pills, medicines to treat anxiety, antihistamines, or tranquillisers. The use of such other drugs at 
the same time as Instanyl, may cause deep sedation and affect your ability to breath, which may 
lead to come and be life-threatening.

- any medicines that might have an effect on the way in which your body breaks down Instanyl, 
such as:
 ritonavir, nelfinavir, amprenavir, and fosamprenavir (medicines that help control HIV 

infection);
 CYP3A4 inhibitors such as ketoconazole, itraconazole, or fluconazole (used for treatment 

of fungal infections);
 troleandomycin, clarithromycin, or erythromycin (medicines for treatment of bacterial 

infections);
 aprepitant (used to treat severe nausea);
 diltiazem and verapamil (medicines for treatment of high blood pressure or heart 

diseases).
- medicines called Monoamine Oxidase Inhibitors (MAOI) used for severe depression, even if 

you have been treated with one in the past 2 weeks.
- The risk of side effects increases if you are taking medicines such as certain antidepressants or 

antipsychotics. Instanyl may interact with these medicines and you may experience mental 
status changes (e.g. agitation, hallucinations, coma), and other effects such as body temperature 



98

above 38 °C, increase in heart rate, unstable blood pressure, and exaggeration of reflexes, 
muscular rigidity, lack of coordination and/or gastrointestinal symptoms (e.g. nausea, vomiting, 
diarrhoea). Your doctor will tell you whether Instanyl is suitable for you.

- medicines called partial agonist/antagonists e.g. buprenorphine, nalbuphine and pentazocine 
(medicines for treatment of pain). You could experience symptoms of withdrawal syndrome
(nausea, vomiting, diarrhoea, anxiety, chills, tremor, and sweating).

- other medicines taken via the nose, especially oxymetazoline, xylometazoline and similar 
medicines, which are used for relief of nose congestions.

Instanyl with food, drink and alcohol
Do not drink alcohol whilst being treated with Instanyl, as it can increase the risk of experiencing 
dangerous side effects.

Pregnancy and breast-feeding
If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby ask 
your doctor or pharmacist for advice before taking any medicine.

Instanyl should not be used during pregnancy unless you have discussed this with your doctor.

Instanyl should not be used during childbirth because fentanyl may cause serious breathing problems 
in the new-born child.

Fentanyl can get into breast milk and may cause side effects in the breast-fed infant. Do not use
Instanyl if you are breast-feeding. You should not start breast-feeding until at least 5 days after the last
dose of Instanyl.

Driving and using machines
You should not drive or use machinery whilst being treated with Instanyl. Instanyl can cause 
dizziness, drowsiness and visual disturbances, which may affect your ability to drive or use machines.

3. How to use Instanyl

Always use this medicine exactly as your doctor has told you. Check with your doctor or pharmacist if 
you are not sure.

The dose of Instanyl is independent of your usual cancer pain treatment.

When you first start using Instanyl, your doctor will work with you to find the dose that will relieve 
your breakthrough pain.
The initial dose is one puff of 50 micrograms in one nostril each time you have an episode of 
breakthrough pain. During the determination of your right dose, your doctor may instruct you to 
change to a higher dose. 

If your breakthrough pain is not relieved after 10 minutes, you may use only one puff more for this 
episode.
Generally you should wait 4 hours before treating another episode of breakthrough pain. On 
exceptional occasions where a new episode occurs earlier, you can use Instanyl to treat it but you must 
wait at least 2 hours before doing so. If you regularly have breakthrough pain episodes that are less 
than 4 hours apart, contact your doctor as your usual cancer pain treatment may have to be changed.

You can use Instanyl to treat up to four episodes of breakthrough pain per day.

If you experience more than four episodes of breakthrough pain per day, contact your doctor, as your 
usual cancer pain treatment may have to be changed.



99

Do not change the dose of Instanyl or your other pain medicines on your own. Change in dose must be 
done together with your doctor.

Instanyl is for nasal use.

Please read the instruction for use at the end of this leaflet to learn how to use Instanyl.

If you use more Instanyl than you should or if you think someone has accidentally used Instanyl
You should contact your doctor, hospital or emergency room for assessment of the risk and for advice 
if you have taken more Instanyl than you should.

Symptoms of overdose are: 
Sleepiness, drowiness, dizziness, reduced body temperature, slow heart beat, difficulties coordinating 
arms and legs.
In serious cases taking too much Instanyl may cause coma, sedation, convulsions or severe breathing 
difficulties (very slow or shallow breathing).
If you feel any of the above symptoms you should seek immediate medical assistance.

Note to carers
If you see the person taking Instanyl suddenly acting slowly, having difficulties breathing or if you 
have difficulties waking the person up:
- you should immediately call for emergency help.
- while waiting for the emergency help, you must try to keep the person awake by talking to or 

gently shaking the person every now and then.
- if the person has difficulty breathing, you should prompt the person to breathe in every 

5-10 seconds.
- if the person has stopped breathing, you should attempt to resuscitate her/him until emergency 

help arrives.

If you think someone has accidentally taken Instanyl, please seek immediate medical assistance. Try to 
keep the person awake until emergency help arrives.
If someone has accidentally taken Instanyl, they may have the same symptoms as described above for 
overdose.

If you forget to use Instanyl
If the breakthrough pain is still ongoing, you may take Instanyl as prescribed by your doctor. If the 
breakthrough pain has stopped, do not take Instanyl until the next episode of breakthrough pain occurs.

If you stop using Instanyl
You should discontinue Instanyl when you no longer have any breakthrough pain. You should 
however continue to take your usual pain relieving medicine to treat your cancer pain. Contact your 
doctor to confirm the correct dose of your usual medicine if you are not sure.
You may experience withdrawal symptoms similar to the possible side effects of Instanyl when 
discontinuing Instanyl. If you experience withdrawal symptoms, you should contact your doctor. Your 
doctor will evaluate if you need medicine to reduce or eliminate the withdrawal symptoms.

If you have any further questions on the use of this product, ask your doctor or pharmacist.

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody gets them.
The side effects will often stop or reduce in intensity with continued use of the product.



100

Discontinue the treatment and contact your doctor, hospital or emergency room immediately, if 
you:
- experience severe breathing difficulties.
- have a rattling sound when you breathe in.
- have convulsive pain.
- experience extreme dizziness.
These side effects can be very serious.

Other side effects reported after use of Instanyl:

Common (may affect up to 1 in 10 people):
Sleepiness, dizziness even with difficulties keeping balance, headache, irritation of the throat, nausea, 
vomiting, flushing, feeling very warm, excessive sweating.

Uncommon (may affect up to 1 in 100 people):
Sleeplessness, drowsiness, convulsive muscle contractions, abnormal sensation of the skin even 
unpleasant, change of taste, motion sickness, low blood pressure, severe breathing problems, nose 
bleeds, nasal ulcer, runny nose, constipation, inflammation of the mouth, dry mouth, skin pain, itching 
of the skin, fever.

Not known (frequency cannot be estimated from the available data):
Fall, diarrhoea, convulsions (fits), loss of consciousness, swelling of arms or legs, seeing or hearing 
things that are not really there (hallucinations), drug dependence (addiction), drug abuse, fatigue, 
malaise, withdrawal syndrome (may manifest by the occurrence of the following side effects nausea, 
vomiting, diarrhoea, anxiety, chills, tremor, and sweating), shortness of breath.

There have also been reports of patients developing a hole in the septum of the nose – the structure, 
which separates the nostrils.

Prolonged treatment with fentanyl during pregnancy may cause withdrawal symptoms in the newborn 
which can be life-threatening (see section 2)

You should tell your doctor if you experience recurrent episodes of nose bleeding or nasal discomfort.

Reporting of side effects
If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects 
not listed in this leaflet. You can also report side effects directly via the national reporting system listed 
in Appendix V. By reporting side effects you can help provide more information on the safety of this 
medicine.

5. How to store Instanyl

The pain-relieving medicine in Instanyl is very strong and can be life-threatening to children. 
Instanyl must be kept out of reach and sight of children. 
Do not use Instanyl after the expiry date which is stated on the carton and the single-dose container 
after EXP. The expiry date refers to the last day of that month. 
Store below 30C. Keep the blister in the outer carton. Keep stored upright.

Instanyl can be harmful to other people, especially children. Do not throw away any medicines via 
wastewater or household waste. Any unused single-dose containers should be returned systematically 
and suitably in the child-resistant blister and discarded according to local requirements or returned to 
the pharmacy. Ask your pharmacist how to dispose of medicines you no longer use. These measures 
will help to protect the environment.



101

6. Contents of the pack and other information

What Instanyl contains
The active substance is fentanyl. The content is:
50 micrograms: 1 dose (100 microlitres) contains fentanyl citrate equivalent to 50 micrograms 
fentanyl.
100 micrograms: 1 dose (100 microlitres) contains fentanyl citrate equivalent to 100 micrograms 
fentanyl.
200 micrograms: 1 dose (100 microlitres) contains fentanyl citrate equivalent to 200 micrograms 
fentanyl.

The other ingredients are sodium dihydrogen phosphate dihydrate, disodium phosphate dihydrate, and 
water for injections.

What Instanyl looks like and contents of the pack
Instanyl is a nasal spray, solution in a single-dose spray container. The solution is clear and colourless.

The single-dose container contains 1 dose of Instanyl and and is supplied in a child-resistant blister. 
Instanyl comes in different pack sizes of 2, 6, 8 and 10 single-dose containers.
Not all pack sizes may be marketed.

The labelling of the three Instanyl strengths is differentiated by colour: 
50 micrograms labelling is orange.
100 micrograms labelling is purple.
200 micrograms labelling is greenish-blue.

Marketing Authorisation Holder 
Takeda Pharma A/S
Dybendal Alle 10
DK-2630 Taastrup
Denmark

Manufacturer
Takeda Pharma A/S
Dybendal Alle 10
DK-2630 Taastrup
Denmark

Takeda GmbH
Robert-Bosch-Strasse 8
D – 78224 Singen
Germany

Curida AS
Solbærvegen 5
NO-2409 Elverum
Norway

For any information about this medicine, please contact the local representative of the Marketing 
Authorisation Holder.

België/Belgique/Belgien/Luxembourg/
Luxemburg
Takeda Belgium
Tél/Tel: +32 2 464 06 11
takeda-belgium@takeda.com

Lietuva
Takeda, UAB
Tel: +370 521 09 070



102

България
Такеда България
Тел.: + 359 2 958 27 36

Magyarország 
Takeda Pharma Kft.
Tel.: +361 2707030 

Česká republika
Takeda Pharmaceuticals Czech Republic s.r.o.
Tel: + 420 234 722 722

Malta / Κύπρος
Takeda Pharma A/S
Tel/Τηλ: +45 46 77 11 11

Danmark
Takeda Pharma A/S
Tlf: +45 46 77 11 11

Nederland
Takeda Nederland bv
Tel: +31 23 56 68 777

Deutschland
Takeda GmbH
Tel: +49 (0) 800 825 3325
medinfo@takeda.de

Norge
Takeda AS
Tlf: +47 6676 3030
infonorge@takeda.com

Eesti
Takeda Pharma AS
Tel: +372 6177 669
info@takeda.ee

Österreich
Takeda Pharma Ges.m.b.H. 
Tel: +43 (0) 800 20 80 50 

Ελλάδα
TAKEDA ΕΛΛΑΣ Α.Ε.
Τηλ: +30 210 6387800
gr.info@takeda.com

Polska
Takeda Pharma sp. z o.o.
Tel.: +48 22 608 13 00

España
Takeda Farmacéutica España S.A.
Tel: +34 917 90 42 22
spain@takeda.com

Portugal
Takeda Farmacêuticos Portugal, Lda.
Tel: + 351 21 120 1457

France
Takeda France S.A.S
Tél: + 33 1 46 25 16 16

România 
Takeda Pharmaceuticals SRL
Tel: +40 21 335 03 91

Hrvatska
Takeda Pharmaceuticals Croatia d.o.o
Tel: +385 1 377 88 96

Slovenija
Takeda GmbH Podružnica Slovenija
Tel:+386 (0) 59 082 480

Ireland
Takeda Products Ireland Ltd.
Tel: +353 (0) 1 6420021

Slovenská republika
Takeda Pharmaceuticals Slovakia s.r.o.
Tel: +421 (2) 20 602 600

Ísland
Vistor hf.
Sími: +354 535 7000
vistor@vistor.is

Suomi/Finland
Takeda Oy
Puh/Tel: +358 20 746 5000
infoposti@takeda.com

Italia
Takeda Italia S.p.A.
Tel: +39 06 502601

Sverige
Takeda Pharma AB
Tel: +46 8 731 28 00
infosweden@takeda.com



103

Κύπρος
Takeda Pharma A/S
Τηλ: +45 46 77 11 11

Latvija
Takeda Latvia SIA
Tel: +371 67840082

United Kingdom
Takeda UK Ltd
Tel: +44 (0)1628 537 900

This leaflet was last revised in {MM/YYYY}.

Detailed information on this medicine is available on the European Medicines Agency web site: 
http://www.ema.europa.eu.



104

INSTRUCTIONS FOR USE OF INSTANYL SINGLE-DOSE NASAL SPRAY

Please read the following instructions carefully to learn how to use Instanyl single-dose nasal spray:

 Each single-dose container is sealed in a child-resistant blister. Do not open the blister before you 
are ready to use the spray. Each single-dose container contains only one dose of Instanyl. Do not 
test before use.

 To open cut with scissors along the line (above the scissors symbol) on the blister. Hold the edge 
of the foil, peel the foil back and take the nasal spray out.

 Blow your nose if it feels blocked or you have a cold.

 Gently hold the single-dose container with your thumb supporting it at the plunger at the bottom 
and your index and middle finger on either side of the spray tip (see drawing). Do not press the 
plunger yet. 

 Block one nostril by placing your other index finger against the side of your nose and insert the 
spray tip into the other nostril (approximately 1 cm). It does not matter which nostril you use. If 
you have to take a second dose after 10 minutes to get sufficient pain relief, this dose should be 
taken in the other nostril.

 Keep your head upright

 Press the plunger upwards firmly to release the dose with your thumb while inhaling gently 
through the nose and then remove the spray container from the nose. You may not feel the dose in 
your nose, but you have received it when the plunger has been pressed up.

Your single-dose container is now empty



105

Package leaflet: Information for the user

Instanyl 50 micrograms/dose nasal spray, solution
Instanyl 100 micrograms/dose nasal spray, solution
Instanyl 200 micrograms/dose nasal spray, solution

fentanyl

Read all of this leaflet carefully before you start using this medicine because it contains 
important information for you.
- Keep this leaflet. You may need to read it again.
- If you have any further questions, ask your doctor or pharmacist.
- This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, 

even if their signs of illness are the same as yours.
- If you get any side effects, talk to your doctor, nurse or pharmacist. This includes any possible 

side effects not listed in this leaflet. See section 4.

What is in this leaflet

1. What Instanyl is and what it is used for
2. What you need to know before you use Instanyl
3. How to use Instanyl
4. Possible side effects
5. How to store Instanyl
6. Contents of the pack and other information

1. What Instanyl is and what it is used for

Instanyl contains the active substance fentanyl and belongs to a group of strong painkillers called 
opioids. Opioids act by blocking the pain signals to the brain. 
Instanyl acts rapidly and is used for relieving breakthrough pain in adult cancer patients already treated 
with opioids for their usual pain. Breakthrough pain is an additional sudden pain that occurs despite 
you having taken your usual opioid pain relieving medicines.

2. What you need to know before you use Instanyl

Do not use Instanyl
- if you are allergic to fentanyl or any of the other ingredients of this medicine (listed in 

section 6).
- if you are not regularly using a prescribed opioid medicine (e.g codeine, fentanyl, 

hydromorphone, morphine, oxycodone, pethidine), every day on a regular schedule, for at least 
a week, to control your persistent pain. If you have not been using these medicines you must not 
use Instanyl, because it may increase the risk that breathing could become dangerously slow 
and/or shallow, or even stop.

- If you are taking a medicine which contains sodium oxybate.
- if you suffer from short-term pain other than breakthrough pain.
- if you have serious difficulties breathing or suffer from a serious obstructive lung disease.
- if you have previously received facial radiotherapy.
- if you suffer from recurrent episodes of nose bleeding.

Warnings and precautions
Talk to your doctor before using Instanyl, especially:
- if you suffer from a long-term obstructive lung disease, your breathing may be impaired by 

Instanyl.
- if you have problems with your heart especially slow heart rate, low blood pressure or low 

blood volume.



106

- if you have problems with your liver or kidneys.
- if you have problems with your brain function, e.g. due to a brain tumour, a head injury or 

increased intracranial pressure.
- if you have ever developed adrenal insufficiency or lack of sex hormones (androgen deficiency) 

with opioid use.
- if you take antidepressants or antipsychotics, please refer to the section ‘Other medicines and 

Instanyl’.
- if you take medicines called partial agonist/antagonists e.g. buprenorphine, nalbuphine and 

pentazocine (medicines for treatment of pain) as you may experience symptoms of withdrawal 
syndrome. Please refer to the section Other medicines and Instanyl for more information.

- if you use other nasal spray products, e.g. for common cold or allergy.

If you experience difficulties breathing while being treated with Instanyl, it is very important 
that you contact your doctor or hospital immediately.

Consult your doctor while using Instanyl, if:
- you experience pain or increased sensitivity to pain (hyperalgesia) which does not respond to a 

higher dosage of your medicine as prescribed by your doctor.
- you experience a combination of the following symptoms: nausea, vomiting, anorexia, fatigue, 

weakness, dizziness and low blood pressure. Together these symptoms may be a sign of a 
potentially life-threatening condition called adrenal insufficiency, a condition in which the 
adrenal glands do not produce enough hormones.

If you experience recurrent nose bleeding or nasal discomfort whilst being treated with Instanyl, you 
must contact your doctor, who will consider alternative treatment for your breakthrough pain.

If you think you are becoming dependent on Instanyl, it is important that you inform you doctor.

Children and adolescents
Instanyl should not be used in children and adolescents under 18 years of age.

Other medicines and Instanyl
Tell your doctor or pharmacist if you are taking, have recently taken or might take any other 
medicines, including medicines obtained without a prescription.

Instanyl may affect or be affected by other medicines.
Special care should be taken if you are treated with any of the following medicines:
- any medicines which might normally make you sleepy (have a sedative effect) such as sleeping 

pills, medicines to treat anxiety, antihistamines, or tranquillisers. The use of such other drugs at 
the same time as Instanyl, may cause deep sedation and affect your ability to breath, which may 
lead to coma and be life-threatening.

- any medicines that might have an effect on the way in which your body breaks down Instanyl, 
such as:
 ritonavir, nelfinavir, amprenavir, and fosamprenavir (medicines that help control HIV 

infection);
 CYP3A4 inhibitors such as ketoconazole, itraconazole, or fluconazole (used for treatment 

of fungal infections);
 troleandomycin, clarithromycin, or erythromycin (medicines for treatment of bacterial 

infections);
 aprepitant (used to treat severe nausea);
 diltiazem and verapamil (medicines for treatment of high blood pressure or heart 

diseases).
- medicines called Monoamine Oxidase Inhibitors (MAOI) used for severe depression, even if 

you have been treated with one in the past 2 weeks.
- The risk of side effects increases if you are taking medicines such as certain antidepressants or 

antipsychotics. Instanyl may interact with these medicines and you may experience mental 
status changes (e.g. agitation, hallucinations, coma), and other effects such as body temperature 



107

above 38 °C, increase in heart rate, unstable blood pressure, and exaggeration of reflexes, 
muscular rigidity, lack of coordination and/or gastrointestinal symptoms (e.g. nausea, vomiting, 
diarrhoea). Your doctor will tell you whether Instanyl is suitable for you.

- medicines called partial agonist/antagonists e.g. buprenorphine, nalbuphine and pentazocine 
(medicines for treatment of pain). You could experience symptoms of withdrawal syndrome 
(nausea, vomiting, diarrhoea, anxiety, chills, tremor, and sweating).

- Other medicines taken via the nose, especially oxymetazoline, xylometazoline and similar 
medicines, which are used for relief of nose congestions.

Instanyl with food, drink and alcohol
Do not drink alcohol whilst being treated with Instanyl, as it can increase the risk of experiencing 
dangerous side effects.

Pregnancy and breast-feeding
If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby ask 
your doctor or pharmacist for advice before taking any medicine.

Instanyl should not be used during pregnancy unless you have discussed this with your doctor.

Instanyl should not be used during childbirth because fentanyl may cause serious breathing problems 
in the new-born child.

Fentanyl can get into breast milk and may cause side effects in the breast-fed infant. Do not use 
Instanyl if you are breast-feeding. You should not start breast-feeding until at least 5 days after the 
last dose of Instanyl.

Driving and using machines
You should not drive or use machinery whilst being treated with Instanyl. Instanyl can cause 
dizziness, drowsiness and visual disturbances, which may affect your ability to drive or use machines.

3. How to use Instanyl

Always use this medicine exactly as your doctor has told you. Check with your doctor or pharmacist if
you are not sure.

The dose of Instanyl is independent of your usual cancer pain treatment.

When you first start using Instanyl, your doctor will work with you to find the dose that will relieve 
your breakthrough pain.
The initial dose is one puff of 50 micrograms in one nostril each time you have an episode of 
breakthrough pain. During the determination of your right dose, your doctor may instruct you to 
change to a higher dose.

If your breakthrough pain is not relieved after 10 minutes, you may use only one puff more for this 
episode. 
Generally you should wait 4 hours before treating another episode of breakthrough pain. On 
exceptional occasions where a new episode occurs earlier, you can use Instanyl to treat it but you must 
wait at least 2 hours before doing so. If you regularly have breakthrough pain episodes that are less 
than 4 hours apart, contact your doctor as your usual cancer pain treatment may have to be changed.

You can use Instanyl to treat up to four episodes of breakthrough pain per day.

If you experience more than four episodes of breakthrough pain per day, contact your doctor, as your 
usual cancer pain treatment may have to be changed.



108

Do not change the dose of Instanyl or your other pain medicines on your own. Change in dose 
must be done together with your doctor.

Instanyl incorporates an electronic dose counter, and a lock out period between doses to reduce the 
risk of overdose, and helps you to use it adequately.The dose counter enables you, and your doctor, to 
monitor and adapt your use. After two doses are taken within 60 minutes, Instanyl will lock for a 
period of 2 hours, from the first dose taken, until another dose can be administered. 

Instanyl is for nasal use.

Please read the instruction for use at the end of this leaflet to learn how to use the nasal spray.

If you use more Instanyl than you should or if you think someone has accidentally used Instanyl
You should contact your doctor, hospital or emergency room for assessment of the risk and for advice 
if you have taken more Instanyl than you should.

Symptoms of overdose are:
Sleepiness, drowiness, dizziness, reduced body temperature, slow heart beat, difficulties coordinating 
arms and legs.
In serious cases taking too much Instanyl may cause coma, sedation, convulsions or severe breathing 
difficulties (very slow or shallow breathing).
If you feel any of the above symptoms you should seek immediate medical assistance.

Note to carers
If you see the person taking Instanyl suddenly acting slowly, having difficulties breathing or if you 
have difficulties waking the person up:
- you should immediately call for emergency help.
- while waiting for the emergency help, you must try to keep the person awake by talking to or 

gently shaking the person every now and then.
- if the person has difficulty breathing, you should prompt the person to breathe in every 

5-10 seconds.
- if the person has stopped breathing, you should attempt to resuscitate her/him until emergency 

help arrives.

If you think someone has accidentally taken Instanyl, please seek immediate medical assistance. Try to 
keep the person awake until emergency help arrives.
If someone has accidentally taken Instanyl, they may have the same symptoms as described above for 
overdose.

If you forget to use Instanyl
If the breakthrough pain is still ongoing, you may take Instanyl as prescribed by your doctor. If the 
breakthrough pain has stopped, do not take Instanyl until the next episode of breakthrough pain occurs. 

If you stop using Instanyl
You should discontinue Instanyl when you no longer have any breakthrough pain. You should 
however continue to take your usual pain relieving medicine to treat your cancer pain. Contact your 
doctor to confirm the correct dose of your usual medicine if you are not sure.
You may experience withdrawal symptoms similar to the possible side effects of Instanyl when 
discontinuing Instanyl. If you experience withdrawal symptoms, you should contact your doctor. Your 
doctor will evaluate if you need medicine to reduce or eliminate the withdrawal symptoms.

If you have any further questions on the use of this product, ask your doctor or pharmacist.



109

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody gets them.
The side effects will often stop or reduce in intensity with continued use of the product.

Discontinue the treatment and contact your doctor, hospital or emergency room immediately, if 
you:
- experience severe breathing difficulties.
- have a rattling sound when you breathe in.
- have convulsive pain.
- experience extreme dizziness.
These side effects can be very serious.

Other side effects reported after use of Instanyl:

Common (may affect up to 1 in 10 people):
Sleepiness, dizziness even with difficulties keeping balance, headache, irritation of the throat, nausea, 
vomiting, flushing, feeling very warm, excessive sweating.

Uncommon (may affect up to 1 in 100 people):
Sleeplessness, drowsiness, convulsive muscle contractions, abnormal sensation of the skin even 
unpleasant, change of taste, motion sickness, low blood pressure, severe breathing problems, nose 
bleeds, nasal ulcer, runny nose, constipation, inflammation of the mouth, dry mouth, skin pain, itching 
of the skin, fever.

Not known (frequency cannot be estimated from the available data):
Fall, diarrhoea, convulsions (fits), loss of consciousness, swelling of arms or legs, seeing or hearing 
things that are not really there (hallucinations), drug dependence (addiction), drug abuse, fatigue, 
malaise, withdrawal syndrome (may manifest by the occurrence of the following side effects nausea, 
vomiting, diarrhoea, anxiety, chills, tremor, and sweating), shortness of breath.

There have also been reports of patients developing a hole in the septum of the nose – the structure, 
which separates the nostrils.

Prolonged treatment with fentanyl during pregnancy may cause withdrawal symptoms in the newborn 
which can be life-threatening (see section 2)

You should tell your doctor if you experience recurrent episodes of nose bleeding or nasal discomfort.

Reporting of side effects
If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not 
listed in this leaflet. You can also report side effects directly via the national reporting system listed in 
Appendix V. By reporting side effects you can help provide more information on the safety of this 
medicine.

5. How to store Instanyl

The pain-relieving medicine in Instanyl is very strong and can be life-threatening to children. 
Instanyl must be kept out of the sight and reach of children. Always close after use by puting the 
child-resistant cap back on to the nasal spray.
Do not use Instanyl after the expiry date which is stated on the nasal spray after EXP. The expiry date 
refers to the last day of the month.
Store below 30C. Do not freeze. If Instanyl nasal spray is frozen the spray pump may crack. If 
uncertain of how the pump has been stored, you should check the spray pump before use.



110

Instanyl that has passed the expiry date or is no longer required, may still contain enough medicine to 
be harmful to other people, especially children.

This instrument is labelled in accordance with the EU Waste Electrical and Electronic 
Equipment Directive (WEEE). Do not throw away any medicines via wastewater or household 
waste. Any used or unused nasal spray should be returned systematically and discarded 
according to local requirements or returned to the pharmacy. Ask your pharmacist how to 
dispose of medicines you no longer use. These measures will help to protect the environment.

6. Contents of the pack and other information

What Instanyl contains
The active substance is fentanyl. The content is:
50 micrograms/dose: 1 ml contains fentanyl citrate equivalent to 500 micrograms fentanyl. 1 puff 
(100 microlitres) contains 50 micrograms fentanyl.
100 micrograms/dose: 1 ml contains fentanyl citrate equivalent to 1,000 micrograms fentanyl. 1 puff 
(100 microlitres) contains 100 micrograms fentanyl.
200 micrograms/dose: 1 ml contains fentanyl citrate equivalent to 2,000 micrograms fentanyl. 1 puff 
(100 microlitres) contains 200 micrograms fentanyl.

The other ingredients are sodium dihydrogen phosphate dihydrate, disodium phosphate dihydrate, and 
purified water.

What Instanyl looks like and contents of the pack
Instanyl DoseGuard is a nasal spray, solution. The solution is clear and colourless. It is contained in a 
nasal spray with a metering pump, an electronic display, a dose counter, an in-built lock-out 
mechanism and a child-resistant cap.
The nasal spray comes in four different pack sizes: 2.0 ml (equal to 10 doses), 3.2 ml (equal to 
20 doses), 4.3 ml (equal to 30 doses) and 5.3 ml (equal to 40 doses).
Not all pack sizes may be marketed.

The labelling of the three Instanyl strengths is differentiated by colour:
50 micrograms/dose labelling is orange.
100 micrograms/dose labelling is purple.
200 micrograms/dose labelling is greenish-blue.

Marketing Authorisation Holder 
Takeda Pharma A/S
Dybendal Alle 10
DK-2630 Taastrup
Denmark

Manufacturer
Takeda GmbH
Robert-Bosch-Strasse 8
D – 78224 Singen
Germany



111

For any information about this medicine, please contact the local representative of the Marketing 
Authorisation Holder.

België/Belgique/Belgien/Luxembourg/
Luxemburg
Takeda Belgium
Tél/Tel: +32 2 464 06 11
takeda-belgium@takeda.com

Lietuva
Takeda, UAB
Tel: +370 521 09 070

България
Такеда България
Тел.: + 359 2 958 27 36

Magyarország 
Takeda Pharma Kft.
Tel.: +361 2707030 

Česká republika
Takeda Pharmaceuticals Czech Republic s.r.o.
Tel: + 420 234 722 722

Malta / Κύπρος
Takeda Pharma A/S
Tel/Τηλ: +45 46 77 11 11

Danmark 
Takeda Pharma A/S
Tlf: +45 46 77 11 11

Nederland
Takeda Nederland bv
Tel: +31 23 56 68 777

Deutschland
Takeda GmbH
Tel: +49 (0) 800 825 3325
medinfo@takeda.de

Norge
Takeda AS
Tlf: +47 6676 3030
infonorge@takeda.com

Eesti
Takeda Pharma AS
Tel: +372 6177 669
info@takeda.ee

Österreich
Takeda Pharma Ges.m.b.H. 
Tel: +43 (0) 800 20 80 50 

Ελλάδα
TAKEDA ΕΛΛΑΣ Α.Ε.
Τηλ: +30 210 6387800
gr.info@takeda.com

Polska
Takeda Pharma sp. z o.o.
Tel.: +48 22 608 13 00

España
Takeda Farmacéutica España S.A.
Tel: +34 917 90 42 22
spain@takeda.com

Portugal
Takeda Farmacêuticos Portugal, Lda.
Tel: + 351 21 120 1457

France
Takeda France S.A.S
Tél: +33 1 46 25 16 16 

România 
Takeda Pharmaceuticals SRL
Tel: +40 21 335 03 91

Hrvatska
Takeda Pharmaceuticals Croatia d.o.o
Tel: +385 1 377 88 96

Slovenija
Takeda GmbH Podružnica Slovenija
Tel: +386 (0) 59 082 480

Ireland
Takeda Products Ireland Ltd.
Tel: +353 (0) 1 6420021

Slovenská republika
Takeda Pharmaceuticals Slovakia s.r.o.
Tel: +421 (2) 20 602 600



112

Ísland
Vistor hf.
Sími: +354 535 7000
vistor@vistor.is

Suomi/Finland
Takeda Oy
Puh/Tel: +358 20 746 5000
infoposti@takeda.com

Italia
Takeda Italia S.p.A.
Tel: +39 06 502601

Sverige
Takeda Pharma AB
Tel: +46 8 731 28 00
infosweden@takeda.com

Κύπρος
Takeda Pharma A/S
Τηλ: +45 46 77 11 11

Latvija
Takeda Latvia SIA
Tel: +371 67840082

United Kingdom
Takeda UK Ltd
Tel: +44 (0)1628 537 900

This leaflet was last revised in {MM/YYYY}.

Detailed information on this medicine is available on the European Medicines Agency web site: 
http://www.ema.europa.eu.



113

INSTRUCTIONS FOR USE OF INSTANYL

Please read the following instructions carefully to learn how to use the Instanyl nasal spray.

The Instanyl nasal spray has:
- An in-built lock-out mechanism which controls how often the nasal spray can be used
- A child-resistant cap, which must be put on the nasal spray, when the nasal spray is not used 
- An electronic display which:

 gives instruction on number of priming strokes 
 shows the number of doses left
 shows whether the nasal spray is locked or ready for use

How to remove and re-attach the child-resistant cap

Remove the child-resistant cap by pressing on both sides of the 
cap, and then turn the cap counter clockwise and lift it off.

To re-attach, place the child-resistant cap on the nasal spray and 
turn the cap clockwise. 

Always close after use by putting the child-resistant cap back 
on to the nasal spray.



114

Preparing the Instanyl nasal spray

Before using the nasal spray for the first time, it must be 
pumped 5 times (primed) to give a full dose of Instanyl.

During this priming process product will be expelled. 
Therefore:

Priming should be performed in a well ventilated area. 

Do not point the nasal spray in the direction of yourself
and other people.

Do not point in the direction of surfaces and objects that 
could come into contact with other people, particularly 
children. 

1. Press on the white button on the side of the nasal spray. 
The display will now turn on and show ‘P5’. 

2. Hold the nasal spray upright and pump the nasal spray 
once in the air. The display now shows ‘P4’ and a lock 
symbol appears.

3. When the lock symbol starts flashing, press the white 
side button; the lock symbol disappears in the display. 

4. Hold the nasal spray upright and pump the nasal spray 
in the air again. The display now shows ‘P3’ and the 
lock symbol. 

5. Repeat this procedure for ‘P2’ and ‘P1’ (press the white 
button and pump) until the display changes to show the 
number of doses in the nasal spray (i.e. 10, 20, 30 or 
40 doses) and flashing lock symbol.

The nasal spray is now ready for use.
Depending on the nasal spray, the starting number can be 10, 
20, 30 or 40.



115

How to use Instanyl nasal spray

The nasal spray can only be used when the lock symbol is not visible in the display.

1. Blow your nose if it feels blocked or you have a cold.
2. You should sit or stand in upright position.
3. Hold the nasal spray upright.
4. Press the white button on the side of the nasal spray (the 

flashing lock symbol disappears).
5. Bend your head slightly forward.
6. Close one nostril by placing your finger against the side of 

your nose and insert the spray tip into the other nostril.
7. Press the pump down completely with two fingers one time 

while breathing through the nose.
8. You will hear a ‘click’ sound when the pump is pressed 

down completely and the nasal spray has delivered the 
dose.

9. The display counts down one number and the lock symbol 
is displayed shortly. 

10. If after 10 minutes you need a second dose of Instanyl to 
relieve your pain, repeat step 1 to 7 in the other nostril.

11. Remember to clean the nasal spray tip after use with a clean 
tissue, and then discard afterwards.

Remember to press the white button on the side before 
pumping the nasal spray.

Remember to always put the child-resistant cap back on to 
the nasal spray and close it after use.

The nasal spray allows for up to two doses per breakthrough 
pain episodes. 

After the second dose within 1 hour the nasal spray is locked. 
The lock symbol appears in the display together with a 
countdown-clock symbol, which shows the remaining time left 
of the locking period (each black mark equals 10 minutes).
When the time has passed the lock symbol starts flashing.
The nasal spray is now ready for use, when the next 
breakthrough pain episode occurs. 
You should wait for 4 hours before treating the next episode of 
breakthrough pain. 
You can use Instanyl to treat up to 4 episodes of breakthrough 
pain per day. If you experience more than 4 episodes of 
breakthrough pain per day, you should contact your doctor as 
your usual cancer pain treatment may have to be changed.

The nasal spray is empty when the display shows ‘0’ and the 
lock symbol appears.

Do not throw away Instanyl via wastewater or household waste. 
Any used or unused nasal spray should be returned 
systematically and discarded according to local requirements or 
returned to the pharmacy. Ask your pharmacist.



116

If you have not used Instanyl for 7 days or more, the nasal spray 
must be primed again by spraying once before the next dose is 
taken. This is indicated by a ‘P’ in the display.

During this priming process product will be expelled. 
Therefore:

Priming should be performed in a well ventilated area. 

Do not point the nasal spray in the direction of yourself and 
other people.

Do not point in the direction of surfaces and objects that 
could come into contact with other people, particularly 
children. 
Once primed, the display shows the number of doses left and the 
nasal spray is ready for use again.

If the display shows a battery symbol, this means that the battery 
life is about to run out. The number of doses in the display 
changes to ‘5’. This is the approximate number of doses that can 
be delivered from the nasal spray, before the battery is too low 
and the display turns off. 
If the battery symbol appears in the display, it is recommended 
that you contact your doctor to get a new nasal spray. 



117

Symbols in the 
electronic display

Explanation

The nasal spray must be pumped 5 times (primed), before it can be used (see 
section ‘Preparing the Instanyl nasal spray’). The display counts downward 
after each pump (P5, P4, P3, P2 and P1). The nasal spray is ready, when the 
display shows the number of doses (i.e. 10, 20, 30 or 40 doses).

When priming, please refer to the above safety instructions.

The nasal spray has not been used for 7 days or more. 
The ‘P’ symbol disappears from the display, when the nasal spray is primed 
again, by spraying once. 

When priming, please refer to the above safety instructions

LOCK symbol
The nasal spray is locked and cannot be used.
The lock symbol starts flashing, when the locking period is over. The symbol 
disappears from the display, when the white button on the side of the nasal 
spray is pressed.

COUNTDOWN-CLOCK symbol
Shows how much time is left of the locking period. 
The countdown-clock is counting downwards. Each black mark equals 
10 minutes; the maximum locking period is 2 hours. 
The COUNTDOWN-CLOCK symbol is displayed together with the 
LOCK-symbol.

The number of doses left in the nasal spray. After each dose, the number is 
counting downwards on the display. Depending on the nasal spray, the starting 
number can be 10, 20, 30 or 40.

BATTERY symbol
The battery life is about to run out. The number of doses in the display changes 
to 5. This is the approximate number of doses that can be delivered from the 
nasal spray, before the battery is too low and the display turns off. The battery 
cannot be replaced and you need to get a new nasal spray.

If you experience that the nasal spray does not work as described in the “Instructions for use” 
please contact your doctor or pharmacist.


	SUMMARY OF PRODUCT CHARACTERISTICS
	A. MANUFACTURERS RESPONSIBLE FOR BATCH RELEASE
	B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE
	C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETINGAUTHORISATION
	D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE ANDEFFECTIVE USE OF THE MEDICINAL PRODUCT
	A. LABELLING
	B. PACKAGE LEAFLET