Signifor

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ANNEX I 
 

SUMMARY OF PRODUCT CHARACTERISTICS 

 



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1. NAME OF THE MEDICINAL PRODUCT 
 
Signifor 0.3 mg solution for injection 
Signifor 0.6 mg solution for injection 
Signifor 0.9 mg solution for injection 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
Signifor 0.3 mg solution for injection 
One ampoule of 1 ml contains 0.3 mg pasireotide (as pasireotide diaspartate). 
 
Signifor 0.6 mg solution for injection 
One ampoule of 1 ml contains 0.6 mg pasireotide (as pasireotide diaspartate). 
 
Signifor 0.9 mg solution for injection 
One ampoule of 1 ml contains 0.9 mg pasireotide (as pasireotide diaspartate). 
 
For the full list of excipients, see section 6.1. 
 
 
3. PHARMACEUTICAL FORM 

 
Solution for injection (injection). 
 
Clear, colourless solution. 
 
 
4. CLINICAL PARTICULARS 

 
4.1 Therapeutic indications 
 
Treatment of adult patients with Cushing’s disease for whom surgery is not an option or for whom 
surgery has failed. 
 
4.2 Posology and method of administration 

 
Posology 
 
The recommended initial dose is 0.6 mg pasireotide by subcutaneous injection twice a day. 
 
Two months after the start of Signifor therapy, patients should be evaluated for clinical benefit. 
Patients who experience a significant reduction in urinary free cortisol (UFC) levels should continue to 
receive Signifor for as long as benefit is derived. A dose increase to 0.9 mg may be considered based 
on the response to the treatment, as long as the 0.6 mg dose is well tolerated by the patient. Patients 
who have not responded to Signifor after two months of treatment should be considered for 
discontinuation. 
 
Management of suspected adverse reactions at any time during the treatment may require temporary 
dose reduction of Signifor. Dose reduction by decrements of 0.3 mg twice a day is suggested. 
 
If a dose of Signifor is missed, the next injection should be administered at the scheduled time. Doses 
should not be doubled to make up for a missed dose. 
 
Switch from intramuscular to subcutaneous formulation 

 
There are no clinical data available on switching from the intramuscular to the subcutaneous 



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pasireotide formulation. If such a switch should be required, it is recommended to maintain an interval 
of at least 28 days between the last intramuscular injection and the first subcutaneous injection, and to 
initiate the subcutaneous injections at a dose of 0.6 mg pasireotide twice a day. The patient should be 
monitored for response and tolerability and further dose adjustments may be needed. 
 
Special populations 

 
Paediatric population 
The safety and efficacy of Signifor in children and adolescents aged 0 to 18 years have not been 
established. No data are available. 
 
Elderly patients (≥65 years) 
Data on the use of Signifor in patients older than 65 years are limited, but there is no evidence to 
suggest that dose adjustment is required in these patients (see section 5.2). 
 
Renal impairment 
No dose adjustment is required in patients with impaired renal function (see section 5.2). 
 
Hepatic impairment 
Dose adjustment is not required in patients with mildly impaired hepatic function (Child Pugh A). The 
recommended initial dose for patients with moderate hepatic impairment (Child Pugh B) is 0.3 mg 
twice a day (see section 5.2). The maximum recommended dose for these patients is 0.6 mg twice a 
day. Signifor should not be used in patients with severe hepatic impairment (Child Pugh C) (see 
sections 4.3 and 4.4). 
 
Method of administration 
 
Signifor is to be administered subcutaneously by self injection. Patients should receive instructions 
from the physician or a healthcare professional on how to inject Signifor subcutaneously. 
 
Use of the same injection site for two consecutive injections is not recommended. Sites showing signs 
of inflammation or irritation should be avoided. Preferred injection sites for subcutaneous injections 
are the top of the thighs and the abdomen (excluding the navel or waistline). 
 
For further details on handling, see section 6.6. 
 
4.3 Contraindications 
 
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. 
 
Severe hepatic impairment (Child Pugh C). 
 
4.4 Special warnings and precautions for use 

 
Glucose metabolism 
 
Alterations in blood glucose levels have been frequently reported in healthy volunteers and patients 
treated with pasireotide. Hyperglycaemia and, less frequently, hypoglycaemia, were observed in 
subjects participating in clinical studies with pasireotide (see section 4.8). 
 
The degree of hyperglycaemia appeared to be higher in patients with pre-diabetic conditions or 
established diabetes mellitus. During the pivotal study, HbA1c levels increased significantly and 
stabilised but did not return to baseline values (see section 4.8). More cases of discontinuation and a 
higher reporting rate of severe adverse events due to hyperglycaemia were reported in patients treated 
with the dose of 0.9 mg twice daily. 
 
The development of hyperglycaemia appears to be related to decreases in secretion of insulin 



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(particularly in the post-dose period) and of incretin hormones (i.e. glucagon-like peptide-1 [GLP-1] 
and glucose-dependent insulinotropic polypeptide [GIP]). 
 
Glycaemic status (fasting plasma glucose/haemoglobin A1c [FPG/HbA1c]) should be assessed prior to 
starting treatment with pasireotide. FPG/HbA1c monitoring during treatment should follow established 
guidelines. Self monitoring of blood glucose and/or FPG assessments should be done weekly for the 
first two to three months and periodically thereafter, as clinically appropriate, as well as over the first 
two to four weeks after any dose increase. In addition, monitoring of FPG 4 weeks and HbA1c 
3 months after the end of the treatment should be performed. 
 
If hyperglycaemia develops in a patient being treated with Signifor, the initiation or adjustment of 
antidiabetic treatment is recommended, following the established treatment guidelines for the 
management of hyperglycaemia. If uncontrolled hyperglycaemia persists despite appropriate medical 
management, the dose of Signifor should be reduced or Signifor treatment discontinued (see also 
section 4.5). 
 
There have been post-marketing cases of ketoacidosis with Signifor in patients with and without a 
history of diabetes. Patients who present with signs and symptoms consistent with severe metabolic 
acidosis should be assessed for ketoacidosis regardless of diabetes history. 
 
In patients with poor glycaemic control (as defined by HbA1c values >8% while receiving anti-diabetic 
therapy), diabetes management and monitoring should be intensified prior to initiation and during 
pasireotide therapy. 
 
Liver tests 
 
Mild transient elevations in aminotransferases are commonly observed in patients treated with 
pasireotide. Rare cases of concurrent elevations in ALT (alanine aminotransferase) greater than 
3 x ULN and bilirubin greater than 2 x ULN have also been observed (see section 4.8). Monitoring of 
liver function is recommended prior to treatment with pasireotide and after one, two, four, eight and 
twelve weeks during treatment. Thereafter liver function should be monitored as clinically indicated. 
 
Patients who develop increased transaminase levels should be monitored with a second liver function 
evaluation to confirm the finding. If the finding is confirmed, the patient should be followed with 
frequent liver function monitoring until values return to pre-treatment levels. Therapy with pasireotide 
should be discontinued if the patient develops jaundice or other signs suggestive of clinically 
significant liver dysfunction, in the event of a sustained increase in AST (aspartate aminotransferase) 
or ALT of 5 x ULN or greater, or if ALT or AST elevations greater than 3 x ULN occur concurrently 
with bilirubin elevations greater than 2 x ULN. Following discontinuation of treatment with 
pasireotide, patients should be monitored until resolution. Treatment should not be restarted. 
 
Cardiovascular related events 
 
Bradycardia has been reported with the use of pasireotide (see section 4.8). Careful monitoring is 
recommended in patients with cardiac disease and/or risk factors for bradycardia, such as history of 
clinically significant bradycardia or acute myocardial infarction, high-grade heart block, congestive 
heart failure (NYHA Class III or IV), unstable angina, sustained ventricular tachycardia, ventricular 
fibrillation. Dose adjustment of medicinal products such as beta blockers, calcium channel blockers, or 
medicinal products to control electrolyte balance, may be necessary (see also section 4.5). 
 
Pasireotide has been shown to prolong the QT interval on the ECG in two dedicated healthy volunteer 
studies. The clinical significance of this prolongation is unknown. 
 
In clinical studies in Cushing’s disease patients, QTcF of >500 msec was observed in two out of 
201 patients. These episodes were sporadic and of single occurrence with no clinical consequence 
observed. Episodes of torsade de pointes were not observed either in those studies or in clinical studies 
in other patient populations. 



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Pasireotide should be used with caution and the benefit risk carefully weighed in patients who are at 
significant risk of developing prolongation of QT, such as those: 
- with congenital long QT syndrome. 
- with uncontrolled or significant cardiac disease, including recent myocardial infarction, 

congestive heart failure, unstable angina or clinically significant bradycardia. 
- taking antiarrhythmic medicinal products or other substances that are known to lead to QT 

prolongation (see section 4.5). 
- with hypokalaemia and/or hypomagnesaemia. 
 
Monitoring for an effect on the QTc interval is advisable and ECG should be performed prior to the 
start of Signifor therapy, one week after the beginning of the treatment and as clinically indicated 
thereafter. Hypokalaemia and/or hypomagnesaemia must be corrected prior to administration of 
Signifor and should be monitored periodically during therapy. 
 
Hypocortisolism 
 
Treatment with Signifor leads to rapid suppression of ACTH (adrenocorticotropic hormone) secretion 
in Cushing’s disease patients. Rapid, complete or near-complete suppression of ACTH may lead to a 
decrease in circulating levels of cortisol and potentially to transient hypocortisolism/hypoadrenalism. 
 
It is therefore necessary to monitor and instruct patients on the signs and symptoms associated with 
hypocortisolism (e.g. weakness, fatigue, anorexia, nausea, vomiting, hypotension, hyperkalaemia, 
hyponatraemia, hypoglycaemia). In the event of documented hypocortisolism, temporary exogenous 
steroid (glucocorticoid) replacement therapy and/or dose reduction or interruption of Signifor therapy 
may be necessary. 
 
Gallbladder and related events 
 
Cholelithiasis (gallstones) is a recognised adverse reaction associated with long-term use of 
somatostatin analogues and has frequently been reported in clinical studies with pasireotide (see 
section 4.8). There have been post-marketing cases of cholangitis in patients taking Signifor, which in 
the majority of cases was reported as a complication of gallstones. Ultrasonic examination of the 
gallbladder before and at 6 to 12 month intervals during Signifor therapy is therefore recommended. 
The presence of gallstones in Signifor-treated patients is largely asymptomatic; symptomatic stones 
should be managed according to clinical practice. 
 
Pituitary hormones 
 
As the pharmacological activity of pasireotide mimics that of somatostatin, inhibition of pituitary 
hormones other than ACTH cannot be ruled out. Monitoring of pituitary function (e.g. TSH/free T4, 
GH/IGF-1) before and periodically during Signifor therapy should therefore be considered, as 
clinically appropriate. 
 
Effect on female fertility 
 
The therapeutic benefits of a reduction or normalisation of serum cortisol levels in female patients 
with Cushing’s disease could potentially restore fertility. Female patients of childbearing potential 
should be advised to use adequate contraception during treatment with Signifor (see section 4.6). 
 
Renal impairment 
 
Due to the increase in unbound drug exposure, Signifor should be used with caution in patients with 
severe renal impairment or end stage renal disease (see section 5.2). 
 



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Sodium content 
 
This medicinal product contains less than 1 mmol (23 mg) sodium per dose, i.e. it is essentially 
‘sodium-free’. 
 
4.5 Interaction with other medicinal products and other forms of interaction 
 
Anticipated pharmacokinetic interactions resulting in effects on pasireotide 
 

The influence of the P-gp inhibitor verapamil on the pharmacokinetics of subcutaneous pasireotide 
was tested in a drug-drug interaction study in healthy volunteers. No change in the pharmacokinetics 
(rate or extent of exposure) of pasireotide was observed. 
 
Anticipated pharmacokinetic interactions resulting in effects on other medicinal products 
 
Pasireotide may decrease the relative bioavailability of ciclosporin. Concomitant administration of 
pasireotide and ciclosporin may require adjustment of the ciclosporin dose to maintain therapeutic 
levels. 
 
Anticipated pharmacodynamic interactions 
 
Medicinal products that prolong the QT interval 
Pasireotide should be used with caution in patients who are concomitantly receiving medicinal 
products that prolong the QT interval, such as class Ia antiarrhythmics (e.g. quinidine, procainamide, 
disopyramide), class III antiarrhythmics (e.g. amiodarone, dronedarone, sotalol, dofetilide, ibutilide), 
certain antibacterials (intravenous erythromycin, pentamidine injection, clarithromycin, moxifloxacin), 
certain antipsychotics (e.g. chlorpromazine, thioridazine, fluphenazine, pimozide, haloperidol, 
tiapride, amisulpride, sertindole, methadone), certain antihistamines (e.g. terfenadine, astemizole, 
mizolastine), antimalarials (e.g. chloroquine, halofantrine, lumefantrine), certain antifungals 
(ketoconazole, except in shampoo) (see also section 4.4). 
 
Bradycardic medicinal products 
Clinical monitoring of heart rate, notably at the beginning of treatment, is recommended in patients 
receiving pasireotide concomitantly with bradycardic medicinal products, such as beta blockers (e.g. 
metoprolol, carteolol, propranolol, sotalol), acetylcholinesterase inhibitors (e.g. rivastigmine, 
physostigmine), certain calcium channel blockers (e.g. verapamil, diltiazem, bepridil), certain 
antiarrhythmics (see also section 4.4). 
 
Insulin and antidiabetic medicinal products 
Dose adjustments (decrease or increase) of insulin and antidiabetic medicinal products (e.g. 
metformin, liraglutide, vildagliptin, nateglinide) may be required when administered concomitantly 
with pasireotide (see also section 4.4). 
 
4.6 Fertility, pregnancy and lactation 
 
Pregnancy 
 
There is a limited amount of data from the use of pasireotide in pregnant women. Studies in animals 
have shown reproductive toxicity (see section 5.3). Pasireotide is not recommended for use during 
pregnancy and in women of childbearing potential who are not using contraception (see section 4.4). 
 
Breast-feeding 
 
It is unknown whether pasireotide is excreted in human milk. Available data in rats have shown 
excretion of pasireotide in milk (see section 5.3). Breast-feeding should be discontinued during 
treatment with Signifor. 
 



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Fertility 
 
Studies in rats have shown effects on female reproductive parameters (see section 5.3). The clinical 
relevance of these effects in humans is unknown. 
 
4.7 Effects on ability to drive and use machines 

 
Signifor may have a minor influence on the ability to drive and use machines. Patients should be 
advised to be cautious when driving or using machines if they experience fatigue, dizziness or 
headache during treatment with Signifor. 
 
4.8 Undesirable effects 

 
Summary of the safety profile 
 
A total of 201 Cushing’s disease patients received Signifor in phase II and III studies. The safety 
profile of Signifor was consistent with the somatostatin analogue class, except for the occurrence of 
hypocortisolism and degree of hyperglycaemia. 
 
The data described below reflect exposure of 162 Cushing’s disease patients to Signifor in the 
phase III study. At study entry patients were randomised to receive twice-daily doses of either 0.6 mg 
or 0.9 mg Signifor. The mean age of patients was approximately 40 years and the majority of patients 
(77.8%) were female. Most (83.3%) patients had persistent or recurrent Cushing’s disease and few 
(≤5%) in either treatment group had received previous pituitary irradiation. The median exposure to 
the treatment up to the cut-off date of the primary efficacy and safety analysis was 10.37 months 
(0.03-37.8), with 66.0% of patients having at least six months’ exposure. 
 
Grade 1 and 2 adverse reactions were reported in 57.4% of patients. Grade 3 adverse reactions were 
observed in 35.8% of patients and Grade 4 adverse reactions in 2.5% of patients. Grade 3 and 4 
adverse reactions were mostly related to hyperglycaemia. The most common adverse reactions 
(incidence ≥10%) were diarrhoea, nausea, abdominal pain, cholelithiasis, injection site reactions, 
hyperglycaemia, diabetes mellitus, fatigue and glycosylated haemoglobin increased. 
 
Tabulated list of adverse reactions 
 
Adverse reactions reported up to the cut-off date of the analysis are presented in Table 1. Adverse 
reactions are listed according to MedDRA primary system organ class. Within each system organ 
class, adverse reactions are ranked by frequency. Within each frequency grouping, adverse reactions 
are presented in the order of decreasing seriousness. Frequencies were defined as follows: Very 
common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); not known (cannot be 
estimated from the available data). 
 



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Table 1 Adverse reactions in the phase III study and from post-marketing experience in 

Cushing’s disease patients 

 
System Organ 

Class 

Very common Common Uncommon Not known 

Blood and 

lymphatic 

system disorders 

  Anaemia  

Endocrine 

disorders 
 Adrenal 

insufficiency 
  

Metabolism and 

nutrition 

disorders 

Hyperglycaemia, 
diabetes mellitus 

Decreased 
appetite, type 2 
diabetes mellitus, 
glucose tolerance 
impaired 

 Diabetic 
ketoacidosis 

Nervous system 

disorders 
 Headache, 

dizziness 
  

Cardiac 

disorders 
 Sinus 

bradycardia, QT 
prolongation 

  

Vascular 

disorders 

 Hypotension   

Gastrointestinal 

disorders 
Diarrhoea, 
abdominal pain, 
nausea 

Vomiting, 
abdominal pain 
upper 

  

Hepatobiliary 

disorders 
Cholelithiasis Cholecystitis *, 

cholestasis 
  

Skin and 

subcutaneous 

tissue disorders 

 Alopecia, pruritus   

Musculoskeletal 

and connective 

tissue disorders 

 Myalgia, 
arthralgia 

  

General 

disorders and 

administration 

site conditions 

Injection site 
reaction, fatigue 

   

Investigations Glycosylated 
haemoglobin 
increased 

Gamma 
glutamyltransfera
se increased, 
alanine 
aminotransferase 
increased, 
aspartate 
aminotransferase 
increased, lipase 
increased, blood 
glucose 
increased, blood 
amylase 
increased, 
prothrombin time 
prolonged 

  

* Cholecystitis includes cholecystitis acute 
 



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Description of selected adverse reactions 
 
Glucose metabolism disorders 
Elevated glucose was the most frequently reported Grade 3 laboratory abnormality (23.2% of patients) 
in the phase III study in Cushing’s disease patients. Mean HbA1c increases were less pronounced in 
patients with normal glycaemia (n=62 overall) at study entry (i.e. 5.29% and 5.22% at baseline and 
6.50% and 6.75% at month 6 for the 0.6 and 0.9 mg twice daily dose groups, respectively) relative to 
pre-diabetic patients (i.e. n=38 overall; 5.77% and 5.71% at baseline and 7.45% and 7.13% at 
month 6) or diabetic patients (i.e. n=54 overall; 6.50% and 6.42% at baseline and 7.95% and 8.30% at 
month 6). Mean fasting plasma glucose levels commonly increased within the first month of treatment, 
with decreases and stabilisation observed in subsequent months. Fasting plasma glucose and HbA1c 
values generally decreased over the 28 days following pasireotide discontinuation but remained above 
baseline values. Long-term follow-up data are not available. Patients with baseline HbA1c ≥7% or who 
were taking antidiabetic medicinal products prior to randomisation tended to have higher mean 
changes in fasting plasma glucose and HbA1c relative to other patients. Adverse reactions of 
hyperglycaemia and diabetes mellitus led to study discontinuation in 5 (3.1%) and 4 (2.5%) patients, 
respectively. One case of ketosis and one case of ketoacidosis have been reported during 
compassionate use of Signifor. 
 
Monitoring of blood glucose levels in patients treated with Signifor is recommended (see section 4.4). 
 
Gastrointestinal disorders 
Gastrointestinal disorders were frequently reported with Signifor. These reactions were usually of low 
grade, required no intervention and improved with continued treatment. 
 
Injection site reactions 
Injection site reactions were reported in 13.6% of patients enrolled in the phase III study in Cushing’s 
disease. Injection site reactions were also reported in clinical studies in other populations. The 
reactions were most frequently reported as local pain, erythema, haematoma, haemorrhage and 
pruritus. These reactions resolved spontaneously and required no intervention. 
 
Liver enzymes 
Transient elevations in liver enzymes have been reported with the use of somatostatin analogues and 
were also observed in patients receiving pasireotide in clinical studies. The elevations were mostly 
asymptomatic, of low grade and reversible with continued treatment. Rare cases of concurrent 
elevations in ALT greater than 3 x ULN and bilirubin greater than 2 x ULN have been observed. All 
cases of concurrent elevations were identified within ten days of initiation of treatment with Signifor. 
The patients recovered without clinical sequelae and liver function test results returned to baseline 
values after discontinuation of treatment. 
 
Monitoring of liver enzymes is recommended before and during treatment with Signifor (see 
section 4.4), as clinically appropriate. 
 
Pancreatic enzymes 
Asymptomatic elevations in lipase and amylase were observed in patients receiving pasireotide in 
clinical studies. The elevations were mostly low grade and reversible while continuing treatment. 
Pancreatitis is a potential adverse reaction associated with the use of somatostatin analogues due to the 
association between cholelithiasis and acute pancreatitis. 
 
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. 
 

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


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4.9 Overdose 
 
Doses up to 2.1 mg twice a day have been used in healthy volunteers, with the adverse reaction 
diarrhoea being observed at a high frequency. 
 
In the event of overdose, it is recommended that appropriate supportive treatment be initiated, as 
dictated by the patient’s clinical status, until resolution of the symptoms. 
 
 
5. PHARMACOLOGICAL PROPERTIES 
 
5.1 Pharmacodynamic properties 
 
Pharmacotherapeutic group: Pituitary and hypothalamic hormones and analogues, somatostatin and 
analogues, ATC code: H01CB05 
 
Mechanism of action 
 
Pasireotide is a novel cyclohexapeptide, injectable somatostatin analogue. Like the natural peptide 
hormones somatostatin-14 and somatostatin-28 (also known as somatotropin release inhibiting factor 
[SRIF]) and other somatostatin analogues, pasireotide exerts its pharmacological activity via binding 
to somatostatin receptors. Five human somatostatin receptor subtypes are known: hsst1, 2, 3, 4, and 5. 
These receptor subtypes are expressed in different tissues under normal physiological conditions. 
Somatostatin analogues bind to hsst receptors with different potencies (see Table 2). Pasireotide binds 
with high affinity to four of the five hssts. 
 
Table 2 Binding affinities of somatostatin (SRIF-14), pasireotide, octreotide and lanreotide 

to the five human somatostatin receptor subtypes (hsst1-5) 

 
Compound hsst1 hsst2 hsst3 hsst4 hsst5 

Somatostatin 
(SRIF-14) 

0.930.12 0.150.02 0.560.17 1.50.4 0.290.04 

Pasireotide 9.30.1 1.00.1 1.50.3 >1,000 0.160.01 
Octreotide 28080 0.380.08 7.11.4 >1,000 6.31.0 
Lanreotide 18020 0.540.08 149 23040 175 

Results are the meanSEM of IC50 values expressed as nmol/l. 
 
Pharmacodynamic effects 
 
Somatostatin receptors are expressed in many tissues, especially in neuroendocrine tumours in which 
hormones are excessively secreted, including ACTH in Cushing’s disease. 
 
In vitro studies have shown that corticotroph tumour cells from Cushing’s disease patients display a 
high expression of hsst5, whereas the other receptor subtypes either are not expressed or are expressed 
at lower levels. Pasireotide binds and activates four of the five hssts, especially hsst5, in corticotrophs 
of ACTH-producing adenomas, resulting in inhibition of ACTH secretion. 
 
Clinical efficacy and safety 
 
A phase III, multicentre, randomised study was conducted to evaluate the safety and efficacy of 
different dose levels of Signifor over a twelve-month treatment period in Cushing’s disease patients 
with persistent or recurrent disease or de novo patients for whom surgery was not indicated or who 
refused surgery. 
 
The study enrolled 162 patients with a baseline UFC >1.5 x ULN who were randomised in a 1:1 ratio 
to receive a subcutaneous dose of either 0.6 mg or 0.9 mg Signifor twice daily. After three months of 



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treatment, patients with a mean 24-hour UFC ≤2 x ULN and below or equal to their baseline value 
continued blinded treatment at the randomised dose until month 6. Patients who did not meet these 
criteria were unblinded and the dose was increased by 0.3 mg twice daily. After the initial 6 months in 
the study, patients entered an additional 6-month open-label treatment period. If response was not 
achieved at month 6 or if the response was not maintained during the open-label treatment period, 
dosage could be increased by 0.3 mg twice daily. The dose could be reduced by decrements of 0.3 mg 
twice daily at any time during the study for reasons of intolerability. 
 
The primary efficacy end-point was the proportion of patients in each arm who achieved normalisation 
of mean 24-hour UFC levels (UFC ≤ULN) after 6 months of treatment and who did not have a dose 
increase (relative to randomised dose) during this period. Secondary end-points included, among 
others, changes from baseline in: 24-hour UFC, plasma ACTH, serum cortisol levels, and clinical 
signs and symptoms of Cushing’s disease. All analyses were conducted based on the randomised dose 
groups. 
 
Baseline demographics were well balanced between the two randomised dose groups and consistent 
with the epidemiology of the disease. The mean age of patients was approximately 40 years and the 
majority of patients (77.8%) were female. Most patients (83.3%) had persistent or recurrent Cushing’s 
disease and few (≤5%) in either treatment group had received previous pituitary irradiation. 
 
Baseline characteristics were balanced between the two randomised dose groups, except for marked 
differences in the mean value of baseline 24-hour UFC (1156 nmol/24 h for the 0.6 mg twice daily 
group and 782 nmol/24 h for the 0.9 mg twice daily group; normal range 30-145 nmol/24 h). 
 
Results 
At month 6, normalisation of mean UFC levels was observed in 14.6% (95% CI 7.0-22.3) and 26.3% 
(95% CI 16.6-35.9) of patients randomised to pasireotide 0.6 mg and 0.9 mg twice daily, respectively. 
The study met the primary efficacy objective for the 0.9 mg twice-daily group as the lower limit of the 
95% CI is greater than the pre-specified 15% boundary. The response in the 0.9 mg dose arm seemed 
to be higher for patients with lower mean UFC at baseline. The responder rate at month 12 was 
comparable to month 6, with 13.4% and 25.0% in the 0.6 mg and 0.9 mg twice-daily groups, 
respectively. 
 
A supportive efficacy analysis was conducted in which patients were further classified into 3 response 
categories regardless of up-titration at month 3: Fully controlled (UFC ≤1.0 x ULN), partially 
controlled (UFC >1.0 x ULN but with a reduction in UFC ≥50% compared to baseline) or 
uncontrolled (reduction in UFC <50%). The total proportion of patients with either full or partial mean 
UFC control at month 6 was 34% and 41% of the randomised patients to the 0.6 mg and 0.9 mg dose, 
respectively. Patients uncontrolled at both month 1 and month 2 are likely (90%) to remain 
uncontrolled at months 6 and 12. 
 
In both dose groups, Signifor resulted in a decrease in mean UFC after 1 month of treatment which 
was maintained over time. 
 
Decreases were also demonstrated by the overall percentage of change in mean and median UFC 
levels at month 6 and 12 as compared to baseline values (see Table 3). Reductions in plasma ACTH 
levels were also observed at each time point for each dose group. 
 
Table 3 Percentage change in mean and median UFC levels per randomised dose group at 



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month 6 and month 12 compared to baseline values 

 
 Pasireotide 0.6 mg twice 

daily 
% change (n) 

Pasireotide 0.9 mg twice 
daily 

% change (n) 
Mean change in UFC 
(% from baseline) 

Month 6 -27.5* (52) -48.4 (51) 
Month 12 -41.3 (37) -54.5 (35) 

Median change in UFC 
(% from baseline) 

Month 6 -47.9 (52) -47.9 (51) 
Month 12 -67.6 (37) -62.4 (35) 

* Includes one patient with significant outlying results who had a percent change from baseline of 
+542.2%. 

 
Decreases in sitting systolic and diastolic blood pressure, body mass index (BMI) and total cholesterol 
were observed in both dose groups at month 6. Overall reductions in these parameters were observed 
in patients with full and partial mean UFC control but tended to be greater in patients with normalised 
UFC. Similar trends were observed at month 12. 
 
Paediatric population 
 
The European Medicines Agency has waived the obligation to submit the results of studies with 
Signifor in all subsets of the paediatric population in pituitary-dependant Cushing’s disease, 
overproduction of pituitary ACTH and pituitary dependant hyperadrenocorticism (see section 4.2 for 
information on paediatric use). 
 
5.2 Pharmacokinetic properties 
 
Absorption 
 
In healthy volunteers, pasireotide is rapidly absorbed and peak plasma concentration is reached within 
0.25-0.5 h. Cmax and AUC are approximately dose-proportional following administration of single and 
multiple doses. 
 
No studies have been conducted to evaluate the bioavailability of pasireotide in humans. 
 
Distribution 
 
In healthy volunteers, pasireotide is widely distributed with large apparent volume of distribution 
(Vz/F >100 litres). Distribution between blood cells and plasma is concentration independent and 
shows that pasireotide is primarily located in the plasma (91%). Plasma protein binding is moderate 
(88%) and independent of concentration. 
 
Based on in vitro data pasireotide appears to be a substrate of efflux transporter P-gp (P-glycoprotein). 
Based on in vitro data pasireotide is not a substrate of the efflux transporter BCRP (breast cancer 
resistance protein) nor of the influx transporters OCT1 (organic cation transporter 1), OATP (organic 
anion-transporting polypeptide) 1B1, 1B3 or 2B1. At therapeutic dose levels pasireotide is also not an 
inhibitor of UGT1A1, OATP, 1B1 or 1B3, P-gp, BCRP, MRP2 and BSEP. 
 
Biotransformation 
 
Pasireotide is metabolically highly stable and in vitro data show that pasireotide is not a substrate, 
inhibitor or inducer of any major enzymes of CYP450. In healthy volunteers, pasireotide is 
predominantly found in unchanged form in plasma, urine and faeces. 
 
Elimination 
 
Pasireotide is eliminated mainly via hepatic clearance (biliary excretion), with a small contribution of 
the renal route. In a human ADME study 55.9±6.63% of the radioactive dose was recovered over the 



13 

first 10 days after administration, including 48.3±8.16% of the radioactivity in faeces and 7.63±2.03% 
in urine. 
 
Pasireotide demonstrates low clearance (CL/F ~7.6 litres/h for healthy volunteers and ~3.8 litres/h for 
Cushing’s disease patients). Based on the accumulation ratios of AUC, the calculated effective 
half-life (t1/2,eff) in healthy volunteers was approximately 12 hours. 
 
Linearity and time dependency 
 
In Cushing’s disease patients, pasireotide demonstrates linear and time-independent pharmacokinetics 
in the dose range of 0.3 mg to 1.2 mg twice a day. Population pharmacokinetic analysis suggests that 
based on Cmax and AUC, 90% of steady state in Cushing’s disease patients is reached after 
approximately 1.5 and 15 days, respectively. 
 
Special populations 
 
Paediatric population 
No studies have been performed in paediatric patients. 
 
Patients with renal impairment 
Renal clearance has a minor contribution to the elimination of pasireotide in humans. In a clinical 
study with single subcutaneous dose administration of 900 µg pasireotide in subjects with impaired 
renal function, renal impairment of mild, moderate or severe degree, or end stage renal disease 
(ESRD) did not have a significant impact on total pasireotide plasma exposure. The unbound plasma 
pasireotide exposure (AUCinf,u) was increased in subjects with renal impairment (mild: 33%; moderate: 
25%, severe: 99%, ESRD: 143%) compared to control subjects. 
 
Patients with hepatic impairment 
In a clinical study in subjects with impaired hepatic function (Child-Pugh A, B and C), statistically 
significant differences were found in subjects with moderate and severe hepatic impairment 
(Child-Pugh B and C). In subjects with moderate and severe hepatic impairment, AUCinf was 
increased 60% and 79%, Cmax was increased 67% and 69%, and CL/F was decreased 37% and 44%, 
respectively. 
 
Elderly patients (≥65 years) 
Age has been found to be a covariate in the population pharmacokinetic analysis of Cushing’s disease 
patients. Decreased total body clearance and increased pharmacokinetic exposures have been seen 
with increasing age. In the studied age range 18-73 years, the area under the curve at steady state for 
one dosing interval of 12 hours (AUCss) is predicted to range from 86% to 111% of that of the typical 
patient of 41 years. This variation is moderate and considered of minor significance considering the 
wide age range in which the effect was observed. 
 
Data on Cushing’s disease patients older than 65 years are limited but do not suggest any clinically 
significant differences in safety and efficacy in relation to younger patients. 
 
Demographics 
Population pharmacokinetic analyses of Signifor suggest that race and gender do not influence 
pharmacokinetic parameters. 
 
Body weight has been found to be a covariate in the population pharmacokinetic analysis of Cushing’s 
disease patients. For a range of 60-100 kg the reduction in AUCss with increasing weight is predicted 
to be approximately 27%, which is considered moderate and of minor clinical significance. 
 
5.3 Preclinical safety data 
 
Non-clinical safety data reveal no special hazard for humans based on conventional studies of safety 
pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential, toxicity to reproduction 



14 

and development. Most findings seen in repeated toxicity studies were reversible and attributable to 
the pharmacology of pasireotide. Effects in non-clinical studies were observed only at exposures 
considered sufficiently in excess of the maximum human exposure indicating little relevance to 
clinical use. 
 
Pasireotide was not genotoxic in in vitro and in vivo assays. 
 
Carcinogenicity studies conducted in rats and transgenic mice did not identify any carcinogenic 
potential. 
 
Pasireotide did not affect fertility in male rats but, as expected from the pharmacology of pasireotide, 
females presented abnormal cycles or acyclicity, and decreased numbers of corpora lutea and 
implantation sites. Embryo toxicity was seen in rats and rabbits at doses that caused maternal toxicity 
but no teratogenic potential was detected. In the pre- and postnatal study in rats, pasireotide had no 
effects on labour and delivery, but caused slight retardation in the development of pinna detachment 
and reduced body weight of the offspring. 
 
Available toxicological data in animals have shown excretion of pasireotide in milk. 
 
 
6. PHARMACEUTICAL PARTICULARS 

 
6.1 List of excipients 

 
Mannitol 
Tartaric acid 
Sodium hydroxide 
Water for injections 
 
6.2 Incompatibilities 
 
In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal 
products. 
 
6.3 Shelf life 
 
3 years 
 
6.4 Special precautions for storage 
 
Store in the original package in order to protect from light. 
 
6.5 Nature and contents of container 

 
One-point-cut colourless, type I glass ampoule containing 1 ml of solution. 
 
Each ampoule is packed in a cardboard tray which is placed in an outer box. 
 
Packs containing 6 ampoules or multipacks containing 18 (3 x 6), 30 (5 x 6) or 60 (10 x 6) ampoules. 
 
Not all pack sizes may be marketed. 
 
6.6 Special precautions for disposal and other handling 
 
Signifor solution for injection should be free of visible particles, clear and colourless. Do not use 
Signifor if the solution is not clear or contains particles. 
 



15 

For information on the instructions for use, please see the end of the package leaflet “How to inject 
Signifor”. 
 
Any unused medicinal product or waste material should be disposed of in accordance with local 
requirements. 
 
 
7. MARKETING AUTHORISATION HOLDER 
 
Recordati Rare Diseases 
Immeuble Le Wilson 
70 avenue du Général de Gaulle 
92800 Puteaux 
France 
 
 
8. MARKETING AUTHORISATION NUMBER(S) 

 
Signifor 0.3 mg solution for injection 
EU/1/12/753/001-004 
 
Signifor 0.6 mg solution for injection 
EU/1/12/753/005-008 
 
Signifor 0.9 mg solution for injection 
EU/1/12/753/009-0012 
 
 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
Date of first authorisation: 24 April 2012 
Date of latest renewal: 18 November 2016 
 
 
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 



16 

1. NAME OF THE MEDICINAL PRODUCT 
 
Signifor 10 mg powder and solvent for suspension for injection 
Signifor 20 mg powder and solvent for suspension for injection 
Signifor 30 mg powder and solvent for suspension for injection 
Signifor 40 mg powder and solvent for suspension for injection 
Signifor 60 mg powder and solvent for suspension for injection 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
Signifor 10 mg powder and solvent for suspension for injection 
One vial contains 10 mg pasireotide (as pasireotide pamoate). 
 
Signifor 20 mg powder and solvent for suspension for injection 
One vial contains 20 mg pasireotide (as pasireotide pamoate). 
 
Signifor 30 mg powder and solvent for suspension for injection 
One vial contains 30 mg pasireotide (as pasireotide pamoate). 
 
Signifor 40 mg powder and solvent for suspension for injection 
One vial contains 40 mg pasireotide (as pasireotide pamoate). 
 
Signifor 60 mg powder and solvent for suspension for injection 
One vial contains 60 mg pasireotide (as pasireotide pamoate). 
 
For the full list of excipients, see section 6.1. 
 
 
3. PHARMACEUTICAL FORM 

 
Powder and solvent for suspension for injection (powder for injection). 
 
Powder: slightly yellowish to yellowish powder. 
 
Solvent: clear, colourless to slightly yellow or slightly brown solution. 
 
 
4. CLINICAL PARTICULARS 

 
4.1 Therapeutic indications 
 
Treatment of adult patients with acromegaly for whom surgery is not an option or has not been 
curative and who are inadequately controlled on treatment with another somatostatin analogue. 
 
Treatment of adult patients with Cushing’s disease for whom surgery is not an option or for whom 
surgery has failed. 
 
The 60 mg strength is only to be used in the treatment of acromegaly. 
 
4.2 Posology and method of administration 

 
Posology 
 
Acromegaly 

The recommended initial dose for the treatment of acromegaly is 40 mg of pasireotide every 4 weeks. 
 



17 

The dose may be increased to a maximum of 60 mg for patients whose growth hormone (GH) and/or 
insulin-like growth factor-1 (IGF-1) levels are not fully controlled after 3 months of treatment with 
Signifor at 40 mg. 
 
Management of suspected adverse reactions or over-response to treatment (IGF-1 < lower limit of 
normal) may require temporary dose reduction of Signifor. The dose may be decreased either 
temporarily or permanently. 
 
Cushing’s disease 

The recommended initial dose for the treatment of Cushing’s disease is 10 mg of pasireotide by deep 
intramuscular injection every 4 weeks. 
 
The patient should be evaluated for clinical benefit after the first month of treatment and periodically 
thereafter. The dose may be titrated every 2 to 4 months based on response and tolerability. The 
maximum dose of Signifor in Cushing’s disease is 40 mg every 4 weeks. If no clinical benefit is 
observed, the patient should be considered for discontinuation. 
 
Management of suspected adverse reactions or over-response to treatment (cortisol levels < lower 
limit of normal) may require dose reduction, interruption or discontinuation of Signifor. 
 
Switch from subcutaneous to intramuscular formulation in Cushing’s disease 

There are no clinical data available on switching from the subcutaneous to the intramuscular 
pasireotide formulation. If such a switch should be required, the recommended initial dose for the 
treatment of Cushing’s disease is 10 mg of pasireotide by deep intramuscular injection every 4 weeks. 
The patient should be monitored for response and tolerability and further dose adjustments may be 
needed. 
 
Missed dose 

If a dose of Signifor is missed the missed injection should be administered as soon as possible. The 
next dose should then be planned for 4 weeks after the injection is administered in order to resume the 
normal schedule of one dose every 4 weeks. 
 
Special populations 

 
Elderly patients (≥65 years) 

Data on the use of Signifor in patients older than 65 years are limited, but there is no evidence to 
suggest that dose adjustment is required in these patients (see section 5.2). 
 
Renal impairment 

No dose adjustment is required in patients with impaired renal function (see section 5.2). 
 
Hepatic impairment 

Dose adjustment is not required in patients with mildly impaired hepatic function (Child Pugh A). 
 
Acromegaly: the recommended initial dose for acromegaly patients with moderate hepatic impairment 
(Child Pugh B) is 20 mg every 4 weeks, and the maximum recommended dose for these patients is 
40 mg every 4 weeks (see section 5.2). 
 
Cushings disease: the recommended initial dose for Cushing’s disease patients with moderate hepatic 
impairment (Child Pugh B) is 10 mg every 4 weeks, and the maximum recommended dose for these 
patients is 20 mg every 4 weeks (see section 5.2). 
 
Signifor should not be used in patients with severe hepatic impairment (Child Pugh C) (see 
sections 4.3 and 4.4). 
 

Paediatric population 

The safety and efficacy of Signifor in children and adolescents aged 0 to 18 years have not been 



18 

established. No data are available. 
 
Method of administration 
 
Signifor is to be administered by deep intramuscular injection by a trained healthcare professional. 
Signifor suspension must only be prepared immediately before administration. 
 
The site of repeat intramuscular injections should be alternated between the left and right gluteal 
muscle. 
 
For instructions on reconstitution of the medicinal product before administration, see section 6.6. 
 
4.3 Contraindications 
 
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. 
 
Severe hepatic impairment (Child Pugh C). 
 
4.4 Special warnings and precautions for use 

 
Glucose metabolism 
 
Alterations in blood glucose levels have been frequently reported in healthy volunteers and patients 
treated with pasireotide. Hyperglycaemia and, less frequently, hypoglycaemia, were observed in 
subjects participating in clinical studies with pasireotide (see section 4.8). 
 
In patients who developed hyperglycaemia, the condition generally appeared to respond to antidiabetic 
therapy. Dose reductions or discontinuation of treatment with pasireotide due to hyperglycaemia were 
infrequent in clinical studies with pasireotide. 
 
The development of hyperglycaemia appears to be related to decreases in secretion of insulin and of 
incretin hormones (i.e. glucagon-like peptide-1 [GLP-1] and glucose-dependent insulinotropic 
polypeptide [GIP]). 
 
Glycaemic status (fasting plasma glucose/haemoglobin A1c [FPG/HbA1c]) should be assessed prior to 
starting treatment with pasireotide. FPG/HbA1c monitoring during treatment should follow established 
guidelines. Self monitoring of blood glucose and/or FPG assessments should be done weekly for the 
first three months and periodically thereafter, as clinically appropriate, as well as over the first four to 
six weeks after any dose increase. In addition, monitoring of FPG 4 weeks and HbA1c 3 months after 
the end of the treatment should be performed. 
 
If hyperglycaemia develops in a patient being treated with Signifor, the initiation or adjustment of 
antidiabetic treatment is recommended, following the established treatment guidelines for the 
management of hyperglycaemia. If uncontrolled hyperglycaemia persists despite appropriate medical 
management, the dose of Signifor should be reduced or Signifor treatment discontinued (see also 
section 4.5). 
 
There have been post-marketing cases of ketoacidosis with Signifor in patients with and without a 
history of diabetes. Patients who present with signs and symptoms consistent with severe metabolic 
acidosis should be assessed for ketoacidosis regardless of diabetes history. 
 
In patients with poor glycaemic control (as defined by HbA1c values >8% while receiving anti-diabetic 
therapy), diabetes management and monitoring should be intensified prior to initiation and during 
pasireotide therapy. 
 



19 

Liver tests 
 
Mild transient elevations in aminotransferases are commonly observed in patients treated with 
pasireotide. Rare cases of concurrent elevations in ALT (alanine aminotransferase) greater than 
3 x ULN and bilirubin greater than 2 x ULN have also been observed (see section 4.8). Monitoring of 
liver function is recommended prior to treatment with pasireotide intramuscular use and after the first 
two to three weeks, then monthly for three months on treatment. Thereafter liver function should be 
monitored as clinically indicated. 
 
Patients who develop increased transaminase levels should be monitored frequently until values return 
to pre-treatment levels. Therapy with pasireotide should be discontinued if the patient develops 
jaundice or other signs suggestive of clinically significant liver dysfunction, in the event of a sustained 
increase in AST (aspartate aminotransferase) or ALT of 5 x ULN or greater, or if ALT or AST 
elevations greater than 3 x ULN occur concurrently with bilirubin elevations greater than 2 x ULN. 
Following discontinuation of treatment with pasireotide, patients should be monitored until resolution. 
Treatment should not be restarted if the liver function abnormalities are suspected to be related to 
pasireotide. 
 
Cardiovascular related events 
 
Bradycardia has been reported with the use of pasireotide (see section 4.8). Careful monitoring is 
recommended in patients with cardiac disease and/or risk factors for bradycardia, such as history of 
clinically significant bradycardia or acute myocardial infarction, high-grade heart block, congestive 
heart failure (NYHA Class III or IV), unstable angina, sustained ventricular tachycardia, ventricular 
fibrillation. Dose adjustment of medicinal products such as beta blockers, calcium channel blockers, or 
medicinal products to control electrolyte balance, may be necessary (see also section 4.5). 
 
Pasireotide has been shown to prolong the QT interval on the ECG in two dedicated healthy volunteer 
studies performed with the subcutaneous formulation. The clinical significance of this prolongation is 
unknown. The phase III clinical studies in acromegaly patients did not identify any clinically 
meaningful differences in the QT prolongation events between pasireotide intramuscular use and the 
somatostatin analogues which were tested as active comparator. All QT-related events were transient 
and resolved without therapeutic intervention. 
 
Episodes of torsade de pointes were not observed in any clinical study with pasireotide. 
 
Pasireotide should be used with caution and the benefit risk carefully weighed in patients who are at 
significant risk of developing prolongation of QT, such as those: 
- with congenital long QT syndrome. 
- with uncontrolled or significant cardiac disease, including recent myocardial infarction, 

congestive heart failure, unstable angina or clinically significant bradycardia. 
- taking antiarrhythmic medicinal products or other substances that are known to lead to QT 

prolongation (see section 4.5). 
- with hypokalaemia and/or hypomagnesaemia. 
 
A baseline ECG is recommended prior to initiating therapy with Signifor. Monitoring for an effect on 
the QTc interval is advisable 21 days after the beginning of the treatment and as clinically indicated 
thereafter. Hypokalaemia and/or hypomagnesaemia must be corrected prior to administration of 
Signifor and should be monitored periodically during therapy. 
 
Hypocortisolism 
 
The suppression of ACTH (adrenocorticotropic hormone) secretion can result in hypocortisolism in 
patients treated with Signifor. It is therefore necessary to monitor and instruct patients on the signs and 
symptoms associated with hypocortisolism (e.g. weakness, fatigue, anorexia, nausea, vomiting, 
hypotension, hyperkalaemia, hyponatraemia, hypoglycaemia). In the event of documented 
hypocortisolism, temporary exogenous steroid (glucocorticoid) replacement therapy and/or dose 



20 

reduction or interruption of Signifor therapy may be necessary. Rapid decreases in cortisol levels may 
be associated with decreases in white blood cell count. 
 
Gallbladder and related events 
 
Cholelithiasis (gallstones) is a recognised adverse reaction associated with somatostatin analogues and 
has frequently been reported in clinical studies with pasireotide (see section 4.8). There have been 
post-marketing cases of cholangitis in patients taking Signifor, which in the majority of cases was 
reported as a complication ofgallstones. Ultrasonic examination of the gallbladder before and at 6 to 
12 month intervals during Signifor therapy is therefore recommended. The presence of gallstones in 
Signifor-treated patients is largely asymptomatic; symptomatic stones should be managed according to 
clinical practice. 
 
Pituitary hormones 
 
As the pharmacological activity of pasireotide mimics that of somatostatin, inhibition of pituitary 
hormones other than GH and/or IGF-1 in patients with acromegaly and ACTH/cortisol in patients with 
Cushing’s disease cannot be ruled out. Monitoring of pituitary function (e.g. TSH/free T4) before and 
periodically during Signifor therapy should therefore be considered, as clinically appropriate. 
 
Effect on female fertility 
 
The therapeutic benefits of a reduction in growth hormone (GH) levels and normalisation of 
insulin-like growth factor 1 (IGF-1) concentration in female acromegalic patients and of a reduction or 
normalisation of serum cortisol levels in female patients with Cushing’s disease could potentially 
restore fertility. Female patients of childbearing potential should be advised to use adequate 
contraception if necessary during treatment with Signifor (see section 4.6). 
 
Coagulation abnormalities 
 
Patients with significantly increased prothrombin time (PT) and partial thromboplastin time (PTT) 
values or patients receiving coumarin-derivative or heparin-derivative anticoagulants were excluded 
from clinical studies with pasireotide as the safety of the combination with such anticoagulants has not 
been established. If concomitant use of coumarin-derivative or heparin-derivative anticoagulants with 
Signifor intramuscular use cannot be avoided, patients should be monitored regularly for alterations in 
their coagulation parameters (PT and PTT) and the anticoagulant dose adjusted accordingly. 
 
Renal impairment 
 
Due to the increase in unbound drug exposure, Signifor should be used with caution in patients with 
severe renal impairment or end stage renal disease (see section 5.2). 
 
Sodium content 
 
This medicinal product contains less than 1 mmol (23 mg) sodium per dose, i.e. it is essentially 
‘sodium-free’. 
 
4.5 Interaction with other medicinal products and other forms of interaction 
 
Anticipated pharmacokinetic interactions resulting in effects on pasireotide 
 

The influence of the P-gp inhibitor verapamil on the pharmacokinetics of subcutaneous pasireotide 
was tested in a drug-drug interaction study in healthy volunteers. No change in the pharmacokinetics 
(rate or extent of exposure) of pasireotide was observed. 
 



21 

Anticipated pharmacokinetic interactions resulting in effects on other medicinal products 
 
Pasireotide may decrease the relative bioavailability of ciclosporin. Concomitant administration of 
pasireotide and ciclosporin may require adjustment of the ciclosporin dose to maintain therapeutic 
levels. 
 
Anticipated pharmacodynamic interactions 
 
Medicinal products that prolong the QT interval 

Pasireotide should be used with caution in patients who are concomitantly receiving medicinal 
products that prolong the QT interval, such as class Ia antiarrhythmics (e.g. quinidine, procainamide, 
disopyramide), class III antiarrhythmics (e.g. amiodarone, dronedarone, sotalol, dofetilide, ibutilide), 
certain antibacterials (intravenous erythromycin, pentamidine injection, clarithromycin, moxifloxacin), 
certain antipsychotics (e.g. chlorpromazine, thioridazine, fluphenazine, pimozide, haloperidol, 
tiapride, amisulpride, sertindole, methadone), certain antihistamines (e.g. terfenadine, astemizole, 
mizolastine), antimalarials (e.g. chloroquine, halofantrine, lumefantrine), certain antifungals 
(ketoconazole, except in shampoo) (see also section 4.4). 
 
Bradycardic medicinal products 

Clinical monitoring of heart rate, notably at the beginning of treatment, is recommended in patients 
receiving pasireotide concomitantly with bradycardic medicinal products, such as beta blockers (e.g. 
metoprolol, carteolol, propranolol, sotalol), acetylcholinesterase inhibitors (e.g. rivastigmine, 
physostigmine), certain calcium channel blockers (e.g. verapamil, diltiazem, bepridil), certain 
antiarrhythmics (see also section 4.4). 
 
Insulin and antidiabetic medicinal products 

Dose adjustments (decrease or increase) of insulin and antidiabetic medicinal products (e.g. 
metformin, liraglutide, vildagliptin, nateglinide) may be required when administered concomitantly 
with pasireotide (see also section 4.4). 
 
4.6 Fertility, pregnancy and lactation 
 
Pregnancy 
 
There is a limited amount of data from the use of pasireotide in pregnant women. Studies in animals in 
which pasireotide was administered via the subcutaneous route have shown reproductive toxicity (see 
section 5.3). Pasireotide is not recommended for use during pregnancy and in women of childbearing 
potential who are not using contraception (see section 4.4). 
 
Breast-feeding 
 
It is unknown whether pasireotide is excreted in human milk. Available data in rats in which 
pasireotide was administered via the subcutaneous route have shown excretion of pasireotide in milk 
(see section 5.3). Breast-feeding should be discontinued during treatment with Signifor. 
 
Fertility 
 
Studies in rats in which pasireotide was administered via the subcutaneous route have shown effects 
on female reproductive parameters (see section 5.3). The clinical relevance of these effects in humans 
is unknown. 
 
4.7 Effects on ability to drive and use machines 

 
Signifor may have a minor influence on the ability to drive and use machines. Patients should be 
advised to be cautious when driving or using machines if they experience fatigue, dizziness or 
headache during treatment with Signifor. 
 



22 

4.8 Undesirable effects 

 
Summary of the safety profile 
 
The safety profile of pasireotide intramuscular use is consistent with the somatostatin analogue class, 
except for the higher degree and frequency of hyperglycaemia seen with pasireotide intramuscular use. 
The safety profile of pasireotide intramuscular use was largely similar between the acromegaly and 
Cushing’s disease indications. 
 
Acromegaly 

In acromegaly, the safety assessment was made based on 491 patients who received pasireotide 
(419 patients received pasireotide intramuscular use and 72 received pasireotide subcutaneous use) in 
phase I, II and III studies. The most common adverse reactions (incidence ≥1/10) from the pooled 
safety data from the phase III studies C2305 and C2402 were (in decreasing order): diarrhoea (most 
common in study C2305), cholelithiasis, hyperglycaemia (most common in study C2402) and diabetes 
mellitus. Common Toxicity Criteria (CTC) Grade 3 and 4 adverse reactions were mostly related to 
hyperglycaemia. 
 
Cushing’s disease 

In Cushing’s disease, the safety assessment of the intramuscular formulation was made based on 
150 patients who received pasireotide in the phase III study G2304 (median duration of exposure: 
57 weeks). Patients were randomised in a 1:1 ratio to receive starting doses of either 10 mg or 30 mg 
pasireotide, with a possibility to up-titrate to a maximum dose of 40 mg every 28 days. The most 
common adverse reactions (incidence ≥1/10) in the phase III study G2304 were hyperglycaemia, 
diarrhoea, cholelithiasis and diabetes mellitus. The frequency and severity of adverse reactions tended 
to be higher with the higher starting dose of 30 mg, but this was not consistent for all adverse 
reactions. 
 
Tabulated list of adverse reactions 
 
The adverse reactions in Table 1 include events reported in the pivotal studies with the intramuscular 
formulation in patients with acromegaly and with Cushing’s disease. Adverse reactions are listed 
according to MedDRA primary system organ class. Within each system organ class, adverse reactions 
are ranked by frequency. Within each frequency grouping, adverse reactions are presented in the order 
of decreasing seriousness. Frequencies were defined as follows: Very common (≥1/10); common 
(≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); not known (cannot be estimated from the 
available data). 
 



23 

Table 1 Adverse reactions by preferred term for pasireotide intramuscular use 

 
System Organ 

Class 

Very common Common Uncommon Not known 

Blood and 

lymphatic 

system disorders 

 Anaemia   

Endocrine 

disorders 
 Adrenal 

insufficiency* 
  

Metabolism and 

nutrition 

disorders 

Hyperglycaemia, 
diabetes mellitus 

Type 2 diabetes 
mellitus, glucose 
tolerance 
impaired, 
decreased 
appetite 

 Diabetic 
ketoacidosis 

Nervous system 

disorders 
 Headache, 

dizziness 
  

Cardiac 

disorders 
 Sinus 

bradycardia*, QT 
prolongation 

  

Gastrointestinal 

disorders 
Diarrhoea, 
nausea, 
abdominal pain* 

Abdominal 
distension, 
vomiting 

  

Hepatobiliary 

disorders 
Cholelithiasis Cholecystitis*, 

cholestasis 
  

Skin and 

subcutaneous 

tissue disorders 

 Alopecia, pruritus   

General 

disorders and 

administration 

site conditions 

Fatigue* Injection site 
reaction* 

  

Investigations  Glycosylated 
haemoglobin 
increased, alanine 
aminotransferase 
increased, 
aspartate 
aminotransferase 
increased, 
gamma-
glutamyltransfera
se increased, 
blood glucose 
increased, blood 
creatine 
phosphokinase 
increased, lipase 
increased 

Amylase 
increased, 
prothrombin time 
prolonged 

 

* Grouped terms: Adrenal insufficiency includes adrenal insufficiency and blood cortisol 
decreased. Sinus bradycardia includes bradycardia and sinus bradycardia. Abdominal pain 
includes abdominal pain and abdominal pain upper. Injection site reaction includes injection 
site pain, injection site nodule, injection site discomfort, injection site bruising, injection site 
pruritus, injection site reaction, injection site hypersensitivity and injection site swelling. 
Cholecystitis includes cholecystitis acute and cholecystitis chronic. Fatigue includes fatigue 
and asthenia. 

 



24 

Description of selected adverse reactions 
 
Glucose metabolism disorders 

Acromegaly 

In acromegaly patients elevated fasting glucose level was the most frequently reported 
grade 3/4 laboratory abnormality in the two phase III studies. In study C2305, grade 3 elevated fasting 
glucose levels were reported in 9.7% and 0.6% and grade 4 in 0.6% and 0% of acromegaly patients 
treated with pasireotide intramuscular use and octreotide intramuscular use, respectively. In study 
C2402, grade 3 elevated fasting glucose levels were reported in 14.3% and 17.7% of acromegaly 
patients treated with pasireotide intramuscular use 40 mg and 60 mg respectively, and in no patients in 
the active control group. Two cases of hyperglycaemia-related emergencies (diabetic ketoacidosis and 
diabetic hyperglycaemic coma) were reported following a dose increase of pasireotide to 60 mg in 
medical treatment naïve patients; one in a patient with untreated hyperglycaemia and HbA1c >8% 
prior to initiation of pasireotide and the other in a patient with untreated hyperglycaemia and a fasting 
plasma glucose of 359 mg/dl, respectively. In both studies, mean FPG and HbA1c levels peaked within 
the first three months of treatment with pasireotide intramuscular use. In medically naïve patients 
(study C2305), the mean absolute increase in FPG and HbA1c was similar at most of the time points 
for all patients treated with pasireotide intramuscular use irrespective of baseline values. 
 
The degree and frequency of hyperglycaemia observed in the two pivotal studies in acromegaly 
patients were higher with Signifor intramuscular use than with active control (octreotide intramuscular 
use or lanreotide deep subcutaneous injection). In a pooled analysis of the two pivotal studies, the 
overall incidence of hyperglycaemia-related adverse reactions was 58.6% (all grades) and 9.9% (CTC 
Grade 3 and 4) for Signifor intramuscular use versus 18.0% (all grades) and 1.1% (CTC Grade 3 and 
4) for the active control. In the pivotal study with patients inadequately controlled on another 
somatostatin analogue, the proportion of patients not previously treated with anti-diabetic agents who 
required commencement of anti-diabetic therapy during the study was 17.5% and 16.1% in the 
Signifor 40 mg and 60 mg arms compared to 1.5% in the active control arm. In the pivotal study with 
patients who did not receive prior medical treatment, the proportion of patients who required 
commencement of anti-diabetic therapy during the study was 36% in the Signifor arm compared to 
4.4% in the active control arm. 
 
Cushing’s disease 

In Cushing’s disease patients, elevated FPG levels was the most frequently reported CTC Grade 3 
laboratory abnormality (14.7% of patients) in the phase III study G2304; with no cases of Grade 4 
reported. Mean HbA1c increases were less pronounced in patients with normal glycaemia at study 
entry in comparison to pre-diabetic patients or diabetic patients. Mean FPG levels commonly 
increased within the first month of treatment with decreases and stabilisation observed in subsequent 
months. FPG and HbA1c increases were dose-dependent, and values generally decreased following 
pasireotide intramuscular use discontinuation but remained above baseline values. The overall 
incidence of hyperglycaemia-related adverse reactions was 75.3% (all grades) and 22.7% (CTC 
Grade 3). Adverse reactions of hyperglycaemia and diabetes mellitus led to study discontinuation in 3 
(2.0%) and 4 patients (2.7%), respectively. 
 
The elevations of fasting plasma glucose and HbA1c observed with pasireotide intramuscular use 
treatment are reversible after discontinuation. 
 
Monitoring of blood glucose levels in patients treated with Signifor is recommended (see section 4.4). 
 
Gastrointestinal disorders 

Gastrointestinal disorders were frequently reported with Signifor. These reactions were usually of low 
grade, required no intervention and improved with continued treatment. In acromegaly patients, 
gastrointestinal disorders were less frequent in inadequately controlled patients compared to medically 
naïve patients. 
 
Injection site reactions 

In the phase III studies, injection site related reactions (e.g. injection site pain, injection site 



25 

discomfort) were mostly grade 1 or 2 in severity. The incidence of such events was highest in the first 
3 months of treatment. In the acromegaly studies, the events were comparable between pasireotide 
intramuscular use and octreotide intramuscular use treated patients, and were less frequent in 
inadequately controlled patients compared to medically naïve patients. 
 
QT prolongation 

In the acromegaly study C2305, the proportion of patients with newly occurring notable QT/QTc 
intervals was comparable between pasireotide intramuscular use and octreotide intramuscular use 
groups up to crossover, with few notable outlying values. QTcF >480 ms was reported for 3 versus 
2 patients in the pasireotide intramuscular use and octreotide intramuscular use groups, respectively, 
and QTcF >60 ms prolonged from baseline was reported for 2 versus 1 patients in the respective 
groups. In study C2402, the only notable outlier was a QTcF value >480 ms in 1 patient in the 
pasireotide intramuscular use 40 mg group. In the Cushing’s disease study G2304, a QTcF value 
>480 ms was reported for 2 patients. No QTcF values >500 ms were observed in any of the pivotal 
studies. 
 
Liver enzymes 

Transient elevations in liver enzymes have been reported with the use of somatostatin analogues and 
were also observed in healthy subjects and patients receiving pasireotide in clinical studies. The 
elevations were mostly asymptomatic, of low grade and reversible with continued treatment. A few 
cases of concurrent elevations in ALT greater than 3 x ULN and bilirubin greater than 2 x ULN have 
been observed with the subcutaneous formulation, however not in patients treated with pasireotide 
intramuscular use. All observed cases of concurrent elevations were identified within ten days of 
initiation of treatment. The patients recovered without clinical sequelae and liver function test results 
returned to baseline values after discontinuation of treatment. 
 
Monitoring of liver enzymes is recommended before and during treatment with Signifor (see 
section 4.4), as clinically appropriate. 
 
Pancreatic enzymes 

Asymptomatic elevations in lipase and amylase were observed in patients receiving pasireotide in 
clinical studies. The elevations were mostly low grade and reversible while continuing treatment. 
Pancreatitis is a potential adverse reaction associated with the use of somatostatin analogues due to the 
association between cholelithiasis and acute pancreatitis. 
 
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 
 
In the event of overdose, it is recommended that appropriate supportive treatment be initiated, as 
dictated by the patient’s clinical status, until resolution of the symptoms. 
 
 
5. PHARMACOLOGICAL PROPERTIES 
 
5.1 Pharmacodynamic properties 
 
Pharmacotherapeutic group: Pituitary and hypothalamic hormones and analogues, somatostatin and 
analogues, ATC code: H01CB05 
 

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


26 

Mechanism of action 
 
Pasireotide is a cyclohexapeptide, injectable somatostatin analogue. Like the natural peptide hormones 
somatostatin-14 and somatostatin-28 (also known as somatotropin release inhibiting factor [SRIF]) 
and other somatostatin analogues, pasireotide exerts its pharmacological activity via binding to 
somatostatin receptors. Five human somatostatin receptor subtypes are known: hsst1, 2, 3, 4, and 5. 
These receptor subtypes are expressed in different tissues under normal physiological conditions. 
Somatostatin analogues bind to hsst receptors with different potencies (see Table 2). Pasireotide binds 
with high affinity to four of the five hssts. 
 
Table 2 Binding affinities of somatostatin (SRIF-14), pasireotide, octreotide and lanreotide 

to the five human somatostatin receptor subtypes (hsst1-5) 

 
Compound hsst1 hsst2 hsst3 hsst4 hsst5 

Somatostatin 
(SRIF-14) 

0.930.12 0.150.02 0.560.17 1.50.4 0.290.04 

Pasireotide 9.30.1 1.00.1 1.50.3 >1,000 0.160.01 
Octreotide 28080 0.380.08 7.11.4 >1,000 6.31.0 
Lanreotide 18020 0.540.08 149 23040 175 

Results are the meanSEM of IC50 values expressed as nmol/l. 
 
Pharmacodynamic effects 
 
Somatostatin receptors are expressed in many tissues, especially in neuroendocrine tumours in which 
hormones are excessively secreted, including GH in acromegaly and ACTH in Cushing’s disease. 
 
In vitro studies have shown that corticotroph tumour cells from Cushing’s disease patients display a 
high expression of hsst5, whereas the other receptor subtypes either are not expressed or are expressed 
at lower levels. Pasireotide binds and activates four of the five hssts, especially hsst5, in corticotrophs 
of ACTH producing adenomas, resulting in inhibition of ACTH secretion. 
 
Due to its broad binding profile to somatostatin receptors, pasireotide has the potential to stimulate 
both hsst2 and hsst5 subtype receptors relevant for inhibition of GH and IGF-1 secretion and therefore 
to be effective for the treatment of acromegaly. 
 
Glucose metabolism 

In a randomised double-blinded mechanism study conducted in healthy volunteers, the development of 
hyperglycaemia with pasireotide administered as pasireotide subcutaneous use at doses of 0.6 and 
0.9 mg twice a day was related to significant decreases in insulin secretion as well as incretin 
hormones (i.e. glucagon-like peptide-1 [GLP-1] and glucose-dependent insulinotropic polypeptide 
[GIP]). Pasireotide did not affect insulin sensitivity. 
 
Clinical efficacy and safety 
 
The efficacy of pasireotide intramuscular use has been demonstrated in two phase III, multicentre 
studies in acromegaly patients and in one phase III, multicentre study in Cushing’s disease patients. 
 
Acromegaly study C2402, inadequately controlled patients 
Study C2402 was a phase III, multicentre, randomised, parallel-group, three-arm study of double-blind 
pasireotide intramuscular use 40 mg and 60 mg versus open-label octreotide intramuscular use 30 mg 
or lanreotide deep subcutaneous injection 120 mg in patients with inadequately controlled acromegaly. 
A total of 198 patients were randomised to receive pasireotide intramuscular use 40 mg (n=65), 
pasireotide intramuscular use 60 mg (n=65) or active control (n=68). 192 patients were treated. A total 
of 181 patients completed the core phase (24 weeks) of the study. 
 
Inadequately controlled patients in study C2402 are defined as patients with a mean GH concentration 



27 

of a 5-point profile over a 2-hour period >2.5 μg/l and sex- and age-adjusted IGF-1 >1.3 × ULN. 
Patients had to be treated with maximum indicated doses of octreotide intramuscular use (30 mg) or 
lanreotide deep subcutaneous injection (120 mg) for at least 6 months prior to randomisation. 
Three-quarters of patients had previously been treated with octreotide intramuscular use and a quarter 
with lanreotide deep subcutaneous injection. Nearly half of the patients had additional prior medical 
treatment for acromegaly other than somatostatin analogues. Two-thirds of all patients had undergone 
prior surgery. Baseline mean GH was 17.6 µg/l, 12.1 µg/l and 9.5 µg/l, in the 40 mg, 60 mg and active 
control groups, respectively. IGF-1 mean values at baseline were 2.6, 2.8 and 2.9 x ULN, respectively. 
 
The primary efficacy endpoint was to compare the proportion of patients achieving biochemical 
control (defined as mean GH levels <2.5 μg/l and normalisation of sex- and age-adjusted IGF-1) at 
week 24 with pasireotide intramuscular use 40 mg or 60 mg versus continued treatment with active 
control (octreotide intramuscular use 30 mg or lanreotide deep subcutaneous injection 120 mg), 
separately. The study met its primary efficacy endpoint for both pasireotide intramuscular use doses. 
The proportion of patients achieving biochemical control was 15.4% (p-value = 0.0006) and 20.0% 
(p-value <0.0001) for pasireotide intramuscular use 40 mg and 60 mg, respectively at 24 weeks 
compared with zero in the active control arm (Table 3). 
 
Table 3 Key results at week 24 (Study C2402) 
 
 Signifor 

intramuscular use 

40 mg 

N=65 

n (%), p value 

Signifor 

intramuscular use 

60 mg 

N=65 

n (%), p value 

Active control 

N=68 

n (%) 

GH<2.5 μg/l and normalised 
IGF-1* 

10 (15.4%), p=0.0006 13 (20.0%), 
p<0.0001 

0 (0%) 

Normalisation of IGF-1 16 (24.6%), p<0.0001 17 (26.2%), 
p<0.0001 

0 (0%) 

GH<2.5 μg/l 23 (35.4%) 28 (43.1%) 9 (13.2%) 
* Primary endpoint (patients with IGF-1< lower limit of normal (LLN) were not considered 
“responders”). 
 
In patients treated with pasireotide intramuscular use in whom reductions in GH and IGF-1 levels 
were observed, these changes occurred during the first 3 months of treatment and were maintained up 
to week 24. 
 
The proportion of patients with a reduction or no change in pituitary tumour volume at week 24 was 
81.0% and 70.3% on pasireotide intramuscular use 40 and 60 mg, and 50.0% on active control. 
Furthermore, a higher proportion of patients on pasireotide intramuscular use (18.5% and 10.8% for 
40 mg and 60 mg, respectively) than active comparator (1.5%) achieved a reduction in tumour volume 
of at least 25%. 
 
Health-related quality of life measured by AcroQol indicated statistically significant improvements 
from baseline to week 24 in the Physical, Psychological-Appearance and Global scores for the 60 mg 
group and the Physical sub-score for the 40mg group. Changes for the octreotide intramuscular use or 
lanreotide deep subcutaneous injection group were not statistically significant. The improvement 
observed up to week 24 between the treatment groups was also not statistically significant. 
 
Acromegaly study C2305 patients who had no prior medical treatment 
A phase III multicentre, randomised, blinded study was conducted to assess the safety and efficacy of 
pasireotide intramuscular use versus octreotide intramuscular use in medically naïve patients with 
active acromegaly. A total of 358 patients were randomised and treated. Patients were randomised in a 
1:1 ratio to one of two treatment groups in each of the following two strata: 1) patients who had 
undergone one or more pituitary surgeries but had not been treated medically or 2) de novo patients 
presenting a visible pituitary adenoma on MRI who had refused pituitary surgery or for whom 
pituitary surgery was contraindicated. 



28 

 
The two treatment groups were well balanced in terms of baseline demographics and disease 
characteristics. 59.7% and 56% of patients in the pasireotide intramuscular use and octreotide 
intramuscular use treatment groups, respectively, were patients without previous pituitary surgery (de 
novo). 
 
The starting dose was 40 mg for pasireotide intramuscular use and 20 mg for octreotide intramuscular 
use. Dose increase for efficacy was allowed at the discretion of the investigators after three and six 
months of treatment if biochemical parameters showed a mean GH ≥2.5 µg/l and/or IGF-1 >ULN (age 
and sex related). Maximum allowed dose was 60 mg for pasireotide intramuscular use and 30 mg for 
octreotide intramuscular use. 
 
The primary efficacy endpoint was the proportion of patients with a reduction of mean GH level to 
<2.5 μg/l and the normalisation of IGF-1 to within normal limits (age and sex related) at month 12. 
The primary efficacy endpoint was met; the percentage of patients achieving biochemical control was 
31.3% and 19.2% for pasireotide intramuscular use and octreotide intramuscular use, respectively, 
demonstrating a statistically significant superior result favouring pasireotide intramuscular use 
(p-value = 0.007) (Table 4). 
 
Table 4 Key results at month 12 - phase III study in acromegaly patients 
 

 Pasireotide 
intramuscular use 

n (%) 

N=176 

Octreotide 

intramuscular use 

n (%) 

N=182 

p-value 

GH <2.5 μg/l and normalised IGF-1* 31.3% 19.2% p=0.007 
GH <2.5 μg/l and IGF-1 ≤ULN 35.8% 20.9% - 
Normalised IGF-1 38.6% 23.6% p=0.002 
GH <2.5 μg/l 48.3% 51.6% p=0.536 

* Primary endpoint (patients with IGF-1 <lower limit of normal (LLN) were not considered 
“responders”). 
ULN = upper limit of normal 
 
Biochemical control was achieved early in the study (i.e. month 3) by a higher proportion of patients 
in the pasireotide intramuscular use arm than in the octreotide intramuscular use arm (30.1% and 
21.4%) and was maintained in all subsequent evaluations during the core phase. 
 
At month 12, reduction in tumour volume was comparable between the treatment groups and in 
patients with and without previous pituitary surgery. The proportion of patients with a reduction of 
tumour volume greater than 20% at month 12 was 80.8% for pasireotide intramuscular use and 77.4% 
for octreotide intramuscular use. 
 
Health-related quality of life measured by AcroQol indicated statistically significant improvements in 
the Physical, Psychological-Appearance and Global scores in both treatment groups at month 12. 
Mean improvements from baseline were greater for pasireotide intramuscular use than for octreotide 
intramuscular use with no statistical significance. 
 
Extension phase 

At the end of the core phase, patients achieving biochemical control or benefiting from the treatment 
as assessed by the investigator could continue to be treated in the extension phase with the study 
treatment to which they were initially randomised. 
 
During the extension phase, 74 patients continued receiving pasireotide intramuscular use and 
46 patients continued with octreotide intramuscular use treatment. At month 25, 48.6% of patients 
(36/74) in the pasireotide intramuscular use group and 45.7% (21/46) in the octreotide intramuscular 
use group achieved biochemical control. The percentage of patients who had mean GH values 
<2.5 µg/l and normalisation of IGF-1 at the same time point was also comparable between the two 



29 

treatment arms. 
 
During the extension phase, tumour volume continued to decrease. 
 
Crossover phase 

At the end of the core phase, patients not adequately responding to their initial therapy were allowed to 
switch treatment. 81 patients were crossed over from octreotide intramuscular use to pasireotide 
intramuscular use, and 38 patients were crossed over from pasireotide intramuscular use to octreotide 
intramuscular use. 
 
Twelve months after crossover, the percentage of patients achieving biochemical control was 17.3% 
(14/81) for pasireotide intramuscular use and 0% (0/38) for octreotide intramuscular use. The 
percentage of patients achieving biochemical control, including those patients with IGF-1 <LLN was 
25.9% in the pasireotide intramuscular use group and 0% in the octreotide intramuscular use group. 
 
Further decrease in tumour volume was observed at month 12 after crossover for both treatment 
groups, and was higher in patients who crossed over to pasireotide intramuscular use (-24.7%) than in 
patients who crossed over to octreotide intramuscular use (-17.9%). 
 
Cushing’s disease study G2304 
The efficacy and safety of pasireotide intramuscular use was evaluated in a phase III, multicentre 
study over a 12-month treatment period in Cushing’s disease patients with persistent or recurrent 
disease or de novo patients for whom surgery was not indicated or who refused surgery. The eligibility 
criteria included a mean urinary free cortisol (mUFC) value of between 1.5 and 5 times upper limit of 
normal (ULN) at screening. The study enrolled 150 patients. The mean age was 35.8 years, and the 
majority of patients were female (78.8%). Most patients (82.0%) had undergone prior pituitary 
surgery, and the mean baseline mUFC was 470 nmol/24h (ULN: 166.5 nmol/24h). 
 
Patients were randomised in a 1:1 ratio to a starting dose of either 10 mg or 30 mg pasireotide 
intramuscular use every 4 weeks. After four months of treatment, patients with mUFC ≤1.5xULN 
continued on the blinded dose to which they were randomised, and patients with mUFC >1.5xULN 
had their doses increased in a blinded manner from 10 mg to 30 mg, or from 30 mg to 40 mg, provided 
there were no tolerability concerns. Additional dose adjustments (up to a maximum of 40 mg) were 
allowed at months 7 and 9 of the core phase. The primary efficacy end point was the proportion of 
patients in each arm who achieved mean 24-hour UFC levels ≤ULN after 7 months of treatment, 
regardless of prior dose increase. Secondary end points included changes from baseline in: 24-hour 
UFC, plasma ACTH, serum cortisol levels, and clinical signs and symptoms of Cushing’s disease. All 
analyses were conducted based on the randomised dose groups. 
 
Results 

The study met the primary efficacy objective for both dose groups (lower bound of the 95% CI for the 
response rate of each treatment arm >15%). At month 7, a mUFC response was achieved in 41.9% and 
40.8% of patients randomised to starting doses of 10 mg and 30 mg, respectively. The proportion of 
patients who either attained mUFC ≤ULN or a mUFC reduction from baseline of at least 50% was 
50.0% in the 10 mg dose group and 56.6% in the 30 mg dose groups (Table 5). 
 
In both dose groups, Signifor resulted in a decrease in mean UFC after 1 month of treatment, and this 
was maintained over time. Decreases were also demonstrated by the overall percentage change from 
baseline in mean and median mUFC levels at month 7 and 12. Reductions in serum cortisol and 
plasma ACTH levels were also observed at month 7 and 12 for each dose group. 
 



30 

Table 5 Key results - phase III study in Cushing’s disease patients (intramuscular 
formulation) 

 
 Pasireotide 10 mg 

N=74 

Pasireotide 30 mg 

N=76 

Percentage of patients with:   
 mUFC ≤ULN at Month 7 (95% CI) * 41.9 (30.5, 53.9) 40.8 (29.7, 52.7) 
 mUFC ≤ULN and no prior dose increase 

at Month 7 (95% CI) 
28.4 (18.5, 40.1) 31.6 (21.4, 43.3) 

 mUFC ≤ULN or ≥50% decrease from 
baseline at month 7 (95% CI) 

50.0 (38.1, 61.9) 56.6 (44.7, 67.9) 

Median (min, max) % mUFC change from 
baseline at month 7 

-47.9 (-94.2, 651.1) -48.5 (-99.7, 181.7) 

Median (min, max) % mUFC change from 
baseline at month 12 

-52.5 (-96.9, 332.8) -51.9 (-98.7, 422.3) 

* Primary endpoint using LOCF (last observation carried forward) 
mUFC: mean urinary free cortisol; ULN: upper limit of normal; CI: confidence interval 
 
Decreases in systolic and diastolic blood pressure and in body weight were observed in both dose 
groups at month 7. Overall reductions in these parameters tended to be greater in patients that were 
mUFC responders. Similar trends were observed at month 12. 
 
At month 7, most patients demonstrated either improvement in or stable signs of Cushing’s disease 
such as hirsuitism, striae, bruising and muscle strength. Facial rubor improved in 43.5% (47/108) of 
patients, and more than a third of patients demonstrated improvement in supraclavicular fat pad 
(34.3%) and dorsal fat pad (34.6%). Similar results were also seen at month 12. 
 
Health-related quality of life was assessed by a disease-specific patient-reported outcome measure 
(CushingQoL) and a generic quality of life measure (SF-12v2 General Health Survey). Improvements 
were observed in both dose groups for CushingQoL and the Mental Component Summary (MCS) of 
SF-12v2, but not for the Physical Component Summary (PCS) of SF-12v2. 
 
Paediatric population 
 
The European Medicines Agency has waived the obligation to submit the results of studies with 
Signifor in all subsets of the paediatric population in acromegaly and pituitary gigantism, and in 
pituitary dependant Cushing’s disease, overproduction of pituitary ACTH and pituitary dependant 
hyperadrenocorticism (see section 4.2 for information on paediatric use). 
 
5.2 Pharmacokinetic properties 
 
Pasireotide for intramuscular use is formulated as microspheres for long-acting release. After a single 
injection, the plasma pasireotide concentration shows an initial burst release on the injection day, 
followed by a dip from day 2 to day 7, then a slow increase to maximum concentration around day 21, 
and a slow declining phase over the next weeks, concomitant with the terminal degradation phase of 
the polymer matrix of the dosage form. 
 
Absorption 
 
The relative bioavailability of pasireotide intramuscular use over pasireotide subcutaneous use is 
complete. No studies have been conducted to evaluate the absolute bioavailability of pasireotide in 
humans. 
 
Distribution 
 
In healthy volunteers, pasireotide intramuscular use is widely distributed with large apparent volume 
of distribution (Vz/F >100 litres). Distribution between blood cells and plasma is concentration 



31 

independent and shows that pasireotide is primarily located in the plasma (91%). Plasma protein 
binding is moderate (88%) and independent of concentration. 
 
Based on in vitro data pasireotide appears to be a substrate of efflux transporter P-gp (P-glycoprotein). 
Based on in vitro data pasireotide is not a substrate of the efflux transporter BCRP (breast cancer 
resistance protein) nor of the influx transporters OCT1 (organic cation transporter 1), OATP (organic 
anion-transporting polypeptide) 1B1, 1B3 or 2B1. At therapeutic dose levels pasireotide is also not an 
inhibitor of UGT1A1, OATP1B1 or 1B3, OAT1 or OAT3, OCT1 or OCT2, P-gp, BCRP, MRP2 and 
BSEP. 
 
Biotransformation 
 
Pasireotide is metabolically highly stable and in vitro data show that pasireotide is not a substrate, 
inhibitor or inducer of CYP450. In healthy volunteers, pasireotide is predominantly found in 
unchanged form in plasma, urine and faeces. 
 
Elimination 
 
Pasireotide is eliminated mainly via hepatic clearance (biliary excretion), with a small contribution of 
the renal route. In a human ADME study 55.9±6.63% of the radioactive pasireotide subcutaneous dose 
was recovered over the first 10 days after administration, including 48.3±8.16% of the radioactivity in 
faeces and 7.63±2.03% in urine. 
 
The apparent clearance (CL/F) of pasireotide intramuscular use in healthy volunteers is on average 
4.5-8.5 litres/h. Based on population pharmacokinetic (PK) analyses, the estimated CL/F was 
approximately 4.8 to 6.5 litres/h for typical Cushing’s disease patients, and approximately 5.6 to 
8.2 litres/h for typical acromegaly patients. 
 
Linearity and time dependency 
 
Pharmacokinetic steady state for pasireotide intramuscular use is achieved after three months. 
Following multiple monthly doses, pasireotide intramuscular use demonstrates approximately 
dose-proportional pharmacokinetic exposures in the dose range of 10 mg to 60 mg every 4 weeks. 
 
Special populations 
 
Paediatric population 

No studies have been performed in paediatric patients. 
 
Patients with renal impairment 

Renal clearance has a minor contribution to the elimination of pasireotide in humans. In a clinical 
study with single subcutaneous dose administration of 900 µg pasireotide in subjects with impaired 
renal function, renal impairment of mild, moderate or severe degree, or end stage renal disease 
(ESRD) did not have a significant impact on total pasireotide plasma exposure. The unbound plasma 
pasireotide exposure (AUCinf,u) was increased in subjects with renal impairment (mild: 33%; moderate: 
25%, severe: 99%, ESRD: 143%) compared to control subjects. 
 
Patients with hepatic impairment 

No clinical studies in subjects with liver impairment have been performed with pasireotide 
intramuscular use. In a clinical study of a single subcutaneous dose of pasireotide in subjects with 
impaired hepatic function, statistically significant differences were found in subjects with moderate 
and severe hepatic impairment (Child-Pugh B and C). In subjects with moderate and severe hepatic 
impairment, AUCinf was increased 60% and 79%, Cmax was increased 67% and 69%, and CL/F was 
decreased 37% and 44%, respectively. 
 
Elderly patients (≥65 years) 

Age is not a significant covariate in the population pharmacokinetic analysis of patients. 



32 

 
Demographics 

Population PK analyses of pasireotide intramuscular use suggest that race does not influence PK 
parameters. PK exposures had a slight correlation with body weight in the study with medical 
treatment naïve patients, but not in the study with inadequately controlled patients. Female acromegaly 
patients had a higher exposure of 32% and 51% compared to male patients in studies with medical 
treatment naïve patients and inadequately controlled patients, respectively; these differences in 
exposure were not clinically relevant based on efficacy and safety data. 
 
5.3 Preclinical safety data 
 
Non-clinical safety data from studies performed with pasireotide administered via the subcutaneous 
route reveal no special hazard for humans based on conventional studies of safety pharmacology, 
repeated dose toxicity, genotoxicity and carcinogenic potential. Additionally, tolerability and repeated 
dose toxicity studies were conducted with pasireotide via the intramuscular route. Most findings seen 
in repeated toxicity studies were reversible and attributable to the pharmacology of pasireotide. Effects 
in non-clinical studies were observed only at exposures considered sufficiently in excess of the 
maximum human exposure indicating little relevance to clinical use. 
 
Pasireotide administered via the subcutaneous route did not affect fertility in male rats but, as expected 
from the pharmacology of pasireotide, females presented abnormal cycles or acyclicity, and decreased 
numbers of corpora lutea and implantation sites. Embryo toxicity was seen in rats and rabbits at doses 
that caused maternal toxicity but no teratogenic potential was detected. In the pre- and postnatal study 
in rats, pasireotide had no effects on labour and delivery, but caused slight retardation in the 
development of pinna detachment and reduced body weight of the offspring. 
 
Available toxicological data in animals have shown excretion of pasireotide in milk. 
 
 
6. PHARMACEUTICAL PARTICULARS 

 
6.1 List of excipients 

 
Powder 
 
Poly(D,L-lactide-co-glycolide) (50-60:40-50) 
Poly(D,L-lactide-co-glycolide) (50:50) 
 
Solvent 
 
Carmellose sodium 
Mannitol 
Poloxamer 188 
Water for injections 
 
6.2 Incompatibilities 
 
In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal 
products. 
 
6.3 Shelf life 
 
3 years 
 
6.4 Special precautions for storage 
 
Store in a refrigerator (2°C – 8°C). Do not freeze. 



33 

 
6.5 Nature and contents of container 

 
Powder: brownish vial (glass) with rubber stopper (chlorobutyl rubber), containing the active 
substance (pasireotide). 
Solvent: colourless pre-filled syringe (glass) with front and plunger stopper (chlorobutyl rubber), 
containing 2 ml solvent. 
 
Unit packs (all strengths): each unit pack contains a blister tray with one injection kit (one vial and, in 
a separate sealed section, one pre-filled syringe, one vial adapter and one safety-engineered needle for 
injection). 
 
Multipacks (40 mg and 60 mg strengths only): each multipack contains 3 intermediate cartons, each 
containing a blister tray with one injection kit (one vial and, in a separate sealed section, one pre-filled 
syringe, one vial adapter and one safety engineered needle for injection). 
 
Not all pack sizes or strengths may be marketed. 
 
6.6 Special precautions for disposal and other handling 
 
There are two critical steps in the reconstitution of Signifor. Not following them could result in 
failure to deliver the injection appropriately. 

 The injection kit must reach room temperature. Remove the injection kit from the fridge and 
let the kit stand at room temperature for a minimum of 30 minutes before reconstitution, but do 
not exceed 24 hours. 

 After adding the solvent, shake the vial moderately for a minimum of 30 seconds until a 
uniform suspension is formed. 

 
Included in the injection kit: 
a One vial containing the powder 
b One pre-filled syringe containing the solvent 
c One vial adapter for medicinal product reconstitution 
d One safety injection needle (20G x 1.5″) 
 
Follow the instructions below carefully to ensure proper reconstitution of Signifor powder and solvent 
for suspension for injection before deep intramuscular injection. 
 
Signifor suspension must only be prepared immediately before administration. 
 
Signifor should only be administered by a trained healthcare professional. 
 
To prepare Signifor for deep intramuscular injection, please adhere to the following instructions: 
 

1. Remove the Signifor injection kit from refrigerated storage. ATTENTION: It is 
essential to start the reconstitution process only after the injection kit reaches room 

temperature. Let the kit stand at room temperature for a minimum of 30 minutes 



34 

before reconstitution, but do not exceed 24 hours. If not used within 24 hours, the 
injection kit can be returned to the fridge. 

2. Remove the plastic cap from the vial and clean the rubber stopper of the vial with an 
alcohol wipe. 

3. Remove the lid film of the vial adapter packaging, but do NOT remove the vial adapter 
from its packaging. 

4. Holding the vial adapter packaging, position the vial adapter on top of the vial and push it 
fully down so that it snaps in place, confirmed by a “click”. 

5. Remove the packaging from the vial adapter by lifting it straight up. 
6. Remove the cap from the syringe pre-filled with solvent and screw the syringe onto the 

vial adapter. 
7. Slowly push the plunger all the way down to transfer all the solvent in the vial. 
8. ATTENTION: Keep the plunger pressed and shake the vial moderately for a minimum 

of 30 seconds so that the powder is completely suspended. Repeat moderate shaking 
for another 30 seconds if the powder is not completely suspended. 

9. Turn syringe and vial upside down, slowly pull the plunger back and draw the entire 
content from the vial into the syringe. 

10. Unscrew the syringe from the vial adapter. 
11. Screw the safety injection needle onto the syringe. 
12. Pull the protective cover straight off the needle. To avoid sedimentation, you may gently 

shake the syringe to maintain a uniform suspension. Gently tap the syringe to remove any 
visible bubbles and expel them from the syringe. The reconstituted Signifor is now ready 
for immediate administration. 

13. Signifor must be given only by deep intramuscular injection. Prepare the injection site 
with an alcohol wipe. Insert the needle fully into the left or right gluteus at a 90° angle to 
the skin. Slowly pull back the plunger to check that no blood vessel has been penetrated 
(reposition if a blood vessel has been penetrated). Slowly depress the plunger until the 
syringe is empty. Withdraw the needle from the injection site and activate the safety 
guard. 

14. Activate the safety guard over the needle, in one of the two methods shown: 
- either press the hinged section of the safety guard down onto a hard surface 
- or push the hinge forward with your finger 
An audible “click” confirms proper activation. Dispose of syringe immediately in a 
sharps container. 

 
Any unused medicinal product or waste material should be disposed of in accordance with local 
requirements. 
 
 
7. MARKETING AUTHORISATION HOLDER 
 
Recordati Rare Diseases 
Immeuble Le Wilson 
70 avenue du Général de Gaulle 
92800 Puteaux 
France 
 
 
8. MARKETING AUTHORISATION NUMBER(S) 

 
Signifor 10 mg powder and solvent for suspension for injection 
EU/1/12/753/018 
 
Signifor 20 mg powder and solvent for suspension for injection 
EU/1/12/753/013 
 



35 

Signifor 30 mg powder and solvent for suspension for injection 
EU/1/12/753/019 
 
Signifor 40 mg powder and solvent for suspension for injection 
EU/1/12/753/014-015 
 
Signifor 60 mg powder and solvent for suspension for injection 
EU/1/12/753/016-017 
 
 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
Date of first authorisation: 24 April 2012 
Date of latest renewal: 18 November 2016 
 
 
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 
  



36 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX II 

 
A. MANUFACTURER(S) 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 

 
 



37 

A. MANUFACTURER(S) RESPONSIBLE FOR BATCH RELEASE 

 
Name and address of the manufacturer responsible for batch release 
Novartis Pharma GmbH 
Roonstrasse 25 
D-90429 Nuremberg 
Germany 
 
Recordati Rare Diseases 
Immeuble Le Wilson 
70 avenue du Général de Gaulle 
92800 Puteaux 
France 
 
Recordati Rare Diseases 
Eco River Parc 
30 rue des Peupliers 
92000 Nanterre 
France 
 
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 medical prescription. 
 
 
C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING 

AUTHORISATION 

 
 Periodic Safety Update Reports 
 
The requirements for submission of periodic safety update reports 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. 
 
 
D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND 

EFFECTIVE USE OF THE MEDICINAL PRODUCT 

 
 Risk Management Plan (RMP) 
 
The 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. 

 
  



38 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX III 

 
LABELLING AND PACKAGE LEAFLET 

 
  



39 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

A. LABELLING 
  



40 

 
PARTICULARS TO APPEAR ON THE OUTER PACKAGING 

 
CARTON 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Signifor 0.3 mg solution for injection 
pasireotide 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 

 
1 ml solution for injection contains 0.3 mg pasireotide (as pasireotide diaspartate). 
 
 
3. LIST OF EXCIPIENTS 
 
Also contains: Mannitol, tartaric acid, sodium hydroxide, water for injections. See package leaflet for 
further information. 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
Solution for injection 
 
6 ampoules 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Single use. 
Read the package leaflet before use. 
Subcutaneous 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 
 
 
9. SPECIAL STORAGE CONDITIONS 
 
Store in the original package in order to protect from light. 
 



41 

 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 

APPROPRIATE 

 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 

 

Recordati Rare Diseases 
Immeuble Le Wilson 
70 avenue du Général de Gaulle 
92800 Puteaux 
France 
 
 
12. MARKETING AUTHORISATION NUMBER(S) 

 
EU/1/12/753/001 6 ampoules 

 
 
13. BATCH NUMBER 

 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE 
 

 
16. INFORMATION IN BRAILLE 

 
Signifor 0.3 mg 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 

 
2D barcode carrying the unique identifier included. 
 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 

 
PC: 
SN: 
NN: 
  



42 

 
PARTICULARS TO APPEAR ON THE OUTER PACKAGING 

 
INTERMEDIATE CARTON OF MULTIPACK (WITHOUT BLUE BOX) 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Signifor 0.3 mg solution for injection 
pasireotide 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 

 
1 ml solution for injection contains 0.3 mg pasireotide (as pasireotide diaspartate). 
 
 
3. LIST OF EXCIPIENTS 
 
Also contains: Mannitol, tartaric acid, sodium hydroxide, water for injections. See package leaflet for 
further information. 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
Solution for injection 
 
6 ampoules. Component of a multipack. Not to be sold separately. 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Single use. 
Read the package leaflet before use. 
Subcutaneous 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 
 
 
9. SPECIAL STORAGE CONDITIONS 
 
Store in the original package in order to protect from light. 
 



43 

 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 

APPROPRIATE 

 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 

 

Recordati Rare Diseases 
Immeuble Le Wilson 
70 avenue du Général de Gaulle 
92800 Puteaux 
France 
 
 
12. MARKETING AUTHORISATION NUMBER(S) 

 
EU/1/12/753/002 18 ampoules (3x6) 
EU/1/12/753/003 30 ampoules (5x6) 
EU/1/12/753/004 60 ampoules (10x6) 

 
 
13. BATCH NUMBER 

 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE 
 

 
16. INFORMATION IN BRAILLE 

 
Signifor 0.3 mg 
  



44 

 
PARTICULARS TO APPEAR ON THE OUTER PACKAGING 

 
OUTER CARTON OF MULTIPACK (INCLUDING BLUE BOX) 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Signifor 0.3 mg solution for injection 
pasireotide 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 

 
1 ml solution for injection contains 0.3 mg pasireotide (as pasireotide diaspartate). 
 
 
3. LIST OF EXCIPIENTS 
 
Also contains: Mannitol, tartaric acid, sodium hydroxide, water for injections. See package leaflet for 
further information. 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
Solution for injection 
 
Multipack: 18 (3 packs of 6) ampoules. 
Multipack: 30 (5 packs of 6) ampoules. 
Multipack: 60 (10 packs of 6) ampoules. 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Single use. 
Read the package leaflet before use. 
Subcutaneous 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 
 
 



45 

9. SPECIAL STORAGE CONDITIONS 
 
Store in the original package in order to protect from light. 
 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 

APPROPRIATE 

 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 

 

Recordati Rare Diseases 
Immeuble Le Wilson 
70 avenue du Général de Gaulle 
92800 Puteaux 
France 
 
 
12. MARKETING AUTHORISATION NUMBER(S) 

 
EU/1/12/753/002 18 ampoules (3x6) 
EU/1/12/753/003 30 ampoules (5x6) 
EU/1/12/753/004 60 ampoules (10x6) 

 
 
13. BATCH NUMBER 

 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE 
 

 
16. INFORMATION IN BRAILLE 

 
Signifor 0.3 mg 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 

 
2D barcode carrying the unique identifier included. 
 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 

 
PC: 
SN: 
NN: 
 
  



46 

 
MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS 

 
AMPOULE LABEL 

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

 
Signifor 0.3 mg injection 
pasireotide 
SC 
 
 
2. METHOD OF ADMINISTRATION 

 
 
3. EXPIRY DATE 

 
EXP 
 
 
4. BATCH NUMBER 

 
Lot 
 
 
5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 

 
1 ml 
 
 
6. OTHER 

 
  



47 

 
PARTICULARS TO APPEAR ON THE OUTER PACKAGING 

 
CARTON 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Signifor 0.6 mg solution for injection 
pasireotide 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 

 
1 ml solution for injection contains 0.6 mg pasireotide (as pasireotide diaspartate). 
 
 
3. LIST OF EXCIPIENTS 
 
Also contains: Mannitol, tartaric acid, sodium hydroxide, water for injections. See package leaflet for 
further information. 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
Solution for injection 
 
6 ampoules 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Single use. 
Read the package leaflet before use. 
Subcutaneous 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 
 
 
9. SPECIAL STORAGE CONDITIONS 
 
Store in the original package in order to protect from light. 
 



48 

 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 

APPROPRIATE 

 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 

 

Recordati Rare Diseases 
Immeuble Le Wilson 
70 avenue du Général de Gaulle 
92800 Puteaux 
France 
 
 
12. MARKETING AUTHORISATION NUMBER(S) 

 
EU/1/12/753/005 6 ampoules 

 
 
13. BATCH NUMBER 

 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE 
 

 
16. INFORMATION IN BRAILLE 

 
Signifor 0.6 mg 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 

 
2D barcode carrying the unique identifier included. 
 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 

 
PC: 
SN: 
NN: 
  



49 

 
PARTICULARS TO APPEAR ON THE OUTER PACKAGING 

 
INTERMEDIATE CARTON OF MULTIPACK (WITHOUT BLUE BOX) 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Signifor 0.6 mg solution for injection 
pasireotide 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 

 
1 ml solution for injection contains 0.6 mg pasireotide (as pasireotide diaspartate). 
 
 
3. LIST OF EXCIPIENTS 
 
Also contains: Mannitol, tartaric acid, sodium hydroxide, water for injections. See package leaflet for 
further information. 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
Solution for injection 
 
6 ampoules. Component of a multipack. Not to be sold separately. 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Single use. 
Read the package leaflet before use. 
Subcutaneous 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 
 
 
9. SPECIAL STORAGE CONDITIONS 
 
Store in the original package in order to protect from light. 
 



50 

 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 

APPROPRIATE 

 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 

 

Recordati Rare Diseases 
Immeuble Le Wilson 
70 avenue du Général de Gaulle 
92800 Puteaux 
France 
 
 
12. MARKETING AUTHORISATION NUMBER(S) 

 
EU/1/12/753/006 18 ampoules (3x6) 
EU/1/12/753/007 30 ampoules (5x6) 
EU/1/12/753/008 60 ampoules (10x6) 

 
 
13. BATCH NUMBER 

 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE 
 

 
16. INFORMATION IN BRAILLE 

 
Signifor 0.6 mg 
  



51 

 
PARTICULARS TO APPEAR ON THE OUTER PACKAGING 

 
OUTER CARTON OF MULTIPACK (INCLUDING BLUE BOX) 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Signifor 0.6 mg solution for injection 
pasireotide 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 

 
1 ml solution for injection contains 0.6 mg pasireotide (as pasireotide diaspartate). 
 
 
3. LIST OF EXCIPIENTS 
 
Also contains: Mannitol, tartaric acid, sodium hydroxide, water for injections. See package leaflet for 
further information. 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
Solution for injection 
 
Multipack: 18 (3 packs of 6) ampoules. 
Multipack: 30 (5 packs of 6) ampoules. 
Multipack: 60 (10 packs of 6) ampoules. 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Single use. 
Read the package leaflet before use. 
Subcutaneous 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 
 
 



52 

9. SPECIAL STORAGE CONDITIONS 
 
Store in the original package in order to protect from light. 
 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 

APPROPRIATE 

 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 

 

Recordati Rare Diseases 
Immeuble Le Wilson 
70 avenue du Général de Gaulle 
92800 Puteaux 
France 
 
 
12. MARKETING AUTHORISATION NUMBER(S) 

 
EU/1/12/753/006 18 ampoules (3x6) 
EU/1/12/753/007 30 ampoules (5x6) 
EU/1/12/753/008 60 ampoules (10x6) 

 
 
13. BATCH NUMBER 

 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE 
 

 
16. INFORMATION IN BRAILLE 

 
Signifor 0.6 mg 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 

 
2D barcode carrying the unique identifier included. 
 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 

 
PC: 
SN: 
NN: 
 
  



53 

 
MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS 

 
AMPOULE LABEL 

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

 
Signifor 0.6 mg injection 
pasireotide 
SC 
 
 
2. METHOD OF ADMINISTRATION 

 
 
3. EXPIRY DATE 

 
EXP 
 
 
4. BATCH NUMBER 

 
Lot 
 
 
5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 

 
1 ml 
 
 
6. OTHER 

 
  



54 

 
PARTICULARS TO APPEAR ON THE OUTER PACKAGING 

 
CARTON 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Signifor 0.9 mg solution for injection 
pasireotide 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 

 
1 ml solution for injection contains 0.9 mg pasireotide (as pasireotide diaspartate). 
 
 
3. LIST OF EXCIPIENTS 
 
Also contains: Mannitol, tartaric acid, sodium hydroxide, water for injections. See package leaflet for 
further information. 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
Solution for injection 
 
6 ampoules 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Single use. 
Read the package leaflet before use. 
Subcutaneous 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 
 
 
9. SPECIAL STORAGE CONDITIONS 
 
Store in the original package in order to protect from light. 
 



55 

 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 

APPROPRIATE 

 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 

 

Recordati Rare Diseases 
Immeuble Le Wilson 
70 avenue du Général de Gaulle 
92800 Puteaux 
France 
 
 
12. MARKETING AUTHORISATION NUMBER(S) 

 
EU/1/12/753/009 6 ampoules 

 
 
13. BATCH NUMBER 

 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE 
 

 
16. INFORMATION IN BRAILLE 

 
Signifor 0.9 mg 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 

 
2D barcode carrying the unique identifier included. 
 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 

 
PC: 
SN: 
NN: 
  



56 

 
PARTICULARS TO APPEAR ON THE OUTER PACKAGING 

 
INTERMEDIATE CARTON OF MULTIPACK (WITHOUT BLUE BOX) 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Signifor 0.9 mg solution for injection 
pasireotide 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 

 
1 ml solution for injection contains 0.9 mg pasireotide (as pasireotide diaspartate). 
 
 
3. LIST OF EXCIPIENTS 
 
Also contains: Mannitol, tartaric acid, sodium hydroxide, water for injections. See package leaflet for 
further information. 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
Solution for injection 
 
6 ampoules. Component of a multipack. Not to be sold separately. 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Single use. 
Read the package leaflet before use. 
Subcutaneous 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 
 
 
9. SPECIAL STORAGE CONDITIONS 
 
Store in the original package in order to protect from light. 
 



57 

 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 

APPROPRIATE 

 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 

 

Recordati Rare Diseases 
Immeuble Le Wilson 
70 avenue du Général de Gaulle 
92800 Puteaux 
France 
 
 
12. MARKETING AUTHORISATION NUMBER(S) 

 
EU/1/12/753/010 18 ampoules (3x6) 
EU/1/12/753/011 30 ampoules (5x6) 
EU/1/12/753/012 60 ampoules (10x6) 

 
 
13. BATCH NUMBER 

 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE 
 

 
16. INFORMATION IN BRAILLE 

 
Signifor 0.9 mg 
  



58 

 
PARTICULARS TO APPEAR ON THE OUTER PACKAGING 

 
OUTER CARTON OF MULTIPACK (INCLUDING BLUE BOX) 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Signifor 0.9 mg solution for injection 
pasireotide 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 

 
1 ml solution for injection contains 0.9 mg pasireotide (as pasireotide diaspartate). 
 
 
3. LIST OF EXCIPIENTS 
 
Also contains: Mannitol, tartaric acid, sodium hydroxide, water for injections. See package leaflet for 
further information. 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
Solution for injection 
 
Multipack: 18 (3 packs of 6) ampoules. 
Multipack: 30 (5 packs of 6) ampoules. 
Multipack: 60 (10 packs of 6) ampoules. 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Single use. 
Read the package leaflet before use. 
Subcutaneous 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 
 
 



59 

9. SPECIAL STORAGE CONDITIONS 
 
Store in the original package in order to protect from light. 
 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 

APPROPRIATE 

 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 

 

Recordati Rare Diseases 
Immeuble Le Wilson 
70 avenue du Général de Gaulle 
92800 Puteaux 
France 
 
 
12. MARKETING AUTHORISATION NUMBER(S) 

 
EU/1/12/753/010 18 ampoules (3x6) 
EU/1/12/753/011 30 ampoules (5x6) 
EU/1/12/753/012 60 ampoules (10x6) 

 
 
13. BATCH NUMBER 

 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE 
 

 
16. INFORMATION IN BRAILLE 

 
Signifor 0.9 mg 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 

 
2D barcode carrying the unique identifier included. 
 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 

 
PC: 
SN: 
NN: 
 
  



60 

 
MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS 

 
AMPOULE LABEL 

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

 
Signifor 0.9 mg injection 
pasireotide 
SC 
 
 
2. METHOD OF ADMINISTRATION 

 
 
3. EXPIRY DATE 

 
EXP 
 
 
4. BATCH NUMBER 

 
Lot 
 
 
5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 

 
1 ml 
 
 
6. OTHER 

 
  



61 

 
PARTICULARS TO APPEAR ON THE OUTER PACKAGING 

 
CARTON OF UNIT PACK 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Signifor 10 mg powder and solvent for suspension for injection 
pasireotide 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 

 
One vial contains 10 mg pasireotide (as pasireotide pamoate). 
 
 
3. LIST OF EXCIPIENTS 
 
Also contains: 
Powder: poly(D,L-lactide-co-glycolide) (50-60:40-50), poly(D,L-lactide-co-glycolide) (50:50). 
Solvent: carmellose sodium, mannitol, poloxamer 188, water for injections. 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
Powder and solvent for suspension for injection 
 
1 vial of powder 
1 pre-filled syringe with 2 ml solvent 
1 safety-engineered needle 
1 vial adapter 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Single use. 
Read the package leaflet before use. 
Intramuscular 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 
 
 



62 

9. SPECIAL STORAGE CONDITIONS 
 
Store in a refrigerator. Do not freeze. 
 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 

APPROPRIATE 

 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 

 

Recordati Rare Diseases 
Immeuble Le Wilson 
70 avenue du Général de Gaulle 
92800 Puteaux 
France 
 
 
12. MARKETING AUTHORISATION NUMBER(S) 

 
EU/1/12/753/018 
 
 
13. BATCH NUMBER 

 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE 
 

 
16. INFORMATION IN BRAILLE 

 
Signifor 10 mg 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 

 
2D barcode carrying the unique identifier included. 
 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 

 
PC: 
SN: 
NN: 
 
 
  



63 

 
MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS 

 
VIAL LABEL 
 
 
1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION 
 
Signifor 10 mg powder for injection 
pasireotide 
IM 
 
 
2. METHOD OF ADMINISTRATION 

 
 
3. EXPIRY DATE 
 
EXP 
 
 
4. BATCH NUMBER 
 
Lot 
 
 
5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 
 
10 mg 
 
 
6. OTHER 
 
 
  



64 

 
MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS 

 
PRE-FILLED SYRINGE LABEL 
 
 
1. NAME OF THE MEDICINAL PRODUCT AND ROUTE (S) OF ADMINISTRATION 
 
Solvent for Signifor 
 
 
2. METHOD OF ADMINISTRATION 

 
 
3. EXPIRY DATE 
 
EXP 
 
 
4. BATCH NUMBER 
 
Lot 
 
 
5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 
 
2 ml 
 
 
6. OTHER 
 
  



65 

 
PARTICULARS TO APPEAR ON THE OUTER PACKAGING 

 
CARTON OF UNIT PACK 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Signifor 20 mg powder and solvent for suspension for injection 
pasireotide 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 

 
One vial contains 20 mg pasireotide (as pasireotide pamoate). 
 
 
3. LIST OF EXCIPIENTS 
 
Also contains: 
Powder: poly(D,L-lactide-co-glycolide) (50-60:40-50), poly(D,L-lactide-co-glycolide) (50:50). 
Solvent: carmellose sodium, mannitol, poloxamer 188, water for injections. 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
Powder and solvent for suspension for injection 
 
1 vial of powder 
1 pre-filled syringe with 2 ml solvent 
1 safety-engineered needle 
1 vial adapter 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Single use. 
Read the package leaflet before use. 
Intramuscular 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 
 
 



66 

9. SPECIAL STORAGE CONDITIONS 
 
Store in a refrigerator. Do not freeze. 
 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 

APPROPRIATE 

 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 

 

Recordati Rare Diseases 
Immeuble Le Wilson 
70 avenue du Général de Gaulle 
92800 Puteaux 
France 
 
 
12. MARKETING AUTHORISATION NUMBER(S) 

 
EU/1/12/753/013 
 
 
13. BATCH NUMBER 

 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE 
 

 
16. INFORMATION IN BRAILLE 

 
Signifor 20 mg 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 

 
2D barcode carrying the unique identifier included. 
 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 

 
PC: 
SN: 
NN: 
 
 
  



67 

 
MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS 

 
VIAL LABEL 
 
 
1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION 
 
Signifor 20 mg powder for injection 
pasireotide 
IM 
 
 
2. METHOD OF ADMINISTRATION 

 
 
3. EXPIRY DATE 
 
EXP 
 
 
4. BATCH NUMBER 
 
Lot 
 
 
5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 
 
20 mg 
 
 
6. OTHER 
 
 
  



68 

 
MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS 

 
PRE-FILLED SYRINGE LABEL 
 
 
1. NAME OF THE MEDICINAL PRODUCT AND ROUTE (S) OF ADMINISTRATION 
 
Solvent for Signifor 
 
 
2. METHOD OF ADMINISTRATION 

 
 
3. EXPIRY DATE 
 
EXP 
 
 
4. BATCH NUMBER 
 
Lot 
 
 
5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 
 
2 ml 
 
 
6. OTHER 
 
  



69 

 
PARTICULARS TO APPEAR ON THE OUTER PACKAGING 

 
CARTON OF UNIT PACK 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Signifor 30 mg powder and solvent for suspension for injection 
pasireotide 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 

 
One vial contains 30 mg pasireotide (as pasireotide pamoate). 
 
 
3. LIST OF EXCIPIENTS 
 
Also contains: 
Powder: poly(D,L-lactide-co-glycolide) (50-60:40-50), poly(D,L-lactide-co-glycolide) (50:50). 
Solvent: carmellose sodium, mannitol, poloxamer 188, water for injections. 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
Powder and solvent for suspension for injection 
 
1 vial of powder 
1 pre-filled syringe with 2 ml solvent 
1 safety-engineered needle 
1 vial adapter 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Single use. 
Read the package leaflet before use. 
Intramuscular 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 in a refrigerator. Do not freeze. 
 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 

APPROPRIATE 

 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 

 

Recordati Rare Diseases 
Immeuble Le Wilson 
70 avenue du Général de Gaulle 
92800 Puteaux 
France 
 
 
12. MARKETING AUTHORISATION NUMBER(S) 

 
EU/1/12/753/019 
 
 
13. BATCH NUMBER 

 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE 
 

 
16. INFORMATION IN BRAILLE 

 
Signifor 30 mg 
 
 
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 SMALL IMMEDIATE PACKAGING UNITS 

 
VIAL LABEL 
 
 
1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION 
 
Signifor 30 mg powder for injection 
pasireotide 
IM 
 
 
2. METHOD OF ADMINISTRATION 

 
 
3. EXPIRY DATE 
 
EXP 
 
 
4. BATCH NUMBER 
 
Lot 
 
 
5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 
 
30 mg 
 
 
6. OTHER 
 
 
  



72 

 
MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS 

 
PRE-FILLED SYRINGE LABEL 
 
 
1. NAME OF THE MEDICINAL PRODUCT AND ROUTE (S) OF ADMINISTRATION 
 
Solvent for Signifor 
 
 
2. METHOD OF ADMINISTRATION 

 
 
3. EXPIRY DATE 
 
EXP 
 
 
4. BATCH NUMBER 
 
Lot 
 
 
5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 
 
2 ml 
 
 
6. OTHER 
 
  



73 

 
PARTICULARS TO APPEAR ON THE OUTER PACKAGING 

 
CARTON OF UNIT PACK 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Signifor 40 mg powder and solvent for suspension for injection 
pasireotide 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 

 
One vial contains 40 mg pasireotide (as pasireotide pamoate). 
 
 
3. LIST OF EXCIPIENTS 
 
Also contains: 
Powder: poly(D,L-lactide-co-glycolide) (50-60:40-50), poly(D,L-lactide-co-glycolide) (50:50). 
Solvent: carmellose sodium, mannitol, poloxamer 188, water for injections. 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
Powder and solvent for suspension for injection 
 
1 vial of powder 
1 pre-filled syringe with 2 ml solvent 
1 safety-engineered needle 
1 vial adapter 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Single use. 
Read the package leaflet before use. 
Intramuscular 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 
 
 



74 

9. SPECIAL STORAGE CONDITIONS 
 
Store in a refrigerator. Do not freeze. 
 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 

APPROPRIATE 

 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 

 

Recordati Rare Diseases 
Immeuble Le Wilson 
70 avenue du Général de Gaulle 
92800 Puteaux 
France 
 
 
12. MARKETING AUTHORISATION NUMBER(S) 

 
EU/1/12/753/014 
 
 
13. BATCH NUMBER 

 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE 
 

 
16. INFORMATION IN BRAILLE 

 
Signifor 40 mg 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 

 
2D barcode carrying the unique identifier included. 
 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 

 
PC: 
SN: 
NN: 
  



75 

 
PARTICULARS TO APPEAR ON THE OUTER PACKAGING 

 
INTERMEDIATE CARTON OF MULTIPACK (WITHOUT BLUE BOX) 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Signifor 40 mg powder and solvent for suspension for injection 
pasireotide 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 

 
One vial contains 40 mg pasireotide (as pasireotide pamoate). 
 
 
3. LIST OF EXCIPIENTS 
 
Also contains: 
Powder: poly(D,L-lactide-co-glycolide) (50-60:40-50), poly(D,L-lactide-co-glycolide) (50:50). 
Solvent: carmellose sodium, mannitol, poloxamer 188, water for injections. 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
Powder and solvent for suspension for injection 
 
1 vial of powder + 1 pre-filled syringe with 2 ml solvent+ 1 safety-engineered needle + 1 vial adapter. 
Component of a multipack. Not to be sold separately. 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Single use. 
Read the package leaflet before use. 
Intramuscular 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 
 
 



76 

9. SPECIAL STORAGE CONDITIONS 
 
Store in a refrigerator. Do not freeze. 
 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 

APPROPRIATE 

 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 

 

Recordati Rare Diseases 
Immeuble Le Wilson 
70 avenue du Général de Gaulle 
92800 Puteaux 
France 
 
 
12. MARKETING AUTHORISATION NUMBER(S) 

 
EU/1/12/753/015 Multipack containing 3 intermediate cartons 

 
 
13. BATCH NUMBER 

 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE 
 

 
16. INFORMATION IN BRAILLE 

 
Signifor 40 mg 
  



77 

 
PARTICULARS TO APPEAR ON THE OUTER PACKAGING 

 
OUTER CARTON OF MULTIPACK (INCLUDING BLUE BOX) 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Signifor 40 mg powder and solvent for suspension for injection 
pasireotide 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 

 
One vial contains 40 mg pasireotide (as pasireotide pamoate). 
 
 
3. LIST OF EXCIPIENTS 
 
Also contains: 
Powder: poly(D,L-lactide-co-glycolide) (50-60:40-50), poly(D,L-lactide-co-glycolide) (50:50). 
Solvent: carmellose sodium, mannitol, poloxamer 188, water for injections. 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
Powder and solvent for suspension for injection 
 
Multipack: 3 packs of 1 injection kit 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Single use. 
Read the package leaflet before use. 
Intramuscular 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 
 
 



78 

9. SPECIAL STORAGE CONDITIONS 
 
Store in a refrigerator. Do not freeze. 
 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 

APPROPRIATE 

 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 

 

Recordati Rare Diseases 
Immeuble Le Wilson 
70 avenue du Général de Gaulle 
92800 Puteaux 
France 
 
 
12. MARKETING AUTHORISATION NUMBER(S) 

 
EU/1/12/753/015 Multipack containing 3 intermediate cartons 

 
 
13. BATCH NUMBER 

 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE 
 

 
16. INFORMATION IN BRAILLE 

 
Signifor 40 mg 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 

 
2D barcode carrying the unique identifier included. 
 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 

 
PC: 
SN: 
NN: 
 
  



79 

 
MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS 

 
VIAL LABEL 
 
 
1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION 
 
Signifor 40 mg powder for injection 
pasireotide 
IM 
 
 
2. METHOD OF ADMINISTRATION 

 
 
3. EXPIRY DATE 
 
EXP 
 
 
4. BATCH NUMBER 
 
Lot 
 
 
5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 
 
40 mg 
 
 
6. OTHER 
 
 
  



80 

 
MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS 

 
PRE-FILLED SYRINGE LABEL 
 
 
1. NAME OF THE MEDICINAL PRODUCT AND ROUTE (S) OF ADMINISTRATION 
 
Solvent for Signifor 
 
 
2. METHOD OF ADMINISTRATION 

 
 
3. EXPIRY DATE 
 
EXP 
 
 
4. BATCH NUMBER 
 
Lot 
 
 
5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 
 
2 ml 
 
 
6. OTHER 
 
  



81 

 
PARTICULARS TO APPEAR ON THE OUTER PACKAGING 

 
CARTON OF UNIT PACK 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Signifor 60 mg powder and solvent for suspension for injection 
pasireotide 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 

 
One vial contains 60 mg pasireotide (as pasireotide pamoate). 
 
 
3. LIST OF EXCIPIENTS 
 
Also contains: 
Powder: poly(D,L-lactide-co-glycolide) (50-60:40-50), poly(D,L-lactide-co-glycolide) (50:50). 
Solvent: carmellose sodium, mannitol, poloxamer 188, water for injections. 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
Powder and solvent for suspension for injection 
 
1 vial of powder 
1 pre-filled syringe with 2 ml solvent 
1 safety-engineered needle 
1 vial adapter 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Single use. 
Read the package leaflet before use. 
Intramuscular 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 
 
 



82 

9. SPECIAL STORAGE CONDITIONS 
 
Store in a refrigerator. Do not freeze. 
 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 

APPROPRIATE 

 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 

 

Recordati Rare Diseases 
Immeuble Le Wilson 
70 avenue du Général de Gaulle 
92800 Puteaux 
France 
 
 
12. MARKETING AUTHORISATION NUMBER(S) 

 
EU/1/12/753/016 
 
 
13. BATCH NUMBER 

 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE 
 

 
16. INFORMATION IN BRAILLE 

 
Signifor 60 mg 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 

 
2D barcode carrying the unique identifier included. 
 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 

 
PC: 
SN: 
NN: 
  



83 

 
PARTICULARS TO APPEAR ON THE OUTER PACKAGING 

 
INTERMEDIATE CARTON OF MULTIPACK (WITHOUT BLUE BOX) 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Signifor 60 mg powder and solvent for suspension for injection 
pasireotide 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 

 
One vial contains 60 mg pasireotide (as pasireotide pamoate). 
 
 
3. LIST OF EXCIPIENTS 
 
Also contains: 
Powder: poly(D,L-lactide-co-glycolide) (50-60:40-50), poly(D,L-lactide-co-glycolide) (50:50). 
Solvent: carmellose sodium, mannitol, poloxamer 188, water for injections. 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
Powder and solvent for suspension for injection 
 
1 vial of powder + 1 pre-filled syringe with 2 ml solvent+ 1 safety-engineered needle + 1 vial adapter. 
Component of a multipack. Not to be sold separately. 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Single use. 
Read the package leaflet before use. 
Intramuscular 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 
 
 



84 

9. SPECIAL STORAGE CONDITIONS 
 
Store in a refrigerator. Do not freeze. 
 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 

APPROPRIATE 

 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 

 

Recordati Rare Diseases 
Immeuble Le Wilson 
70 avenue du Général de Gaulle 
92800 Puteaux 
France 
 
 
12. MARKETING AUTHORISATION NUMBER(S) 

 
EU/1/12/753/017 Multipack containing 3 intermediate cartons 

 
 
13. BATCH NUMBER 

 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE 
 

 
16. INFORMATION IN BRAILLE 

 
Signifor 60 mg 
  



85 

 
PARTICULARS TO APPEAR ON THE OUTER PACKAGING 

 
OUTER CARTON OF MULTIPACK (INCLUDING BLUE BOX) 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Signifor 60 mg powder and solvent for suspension for injection 
pasireotide 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 

 
One vial contains 60 mg pasireotide (as pasireotide pamoate). 
 
 
3. LIST OF EXCIPIENTS 
 
Also contains: 
Powder: poly(D,L-lactide-co-glycolide) (50-60:40-50), poly(D,L-lactide-co-glycolide) (50:50). 
Solvent: carmellose sodium, mannitol, poloxamer 188, water for injections. 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
Powder and solvent for suspension for injection 
 
Multipack: 3 packs of 1 injection kit 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Single use. 
Read the package leaflet before use. 
Intramuscular 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 
 
 



86 

9. SPECIAL STORAGE CONDITIONS 
 
Store in a refrigerator. Do not freeze. 
 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 

APPROPRIATE 

 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 

 

Recordati Rare Diseases 
Immeuble Le Wilson 
70 avenue du Général de Gaulle 
92800 Puteaux 
France 
 
 
12. MARKETING AUTHORISATION NUMBER(S) 

 
EU/1/12/753/017 Multipack containing 3 intermediate cartons 

 
 
13. BATCH NUMBER 

 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE 
 

 
16. INFORMATION IN BRAILLE 

 
Signifor 60 mg 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 

 
2D barcode carrying the unique identifier included. 
 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 

 
PC: 
SN: 
NN: 
  



87 

 
MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS 

 
VIAL LABEL 
 
 
1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION 
 
Signifor 60 mg powder for injection 
pasireotide 
IM 
 
 
2. METHOD OF ADMINISTRATION 

 
 
3. EXPIRY DATE 
 
EXP 
 
 
4. BATCH NUMBER 
 
Lot 
 
 
5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 
 
60 mg 
 
 
6. OTHER 
 
 
  



88 

 
MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS 

 
PRE-FILLED SYRINGE LABEL 
 
 
1. NAME OF THE MEDICINAL PRODUCT AND ROUTE (S) OF ADMINISTRATION 
 
Solvent for Signifor 
 
 
2. METHOD OF ADMINISTRATION 

 
 
3. EXPIRY DATE 
 
EXP 
 
 
4. BATCH NUMBER 
 
Lot 
 
 
5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 
 
2 ml 
 
 
6. OTHER 
 
  



89 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

B. PACKAGE LEAFLET 



90 

Package leaflet: Information for the user 

 
Signifor 0.3 mg solution for injection 

Signifor 0.6 mg solution for injection 

Signifor 0.9 mg solution for injection 

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

 
Signifor is a medicine that contains the active substance pasireotide. It is used to treat Cushing’s 
disease in adult patients for whom surgery is not an option or for whom surgery has failed. 
 
Cushing’s disease is caused by an enlargement in the pituitary gland (a gland at the base of the brain) 
called a pituitary adenoma. This leads the body to over-produce a hormone called adrenocorticotropic 
hormone (ACTH), which in turn results in over-production of another hormone called cortisol. 
 
The human body naturally produces a substance called somatostatin, which blocks the production of 
certain hormones, including ACTH. Pasireotide works in a very similar way to somatostatin. Signifor 
is thus able to block the production of ACTH, helping to control the over-production of cortisol and 
improve the symptoms of Cushing’s disease. 
 
If you have any questions about how Signifor works or why this medicine has been prescribed for you, 
ask your doctor. 
 
 
2. What you need to know before you use Signifor 

 
Do not use Signifor 

- if you are allergic to pasireotide or any of the other ingredients of this medicine (listed in 
section 6). 

- if you have severe liver problems. 
 
Warnings and precautions 

Talk to your doctor before using Signifor if you currently have or have ever had: 
- problems with your blood sugar levels, whether too high (as in hyperglycaemia/diabetes) or too 

low (hypoglycaemia); 
- heart problems such as a recent heart attack, congestive heart failure (a type of heart disease 

where the heart cannot pump enough blood around the body) or sudden and oppressive chest 
pain (usually felt as pressure, heaviness, tightening, squeezing or aching across the chest); 



91 

- a heart rhythm disorder, such as an irregular heartbeat or an abnormal electrical signal called 
“prolongation of the QT interval”, or “QT prolongation”; 

- low levels of potassium or magnesium in your blood; 
- gallstones. 
 
During your treatment with Signifor 

- Signifor controls over-production of cortisol. The control may be too strong and you may 
experience signs or symptoms associated with a lack of cortisol, such as extreme weakness, 
tiredness, weight loss, nausea, vomiting or low blood pressure. If this happens, tell your doctor 
immediately. 

- Signifor may cause your blood sugar to increase. Your doctor may want to monitor your blood 
sugar and start treatment with or adjust your antidiabetic medicine. 

- Signifor may lower your heart rate. Your doctor may wish to monitor your heart rate using a 
machine that measures electrical activity of the heart (an “ECG”, or electrocardiogram). If you 
are using medicine to treat a heart condition, your doctor may also need to adjust its dosage. 

- your doctor may also wish to check your gallbladder, liver enzymes and pituitary hormones 
periodically, since these might all be affected by this medicine. 

 
Children and adolescents 

Do not give this medicine to children and adolescents below 18 years old because no data are available 
in this age group. 
 
Other medicines and Signifor 

Signifor may affect the way some other medicines work. If you are using other medicines at the same 
time as Signifor (including medicines obtained without a prescription), your doctor may need to 
monitor your heart more carefully or change the dose of Signifor or the other medicines. Tell your 
doctor or pharmacist if you are using, have recently used or might use any other medicines. Especially, 
tell your doctor if you are using: 
- medicines to treat irregular heartbeat, such as medicines containing disopyramide, 

procainamide, quinidine, sotalol, dofetilide, ibutilide, amiodarone or dronedarone; 
- medicines to treat bacterial infections (by mouth: clarithromycin, moxifloxacin; via injection: 

erythromycin, pentamidine); 
- medicines to treat fungal infections (ketoconazole, except in shampoo); 
- medicines to treat certain psychiatric disorders (chlorpromazine, thioridazine, fluphenazine, 

pimozide, haloperidol, tiapride, amisulpride, sertindole, methadone); 
- medicines to treat hay fever and other allergies (terfenadine, astemizole, mizolastine); 
- medicines used in the prevention or treatment of malaria (chloroquine, halofantrine, 

lumefantrine); 
- medicines to control blood pressure such as: 

 beta blockers (metoprolol, carteolol, propranolol, sotalol) 
 calcium channel blockers (bepridil, verapamil, diltiazem) 
 cholinesterase inhibitors (rivastigmine, physostigmine); 

- medicines to control the balance of electrolytes (potassium, magnesium) in your body. 
 
It is particularly important that you mention any of the following medicines: 
- ciclosporin (used in organ transplantation to reduce the activity of the immune system); 
- medicines to treat blood sugar levels that are too high (as in diabetes) or too low 

(hypoglycaemia), such as: 
 insulin; 
 metformin, liraglutide, vildagliptin, nateglinide (antidiabetic medicines). 

 
Pregnancy, breast-feeding and fertility 

Ask your doctor or pharmacist for advice before using any medicine. 
- You should not use Signifor during pregnancy unless clearly necessary. If you are pregnant or 

think that you may be, it is important to tell your doctor who will discuss with you whether you 
can use Signifor during your pregnancy. 

- You should not breast-feed while using Signifor. It is not known whether Signifor passes into 



92 

breast milk. 
- If you are a sexually active woman, you should use an effective method of contraception during 

treatment. Ask your doctor about the need for contraception before taking this medicine. 
 
Driving and using machines 

Signifor may have a minor effect on the ability to drive and use machines, because some of the side 
effects you may experience while using Signifor, such as dizziness, headache and tiredness, may 
reduce your ability to drive and use machines safely. 
 
Important information about some of the ingredients of Signifor 

Signifor contains less than 1 mmol sodium (23 mg) per dose, which means it is essentially 
“sodium-free”. 
 
 
3. How to use Signifor 

 

Always use this medicine exactly as your doctor has told you. Check with your doctor or pharmacist if 
you are not sure. This medicine comes in an ampoule, i.e. a small glass container. 
 
How much Signifor to use 

The recommended dose is one ampoule of Signifor 0.6 mg twice a day. Using Signifor at the same 
time each day will help you remember when to use your medicine. After you have started treatment, 
your doctor may also decide to increase your dose to one ampoule of Signifor 0.9 mg twice a day. 
 
If side effects occur your doctor may temporarily reduce your dose by 0.3 mg per injection. 
 
If you have liver disease before you start Signifor treatment, your doctor may want to start your 
treatment with a dose of one ampoule of Signifor 0.3 mg twice a day. 
 
Ampoules of Signifor of different strengths (0.3 mg, 0.6 mg and 0.9 mg) are available to match the 
specific dose prescribed by your doctor. 
 
Your doctor will check regularly how you respond to the treatment with Signifor and determine which 
dose is best for you. 
 
How to use Signifor 

Your doctor or nurse will instruct you on how to inject yourself with Signifor. You should also read 
the instructions at the end of this leaflet. If you have any questions, contact your doctor, nurse or 
pharmacist. 
 
Signifor is intended for subcutaneous use. This means that it is injected through a short needle into the 
fatty tissue just under the skin. The thighs and the abdomen are good areas for subcutaneous injection. 
Avoid soreness and skin irritation by choosing a different site from the previous one for each injection. 
You should also avoid injections at sites that are sore or where the skin is irritated. 
 
Do not use Signifor if you notice the solution is not clear or contains particles. The solution should be 
free of visible particles, clear and colourless. 
 
How long to use Signifor 

You should continue using Signifor for as long as your doctor tells you to. 
 
If you use more Signifor than you should 

If you accidentally use more Signifor than your doctor prescribed, immediately contact your doctor, 
nurse or pharmacist. 
 
If you forget to use Signifor 

Do not inject a double dose of Signifor to make up for a forgotten dose. If you forgot to inject a dose 



93 

of Signifor, simply inject the next dose at the scheduled time. 
 
If you stop using Signifor 

If you interrupt your treatment with Signifor your cortisol level may increase again and your 
symptoms may come back. Therefore, do not stop using Signifor unless your doctor tells you to. 
 
If you have any further questions on the use of this medicine, ask your doctor, nurse or pharmacist. 
 
 
4. Possible side effects 
 
Like all medicines, this medicine can cause side effects, although not everybody gets them. 
 
Some side effects may be serious. Tell your doctor straight away if you get any of the following: 

 
Very common (may affect more than 1 in 10 people) 
- Changed level of sugar in the blood. You may experience excessive thirst, high urine output, 

increased appetite with weight loss, tiredness, nausea, vomiting, abdominal pain. 
- Gallstones or associated complications. You may experience fever, chills, yellowing of 

skin/eyes, sudden back pain or pain in the right side of your abdomen. 
- Extreme tiredness. 
 
Common (may affect up to 1 in 10 people) 
- Low cortisol levels. You may experience extreme weakness, tiredness, weight loss, nausea, 

vomiting and low blood pressure. 
- Slow heart beat. 
- Low blood pressure. You may experience dizziness, light headedness and dizziness or fainting 

on standing up. 
- Problems with bile flow (cholestasis). You may experience yellowing of the skin, dark urine, 

pale stools and itching. 
- Inflammation of the gallbladder (cholecystitis). 
 
Other side effects of Signifor may include: 

 
Very common (may affect more than 1 in 10 people) 
- Diarrhoea 
- Nausea 
- Stomach pain 
- Pain at the injection site 
 
Common (may affect up to 1 in 10 people) 
- Prolonged QT interval (an abnormal electrical signal in your heart that can be seen in tests) 
- Loss of appetite 
- Vomiting 
- Headache 
- Dizziness 
- Hair loss 
- Itching (pruritus) 
- Muscle pain (myalgia) 
- Joint pain (arthralgia) 
- Abnormal results of liver function tests 
- Abnormal results of pancreatic function tests 
- Abnormal blood coagulation properties 
 
Uncommon (may affect up to 1 in 100 people) 
- Low level of red blood cells (anaemia) 
 



94 

Not known (frequency cannot be estimated from the available data) 
- Increased levels of ketone bodies (a group of substances produced in the liver) in your urine or 

blood (diabetic ketoacidosis) as a complication of an increased level of sugar in your blood. 
You may experience fruity scented breath, trouble breathing and confusion. 

 
Reporting of side effects 

If you get any side effects, talk to your doctor, nurse 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 Signifor 

 
- Keep this medicine out of the sight and reach of children. 
- Do not use this medicine after the expiry date which is stated on the ampoule label and carton 

after “EXP”. The expiry date refers to the last day of that month. 
- Store in the original package in order to protect from light. 
- Do not throw away any medicines via wastewater or household waste. Ask your pharmacist 

how to throw away medicines you no longer use. These measures will help protect the 
environment. 

 
 
6. Contents of the pack and other information 

 
What Signifor contains 

- The active substance is pasireotide. 
Signifor 0.3 mg: One ampoule of 1 ml solution contains 0.3 mg pasireotide (as pasireotide 
diaspartate). 
Signifor 0.6 mg: One ampoule of 1 ml solution contains 0.6 mg pasireotide (as pasireotide 
diaspartate). 
Signifor 0.9 mg: One ampoule of 1 ml solution contains 0.9 mg pasireotide (as pasireotide 
diaspartate). 

- The other ingredients are mannitol, tartaric acid, sodium hydroxide and water for injections. 
 
What Signifor looks like and contents of the pack 

Signifor solution for injection is a clear, colourless solution in an ampoule. Each ampoule contains 
1 ml of solution for injection. 
 
Signifor is available in packs containing 6 ampoules or in multipacks containing 18 (3 packs of 6), 
30 (5 packs of 6) or 60 (10 packs of 6) ampoules. 
 
Not all strengths or pack sizes may be marketed in your country. 
 
Marketing Authorisation Holder 

Recordati Rare Diseases 
Immeuble Le Wilson 
70 avenue du Général de Gaulle 
92800 Puteaux 
France 
 
Manufacturer 

Novartis Pharma GmbH 
Roonstrasse 25 
D-90429 Nuremberg 
Germany 
 

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


95 

Recordati Rare Diseases 
Immeuble Le Wilson 
70 avenue du Général de Gaulle 
92800 Puteaux 
France 
 
Recordati Rare Diseases 
Eco River Parc 
30 rue des Peupliers 
92000 Nanterre 
France 
 
 
For any information about this medicine, please contact the local representative of the Marketing 
Authorisation Holder: 
België/Belgique/Belgien 
Recordati 
Tél/Tel: +32 2 46101 36 
 

Lietuva 
Recordati AB. 
Tel: + 46 8 545 80 230 
Švedija 
 

България 
Recordati Rare Diseases 
Teл.: +33 (0)1 47 73 64 58 
Франция 
 

Luxembourg/Luxemburg 
Recordati 
Tél/Tel: +32 2 46101 36 
Belgique/Belgien 

Česká republika 
Recordati Rare Diseases 
Tel: +33 (0)1 47 73 64 58 
Francie 
 

Magyarország 
Recordati Rare Diseases 
Tel: +33 (0)1 47 73 64 58 
Franciaország 

Danmark 
Recordati AB. 
Tlf: + 46 8 545 80 230 
Sverige 
 

Malta 

Recordati Rare Diseases 
Tel: +33 1 47 73 64 58 
Franza 

Deutschland 
Recordati Rare Diseases Germany GmbH 
Tel: +49 731 140 554 0 
 

Nederland 
Recordati 
Tel: +32 2 46101 36 
België 
 

Eesti 
Recordati AB. 
Tel: + 46 8 545 80 230 
Rootsi 
 

Norge 

Recordati AB. 
Tlf: + 46 8 545 80 230 
Sverige 

Ελλάδα 
Recordati Hellas 
Τηλ: +30 210 6773822 
 

Österreich 
Recordati Rare Diseases Germany GmbH 
Tel: +49 731 140 554 0 
Deutschland 
 

España 
Recordati Rare Diseases Spain S.L.U. 
Tel: + 34 91 659 28 90 
 

Polska 

Recordati Rare Diseases 
Tel: +33 (0)1 47 73 64 58 
Francja 
 



96 

France 
Recordati Rare Diseases 
Tél: +33 (0)1 47 73 64 58 
 

Portugal 
Jaba Recordati S.A. 
Tel: +351 21 432 95 00 

Hrvatska 
Recordati Rare Diseases 
Tél: +33 (0)1 47 73 64 58 
Francuska 
 

România 
Recordati Rare Diseases 
Tel: +33 (0)1 47 73 64 58 
Franţa 

Ireland 
Recordati Rare Diseases 
Tél: +33 (0)1 47 73 64 58 
France 
 

Slovenija 
Recordati Rare Diseases 
Tel: +33 (0)1 47 73 64 58 
Francija 

Ísland 
Recordati AB. 
Simi: + 46 8 545 80 230 
Svíþjóð 
 

Slovenská republika 
Recordati Rare Diseases 
Tel: +33 (0)1 47 73 64 58 
Francúzsko 

Italia 
Recordati Rare Diseases Italy Srl 
Tel: +39 02 487 87 173 
 

Suomi/Finland 
Recordati AB. 
Puh/Tel : +46 8 545 80 230 
Sverige 
 

Κύπρος 
Recordati Rare Diseases 
Τηλ : +33 1 47 73 64 58 
Γαλλία 
 

Sverige 
Recordati AB. 
Tel : +46 8 545 80 230 

Latvija 
Recordati AB. 
Tel: + 46 8 545 80 230 
Zviedrija 

United Kingdom 

Recordati Rare Diseases UK Ltd. 
Tel: +44 (0)1491 414333 

 
 
 
This leaflet was last revised in 
 
Other sources of information 
Detailed information on this medicine is available on the European Medicines Agency website: 
http://www.ema.europa.eu. There are also links to other websites about rare diseases and treatments. 



97 

INSTRUCTIONS FOR USE OF SIGNIFOR SOLUTION FOR INJECTION 

 
This medicine comes in an ampoule, i.e. a small glass container. Signifor should be administered using 
sterile disposable syringes and injection needles. 
 
Your doctor or nurse will have instructed you on how to use Signifor ampoules. However, before 
using the ampoule, please read the following information carefully. If you are not sure about giving 
yourself the injection or if you have any questions, please ask your doctor or nurse for help. 
 
The injection can be prepared using either two different needles to draw up and inject the solution or 
one short fine injection needle for both steps. Based on the local clinical practice, your doctor or nurse 
will tell you which method to use. Please follow their instructions. 
 
Store Signifor ampoules according to the storage conditions listed on the box. 
 
Important safety information 

Caution: Keep the ampoules out of the reach of children. 

 
What do I need 

To give yourself an injection you will need: 
1. One Signifor ampoule 
2. Alcohol wipes or similar 
3. One sterile syringe 
4. One long thick blunt sterile needle for drawing up the solution (your doctor or nurse will tell 

you if this is needed) 
5. One short fine sterile needle 
6. A sharps container or other rigid closed disposal container 
 
The injection site 

The injection site is the place on your body where you are going to give yourself the injection. 
Signifor is intended for subcutaneous use. This means that it is injected through a short needle into the 
fatty tissue just under the skin. The thighs and the abdomen are good areas for subcutaneous injection. 
Avoid soreness and skin irritation by choosing a different site from the previous one for each injection. 
You should also avoid injections at sites that are sore or where the skin is irritated. 
 
Getting started 

When you are ready to give yourself the injection, carefully follow the steps below: 
- Wash your hands thoroughly with soap and water. 
- Use new disposable needles and syringes every time you give yourself an injection. Use 

syringes and needles only once. Never share needles and syringes. 
- Take the ampoule out of the box. 
- Inspect the ampoule. DO NOT USE if it is broken or if the liquid looks cloudy or contains 

particles. In all these cases, return the entire pack to the pharmacy. 
 
To reduce local discomfort, it is recommended that the solution is at room temperature before 
administration. 
 
Ampoules should be opened just prior to administration, and any unused portion discarded. 
 
Check the expiry date and the dose 

Check the expiry date which is stated on the ampoule label (after “EXP”) and check that the ampoule 
contains the dose that your doctor has prescribed. 
 
DO NOT USE if the medicine has expired or if the dose is incorrect. In both these cases, return 

the entire pack to the pharmacy. 

 



98 

How to inject Signifor 

 

 

 
Step 1: 
Signifor solution for injection is filled in a break-off 
ampoule. The coloured dot on the top part marks the 
position of the breaking point on the neck of the 
ampoule. Tap the ampoule with your finger in order to 
make sure there is no liquid in the top part when you 
open the ampoule. 

 

 

 
Step 2: 

Recommended procedure: hold the ampoule in an 
upright position with the coloured dot facing away 
from you. Hold the base of the ampoule in one hand. 
Keeping your thumbs together above and below the 
neck, break off the top of the ampoule at the breaking 
point. Once the ampoule is open, put it upright on a 
clean, flat surface. 

 

 

 
Step 3: 
Take the sterile syringe and attach the needle to it. If 
you have been told to use two needles, you should use 
the long thick blunt one for this step. 
 
Before you proceed to step 4, clean the injection site 
with an alcohol wipe. 

 



99 

 

 
Step 4: 
Remove the cover from the needle. Put the needle into 
the ampoule and pull the plunger to draw up the entire 
contents of the ampoule into the syringe. 
If you have been told to use two needles, you should 
now replace the long needle with the short one. 

 

 

 
Step 5: 
Hold the syringe in one hand between two fingers with 
your thumb at the bottom of the plunger. Tap the 
syringe with your fingers to get rid of air bubbles. 
Make sure there is no air bubble in the syringe by 
pressing the plunger until the first drop appears on the 
tip of the needle. 
Do not let the needle touch anything. You are now 
ready to inject. 

 

 

 
Step 6: 
Gently pinch the skin at the injection site and, holding 
the needle at an angle of approximately 45 degrees (as 
shown in the picture) insert it into the injection site. 
Pull slightly on the plunger to check that a blood 
vessel has not been punctured. If you see blood in the 
syringe, first remove the needle from the skin, then 
replace the short needle with a new one and insert it 
into a different injection site. 

 

 

 
Step 7: 
Always keeping your skin pinched, slowly press the 
plunger down as far as it will go until all the solution 
is injected. Keep the plunger pressed down and hold 
the syringe in place for 5 seconds. 

 



100 

 

 
Step 8: 
Slowly release the skin fold and gently pull the needle 
out. Put the cover back on the needle. 

 

 

 
Step 9: 
Dispose of the used syringe and needle immediately in 
a sharps container or other rigid closed disposal 
container. Any unused product or waste material 
should be disposed of in accordance with local 
requirements. 

 



101 

Package leaflet: Information for the user 

 
Signifor 10 mg powder and solvent for suspension for injection 

Signifor 20 mg powder and solvent for suspension for injection 

Signifor 30 mg powder and solvent for suspension for injection 

Signifor 40 mg powder and solvent for suspension for injection 

Signifor 60 mg powder and solvent for suspension for injection 

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

 
Signifor is a medicine that contains the active substance pasireotide. It is used to treat acromegaly in 
adult patients. It is also used to treat Cushing’s disease in adult patients for whom surgery is not an 
option or for whom surgery has failed. 
 
Acromegaly 
Acromegaly is caused by a type of tumour called a pituitary adenoma which develops in the pituitary 
gland at the base of the brain. The adenoma leads the body to over-produce hormones that control 
growth of tissues, organs and bones, resulting in an increase in the size of bones and tissues, especially 
in the hands and feet. 
 
Signifor reduces the production of these hormones and possibly also the size of the adenoma. As a 
result, it reduces the symptoms of acromegaly, which include headache, increased sweating, numbness 
of the hands and feet, tiredness and joint pain. 
 
Cushing’s disease 
Cushing’s disease is caused by an enlargement in the pituitary gland (a gland at the base of the brain) 
called a pituitary adenoma. This leads the body to over-produce a hormone called adrenocorticotropic 
hormone (ACTH), which in turn results in over-production of another hormone called cortisol. 
 
The human body naturally produces a substance called somatostatin, which blocks the production of 
certain hormones, including ACTH. Pasireotide works in a very similar way to somatostatin. Signifor 
is thus able to block the production of ACTH, helping to control the over production of cortisol and 
improve the symptoms of Cushing’s disease. 
 
If you have any questions about how Signifor works or why this medicine has been prescribed for you, 
ask your doctor. 
 
 



102 

2. What you need to know before you use Signifor 

 
Do not use Signifor 

- if you are allergic to pasireotide or any of the other ingredients of this medicine (listed in 
section 6). 

- if you have severe liver problems. 
 
Warnings and precautions 

Talk to your doctor before using Signifor if you currently have or have ever had: 
- problems with your blood sugar levels, whether too high (as in hyperglycaemia/diabetes) or too 

low (hypoglycaemia); 
- heart problems such as a recent heart attack, congestive heart failure (a type of heart disease 

where the heart cannot pump enough blood around the body) or sudden and oppressive chest 
pain (usually felt as pressure, heaviness, tightening, squeezing or aching across the chest); 

- a heart rhythm disorder, such as an irregular heartbeat or an abnormal electrical signal called 
“prolongation of the QT interval”, or “QT prolongation”; 

- low levels of potassium or magnesium in your blood; 
- gallstones; 
- or if you are taking anticoagulants (medicines used to reduce the clotting ability of the blood), 

your doctor will monitor your coagulation parameters and may adjust your anticoagulant dose. 
 
During your treatment with Signifor: 
- Signifor may cause your blood sugar to increase. Your doctor may want to monitor your blood 

sugar and start treatment with or adjust your antidiabetic medicine. 
- Signifor controls over-production of cortisol. The control may be too strong and you may 

experience signs or symptoms associated with a lack of cortisol, such as extreme weakness, 
tiredness, weight loss, nausea, vomiting or low blood pressure. If this happens, tell your doctor 
immediately. 

- Signifor may lower your heart rate. Your doctor may wish to monitor your heart rate using a 
machine that measures electrical activity of the heart (an “ECG”, or electrocardiogram). If you 
are using medicine to treat a heart condition, your doctor may also need to adjust its dosage. 

- your doctor may also wish to check your gallbladder, liver enzymes and pituitary hormones 
periodically, since these might all be affected by this medicine. 

 
Children and adolescents 

Do not give this medicine to children and adolescents below 18 years old because no data are available 
in this age group. 
 
Other medicines and Signifor 

Signifor may affect the way some other medicines work. If you are using other medicines at the same 
time as Signifor (including medicines obtained without a prescription), your doctor may need to 
monitor your heart more carefully or change the dose of Signifor or the other medicines. Tell your 
doctor or pharmacist if you are using, have recently used or might use any other medicines. Especially, 
tell your doctor if you are using: 
- medicines used in organ transplantation to reduce the activity of the immune system 

(ciclosporin); 
- medicines to treat blood sugar levels that are too high (as in diabetes) or too low 

(hypoglycaemia) such as: 
 insulin 
 metformin, liraglutide, vildagliptin, nateglinide (antidiabetic medicines); 

- medicines to treat irregular heartbeat, such as medicines containing disopyramide, 
procainamide, quinidine, sotalol, dofetilide, ibutilide, amiodarone or dronedarone; 

- medicines to treat bacterial infections (by mouth: clarithromycin, moxifloxacin; via injection: 
erythromycin, pentamidine); 

- medicines to treat fungal infections (ketoconazole, except in shampoo); 
- medicines to treat certain psychiatric disorders (chlorpromazine, thioridazine, fluphenazine, 

pimozide, haloperidol, tiapride, amisulpride, sertindole, methadone); 



103 

- medicines to treat hay fever and other allergies (terfenadine, astemizole, mizolastine); 
- medicines used in the prevention or treatment of malaria (chloroquine, halofantrine, 

lumefantrine); 
- medicines to control blood pressure such as: 

 beta blockers (metoprolol, carteolol, propranolol, sotalol) 
 calcium channel blockers (bepridil, verapamil, diltiazem) 
 cholinesterase inhibitors (rivastigmine, physostigmine); 

- medicines to control the balance of electrolytes (potassium, magnesium) in your body. 
 
Pregnancy, breast-feeding and fertility 

Ask your doctor or pharmacist for advice before using any medicine. 
- You should not use Signifor during pregnancy unless clearly necessary. If you are pregnant, 

think you may be pregnant or are planning to have a baby, ask your doctor for advice before 
taking this medicine. 

- If you are breast-feeding, ask your doctor for advice before taking this medicine, as it is not 
known whether Signifor passes into breast milk. 

- If you are a sexually active woman, you should use an effective method of contraception during 
treatment. Ask your doctor about the need for contraception before taking this medicine. 

 
Driving and using machines 

Signifor may have a minor effect on the ability to drive and use machines, because some of the side 
effects you may experience while using Signifor, such as headache, dizziness and tiredness, may 
reduce your ability to drive and use machines safely. 
 
Important information about some of the ingredients of Signifor 

Signifor contains less than 1 mmol sodium (23 mg) per dose, which means it is essentially 
“sodium-free”. 
 
 
3. How to use Signifor 

 

This medicine will be given to you by a trained healthcare professional. 
 
How much Signifor to use 

 
Acromegaly 
The recommended starting dose of Signifor in acromegaly is 40 mg every 4 weeks. After you have 
started treatment, your doctor may reassess your dose. This may involve measuring the levels of 
growth hormone or other hormones in your blood. Depending on the results and how you are feeling, 
the dose of Signifor given in each injection may need to be reduced or increased. The dose should not 
exceed 60 mg. If you have liver disease before you start Signifor treatment for acromegaly, your 
doctor may want to start your treatment with a dose of 20 mg. 
 
Cushing’s disease 
The usual starting dose of Signifor in Cushing’s disease is 10 mg every 4 weeks. After you have 
started treatment, your doctor may reassess your dose. This may involve measuring the levels of 
cortisol in your blood or urine. Depending on the results and how you are feeling, the dose of Signifor 
given in each injection may need to be reduced or increased. The dose should not exceed 40 mg. 
 
Your doctor will check regularly how you respond to the treatment with Signifor and determine which 
dose is best for you. 
 
How to use Signifor 

Your doctor or nurse will inject Signifor. If you have any questions, contact your doctor, nurse or 
pharmacist. 
 
Signifor is intended for intramuscular use. This means that it is injected through a needle into the 



104 

muscles of your buttocks. 
 
How long to use Signifor 

This is a long-term treatment, possibly lasting for years. Your doctor will regularly monitor your 
condition to check that the treatment is having the desired effect. Your treatment with Signifor should 
continue for as long as your doctor tells you that it is necessary. 
 
If you stop using Signifor 

If you interrupt your treatment with Signifor your symptoms may come back. Therefore, do not stop 
using Signifor unless your doctor tells you to. 
 
If you have any further questions on the use of this medicine, ask your doctor, nurse or pharmacist. 
 
 
4. Possible side effects 
 
Like all medicines, this medicine can cause side effects, although not everybody gets them. 
 
Some side effects may be serious. Tell your doctor straight away if you get any of the following: 

 
Very common (may affect more than 1 in 10 people) 
- High level of sugar in the blood. You may experience excessive thirst, high urine output, 

increased appetite with weight loss, tiredness, nausea, vomiting, abdominal pain 
- Gallstones or associated complications. You may experience fever, chills, yellowing of 

skin/eyes, sudden back pain or pain in the right side of your abdomen. 
 
Common (may affect up to 1 in 10 people) 
- Low cortisol levels. You may experience extreme weakness, tiredness, weight loss, nausea, 

vomiting and low blood pressure. 
- Slow heart beat. 
- Prolonged QT interval (an abnormal electrical signal in your heart that can be seen in tests). 
- Problems with bile flow (cholestasis). You may experience yellowing of the skin, dark urine, 

pale stools, and itching. 
- Inflammation of the gallbladder (cholecystitis). 
 
Other side effects of Signifor may include: 

 
Very common (may affect more than 1 in 10 people) 
- Diarrhoea 
- Nausea 
- Abdominal pain 
- Fatigue 
 
Common (may affect up to 1 in 10 people) 
- Tiredness, fatigue, pale skin (signs of low level of red blood cells) 
- Loss of appetite 
- Headache 
- Bloating 
- Vomiting 
- Dizziness 
- Pain, discomfort, pruritis and swelling at the injection site 
- Change in liver function test results 
- Abnormal blood test results (sign of high level of creatine phosphokinase, glycosylated 

haemoglobin, lipase in the blood) 
- Hair loss 
 



105 

Uncommon (may affect up to 1 in 100 people) 
- Change in pancreatic function blood test results (amylase) 
- Abnormal blood coagulation properties 
 
Not known (frequency cannot be estimated from the available data) 
- Increased levels of ketone bodies (a group of substances produced in the liver) in your urine or 

blood (diabetic ketoacidosis) as a complication of an increased level of sugar in your blood. 
You may experience fruity scented breath, trouble breathing and confusion. 

 
Reporting of side effects 

If you get any side effects, talk to your doctor, nurse 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 Signifor 

 
- Keep this medicine out of the sight and reach of children. 
- Do not use this medicine after the expiry date which is stated on the carton, vial and pre-filled 

syringe after “EXP”. The expiry date refers to the last day of that month. 
- Store in a refrigerator (2°C-8°C). Do not freeze. 
- Do not throw away any medicines via wastewater or household waste. Ask your pharmacist 

how to throw away medicines you no longer use. These measures will help protect the 
environment. 

 
 
6. Contents of the pack and other information 

 
What Signifor contains 

- The active substance is pasireotide. 
Signifor 10 mg: each vial contains 10 mg pasireotide (as pasireotide pamoate). 
Signifor 20 mg: each vial contains 20 mg pasireotide (as pasireotide pamoate). 
Signifor 30 mg: each vial contains 30 mg pasireotide (as pasireotide pamoate). 
Signifor 40 mg: each vial contains 40 mg pasireotide (as pasireotide pamoate). 
Signifor 60 mg: each vial contains 60 mg pasireotide (as pasireotide pamoate). 

- The other ingredients are: 
- In the powder: poly(D,L-lactide-co-glycolide) (50-60:40-50), 

poly(D,L-lactide-co-glycolide) (50:50). 
- In the solvent: carmellose sodium, mannitol, poloxamer 188, water for injections. 

 
What Signifor looks like and contents of the pack 

Signifor powder is a slightly yellowish to yellowish powder in a vial. The solvent is a clear, colourless 
to slightly yellow or slightly brown solution in a pre-filled syringe. 
 
Signifor 10 mg is available in unit packs containing one vial of powder with 10 mg pasireotide and 
one pre filled syringe with 2 ml solvent. 
Signifor 20 mg is available in unit packs containing one vial of powder with 20 mg pasireotide and 
one pre-filled syringe with 2 ml solvent. 
Signifor 30 mg is available in unit packs containing one vial of powder with 30 mg pasireotide and 
one pre filled syringe with 2 ml solvent. 
Signifor 40 mg is available in unit packs containing one vial of powder with 40 mg pasireotide and 
one pre-filled syringe with 2 ml solvent. 
Signifor 60 mg is available in unit packs containing one vial of powder with 60 mg pasireotide and 
one pre-filled syringe with 2 ml solvent. 
 
Each unit pack contains the vial and pre-filled syringe in a sealed blister tray with one vial adapter and 

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


106 

one safety-engineered needle for injection. 
 
Signifor 40 mg and Signifor 60 mg are also available in multipacks containing 3 intermediate packs. 
 
Not all strengths or pack sizes may be marketed in your country. 
 
Marketing Authorisation Holder 

Recordati Rare Diseases 
Immeuble Le Wilson 
70 avenue du Général de Gaulle 
92800 Puteaux 
France 
 
Manufacturer 

Novartis Pharma GmbH 
Roonstrasse 25 
D-90429 Nuremberg 
Germany 
 
Recordati Rare Diseases 
Immeuble Le Wilson 
70 avenue du Général de Gaulle 
92800 Puteaux 
France 
 
Recordati Rare Diseases 
Eco River Parc 
30 rue des Peupliers 
92000 Nanterre 
France 
 
For any information about this medicine, please contact the local representative of the Marketing 
Authorisation Holder: 
België/Belgique/Belgien 
Recordati 
Tél/Tel: +32 2 46101 36 
 

Lietuva 
Recordati AB. 
Tel: + 46 8 545 80 230 
Švedija 
 

България 
Recordati Rare Diseases 
Teл.: +33 (0)1 47 73 64 58 
Франция 
 

Luxembourg/Luxemburg 
Recordati 
Tél/Tel: +32 2 46101 36 
Belgique/Belgien 

Česká republika 
Recordati Rare Diseases 
Tel: +33 (0)1 47 73 64 58 
Francie 
 

Magyarország 
Recordati Rare Diseases 
Tel: +33 (0)1 47 73 64 58 
Franciaország 

Danmark 
Recordati AB. 
Tlf: + 46 8 545 80 230 
Sverige 
 

Malta 

Recordati Rare Diseases 
Tel: +33 1 47 73 64 58 
Franza 



107 

Deutschland 
Recordati Rare Diseases Germany GmbH 
Tel: +49 731 140 554 0 
 

Nederland 
Recordati 
Tel: +32 2 46101 36 
België 
 

Eesti 
Recordati AB. 
Tel: + 46 8 545 80 230 
Rootsi 
 

Norge 

Recordati AB. 
Tlf: + 46 8 545 80 230 
Sverige 

Ελλάδα 
Recordati Hellas 
Τηλ: +30 210 6773822 
 

Österreich 
Recordati Rare Diseases Germany GmbH 
Tel: +49 731 140 554 0 
Deutschland 
 

España 
Recordati Rare Diseases Spain S.L.U. 
Tel: + 34 91 659 28 90 
 

Polska 

Recordati Rare Diseases 
Tel: +33 (0)1 47 73 64 58 
Francja 
 

France 
Recordati Rare Diseases 
Tél: +33 (0)1 47 73 64 58 
 

Portugal 
Jaba Recordati S.A. 
Tel: +351 21 432 95 00 

Hrvatska 
Recordati Rare Diseases 
Tél: +33 (0)1 47 73 64 58 
Francuska 
 

România 
Recordati Rare Diseases 
Tel: +33 (0)1 47 73 64 58 
Franţa 

Ireland 
Recordati Rare Diseases 
Tél: +33 (0)1 47 73 64 58 
France 
 

Slovenija 
Recordati Rare Diseases 
Tel: +33 (0)1 47 73 64 58 
Francija 

Ísland 
Recordati AB. 
Simi: + 46 8 545 80 230 
Svíþjóð 
 

Slovenská republika 
Recordati Rare Diseases 
Tel: +33 (0)1 47 73 64 58 
Francúzsko 

Italia 
Recordati Rare Diseases Italy Srl 
Tel: +39 02 487 87 173 
 

Suomi/Finland 
Recordati AB. 
Puh/Tel : +46 8 545 80 230 
Sverige 
 

Κύπρος 
Recordati Rare Diseases 
Τηλ : +33 1 47 73 64 58 
Γαλλία 
 

Sverige 
Recordati AB. 
Tel : +46 8 545 80 230 

Latvija 
Recordati AB. 
Tel: + 46 8 545 80 230 
Zviedrija 

United Kingdom 

Recordati Rare Diseases UK Ltd. 
Tel: +44 (0)1491 414333 

 
 
 



108 

This leaflet was last revised in 
 
Other sources of information 
Detailed information on this medicine is available on the European Medicines Agency website: 
http://www.ema.europa.eu. There are also links to other websites about rare diseases and treatments. 



109 

The following information is intended for healthcare professionals only: 

 
INSTRUCTIONS FOR USE OF SIGNIFOR POWDER AND SOLVENT FOR SUSPENSION 

FOR INJECTION 

 
FOR DEEP INTRAMUSCULAR INJECTION ONLY. 
 

ATTENTION: 

 
There are two critical steps in the reconstitution of Signifor. Not following them could result in 
failure to deliver the injection appropriately. 

 

 The injection kit must reach room temperature. Remove the injection kit from the fridge 
and let the kit stand at room temperature for a minimum of 30 minutes before reconstitution, 
but do not exceed 24 hours. 

 After adding the solvent, shake the vial moderately for a minimum of 30 seconds until a 
uniform suspension is formed. 

 
 
Included in the injection kit: 
 

 
 
a One vial containing the powder 
b One pre-filled syringe containing the solvent 
c One vial adapter for medicinal product reconstitution 
d One safety injection needle (20G x 1.5″) 
 
Follow the instructions below carefully to ensure proper reconstitution of Signifor powder and solvent 
for suspension for injection before deep intramuscular injection. 
 
Signifor suspension must only be prepared immediately before administration. 
 
Signifor should only be administered by a trained healthcare professional. 



110 

Step 1 

Remove the Signifor injection kit from 
refrigerated storage. 
ATTENTION: It is essential to start the 

reconstitution process only after the injection 

kit reaches room temperature. Let the kit 

stand at room temperature for a minimum of 

30 minutes before reconstitution, but do not 

exceed 24 hours. 

Note: If not used within 24 hours, the injection kit 
can be returned to the fridge. 

 
 

Step 2 

Remove the plastic cap from the vial and clean 
the rubber stopper of the vial with an alcohol 
wipe. 

 

Remove the lid film of the vial adapter 
packaging, but do NOT remove the vial adapter 
from its packaging. 
 
Holding the vial adapter packaging, position the 
vial adapter on top of the vial and push it fully 
down so that it snaps in place, confirmed by a 
“click”. 

 
Remove the packaging from the vial adapter by 
lifting it straight up as shown. 

 

30 
min 



111 

Step 3 

Remove the cap from the syringe pre-filled with 
solvent and screw the syringe onto the vial 
adapter. 

 

Slowly push the plunger all the way down to 
transfer all the solvent in the vial. 

 
Step 4 

ATTENTION: Keep the plunger pressed and 
shake the vial moderately for a minimum of 
30 seconds so that the powder is completely 
suspended. Repeat moderate shaking for 
another 30 seconds if the powder is not 

completely suspended. 

 

Step 5 

Turn syringe and vial upside down, slowly pull 
the plunger back and draw the entire content from 
the vial into the syringe. 

 

Unscrew the syringe from the vial adapter. 

 



112 

Step 6 

Screw the safety injection needle onto the 
syringe. 

 

Pull the protective cover straight off the needle. 
To avoid sedimentation, you may gently shake 
the syringe to maintain a uniform suspension. 
Gently tap the syringe to remove any visible 
bubbles and expel them from the syringe. The 
reconstituted Signifor is now ready for 
immediate administration. 

 
Step 7 

Signifor must be given only by deep 
intramuscular injection. 
Prepare the injection site with an alcohol wipe. 
Insert the needle fully into the left or right gluteus 
at a 90° angle to the skin. 
Slowly pull back the plunger to check that no 
blood vessel has been penetrated (reposition if a 
blood vessel has been penetrated). 
Slowly depress the plunger until the syringe is 
empty. Withdraw the needle from the injection 
site and activate the safety guard (as shown in 
Step 8). 

 

 

Step 8 

Activate the safety guard over the needle, in one 
of the two methods shown: 
- either press the hinged section of the safety 

guard down onto a hard surface (figure A), 
- or push the hinge forward with your finger 

(figure B). 
An audible “click” confirms proper activation. 
 
Dispose of syringe immediately in a sharps 
container. 

 

 

Injection sites 

angle 


	SUMMARY OF PRODUCT CHARACTERISTICS
	A. MANUFACTURER(S) 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
	A. LABELLING
	B. PACKAGE LEAFLET