SIGNIFOR 0.9mg injectible solution medication leaflet

Signifor 0.3 mg solution for injection

Signifor 0.6 mg solution for injection

Signifor 0.9 mg solution for injection

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.

Solution for injection (injection).

Clear, colourless solution.

Treatment of adult patients with Cushing’s disease for whom surgery is not an option or for whomsurgery has failed.

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 toreceive Signifor for as long as benefit is derived. A dose increase to 0.9 mg may be considered basedon the response to the treatment, as long as the 0.6 mg dose is well tolerated by the patient. Patientswho have not responded to Signifor after two months of treatment should be considered fordiscontinuation.

Management of suspected adverse reactions at any time during the treatment may require temporarydose 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. Dosesshould 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 subcutaneouspasireotide formulation. If such a switch should be required, it is recommended to maintain an intervalof at least 28 days between the last intramuscular injection and the first subcutaneous injection, and toinitiate the subcutaneous injections at a dose of 0.6 mg pasireotide twice a day. The patient should bemonitored for response and tolerability and further dose adjustments may be needed.

The safety and efficacy of Signifor in children and adolescents aged 0 to 18 years have not beenestablished. No data are available.

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

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

Dose adjustment is not required in patients with mildly impaired hepatic function (Child Pugh A). Therecommended initial dose for patients with moderate hepatic impairment (Child Pugh B) is 0.3 mgtwice a day (see section 5.2). The maximum recommended dose for these patients is 0.6 mg twice aday. Signifor should not be used in patients with severe hepatic impairment (Child Pugh C) (seesections 4.3 and 4.4).

Signifor is to be administered subcutaneously by self injection. Patients should receive instructionsfrom 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 signsof inflammation or irritation should be avoided. Preferred injection sites for subcutaneous injectionsare the top of the thighs and the abdomen (excluding the navel or waistline).

For further details on handling, see section 6.6.

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

Severe hepatic impairment (Child Pugh C).

Glucose metabolism

Alterations in blood glucose levels have been frequently reported in healthy volunteers and patientstreated with pasireotide. Hyperglycaemia and, less frequently, hypoglycaemia, were observed insubjects participating in clinical studies with pasireotide (see section 4.8).

The degree of hyperglycaemia appeared to be higher in patients with pre-diabetic conditions orestablished diabetes mellitus. During the pivotal study, HbA1c levels increased significantly andstabilised but did not return to baseline values (see section 4.8). More cases of discontinuation and ahigher reporting rate of severe adverse events due to hyperglycaemia were reported in patients treatedwith the dose of 0.9 mg twice daily.

The development of hyperglycaemia appears to be related to decreases in secretion of insulin(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 tostarting treatment with pasireotide. FPG/HbA1c monitoring during treatment should follow establishedguidelines. Self monitoring of blood glucose and/or FPG assessments should be done weekly for thefirst two to three months and periodically thereafter, as clinically appropriate, as well as over the firsttwo to four weeks after any dose increase. In addition, monitoring of FPG 4 weeks and HbA1c3 months after the end of the treatment should be performed.

If hyperglycaemia develops in a patient being treated with Signifor, the initiation or adjustment ofantidiabetic treatment is recommended, following the established treatment guidelines for themanagement of hyperglycaemia. If uncontrolled hyperglycaemia persists despite appropriate medicalmanagement, the dose of Signifor should be reduced or Signifor treatment discontinued (see alsosection 4.5).

There have been post-marketing cases of ketoacidosis with Signifor in patients with and without ahistory of diabetes. Patients who present with signs and symptoms consistent with severe metabolicacidosis should be assessed for ketoacidosis regardless of diabetes history.

In patients with poor glycaemic control (as defined by HbA1c values >8% while receiving anti-diabetictherapy), diabetes management and monitoring should be intensified prior to initiation and duringpasireotide therapy.

Liver tests

Mild transient elevations in aminotransferases are commonly observed in patients treated withpasireotide. Rare cases of concurrent elevations in ALT (alanine aminotransferase) greater than3 x ULN and bilirubin greater than 2 x ULN have also been observed (see section 4.8). Monitoring ofliver function is recommended prior to treatment with pasireotide and after one, two, four, eight andtwelve 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 functionevaluation to confirm the finding. If the finding is confirmed, the patient should be followed withfrequent liver function monitoring until values return to pre-treatment levels. Therapy with pasireotideshould be discontinued if the patient develops jaundice or other signs suggestive of clinicallysignificant 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 concurrentlywith bilirubin elevations greater than 2 x ULN. Following discontinuation of treatment withpasireotide, 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 isrecommended in patients with cardiac disease and/or risk factors for bradycardia, such as history ofclinically significant bradycardia or acute myocardial infarction, high-grade heart block, congestiveheart failure (NYHA Class III or IV), unstable angina, sustained ventricular tachycardia, ventricularfibrillation. Dose adjustment of medicinal products such as beta blockers, calcium channel blockers, ormedicinal 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 volunteerstudies. 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 of201 patients. These episodes were sporadic and of single occurrence with no clinical consequenceobserved. Episodes of torsade de pointes were not observed either in those studies or in clinical studiesin other patient populations.

Pasireotide should be used with caution and the benefit risk carefully weighed in patients who are atsignificant 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 QTprolongation (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 thestart of Signifor therapy, one week after the beginning of the treatment and as clinically indicatedthereafter. 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) secretionin Cushing’s disease patients. Rapid, complete or near-complete suppression of ACTH may lead to adecrease 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 withhypocortisolism (e.g. weakness, fatigue, anorexia, nausea, vomiting, hypotension, hyperkalaemia,hyponatraemia, hypoglycaemia). In the event of documented hypocortisolism, temporary exogenoussteroid (glucocorticoid) replacement therapy and/or dose reduction or interruption of Signifor therapymay be necessary.

Gallbladder and related events

Cholelithiasis (gallstones) is a recognised adverse reaction associated with long-term use ofsomatostatin analogues and has frequently been reported in clinical studies with pasireotide (seesection 4.8). There have been post-marketing cases of cholangitis in patients taking Signifor, which inthe majority of cases was reported as a complication of gallstones. Ultrasonic examination of thegallbladder 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 stonesshould be managed according to clinical practice.

Pituitary hormones

As the pharmacological activity of pasireotide mimics that of somatostatin, inhibition of pituitaryhormones 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, asclinically appropriate.

Effect on female fertility

The therapeutic benefits of a reduction or normalisation of serum cortisol levels in female patientswith Cushing’s disease could potentially restore fertility. Female patients of childbearing potentialshould be advised to use adequate contraception during treatment with Signifor (see section 4.6).

Due to the increase in unbound drug exposure, Signifor should be used with caution in patients withsevere renal impairment or end stage renal disease (see section 5.2).

This medicinal product contains less than 1 mmol (23 mg) sodium per dose, i.e. it is essentially‘sodium-free’.

Anticipated pharmacokinetic interactions resulting in effects on pasireotide

The influence of the P-gp inhibitor verapamil on the pharmacokinetics of subcutaneous pasireotidewas 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 ofpasireotide and ciclosporin may require adjustment of the ciclosporin dose to maintain therapeuticlevels.

Anticipated pharmacodynamic interactions

Medicinal products that prolong the QT interval

Pasireotide should be used with caution in patients who are concomitantly receiving medicinalproducts 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 patientsreceiving 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), certainantiarrhythmics (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 concomitantlywith pasireotide (see also section 4.4).

There is a limited amount of data from the use of pasireotide in pregnant women. Studies in animalshave shown reproductive toxicity (see section 5.3). Pasireotide is not recommended for use duringpregnancy and in women of childbearing potential who are not using contraception (see section 4.4).

It is unknown whether pasireotide is excreted in human milk. Available data in rats have shownexcretion of pasireotide in milk (see section 5.3). Breast-feeding should be discontinued duringtreatment with Signifor.

Studies in rats have shown effects on female reproductive parameters (see section 5.3). The clinicalrelevance of these effects in humans is unknown.

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

A total of 201 Cushing’s disease patients received Signifor in phase II and III studies. The safetyprofile of Signifor was consistent with the somatostatin analogue class, except for the occurrence ofhypocortisolism and degree of hyperglycaemia.

The data described below reflect exposure of 162 Cushing’s disease patients to Signifor in thephase III study. At study entry patients were randomised to receive twice-daily doses of either 0.6 mgor 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 tothe 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 wereobserved in 35.8% of patients and Grade 4 adverse reactions in 2.5% of patients. Grade 3 and 4adverse 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.

Adverse reactions reported up to the cut-off date of the analysis are presented in Table 1. Adversereactions are listed according to MedDRA primary system organ class. Within each system organclass, adverse reactions are ranked by frequency. Within each frequency grouping, adverse reactionsare presented in the order of decreasing seriousness. Frequencies were defined as follows: Verycommon (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); not known (cannot beestimated from the available data).

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

Cushing’s disease patients

System Organ Very common Common Uncommon Not known

Class

Blood and Anaemialymphaticsystem disorders

Endocrine Adrenaldisorders insufficiency

Metabolism and Hyperglycaemia, Decreased Diabeticnutrition diabetes mellitus appetite, type 2 ketoacidosisdisorders diabetes mellitus,glucose toleranceimpaired

Nervous system Headache,disorders dizziness

Cardiac Sinusdisorders bradycardia, QTprolongation

Vascular Hypotensiondisorders

Gastrointestinal Diarrhoea, Vomiting, Steatorrheadisorders abdominal pain, abdominal pain Faecesnausea upper discoloured

Hepatobiliary Cholelithiasis Cholecystitis *,disorders cholestasis

Skin and Alopecia, pruritussubcutaneoustissue disorders

Musculoskeletal Myalgia,and connective arthralgiatissue disorders

General Injection sitedisorders and reaction, fatigueadministrationsite conditions

Investigations Glycosylated Gammahaemoglobin glutamyltransferaincreased se increased,alanineaminotransferaseincreased,aspartateaminotransferaseincreased, lipaseincreased, bloodglucoseincreased, bloodamylaseincreased,prothrombin timeprolonged

* Cholecystitis includes cholecystitis acute

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 inpatients with normal glycaemia (n=62 overall) at study entry (i.e. 5.29% and 5.22% at baseline and6.50% and 6.75% at month 6 for the 0.6 and 0.9 mg twice daily dose groups, respectively) relative topre-diabetic patients (i.e. n=38 overall; 5.77% and 5.71% at baseline and 7.45% and 7.13% atmonth 6) or diabetic patients (i.e. n=54 overall; 6.50% and 6.42% at baseline and 7.95% and 8.30% atmonth 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 HbA1cvalues generally decreased over the 28 days following pasireotide discontinuation but remained abovebaseline values. Long-term follow-up data are not available. Patients with baseline HbA1c ≥7% or whowere taking antidiabetic medicinal products prior to randomisation tended to have higher meanchanges in fasting plasma glucose and HbA1c relative to other patients. Adverse reactions ofhyperglycaemia 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 duringcompassionate use of Signifor.

Monitoring of blood glucose levels in patients treated with Signifor is recommended (see section 4.4).

Gastrointestinal disorders were frequently reported with Signifor. These reactions were usually of lowgrade, required no intervention and improved with continued treatment.

Injection site reactions were reported in 13.6% of patients enrolled in the phase III study in Cushing’sdisease. Injection site reactions were also reported in clinical studies in other populations. Thereactions were most frequently reported as local pain, erythema, haematoma, haemorrhage andpruritus. These reactions resolved spontaneously and required no intervention.

Transient elevations in liver enzymes have been reported with the use of somatostatin analogues andwere also observed in patients receiving pasireotide in clinical studies. The elevations were mostlyasymptomatic, of low grade and reversible with continued treatment. Rare cases of concurrentelevations in ALT greater than 3 x ULN and bilirubin greater than 2 x ULN have been observed. Allcases 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 baselinevalues after discontinuation of treatment.

Monitoring of liver enzymes is recommended before and during treatment with Signifor (seesection 4.4), as clinically appropriate.

Pancreatic enzymes

Asymptomatic elevations in lipase and amylase were observed in patients receiving pasireotide inclinical 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 theassociation between cholelithiasis and acute pancreatitis.

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

Doses up to 2.1 mg twice a day have been used in healthy volunteers, with the adverse reactiondiarrhoea being observed at a high frequency.

In the event of overdose, it is recommended that appropriate supportive treatment be initiated, asdictated by the patient’s clinical status, until resolution of the symptoms.

Pharmacotherapeutic group: Pituitary and hypothalamic hormones and analogues, somatostatin andanalogues, ATC code: H01CB05

Pasireotide is a novel cyclohexapeptide, injectable somatostatin analogue. Like the natural peptidehormones somatostatin-14 and somatostatin-28 (also known as somatotropin release inhibiting factor[SRIF]) and other somatostatin analogues, pasireotide exerts its pharmacological activity via bindingto 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 bindswith high affinity to four of the five hssts.

Table 2 Binding affinities of somatostatin (SRIF-14), pasireotide, octreotide and lanreotideto the five human somatostatin receptor subtypes (hsst1-5)

Compound hsst1 hsst2 hsst3 hsst4 hsst5

Somatostatin 0.93±0.12 0.15±0.02 0.56±0.17 1.5±0.4 0.29±0.04(SRIF-14)

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.

Somatostatin receptors are expressed in many tissues, especially in neuroendocrine tumours in whichhormones are excessively secreted, including ACTH in Cushing’s disease.

In vitro studies have shown that corticotroph tumour cells from Cushing’s disease patients display ahigh expression of hsst5, whereas the other receptor subtypes either are not expressed or are expressedat lower levels. Pasireotide binds and activates four of the five hssts, especially hsst5, in corticotrophsof ACTH-producing adenomas, resulting in inhibition of ACTH secretion.

A phase III, multicentre, randomised study was conducted to evaluate the safety and efficacy ofdifferent dose levels of Signifor over a twelve-month treatment period in Cushing’s disease patientswith persistent or recurrent disease or de novo patients for whom surgery was not indicated or whorefused surgery.

The study enrolled 162 patients with a baseline UFC >1.5 x ULN who were randomised in a 1:1 ratioto receive a subcutaneous dose of either 0.6 mg or 0.9 mg Signifor twice daily. After three months oftreatment, patients with a mean 24-hour UFC ≤2 x ULN and below or equal to their baseline valuecontinued blinded treatment at the randomised dose until month 6. Patients who did not meet thesecriteria were unblinded and the dose was increased by 0.3 mg twice daily. After the initial 6 months inthe study, patients entered an additional 6-month open-label treatment period. If response was notachieved 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 mgtwice 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 normalisationof mean 24-hour UFC levels (UFC ≤ULN) after 6 months of treatment and who did not have a doseincrease (relative to randomised dose) during this period. Secondary end-points included, amongothers, changes from baseline in: 24-hour UFC, plasma ACTH, serum cortisol levels, and clinicalsigns and symptoms of Cushing’s disease. All analyses were conducted based on the randomised dosegroups.

Baseline demographics were well balanced between the two randomised dose groups and consistentwith the epidemiology of the disease. The mean age of patients was approximately 40 years and themajority of patients (77.8%) were female. Most patients (83.3%) had persistent or recurrent Cushing’sdisease and few (≤5%) in either treatment group had received previous pituitary irradiation.

Baseline characteristics were balanced between the two randomised dose groups, except for markeddifferences in the mean value of baseline 24-hour UFC (1156 nmol/24 h for the 0.6 mg twice dailygroup and 782 nmol/24 h for the 0.9 mg twice daily group; normal range 30-145 nmol/24 h).

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 the95% CI is greater than the pre-specified 15% boundary. The response in the 0.9 mg dose arm seemedto be higher for patients with lower mean UFC at baseline. The responder rate at month 12 wascomparable 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 responsecategories regardless of up-titration at month 3: Fully controlled (UFC ≤1.0 x ULN), partiallycontrolled (UFC >1.0 x ULN but with a reduction in UFC ≥50% compared to baseline) oruncontrolled (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 remainuncontrolled at months 6 and 12.

In both dose groups, Signifor resulted in a decrease in mean UFC after 1 month of treatment whichwas maintained over time.

Decreases were also demonstrated by the overall percentage of change in mean and median UFClevels at month 6 and 12 as compared to baseline values (see Table 3). Reductions in plasma ACTHlevels 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 atmonth 6 and month 12 compared to baseline values

Pasireotide 0.6 mg twice Pasireotide 0.9 mg twicedaily daily% change (n) % change (n)

Mean change in UFC Month 6 -27.5* (52) -48.4 (51)(% from baseline) Month 12 -41.3 (37) -54.5 (35)

Median change in UFC Month 6 -47.9 (52) -47.9 (51)(% from baseline) 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 cholesterolwere observed in both dose groups at month 6. Overall reductions in these parameters were observedin 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.

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 forinformation on paediatric use).

In healthy volunteers, pasireotide is rapidly absorbed and peak plasma concentration is reached within0.25-0.5 h. Cmax and AUC are approximately dose-proportional following administration of single andmultiple doses.

No studies have been conducted to evaluate the bioavailability of pasireotide in humans.

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 andshows 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 cancerresistance protein) nor of the influx transporters OCT1 (organic cation transporter 1), OATP (organicanion-transporting polypeptide) 1B1, 1B3 or 2B1. At therapeutic dose levels pasireotide is also not aninhibitor of UGT1A1, OATP, 1B1 or 1B3, P-gp, BCRP, MRP2 and BSEP.

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 ispredominantly found in unchanged form in plasma, urine and faeces.

Pasireotide is eliminated mainly via hepatic clearance (biliary excretion), with a small contribution ofthe renal route. In a human ADME study 55.9±6.63% of the radioactive dose was recovered over thefirst 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 effectivehalf-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 pharmacokineticsin the dose range of 0.3 mg to 1.2 mg twice a day. Population pharmacokinetic analysis suggests thatbased on Cmax and AUC, 90% of steady state in Cushing’s disease patients is reached afterapproximately 1.5 and 15 days, respectively.

No studies have been performed in paediatric patients.

Renal clearance has a minor contribution to the elimination of pasireotide in humans. In a clinicalstudy with single subcutaneous dose administration of 900 µg pasireotide in subjects with impairedrenal 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 plasmapasireotide exposure (AUCinf,u) was increased in subjects with renal impairment (mild: 33%; moderate:25%, severe: 99%, ESRD: 143%) compared to control subjects.

In a clinical study in subjects with impaired hepatic function (Child-Pugh A, B and C), statisticallysignificant 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 wasincreased 60% and 79%, Cmax was increased 67% and 69%, and CL/F was decreased 37% and 44%,respectively.

Age has been found to be a covariate in the population pharmacokinetic analysis of Cushing’s diseasepatients. Decreased total body clearance and increased pharmacokinetic exposures have been seenwith increasing age. In the studied age range 18-73 years, the area under the curve at steady state forone dosing interval of 12 hours (AUCss) is predicted to range from 86% to 111% of that of the typicalpatient of 41 years. This variation is moderate and considered of minor significance considering thewide 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 clinicallysignificant differences in safety and efficacy in relation to younger patients.

Demographics

Population pharmacokinetic analyses of Signifor suggest that race and gender do not influencepharmacokinetic parameters.

Body weight has been found to be a covariate in the population pharmacokinetic analysis of Cushing’sdisease patients. For a range of 60-100 kg the reduction in AUCss with increasing weight is predictedto be approximately 27%, which is considered moderate and of minor clinical significance.

Non-clinical safety data reveal no special hazard for humans based on conventional studies of safetypharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential, toxicity to reproductionand development. Most findings seen in repeated toxicity studies were reversible and attributable tothe pharmacology of pasireotide. Effects in non-clinical studies were observed only at exposuresconsidered sufficiently in excess of the maximum human exposure indicating little relevance toclinical use.

Pasireotide was not genotoxic in in vitro and in vivo assays.

Carcinogenicity studies conducted in rats and transgenic mice did not identify any carcinogenicpotential.

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 andimplantation sites. Embryo toxicity was seen in rats and rabbits at doses that caused maternal toxicitybut no teratogenic potential was detected. In the pre- and postnatal study in rats, pasireotide had noeffects on labour and delivery, but caused slight retardation in the development of pinna detachmentand reduced body weight of the offspring.

Available toxicological data in animals have shown excretion of pasireotide in milk.

Mannitol

Tartaric acid

Sodium hydroxide

Water for injections

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinalproducts.

3 years

Store in the original package in order to protect from light.

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.

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.

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 localrequirements.

Recordati Rare Diseases

Tour Hekla52 avenue du Général de Gaulle92800 Puteaux

France

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

Date of first authorisation: 24 April 2012

Date of latest renewal: 18 November 2016

Detailed information on this medicinal product is available on the website of the European Medicines

Agency http://www.ema.europa.eu