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.

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 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.

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 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.

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.

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).

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

Steatorrhea Faeces discoloured

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-glutamyltransferase 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.

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 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: Yellow Card Scheme, Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

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.