Signifor La 20, 40, 60 mg Powder for suspension for injection

Treatment of acromegaly as second-line therapy after pituitary surgery (or when surgery is not feasible), in patients inadequately responding to other somatostatin analogues (SSAs) or where other SSAs cannot be used.

Posology
General target population
u2022 The recommended initial dose of SIGNIFOR LA is 40 mg administered by deep intramuscular injection every 4 weeks (28 days).
u2022 The dose may be increased to a maximum of 60 mg for patients whose GH and/or IGF-1 levels are not fully controlled after 3 months of treatment with SIGNIFOR LA at 40 mg.
u2022 Management of suspected adverse reactions or over-response to treatment (IGF-1 < lower limit of normal) may require dose reduction of SIGNIFOR LA.
u2022 The dose may be decreased either temporarily or permanently by 20 mg decrements.
Missed dose
If a dose of SIGNIFOR LA 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 (u2265 65 years): Data on the use of SIGNIFOR LA 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).
Patients with renal impairment:
u2022 No dose adjustment is required in patients with impaired renal function.
Patients with hepatic impairment:
u2022 Dose adjustment is not required in patients with mildly impaired hepatic function (Child-Pugh A).
u2022 For patients with moderately impaired hepatic function (Child-Pugh B) the recommended initial dose is 20 mg every 4 weeks and the maximum recommended dose is 40 mg every 4 weeks. SIGNIFOR LA should not be used in patients with severe hepatic impairment (Child Pugh C) (see section 4.3).
Paediatric patients
u2022 SIGNIFOR LA is not recommended for use in paediatric patients with acromegaly as there are no clinical data available in patients under 18 years of age.
Method of administration
u2022 SIGNIFOR LA should only be administered by deep intramuscular injection by a trained healthcare professional.
u2022 SIGNIFOR LA suspension must only be prepared immediately before administration.
u2022 The site of repeat intramuscular injections should be alternated between the left and right gluteal muscle (see section 4.2 u2018Instructions for useu2019).

u2022 Hypersensitivity to pasireotide or any of the excipients of SIGNIFOR LA (see section 6.1).
u2022 Severe hepatic impairment (Child Pugh C).

Glucose metabolism
u2022 Alterations in blood glucose levels have been frequently reported in healthy volunteers and patients treated with pasireotide as contained in SIGNIFOR LA.
u2022 Hyperglycaemia and, less frequently, hypoglycaemia were observed in subjects participating in clinical studies with pasireotide (see section 4.8).
u2022 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.
u2022 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]).
u2022 Glycaemic status (fasting plasma glucose/hemoglobin A1c [FPG/HbA1c]) should be assessed prior to starting treatment with SIGNIFOR LA.
u2022 FPG/HbA1c monitoring during treatment should follow established guidelines.
u2022 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.
u2022 Monitoring of FPG 4 weeks and HbA1c 3 months after the end of the treatment should be performed.
u2022 If hyperglycaemia develops in a patient treated with SIGNIFOR LA, the initiation or adjustment of anti-diabetic treatment is recommended, following the established treatment guidelines for the management of hyperglycaemia.
u2022 If uncontrolled hyperglycaemia persists despite appropriate medical management the dose of SIGNIFOR LA should be reduced or the treatment discontinued (see section 4.5).
u2022 There have been post-marketing cases of ketoacidosis with SIGNIFOR LA 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.
u2022 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 SIGNIFOR LA therapy.
Liver tests
u2022 Mild transient elevations in aminotransferases are commonly observed in patients treated with SIGNIFOR LA. Rare cases of concurrent elevations in ALT (alanine aminotransferase) greater than 3 x ULN (upper limit normal) and bilirubin greater than 2 x ULN have also been observed (see section 4.8).
u2022 Monitoring of liver function is recommended prior to treatment with SIGNIFOR LA, and after the first 2 to 3 weeks, then monthly for 3 months on treatment. Thereafter, liver function should be monitored as clinically indicated.
u2022 Patients who develop increased transaminase levels should be monitored frequently until values return to pre-treatment levels.
u2022 Therapy with SIGNIFOR LA should be discontinued if the patient develops jaundice or other signs suggestive of clinically significant liver impairment, 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.
u2022 Following discontinuation of treatment with SIGNIFOR LA, patients should be monitored until resolution. Treatment should not be restarted if the liver function abnormalities are suspected to be related to SIGNIFOR LA.
Cardiovascular related events
u2022 Bradycardia has been reported with the use of pasireotide as contained in SIGNIFOR LA (see section 4.8).
u2022 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, should be carefully monitored.
u2022 Dose adjustments of medicines such as beta-blockers, calcium channel blockers, or medicines to control electrolyte balance, may be necessary (see section 4.5).
u2022 Pasireotide has been shown to prolong the QT interval in healthy subjects.
u2022 All QT-related events were transient and resolved without therapeutic intervention.
u2022 Episodes of torsade de pointes were not observed in any clinical study with pasireotide.
u2022 Pasireotide should be used with caution in patients who are at significant risk of developing prolongation of QT, such as those:
o with congenital long QT syndrome;
o with uncontrolled or significant cardiac disease including recent myocardial infarction, congestive heart failure, unstable angina or clinically significant bradycardia;
o taking anti-arrhythmic medicines or other medicines that are known to lead to QT prolongation;
o hypokalaemia and/or hypomagnesaemia.
A baseline ECG is recommended prior to initiating therapy with SIGNIFOR LA. Monitoring for an effect on the QTc interval is advisable 21 days after initiating therapy and as clinically indicated. Hypokalaemia or hypomagnesaemia must be corrected prior to SIGNIFOR LA administration and should be monitored periodically during therapy.
Hypocortisolism
u2022 The suppression of ACTH (adrenocorticotropic hormone) secretion can result in hypocortisolism in patients treated with SIGNIFOR LA.
u2022 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).
u2022 In the event of documented hypocortisolism, temporary exogenous steroid (glucocorticoid) replacement therapy and/or dose reduction or interruption of treatment with SIGNIFOR LA may be necessary.
u2022 Rapid decreases in cortisol levels may be associated with decreases in white blood cell count.
Gallbladder and related events
u2022 Cholelithiasis (gallstones) is a recognised adverse medicine reaction associated with long-term use of somatostatin analogues and has frequently been reported in clinical studies with pasireotide (see section 4.8).
u2022 There have been post-marketing cases of cholangitis in patients taking SIGNIFOR LA, which in the majority of cases was reported as a complication of gallstones.
u2022 Ultrasonic examination of the gallbladder before, and at 6- to 12-month intervals during SIGNIFOR LA therapy is therefore recommended.
u2022 The presence of gallstones in SIGNIFOR LA-treated patients is often largely asymptomatic. However, symptomatic stones should be managed according to clinical practice.
Pituitary hormones
u2022 Deficiency of pituitary secreted hormones is common after trans-sphenoidal surgery and radiation therapy of the pituitary gland.
u2022 As the pharmacological activity of pasireotide mimics that of somatostatin, inhibition of pituitary hormones, other than GH and/or IGF-1 may occur.
u2022 Therefore, monitoring of pituitary function (e.g. TSH/free T4) prior to initiation of therapy with SIGNIFOR LA and periodically during treatment should be conducted as clinically appropriate.

Anticipated pharmacokinetic interactions resulting in effects on pasireotide:
u2022 The influence of a P-gp inhibitor on pharmacokinetics of pasireotide administered as pasireotide subcutaneous injection has been tested in an interaction study with co-administration of verapamil in healthy volunteers. No change in the rate or extent of pasireotide availability was observed.
Anticipated pharmacokinetic interactions resulting in effects on other medicines:
Pasireotide may decrease the relative bioavailability of ciclosporin. Concomitant administration of SIGNIFOR LA and ciclosporin may require adjustment of the ciclosporin dose to maintain therapeutic levels of the medicine.
Anticipated pharmacodynamic interactions:
Medicines that prolong QT interval
Caution is required when co-administering SIGNIFOR LA with medicines that may prolong the QT interval such as:
u2022 class Ia dysrhythmics (e.g. quinidine, procainamide, disopyramide);
u2022 class III dysrhythmics (e.g. amiodarone, dronedarone, sotalol, dofetilide, ibutilide),
u2022 certain antibacterials (intravenous erythromycin, pentamidine injection, clarithromycin, moxifloxacin);
u2022 certain antipsychotics (e.g. chlorpromazine, thioridazine, fluphenazine, pimozide, haloperidol, tiapride, amisulpride, sertindole, methadone);
u2022 certain antihistamines (e.g. terfenadine, astemizole, mizolastine);
u2022 antimalarials (e.g. chloroquine, halofantrine, lumefantrine);
u2022 certain antifungals (ketoconazole, except in shampoo) (see section 4.4).
Bradycardic medicines
Clinical monitoring of heart rate, notably at the beginning of treatment, is recommended in patients receiving SIGNIFOR LA concomitantly with:
u2022 bradycardic medicines, such as beta blockers (e.g. metoprolol, carteolol, propranolol, sotalol);
u2022 acetylcholinesterase inhibitors (e.g. rivastigmine, physostigmine);
u2022 certain calcium channel blockers (e.g. verapamil, diltiazem, bepridil),
u2022 certain antiarrhythmics (see also section 4.4).
Insulin and antidiabetic medicines
u2022 Dose adjustments (decrease or increase) of insulin and antidiabetic medicines (e.g. metformin, liraglutide, vildagliptin, nateglinide) may be required when administered concomitantly with SIGNIFOR LA (see also section 4.4).

Women of childbearing potential/ Contraception in males and females
SIGNIFOR LA is not recommended for use in women of childbearing potential who are not using contraception (see section 4.4).
Pregnancy
Safety in pregnancy and lactation have not been established. Animal studies showed reproductive toxicity. There is a limited amount of data from the use of pasireotide in pregnant women.
Breastfeeding
It is not known whether pasireotide is excreted in human milk. Available data in rats with pasireotide via the s.c. route have shown excretion of pasireotide in milk. As a risk to the breast-fed child cannot be excluded, SIGNIFOR LA should not be used by the nursing mother.
Fertility
It is unknown whether pasireotide has an effect on human fertility. Studies in rats with pasireotide via the s.c. route have shown effects on female reproductive parameters.

SIGNIFOR LA has minor influence on mental and/or physical abilities to perform or execute tasks or activities requiring mental alertness, judgment and/or sound coordination and vision.
Patients should be advised to be cautious when driving or using machinery if they experience fatigue, dizziness or headache during treatment with SIGNIFOR LA.

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.
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 u22651/10) from the pooled safety data from 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.
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 Cushingu2019s 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 order of decreasing seriousness. Frequencies were defined as follows: Very common (u22651/10); common (u22651/100 to <1/10); uncommon (u22651/1,000 to <1/100); not known (cannot be estimated from the available data).

In overdose, side effects can be precipitated and/or be of increased severity (see section 4.8).
In the event of overdosage, it is recommended that appropriate supportive treatment be initiated, as dictated by the patientu2019s clinical status, until resolution of the symptoms.