Signifor® 20 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
Signifor 20 mg powder and solvent for suspension for injection
One vial contains 20 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.
Powder and solvent for suspension for injection.
Powder: slightly yellowish to yellowish powder.
Solvent: clear, colourless to slightly yellow or slightly brown solution.
Signifor is indicated for the 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.
Posology
The recommended initial dose 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 by 20 mg decrements.
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
Based on limited data from patients with impaired renal function, no dose adjustment is required (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 20 mg every 4 weeks (see section 5.2). The maximum recommended dose for these patients is 40 mg every 4 weeks. 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.
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 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 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% (Common Toxicity Criteria 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.
In acromegaly 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).
Patients with poor glycaemic control (as defined by HbA1c values >8% while receiving antidiabetic therapy) may be at higher risk of developing severe hyperglycaemia and associated complications (e.g. ketoacidosis). In patients with poor glycaemic control, 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
Treatment with Signifor can lead to rapid suppression of ACTH (adrenocorticotropic hormone) secretion. Infrequent cases of hypocortisolism have been reported in clinical studies with pasireotide in acromegaly patients.
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 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). 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 cannot be ruled out. Monitoring of pituitary function (e.g. TSH/free T4, ACTH/cortisol) 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 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.
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).
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
It is not known whether pasireotide has an effect on human fertility. Studies in rats in which pasireotide was administered via the subcutaneous route have shown effects on female reproductive parameters (see section 5.3).
Signifor has no or negligible 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.
Summary of the safety profile
Safety assessment was made based on 491 acromegaly patients who received pasireotide (419 patients received pasireotide intramuscular use and 72 received pasireotide subcutaneous use) in phase I, II and III studies. The safety profile of pasireotide intramuscular use was consistent with the somatostatin analogue class, except for the higher degree and frequency of hyperglycaemia seen with pasireotide intramuscular use.
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 Grade 3 and 4 adverse reactions were mostly related to hyperglycaemia.
Tabulated list of adverse reactions
Pooled analyses of adverse reactions reported up to the cut-off date of the analysis for studies C2305 and C2402 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).
Table 1 Adverse reactions by preferred term for pasireotide intramuscular use in the two phase III studies in acromegaly patients
System Organ Class
|
Very common
(≥1/10)
|
Common
(≥1/100 to <1/10)
|
Uncommon
(≥1/1,000 to <1/100)
|
Blood and lymphatic system disorders
|
|
Anaemia
|
|
Endocrine disorders
|
|
Adrenal insufficiency*
|
|
Metabolism and nutrition disorders
|
Hyperglycaemia, diabetes mellitus
|
Type 2 diabetes mellitus, glucose tolerance impaired
|
|
Nervous system disorders
|
|
Headache, dizziness
|
|
Cardiac disorders
|
|
Sinus bradycardia**, QT prolongation
|
|
Gastrointestinal disorders
|
Diarrhoea
|
Nausea, abdominal distension, abdominal pain
|
|
Hepatobiliary disorders
|
Cholelithiasis
|
|
|
Skin and subcutaneous tissue disorders
|
|
Alopecia
|
|
General disorders and administration site conditions
|
|
Injection site reaction***
|
|
Investigations
|
|
Glycosylated haemoglobin increased, alanine aminotransferase increased, blood glucose increased, blood creatinine phosphokinase increased
|
Amylase increased
|
* Adrenal insufficiency includes the following preferred terms: adrenal insufficiency and blood cortisol decreased.
** Sinus bradycardia includes the following preferred terms: bradycardia and sinus bradycardia.
*** Injection site reaction includes the following preferred terms: injection site pain, injection site nodule, injection site discomfort, injection site bruising, injection site pruritus, injection site reaction and injection site swelling.
|
Description of selected adverse reactions
Glucose metabolism disorders
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 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. 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 all grade 1 or 2 in severity and were comparable between pasireotide intramuscular use and octreotide intramuscular use treated patients. The incidence of such events was highest in the first 3 months of treatment. Injection site reaction-related adverse events were less frequent in inadequately controlled patients compared to medically naïve patients.
QT prolongation
In 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. No patient had a QTcF value >500 ms. 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.
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 with acromegaly 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 Yellow Card Scheme at: www.mhra.gov.uk/yellowcard
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.
Pharmacotherapeutic group: Pituitary and hypothalamic hormones and analogues, somatostatin and analogues, ATC code: H01CB05
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 sst 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
|
>100
|
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.
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.
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 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.
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.
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 eva luations 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 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%).
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 (see section 4.2 for information on paediatric use).
Absorption
The relative bioavailability of pasireotide intramuscular use over pasireotide subcutaneous use is complete. No studies have been conducted to eva luate the 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 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.
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 20 mg to 60 mg every 4 weeks in patients with acromegaly.
Special populations
Paediatric population
No studies have been performed in paediatric patients.
Patients with renal impairment
A clinical study in subjects with impaired renal function is ongoing. Renal clearance has a minor contribution to the elimination of pasireotide in humans. Mild and moderate renal impairment is not expected to significantly impact the circulating levels of pasireotide, but it cannot be excluded that systemic exposure is increased in severe renal impairment.
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 with acromegaly.
Demographics
Population pharmacokinetic (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.
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.
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
In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.
Store in a refrigerator (2°C – 8°C). Do not freeze.
Unit packs containing one brownish vial (glass) with rubber stopper (chlorobutyl rubber) of powder for suspension for injection and one colourless pre-filled syringe (glass) with front and plunger stopper (chlorobutyl rubber) with solvent, co-packaged in a sealed blister tray with one vial adapter and one safety-engineered needle for injection.
Signifor 40 mg and 60mg powder and solvent for suspension for injection
Multipacks containing 3 intermediate cartons, each containing: one brownish vial (glass) with rubber stopper (chlorobutyl rubber) of powder for suspension for injection and one colourless pre-filled syringe (glass) with front and plunger stopper (chlorobutyl rubber) with solvent, co-packaged in a sealed blister tray with one vial adapter and one safety-engineered needle for injection.
Not all pack sizes may be marketed.
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 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.
Novartis Europharm Limited
Frimley Business Park
Camberley GU16 7SR
United Kingdom
Signifor 20 mg powder and solvent for suspension for injection
EU/1/12/753/013
Signifor 40 mg powder and solvent for suspension for injection
EU/1/12/753/014
EU/1/12/753/015
Signifor 60 mg powder and solvent for suspension for injection
EU/1/12/753/016
EU/1/12/753/017
02.03.2015
Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu