Signifor

Signifor

pasireotide

Manufacturer:

Novartis

Distributor:

Zuellig Pharma
Full Prescribing Info
Contents
Pasireotide (as diaspartate).
Description
Signifor contains the following excipients: Mannitol, tartaric acid, sodium hydroxide, water for injections.
Action
Pharmacology: Pharmacodynamics: Somatostatin receptors are expressed in many tissues, especially in neuroendocrine tumors where hormones are excessively secreted including adrenocorticotropic hormone (ACTH) in Cushing's disease. Due to its broad-binding profile to somatostatin receptors, pasireotide has the potential to treat diseases characterized by expression of those receptors in the target tissues.
In vitro studies have shown that corticotroph tumor cells from Cushing's disease patients display a high expression of hsst5 whereas the other receptor subtypes are either not expressed or are expressed at lower levels. Pasireotide binds and activates the hsst receptors of the corticotrophs in ACTH-producing adenomas resulting in inhibition of ACTH secretion. The high affinity of pasireotide for 4 of the 5 hssts, especially to hsst5 (see Table 1), provides the basis for pasireotide to be an effective treatment for Cushing's disease patients.
Glucose Metabolism: In a randomized double-blinded mechanism study conducted in healthy volunteers, the development of hyperglycemia with pasireotide administered as Signifor SC at doses of 600 and 900 mcg twice a day was related to significant decreases in insulin secretion as well as incretin hormones [ie, glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP)]. Pasireotide did not affect insulin sensitivity. In another randomized study conducted in healthy volunteers, the effects of pasireotide on blood glucose were investigated by comparison between administrations of Signifor SC 600 mcg twice a day alone and with co-administration of an anti-hyperglycemic drug (metformin, nateglinide, vildagliptin or liralgutide, respectively. Insulin was not studied) over a 7-day period. Incretin-based therapy (GLP-1 agonists and DDP-IV inhibitors) was most efficacious in treating pasireotide-associated hyperglycemia in healthy volunteers.
Cardiac Electrophysiology: The effect of Signifor on the QT interval was assessed in 2 open-label, controlled, crossover dedicated QT studies. In both studies, an effect of pasireotide on the QTc interval was observed with the maximum placebo-subtracted mean change from baseline occurring at 2-hr post dose. In one of the studies investigating a 1950 mcg twice daily dose, the maximum mean placebo-subtracted QTcF change from baseline was 17.5 ms (90% CI: 15.53; 19.38). In the other study, investigating doses of 600 mcg twice daily and 1950 mcg twice daily, the maximum mean placebo-subtracted QTcI change from baseline was 13.19 ms (90% CI: 11.38; 15.01) and 16.12 ms (90% CI: 14.30; 17.95 ms), respectively. Both pasireotide doses decreased heart rate, with a maximal difference to placebo observed at 1 hr for pasireotide 600 mcg twice daily (-10.39 bpm), and at 0.5 hrs for pasireotide 1950 mcg twice daily (-14.91 bpm). No episodes of Torsade de pointes (transient or sustained) were observed.
Mechanism of Action: Pasireotide is a novel cyclohexapeptide, injectable somatostatin analogue. Like 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 (5) human somatostatin receptor subtypes are known: Hsst 1, 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 1). Pasireotide binds with high affinity to 4 of the 5 hssts.

Click on icon to see table/diagram/image

Clinical Studies: A phase III, multicenter, randomized study was conducted to evaluate the safety and efficacy of different dose levels of Signifor >12-month treatment period in Cushing's disease patients with persistent or recurrent disease or de novo patients for whom surgery was not indicated or who refused surgery.
The study enrolled 162 patients with a baseline ultrafiltration capacity (UFC) >1.5 x upper limit of normal (ULN) who were randomized in a 1:1 ratio to receive a dose of either Signifor 0.6 mg SC twice daily or 0.9 mg SC twice daily. After 3 months of treatment, patients who had a mean 24-hr UFC ≤2 x ULN and below or equal to their baseline values continued blinded treatment at the randomized dose until month 6. Patients who did not meet these criteria were unblinded and the dose was increased by 0.3 mg twice daily. After the initial 6 months in the study, patients entered an additional 6-month open-label treatment period. If response was not achieved at month 6 or the response was not maintained during the open-label treatment period, dosage could be increased by 0.3 mg SC twice daily. The maximum dose administered to patients was 1.2 mg SC twice daily. The dose could be reduced by 0.3 mg twice daily decrements at any time during the study for intolerability.
The primary efficacy endpoint was the proportion of patients in each arm who achieved normalization of mean 24-hr UFC levels (UFC ≤ ULN) after 6 months of treatment and who did not have a dose increase (relative to randomized dose) during this period. Secondary endpoints included, among others, changes from baseline in: 24-hr UFC, plasma adrenocorticotrophic hormone (ACTH), serum cortisol levels, clinical signs and symptoms of Cushing's disease and health-related quality of life (HRQL) as measured by the Cushing QoL. All analyses were conducted based on the randomized dose groups.
Baseline demographics were well balanced between the 2 randomized dose groups and consistent with the epidemiology of the disease. The mean age of patients was approximately 40 years old with a predominance of female patients (77.8%). The majority of the patients had persistent or recurrent Cushing's disease (83.3%) and few patients (≤5%) in either treatment group had received previous pituitary irradiation.
Baseline characteristics were balanced between the 2 randomized dose groups, except for marked differences in the mean value of the baseline 24-hr UFC (1156 nmol/24 hrs for the 0.6 mg twice daily group and 781 nmol/24 hrs for the 0.9 mg twice daily group); normal range 30-145 nmol/24 hrs).
Results: At month 6, normalization of mean UFC levels was observed in 14.6% (95% CI 7-22.3) and 26.3% (95% CI 16.6-35.9) of patients randomized to pasireotide 0.6 mg twice daily. and 0.9 mg twice daily, respectively. The study met the primary efficacy objective for the 0.9 mg twice daily group as the lower limit of the 95% CI is greater than the prespecified 15% boundary. The response in the 0.9-mg dose arm seemed to be higher for patients with lower mean UFC at baseline (see Table 2). The majority of responders (55.6%) at month 6 were also responders at month 12. The responder rate at month 12 was comparable to month 6 with 13.4% and 25% in the 0.6 mg twice daily and 0.9 mg twice daily, respectively.

Click on icon to see table/diagram/image

A supportive efficacy analysis was conducted in which patients were further classified into 3 response categories regardless of up-titration at month 3: Controlled (UFC ≤1 x ULN), partially controlled (UFC >1 x ULN but with a reduction in UFC ≥50% compared to baseline) or uncontrolled (all other patients). The controlled and partially controlled responder rates at month 6, constituted 34% and 41% (0.6 mg twice daily and 0.9 mg twice daily, respectively) of the randomized patients (see Table 3). Patients uncontrolled at both months 1 and 2 were likely (90%) to remain uncontrolled at months 6 and 12.

Click on icon to see table/diagram/image

In both dose groups, Signifor resulted in a rapid and robust decrease in the mean UFC after 1 month of treatment which was maintained over time (see figure). Dose decreases and increases appeared to have minimal effect on UFC response, though some patients experienced further reduction in UFC levels with dose up-titration.

Click on icon to see table/diagram/image

Robust decreases were also demonstrated by the overall percentage of change in the mean and median UFC levels at month 6 and 12 as compared to baseline values (see Table 4). Reductions in mean serum cortisol and plasma ACTH levels were also observed at each time point for each dose group.

Click on icon to see table/diagram/image

Clinically meaningful decreases in sitting systolic and diastolic blood pressure, body mass index (BMI), and total cholesterol were observed in both dose groups at month 6. Overall reductions in these parameters tended to be greater in patients that normalized UFC. Similar trends were observed at month 12, with the addition of serum triglycerides also decreasing at that time point. No clinically meaningful changes in bone mineral density were observed.
There were favorable shifts in all of the studied signs of Cushing's disease in both dose groups at month 6. Facial rubor improved in 36.7% (18/49) and 59.6% (28/47) of patients treated with 0.6 and 0.9 mg twice daily, respectively. More than a 3rd of patients in either treatment group also demonstrated improvement in supraclavicular fat pad and dorsal fat pad. Similar findings were recorded at the month 12 visit.
Baseline mean and median global Cushing QoL scores were similar for the 2 dose groups. At the month 3 visit, patients in both dose groups reported increases in scores, indicating improvement in the patient-reported HRQL. At month 6, median improvements from baseline were 13.2% and 30% in the 0.6 mg and 0.9 mg twice daily dose groups, respectively. At month 12, median improvements from baseline were 26% and 20.6% in the 0.6 mg and 0.9 mg twice daily dose groups, respectively.
Pharmacokinetics: In healthy volunteers, pasireotide demonstrates approximately linear pharmacokinetics (PK) for a wide dose range from 0.0025-1.5 mg. In Cushing's disease patients, pasireotide demonstrates linear dose-exposure relationship in a dose range from 0.3-1.2 mg.
Absorption: In healthy volunteers, pasireotide is rapidly absorbed and peak plasma concentration (Cmax) is reached within time-to-peak plasma concentration (Tmax) 0.25-0.5 hr. Peak plasma concentration and area under the curve (AUC) are approximately dose-proportional following administration of single and multiple doses.
No studies have been conducted to evaluate the bioavailability of pasireotide in humans. Based on data of absolute bioavailability from preclinical studies in rats and monkeys, the absolute bioavailability of pasireotide SC is predicted to be complete in humans.
Food effect is unlikely to occur since Signifor is administered via parenteral route.
Distribution: In healthy volunteers, pasireotide is widely distributed with large apparent volume of distribution (Vz/F >100 L). Distribution between blood 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.
Pasireotide has low passive permeability and is likely to be a substrate of P-gp, but the impact of P-gp on absorption, distribution, metabolism, excretion (ADME) of pasireotide is expected to be low. Pasireotide is not a substrate of breast cancer resistance protein (BCRP), organic cation transporter 1 (OCT1), nor organic anion-transporting polypeptides (OATP) 1B1, 1B3, or 2B1.
Metabolism: Pasireotide was shown to be highly metabolically stable in human liver and kidney microsomes. In healthy volunteers, pasireotide in its unchanged form is the predominant form found in plasma, urine and feces.
Excretion: 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 radioactivity dose was recovered over the first 10 days post dosing, including 48.3±8.16% of the radioactivity in feces and 7.63±2.03% in urine.
The clearance (CL/F) of pasireotide in healthy volunteers and Cushing's disease patients is approximately 6.7 L/hr and 3.8 L/hr, respectively.
Steady-State Pharmacokinetics: Following multiple SC doses, pasireotide demonstrates linear and time-independent pharmacokinetics in the dose range of 0.05-0.6 mg once a day in healthy volunteers, and 0.3-1.2 mg twice a day in Cushing's disease patients. Based on the accumulation ratios of AUC, the calculated effective half-life (t½,eff) in healthy volunteers was approximately 12 hrs (on average between 10 and 13 hrs for 0.05, 0.2 and 0.6 mg everyday doses).
Special Populations: Elderly: Age has been found to be a covariate in the population PK analysis of Cushing's disease patients. Decreased total body clearance and increased PK exposures have been seen with increasing age. In the studied age range 18-73 years, the AUC at steady state for 1 dosing interval of 12 hrs (AUCss) is predicted to range from 86-110% of that of the typical patient of 41 years. This variation is moderate and considered of minor significance considering the wide age range in which the effect was observed.
Data on Cushing’s disease patients >65 years are limited but do not suggest any clinically significant differences in safety and efficacy in relation to younger patients.
Pediatric: No studies have been performed in pediatric patients.
Renal Impairment: Clinical studies have not been performed in patients with impaired renal function. However, renal clearance has a minor contribution to the elimination of pasireotide in humans. Renal function is not expected to significantly impact the circulating levels of pasireotide.
Hepatic Impairment: In a clinical study in subjects with impaired hepatic function (Child-Pugh A, B and C), subjects with moderate and severe hepatic impairment (Child-Pugh B and C) showed significantly higher exposures than subjects with normal hepatic function. Upon correction for covariate effect (age, BMI and albumin) AUCinf was increased by 60% and 79%, Cmax increased by 67% and 69%, and CL/F decreased by 37% and 44% respectively, in the moderate and severe hepatic impairment groups relative to the control group.
Demographics: Population PK analyses of Signifor suggest that race and gender, do not influence PK parameters. Lean body weight, which subtracts the estimated weight of body fat from the total body weight, has been found to be a covariate in the population PK analysis of Cushing's disease patients. In the studied lean body weight range 33-83 kg, the AUCs is predicted to range from 67-134% of that of the typical patient of 49 kg (the corresponding range of total body weight was 43-175 kg, with a median of 77.4 kg). This variation is considered as moderate and of minor clinical significance.
Toxicology: Nonclinical Safety Data: Nonclinical safety studies included safety pharmacology, repeated-dose toxicity, genotoxicity and carcinogenic potential, toxicity to reproduction and development. Most findings seen in repeated toxicity studies were reversible and attributable to the pharmacology of pasireotide. Effects in nonclinical studies were observed only at exposures considered sufficiently in excess of the maximum human exposure indicating little relevance to clinical use.
In safety pharmacology studies, pasireotide had no adverse effects on respiratory or cardiovascular functions. Decreases in general and behavioral activity were observed in mice at the dose of 12 mg/kg, equivalent to approximately 32-fold of the maximum recommended therapeutic human dose (MHRD) based on surface area.
Pasireotide was not genotoxic in a battery of in vitro assays (Ames mutation test in Salmonella and Escherichia coli and mutation test in human peripheral lymphocytes). Pasireotide was not genotoxic in an in vivo rat bone marrow nucleus test at doses up to 50 mg/kg, approximately 250-fold the MHRD based on surface area, mg/m2.
Carcinogenicity studies conducted in rats and transgenic mice did not identify any carcinogenic potential.
In embryofetal development studies in rats and rabbits, pasireotide was not teratogenic at maternally toxic doses (respectively 10 and 5 mg/kg/day) leading to exposures (AUC0-24 hrs), respectively 145- and 40-fold higher than the MHRD. At 10 mg/kg/day in rats, the frequency of early/total resorptions and malrotated limbs was increased. At 5 mg/kg/day in rabbits, increased abortions, reduced fetal weights and ensuing skeletal variations were observed. Reduced fetal weight and ensuing delayed ossification were seen at 1 mg/kg/day (6.5-fold MHRD). Pasireotide had no effects on labour and delivery in rats administered up to 10 mg/kg/day (52-fold higher than the MHRD based on surface area, mg/m2). Available toxicological data in animals have shown excretion of pasireotide in milk. Retardation of physiological growth, attributed to growth hormone (GH) inhibition was observed at 2 mg/kg/day (10-fold higher than the MHRD based on surface area, mg/m2) during a pre- and postnatal study in rats. After weaning, body weight gains in the rat pups exposed to pasireotide were comparable to controls, showing reversibility. Pasireotide did not affect fertility in male rats at doses up to 10 mg/kg/day (a dose 52-fold higher than the MHRD based on surface area, mg/m2). In female rats, as expected from the pharmacology of pasireotide, fertility was decreased at daily doses of 0.1 mg/kg/day (0.6-fold the MHRD based on surface area, mg/m2) as shown by decreased numbers of corpora lutea and implantation sites. Abnormal cycles or acyclicity were observed at 1 mg/kg/day (5-fold higher than the MHRD based on surface area, mg/m2).
Indications/Uses
Treatment of patients with Cushing's disease for whom medical therapy is appropriate.
Dosage/Direction for Use
General Target Population: Adults: Recommended Initial Dose: 0.6 mg by SC injection twice daily. For patients with pre-diabetes or diabetes mellitus an initial dose of 0.6 mg twice daily may be considered (see Precautions).
Management of suspected adverse reactions may require temporary dose reduction of Signifor. Dose reduction by decrements of 0.3 mg twice daily is suggested.
After 2 months of initiating treatment with Signifor, patients should be evaluated for clinical benefit. Patients who experience clinical benefit [clinically meaningful reduction in urinary free cortisol (UFC) levels and/or improvement in signs or symptoms of the disease] should continue therapy with Signifor as long as benefit is derived. Patients who do not experience clinical benefit from Signifor, should be considered for discontinuation.
Individualized dose reduction may be considered for patients with a stable response at the discretion of the treating physician.
Special Populations: Renal Impairment: No dosage adjustment is required in patients with impaired renal function (see Pharmacology under Actions).
Hepatic Impairment: Dose adjustment is not required in patients with mildly impaired hepatic function (Child-Pugh A). The recommended initial dose for patients with moderately impaired hepatic function (Child-Pugh B) is 0.3 mg twice daily (see Pharmacology under Actions). The maximum recommended dose for patients with moderate hepatic impairment is 0.6 mg twice daily. Signifor should not be used in patients with severe hepatic impairment (Child Pugh C) (see Contraindications and Precautions).
Elderly: There are limited data on the use of Signifor in patients >65 years but there is no evidence suggesting that a dose adjustment is required in elderly patients (see Pharmacology under Actions).
Administration: Signifor is to be administered SC by self injection. Patients should receive instructions from the physician or a healthcare professional on how to inject Signifor SC. Use of the same injection site for 2 consecutive injections is not recommended. Sites showing signs of inflammation or irritation should be avoided. Preferred injection sites for SC injections are the top of the thighs and the abdomen (excluding the navel and waistline).
Overdosage
No cases of overdosage have been reported in patients receiving pasireotide SC. Doses up to 2.1 mg twice daily have been used in healthy volunteers with adverse reactions of diarrhea being observed at a high frequency.
In the event of overdosage, it is recommended that appropriate supportive treatment be initiated, as dictated by the patient's clinical status, until resolution of the symptoms.
Contraindications
Hypersensitivity to pasireotide or to any of the excipients of Signifor. Severe hepatic impairment (Child Pugh C).
Special Precautions
Glucose Metabolism: Alterations in blood glucose levels have been seen in healthy volunteers and patients treated with pasireotide. Hyperglycemia, and less frequently hypoglycemia, were observed in subjects participating in clinical trials with pasireotide (see Adverse Reactions).
The development of hyperglycemia appears to be related to decrease in secretion of insulin (particularly in the post-dose period) as well as incretin hormones [ie, glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP)]. The degree of hyperglycemia appeared to be higher in patients with pre-diabetic conditions or established diabetes mellitus. Treatment initiation with antidiabetic agents was associated with decreases in HbA1c <7% and fasting plasma glucose (FPG) <130 mg/dL in 43% and 72% of Cushing's disease patients, respectively. Dose reductions or discontinuation of treatment with pasireotide due to hyperglycemia were infrequent.
Glycemic status (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 2-3 months and periodically thereafter, as clinically appropriate, as well as over the first 2-4 weeks after any dose increase.
After treatment discontinuation, glycemic monitoring (eg, FPG or HbA1c) should be done according to clinical practice.
If hyperglycemia develops in a patient treated with Signifor, the initiation or adjustment of antidiabetic treatment is recommended, following the established treatment guidelines for the management of hyperglycemia.
If uncontrolled hyperglycemia persists despite appropriate medical management, the dose of Signifor, should be reduced or the treatment discontinued.
Cushing's disease patients with poor glycemic control (as defined by HbA1c values >8% while receiving antidiabetic therapy) may be at a higher risk of developing severe hyperglycemia and associated complications (eg, ketoacidosis). In patients with poor glycemic control, diabetes management and monitoring should be intensified prior to initiation and during pasireotide therapy.
Hypocortisolism: Treatment with Signifor leads to a rapid suppression of ACTH secretion in Cushing's disease patients. As with any other successful pituitary directed therapy, rapid and complete or near complete suppression of ACTH may lead to a decrease in circulating levels of cortisol and potentially to transient hypocortisolism/hypoadrenalism. Cases of hypocortisolism have been reported in the phase III study in Cushing's disease patients (see Adverse Reactions), generally within the first 2 months of treatment. Except for 1 case in which treatment was discontinued, all other cases were manageable by reducing the dose of Signifor and/or adding low-dose, short-term glucocorticoid therapy.
It is therefore necessary to monitor and instruct patients on the signs and symptoms associated with hypocortisolism (eg, weakness, fatigue, anorexia, nausea, vomiting, hypotension, hyponatremia or hypoglycemia). In case of documented hypocortisolism, temporary exogenous steroid (glucocorticoid) replacement therapy and/or dose reduction or interruption of treatment with Signifor may be necessary.
Cardiovascular Related Events: Bradycardia has been reported with the use of pasireotide (see Adverse Reactions). Patients with cardiac disease and/or risk factors for bradycardia eg, history of clinically significant bradycardia or acute myocardial infarction, high-grade heart block, congestive heart failure [new york heart association classification [New York Heart Association (NYHA) class III or IV], unstable angina, sustained ventricular tachycardia, ventricular fibrillation, should be carefully monitored. Dose adjustments of drugs eg, β-blockers, calcium channel blockers, or agents to control electrolyte balance, may be necessary.
Pasireotide has been shown to prolong the QT interval on the electrocardiogram (ECG) in 2 healthy volunteer studies (see Pharmacology under Actions). The clinical significance of this prolongation is unknown.
In clinical studies in Cushing's disease patients, QTcF of >500 msec was observed in 2 out of 201 patients. These episodes were sporadic and of single occurrence with no clinical consequence observed. Episodes of Torsade de pointes were not observed either in those studies or in clinical studies in other patient populations.
Pasireotide should be used with caution in patients who are at significant risk of developing prolongation of QT eg, 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 anti-arrhythmic medicinal products or other substances that are known to lead to QT prolongation; with hypokalemia and/or hypomagnesemia.
Monitoring for an effect on the QTc interval is advisable and a baseline ECG is recommended prior to initiating therapy with Signifor and as clinically indicated. Hypokalemia or hypomagnesemia must be corrected prior to Signifor administration and should be monitored periodically during therapy.
Liver Tests: Mild transient elevations in aminotransferases have been commonly observed in healthy subjects and patients treated with pasireotide. A few cases of concurrent elevations in alanine aminotransferase (ALT) >3 x ULN and bilirubin >2 x ULN have also been observed (see Adverse Reactions).
Monitoring of liver function is recommended prior to treatment with Signifor and after the first 1-2 weeks and after 2-3 months on treatment. Thereafter, liver function should be monitored as clinically indicated.
Patients who develop increased transaminase levels should be monitored with a 2nd liver function evaluation to confirm the finding. If the finding is confirmed, the patient should be followed with frequent liver function monitoring until values return to pre-treatment levels. Therapy with pasireotide should be discontinued if the patient develops jaundice or other signs suggestive of clinically significant liver impairment, in the event of a sustained increase in aspartate aminotransferase (AST) or ALT of ≥5 x ULN, or if ALT or AST elevations >3 x ULN occur concurrently with bilirubin elevations >2 x ULN. Following discontinuation of treatment with pasireotide, patients should be monitored until resolution. Treatment should not be restarted.
Gallbladder and Related Events: Cholelithiasis is a recognized adverse drug reaction associated with long-term use of somatostatin analogues and has been frequently reported in clinical studies with pasireotide (see Adverse Reactions). 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: Deficiency of pituitary secreted hormones is common after trans-sphenoidal surgery and even more frequently observed post-radiation therapy of the pituitary gland. Cushing's disease patients with persistent or recurrent disease might therefore present with deficiency of ≥1 pituitary hormones. As the pharmacological activity of pasireotide mimics that of somatostatin, inhibition of pituitary hormones, other than ACTH, cannot be ruled out. Therefore, monitoring of pituitary function [eg, thyroid stimulating hormone (TSH)/free T4, GH/IGF-1] prior to initiation of therapy with Signifor and periodically during treatment should be conducted as clinically appropriate.
Drug-Drug Interactions: Pasireotide may decrease the relative bioavailability of cyclosporine (see Interactions). Concomitant administration of Signifor and cyclosporine may require adjustment of the cyclosporine dose to maintain therapeutic levels of the drug.
Impairment of Fertility: It is unknown whether pasireotide has an effect on human fertility. Studies in rats have shown effects on female reproductive parameters (see Pharmacology: Toxicology: Nonclinical Safety Data under Actions).
Labour and Delivery: No data in humans are available. Studies in rats have shown no effects on labour and delivery (see Pharmacology: Toxicology: Preclinical Safety Data under Actions).
Use in Pregnancy: There are no adequate and well-controlled studies in pregnant women. Studies in animals have shown reproductive toxicity (see Pharmacology: Toxicology: Preclinical Safety Data under Actions). The potential risk for humans is not known. Signifor should only be prescribed to pregnant women under compelling circumstances.
Use in Lactation: It is not known whether pasireotide is excreted in human milk. Available data in rats have shown excretion of pasireotide in milk (see Pharmacology: Toxicology: Preclinical Safety Data under Actions). As a risk to the breastfed child cannot be excluded, Signifor should not be used by the nursing mother.
Use in Children: Signifor is not recommended for use in pediatric Cushing's disease patients as there are no clinical data available in patients <18 years.
Use In Pregnancy & Lactation
Use in Pregnancy: There are no adequate and well-controlled studies in pregnant women. Studies in animals have shown reproductive toxicity (see Pharmacology: Toxicology: Preclinical Safety Data under Actions). The potential risk for humans is not known. Signifor should only be prescribed to pregnant women under compelling circumstances.
Use in Lactation:
It is not known whether pasireotide is excreted in human milk. Available data in rats have shown excretion of pasireotide in milk (see Pharmacology: Toxicology: Preclinical Safety Data under Actions). As a risk to the breastfed child cannot be excluded, Signifor should not be used by the nursing mother.
Adverse Reactions
A total of 201 Cushing's disease patients received Signifor in phase II and phase III studies. The safety profile of Signifor was consistent with the somatostatin analogue class, except for the occurrence of hypocortisolism and degree of hyperglycemia.
The data described as follows reflect exposure of 162 Cushing's disease patients to Signifor in the phase III study. At study entry, patients were randomized to receive twice daily doses of either Signifor 0.6 mg or 0.9 mg. The mean age of patients was approximately 40 years old with a predominance of female patients (77.8%). The majority of the patients had persistent or recurrent Cushing's disease (83.3%) and few patients (≤5%) in either treatment group had received previous pituitary irradiation. The median exposure to the treatment up to the cut-off date of the primary efficacy and safety analysis was 10.37 months (0.03-37.8) with 67.9% of patients having at least 6 months exposure.
The frequency and severity of adverse drug reactions (ADRs) was comparable between the 2 dose groups. Grade 1 and 2 ADRs were reported in 57.4% of patients. Grade 3 ADRs were observed in 35.8% of patients and grade 4 ADRs were observed in 2.5% of patients. Grade 3 and 4 ADRs were mostly related to hyperglycemia. The most common ADRs (incidence ≥10%) were diarrhea, nausea, abdominal pain, cholelithiasis, hyperglycemia, diabetes mellitus, fatigue and increased glycosylated hemoglobin. There were no deaths during the study. Adverse reactions reported up to the cut-off date of the analysis, suspected to be drug related by the investigators and with an overall frequency >5% are presented in Table 5 by randomized dose group and overall.
Adverse drug reactions are listed according to MedDRA primary system organ class. Within each system organ class, ADRs are ranked by frequency, with the most frequent reactions first. Frequencies were defined as follows: Very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1000 to <1/100) (see Table 5).

Click on icon to see table/diagram/image

Other Notable ADRs which Occurred with a Frequency <5% Were: Cardiac Disorders: Common: Sinus bradycardia (overall 4.3%); QT prolongation (overall 3.7%).
Vascular Disorders: Common: Hypotension (overall 3.7%).
Blood and Lymphatic Disorders: Uncommon: Anemia (overall 0.6%).
Investigations: Common: Increased blood amylase (overall 2.5%) and prolonged prothrombin time (overall 1.2%).
Description of Selected ADRs: Glucose Metabolism Disorders: Elevated FPG levels was the most frequently reported grade 3 laboratory abnormality (23.2% of patients) in the phase III study in Cushing's disease patients. Mean HbA1c increases were less pronounced in patients with normal glycemia at study entry in comparison to pre-diabetic patients or diabetic patients (see Table 6).

Click on icon to see table/diagram/image

Mean fasting plasma glucose levels commonly increased within the 1st month of treatment with decreases and stabilization observed in subsequent months. Fasting plasma glucose and HbA1c values generally decreased over the 28 days following pasireotide discontinuation but remained above baseline values. Long-term follow-up data are not available. Adverse reactions of hyperglycemia and diabetes mellitus led to study discontinuation in 5 (3.1%) and 4 patients (2.5%), respectively.
Monitoring of blood glucose levels in patients treated with Signifor is recommended (see Precautions).
Gastrointestinal Disorders: As with other somatostatin analogues, gastrointestinal disorders were frequently reported with the use of Signifor. These events were usually of low grade, required no intervention and improved with continued treatment.
Injection Site Reactions: Injection site reactions were reported in 13.6% of patients enrolled in the phase III trial in Cushing's disease. Injection site reactions have also been reported in clinical trials in other populations. The events were most frequently reported as local pain, erythema, hematoma, hemorrhage and pruritus. These events resolved spontaneously and required no intervention.
Thyroid Function: Central hypothyroidism is a commonly described comorbidity in Cushing’s disease. Thyroid dysfunction is also a common adverse reaction associated with the use somatostatin analogs.
Hypothyroidism with the use of Signifor was reported for 7 patients participating in the phase III study in Cushing's disease, 2 of which were considered to be drug-related by the investigator. However, all 7 patients presented with a TSH close to or below the lower limit of normal at study entry, which precludes establishing a conclusive relationship between the adverse event and the use of Signifor.
Liver Enzymes: Transient elevations in liver enzymes have been reported with the use of somatostatin analogs 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 >3 x ULN and bilirubin >2 x ULN have been observed. All cases of concurrent elevations were identified within 10 days of initiation of treatment with Signifor. The individuals recovered without clinical sequelae and liver function test results returned to baseline values after discontinuation of treatment.
Monitoring of liver enzymes is recommended prior and during treatment with Signifor (see Precautions), as clinically appropriate.
Pancreatic Enzymes: Asymptomatic elevations in lipase and amylase have been 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 analogs due to the association between cholelithiasis and acute pancreatitis.
Drug Interactions
No clinical studies have been performed to assess drug-drug interaction potential.
Pasireotide has moderate protein-binding and is metabolically highly stable. Pasireotide appears to be a substrate of efflux transporter P-glycoprotein (P-gp) but is not an inhibitor or inducer of P-gp. In addition, at therapeutic dose levels, pasireotide is not expected to be: A substrate, inhibitor or inducer of any major enzymes of CYP450; a substrate of the efflux transporter breast cancer resistance protein (BCRP) nor of the influx transporters organic cation transporter 1 (OCT1) and organic anion-transporting polypeptide (OATP) 1B1, 1B3 or 2B1; an inhibitor of uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1), influx transporter OATP 1B1 or 1B3, efflux transporter multiresistance protein 2 (MRP2) or bile salt export pump (BSEP).
Based on all these in vitro data, the potential for protein-binding, metabolism and/or transporter-mediated drug-drug interactions is low between pasireotide and co-medications in vivo.
Caution is required when co-administering Signifor with anti-arrhythmic medicines and other drugs that may prolong the QT interval (see Precautions).
Anticipated Interactions Resulting in Effects on Other Drugs: Limited published data suggest that somatostatin analogs might have an indirect effect in decreasing the metabolic clearance of compounds metabolized by CYP450 enzymes, via suppression of growth hormone secretion. The possibility that pasireotide may exert such an indirect effect cannot be excluded based on available data. Caution should be exercised when administering pasireotide concomitantly with drugs possessing a low therapeutic index and which are metabolized mainly by CYP3A4 (eg, quinidine, terfenadine).
In dogs, pasireotide has been found to decrease blood level of cyclosporine by reducing its intestinal absorption. It is unknown whether such interaction occurs in humans. Therefore, dose adjustments of cyclosporine may be required when co-administering pasireotide and cyclosporine (see Precautions).
Limited data with other somatostatin analogues suggest that co-administration with bromocriptine may increase the availability of bromocriptine. Available data cannot exclude the possibility that pasireotide may exert such an effect.
Incompatibilities: No compatibility data with other products have been generated. Pasireotide solution for injection is to be used without any dilution and must not to be mixed with other medicinal products.
Caution For Usage
Instructions for Use, Handling and Disposal: The Injection Site: The injection site is the place on the body where injection is administered. Signifor is intended for SC use. This means that it is injected through a short needle into the fatty tissue just under the skin. The thighs and the abdomen are good areas for SC injection. Avoid soreness and skin irritation by choosing a different site from the previous one for each injection. Avoid injections at sites that are sore or where the skin is irritated.
Getting Started: Carefully follow the steps as follows when injection is to be administered: Wash hands thoroughly with soap and water. Always use a new disposable needle and syringe every time an injection is to be administered. Use syringes and needles only once. Never share needles and syringes with someone else. Take the ampule out of the box. Carefully inspect the ampule. Do not use if it is broken or if the liquid looks cloudy or contains particles. In all these cases, return the entire pack to the pharmacy.
Check the Expiry Date and the Dose: Check the expiry date which is stated on the carton and ampule label and check that it is the dose the physician has prescribed.
Do not use if the medicine has expired or if the dose is incorrect. In both these cases, return the entire pack to the pharmacy.
How to Inject Signifor: Clean the injection site selected with an alcohol swab.
Step 1: Signifor solution for injection is filled in a snap-off ampule. Tap the ampule with the finger in order to make sure there is no liquid in the lid when opening the ampule.
Step 2: Open ampule by snapping off the top at the line marked on the ampule neck. Once open, put the ampule upright on a clean, flat surface.
Step 3: Take the sterile syringe and attach the needle to it. Remove the cover from the needle.
Step 4: Put the needle into the ampule and pull the plunger to draw the entire contents of the ampule into the syringe.
Step 5: Hold the syringe in 1 hand between 2 fingers with the thumb at the bottom of the plunger. Tap the syringe with the fingers to get rid of air bubbles. Make sure there is no air bubble in the syringe by pressing the plunger until the 1st drop appears on the tip of the needle. Do not let the needle touch anything. Signifor is ready to be injected.
Step 6: Gently pinch the skin at the injection site and, holding the needle at an angle of approximately 45° insert it into the injection site. Pull slightly on the plunger to check that a blood vessel has not been punctured. If blood is seen in the syringe, remove the needle and insert it into a different injection site.
Step 7: Always keep the skin pinched, slowly press down the plunger as far as it will go until all the solution is injected. Keep the plunger pressed down and hold the syringe in place for 5 sec.
Step 8: Slowly release the skin fold and gently pull the needle out. Put the cover back on the needle.
Step 9: Dispose of the used syringe and needle immediately in a sharps container or other rigid closed disposal container. Any unused product or waste material should be disposed of in accordance with local requirements.
ATC Classification
H01CB05 - pasireotide ; Belongs to the class of antigrowth hormone. Used in hypothalamic hormone preparations.
Presentation/Packing
Soln for inj (amp) 0.6 mg/mL x 1 x 6's. 0.9 mg/mL x 1 x 6's.
Register or sign in to continue
Asia's one-stop resource for medical news, clinical reference and education
Sign up for free
Already a member? Sign in