Signifor Lar Drug Information
Generic name: PASIREOTIDE
Uses of Signifor Lar
Acromegaly
SIGNIFOR LAR is indicated for the treatment of patients with acromegaly who have had an inadequate response to surgery and/or for whom surgery is not an option.
Cushing's Disease
SIGNIFOR LAR is indicated for the treatment of patients with Cushing's disease for whom pituitary surgery is not an option or has not been curative.
Dosage & Administration of Signifor Lar
| 10 mg | 10 mg/2 mL |
|---|---|
| 20 mg | 20 mg/2 mL |
| 30 mg | 30 mg/2 mL |
| 40 mg | 40 mg/2 mL |
| 60 mg | 60 mg/2 mL |
Side Effects of Signifor Lar
Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in clinical trials of a drug cannot be directly compared to rates in clinical trials of another drug and may not reflect the rates observed in practice. Drug-Naïve Patients With Acromegaly The data described in Table 1 are derived from an active-controlled trial in patients with acromegaly naïve to previous drug therapy . The data reflect exposure of 178 patients with acromegaly to SIGNIFOR LAR for a mean duration of 43 weeks. In the overall study population, 52% were female and the average age of patients was 45 years.
Table 1 presents common adverse reactions associated with SIGNIFOR LAR in this study. These adverse reactions were not present at baseline or, if present, worsened from baseline and occurred in at least 5% of patients treated with SIGNIFOR LAR. Table 1 – Adverse Reactions Occurring in Greater Than or Equal to 5% of Patients Exposed to SIGNIFOR LAR in Patients With Acromegaly Naïve to Drug Therapy a Diabetes mellitus includes the following PTs: diabetes mellitus and type 2 diabetes mellitus. b Sinus bradycardia includes the following PTs: bradycardia and sinus bradycardia. c Injection-site reaction related AEs includes the following PTs: injection-site pain, injection-site reaction, injection-site haematoma, injection-site pruritus, injection-site swelling, injection-site erythema. Adverse Reaction Type SIGNIFOR LAR (40-60 mg) % N = 178 Active Comparator % N = 180 Hyperglycemia Related Adverse Reactions Hyperglycemia 29 8 Diabetes mellitus a 26 4 Blood glucose increased 8 2 Glycosylated hemoglobin increased 6 2 Hypoglycemia 5 7 Gastrointestinal Related Adverse Reactions Diarrhea 39 45 Abdominal pain 18 22 Nausea 14 22 Abdominal distension 12 12 Vomiting 8 7 Abdominal pain upper 6 8 Hepatobiliary Related Adverse Reactions Cholelithiasis 26 36 Cardiac Related Adverse Reactions Sinus bradycardia b 10 7 Hypertension 8 7 Nervous System Related Adverse Reactions Headache 19 26 Dizziness 10 11 Skin Related Adverse Reactions Alopecia 18 19 Infections Related Adverse Reactions Nasopharyngitis 16 16 Influenza 8 4 Upper respiratory tract infection 7 3 Cough 5 8 Laboratory Related Adverse Reactions Blood creatine phosphokinase increased 13 12 Alanine aminotransferase increased 8 4 Aspartate aminotransferase increased 6 4 Lipase increased 6 7 Weight decreased 5 4 General and Injection-Site Related Adverse Reactions Fatigue 10 10 Injection-site reaction c 7 7 Musculoskeletal and Connective Tissue Related Adverse Reactions Arthralgia 10 12 Back pain 8 11 Pain in extremity 7 4 Blood Related Adverse Reactions Anemia 6 6 Other notable adverse reactions which occurred with a frequency of 5% or less for SIGNIFOR LAR were: adrenal insufficiency (3%); glucose tolerance impaired (1%); QT-prolongation (4%); blood amylase increased (2%). Patients With Acromegaly Inadequately Controlled on Other Somatostatin Analogs at Baseline The data described in Table 2 are derived from an active-controlled study in patients with acromegaly inadequately controlled at baseline on other somatostatin analogs . These data reflect exposure of 63 and 62 patients to SIGNIFOR LAR 40 mg and 60 mg, respectively, for a mean duration of 24 weeks.
In the overall study population, 56% were female and the average age of patients was 45 years. Table 2 presents common adverse reactions associated with SIGNIFOR LAR in this study. These common adverse reactions were not present at baseline, or if present, worsened from baseline and occurred in at least 5% of patients treated with SIGNIFOR LAR. Table 2 – Adverse Reactions Occurring in Greater Than or Equal to 5% of Patients Exposed to SIGNIFOR LAR in Patients With Acromegaly Previously Treated With Other Somatostatin Analogs a Diabetes mellitus includes the following PTs: diabetes mellitus and type 2 diabetes mellitus.
Adverse Drug Reactions SIGNIFOR LAR 40 mg % N = 63 SIGNIFOR LAR 60 mg % N = 62 Active Comparators % N = 66 Hyperglycemia Related Adverse Reactions Hyperglycemia 33 30 14 Diabetes mellitus a 21 31 9 Blood glucose increased 5 7 0 Hypoglycemia 3 7 0 Gastrointestinal Related Adverse Reactions Diarrhea 16 19 5 Abdominal pain 8 8 3 Nausea 3 7 3 Hepatobiliary Related Adverse Reactions Cholelithiasis 10 13 14 Cardiac Related Adverse Reactions Atrioventricular block first degree 6 0 0 Nervous System Related Adverse Reactions Headache 14 3 5 Dizziness 8 2 3 Skin and Subcutaneous Tissue Related Adverse Reactions Alopecia 2 7 0 Infections Related Adverse Reactions Nasopharyngitis 6 11 3 Blood Related Adverse Reactions Anemia 6 3 3 Other notable adverse reactions which occurred with a frequency of 5% or less in the SIGNIFOR LAR 40 mg, SIGNIFOR LAR 60 mg arm, respectively, were adrenal insufficiency (2% and 0%) and glucose tolerance impaired (3% and 5%). Patients With Cushing's Disease The data described in Table 3 are derived from a randomized clinical study in 150 patients with Cushing's disease . These data reflect exposure of 74 and 76 patients to SIGNIFOR LAR at a starting dose of 10 mg and 30 mg once every 28 days, respectively, for a mean duration of 68 weeks. In the overall study population, 79% of patients were female and the average age was 39 years at study entry. Table 3 presents common adverse reactions which were not present at baseline or, if present, worsened from baseline and occurred in at least 5% of patients treated with SIGNIFOR LAR. Table 3 – Adverse Reactions Occurring in Greater Than or Equal to 5% of Patients Exposed to SIGNIFOR LAR in Patients With Cushing's Disease a Diabetes mellitus consists of the two terms: diabetes mellitus and type 2 diabetes mellitus. b Abdominal pain includes the term abdominal pain upper. c Sinus bradycardia includes the term bradycardia. d Fatigue includes the term asthenia.
Adverse Reactions Overall % N = 150 Endocrine Related Adverse Reactions Adrenal insufficiency 7 Blood cortisol decreased 5 Hyperglycemia Related Adverse Reactions Hyperglycemia 47 Diabetes mellitus a 27 Hypoglycemia 15 Blood glucose increased 9 Glycosylated hemoglobin (HbA1C) increased 5 Gastrointestinal Related Adverse Reactions Diarrhea 39 Nausea 21 Abdominal pain b 23 Constipation 7 Abdominal distension 5 Flatulence 5 Vomiting 5 Hepatobiliary Related Adverse Reactions Cholelithiasis 33 Gamma-glutamyltransferase increased 9 Alanine aminotransferase increased 7 Cardiac Related Adverse Reactions Hypertension 15 Hypotension 6 Sinus bradycardia c 5 General Related Adverse Reactions Fatigue d 27 Edema peripheral 14 Musculoskeletal and Connective Tissue Related Adverse Reactions Back pain 11 Arthralgia 8 Pain in extremity 7 Myalgia 5 Metabolism and Nutrition Related Adverse Reactions Decreased appetite 10 Hyperuricemia 7 Hypercholesterolemia 6 Blood Related Adverse Reactions Anemia 5 Other adverse reactions which occurred at a frequency less than 5% were cholestasis (4%), glucose tolerance impaired (3%), aspartate aminotransferase increased (3%), vomiting (3%), lipase increased (3%), injection-site reactions (2%), ECG QT prolonged (1%), cholecystitis (1%), amylase increased (1%), and prothrombin time prolonged (1%). Hyperglycemia The average FPG levels in patients with acromegaly naïve to drug therapy study across visits is shown in Figure 2 below. Figure 2. Mean Fasting Plasma Glucose (mg/dL) By Visit in the Study of Patients With Acromegaly Naïve to Drug Therapy Numbers of patients with a glucose value at the given timepoint in the SIGNIFOR LAR/Active comparator arms are displayed as xxx/xxx on the x axis. Pancreatic Enzyme Elevation and Pancreatitis Asymptomatic elevations in lipase and alpha amylase were observed in 30% and 20% of patients receiving SIGNIFOR LAR in the drug naïve study in acromegaly, and in 1% and 3% of patients receiving SIGNIFOR LAR in the study of acromegaly patients previously treated.
In the drug-naïve study, 2 acromegaly patients receiving SIGNIFOR LAR developed pancreatitis. In the Cushing's disease study, increased lipase was observed in 4% of patients, and 1 patient developed pancreatitis. Pancreatitis is a potential adverse reaction associated with the use of SIGNIFOR LAR due to the association between cholelithiasis and acute pancreatitis.
Figure 2. Mean Fasting Plasma Glucose (mg/dL) By Visit in the Study of Patients With Acromegaly Naïve to Drug Therapy*
Postmarketing Experience Additional adverse reactions have been identified during post-approval use of
SIGNIFOR LAR. Because these reactions are reported voluntarily from a population of uncertain size, it is generally not possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Cholelithiasis resulting in complications, including cholecystitis and cholangitis, which have sometimes required cholecystectomy
Warnings & Cautions for Signifor Lar
Hyperglycemia, Diabetes, and Ketoacidosis
SIGNIFOR LAR can cause increases in blood glucose levels which are sometimes severe. There have been postmarketing cases of ketoacidosis with SIGNIFOR LAR in patients with history of diabetes and in patients without history of diabetes. In the acromegalic patient study, 5 patients naïve to drug therapy treated with SIGNIFOR LAR (2 of whom were normoglycemic at baseline) and none in the active comparator group were hospitalized for hyperglycemia (blood glucose range 359-506 mg/dL). Two additional patients who had received active comparator in the main trial and were switched to SIGNIFOR LAR in the extension trial, were hospitalized for elevated glucose levels while on SIGNIFOR LAR; one of those patients developed diabetic ketoacidosis.
In the Cushing's disease study, 2 patients were hospitalized for elevated blood glucose. In clinical studies for acromegaly and Cushing's disease, SIGNIFOR LAR caused an increase in the incidence of diabetes and prediabetes. A majority of patients, including those with normal glucose tolerance, prediabetes and diabetes, experienced increased glucose levels within the first 3 months of treatment.
In the drug-naïve acromegaly study, the prevalence of diabetes increased from 30% at baseline to 60% at Month 12. In the study evaluating acromegaly patients previously treated with somatostatin analogs, the prevalence of diabetes increased from 71% at baseline to 87% at Month 6 in patients treated with SIGNIFOR LAR 40 mg, and from 60% to 84% in patients treated with SIGNIFOR LAR 60 mg. In the Cushing's disease study, the prevalence of diabetes increased from 40% at baseline to 56% at Month 12. Patients with poor baseline glycemic control are at higher risk of developing severe hyperglycemia. Assess FPG and HbA1c prior to starting treatment with SIGNIFOR LAR . In patients with poorly controlled diabetes mellitus, optimize anti-diabetic treatment before SIGNIFOR LAR initiation.
Monitor blood glucose weekly for the first 3 months after initiating SIGNIFOR LAR and the first 4- to 6 weeks after dose increases. Continue monitoring thereafter, as clinically appropriate. Patients who develop significant hyperglycemia on SIGNIFOR LAR may require initiation of anti-diabetic treatment or adjustment in their current anti-diabetic treatment.
The optimal treatment for the management of SIGNIFOR LAR-induced hyperglycemia is not known. If hyperglycemia cannot be controlled despite medical management, reduce the dose of SIGNIFOR LAR or discontinue SIGNIFOR LAR. Assess FPG and HbA1c after SIGNIFOR LAR discontinuation, if indicated. Patients receiving anti-diabetic treatment may require more frequent blood glucose monitoring and dose adjustment to their anti-diabetic drug therapy to mitigate the risk of hypoglycemia after discontinuing SIGNIFOR LAR. Patients who present with signs and symptoms consistent with severe metabolic acidosis should be assessed for ketoacidosis regardless of diabetes history.
In some reported post-marketing cases of ketoacidosis in patients taking SIGNIFOR LAR, factors predisposing to ketoacidosis such as acute illness, infection, pancreatic disorders (e.g., pancreatic malignancy or pancreatic surgery), and alcohol abuse were present. If ketoacidosis is suspected, discontinue SIGNIFOR LAR and promptly evaluate and treat the patient.
Bradycardia and QT Prolongation Bradycardia Bradycardia has been reported with the use
of SIGNIFOR LAR . Patients with cardiac disease and/or risk factors for bradycardia, such as history of clinically significant bradycardia, high-grade heart block, or concomitant use of drugs associated with bradycardia, should be monitored. Adjustments in the dose of drugs known to slow the heart rate (e.g., beta-blockers, calcium channel blockers) and correction of electrolyte disturbances may be necessary when initiating or during the course of SIGNIFOR LAR treatment. QT Prolongation In cardiac electrophysiology studies (i.e., thorough QT studies) with pasireotide via subcutaneous route, QT prolongation occurred at therapeutic and supra-therapeutic doses . In the clinical studies, a corrected QT interval (i.e., QTcF) of greater than 480 ms was reported in 6 patients and an increase in the QTcF from baseline of greater than 60 ms was reported for seven patients on SIGNIFOR LAR. No patient on SIGNIFOR LAR had a QTcF value of greater than 500 ms . SIGNIFOR LAR should be used with caution in patients who are at significant risk of developing prolongation of the QT interval, such as those listed below: with congenital long QT prolongation with uncontrolled or significant cardiac disease including recent myocardial infarction, congestive heart failure, unstable angina or clinically significant bradycardia on anti-arrhythmic therapy or other substances that are known to lead to QT prolongation with hypokalemia and/or hypomagnesemia A baseline ECG is recommended prior to initiating therapy with SIGNIFOR LAR. Monitoring for an effect on the QT interval at the time of maximum drug concentration (21 days after injection) should be obtained in patients at risk.
Hypokalemia or hypomagnesemia must be corrected prior to initiating SIGNIFOR LAR and should be monitored periodically during therapy.
Liver Test Elevations Increases in liver enzymes have been observed with
SIGNIFOR LAR. In all Phase 3 acromegaly studies and across all doses, alanine aminostransferase (ALT) or aspartate aminotransferase (AST) elevations greater than 3 times the upper limit of normal (ULN) were observed in 4% of acromegaly patients and ALT or AST elevations greater than 5 times the ULN were observed in 1% of acromegaly patients treated with SIGNIFOR LAR. In the Phase 3 Cushing's disease study and across all doses, ALT or AST elevations greater than 3 times the ULN were observed in 14% of Cushing's disease patients and ALT or AST elevations greater than 5 times the ULN were observed in 5% of Cushing's disease patients treated with SIGNIFOR LAR. Assessment of liver function is recommended prior to treatment with SIGNIFOR LAR, and after the first 2- to 3 weeks, then monthly for 3 months. Thereafter, liver function should be monitored as clinically indicated. Patients who develop increased transaminase levels, should be monitored until values return to pre-treatment levels.
Treatment with SIGNIFOR LAR should be discontinued if signs or symptoms suggestive of clinically significant liver impairment develop. Following discontinuation of treatment with SIGNIFOR LAR, patients should be monitored until resolution. Treatment should not be restarted, if the liver function abnormalities are suspected to be related to SIGNIFOR LAR.
Cholelithiasis and Complications of Cholelithiasis Cholelithiasis was reported in 33% of drug-naïve
and 10% of inadequately controlled (40 mg dose) acromegaly patients treated with SIGNIFOR LAR in clinical trials . Cholelithiasis was reported in 33% of Cushing's disease patients treated with SIGNIFOR LAR. There have been postmarketing reports of cholelithiasis (gallstones) resulting in complications, including cholecystitis or cholangitis and requiring cholecystectomy in patients taking SIGNIFOR LAR. Patients should be monitored periodically. If complications of cholelithiasis are suspected, discontinue SIGNIFOR LAR and treat appropriately.
Pituitary Hormone Deficiency(ies) Suppression of anterior pituitary hormones may occur on
SIGNIFOR LAR. Monitoring pituitary function (e.g., thyroid, adrenal, gonadal) prior to initiation of therapy with SIGNIFOR LAR, as well as periodically during treatment, as clinically appropriate, is recommended. Patients should be monitored for and instructed on the signs and symptoms of adrenal insufficiency during therapy. If adrenal insufficiency is suspected, it should be confirmed and treated per standard of care with exogenous glucocorticoids at replacement doses.
Steatorrhea and Malabsorption of Dietary Fats New onset steatorrhea, stool discoloration and
loose stools have been reported in patients receiving somatostatin analogs, including pasireotide products. Somatostatin analogs reversibly inhibit secretion of pancreatic enzymes and bile acids, which may result in malabsorption of dietary fats and subsequent symptoms of steatorrhea, loose stools, abdominal bloating, and weight loss. If new occurrence or worsening of these symptoms are reported in patients receiving SIGNIFOR LAR, evaluate patients for potential pancreatic exocrine insufficiency and manage accordingly.
Drug Interactions with Signifor Lar
Effect of Other Drugs on
SIGNIFOR LAR Drugs That Prolong QT Co-administration of drugs that prolong the QT interval with SIGNIFOR LAR may have additive effects on the prolongation of the QT interval. Monitoring effects on the QT interval at 21 days is recommended .
Effect of
SIGNIFOR LAR on Other Drugs Cyclosporine Concomitant administration of cyclosporine with SIGNIFOR LAR may decrease the relative bioavailability of cyclosporine and, therefore, dose adjustment of cyclosporine to maintain therapeutic levels may be necessary. Bromocriptine Co-administration of SIGNIFOR LAR with bromocriptine may increase the blood levels of bromocriptine. Dose reduction of bromocriptine may be necessary.
Pregnancy Safety for Signifor Lar
Pregnancy Risk Summary The limited data with SIGNIFOR LAR in pregnant women are insufficient to inform a drug-associated risk for major birth defects and miscarriage. In embryo-fetal development studies in rabbits, findings indicating a developmental delay were observed with subcutaneous administration of pasireotide during organogenesis at doses less than the exposure in humans at the highest recommended dose; maternal toxicity was not observed at this dose (see Data ). The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2%-4% and 15%-20%, respectively.
Data Animal Data In embryo-fetal development studies in rats given 1 mg/kg/day, 5 mg/kg/day, and 10 mg/kg/day subcutaneously throughout organogenesis, maternal toxicity was observed at all doses, including the lowest dose tested which had exposures 12 times higher than that at the maximum therapeutic dose based on area under the curve (AUC) comparisons across species. An increased incidence of early/total resorptions and malrotated limbs was observed in rats at 10 mg/kg/day. At 10 mg/kg/day in rats, the maternal systemic exposure (AUC) was 42179 ng*hr/mL, approximately 106 times the exposure in humans at the highest recommended dose of 60 mg SIGNIFOR LAR administered as an intramuscular injection once every 4 weeks.
In embryo-fetal development studies in rabbits given 0.05 mg/kg/day, 1 mg/kg/day, and 5 mg/kg/day subcutaneously through organogenesis, maternal toxicity was observed at 1 mg/kg/day, at a maternal systemic exposure (AUC) of 1906 ng*hr/mL, approximately 5 times higher than the maximum human therapeutic exposure. An increased incidence of unossified forepaw phalanx, indicative of a developmental retardation, was observed in rabbits at 0.05 mg/kg/day, with maternal systemic exposures less than the systemic exposure in humans at the highest recommended dose. In pre- and post-natal developmental studies in rats given subcutaneous doses of 2 mg/kg/day, 5 mg/kg/day, and 10 mg/kg/day during gestation through lactation and weaning, maternal toxicity was observed at all doses including the lowest dose (9 times higher than the maximum therapeutic dose based on surface area comparisons across species). Retardation of physiological growth, attributed to GH inhibition was observed at 2 mg/kg/day during a pre- and post-natal study in rats.
After weaning, body weight gains in the rat pups (F1 generation) exposed to pasireotide were comparable to controls, showing reversibility of this developmental delay.
Pediatric Use of Signifor Lar
Pediatric Use Safety and effectiveness of SIGNIFOR LAR have not been established in pediatric patients.
Overdosage Information for Signifor Lar
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. Up-to-date information about the treatment of overdose can be obtained from a certified Regional Poison Center. In the event of an overdose, contact the National Capital Poison Center at 1-800-222-1222 or www.poison.org.
Clinical Studies of Signifor Lar
Drug-Naïve Patients with Acromegaly
A multicenter, randomized, double-blind study was conducted to assess the safety and efficacy of SIGNIFOR LAR in patients with active acromegaly. A total of 358 patients naïve to drugs used to treat acromegaly were randomized in a 1:1 ratio to SIGNIFOR LAR or another somatostatin analog active comparator. Randomization was stratified based on previous pituitary surgical status (e.g., at least 1 prior pituitary surgery versus no prior pituitary surgery). In the overall study population, 52% were female and the average age of patients was 45 years.
Sixty percent of patients were Caucasian, 23% Asian, 12% Other, 3% American Indian, and 2% were Black. Forty-two percent of patients had previous pituitary surgery, and 1 patient had a history of pituitary radiation therapy. Median time between diagnosis and trial participation was 6 months.
Median GH was 8.8 mcg/L (range: 0.8-200 mcg/L) and 10.1 mcg/L (range: 0.6-169.6 mcg/L) for SIGNIFOR LAR and active comparator, respectively at baseline. Median standardized IGF-1, defined as IGF-1 value divided by the ULN (i.e., fold above the ULN), was 2.9 (range: 0.9-6.9) and 2.9 (range: 0.8-7.3), for SIGNIFOR LAR and active comparator, respectively, at baseline. The starting dose of SIGNIFOR LAR was 40 mg.
Dose increase was allowed in both arms, at the discretion of investigators, after 3 and 6 months of treatment if mean GH was greater than or equal to 2.5 mcg/L and/or IGF-1 was greater than the ULN for age and sex. The maximum allowed dose for SIGNIFOR LAR was 60 mg. The maximum dose of the active comparator was not used in this trial because the trial was multi-national and the maximum dose approved in the US was not approved in all participating countries.
The efficacy endpoint was the proportion of patients with a mean GH level less than 2.5 mcg/L and a normal IGF-1 levels at month 12 (age- and sex-adjusted) (see Table 5, Figure 3, and Figure 4). The proportion of patients achieving this level of control was 31.3% and 19.2% for SIGNIFOR LAR and active comparator, respectively. The changes in mean GH and IGF-1 levels by study visits in subjects with a measurement at these visits (observed cases) are shown in Figures 3 and 4. Table 5 – Results at Month 12 in Drug-Naïve Patients Study SIGNIFOR LAR (40-60 mg) % N = 176 Active Comparator c % N = 182 GH < 2.5 mcg/L and normalized IGF-1 a 31.3% b 19.2% GH < 2.5 mcg/L and IGF-1 ≤ ULN 35.8% 20.9% Normalized IGF-1 38.6% b 23.6% GH < 2.5 mcg/L 48.3% 51.6% a Primary endpoint. ULN = Upper limit of normal. b p-value < 0.01 for treatment difference. c The maximum dose approved for use in the United States was not used in this trial but the majority of patients were receiving the dose most commonly used in the United States to treat acromegaly.
Figure 3. Mean GH (mcg/L) Levels By Visit in Drug Naïve Patient Study Numbers of patients with a GH value at the given timepoint for SIGNIFOR LAR/Active comparator arm are displayed as xxx/xxx on the x-axis. Figure 4. Mean Standardized IGF-1 Levels Fold above the upper limit of normal for the assay By Visit in Drug Naïve Patient Study Numbers of patients with an IGF-1 value at the given timepoint for SIGNIFOR LAR/Active comparator arm are displayed as xxx/xxx on the x axis. Biochemical control was achieved by Month 3 in 30.1% of patients in the SIGNIFOR LAR arm.
Ninety-eight percent of patients treated with SIGNIFOR LAR had either a reduction or no change in tumor volume from baseline assessed by MRI at Month 12. The median (range) change in tumor volume was a reduction of 39.8% (-97.6% to 16.9%). Additionally, ring size and acromegaly symptoms score (i.e., headache, fatigue, perspiration, paresthesia, and osteoarthralgia) were followed. At Month 12, reductions in ring size and in symptom severity scores in both treatment groups compared to baseline were noted. Figure 3: Mean GH (mcg/L) Levels By Visit in Drug Naïve Patient Study* Figure 4: Mean Standardized IGF-1 Levels* By Visit in Drug Naïve Patient Study**
Patients with Acromegaly Inadequately Controlled on Other Somatostatin Analogs
A multicenter, randomized, 3-arm study was conducted in patients with acromegaly inadequately controlled on somatostatin analogs. Patients were randomized to double-blind SIGNIFOR LAR 40 mg (n = 65) or SIGNIFOR LAR 60 mg (n = 65) or to continued open-label pretrial somatostatin analog therapies at maximal or near maximal doses (n = 68). A total of 181 patients completed the 6-month trial. Inadequate control was defined as a GH concentration of greater than 2.5 mcg/L (i.e., mean of 5 samples over 2 hours) and a sex- and age-adjusted IGF-1 level greater than 1.3 times the upper limit of normal.
Patients were required to have been treated with other somatostatin analogs for at least 6 months prior to randomization. Note that the maximum dose for one of the active comparators approved for use in the United States was not used in this multinational trial; approximately 75% of the population in the comparator group was receiving this active comparator. In the overall study population, 56% were female and the average age of patients was 45 years.
Eighty-one percent of patients were Caucasian, 7% Other, 8% Black, 2% American Indian, and 2% Asian. The percentage of patients with previous pituitary surgery in the SIGNIFOR LAR 40 mg and 60 mg arms, and in the active control arm was 77%, 63%, and 60%, respectively. Three percent of patients in the SIGNIFOR LAR groups and 7% of patients in the active control arm had prior radiation therapy.
Median (range) time from diagnosis to participation in this trial was 50 (10-337) months, 55 (8-357) months, and 54 (8-357) months in the SIGNIFOR LAR 40 mg, 60 mg and the pretrial therapy arms, respectively. At baseline, median (range) GH was 7.1 (1.0-200) mcg/L, 5.3 (1.4-113.8) mcg/L and 6.1 (1.0-92.4) mcg/L in the SIGNIFOR LAR 40 mg, 60 mg and the pretrial therapy arms, respectively. Baseline median standardized IGF-1 (defined as IGF-1 value divided by the ULN) values were 2.3, 2.6 and 2.9 in the SIGNIFOR LAR 40 mg, 60 mg and the pretrial therapy arms, respectively.
The efficacy endpoint was the proportion of patients with a mean GH level less than 2.5 mcg/L and normal IGF-1 levels at week 24. The primary analysis compared SIGNIFOR LAR 60 mg and 40 mg to continued pretrial therapy (i.e., no change in treatment). The proportion of patients achieving biochemical control was 15.4% and 20.0% for SIGNIFOR LAR 40 mg and 60 mg, respectively, at 6 months. Biochemical control was achieved by Month 3 in 15.4% and 18.5% of patients in the SIGNIFOR LAR 40 mg and 60 mg arms, respectively. Table 6 – Results at 6 Months in Inadequately Controlled Patient Study a Primary endpoint (patients with IGF-1 < lower limit of normal (LLN) were not considered as "responders"). b For one of the active comparators, the maximum dose approved for use in the United States was not used in this trial but the majority of patients were receiving the dose most commonly used in the United States to treat acromegaly.
SIGNIFOR LAR 40 mg % N = 65 SIGNIFOR LAR 60 mg % N = 65 Continued Pre-Trial Therapy Control Arm b % N = 68 GH < 2.5 mcg/L and normalized IGF-1 a 15.4% 20.0% 0% Normalization of IGF-1 24.6% 26.2% 0% GH < 2.5 mcg/L 35.4% 43.1% 13.2% Eighty-one percent and 70% of patients treated with SIGNIFOR LAR 40 mg and 60 mg, respectively, had either a reduction or no change in tumor volume from baseline assessed by MRI at Month 6. The median (range) change in tumor volume was a reduction of -10.4% (-74.5% to 19.4%) and -6.3% (-66.7% to 14.5%) from baseline for SIGNIFOR LAR 40 mg and 60 mg, respectively.
Patients with Cushing's Disease
A Phase 3, randomized, double-blind, multicenter study was conducted to evaluate the safety and efficacy of two dose regimens of SIGNIFOR LAR over a 12-month treatment period in patients with persistent or recurrent Cushing's disease, or de novo patients who were not considered candidates for pituitary surgery. The study enrolled 150 patients with a screening mean urinary free cortisol level (mUFC) ≥ 1.5 and ≤ 5 x ULN, who were randomized in a 1:1 ratio to receive a SIGNIFOR LAR starting dose of either 10 mg intramuscularly once every 28 days or 30 mg intramuscularly once every 28 days. Randomization was stratified by values of mUFC at screening (1.5 to < 2 x ULN versus 2 to 5 x ULN, respectively). After four months of treatment, patients who had a mUFC ≤ 1.5 x ULN continued on the blinded dose to which they were randomized.
Patients with a mUFC > 1.5 x ULN at Month 4 had their doses increased in a blinded manner from 10 mg to 30 mg, or from 30 mg to 40 mg, provided there were no tolerability concerns. Additional dose increases were allowed at Month 7 and Month 9 (by one dose level if the mUFC was > 1 x ULN). Dose reduction by one dose level for tolerability was allowed in a blinded fashion for the first seven months, with a minimum dose level of 5 mg. After the first seven months, blinded down titration of more than one dose level was allowed at any month.
After twelve months of treatment (core phase), patients had the option to enter an extension to continue to receive SIGNIFOR LAR if they benefited from treatment. The primary efficacy endpoint was the proportion of patients in each arm who were mUFC responders (mUFC ≤ ULN) after seven months of treatment, with or without up-titration at Month 4. The key secondary endpoint was the proportion of patients in each arm who were mUFC responders after seven months of treatment and who did not up-titrate the dose prior to Month 7. The pre-specified boundary of the lower limit of the 95% confidence interval (CI) for efficacy for both the primary and key secondary endpoints was 15%. Patients with missing mUFC assessment at Month 7 were classified as non-responders. Other secondary endpoints included changes from baseline in 24-hour UFC, plasma ACTH, and serum cortisol levels.
All analyses were conducted based on the randomized dose groups. Baseline demographics and disease history were well balanced between the two randomized dose groups and consistent with the epidemiology of the disease. The mean age of patients was approximately 38.5 years with a predominance of female patients (78.7%). The majority of the patients had persistent or recurrent Cushing's disease (82.0%). The median value of the baseline 24-hour mUFC for all patients was 396.9 nmol/24 hours (ULN: 166.5 nmol/24 hours). About three-quarters of all randomized patients completed seven months of treatment, and about two-thirds of all randomized patients completed twelve months of treatment.
The study met the primary efficacy objective for both dose groups. Patients were considered responders if they remained on treatment until at least Month 7 and achieved a Month 7 mUFC ≤ 1 x ULN, regardless of up-titration at Month 4. The proportion of patients with mUFC response at Month 7 was 39.2% (95% CI: 28.0, 51.2) in the 10 mg arm and 40.8% (95% CI: 29.7, 52.7) in the 30 mg arm. The responder rate at Month 12 was 35.1% (26/74) and 25.0% (19/76) in the 10 mg and 30 mg starting dose groups, respectively.
Table 7 – Response Rates at Month 7 per Randomized Dose Group and According to Screening mUFC There were 17 (23.0%) patients in 10 mg arm and 9 (11.8%) in the 30 mg arm with missing value mUFC assessments at Month 7 who were classified as non-responders. Pasireotide LAR 10 mg Every 28 Days Pasireotide LAR 30 mg Every 28 Days Screening mUFC category n/N (%) 95% CI n/N (%) 95% CI All patients 29/74 31/76 ≥ 1.5 x ULN to < 2 x ULN 11/25 13/25 ≥ 2 x ULN to ≤ 5 x ULN 18/49 18/51 The study met the key secondary efficacy objective for both dose groups. At Month 4, 31/74 (41.9%) and 28/76 (36.8%) patients were up-titrated in the pasireotide LAR 10 mg and 30 mg arms, respectively.
When all patients who up-titrated prior to Month 7 were counted as non-responders, Month 7 mUFC response was observed in 25.7% (95% CI: 16.2 to 37.2) and 31.6% (95% CI: 21.4 to 43.3) of patients randomized to pasireotide LAR at a starting dose of 10 mg once every 28 days and 30 mg once every 28 days, respectively. A secondary efficacy analysis was conducted for the combined proportion of patients who attained mUFC ≤ ULN (controlled) or had at least 50% reduction in mUFC (partially controlled) in the core phase of the study. The combined rate of controlled or partially controlled responders at Month 7 constituted 44.6% and 53.9% of patients randomized to the 10 mg and 30 mg dose groups, respectively (Table 8). Table 8 – Response Rates at Month 7 per Randomized Dose Group - Supportive Efficacy Analysis Response Category Pasireotide LAR 10 mg Every 28 Days (N = 74) n (%) Pasireotide LAR 30 mg Every 28 Days (N = 76) n (%) Controlled (mUFC ≤ ULN) 29 (39.2%) 31 (40.8%) Partially controlled (≥ 50% reduction in mUFC) 4 (5.4%) 10 (13.2%) Combined 33 (44.6%) 41 (53.9%) Decreases in median mUFC levels at Month 7 compared to baseline, as measured by overall percentage of reduction, are shown in Table 9. Reductions in serum cortisol and plasma ACTH levels were also observed at Months 7 and 12 for each dose group.
Table 9 – Median Percentage Change from Baseline in Mean Urinary Free Cortisol (mUFC) at Month 7 by Randomized Dose Group Note: Median % change from baseline in mUFC at Month 7 are calculated by imputing missing values with the worst observed % change in mUFC at Month 7 within each treatment group. Pasireotide LAR 10 mg Every 28 Days % change Pasireotide LAR 30 mg Every 28 Days % change mUFC levels (nmol/24hr) Baseline N Mean (SD) Median 74 462.6 409.8 76 477.1
Drug information sourced from the FDA. This content is for informational purposes only and does not constitute medical advice. Consult a healthcare professional before making any medication decisions.
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