Warnings and Precautions: Hyperglycemia and Diabetes: SIGNIFOR LAR can cause increases in blood glucose levels which are sometimes severe. Patients with poor baseline glycemic control are at…+
A multicenter, randomized, double-blind study was conducted to assess the safety and efficacy of SIGNIFOR® LAR (pasireotide) for injectable suspension in patients with active acromegaly. A total of 358 patients naive to drugs used to treat acromegaly were randomized in a 1:1 ratio to SIGNIFOR® LAR or another somatostatin analog active comparator.1
INADEQUATELY CONTROLLED PATIENTS
A multicenter, randomized, 3-arm trial was conducted in patients with acromegaly inadequately controlled on somatostatin analogs (SSAs). Patients were randomized to double-blind SIGNIFOR® LAR 40 mg (n=65) or SIGNIFOR® LAR 60 mg (n=65) or to continued open-label pre-trial somatostatin analog therapies at maximal or near maximal doses (n=68). A total of 181 patients completed the 6-month trial.1
PRIMARY END POINT
NORMALIZATION OF GH AND IGF-1 RESULTS AT MONTH 12 IN DRUG NAIVE PATIENTS
GH, growth hormone; IGF-1, insulin-like growth factor 1.
a In a Phase III, multicenter, double-blind study, a total of 358 drug-naive patients with acromegaly were randomized 1:1 and treated with SIGNIFOR® LAR (pasireotide) for injectable suspension or another somatostatin analog active comparator. Randomization was stratified based on previous pituitary surgical status; the post-surgery group had ≥1 prior pituitary surgery and the de novo group had a visible pituitary adenoma on MRI but refused surgery or were contraindicated for surgery. The primary end point was the proportion of patients with a reduction of mean GH level (<2.5 μg/L) and age- and sex-normalized IGF-1.1,2
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.1
Ninety-eight percent 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%)
Warnings and Precautions
Liver enzyme test elevations are associated with SIGNIFOR® LAR (pasireotide) for injectable suspension use. Liver function tests are recommended prior to and during treatment 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 pretreatment levels. Treatment with SIGNIFOR® LAR should be discontinued if signs or symptoms suggestive of clinically significant liver impairment develop.
Cholelithiasis is associated with SIGNIFOR® LAR use. Patients should be monitored periodically.
Suppression of pituitary hormones other than GH/IGF-1, may occur on SIGNIFOR LAR. Monitoring pituitary function (eg, 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.
SECONDARY END POINTS
Reductions in ring size and in symptom severity scores (ie, headache, fatigue, perspiration, paresthesia, and osteoarthralgia) in both treatment groups compared to baseline were noted at Month 12 in medically naive patients.1
INADEQUATELY CONTROLLED PATIENTS
PRIMARY END POINT
NORMALIZATION OF GH AND IGF-1 RESULTS AT WEEK 24 IN PATIENTS INADEQUATELY CONTROLLED ON OTHER SOMATOSTATIN ANALOGS
GH, growth hormone; IGF-1, insulin-like growth factor 1; SSA, somatostatin analog.
a In a Phase III, multicenter, randomized, parallel-group, three-arm study, a total of 198 patients with acromgaly that were inadequately controlled (defined as a GH concentration of >2.5 µg/L [ie, mean of 5 samples over 2 hours] and a sex- and age-adjusted IGF-1 level >1.3 times the upper limit of normal) on a first-generation SSA were randomized to received SIGNIFOR® LAR (pasireotide) for injectable suspension 40 mg (n=65), SIGNIFOR LAR 60 mg (N=65), or open-label continued pretrial SSA therapies (n=68); 181 patients completed the 6-month trial. Patients had to be treated with other SSAs for at least 6 months prior to randomization. The efficacy end point was the proportion of patients achieving biochemical control (a mean GH level less than 2.5 µg/L and normal IGF-1 levels) at Week 241.
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.
Drug Interactions: Caution is required when co-administering SIGNIFOR® LAR (pasireotide) for injectable suspension with anti-arrhythmics, drugs that prolong QT, cyclosporine, and bromocriptine.
SECONDARY END POINTS
GH REDUCTION, IGF-1 NORMALIZATION, AND TUMOR VOLUME DATA
Secondary end points showed an option for patients inadequately controlled on first-generation SSAs.
a 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.
IGF-1 reduction was achieved by 24.6% of SIGNIFOR® LAR (pasireotide) for injectable suspension 40 mg patients and 26.2% of SIGNIFOR® LAR 60 mg patients vs no patients on first-generation SSAs.
GH control (<2.5 μg/L) was achieved by 35.4% of SIGNIFOR® LAR 40 mg patients and 43.1% of SIGNIFOR LAR 60 mg patients vs 13.2% of patients on first-generation SSAs.
Adverse Reactions: The most common adverse reactions occurring in ≥20% of patients in clinical trials are: diarrhea, cholelithiasis, hyperglycemia, and diabetes mellitus.
SIGNIFOR® LAR (pasireotide) for injectable suspension, for intramuscular use
SIGNIFOR LAR is a somatostatin analog 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.
IMPORTANT SAFETY INFORMATION
Warnings and Precautions:
Hyperglycemia and Diabetes: SIGNIFOR LAR can cause increases in blood glucose levels which are sometimes severe. Patients with poor baseline glycemic control are at higher risk of developing severe hyperglycemia.
A majority of patients, including those with normal glucose tolerance, pre-diabetes and diabetes, experienced increased glucose levels within the first 2 to 3 months of treatment with SIGNIFOR LAR.
Fasting plasma glucose and hemoglobin A1c should be assessed prior to starting treatment with SIGNIFOR LAR. In patients with poorly controlled diabetes mellitus, anti-diabetic treatment should be optimized before SIGNIFOR LAR treatment is started. Blood glucose monitoring should be done weekly for the first 3 months after initiating SIGNIFOR LAR and the first 4 to 6 weeks after dose increases. Periodic monitoring should continue thereafter, as clinically appropriate.
Patients who develop significant hyperglycemia on SIGNIFOR LAR may require initiation of anti-diabetic therapy(ies) or adjustment in the dose or type of anti-diabetic therapy(ies) per standard of care. The optimal treatment for the management of SIGNIFOR LAR-induced hyperglycemia is not known. If hyperglycemia cannot be controlled, despite medical management, the dose of SIGNIFOR LAR should be reduced or discontinued.
After treatment discontinuation, fasting plasma glucose and hemoglobin A1c should be assessed if indicated. Patients on anti-diabetic therapy discontinuing SIGNIFOR LAR may require more frequent blood glucose monitoring and anti-diabetic dose adjustment to mitigate the risk of hypoglycemia.
Bradycardia and QT Prolongation
Bradycardia has been reported with the use of SIGNIFOR LAR. Patients with cardiac disease and/or risk factor 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.
SIGNIFOR LAR is associated with QT prolongation and should be used with caution in patients who are at significant risk of developing prolongation of the QT interval. A baseline ECG is recommended prior to initiating therapy with SIGNIFOR LAR and periodically while on treatment. 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. ALT or AST elevation greater than 3 times the upper limit of normal (ULN) were observed in 3% of patients and ALT or AST elevation greater than 5 times the upper limit of normal (ULN) were observed in 1% of 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.
Adverse reactions associated with SIGNIFOR LAR and occurring in ≥20% of patients were diarrhea, cholelithiasis, hyperglycemia and diabetes mellitus.
Caution is advised when co-administering drugs that prolong the QT interval with SIGNIFOR LAR
The following drugs may require monitoring and possible dose adjustment when used with SIGNIFOR LAR: cyclosporine and bromocriptine
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