Drug Safety-related Labeling Changes (SrLC)
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Guide
Drug Safety-related Labeling Changes (SrLC) Database
| ANDA | Abbreviated New Drug Application |
| BLA | Biologics License Application |
| CDER | Center for Drug Evaluation and Research |
| MG | Medication Guide |
| NDA | New Drug Application |
| PCI | Patient Counseling Information |
| PI | Patient Information |
| PLR | Physician Labeling Rule |
| PLLR | Pregnancy and Lactation Labeling Rule |
| Italics | For the most part, italics indicate an FDA comment such as:
Additions and/or revisions underlined These italics usually appear at the beginning of the section. In some cases, italics may be an inherent part of the label, and will most often appear in the body of the section. |
| Underlines | Any text that is underlined indicates text that has been added or revised. There are exceptions where underlining occurs in a section subtitle or heading. This is the case when there is just one word underlined in the body of the text. |
Sections
| BW | Box Warning |
| WP | Warnings and Precautions all in one section (PLR-format) Warnings as one section (pre-PLR format) Precautions as one section (pre-PLR format) |
| AR | Adverse Reactions (in pre-PLR format, this may be a subheading under precautions). |
| DI | Drug Interactions (in pre-PLR format, this may be a subheading under precautions). |
| USP | Use in Specific Populations (Inclusive on one or more of the following: Pregnancy; Lactation (PLLR- format); Nursing Mothers (pre-PLLR format); Females and Males of Reproductive Potential (PLLR format only); Pediatric Use, Geriatric Use, Renal Impairment, Hepatic Impairment, Sex, Race (these last six may be a subheading of precautions if label in pre-PLLR format. |
| PCI/PI/MG | Patient Counseling Information (PLR format only) - summarizes the information that a health care provider should convey to a patient (or caregiver when applicable) when a counseling discussion is taking place (e.g., a physician prescribing a drug during an office visit, a nurse providing discharge instructions at a hospital, or a pharmacist conveying information at a pharmacy). Patient Information - FDA approved patient labeling. Medication Guide - paper handouts that come with many prescription medicines. The guides address issues that are specific to particular drugs and drug classes, and they contain FDA-approved information that can help patients avoid serious adverse events. |
Only NDAs and CDER regulated BLAs are included in this database. ANDAs are not included.
Applications that remain active, even if the product has been discontinued, undergo safety-related labeling changes.
SIGNIFOR LAR (NDA-203255)
(PASIREOTIDE PAMOATE)
Safety-related Labeling Changes Approved by FDA Center for Drug Evaluation and Research (CDER)
06/29/2018 (SUPPL-4)
5 Warnings and Precautions
5.1 Hyperglycemia and Diabetes(additions underlined)
SIGNIFOR LAR can cause increases in blood glucose levels which are sometimes severe. In the study of patients with acromegaly, five patients naïve to drug therapy exposed to SIGNIFOR LAR (two of whom were normoglycemic at baseline) were hospitalized for blood glucose in the range of 359–506 mg/dL and none in the active comparator group. 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 treatment during the extension; one of those patients developed diabetic ketoacidosis. In the Cushing’s disease study, two patients were hospitalized for elevated blood glucose. Patients with poor baseline glycemic control are at higher risk of developing severe hyperglycemia.
In clinical studies for acromegaly and Cushing’s disease, treatment with SIGNIFOR LAR caused an increase in the incidence of diabetes and pre-diabetes. A majority of patients, including those with normal glucose tolerance, pre-diabetes and diabetes, experienced increased glucose levels within the first 3 months of treatment with SIGNIFOR LAR.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.
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 per standard of care before SIGNIFOR LAR treatment is started. Blood glucose monitoring should be done weekly for the first three months after initiating SIGNIFOR LAR and the first four to six weeks after dose increases.
Periodic monitoring should continue thereafter, as clinically appropriate.
…
(additions underlined)
…
QT Prolongation
In cardiac electrophysiology studies (i.e., thorough QT studies) with Signifor s.c., 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 six 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.
…
(additions underlined)
Increases in liver enzymes have been observed with SIGNIFOR LAR. In all Phase 3 acromegaly studies and across all doses, alanine aminostranferase (ALT) or aspartate aminotransferase (AST) elevations greater than three times the upper limit of normal (ULN) were observed in 4% of acromegaly patients and ALT or AST elevations greater than five 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, alanine aminostranferase (ALT) or aspartate aminotransferase (AST) elevations greater than three times the upper limit of normal (ULN) were observed in 14% of Cushing’s Disease patients and ALT or AST elevations greater than five times the ULN were observed in 5% of Cushing’s Disease patients treated with SIGNIFOR LAR.
…
(additions
underlined)
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. Patients should be monitored periodically.
(addition underlined)
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.
6 Adverse Reactions
6.1 Clinical Trials Experience(additions underlined)
…
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.
(please refer to label to view Table 3)
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%), electrocardiogram QT prolonged (1%), cholecystitis (1%), amylase increased (1%), and prothrombin time prolonged (1%).
…
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, two acromegaly patients receiving SIGNIFOR LAR developed pancreatitis. In the Cushing’s disease study, increased lipase was observed in 4% of patients, and one 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.
8 Use in Specific Populations
8.3 Females and Males of Reproductive Potential(additions underlined)
…
Similarly, the therapeutic benefits of a reduction or normalization of serum cortisol levels in female patients with Cushing’s disease treated with pasireotide may also lead to improved fertility.
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
PATIENT COUNSELING INFORMATION(additions underlined)
Advise the patient to read the FDA-approved patient labeling (Patient Information).
Instruct patients on the importance of adhering to their return visit schedule.
Advise patients that SIGNIFOR LAR should only be administered by a trained health care professional.
Hyperglycemia and Diabetes
Advise patients to assess fasting plasma glucose and HbA1c prior to starting treatment with Signifor LAR and advise patients to consistently monitor blood glucose levels, particularly after the start of treatment or after dose changes, so that appropriate action can be taken.
Bradycardia and QT Prolongation
Advise patients that an ECG will be taken before treatment and periodically thereafter. Advise patients with cardiac disease and with risk factors for QT prolongation and bradycardia that adjustments in cardiac medications may be made and electrolyte disturbances may require correction.
Liver Test Elevations
Advise patients that liver function will be assessed prior to starting treatment with Signifor LAR and will be closely monitored for the first three months of treatment and thereafter as clinically indicated
Cholelithiasis
Advise patients that the gallbladder will be monitored by ultrasound periodically. Pituitary Hormone Deficiency(ies)
Advise patients that monitoring of anterior pituitary function will be performed periodically.