Signifor

Warnings
Precautions

WARNINGS

Included as part of the PRECAUTIONS section.

PRECAUTIONS

Hypocortisolism

Treatment with SIGNIFOR leads to suppression of adrenocorticotropic hormone (ACTH) secretion in Cushing's disease. Suppression of ACTH may lead to a decrease in circulating levels of cortisol and potentially hypocortisolism.

Monitor and instruct patients on the signs and symptoms associated with hypocortisolism (e.g. weakness, fatigue, anorexia, nausea, vomiting, hypotension, hyponatremia or hypoglycemia). If hypocortisolism occurs, consider temporary dose reduction or interruption of treatment with SIGNIFOR, as well as temporary, exogenous glucocorticoid replacement therapy.

Hyperglycemia and Diabetes

Elevations in blood glucose levels have been seen in healthy volunteers and patients treated with SIGNIFOR . In the Phase III trial, the development of pre-diabetes and diabetes was observed [see Clinical Studies]. In this trial, nearly all patients—including those with normal glucose status at baseline, pre-diabetes, and diabetes—developed worsening glycemia in the first two weeks of treatment. Cushing's disease patients with poor glycemic control (as defined by HbA1c values > 8% while receiving anti-diabetic therapy) may be at a higher risk of developing severe hyperglycemia and associated complications, e.g. ketoacidosis.

Because of this predictable adverse reaction, the glycemic status [fasting plasma glucose (FPG) or hemoglobin A1c (HbA1c)] should be assessed prior to starting treatment with SIGNIFOR. In patients with uncontrolled diabetes mellitus intensive anti-diabetic therapy should be initiated prior to treatment with SIGNIFOR. Self-monitoring of blood glucose and/or FPG assessments should be done every week for the first two to three months and periodically thereafter, as clinically appropriate. After treatment discontinuation, glycemic monitoring (e.g. FPG or HbA1c) should be done according to clinical practice. Patients who were initiated on anti-diabetic therapy as a result of SIGNIFOR may require closer monitoring after discontinuation of SIGNIFOR, especially if the anti-diabetic therapy has a risk of causing hypoglycemia.

If hyperglycemia develops in a patient treated with SIGNIFOR, the initiation or adjustment of anti-diabetic treatment is recommended. The optimal treatment for the management of SIGNIFOR-induced hyperglycemia is not known. If uncontrolled hyperglycemia persists, despite appropriate medical management, the dose of SIGNIFOR should be reduced or discontinued.

Bradycardia and QT Prolongation

Bradycardia

Bradycardia has been reported with the use of SIGNIFOR [see ADVERSE REACTIONS]. 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 carefully monitored. Dose adjustments of beta-blockers, calcium channel blockers, or correction of electrolyte disturbances may be necessary.

QT Prolongation

SIGNIFOR is associated with QT prolongation. In two thorough QT studies with SIGNIFOR, QT prolongation occurred at therapeutic and supra-therapeutic doses. SIGNIFOR should be used with caution in patients who are at significant risk of developing prolongation of QTc, such as those [see CLINICAL PHARMACOLOGY]:

A baseline ECG is recommended prior to initiating therapy with SIGNIFOR and monitoring for an effect on the QTc interval is advisable. Hypokalemia and hypomagnesemia must be corrected prior to SIGNIFOR administration and should be monitored periodically during therapy.

Liver Test Elevations

In the Phase III trial, 5% of patients had an ALT or AST level greater than 3 times the upper limit of normal (ULN). In the entire clinical development program of SIGNIFOR, there were 4 cases of concurrent elevations in ALT (alanine aminotransferase) greater than 3 x ULN and bilirubin greater than 2 x ULN: one patient with Cushing's disease and three healthy volunteers [see ADVERSE REACTIONS]. In these cases, total bilirubin elevations were seen either concomitantly or preceding the transaminase elevation.

Monitoring of liver tests should be done after 1 to 2 weeks on treatment, then monthly for 3 months, and every 6 months thereafter. If ALT is normal at baseline and elevations of ALT of 3-5 times the ULN are observed on treatment, repeat the test within a week or within 48 hours if exceeding 5 times ULN. If ALT is abnormal at baseline and elevations of ALT of 3-5 times the baseline values are observed on treatment, repeat the test within a week or sooner if exceeding 5 times ULN. Tests should be done in a laboratory that can provide same-day results. If the values are confirmed or rising, interrupt SIGNIFOR treatment and investigate for probable cause of the findings, which may or may not be SIGNIFOR-related. Serial measures of ALT, aspartate aminotransferase, alkaline phosphatase, and total bilirubin, should be done weekly, or more frequently, if any value exceeds 5 times the baseline value in case of abnormal baselines or 5 times the ULN in case of normal baselines. If resolution of abnormalities to normal or near normal occurs, resuming treatment with SIGNIFOR may be done cautiously, with close observation, and only if some other likely cause has been found.

Cholelithiasis

Cholelithiasis has been frequently reported in clinical studies with SIGNIFOR [see ADVERSE REACTIONS]. Ultrasonic examination of the gallbladder before, and at 6- to 12-month intervals during SIGNIFOR therapy is recommended.

Monitoring for Deficiency of Pituitary Hormones

As the pharmacological activity of SIGNIFOR mimics that of somatostatin, inhibition of pituitary hormones, other than ACTH, may occur. Monitoring of pituitary function (e.g., TSH/free T4, GH/IGF-1) should occur prior to initiation of therapy with SIGNIFOR and periodically during treatment should be considered as clinically appropriate. Patients who have undergone transsphenoidal surgery and pituitary irradiation are particularly at increased risk for deficiency of pituitary hormones.

Patient Counseling Information

See FDA approved patient labeling (Medication Guide and Instructions for Use).

Counsel patients on the following possible significant adverse reactions:

  • Hypocortisolism [see WARNINGS AND PRECAUTIONS]
  • Hyperglycemia and diabetes [see WARNINGS AND PRECAUTIONS]
  • Bradycardia and QT prolongation [see WARNINGS AND PRECAUTIONS]
  • Liver test elevations [see WARNINGS AND PRECAUTIONS]
  • Cholelithiasis [see WARNINGS AND PRECAUTIONS]
  • Pituitary hormone deficiency [see WARNINGS AND PRECAUTIONS].

Instruct the patients on the proper use of SIGNIFOR, including instructions to:

  • Carefully review the Medication Guide.
  • Do not reuse unused portions of SIGNIFOR ampules and properly dispose of the ampules after use.
  • Avoid multiple injections at or near the same site within short periods of time.

For instructions on the use of SIGNIFOR glass ampules, refer to the Medication Guide.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis

A life-time carcinogenicity study was conducted in rats and transgenic mice. Rats were given daily subcutaneous doses of pasireotide at 0.01, 0.05, 0.3 mg/kg/day for 104 weeks. There were no drug-related tumors in rats at exposures up to 7-fold higher than the maximum recommended clinical exposure at the 1.8 mg/day dose. Mice were given subcutaneous doses of pasireotide at 0.5, 1.0, 2.5 mg/kg/day for 26 weeks and did not identify any carcinogenic potential.

Mutagenesis

Pasireotide was not genotoxic in a battery of in vitro assays (Ames mutation test in Salmonella and E coli. and mutation test in human peripheral lymphocytes). Pasireotide was not genotoxic in an in vivo rat bone marrow nucleus test.

Impairment of Fertility

Subcutaneous dosing at 0.1 mg/kg/day before mating and continuing into gestation in rats at exposures less than the human clinical exposure based on body surface area comparisons across species resulted in statistically significant increased implantation loss and decreased viable fetuses, corpora lutea, and implantation sites. Abnormal cycles or acyclicity were observed at 1 mg/kg/day (5-fold higher than the maximum therapeutic exposure based on surface area, comparisons across species).

Use In Specific Populations

Pregnancy

Pregnancy Category C

There are no adequate and well-controlled studies in pregnant women. Reproduction studies have been performed in rats and rabbits which showed evidence of harm to the fetus due to pasireotide at therapeutic exposures. Animal reproduction studies are not always predictive of human response. This drug should be used during pregnancy only if clearly needed.

Dosing in rats before mating and continuing into gestation at exposures less than the human clinical exposure based on body surface area comparisons across species, resulted in adverse fertility effects including: statistically significant increased implantation loss and decreased viable fetuses, corpora lutea, and implantation sites. Abnormal cycles or acyclicity were observed at systemic exposure 5-fold higher than the maximum therapeutic exposure based on surface area, comparisons across species [see Nonclinical Toxicology].

In embryofetal development studies in rats given 1, 5, and 10 mg/kg/day subcutaneously throughout organogenesis, maternal toxicity was observed at all doses, including the lowest dose tested which had exposures 4-times higher than that at the maximum therapeutic dose based on AUC comparisons across species.

In embryofetal development studies in rabbits given 0.05, 1, and 5 mg/kg/day subcutaneously through organogenesis, maternal toxicity was observed at 1 mg/kg/day at an exposure 7-times higher than the maximum therapeutic exposure. Treatment related increased incidence of skeletal malformations were observed at 0.05 mg/kg/day, exposures less than the maximum therapeutic exposure based on AUC comparisons across species.

In pre- and post-natal developmental studies in rats given subcutaneous doses of 2, 5, and 10 mg/kg/day during gestation through lactation and weaning, maternal toxicity was observed at all doses including the lowest dose (12-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 postnatal 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.

Labor and Delivery

No data in humans are available. Studies in rats have shown no effects on labor and delivery [see Nonclinical Toxicology].

Nursing Mothers

It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when SIGNIFOR is administered to a nursing woman [see Nonclinical Toxicology]. Pasireotide was excreted into rat milk at levels 30% of the plasma level. As a risk to the breastfed child cannot be excluded, SIGNIFOR should not be used by the nursing mother.

Pediatric Use

Safety and effectiveness of SIGNIFOR have not been established in pediatric patients.

Geriatric Use

Clinical studies of SIGNIFOR did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger patients. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and concomitant disease or other drug therapy [see CLINICAL PHARMACOLOGY].

Hepatic Impairment

Dose adjustment is not required in patients with mild impaired hepatic function (Child-Pugh A), but is required for patients with moderately impaired hepatic function (Child-Pugh B) [see DOSAGE AND ADMINISTRATION and CLINICAL PHARMACOLOGY]. Avoid the use of SIGNIFOR in patients with severe hepatic impairment (Child-Pugh C).

Renal Impairment

No dosage adjustment of SIGNIFOR in patients with impaired renal function is required [see CLINICAL PHARMACOLOGY].

Last reviewed on RxList: 1/3/2013
This monograph has been modified to include the generic and brand name in many instances.

Warnings
Precautions
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