Clinically significant adverse reactions that appear in other sections of the labeling include:
- 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 PRECAUTIONSC]
- Pituitary Hormone Deficiency [see WARNINGS AND PRECAUTIONS]
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.
A total of 162 Cushing's disease patients were exposed to SIGNIFOR in the Phase III study [see Clinical Studies]. At study entry, patients were randomized to receive twice a day (b.i.d.) doses of either 0.6 mg or 0.9 mg of SIGNIFOR given subcutaneously. The mean age of patients was approximately 40 years old with a predominance of female patients (78%). The majority of the patients had persistent or recurrent Cushing's disease (83%) and few patients ( ≤ 5%) in either treatment group had received previous pituitary irradiation. The median exposure to the treatment was 10.4 months (0.0337.8) with 68% of patients having at least six-months exposure.
In the Phase III trial, adverse reactions were reported in 98% of patients. The most common adverse reactions (frequency ≥ 20% in either group) were diarrhea, nausea, hyperglycemia, cholelithiasis, headache, abdominal pain, fatigue, and diabetes mellitus. There were no deaths during the study. Serious adverse events were reported in 25% of patients. Adverse events leading to study discontinuation were reported in 17% of patients.
Adverse reactions with an overall frequency higher than 5% are presented in Table 1 by randomized dose group and overall. Adverse reactions are ranked by frequency, with the most frequent reactions listed first.
Table 1 :Adverse reactions
[n (%)] with an overall frequency of more than 5% in the combined dose group in
the Phase III study in Cushing’s disease patients
|SIGNIFOR 0.6 mg bid
|SIGNIFOR 0.9 mg bid
|Diarrhea||48 (59)||46 (58)||94 (58)|
|Nausea||38 (46)||46 (58)||84 (52)|
|Hyperglycemia||31 (38)||34 (43)||65 (40)|
|Cholelithiasis||25 (30)||24 (30)||49 (30)|
|Headache||23 (28)||23 (29)||46 (28)|
|Abdominal pain||19 (23)||20 (25)||39 (24)|
|Fatigue||12 (15)||19(24)||31 (19)|
|Diabetes mellitus||13 (16)||16 (20)||29 (18)|
|Injection site reactions||14 (17)||14 (18)||28 (17)|
|Nasopharyngitis||10 (12)||11 (14)||21 (13)|
|Alopecia||10 (12)||10 (13)||20 (12)|
|Asthenia||13 (16)||5 (6)||18 (11)|
|Glycosylated hemoglobin increased||10 (12)||8 (10)||18 (11)|
|Alanine aminotransferase increased||11 (13)||6 (8)||17 (10)|
|Gamma-glutamyl transferase increased||10 (12)||7 (9)||17 (10)|
|Edema peripheral||9 (11)||8 (10)||17 (10)|
|Abdominal pain upper||10 (12)||6 (8)||16 (10)|
|Decreased appetite||7 (9)||9 (11)||16 (10)|
|Hypercholesterolemia||7 (9)||9 (11)||16 (10)|
|Hypertension||8 (10)||8 (10)||16 (10)|
|Dizziness||8 (10)||7 (9)||15 (9)|
|Hypoglycemia||12 (15)||3 (4)||15 (9)|
|Type 2 diabetes mellitus||10 (12)||5 (6)||15 (9)|
|Anxiety||5 (6)||9 (11)||14 (9)|
|Influenza||9 (11)||5 (6)||14 (9)|
|Insomnia||3 (4)||11 (14)||14 (9)|
|Myalgia||10 (12)||4 (5)||14 (9)|
|Arthralgia||5 (6)||8 (10)||13 (8)|
|Pruritus||6 (7)||7 (9)||13 (8)|
|Lipase increased||7 (9)||5 (6)||12 (7)|
|Constipation||7 (9)||4 (5)||11 (7)|
|Hypotension||5 (6)||6 (8)||11 (7)|
|Vomiting||3 (4)||8 (10)||11 (7)|
|Back pain||4 (5)||6 (8)||10 (6)|
|Dry skin||5 (6)||5 (6)||10 (6)|
|Electrocardiogram QT prolonged||5 (6)||5 (6)||10 (6)|
|Hypokalemia||6 (7)||4 (5)||10 (6)|
|Pain in extremity||6 (7)||4 (5)||10 (6)|
|Sinus bradycardia||8 (10)||2 (3)||10 (6)|
|Vertigo||4 (5)||6 (8)||10 (6)|
|Abdominal distension||4 (5)||5 (6)||9 (6)|
|Adrenal insufficiency||4 (5)||5 (6)||9 (6)|
|Aspartate aminotransferase increased||6 (7)||3 (4)||9 (6)|
|Blood glucose increased||6 (7)||3 (4)||9 (6)|
Gastrointestinal disorders, predominantly diarrhea, nausea, abdominal pain and vomiting were reported frequently in the Phase III trial (see Table 1). These events began to develop primarily during the first month of treatment with SIGNIFOR and required no intervention.
Hyperglycemia and Diabetes
Hyperglycemia-related terms were reported frequently in the Phase III trial. For all patients, these terms included: hyperglycemia (40%), diabetes mellitus (18%), increased HbA1c (11%), and type 2 diabetes mellitus (9%). In general, increases in fasting plasma glucose (FPG) and hemoglobin A1c (HbA1c) were seen soon after initiation of SIGNIFOR and were sustained during the treatment period. In the SIGNIFOR 0.6 mg group, mean fasting plasma glucose (FPG) levels increased from 98.6 mg/dL at baseline to 125.1 mg/dL at Month 6. In the SIGNIFOR 0.9 mg group, mean fasting plasma glucose (FPG) levels increased from 97.0 mg/dL at baseline to 128.0 mg/dL at Month 6. In the SIGNIFOR 0.6 mg group, HbA1c increased from 5.8% at baseline to 7.2% at Month 6. In the SIGNIFOR 0.9 mg group, HbA1c increased from 5.8% at baseline to 7.3% at Month 6 [see WARNINGS AND PRECAUTIONS].
At one month follow-up visits following discontinuation of SIGNIFOR, mean FPG and HbA1c levels decreased but remained above baseline values. Long-term follow-up data are not available.
Elevated Liver Tests
In the Phase III trial, there were transient mean elevations in aminotransferase values in patients treated with SIGNIFOR. Mean values returned to baseline levels by Month 4 of treatment. The elevations were not associated with clinical symptoms of hepatic disease.
In the clinical development program of SIGNIFOR, there were 4 patients with concurrent elevations in ALT greater than 3 x ULN and bilirubin greater than 2 x ULN: one patient with Cushing's disease and three healthy volunteers [see WARNINGS AND PRECAUTIONS]. In all four cases, the elevations were noted within the first 10 days of treatment. In all of these cases, total bilirubin elevations were seen either concomitantly or preceding the transaminase elevation. The patient with Cushing's disease developed jaundice. All four cases had resolution of the laboratory abnormalities with discontinuation of SIGNIFOR.
Cases of hypocortisolism were reported in the Phase III study in Cushing's disease patients [see ADVERSE REACTIONS and Clinical Studies]. The majority of cases were manageable by reducing the dose of SIGNIFOR and/or adding low-dose, short-term glucocorticoid therapy [see WARNINGS AND PRECAUTIONS].
Injection Site Reactions
Injection site reactions were reported in 17% of patients enrolled in the Phase III trial in Cushing's disease. The events were most frequently reported as local pain, erythema, hematoma, hemorrhage, and pruritus. These events resolved spontaneously and required no intervention.
Hypothyroidism with the use of SIGNIFOR was reported for seven patients participating in the Phase III study in Cushing's disease. All seven patients presented with a TSH close to or below the lower limit at study entry which precludes establishing a conclusive relationship between the adverse event and the use of SIGNIFOR.
Other Abnormal Laboratory Findings
Asymptomatic and reversible elevations in lipase and amylase were observed in patients receiving SIGNIFOR in clinical studies. Pancreatitis is a potential adverse reaction associated with the use of somatostatin analogs due to the association between cholelithiasis and acute pancreatitis.
For hemoglobin levels, mean decreases that remained within normal range were observed. Also, post-baseline elevations in PT and PTT were noted in 33% and 47% of patients, respectively. The PT and PTT elevations were minimal.
These laboratory findings are of unclear clinical significance.
Read the Signifor (pasireotide diaspartate for injection) Side Effects Center for a complete guide to possible side effects
Effects Of Other Drugs On SIGNIFOR
Drugs that Prolong QT
Co-administration of drugs that prolong the QT interval with SIGNIFOR may have additive effects on the prolongation of the QT interval. Caution is required when co-administering SIGNIFOR with drugs that may prolong the QT interval [see WARNINGS AND PRECAUTIONS].
Effects Of SIGNIFOR On Other Drugs
Concomitant administration of cyclosporine with pasireotide may decrease the relative bioavailability of cyclosporine and, therefore, dose adjustment of cyclosporine to maintain therapeutic levels may be necessary.
Co-administration of somatostatin analogues with bromocriptine may increase the blood levels of bromocriptine. Dose reduction of bromocriptine may be necessary.This monograph has been modified to include the generic and brand name in many instances.
Last reviewed on RxList: 4/7/2015
Additional Signifor Information
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