SIGNIFOR SIDE EFFECTS
- Generic Name: pasireotide diaspartate for injection
- Brand Name: Signifor
SIDE EFFECTS
Clinically significant adverse reactions that appear in other sections of the labeling include:
- Hypocortisolism
- Hyperglycemia and Diabetes
- Bradycardia and QT prolongation
- Liver Test Elevations
- Cholelithiasis and Complications of Cholelithiasis
- Pituitary Hormone Deficiency
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. At study entry, patients were randomized to receive twice a day 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 6-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 twice a day N = 82 |
SIGNIFOR 0.9 mg twice a day N = 80 |
Overall N = 162 |
|
| 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) |
Other notable adverse reactions which occurred with a frequency less than 5% were: anemia (4%), blood amylase increased (2%), and prothrombin time prolonged (2%).
Gastrointestinal Disorders
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%), type 2 diabetes mellitus (9%). In general, increases in FPG and HbA1c were seen soon after initiation of SIGNIFOR and were sustained during the treatment period. In the SIGNIFOR 0.6 mg group, mean 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 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.
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 3 healthy volunteers. In all 4 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 4 cases had resolution of the laboratory abnormalities with discontinuation of SIGNIFOR.
Hypocortisolism
Cases of hypocortisolism were reported in the Phase III study in Cushing’s disease patients. The majority of cases were manageable by reducing the dose of SIGNIFOR and/or adding low-dose, short-term glucocorticoid therapy.
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.
Thyroid Function
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 prothrombin time (PT) and partial thromboplastin time (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.
Postmarketing Experience
Additional adverse reactions have been identified during postapproval use of SIGNIFOR. 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
SRC: NLM .