6 ADVERSE REACTIONS

Clinically significant adverse reactions that appear in other sections of the labeling include:

Hyperglycemia, Diabetes, and Ketoacidosis [see Warnings and Precautions (5.1)]
Bradycardia and QT Prolongation [see Warnings and Precautions (5.2)]
Liver Test Elevations [see Warnings and Precautions (5.3)]
Cholelithiasis and Complications of Cholelithiasis [see Warnings and Precautions (5.4)]
Pituitary Hormone Deficiency(ies) [see Warnings and Precautions (5.5)]
Steatorrhea and Malabsorption of Dietary Fats [see Warnings and Precautions (5.6)]

6.1 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.

Drug-Naïve Patients With Acromegaly

The data described in Table 1 are derived from an active-controlled trial in patients with acromegaly naïve to previous drug therapy [see Clinical Studies (14.1)]. The data reflect exposure of 178 patients with acromegaly to SIGNIFOR LAR for a mean duration of 43 weeks. In the overall study population, 52% were female and the average age of patients was 45 years.

Table 1 presents common adverse reactions associated with SIGNIFOR LAR in this study. These adverse reactions were not present at baseline or, if present, worsened from baseline and occurred in at least 5% of patients treated with SIGNIFOR LAR.

Table 1 – Adverse Reactions Occurring in Greater Than or Equal to 5% of Patients Exposed to SIGNIFOR LAR in Patients With Acromegaly Naïve to Drug Therapy
aDiabetes mellitus includes the following PTs: diabetes mellitus and type 2 diabetes mellitus. bSinus bradycardia includes the following PTs: bradycardia and sinus bradycardia. cInjection-site reaction related AEs includes the following PTs: injection-site pain, injection-site reaction, injection-site haematoma, injection-site pruritus, injection-site swelling, injection-site erythema.
Adverse Reaction Type	SIGNIFOR LAR (40-60 mg) % N = 178	Active Comparator % N = 180
Hyperglycemia Related Adverse Reactions
Hyperglycemia	29	8
Diabetes mellitusa	26	4
Blood glucose increased	8	2
Glycosylated hemoglobin increased	6	2
Hypoglycemia	5	7
Gastrointestinal Related Adverse Reactions
Diarrhea	39	45
Abdominal pain	18	22
Nausea	14	22
Abdominal distension	12	12
Vomiting	8	7
Abdominal pain upper	6	8
Hepatobiliary Related Adverse Reactions
Cholelithiasis	26	36
Cardiac Related Adverse Reactions
Sinus bradycardiab	10	7
Hypertension	8	7
Nervous System Related Adverse Reactions
Headache	19	26
Dizziness	10	11
Skin Related Adverse Reactions
Alopecia	18	19
Infections Related Adverse Reactions
Nasopharyngitis	16	16
Influenza	8	4
Upper respiratory tract infection	7	3
Cough	5	8
Laboratory Related Adverse Reactions
Blood creatine phosphokinase increased	13	12
Alanine aminotransferase increased	8	4
Aspartate aminotransferase increased	6	4
Lipase increased	6	7
Weight decreased	5	4
General and Injection-Site Related Adverse Reactions
Fatigue	10	10
Injection-site reactionc	7	7
Musculoskeletal and Connective Tissue Related Adverse Reactions
Arthralgia	10	12
Back pain	8	11
Pain in extremity	7	4
Blood Related Adverse Reactions
Anemia	6	6

Other notable adverse reactions which occurred with a frequency of 5% or less for SIGNIFOR LAR were: adrenal insufficiency (3%); glucose tolerance impaired (1%); QT-prolongation (4%); blood amylase increased (2%).

Patients With Acromegaly Inadequately Controlled on Other Somatostatin Analogs at Baseline

The data described in Table 2 are derived from an active-controlled study in patients with acromegaly inadequately controlled at baseline on other somatostatin analogs [see Clinical Studies (14.2)]. These data reflect exposure of 63 and 62 patients to SIGNIFOR LAR 40 mg and 60 mg, respectively, for a mean duration of 24 weeks. In the overall study population, 56% were female and the average age of patients was 45 years.

Table 2 presents common adverse reactions associated with SIGNIFOR LAR in this study. These common adverse reactions were not present at baseline, or if present, worsened from baseline and occurred in at least 5% of patients treated with SIGNIFOR LAR.

Table 2 – Adverse Reactions Occurring in Greater Than or Equal to 5% of Patients Exposed to SIGNIFOR LAR in Patients With Acromegaly Previously Treated With Other Somatostatin Analogs
aDiabetes mellitus includes the following PTs: diabetes mellitus and type 2 diabetes mellitus.
Adverse Drug Reactions	SIGNIFOR LAR 40 mg % N = 63	SIGNIFOR LAR 60 mg % N = 62	Active Comparators % N = 66
Hyperglycemia Related Adverse Reactions
Hyperglycemia	33	30	14
Diabetes mellitusa	21	31	9
Blood glucose increased	5	7	0
Hypoglycemia	3	7	0
Gastrointestinal Related Adverse Reactions
Diarrhea	16	19	5
Abdominal pain	8	8	3
Nausea	3	7	3
Hepatobiliary Related Adverse Reactions
Cholelithiasis	10	13	14
Cardiac Related Adverse Reactions
Atrioventricular block first degree	6	0	0
Nervous System Related Adverse Reactions
Headache	14	3	5
Dizziness	8	2	3
Skin and Subcutaneous Tissue Related Adverse Reactions
Alopecia	2	7	0
Infections Related Adverse Reactions
Nasopharyngitis	6	11	3
Blood Related Adverse Reactions
Anemia	6	3	3

Other notable adverse reactions which occurred with a frequency of 5% or less in the SIGNIFOR LAR 40 mg, SIGNIFOR LAR 60 mg arm, respectively, were adrenal insufficiency (2% and 0%) and glucose tolerance impaired (3% and 5%).

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 [see Clinical Studies (14.3)]. 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.

Table 3 – Adverse Reactions Occurring in Greater Than or Equal to 5% of Patients Exposed to SIGNIFOR LAR in Patients With Cushing's Disease
aDiabetes mellitus consists of the two terms: diabetes mellitus and type 2 diabetes mellitus. bAbdominal pain includes the term abdominal pain upper. cSinus bradycardia includes the term bradycardia. dFatigue includes the term asthenia.
Adverse Reactions	Overall % N = 150
Endocrine Related Adverse Reactions
Adrenal insufficiency	7
Blood cortisol decreased	5
Hyperglycemia Related Adverse Reactions
Hyperglycemia	47
Diabetes mellitusa	27
Hypoglycemia	15
Blood glucose increased	9
Glycosylated hemoglobin (HbA1C) increased	5
Gastrointestinal Related Adverse Reactions
Diarrhea	39
Nausea	21
Abdominal painb	23
Constipation	7
Abdominal distension	5
Flatulence	5
Vomiting	5
Hepatobiliary Related Adverse Reactions
Cholelithiasis	33
Gamma-glutamyltransferase increased	9
Alanine aminotransferase increased	7
Cardiac Related Adverse Reactions
Hypertension	15
Hypotension	6
Sinus bradycardiac	5
General Related Adverse Reactions
Fatigued	27
Edema peripheral	14
Musculoskeletal and Connective Tissue Related Adverse Reactions
Back pain	11
Arthralgia	8
Pain in extremity	7
Myalgia	5
Metabolism and Nutrition Related Adverse Reactions
Decreased appetite	10
Hyperuricemia	7
Hypercholesterolemia	6
Blood Related Adverse Reactions
Anemia	5

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%), ECG QT prolonged (1%), cholecystitis (1%), amylase increased (1%), and prothrombin time prolonged (1%).

Hyperglycemia

The average FPG levels in patients with acromegaly naïve to drug therapy study [see Clinical Studies (14.1)] across visits is shown in Figure 2 below.

*: Numbers of patients with a glucose value at the given timepoint in the SIGNIFOR LAR/Active comparator arms are displayed as xxx/xxx on the x axis.

Figure 2. Mean Fasting Plasma Glucose (mg/dL) By Visit in the Study of Patients With Acromegaly Naïve to Drug Therapy*

Figure 2. Mean Fasting Plasma Glucose (mg/dL) By Visit in the Study of Patients With Acromegaly Naïve to Drug Therapy*

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, 2 acromegaly patients receiving SIGNIFOR LAR developed pancreatitis. In the Cushing's disease study, increased lipase was observed in 4% of patients, and 1 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.

6.2 Postmarketing Experience

Additional adverse reactions have been identified during post-approval use of SIGNIFOR LAR. 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