Sandostatin LAR Depot (Page 2 of 6)

5.2 Hyperglycemia and Hypoglycemia

Octreotide alters the balance between the counter-regulatory hormones, insulin, glucagon, and growth hormone (GH), which may result in hypoglycemia or hyperglycemia. Blood glucose levels should be monitored when SANDOSTATIN LAR DEPOT treatment is initiated, or when the dose is altered. Anti-diabetic treatment should be adjusted accordingly [see Adverse Reactions (6)].

5.3 Thyroid Function Abnormalities

Octreotide suppresses the secretion of thyroid-stimulating hormone (TSH), which may result in hypothyroidism. Baseline and periodic assessment of thyroid function (TSH, total and/or free T4 ) is recommended during chronic octreotide therapy [see Adverse Reactions (6)].

5.4 Cardiac Function Abnormalities

In both acromegalic and carcinoid syndrome patients, bradycardia, arrhythmias and conduction abnormalities have been reported during octreotide therapy. Other electrocardiogram (ECG) changes were observed such as QT prolongation, axis shifts, early repolarization, low voltage, R/S transition, early R wave progression, and nonspecific ST-T wave changes. The relationship of these events to octreotide acetate is not established because many of these patients have underlying cardiac disease. Dose adjustments in drugs such as beta-blockers that have bradycardic effects may be necessary. In one acromegalic patient with severe congestive heart failure (CHF), initiation of Sandostatin Injection-therapy resulted in worsening of CHF with improvement when drug was discontinued. Confirmation of a drug effect was obtained with a positive rechallenge [see Adverse Reactions (6)].

5.5 Nutrition

Octreotide may alter absorption of dietary fats.

Depressed vitamin B12 levels and abnormal Schilling tests have been observed in some patients receiving octreotide therapy, and monitoring of vitamin B12 levels is recommended during therapy with SANDOSTATIN LAR DEPOT.

Octreotide has been investigated for the reduction of excessive fluid loss from the GI tract in patients with conditions producing such a loss. If such patients are receiving total parenteral nutrition (TPN), serum zinc may rise excessively when the fluid loss is reversed. Patients on TPN and octreotide should have periodic monitoring of zinc levels.

5.6 Monitoring: Laboratory Tests

Laboratory tests that may be helpful as biochemical markers in determining and following patient response depend on the specific tumor. Based on diagnosis, measurement of the following substances may be useful in monitoring the progress of therapy [see Dosage and Administration (2.1, 2.2)].

Acromegaly: Growth Hormone, IGF-1 (somatomedin C)

Carcinoid: 5-HIAA (urinary 5-hydroxyindole acetic acid), plasma serotonin, plasma Substance P

VIPoma: VIP (plasma vasoactive intestinal peptide) baseline and periodic total and/or free T4 measurements should be performed during chronic therapy

5.7 Drug Interactions

Octreotide has been associated with alterations in nutrient absorption, so it may have an effect on absorption of orally administered drugs. Concomitant administration of octreotide injection with cyclosporine may decrease blood levels of cyclosporine [see Drug Interactions (7.1)].

6 ADVERSE REACTIONS

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trial of another drug and may not reflect the rates observed in practice.

Acromegaly

The safety of SANDOSTATIN LAR DEPOT in the treatment of acromegaly has been evaluated in three Phase 3 studies in 261 patients, including 209 exposed for 48 weeks and 96 exposed for greater than 108 weeks. SANDOSTATIN LAR DEPOT was studied primarily in a double-blind, cross-over manner. Patients on subcutaneous Sandostatin Injection were switched to the LAR formulation followed by an open-label extension. The population age range was 14 to 81 years old and 53% were female. Approximately 35% of these acromegaly patients had not been treated with surgery and/or radiation. Most patients received a starting dose of 20 mg every 4 weeks intramuscularly. Dose was up or down titrated based on efficacy and tolerability to a final dose between 10 mg to 60 mg every 4 weeks. Table 1 below reflects adverse events from these studies regardless of presumed causality to study drug.

Table 1. Adverse Events Occurring in ≥ 10% of Acromegalic Patients in the Phase 3 Studies
Abbreviation: AEs, adverse events.
WHO Preferred Term Phase 3 Studies (Pooled) Number (%) of Subjects with AEs 10 mg/20 mg/30 mg (n = 261) n (%)
Diarrhea 93 (35.6)
Abdominal Pain 75 (28.7)
Flatulence 66 (25.3)
Influenza-Like Symptoms 52 (19.9)
Constipation 46 (17.6)
Headache 40 (15.3)
Anemia 40 (15.3)
Injection-Site Pain 36 (13.8)
Cholelithiasis 35 (13.4)
Hypertension 33 (12.6)
Dizziness 30 (11.5)
Fatigue 29 (11.1)

The safety of SANDOSTATIN LAR DEPOT in the treatment of acromegaly was also evaluated in a postmarketing randomized Phase 4 study. One-hundred four (104) patients were randomized to either pituitary surgery or 20 mg of SANDOSTATIN LAR DEPOT. All the patients were treatment naïve (‘de novo’). Crossover was allowed according to treatment response and a total of 76 patients were exposed to Sandostatin LAR. Approximately half of the patients initially randomized to SANDOSTATIN LAR DEPOT were exposed to SANDOSTATIN LAR DEPOT up to 1 year. The population age range was between 20 to 76 years old, 45% were female, 93% were Caucasian, and 1% Black. The majority of these patients were exposed to 30 mg every 4 weeks. Table 2 below reflects the adverse events occurring in this study regardless of presumed causality to study drug.

Table 2. Adverse Events Occurring in ≥ 10% of Acromegalic Patients in Phase 4 Study
WHO Preferred Term Phase 4 Study SANDOSTATIN LAR DEPOT N = 76 n (%) Phase 4 Study Surgery N = 64 n (%)
Diarrhea 36 (47.4) 2 (3.1)
Cholelithiasis 29 (38.2) 3 (4.7)
Abdominal Pain 19 (25.0) 2 (3.1)
Nausea 12 (15.8) 5 (7.8)
Alopecia 10 (13.2) 5 (7.8)
Injection-Site Pain 9 (11.8) 0
Abdominal Pain Upper 8 (10.5) 0
Headache 8 (10.5) 6 (9.4)
Epistaxis 0 7 (10.9)

Gallbladder Abnormalities

Single doses of Sandostatin Injection have been shown to inhibit gallbladder contractility and decrease bile secretion in normal volunteers. In clinical trials with Sandostatin Injection (primarily patients with acromegaly or psoriasis) in patients who had not previously received octreotide, the incidence of biliary tract abnormalities was 63% (27% gallstones, 24% sludge without stones, 12% biliary duct dilatation). The incidence of stones or sludge in patients who received Sandostatin Injection for 12 months or longer was 52%. The incidence of gallbladder abnormalities did not appear to be related to age, sex, or dose but was related to duration of exposure.

In clinical trials, 52% of acromegalic patients, most of whom received SANDOSTATIN LAR DEPOT for 12 months or longer, developed new biliary abnormalities including gallstones, microlithiasis, sediment, sludge, and dilatation. The incidence of new cholelithiasis was 22%, of which 7% were microstones.

Across all trials, a few patients developed acute cholecystitis, ascending cholangitis, biliary obstruction, cholestatic hepatitis, or pancreatitis during octreotide therapy or following its withdrawal. One patient developed ascending cholangitis during Sandostatin Injection therapy and died. Despite the high incidence of new gallstones in patients receiving octreotide, 1% of patients developed acute symptoms requiring cholecystectomy.

Glucose Metabolism — Hypoglycemia/Hyperglycemia

In acromegaly patients treated with either Sandostatin Injection or SANDOSTATIN LAR DEPOT, hypoglycemia occurred in approximately 2% and hyperglycemia in approximately 15% of patients [see Warnings and Precautions (5.2)].

Hypothyroidism

In acromegaly patients receiving Sandostatin Injection, 12% developed biochemical hypothyroidism, 8% developed goiter, and 4% required initiation of thyroid replacement therapy while receiving Sandostatin Injection. In acromegalic patients treated with SANDOSTATIN LAR DEPOT, hypothyroidism was reported as an adverse event in 2% and goiter in 2%. Two patients receiving SANDOSTATIN LAR DEPOT required initiation of thyroid hormone replacement therapy [see Warnings and Precautions (5.3)].

Cardiac

In acromegalic patients, sinus bradycardia (< 50 bpm) developed in 25%; conduction abnormalities occurred in 10% and arrhythmias developed in 9% of patients during Sandostatin Injection-therapy. The relationship of these events to octreotide acetate is not established because many of these patients have underlying cardiac disease [see Warnings and Precautions (5.4)].

Gastrointestinal

The most common symptoms are gastrointestinal. The overall incidence of the most frequent of these symptoms in clinical trials of acromegalic patients treated for approximately 1 to 4 years is shown in Table 3.

Table 3. Number (%) of Acromegalic Patients With Common GI Adverse Events
Adverse Event Sandostatin Injection S.C. Three Times Daily n = 114 SANDOSTATIN LAR DEPOT Every 28 Days n = 261
n % n %
Diarrhea 66 (57.9) 95 (36.4)
Abdominal Pain or Discomfort 50 (43.9) 76 (29.1)
Nausea 34 (29.8) 27 (10.3)
Flatulence 15 (13.2) 67 (25.7)
Constipation 10 (8.8) 49 (18.8)
Vomiting 5 (4.4) 17 (6.5)

Only 2.6% of the patients on Sandostatin Injection in US clinical trials discontinued therapy due to these symptoms. No acromegalic patient receiving SANDOSTATIN LAR DEPOT discontinued therapy for a GI event.

In patients receiving SANDOSTATIN LAR DEPOT, the incidence of diarrhea was dose related. Diarrhea, abdominal pain, and nausea developed primarily during the first month of treatment with SANDOSTATIN LAR DEPOT. Thereafter, new cases of these events were uncommon. The vast majority of these events were mild-to-moderate in severity.

In rare instances, gastrointestinal adverse effects may resemble acute intestinal obstruction, with progressive abdominal distention, severe epigastric pain, abdominal tenderness, and guarding.

Dyspepsia, steatorrhea, discoloration of feces, and tenesmus were reported in 4% to 6% of patients.

In a clinical trial of carcinoid syndrome, nausea, abdominal pain, and flatulence were reported in 27% to 38% and constipation or vomiting in 15% to 21% of patients treated with SANDOSTATIN LAR DEPOT. Diarrhea was reported as an adverse event in 14% of patients, but since most of the patients had diarrhea as a symptom of carcinoid syndrome, it is difficult to assess the actual incidence of drug-related diarrhea.

Pain at the Injection Site

Pain on injection, which is generally mild-to-moderate, and short-lived (usually about 1 hour) is dose related, being reported by 2%, 9%, and 11% of acromegalic patients receiving doses of 10 mg, 20 mg, and 30 mg, respectively, of SANDOSTATIN LAR DEPOT. In carcinoid patients, where a diary was kept, pain at the injection site was reported by about 20%-25% at a 10-mg dose and about 30%-50% at the 20-mg and 30-mg dose.

Antibodies to Octreotide

Studies to date have shown that antibodies to octreotide develop in up to 25% of patients treated with octreotide acetate. These antibodies do not influence the degree of efficacy response to octreotide; however, in two acromegalic patients who received Sandostatin Injection, the duration of GH suppression following each injection was about twice as long as in patients without antibodies. It has not been determined whether octreotide antibodies will also prolong the duration of GH suppression in patients being treated with SANDOSTATIN LAR DEPOT.

Carcinoid and VIPomas

The safety of SANDOSTATIN LAR DEPOT in the treatment of carcinoid tumors and VIPomas has been evaluated in one Phase 3 study. Study 1 randomized 93 patients with carcinoid syndrome to SANDOSTATIN LAR DEPOT 10 mg, 20 mg, or 30 mg in a blind fashion or to open-label Sandostatin Injection subcutaneously. The population age range was between 25 to 78 years old and 44% were female, 95% were Caucasian and 3% Black. All the patients had symptom control on their previous Sandostatin subcutaneous treatment. 80 patients finished the initial 24 weeks of Sandostatin exposure in Study 1. In Study 1, comparable numbers of patients were randomized to each dose. Table 4 below reflects the adverse events occurring in ≥ 15% of patients regardless of presumed causality to study drug.

Table 4. Adverse Events Occurring in ≥ 15% of Carcinoid Tumor and VIPoma Patients in Study 1
Number (%) of Subjects With AEs (n = 93)
WHO Preferred Term S.C. N = 26 10 mg N = 22 20 mg N = 20 30 mg N = 25
Abdominal Pain 8 (30.8) 8 (35.4) 2 (10.0) 5 (20.0)
Arthropathy 5 (19.2) 2 (9.1) 3 (15.0) 2 (8.0)
Back Pain 7 (26.9) 6 (27.3) 2 (10.0) 2 (8.0)
Dizziness 4 (15.4) 4 (18.2) 4 (20.0) 5 (20.0)
Fatigue 3 (11.5) 7 (31.8) 2 (10.0) 2 (8.0)
Flatulence 3 (11.5) 2 (9.1) 2 (10.0) 4 (16.0)
Generalized Pain 4 (15.4) 2 (9.1) 3 (15.0) 1 (4.0)
Headache 5 (19.2) 4 (18.2) 6 (30.0) 4(16.0)
Musculoskeletal Pain 4 (15.4) 0 1 (5.0) 0
Myalgia 0 4 (18.2) 1 (5.0) 1 (4.0)
Nausea 8 (30.8) 9 (40.9) 6 (30.0) 6 (24.0)
Pruritus 0 4 (18.2) 0 0
Rash 1 (3.8) 0 3 (15.0) 0
Sinusitis 4 (15.4) 0 1 (5.0) 3 (12.0)
URTI 6 (23.1) 4 (18.2) 2 (10.0) 3 (12.0)
Vomiting 3 (11.5) 0 0 4 (16.0)

Gallbladder Abnormalities

In clinical trials, 62% of malignant carcinoid patients, who received SANDOSTATIN LAR DEPOT for up to 18 months, developed new biliary abnormalities including jaundice, gallstones, sludge, and dilatation. New gallstones occurred in a total of 24% of patients.

Glucose Metabolism — Hypoglycemia/Hyperglycemia

In carcinoid patients, hypoglycemia occurred in 4% and hyperglycemia in 27% of patients treated with SANDOSTATIN LAR DEPOT [see Warnings and Precautions (5.2)].

Hypothyroidism

In carcinoid patients, hypothyroidism has only been reported in isolated patients and goiter has not been reported [see Warnings and Precautions (5.3)].

Cardiac

Electrocardiograms were performed only in carcinoid patients receiving SANDOSTATIN LAR DEPOT. In carcinoid syndrome patients, sinus bradycardia developed in 19%, conduction abnormalities occurred in 9%, and arrhythmias developed in 3%. The relationship of these events to octreotide acetate is not established because many of these patients have underlying cardiac disease [see Warnings and Precautions (5.4)].

Other Clinical Studies Adverse Events

Other clinically significant adverse events (relationship to drug not established) in acromegalic and/or carcinoid syndrome patients receiving SANDOSTATIN LAR DEPOT were malignant hyperpyrexia, cerebral vascular disorder, rectal bleeding, ascites, pulmonary embolism, pneumonia, and pleural effusion.

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