In this section, you will find the following information
about Sandostatin® LAR Depot (octreotide acetate for
injectable suspension):
- Clinical Effectiveness
- Pharmacokinetics of Sandostatin® LAR Depot
- Clinical Study Design for Sandostatin® LAR Depot Efficacy Determinations
- Patients Reporting Clinical Symptoms
- Conclusions: Efficacy Profile for Sandostatin® LAR Depot in Acromegaly
Clinical Effectiveness1
Sandostatin® LAR Depot (octreotide acetate for injectable suspension) is a 28-day long-acting formulation of a proven medication, subcutaneously injected immediate release Sandostatin® (octreotide acetate) Injection. How can a 28-day long-acting formulation maintain the clinical effectiveness of a daily-injected formulation?
- Sandostatin® LAR Depot maintains all of the clinical and pharmacological characteristics of the immediate-release dosage form (immediate release Sandostatin® Injection)
- Sandostatin® LAR Depot incorporates octreotide into microspheres of the biodegradable glucose star polymer, D,L-lactic, and glycolic acids copolymer
- Slow drug release accompanies the biodegradation of the polymer ester bond through hydrolysis
- Sandostatin® LAR Depot has a different pharmacokinetic profile than immediate release Sandostatin® Injection, allowing for once-monthly injections
- Sandostatin® LAR Depot formulation releases octreotide slowly over time
Pharmacokinetics of Sandostatin® LAR Depot
In patients with acromegaly, the octreotide concentrations after single intramuscular injections of 10-mg, 20-mg, and 30-mg Sandostatin® LAR Depot are dose proportional1 and offer a smooth PK profile2. Following multiple doses of Sandostatin® LAR Depot given every 4 weeks, steady-state octreotide serum concentrations are achieved after the third injection1. In a phase II trial, doses of 20-mg and 30-mg Sandostatin® LAR Depot given every 4 weeks produced steady-state octreotide concentrations of approximately 1.2 ng/mL and 2.1 ng/mL at trough and 1.6 ng/mL and 2.6 ng/mL at peak, respectively1. Peak-to-trough variation in octreotide concentrations ranged from 44% to 68%, compared to the 163% to 209% variation encountered with the daily subcutaneous tid regimen of immediate release Sandostatin® Injection1.
Sandostatin® LAR Depot has not been studied in patients with renal or hepatic impairment.
Clinical Study Design for Sandostatin® LAR Depot Efficacy Determinations1
The efficacy of Sandostatin® LAR Depot for treatment of acromegaly was examined in 3 major trials.
- In Studies 1 and 2, 101 patients were enrolled. Treatment was monitored for 27 months
- In Study 3, 151 patients were enrolled. Treatment was monitored for 12 months
The primary efficacy variable in these trials was GH level. Secondary efficacy variables were IGF-1 level and clinical symptoms/signs of acromegaly. Adverse events and vital signs were also monitored.
Because Sandostatin® LAR Depot is appropriate for patients who have been shown to respond to and tolerate immediate release Sandostatin® Injection, clinical trials of Sandostatin® LAR Depot were performed in patients who had been receiving immediate release Sandostatin® Injection for periods ranging from a few weeks to more than 9 years.
In Studies 1 and 2, patients underwent an initial screening period in which they received 100 µg or 200 µg of immediate release Sandostatin® Injection tid. They were eligible to continue the trial if they were "good responders" (defined in these trials as GH <5 ng/mL and 50% decrease in GH from pretreatment levels).
After demonstrating a response to immediate release Sandostatin® Injection, subjects went through a washout period of 3 days (Study 1) or 14 days (Study 2) to allow GH levels to rise to 5 ng/mL. Most patients then received a single injection of 20 mg or 30 mg of Sandostatin® LAR Depot, and were followed for 60 days.
Patients who had GH <5 ng/mL and 50% decrease in GH from pretreatment levels were eligible to participate in 6-month, 9-month, and 12-month extensions of the trial, in which doses of 20 mg, 30 mg, or 40 mg (individually titrated to maintain GH levels at <5 ng/mL) were provided every 28 days. With the initial trial and extensions, patients were monitored for up to 27 months.
In Study 3, patients underwent an initial screening period in which they received 100 µg to 500 µg of immediate release Sandostatin® Injection, bid or tid, for at least 4 weeks. They were eligible to continue the trial if they achieved a mean 4-hour GH level of <10 ng/mL. Patients were then switched, without washout, to Sandostatin® LAR Depot, which was provided in a dose of 20 mg every 4 weeks for 3 injections. Based on GH levels, subsequent doses were reduced to 10 mg, increased to 30 mg, or maintained at 20 mg for an additional 9 months.
- Of the total 122 patients completing 12 months of treatment3:
- 95% of immediate release Sandostatin® Injection patients and 97% of Sandostatin® LAR Depot patients had GH levels <5 ng/mL during the screening period and end of treatment
- 69% of immediate release Sandostatin® Injection patients and 66% of Sandostatin® LAR Depot patients had GH levels <2.5 ng/mL during the screening period and end of treatment
GH Suppression During Long-term Treatment with Immediate Release Sandostatin® Injection and Sandostatin® LAR Depot3
| GH (ng/mL) | Sandostatin® Injection Screening |
Sandostatin® LAR Depot† During Treatment |
|---|---|---|
| <5 | 95% | 97% |
| ≤2.5% | 69% | 66% |
| *Average of monthly levels of GH over the course of the trial. †N=122. |
||
In all of these trials, mean and median GH levels for patients treated with Sandostatin® LAR Depot were equal to or less than those seen when patients were treated with immediate release Sandostatin® Injection. The investigators concluded that3:
- Sandostatin® LAR Depot maintained GH levels as they had been on immediate release Sandostatin® Injection
- This level of control remained for the entire duration of the trials
IGF-1 Normalization (<500 ng/mL) During Long-term* Treatment with Sandostatin® LAR Depot1,4
| Sandostatin® LAR* Depot | ||
|---|---|---|
| IGF-I | Sandostatin® Injection† Screening |
Sandostatin® LAR Depot† During Treatment |
| IGF-I Normalized | 67% | 67% |
| *During 12 months of treatment †N=122 |
||
Patients Reporting Clinical Symptoms
The clinical trials of Sandostatin® LAR Depot monitored symptoms as a secondary parameter. Improvement in fatigue, perspiration, joint pain, and other symptoms was observed, compared with baseline levels5.
- Clinical symptoms of acromegaly were substantially reduced during treatment1
Patients Reporting Symptoms of Acromegaly with Immediate Release Sandostatin® Injection and Sandostatin® LAR Depot
| Sandostatin® Injection | Sandostatin® LAR Depot | |
|---|---|---|
| Symptom | Baseline | After 12 Months |
| Headache | 54 (35.8%) | 29 (23.6%) |
| Fatigue | 79 (52.3%) | 52 (42.3%) |
| Perspiration | 65 (43.0%) | 22 (17.9%) |
| Joint Pains | 76 (50.3%) | 40 (32.5%) |
| Carpal Tunnel Syndrome | 25 (16.6%) | 13 (10.6%) |
| Paresthesia | 39 (25.8%) | 18 (14.6%) |
| N=151 Data on file3 |
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These findings are consistent with results seen in trials of immediate release Sandostatin® Injection, in which Sandostatin® Injection therapy has reduced acromegaly symptoms. They are also consistent with the documented relationship between reductions in GH/IGF-1 and symptom improvement3.
Conclusions: Efficacy Profile for Sandostatin® LAR Depot in Acromegaly
- Powerful control of IGF-1 and GH1
- The only somatostatin analogue to shrink tumors1
- Normalization of IGF-1 in 51% to 67% of patients1
- Consistent drug exposure, dose to dose1
- Proven strength and a 20-year heritage of success6,7
- Convenient dosing for continuing therapy1
Important Safety Information
Carcinoid Syndrome:
Sandostatin® LAR Depot (octreotide acetate for injectable suspension) is indicated for long-term treatment of the severe diarrhea and flushing episodes associated with metastatic carcinoid tumors and for the long-term treatment of the profuse watery diarrhea associated with VIP-secreting tumors in patients in whom initial treatment with immediate release Sandostatin® (octreotide acetate) Injection has been shown to be effective and tolerated.
Important Safety Information:
As with immediate release Sandostatin® Injection, the most frequently reported drug-related adverse events were biliary disorders (62%), gastrointestinal disorders (14% to 38%), and injection-site pain (20% to 50%). Hypoglycemia (4%), hyperglycemia (27%), sinus bradycardia (19%), conduction abnormalities (9%), and arrhythmias (3%) have been reported.
The controlled clinical trials that support the marketing clearance for Sandostatin® LAR Depot did not include determination of effect on tumor size or rate of growth. Sandostatin® LAR Depot is not indicated for tumor shrinkage.
Acromegaly
Sandostatin® LAR Depot (octreotide acetate for injectable suspension) is indicated for long-term maintenance therapy in acromegalic patients who have had an inadequate response to surgery and/or radiotherapy, or for whom surgery and/or radiotherapy is not an option. The goal of treatment in acromegaly is to reduce GH and IGF-1 levels to normal.
Important Safety Information:
As with immediate release Sandostatin® Injection, the most frequently reported drug-related adverse events were biliary disorders (52%), gastrointestinal disorders (7% to 36%), and injection-site pain (2% to 11%). Hypoglycemia (2%), hyperglycemia (15%), and hypothyroidism (2%) have been reported. While not measured in acromegalic patients receiving Sandostatin® LAR Depot, ECG changes have been reported in patients receiving immediate release Sandostatin® Injection; the degree to which these abnormalities are related to octreotide acetate is not clear, as many acromegalics have cardiovascular disease. You are encouraged to report negative side effects of prescription drugs to the FDA. Visit www.fda.gov/medwatch or call 1-800-FDA-1088.
