Acromegaly

Sandostatin LAR® Depot and Acromegaly

• Immediate Release Sandostatin® Injection
• Immediate Release Sandostatin® Injection Clinical Results
• Advantages of Sandostatin LAR® Depot
• Pharmacokinetic Profile of Sandostatin LAR® Depot
• Clinical Study Design for Sandostatin LAR® Depot Efficacy Determinations
• Patients Reporting Clinical Symptoms
• Safety Profile of Sandostatin LAR® Depot
• Conclusions — Efficacy Profile for Sandostatin LAR® Depot in Acromegaly

Immediate Release Sandostatin® Injection

Octreotide is a potent inhibitor of GH, and adenomas have large numbers of receptor sites for this peptide. Therefore, octreotide administration has proven successful in the treatment of acromegaly (1, 2, 3, 4). Studies show that immediate release Sandostatin® (octreotide acetate) Injection administered provides the following:

• Sandostatin normalizes GH and IGF-1 levels in many patients.
• Normalizes GH levels to below 2.5 ng/mL in 50% to 60% of patients (5).
• Normalization of IGF-1 levels in 50% to 60% of patients (5).
• Rapid response (usually within 30 to 60 minutes), lasting 4 to 6 hours when given subcutaneously (6).

Immediate Release Sandostatin® Injection Clinical Results

Long-term results of 103 acromegalic patients participating in a multicenter trial evaluating the safety and efficacy of immediate release Sandostatin® Injection were reported by Newman et al (4).

• Immediate release Sandostatin® Injection doses of 100 to 500 mcg 3 times a day.
• IGF-1 level normalized in 64% of patients.
• Improvement in clinical symptoms in 83% to 95% of patients.
• Most common adverse events: diarrhea, abdominal discomfort, loose stools, nausea, gallstones, and sludge.

Effect of Octreotide on Mean GH Levels

Advantages of Sandostatin LAR® Depot

A long-lasting formulation of immediate release Sandostatin® Injection — Sandostatin LAR® Depot (octreotide acetate for injectable suspension), is now available for acromegaly.

• Sandostatin LAR® Depot exhibits the pharmacologic activity and safety profile of immediate release Sandostatin® (octreotide acetate) Injection (7, 8, 9, 10).
• Sandostatin LAR® Depot is administered as an intragluteal injection once every 28 days, a regimen which may be preferred by physicians to minimize compliance concerns.
• Serum octreotide concentrations are more stable and consistent with Sandostatin LAR® Depot than with immediate release Sandostatin® Injection.
• Clinical trials of Sandostatin LAR® Depot confirm a therapeutic benefit as good as immediate release Sandostatin® Injection in reducing GH levels, normalizing IGF-1 levels, and in controlling clinical symptoms (11).
• Sandostatin LAR® Depot is generally well-tolerated with an established safety profile.

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 proportional (11). Following multiple doses of Sandostatin LAR® Depot given every 4 weeks, steady-state octreotide serum concentrations are achieved after the third injection (11). 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 respectively (11). Peak-to-trough variation in octreotide concentrations ranged from 44%-68%, compared to the 163%-209% variation encountered with the daily subcutaneous t.i.d. regimen of immediate release Sandostatin® Injection (11).

In patients with carcinoid tumors, mean octreotide concentrations after 6 doses of 10 mg, 20 mg, and 30 mg Sandostatin LAR® Depot administered by IM injection every four weeks were 1.2 ng/mL, 2.5 ng/mL, and 4.2 ng/mL, respectively (11). Concentrations were dose proportional, and steady-state concentrations were reached after two injections of 20 mg and 30 mg and after three injections of 10 mg (11).

Sandostatin LAR® Depot has not been studied in patients with renal or hepatic impairment.

Clinical Study Design for Sandostatin LAR® Depot Efficacy Determinations

The efficacy of Sandostatin LAR® Depot (octreotide acetate for injectable suspension) 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 √g or 200 √g 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 √g/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 √g/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 √g to 500 √g 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 treatment (11):
  • 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® Depot (11)

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 that (11).

• 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 √g/L) During Long-Term* Treatment with Sandostatin LAR® Depot (11)

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 levels.

• Clinical symptoms of acromegaly were substantially reduced during treatment.
• All reported symptoms were less frequent after 12 months of Sandostatin LAR® Depot once-monthly treatment than with immediate release Sandostatin® Injection.

Patients Reporting Symptoms of Acromegaly with Immediate Release Sandostatin® Injection and Sandostatin LAR® Depot

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 improvement.

Safety Profile of Sandostatin LAR® Depot

Safety data were obtained from all 3 trials with the following results:

• Clinical symptoms of acromegaly were reduced during treatment.
• All reported symptoms were less frequent after 12 months of Sandostatin LAR® Depot once-monthly treatment than with immediate release Sandostatin® Injection.
• The body system most commonly affected in acromegalic patients treated for 12 to 30 months was the GI system (11).
• Diarrhea, abdominal pain, and nausea developed primarily during the first month of treatment with Sandostatin LAR® Depot, with new cases occurring infrequently later in treatment.
• Many other adverse events also diminished in frequency with continued therapy, with no statistically significant differences noted between the 20-mg and 30-mg groups (12).
• Local tolerability at the injection site was demonstrated; injection-site reactions were generally mild to moderate and dose-related (11).
• Short-lived injection-site pain after IM administration-discomfort lasting usually less than 1 hour-was reported in 2%, 9%, and 11% of patients, respectively, receiving 10 mg, 20 mg, and 30 mg of Sandostatin LAR® Depot (11, 12).

Conclusions—Efficacy Profile for Sandostatin LAR® Depot in Acromegaly

• Consistent therapeutic serum octreotide concentrations.
• Suppression of GH and IGF-1 in response to Sandostatin LAR® Depot in single-injection and long-term clinical trials .
• Long-term suppression of GH to <2.5 ng/mL in 47% to 66% of patients and <1 ng/mL in 11% to 23% of patients (11).
• Normalization of IGF-1 in 51% to 67% of patients of patients (11).
• Substantial improvement in clinical symptoms.