Sandostatin LAR

Pregnancy category: B

Lactation: Whether octreotide crosses into breast milk is not known; avoid giving to lactating women

Pregnancy Categories

A:Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

B:May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

C:Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

D:Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

X:Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

NA:Information not available.

IV Incompatibilities

Fat emulsion 10%

IV Preparation

Common diluent: 50-100 μg/50 mL NS

Common diluent for continuous IV infusion: 1200 μg/250 mL NS

Minimum volume: 50 mL NS

IV/IM Administration

IM

• Administer suspension (depot injection) immediately after reconstitution; inject into gluteal muscle, avoiding deltoid

IV

• IV administration may be IVP, IVPB, or continuous infusion
• Regular injection only: IVP should be administered undiluted over 3 minutes
• IVPB: Administer over 15-30 minutes
• Continuous infusion: 25-50 μg/hr for treatment of esophageal variceal bleeding
• Do not use if solution contains particles or is discolored

Storage

Refrigerate solution

Ampule may be stored at room temp for up to 14 days when protected from light

: Octreotide acetate can alter nutrient absorption and may interfere with the absorption of some orally taken medications.

Use of octreotide acetate with cyclosporine (Gengraf) may decrease blood levels of cyclosporine and result in transplant rejection.

If taken with octreotide acetate, dose adjustments may be required for some medications including insulin, oral anti-diabetes medicines, beta blockers, calcium channel blockers (CCBs), and agents used to control fluid and electrolyte balance.

Octreotide may decrease the removal of certain drugs broken down by the CYP3A4 liver enzymes. Therefore, octreotide should be used cautiously with other drugs that are extensively metabolized by these enzymes or those that have a low therapeutic index.

Co-administration of octreotide and bromocriptine may increase the blood levels of bromocriptine (Cycloset).

• Sandostatin LAR Depot should be administered by a trained healthcare provider. It is important to closely follow the mixing instructions included in the packaging. Sandostatin LAR Depot must be administered immediately after mixing.
  
• Do not directly inject diluent without preparing suspension.
  
• The recommended needle size for administration of Sandostatin LAR Depot is the 1½” 19 gauge safety injection needle (supplied in the drug product kit). For patients with a greater skin to muscle depth, a size 2” 19 gauge needle (not supplied) may be used.
  
• Sandostatin LAR Depot should be administered intramuscularly in the gluteal region at 4-week intervals. Administration of Sandostatin LAR Depot at intervals greater than 4 weeks is not recommended.
  
• Injection sites should be rotated in a systematic manner to avoid irritation. Deltoid injections should be avoided due to significant discomfort at the injection site when given in that area.
  
• Sandostatin LAR Depot should never be administered intravenously or subcutaneously.

The following dosage regimens are recommended.

     Acromegaly

Patients Not Currently Receiving Octreotide Acetate

Patients not currently receiving octreotide acetate should begin therapy with Sandostatin Injection given subcutaneously in an initial dose of 50 mcg three times daily which may be titrated. Most patients require doses of 100 mcg to 200 mcg three times daily for maximum effect but some patients require up to 500 mcg three times daily.

Patients should be maintained on Sandostatin Injection subcutaneous for at least 2 weeks to determine tolerance to octreotide. Patients who are considered to be “responders” to the drug, based on GH and IGF-1 levels and who tolerate the drug can then be switched to Sandostatin LAR Depot in the dosage scheme described below (Patients Currently Receiving Sandostatin Injection).

Patients Currently Receiving Sandostatin Injection

Patients currently receiving Sandostatin Injection can be switched directly to Sandostatin LAR Depot in a dose of 20 mg given IM intragluteally at 4-week intervals for 3 months. After 3 months, dosage may be adjusted as follows:

• GH ≤2.5 ng/mL, IGF-1 normal, and clinical symptoms controlled: maintain Sandostatin LAR Depot dosage at 20 mg every 4 weeks.
  
• GH >2.5 ng/mL, IGF-1 elevated, and/or clinical symptoms uncontrolled, increase Sandostatin LAR Depot dosage to 30 mg every 4 weeks.
  
• GH ≤1 ng/mL, IGF-1 normal, and clinical symptoms controlled, reduce Sandostatin LAR Depot dosage to 10 mg every 4 weeks.
  
• If GH, IGF-1, or symptoms are not adequately controlled at a dose of 30 mg, the dose may be increased to 40 mg every 4 weeks. Doses higher than 40 mg are not recommended.

In patients who have received pituitary irradiation, Sandostatin LAR Depot should be withdrawn yearly for approximately 8 weeks to assess disease activity. If GH or IGF-1 levels increase and signs and symptoms recur, Sandostatin LAR Depot therapy may be resumed.

     Carcinoid Tumors and VIPomas

Patients Not Currently Receiving Octreotide Acetate

Patients not currently receiving octreotide acetate should begin therapy with Sandostatin Injection given subcutaneously. The suggested daily dosage for carcinoid tumors during the first 2 weeks of therapy ranges from 100-600 mcg/day in 2-4 divided doses (mean daily dosage is 300 mcg). Some patients may require doses up to 1500 mcg/day. The suggested daily dosage for VIPomas is 200-300 mcg in 2-4 divided doses (range 150-750 mcg); dosage may be adjusted on an individual basis to control symptoms but usually doses above 450 mcg/day are not required.

Sandostatin Injection should be continued for at least 2 weeks. Thereafter, patients who are considered “responders” to octreotide acetate and who tolerate the drug may be switched to Sandostatin LAR Depot in the dosage regimen as described below (Patients Currently Receiving Sandostatin Injection).

Patients Currently Receiving Sandostatin Injection

Patients currently receiving Sandostatin Injection can be switched to Sandostatin LAR Depot in a dosage of 20 mg given IM intragluteally at 4-week intervals for 2 months. Because of the need for serum octreotide to reach therapeutically effective levels following initial injection of Sandostatin LAR Depot, carcinoid tumor and VIPoma patients should continue to receive Sandostatin Injection subcutaneously for at least 2 weeks in the same dosage they were taking before the switch. Failure to continue subcutaneous injections for this period may result in exacerbation of symptoms. (Some patients may require 3 or 4 weeks of such therapy.)

After 2 months, dosage may be adjusted as follows:

• If symptoms are adequately controlled, consider a dose reduction to 10 mg for a trial period. If symptoms recur, dosage should then be increased to 20 mg every 4 weeks. Many patients can, however, be satisfactorily maintained at a 10-mg dose every 4 weeks.
  
• If symptoms are not adequately controlled, increase Sandostatin LAR Depot to 30 mg every 4 weeks. Patients who achieve good control on a 20-mg dose may have their dose lowered to 10 mg for a trial period. If symptoms recur, dosage should then be increased to 20 mg every 4 weeks.
  
• Dosages higher than 30 mg are not recommended.

Despite good overall control of symptoms, patients with carcinoid tumors and VIPomas often experience periodic exacerbation of symptoms (regardless of whether they are being maintained on Sandostatin Injection or Sandostatin LAR Depot). During these periods they may be given Sandostatin Injection subcutaneously for a few days at the dosage they were receiving prior to switching to Sandostatin LAR Depot. When symptoms are again controlled, the Sandostatin Injection subcutaneous can be discontinued.

     Special Populations: Renal Impairment

In patients with renal failure requiring dialysis, the starting dose should be 10 mg every 4 weeks. In other patients with renal impairment, the starting dose should be similar to a nonrenal patient (i.e., 20 mg every 4 weeks) [see Clinical Pharmacology (12)].

     Special Populations: Hepatic Impairment – Cirrhotic Patients

In patients with established cirrhosis of the liver, the starting dose should be 10 mg every 4 weeks [see Clinical Pharmacology (12.3)].

     Cyclosporine

Concomitant administration of octreotide injection with cyclosporine may decrease blood levels of cyclosporine and result in transplant rejection.

     Insulin and Oral Hypoglycemic Drugs

Octreotide inhibits the secretion of insulin and glucagon. Therefore, blood glucose levels should be monitored when Sandostatin LAR treatment is initiated or when the dose is altered and antidiabetic treatment should be adjusted accordingly.

     Bromocriptine

Concomitant administration of octreotide and bromocriptine increases the availability of bromocriptine.

     Other Concomitant Drug Therapy

Concomitant administration of bradycardia-inducing drugs (e.g., beta-blockers) may have an additive effect on the reduction of heart rate associated with octreotide. Dose adjustments of concomitant medication may be necessary.

Octreotide has been associated with alterations in nutrient absorption, so it may have an effect on absorption of orally administered drugs.

     Drug Metabolism Interactions

Limited published data indicate that somatostatin analogs may decrease the metabolic clearance of compounds known to be metabolized by cytochrome P450 enzymes, which may be due to the suppression of growth hormone. Since it cannot be excluded that octreotide may have this effect, other drugs mainly metabolized by CYP3A4 and which have a low therapeutic index (e.g., quinidine, terfenadine) should therefore be used with caution.

     Pregnancy

Pregnancy Category B

There are no adequate and well-controlled studies in pregnant women. Reproduction studies have been performed in rats and rabbits at doses up to 16x the highest recommended human dose and have revealed no evidence of harm to the fetus due to octreotide. However, because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed [see Nonclinical Toxicology (13.2)].

     Nursing Mothers

It is not known whether octreotide is excreted into human milk. Because many drugs are excreted in human milk, caution should be exercised when Sandostatin LAR Depot is administered to a nursing woman.

     Pediatric Use

Safety and efficacy of Sandostatin LAR Depot in the pediatric population have not been demonstrated.

No formal controlled clinical trials have been performed to evaluate the safety and effectiveness of Sandostatin LAR Depot in pediatric patients under 6 years of age. In postmarketing reports, serious adverse events, including hypoxia, necrotizing enterocolitis, and death, have been reported with Sandostatin use in children, most notably in children under 2 years of age. The relationship of these events to octreotide has not been established as the majority of these pediatric patients had serious underlying comorbid conditions.

The efficacy and safety of Sandostatin LAR Depot was examined in a single randomized, double-blind, placebo-controlled, 6-month pharmacokinetics study in 60 pediatric patients age 6-17 years with hypothalamic obesity resulting from cranial insult. The mean octreotide concentration after 6 doses of 40 mg Sandostatin LAR Depot administered by IM injection every four weeks was approximately 3 ng/mL. Steady-state concentrations were achieved after 3 injections of a 40 mg dose. Mean BMI increased 0.1 kg/m2 in Sandostatin LAR Depot-treated subjects compared to 0.0 kg/m2 in saline control-treated subjects. Efficacy was not demonstrated. Diarrhea occurred in 11 of 30 (37%) patients treated with Sandostatin LAR Depot. No unexpected adverse events were observed. However, with Sandostatin LAR Depot 40 mg once a month, the incidence of new cholelithiasis in this pediatric population (33%) was higher than that seen in other adult indications such as acromegaly (22%) or malignant carcinoid syndrome (24%), where Sandostatin LAR Depot was dosed at 10 to 30 mg once a month.

     Geriatric Use

Clinical studies of Sandostatin did not include sufficient numbers of subjects age 65 years and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

     Renal Impairment

In patients with renal failure requiring dialysis, the starting dose should be 10 mg. This dose should be up titrated based on clinical response and speed of response as deemed necessary by the physician. In patients with mild, moderate, or severe renal impairment there is no need to adjust the starting dose of Sandostatin. The maintenance dose should be adjusted thereafter based on clinical response and tolerability as in nonrenal patients [see Clinical Pharmacology (12)].

     Hepatic Impairment-Cirrhotic Patients

In patients with established liver cirrhosis, the starting dose should be 10 mg. This dose should be up titrated based on clinical response and speed of response as deemed necessary by the physician. Once at a higher dose, patient should be maintained or dose adjusted based on response and tolerability as in any noncirrhotic patients [see Clinical Pharmacology (12)].

No frank overdose has occurred in any patient to date. Sandostatin Injection given in intravenous bolus doses of 1 mg (1000 mcg) to healthy volunteers did not result in serious ill effects, nor did doses of 30 mg (30,000 mcg) given intravenously over 20 minutes and of 120 mg (120,000 mcg) given intravenously over 8 hours to research patients. Doses of 2.5 mg (2500 mcg) of Sandostatin Injection subcutaneously have, however, caused hypoglycemia, flushing, dizziness, and nausea.

Up-to-date information about the treatment of overdose can often be obtained from a certified Regional Poison Control Center. Telephone numbers of certified Regional Poison Control Centers are listed in the Physicians’ Desk Reference®**.

Mortality occurred in mice and rats given 72 mg/kg and 18 mg/kg intravenously, respectively, of octreotide.

Octreotide is the acetate salt of a cyclic octapeptide. It is a long-acting octapeptide with pharmacologic properties mimicking those of the natural hormone somatostatin. Octreotide is known chemically as L-Cysteinamide, D-phenylalanyl-L-cysteinyl-L-phenylalanyl-D-tryptophyl-L-lysyl-L-threonyl-N-[2-hydroxy-1- (hydroxy-methyl) propyl]-, cyclic (2→7)-disulfide; [R-(R*,R*)].

The molecular weight of octreotide is 1019.3 (free peptide, C49H66N10O10S2) and its amino acid sequence is:

Sandostatin LAR Depot is available in a vial containing the sterile drug product, which when mixed with diluent, becomes a suspension that is given as a monthly intragluteal injection. The octreotide is uniformly distributed within the microspheres which are made of a biodegradable glucose star polymer, D,L-lactic and glycolic acids copolymer. Sterile mannitol is added to the microspheres to improve suspendability.

Sandostatin LAR Depot is available as: sterile 6-mL vials in 3 strengths delivering 10 mg, 20 mg, or 30 mg octreotide-free peptide. Each vial of Sandostatin LAR Depot delivers:

     Acromegaly

The clinical trials of Sandostatin LAR Depot were performed in patients who had been receiving Sandostatin Injection for a period of weeks to as long as 10 years. The acromegaly studies with Sandostatin LAR Depot described below were performed in patients who achieved GH levels of <10 ng/mL (and, in most cases <5 ng/mL) while on subcutaneous Sandostatin Injection. However, some patients enrolled were partial responders to subcutaneous Sandostatin Injection, i.e., GH levels were reduced by >50% on subcutaneous Sandostatin Injection compared to the untreated state, although not suppressed to <5 ng/mL.

Sandostatin LAR Depot was evaluated in three clinical trials in acromegalic patients.

In two of the clinical trials, a total of 101 patients were entered who had, in most cases, achieved a GH level <5 ng/mL on Sandostatin Injection given in doses of 100 mcg or 200 mcg three times daily. Most patients were switched to 20 mg or 30 mg doses of Sandostatin LAR Depot given once every 4 weeks for up to 27 to 28 injections. A few patients received doses of 10 mg and a few required doses of 40 mg. Growth hormone and IGF-1 levels were at least as well controlled with Sandostatin LAR Depot as they had been on Sandostatin Injection and this level of control remained for the entire duration of the trials.

A third trial was a 12-month study that enrolled 151 patients who had a GH level <10 ng/mL after treatment with Sandostatin Injection (most had levels <5 ng/mL). The starting dose of Sandostatin LAR Depot was 20 mg every 4 weeks for 3 doses. Thereafter, patients received 10 mg, 20 mg, or 30 mg every 4 weeks, depending upon the degree of GH suppression [see Dosage and Administration (2)]. Growth hormone and IGF-1 were at least as well controlled on Sandostatin LAR Depot as they had been on Sandostatin Injection.

Table 5 summarizes the data on hormonal control (GH and IGF-1) for those patients in the first two clinical trials who received all 27 to 28 injections of Sandostatin LAR Depot.

For the 88 patients in Table 5, a mean GH level of <2.5 ng/mL was observed in 47% receiving Sandostatin LAR Depot. Over the course of the trials, 42% of patients maintained mean growth hormone levels of <2.5 ng/mL and mean normal IGF-1 levels.

Table 6 summarizes the data on hormonal control (GH and IGF-1) for those patients in the third clinical trial who received all 12 injections of Sandostatin LAR Depot.

For the 122 patients in Table 6, who received all 12 injections in the third trial, a mean GH level of <2.5 ng/mL was observed in 66% receiving Sandostatin LAR Depot. Over the course of the trial, 57% of patients maintained mean growth hormone levels of <2.5 ng/mL and mean normal IGF-1 levels. In comparing the hormonal response in these trials, note that a higher percentage of patients in the third trial suppressed their mean GH to <5 ng/mL on subcutaneous Sandostatin Injection, 95%, compared to 78% across the two previous trials.

In all three trials, GH, IGF-1, and clinical symptoms were similarly controlled on Sandostatin LAR Depot as they had been on Sandostatin Injection.

Of the 25 patients who completed the trials and were partial responders to Sandostatin Injection (GH >5.0 ng/mL but reduced by >50% relative to untreated levels), 1 patient (4%) responded to Sandostatin LAR Depot with a reduction of GH to <2.5 ng/mL and 8 patients (32%) responded with a reduction of GH to <5.0 ng/mL.

Two open-label clinical studies investigated a 48-week treatment with Sandostatin LAR Depot in 143 untreated (de novo) acromegalic patients. The median reduction in tumor volume was 20.6% in Study 1 (49 patients) at 24 weeks and 24.5% in Study 2 (94 patients) at 24 weeks and 36.2% at 48 weeks.

     Carcinoid Syndrome

A 6-month clinical trial of malignant carcinoid syndrome was performed in 93 patients who had previously been shown to be responsive to Sandostatin Injection. Sixty-seven (67) patients were randomized at baseline to receive double-blind doses of 10 mg, 20 mg, or 30 mg Sandostatin LAR Depot every 28 days and 26 patients continued, unblinded, on their previous Sandostatin Injection regimen (100-300 mcg three times daily).

In any given month after steady-state levels of octreotide were reached, approximately 35%-40% of the patients who received Sandostatin LAR Depot required supplemental subcutaneous Sandostatin Injection therapy usually for a few days, to control exacerbation of carcinoid symptoms. In any given month, the percentage of patients randomized to subcutaneous Sandostatin Injection who required supplemental treatment with an increased dose of Sandostatin Injection was similar to the percentage of patients randomized to Sandostatin LAR Depot. Over the 6-month treatment period, approximately 50%-70% of patients who completed the trial on Sandostatin LAR Depot required subcutaneous Sandostatin Injection supplemental therapy to control exacerbation of carcinoid symptoms although steady-state serum Sandostatin LAR Depot levels had been reached.

Table 7 presents the average number of daily stools and flushing episodes in malignant carcinoid patients.

Overall, mean daily stool frequency was as well controlled on Sandostatin LAR Depot as on Sandostatin Injection (approximately 2-2.5 stools/day).

Mean daily flushing episodes were similar at all doses of Sandostatin LAR Depot and on Sandostatin Injection (approximately 0.5-1 episode/day).

In a subset of patients with variable severity of disease, median 24 hour urinary 5-HIAA (5-hydroxyindole acetic acid) levels were reduced by 38%-50% in the groups randomized to Sandostatin LAR Depot.

The reductions are within the range reported in the published literature for patients treated with octreotide (about 10%-50%).

Seventy-eight (78) patients with malignant carcinoid syndrome who had participated in this 6-month trial, subsequently participated in a 12-month extension study in which they received 12 injections of Sandostatin LAR Depot at 4-week intervals. For those who remained in the extension trial, diarrhea and flushing were as well controlled as during the 6-month trial. Because malignant carcinoid disease is progressive, as expected, a number of deaths (8 patients: 10%) occurred due to disease progression or complications from the underlying disease. An additional 22% of patients prematurely discontinued Sandostatin LAR Depot due to disease progression or worsening of carcinoid symptoms.

Sandostatin LAR Depot is available in single-use kits containing a 6-mL vial of 10 mg, 20 mg or 30 mg strength, a syringe containing 2 mL of diluent, one vial adapter, and one sterile 1½” 19 gauge safety injection needle. An instruction booklet for the preparation of drug suspension for injection is also included with each kit.

Drug Product Kits

10 mg kit       NDC 0078-0811-81

20 mg kit       NDC 0078-0818-81

30 mg kit       NDC 0078-0825-81

Demonstration kit       0078-9825-81

For prolonged storage, Sandostatin LAR Depot should be stored at refrigerated temperatures between 2°C to 8°C (36°F to 46°F) and protected from light until the time of use. Sandostatin LAR Depot drug product kit should remain at room temperature for 30-60 minutes prior to preparation of the drug suspension. However, after preparation the drug suspension must be administered immediately.