Sandostatin Lar 20 mg 1 Vial Novartis

Sandostatin Lar 20 mg 1 Vial Novartis

Brand:NOVARTIS-ALCON Pharmaceuticals
Product Code:317
Availability:In Stock

FULL PRESCRIBING INFORMATION: CONTENTS*

1     INDICATIONS AND USAGE

1.1     Acromegaly

1.2     Carcinoid Tumors

1.3     Vasoactive Intestinal Peptide Tumors (VIPomas)

1.4     Important Limitations of Use

2     DOSAGE AND ADMINISTRATION

2.1     Acromegaly

2.2     Carcinoid Tumors and VIPomas

2.3     Special Populations: Renal Impairment

2.4     Special Populations: Hepatic Impairment – Cirrhotic Patients

3     DOSAGE FORMS AND STRENGTHS

4     CONTRAINDICATIONS

5     WARNINGS AND PRECAUTIONS

5.1     Cholelithiasis and Gallbladder Sludge

5.2     Hyperglycemia and Hypoglycemia

5.3     Thyroid Function Abnormalities

5.4     Cardiac Function Abnormalities

5.5     Nutrition

5.6     Monitoring: Laboratory Tests

5.7     Drug Interactions

6     ADVERSE REACTIONS

6.1     Clinical Studies Experience

6.2     Postmarketing Experience

7     DRUG INTERACTIONS

7.1     Cyclosporine

7.2     Insulin and Oral Hypoglycemic Drugs

7.3     Bromocriptine

7.4     Other Concomitant Drug Therapy

7.5     Drug Metabolism Interactions

8     USE IN SPECIFIC POPULATIONS

8.1     Pregnancy

8.3     Nursing Mothers

8.4     Pediatric Use

8.5     Geriatric Use

8.6     Renal Impairment

8.7     Hepatic Impairment-Cirrhotic Patients

10     OVERDOSAGE

11     DESCRIPTION

12     CLINICAL PHARMACOLOGY

12.1     Mechanism of Action

12.2     Pharmacodynamics

12.3     Pharmacokinetics

13     NONCLINICAL TOXICOLOGY

13.1     Carcinogenesis, Mutagenesis, Impairment of Fertility

13.2     Reproductive Toxicology Studies

14     CLINICAL STUDIES

14.1     Acromegaly

14.2     Carcinoid Syndrome

16     HOW SUPPLIED/STORAGE AND HANDLING

17     PATIENT COUNSELING INFORMATION

*Sections or subsections omitted from the full prescribing information are not listed.

 
FULL PRESCRIBING INFORMATION

1     INDICATIONS AND USAGE

Sandostatin LAR Depot 10 mg, 20 mg, and 30 mg is indicated in patients in whom initial treatment with Sandostatin Injection has been shown to be effective and tolerated.

1.1     Acromegaly

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 [see Clinical Studies (14) and Dosage and Administration (2)].

1.2     Carcinoid Tumors

Long-term treatment of the severe diarrhea and flushing episodes associated with metastatic carcinoid tumors.

1.3     Vasoactive Intestinal Peptide Tumors (VIPomas)

Long-term treatment of the profuse watery diarrhea associated with VIP-secreting tumors.

1.4     Important Limitations of Use

In patients with carcinoid syndrome and VIPomas, the effect of Sandostatin Injection and Sandostatin LAR Depot on tumor size, rate of growth and development of metastases, has not been determined.

2     DOSAGE AND ADMINISTRATION

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” 20 gauge safety injection needle (supplied in the drug product kit). For patients with a greater skin to muscle depth, a size 2” 20 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.

2.1     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.

2.2     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.

2.3     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)].

2.4     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)].

3     DOSAGE FORMS AND STRENGTHS

Sandostatin LAR Depot is available in single-use kits for injectable suspension 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” 20 gauge safety injection needle. An instruction booklet for the preparation of drug suspension for injection is also included with each kit.

4     CONTRAINDICATIONS

None

5     WARNINGS AND PRECAUTIONS

5.1     Cholelithiasis and Gallbladder Sludge

Sandostatin may inhibit gallbladder contractility and decrease bile secretion, which may lead to gallbladder abnormalities or sludge. Patients should be monitored periodically [see Adverse Reactions (6)].

5.2     Hyperglycemia and Hypoglycemia

Octreotide alters the balance between the counter-regulatory hormones, insulin, glucagon, and growth hormone, which may result in hypoglycemia or hyperglycemia. Blood glucose levels should be monitored when Sandostatin LAR treatment is initiated, or when the dose is altered. Antidiabetic 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 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 Studies 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 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 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 14-81 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 10-60 mg every 4 weeks.

The safety of Sandostatin LAR 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. 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 were exposed to Sandostatin LAR up to 1 year. The population age range was between 20-76 years old, 45% were female, 93% were Caucasian, and 1% black. The majority of these patients were exposed to 30 mg every 4 weeks.

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.

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.

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%-6% of patients.

In a clinical trial of carcinoid syndrome, nausea, abdominal pain, and flatulence were reported in 27%-38% and constipation or vomiting in 15%-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 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 10 mg, 20 mg, or 30 mg in a blind fashion or to open-label Sandostatin Injection subcutaneously. The population age range was between 25-78 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.

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