Date of Revision:

March 6, 2008

Submission Control No: 118106

SANDOSTATIN * and LAR * are registered trademarks

Table of Contents

PART I: HEALTH PROFESSIONAL INFORMATION 3

SUMMARY PRODUCT INFORMATION 3 WARNINGS AND PRECAUTIONS 6 ADVERSE REACTIONS 10 DRUG INTERACTIONS 19 DOSAGE AND ADMINISTRATION 21 OVERDOSAGE 28 ACTION AND CLINICAL PHARMACOLOGY 28 DOSAGE FORMS, COMPOSITION AND PACKAGING 31

PART II: SCIENTIFIC INFORMATION 33

PHARMACEUTICAL INFORMATION 33 DETAILED PHARMACOLOGY 36 TOXICOLOGY 39 REFERENCES 46

PART III: CONSUMER INFORMATION SANDOSTATIN * 49

PART III: CONSUMER INFORMATION SANDOSTATIN * LAR * 54

Pr

SANDOSTATIN *

(Octreotide acetate Injection)

Pr

SANDOSTATIN * LAR *

Octreotide (as acetate) for Injectable Suspension

PART I: HEALTH PROFESSIONAL INFORMATION SUMMARY PRODUCT INFORMATION

CONTRAINDICATIONS

SANDOSTATIN * and SANDOSTATIN * LAR * (octreotide acetate) are contraindicated in patients with a known hypersensitivity to octreotide or to any of the excipients.

WARNINGS AND PRECAUTIONS

General

Sudden escape from symptomatic control by SANDOSTATIN * (octreotide acetate) may occur infrequently, with rapid recurrence of severe symptoms. Dosage adjustment therefore may be required. As GH-secreting pituitary tumours may sometimes expand, causing serious complications (e.g. visual field defects), it is essential that all patients treated with SANDOSTATIN * s.c. or SANDOSTATIN * LAR * be carefully monitored. If evidence of tumour expansion appears, alternative procedures may be advisable. Octreotide alters the balance between the counter-regulatory hormones, insulin, glucagon and growth hormone, which may result in hypoglycemia or hyperglycemia. Octreotide also suppresses secretion of thyroid stimulating hormone, which may result in hypothyroidism. Cardiac conduction abnormalities have also occurred during treatment with octreotide.

Carcinogenesis and Mutagenesis

Studies in laboratory animals have demonstrated no mutagenic potential of octreotide acetate. No long-term studies in animals to assess carcinogenicity have been completed. SANDOSTATIN * s.c. did not impair fertility in rats at doses up to 1000 ug/kg/day.

Cardiovascular

In both acromegalic and carcinoid syndrome patients, bradycardia, arrhythmias and conduction abnormalities have been reported during octreotide therapy. Dose adjustments of drugs such as beta-blockers, calcium channel blockers, or agents to control fluid and electrolyte balance, may be necessary. Other EKG changes were observed such as QT prolongation, axis shifts, early repolarization, low voltage, R/S transition, early R wave progression, and non-specific ST-T wave changes. The relationship of these events to octreotide acetate is not established because many of these patients have underlying cardiac disease (see WARNINGS AND PRECAUTIONS). In one acromegalic patient with severe congestive heart failure, 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).

Endocrine and Metabolism

Glucose Metabolism

SANDOSTATIN * therapy is occasionally associated with mild transient hypo- or hyperglycemia but may also result in overt diabetes due to alterations in the balance between the counter- regulatory hormones, insulin, glucagon and growth hormone. Patients should be closely observed on introduction of SANDOSTATIN * therapy and at each change of dosage for symptomatic evidence of hyper- and hypoglycemia. Insulin requirement of patients with type I diabetes mellitus may be reduced by administration of SANDOSTATIN *. In non-diabetics and type II diabetics with partially intact insulin reserves, SANDOSTATIN * administration can result in prandial increases in glycemia. Severe hyperglycemia, subsequent pneumonia, and death following initiation of SANDOSTATIN * (octreotide acetate) Injection therapy was reported in one patient with no history of hyperglycemia. Predicting the effect of SANDOSTATIN * on glucose tolerance in any given patients is not possible at this time. It is recommended that all acromegalic patients have their serum glucose carefully monitored during initiation and titration of therapy with SANDOSTATIN * s.c. or SANDOSTATIN * LAR *. Since following bleeding episodes from esophageal varices, there is an increased risk for the development of insulin-dependent diabetes or for changes in insulin requirement in patients with pre-existing diabetes, an appropriate monitoring of blood glucose is required. It is therefore recommended that glucose tolerance and antidiabetic treatment be periodically monitored during therapy with SANDOSTATIN * s.c. or SANDOSTATIN * LAR *.

Thyroid function

Data on the effect of chronic therapy with SANDOSTATIN * on hypothalamic/pituitary function have not been obtained. A progressive drop in T4 levels has been reported, culminating in clinical and biochemical hypothyroidism after 19 months of therapy in one clinical trial patient (carcinoid) receiving 1500 ug of SANDOSTATIN * s.c. daily. Minimal impairment of thyroid function was recorded in some acromegalic patients following treatment with SANDOSTATIN * LAR *. Therefore, baseline and periodic assessment of thyroid function (TSH, total and/or free T4) should be monitored during chronic therapy with octreotide acetate.

Gastrointestinal

Nutrition

There is evidence that SANDOSTATIN * therapy may alter absorption of dietary fats in some patients. It is suggested that periodic quantitative 72-hour fecal fat and serum carotene determinations be performed to aid in the assessment of possible drug-induced aggravation of fat malabsorption. Depressed vitamin B12 levels and abnormal Schilling's tests have been observed in some patients receiving octreotide therapy, and monitoring of vitamin B12 levels is recommended during therapy with SANDOSTATIN * LAR * (octreotide acetate for injectable suspension). Octreotide has been investigated for the reduction of excessive fluid loss from the G.I. 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.

Hepatic/Biliary/Pancreatic

Gallbladder and Related Events

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 * 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. In clinical trials 62% of malignant carcinoid patients who received SANDOSTATIN * LAR * for up to 18 months developed new biliary abnormalities including gallstones, sludge and dilatation. New gallstones occurred in a total of 24% of patients. 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. It is recommended that patients on extended therapy with SANDOSTATIN * or SANDOSTATIN * LAR * be evaluated periodically (at about 6 to 12-month intervals) using ultrasound evaluations of the gallbladder and bile ducts. Baseline and periodic (at about 6 to 12-month intervals) ultrasonography is recommended during therapy with SANDOSTATIN * and SANDOSTATIN * LAR * to assess the presence of gallstones. If gallstones do occur, they are usually asymptomatic. Symptomatic gallstones should receive medical attention.

Liver Impairment

In patients with liver cirrhosis, the half-life of the drug may be increased, necessitating adjustment of the maintenance dosage.

Patient Information

Careful instruction in sterile subcutaneous and intramuscular injection techniques should be given to the patients and to other persons who may administer SANDOSTATIN * or SANDOSTATIN * LAR * injections (see CONSUMER INFORMATION). Patients with carcinoid tumors and VIPomas should be advised to adhere closely to their scheduled return visits for reinjection in order to minimize exacerbation of symptoms. Patients with acromegaly should also be urged to adhere to their return visit schedule to help assure steady control of GH and IGF-1 levels.

Renal

Renal Impairment

In patients with severe renal failure requiring dialysis, the half-life of the drug may be increased, necessitating adjustment of the maintenance dosage.

Sexual Function/Reproduction

The therapeutic benefits of a reduction in growth hormone (GH) levels and normalization of insulin-like growth factor 1 (IGF-1) concentration in female acromegalic patients could potentially restore fertility. Pregnancy in acromegalic patients may increase the risk of gestational diabetes, hypertension and exacerbation of the underlying cardiac disease, therefore female patients of childbearing potential should be advised to use adequate contraception during treatment with octreotide.

Special Populations

Pregnant Women:

There are no adequate and well-controlled studies in pregnant women. In the post-marketing experience, data on a limited number of pregnancies have been reported in patients on octreotide therapy.

Nursing Women:

It is not known whether octreotide is excreted in human breast milk. Animal studies have shown excretion of octreotide in breast milk. Patients should not breast-feed during SANDOSTATIN * treatment.

Pediatrics:

Experience with SANDOSTATIN * s.c. and SANDOSTATIN * LAR * in the pediatric population is limited.

SANDOSTATIN * Injection has been primarily used in patients with congenital hyperinsulinism (also called nesidioblastosis). The youngest patient to receive the drug was 1 month old. At doses of 1-40 ug/kg body weight/day, the majority of side effects observed were gastrointestinal- steatorrhea, diarrhea, vomiting and abdominal distension. Poor growth has been reported in several patients treated with SANDOSTATIN * Injection for more than 1 year; catch-up growth occurred after SANDOSTATIN * Injection was discontinued. A 16-month-old male with enterocutaneous fistula developed sudden abdominal pain and increased nasogastric drainage and died 8 hours after receiving a single 100 ug subcutaneous dose of SANDOSTATIN * Injection.

Monitoring and 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: Carcinoid: 5-HIAA (urinary 5-hydroxyindole acetic acid), plasma serotonin, plasma Substance P VIPoma: VIP (plasma vasoactive intestinal peptide) Acromegaly: Growth hormone - IGF-1 (somatomedin C). Responsiveness to octreotide may be evaluated by determining growth hormone levels at 1-4 hour intervals for 8-12 hours after subcutaneous injection of SANDOSTATIN * Injection (not SANDOSTATIN * LAR *). Alternatively, a single measurement of IGF-1 (somatomedin C) level may be made two weeks after initiation of SANDOSTATIN * Injection or dosage change. After patients are switched from SANDOSTATIN * Injection to SANDOSTATIN * LAR *, GH and IGF-1 determinations may be made after 3 monthly injections of SANDOSTATIN * LAR *. (Steady-state serum levels of octreotide are reached only after a period of 3 months of monthly injections.) Growth hormone can be determined using the mean of 4 assays taken at 1 hour intervals. Somatomedin C can be determined with a single assay. All GH and IGF-1 determinations should be made 4 weeks after the previous SANDOSTATIN * LAR *. Baseline and periodic total and/or free T4 measurements should be performed during chronic therapy (see WARNINGS AND PRECAUTIONS).

DRUG INTERACTIONS

Drug-Drug Interactions

Many patients with carcinoid syndrome or VIPomas being treated with SANDOSTATIN * s.c. have also been, or are being, treated with many other drugs to control the symptomatology or progression of the disease, generally without serious drug interaction. Included are chemotherapeutic agents, H2 antagonists, antimotility agents, drugs affecting glycemic states, solutions for electrolyte and fluid support or hyperalimentation, antihypertensive diuretics and anti-diarrheal agents. Where symptoms are severe and SANDOSTATIN * therapy is added to other therapies used to control glycemic states, such as sulfonylureas, insulin and diazoxide, to beta blockers, calcium channel blockers or to agents for the control of fluid and electrolyte balance, patients must be monitored closely and adjustment made in the other therapies as the symptoms of the disease are controlled. Evidence currently available suggests these imbalances in fluid and electrolytes or glycemic states are secondary to correction of pre-existing abnormalities and not to a direct metabolic action of SANDOSTATIN *. Adjustment of the dosage of drugs, such as insulin, affecting glucose metabolism may be required following initiation of SANDOSTATIN * therapy in patients with diabetes. Since SANDOSTATIN * has been associated with alterations in nutrient absorption, its effect on absorption of any orally administered drugs should be carefully considered. A single case of transplant rejection episode (renal/whole pancreas) in a patient immunosuppressed with cyclosporine has been reported. SANDOSTATIN * treatment to reduce exocrine secretion and close a fistula in this patient resulted in decreases in blood levels of cyclosporine and may have contributed to the rejection episode. SANDOSTATIN * has also been found to delay the intestinal absorption of cyclosporine or cimetidine. Concomitant administration of octreotide and bromocriptine increases the bioavailability of bromocriptine. Limited published data indicate that somatostatin analogs might 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 the CYP 3A4 and which have a low therapeutic index should therefore be used with caution (e.g. terfenadine, quinidine).

Drug-Food Interactions

Interactions with food have not been established.

Drug-Herb Interactions

Interactions with herbal products have not been established.

Drug-Laboratory Interactions

No known interference exists with clinical laboratory tests, including amine or peptide determinations.

DOSAGE AND ADMINISTRATION

Dosing Considerations

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration. Do not use if particulates and/or discoloration are observed.

Recommended Dose and Dosage Adjustment

SANDOSTATIN * s.c. Ampoules and Multidose Vials

Subcutaneous injection is the recommended route of administration of SANDOSTATIN * (octreotide acetate) for control of symptoms in most instances. Intravenous bolus injections have been used under emergency conditions. Multiple injections at the same site within short periods of time should be avoided. The initial dosage is 50 ug, administered subcutaneously, once or twice daily. Thereafter, the number of injections and dosage may be increased gradually based on patient tolerability, clinical response and effects on levels of tumour-produced hormones (in cases of carcinoid tumours on the urinary excretion of 5-hydroxyindole-acetic acid). Dosage information for patients with specific tumors is listed below. The drug is usually given in a b.i.d or t.i.d schedule.

Carcinoid Tumors

The suggested daily dosage of SANDOSTATIN * during the first two weeks of therapy ranges from 100 to 600 ug per day in two to four divided doses (mean daily dosage is 300 ug). In the clinical studies, the median daily maintenance dosage was approximately 450 ug, but clinical and biochemical benefits were obtained in some patients with as little as 50 ug, while others required doses up to 1500 ug per day. However, experience with doses above 750 ug per day is limited.

VIPomas

Daily dosages of 200 to 300 ug in two to four divided doses are recommended during the initial 2 weeks of therapy (range 150 to 750 ug) to control symptoms of the disease. On an individual basis, dosage may be adjusted to achieve a therapeutic response, but usually doses above 450 ug per day are not required.

Acromegaly

Daily dosages of 100 ug to 300 ug b.i.d. or t.i.d. are recommended at the beginning of treatment. Dosage adjustment should be based on monthly assessment of GH levels and clinical symptoms, and on tolerability. In most patients, the optimal daily dose will be 200 to 300 ug per day. A maximum dose of 1500 ug should not be exceeded. If no relevant reduction of GH levels and no improvement of clinical symptoms have been achieved within 3 months of starting treatment with SANDOSTATIN *, therapy should be discontinued.

Prevention of Complications following Pancreatic Surgery

Daily dosage of 100 ug t.i.d., administered subcutaneously, for 7 consecutive days starting on the day of the operation at least one hour before laparatomy.

Bleeding Gastro-oesophageal Varices in patients with cirrhosis

The recommended dose of SANDOSTATIN * is 25 ug/hour by continuous i.v. infusion for 48 hours. In patients with high risk of rebleeding, infusion should be maintained up to a maximum of 5 days. Immediately prior to use, the contents of the ampoule or multidose vial should be diluted in physiological saline. The volume of dilution will depend on the infusion system used and should be adjusted to ensure a continuous infusion of SANDOSTATIN * at the recommended rate. Once diluted, the solution should be used within 24 hours. Discard unused portion. As with all parenteral drugs, i.v. admixtures should be inspected visually for clarity, particulate matter, precipitation, discoloration and leakage prior to administration, whenever solution and container permit.

SANDOSTATIN * LAR * (Octreotide For Injectable Suspension)

SANDOSTATIN * LAR * may only be administered by deep intragluteal injection. The site of repeat intragluteal injection should be alternated between the left and right gluteal muscle. SANDOSTATIN * LAR * (octreotide acetate for injectable suspension) must be administered under the supervision of a physician. Do not directly inject diluent without preparing suspension. It is important to closely follow the mixing instructions included in the packaging. SANDOSTATIN * LAR * must be administered immediately after mixing. SANDOSTATIN * LAR * should be administered intragluteally at four week intervals. Administration of SANDOSTATIN * LAR * at intervals greater than 4 weeks is not recommended because there is no adequate information on whether such patients could be satisfactorily controlled. Deltoid injections are to be avoided because of significant discomfort at the injection site when given in that area. SANDOSTATIN * LAR * should never be administered by the IV or S.C. routes. The following dosage regimens are recommended.

Acromegaly

For patients who are adequately controlled with SANDOSTATIN * s.c., it is recommended to start treatment with the administration of 20 mg SANDOSTATIN * LAR * at four week intervals for three months. Treatment with SANDOSTATIN * LAR * can be started the day after the last dose of s.c. SANDOSTATIN *. Subsequent dosage adjustments should be based upon serum growth hormone (GH) and insulin-like growth factor 1/somatomedin C (IGF 1) concentrations and clinical symptoms. For patients in whom, within this three month period, clinical symptoms and biochemical parameters (GH, IGF 1) are not fully controlled (GH concentrations still above 2.5 ug/L) the dose may be increased to 30 mg every four weeks. For patients whose serum GH concentrations are consistently below 1 ug/L, whose IGF 1 serum concentrations normalized, and in whom most reversible signs/symptoms of acromegaly have disappeared after three months of treatment with 20 mg, 10 mg SANDOSTATIN * LAR * may be administered every four weeks. However, particularly in this group of patients, it is recommended to closely monitor adequate control of serum GH and IGF 1 concentrations and clinical signs/symptoms at this low dose of SANDOSTATIN * LAR *. For patients in whom surgery, radiotherapy or dopamine agonist treatment is inappropriate, or in the interim period until radiotherapy becomes fully effective, a short test dosing of SANDOSTATIN * s.c. is recommended to assess the response and systemic tolerability of octreotide prior to initiating treatment with SANDOSTATIN * LAR * as described above.

Carcinoid tumours and VIPomas

Patients not currently treated with SANDOSTATIN * s.c. should begin therapy with SANDOSTATIN * s.c. The suggested daily dose during the first two weeks of therapy ranges from 100-600 ug/day in 2-4 divided doses (mean daily dose is 300 ug). Some patients may require doses up to 1500 ug/day. The suggested daily dose for VIPomas is 200-300 ug in 2-4 divided doses (range 150-750 ug); dosage may be adjusted on an individual basis to control symptoms but usually doses above 450 ug/day are not required. SANDOSTATIN * s.c. 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 * in the dosage regimen described below. Patients currently receiving SANDOSTATIN * s.c. can be switched to SANDOSTATIN * LAR * in a dosage of 20 mg i.m. intragluteally at 4-week intervals for 2 months. Gluteal injection sites should be alternated to avoid irritation. Because of the need for serum octreotide to reach therapeutically effective levels following initial injection of SANDOSTATIN * LAR *, carcinoid tumor and VIPoma patients should continue to receive SANDOSTATIN * s.c. for at least two weeks in the same dosage they were taking before the switch. Failure to continue s.c. injections for this period may result in exacerbation of symptoms. Some patients may require 3 or 4 weeks of such therapy. After two months of a 20 mg dosage of SANDOSTATIN * LAR *, dosage may be increased to 30 mg every 4 weeks if symptoms are not adequately controlled. 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. A dose of 10 mg is not recommended as a starting dose, however, because therapeutically effective levels of octreotide are reached more rapidly with a 20 mg dose. Dosages higher than 30 mg are not recommended because there is no information on their usefulness. 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 * s.c. or SANDOSTATIN * LAR *). During these periods they may be given SANDOSTATIN * s.c. for a few days at the dosage they were receiving prior to switch to SANDOSTATIN * LAR *. When symptoms are again controlled, SANDOSTATIN * s.c. can be discontinued.

Administration

Preparation of SANDOSTATINLAR * (Octreotide [as acetate] for Injectable Suspension):

*

SANDOSTATIN * LAR * is supplied in kits containing either: one vial of octreotide [as acetate] for injectable suspension (microspheres for depot suspension), two ampoules (diluent), one 5 mL plastic syringe and 2 needles [40 mm, 19 gauge]. Follow the instructions below carefully to ensure complete saturation of the powder and its uniform suspension before i.m. injection. SANDOSTATIN * LAR * suspension must only be prepared immediately before administration. SANDOSTATIN * LAR * should only be administered by a trained health professional. SANDOSTATIN * LAR * must not be diluted with other products.

OR : one vial of SANDOSTATIN * LAR * 10 mg, 20 mg or 30 mg octreotide [as acetate] for injectable suspension (microspheres for depot suspension) , One syringe (pre-filled with diluent), 2 needles [40 mm, 19 gauge], and an instruction booklet. Follow the instructions below carefully to ensure complete saturation of the powder and its uniform suspension before i.m. injection. SANDOSTATIN * LAR * suspension must only be prepared immediately before administration. SANDOSTATIN * LAR * should only be administered by a trained health professional. SANDOSTATIN * LAR * must not be diluted with other products.

Allow the SANDOSTATIN * LAR * vial and pre-filled syringe with diluent to reach room temperature (approximately 30 to 60 minutes).Remove the plastic cap from the vial containing SANDOSTATIN * LAR *

Remove the cap from the pre-filled syringe with diluent. Attach one of the supplied needles to the pre-filled syringe with diluent. Use only 40 mm, 19 gauge needles. Do not inject the diluent directly without preparing the suspension.

Gently tap the SANDOSTATIN * LAR * vial to ensure that all powder has settled to the bottom. Disinfect the rubber stopper of the vial with an alcohol swab.

Insert the needle through the center of the rubber stopper of the SANDOSTATIN * LAR * vial. Without disturbing the SANDOSTATIN * LAR * powder, gently inject the diluent into the vial by running the diluent down the inside wall of the vial. Do not inject the diluent directly into the powder. Withdraw the needle from the vial.

5. Do not disturb the vial until the diluent has totally wetted the SANDOSTATIN * LAR * powder (approximately 2-5 minutes). After 5 minutes, without inverting the vial, check sides and bottom of vial for dry spots (powder). Powder must be completely saturated before proceeding. If dry spots exist, allow undisturbed wetting to continue and check vial every 30 seconds until saturation is complete. At this stage, prepare the patient for injection.

1. Once complete wetting has occurred, the vial should be moderately swirled for about 30 to 60 seconds or until a uniform milky suspension is achieved. Do not vigorously shake or invert the vial as this may cause the suspension to flocculate, making it unusable.

2. Peel off outer label from the pre-filled syringe with diluent, after product reconstitution.

3. Immediately fill the syringe with air, re-insert the needle through the rubber stopper and slowly inject all of the air into the vial. With the bevel down and the vial tipped at approximately a 45-degree angle (as shown in the diagram), slowly draw the entire contents of the vial into the syringe, without inverting the vial. It is normal for a small amount of residual suspension to remain on the walls and bottom of the vial. This is a calculated overfill.

4. Draw a small amount of air into the syringe to allow the suspended product to move more freely. Rock the syringe gently and constantly to maintain a uniform suspension. Eliminate air from syringe. Change the needle, discarding the first needle and attaching the second supplied needle.

5. Disinfect the injection site with an alcohol swab. Rock the syringe gently and constantly to maintain a uniform suspension. Insert needle deep into right or left gluteus and draw back to ensure that no blood vessel has been penetrated. (If a blood vessel has been penetrated, attach a new 40 mm, 19 gauge needle and select another injection site). Immediately inject contents of entire syringe i.m. slowly with steady pressure. If needle clogs, replace with a new 40 mm, 19 gauge needle.

Note: Record injection site on patient's record and alternate monthly.

SANDOSTATIN * LAR * must be given only by deep intragluteal injection, never intravenously. If a blood vessel has been penetrated, another injection site must be selected. The site of repeat intragluteal injection should be alternated between the left and right gluteal muscle. Do not use the same gluteal region each time (every 4 weeks). As with all parenteral admixtures, the constituted product should be examined for the presence of foreign particulate matter, agglomeration or discolouration. Any defective units should be discarded.

Reconstitution: Parenteral Products:

Solution for continuous i.v. infusion:

Immediately prior to use, the contents of the ampoule or multidose vial should be diluted in physiological saline. The volume of dilution will depend on the infusion system used and should be adjusted to ensure a continuous infusion of SANDOSTATIN * at a rate of 25 ug/hour. The following are examples of dilutions which may be used:

As with all parenteral drugs, i.v. admixtures should be inspected visually for clarity, particulate matter, precipitation, discoloration and leakage prior to administration, whenever solution and container permit. SANDOSTATIN * diluted in physiological saline is stable for 24 hours when stored at room temperature. Discard unused portion. Octreotide acetate is not stable in Total Parenteral Nutrition (TPN) solutions.

OVERDOSAGE

SANDOSTATIN * s.c. Ampoules and Multidose Vials

A limited number of accidental overdoses of SANDOSTATIN * in adults and children have been reported. In adults, the doses ranged from 2,400-6,000 micrograms/day administered by continuous infusion (100-250 micrograms/hour) or subcutaneously (1,500 micrograms t.i.d. ). The adverse events reported were arrhythmia, hypotension, cardiac arrest, brain hypoxia, pancreatitis, hepatitis steatosis, diarrhoea, weakness, lethargy, weight loss, hepatomegaly, and lactic acidosis. In children, the doses ranged from 50 -3,000 microgram/day administered by continuous infusion (2.1-500 micrograms/hour) or subcutaneously (50-100 micrograms). The only adverse event reported was mild hyperglycaemia. No unexpected adverse events have been reported in cancer patients receiving SANDOSTATIN * at doses of 3,000-30,000 micrograms/day in divided doses subcutaneously. The management of overdosage is symptomatic.

SANDOSTATIN * LAR * (Octreotide for Injectable Suspension)

A limited number of accidental overdoses of SANDOSTATIN * LAR * have been reported. The doses ranged from 100 mg to 163 mg/month of SANDOSTATIN * LAR *. The only adverse event reported was hot flushes. Cancer patients receiving doses of SANDOSTATIN * LAR * up to 60 mg/month and up to 90 mg/2 weeks have been reported. These doses were in general well tolerated; however, the following adverse events have been reported: frequent urination, fatigue, depression, anxiety, and lack of concentration. The management of overdosage is symptomatic.

ACTION AND CLINICAL PHARMACOLOGY

Mechanism of Action

General

Octreotide acetate is a synthetic octapeptide analogue of naturally occurring somatostatin with similar pharmacological effects, but with a prolonged duration of action. It inhibits pathologically increased secretion of growth hormone (GH) and of peptides and serotonin produced within the gastro-entero-pancreatic (GEP) endocrine system. In normal healthy subjects, octreotide acetate has been shown to inhibit:

• Release of growth hormone (GH) stimulated by arginine infusion, exercise and insulin-

induced hypoglycemia. Postprandial release of insulin, glucagon, gastrin, other peptides of the GEP endocrine system, and arginine-stimulated release of insulin and glucagon. Thyrotropin releasing hormone (TRH) stimulated release of thyroid stimulating hormone (TSH). The precise mode of action of octreotide acetate on portal hypertension is still unclear. It is thought to reduce splanchnic blood flow primarily by inhibiting vasoactive gastro-intestinal hormone secretion and exerting a direct vasomotor effect on splanchnic vessels, thus reducing portal blood flow. Using human sephanous veins, it has been shown that vasoconstriction is mediated by type 2 somatostatin receptors.

Pharmacokinetics

SANDOSTATIN * s.c. Ampoules and Multidose Vials

After subcutaneous (s.c.) injection of SANDOSTATIN *, octreotide acetate is rapidly and completely absorbed. Peak plasma concentrations are reached within 30 minutes. The half-life after subcutaneous administration is 100 minutes. After intravenous injection the elimination is biphasic with a and b half-lives of approximately 10 and 90 minutes, respectively. The volume of distribution is 0.4 L/Kg body weight and the total body clearance is 160 mL/min. Plasma protein binding amounts to 65% with only negligible amounts bound to red blood cells.

SANDOSTATIN * LAR * (Octreotide as acetate for Injectable Suspension)

In patients with acromegaly, SANDOSTATIN * LAR *, a galenical formulation of octreotide consisting of microspheres for depot suspension suitable for repeat intramuscular administration at intervals of four weeks, delivers consistent and therapeutic octreotide serum concentrations thus consistently lowering GH and normalizing IGF-1 serum concentrations in the majority of patients. In patients with carcinoid tumours and Vasoactive Intestinal Peptide Tumors (VIPomas), treatment with SANDOSTATIN * LAR * provides continuous control of symptoms related to the underlying disease. The pharmacokinetic profile of octreotide acetate after injection of SANDOSTATIN * LAR * reflects the release profile from the polymer matrix and its biodegradation. Once released into the systemic circulation, octreotide distributes according to its known pharmacokinetic properties as described above for SANDOSTATIN * administered subcutaneously. After single intramuscular injections of SANDOSTATIN * LAR *, the serum octreotide concentration reaches a transient initial peak within one hour after administration followed by progressive decrease to a low undetectable octreotide level within 24 hours. After this initial peak on the first day, octreotide remains at sub-therapeutic levels in the majority of patients for the following seven days. Thereafter, octreotide concentrations increase again, and reach plateau concentrations around day 14 and remain relatively constant during the following three to four weeks. The peak level during day 1 is lower than levels during the plateau phase and no more than 0.5% of the total drug release occurs during day 1. After about day 42, the octreotide concentration decreases slowly, concomitantly with the terminal degradation phase of the polymer matrix dosage form. In patients with acromegaly, plateau octreotide concentrations after single doses of 10 mg, 20 mg and 30 mg of SANDOSTATIN * LAR * are 358, 926 and 1710 pg/mL, respectively. Steady state octreotide concentrations reached after three injections at four week intervals, are higher by a factor of approximately 1.6 to 1.8 reaching 1557 and 2384 pg/mL after multiple injections of 20 and 30 mg SANDOSTATIN * LAR *, respectively. In patients with carcinoid tumours, the mean octreotide serum concentrations after six doses of 10 mg, 20 mg and 30 mg of SANDOSTATIN * LAR * administered by intramuscular injection every four weeks were 1231 pg/mL, 2620 pg/mL and 3928 pg/mL, respectively. Concentrations were dose proportional and steady-state concentrations were reached after two injections of 20 and 30 mg and after three injections of 10 mg. In patients with acromegaly, no accumulation of octreotide beyond that expected from overlapping release profiles occurred over a period of up to 28 monthly SANDOSTATIN * LAR * injections.

STORAGE AND STABILITY

SANDOSTATIN * s.c. Ampoules and Multidose Vials Ampoules:

For prolonged storage, SANDOSTATIN * ampoules must be stored at 2 to 8oC. Keep container in the outer carton in order to protect from light. Do not freeze. Keep in a safe place out of reach of children and pets.

Multidose Vials: For prolonged storage, SANDOSTATIN * multidose vials must be stored at 2 to 8oC. Keep container in the outer carton in order to protect from light. Do not freeze. For day-to-day use, both the ampoules and the multidose vials may be stored at room temperature for up to 2 weeks; they must be protected from light. The ampoules should be opened just prior to administration and any unused portion discarded. Keep in a safe place out of reach of children and pets.

SANDOSTATIN * LAR * (Octreotide for Injectable Suspension):

The SANDOSTATIN * LAR * vials must be stored at 2 to 8 oC. Keep vial in the outer carton in order to protect it from light. The vials can remain at room temperature on the day of the injection. However the suspension must only be prepared immediately prior to i.m. injection. The ampoules containing 2 mL of diluent should be stored at 2 to 8 oC. The SANDOSTATIN * LAR * powder, once suspended in the diluent, should be used immediately. Keep in a safe place out of reach of children and pets.

Pre-filled syringe with 2.5 mL diluent: Store the pre-filled syringe with 2.5 mL diluent at 2 to 8 oC. Keep in a safe place out of reach of children and pets.

DOSAGE FORMS, COMPOSITION AND PACKAGING

SANDOSTATIN * Ampoules and Multidose Vials

SANDOSTATIN * (octreotide acetate) is supplied in 1 mL ampoules, each containing 50, 100 or 500 ug of octreotide as acetate. SANDOSTATIN * is available in boxes of 5 ampoules. SANDOSTATIN * is also available in 5 mL multidose vials. Each vial contains 1000 ug of octreotide as acetate (200 ug/mL).

SANDOSTATINLAR * is supplied in kits containing

*

either: One single dose vial of SANDOSTATIN * LAR * (Octreotide for Injectable Suspension) containing 10, 20 or 30 mg octreotide (as actetate) slow release. Two ampoules each containing 2mL of diluent. One injection set consisting of 1 plastic 5-mL syringe and 2 needles [40 mm, 19 gauge]. OR: One single dose vial of SANDOSTATIN * LAR * (Octreotide for Injectable Suspension) containing 10, 20 or 30 mg of octreotide (as acetate) slow release. A pre-filled glass syringe containing 2.5 mL of diluent. 2 needles [40 mm, 19 gauge]. an instruction booklet.

Composition of SANDOSTATIN * Ampoules

Water for Injection, q.s. 1.0 mL

Present as octreotide acetate

Sodium hydrogen carbonate is added to provide a buffered solution pH 4.2 +- 0.2.

Composition of SANDOSTATIN * Multidose Vials

Water for Injection, q.s. 1.0 mL

Present as octreotide acetate

Sodium hydrogen carbonate is added to provide a buffered solution pH 4.2 +- 0.2.

Composition of the diluent for SANDOSTATIN * LAR * (Octreotide for Injectable Suspension)

Composition of the pre-filled syringe (with diluent) for SANDOSTATIN * LAR * (Octreotide for Injectable Suspension)

Composition of SANDOSTATIN * LAR * (Octreotide for Injectable Suspension)

Octreotide as free peptide

PART II: SCIENTIFIC INFORMATION

PHARMACEUTICAL INFORMATION

Drug Substance

Proper name: octreotide acetate Chemical name: D-Phenylalanyl-L-hemicystyl-L-phenylalanyl-D-tryptophyl-L-lysyl-L threonyl-L-hemicystyl-L-threoninol cyclic(2-7) disulfide acetate Molecular formula and molecular mass: C49H66N10O10S2, x CH3COOH, 1019.3 x 60.05 Structural formula: Physicochemical properties: Octreotide acetate is a bridged octapeptide analogue of somatostatin. It is a white to off-white amorphous lyophilisate, which melts with decomposition; it is very hygroscopic. The values for pka (I) and pka (II) in water are 7.00 and 10.15 respectively. At 25degC, the solubility of octreotide acetate is >10 mg/mL in water; >10 mg/mL in glacial acetic acid and >10 mg/mL in methanol.

CLINICAL TRIALS

The clinical trials of SANDOSTATIN * LAR * (octreotide acetate for injectable suspension) were performed in patients who had been receiving subcutaneous SANDOSTATIN * (octreotide acetate) for a period of weeks to as long as 10 years. The acromegaly studies with SANDOSTATIN * LAR * 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 *. However, some patients enrolled were partial responders to subcutaneous SANDOSTATIN *, i.e., GH levels were reduced by >50% on subcutaneous SANDOSTATIN * Injection compared to the untreated state, although not suppressed to <5 ng/mL.

Acromegaly

SANDOSTATIN * LAR * 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 * given in doses of 100 ug or 200 ug t.i.d. Most patients were switched to 20 mg or 30 mg doses of SANDOSTATIN * LAR * 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 * as they had been on SANDOSTATIN * 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 * (most had levels <5 ng/mL). The starting dose of SANDOSTATIN * LAR * 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. (The recommended regimen for these dosage changes is described under DOSAGE AND ADMINISTRATION.) Growth hormone and IGF-1 were at least as well controlled on SANDOSTATIN * LAR * as they had been on SANDOSTATIN * s.c. Table 4 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 *.

Table 4 Hormonal Response in Acromegalic Patients Receiving 27 to 28 Injections During1 Treatment with SANDOSTATIN * LAR *

Average of monthly levels of GH and IGF-1 over the course of the trials

For the 88 patients in Table 4, a mean GH level of <2.5 ng/mL was observed in 47% receiving SANDOSTATIN * LAR *. 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 5 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 *.

Table 5 Hormonal Response in Acromegalic Patients Receiving 12 Injections During1 Treatment with SANDOSTATIN * LAR *

Average of monthly levels of GH and IGF-1 over the course of the trials

For the 122 patients in Table 5, 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 *. 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 *, 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 * as they had been on SANDOSTATIN *. Of the 25 patients who completed the trials and were partial responders to SANDOSTATIN * (GH >5.0 ng/mL but reduced by >50% relative to untreated levels), 1 patient (4%) responded to SANDOSTATIN * LAR * 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.

Carcinoid Tumors and Vasoactive Intestinal Peptide Tumors (VIPomas)

A 6-month clinical trial of malignant carcinoid syndrome was performed in 93 patients who had previously been shown to be responsive to SANDOSTATIN *. Sixty-seven patients were randomized at baseline to receive, double-blind, doses of 10 mg, 20 mg or 30 mg SANDOSTATIN * LAR * every 28 days and 26 patients continued, unblinded, on their previous SANDOSTATIN * regimen (100-300 ug t.i.d. ). In any given month after steady-state levels of octreotide were reached, approximately 35%-40% of the patients who received SANDOSTATIN * LAR * required supplemental subcutaneous SANDOSTATIN * therapy usually for a few days, to control exacerbation of carcinoid symptoms. In any given month the percentage of patients randomized to subcutaneous SANDOSTATIN *, who required supplemental treatment with an increased dose of SANDOSTATIN *, was similar to the percentage of patients randomized to SANDOSTATIN * LAR *. Over the six-month treatment period approximately 50%-70% of patients who completed the trial on SANDOSTATIN * LAR * required subcutaneous SANDOSTATIN * supplemental therapy to control exacerbation of carcinoid symptoms although steady-state serum SANDOSTATIN * LAR * levels had been reached. Table 6 presents the average number of daily stools and flushing episodes in malignant carcinoid patients.

Table 6 Average No. of Daily Stools and Flushing Episodes (ITT Population)

Overall, mean daily stool frequency was as well controlled on SANDOSTATIN * LAR * as on SANDOSTATIN * (approximately 2 to 2.5 stools/day). Mean daily flushing episodes were similar at all doses of SANDOSTATIN * LAR * and on SANDOSTATIN * (approximately 0.5 to 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 *. The reductions are within the range reported in the published literature for patients treated with octreotide (about 10%-50%).

DETAILED PHARMACOLOGY

Pharmacodynamics

Pharmacodynamic studies with SANDOSTATIN * (octreotide acetate) in animals have shown that it inhibits secretion of basal and/or stimulated GH, insulin, glucagon in the rat and rhesus monkey and of gastric acid, and exocrine pancreatic enzymes in the rat, with greater potency than natural somatostatin. Octreotide acetate seems to possess some degree of specificity of pharmacological action in that it is much more potent in suppressing GH and glucagon levels than insulin levels when compared with somatostatin. In addition to its potency, octreotide acetate has a long duration of action with respect to GH inhibition. Octreotide acetate administration is associated with a minor fall of fasting plasma glucose in monkeys followed by a slight hypersecretion of glucose. In contrast, there occurs a postprandial hyperglycemia, most likely due to an inhibition of insulin. The pharmacological activities of octreotide acetate in man include inhibition of stimulated GH secretion, stimulated TSH levels, insulin and glucagon release, gut hormone secretion, and decreased portal hypertension. This spectrum of activity resembles that obtained with administration of somatostatin in man. The actions of somatostatin are mediated by receptors. Five somatostatin receptor subtypes have been identified. Octreotide displays a high affinity for type 2 receptors, a moderate affinity for type 3 and 5 receptors and a very low affinity for type 1 and 4 receptors.

Pharmacokinetics

Pharmacokinetic studies have been performed in rats, dogs and rhesus monkeys after single and multiple doses. The bioavailability of SANDOSTATIN * after single subcutaneous (s.c.) injection in rats and dogs was approximately 100%. Highest concentrations were found in liver, kidneys, skin and lungs. Octreotide acetate was metabolized in the rat into smaller peptides, e.g. the dipeptide D-tryptophanlysine. However, as biliary and urinary excretion consisted mainly of unchanged drug, hepatic metabolism appeared slight. A biphasic elimination of octreotide acetate from plasma was also obtained with an a-disposition half-life of 0.3 to 0.4 hours and a b- phase between 1.2 and 3.2 hours. Multiple administrations did not change the pharmacokinetics of the drug compared to single administration. In man, octreotide acetate is rapidly and completely absorbed after s.c. injection. Peak plasma concentrations reached after s.c. administration are about half of those obtained after intravenous (i.v.) administration of the same dose. Plasma protein binding is about 65%. The uptake in red blood cells is negligible. After i.v. administration there are two disposition half-lives, a short one of about 10 minutes and a longer one of about 1.5 hours. After s.c. administration to healthy volunteers, the final disposition half-life is about 1.5 hours, the volume of distribution is 6 L and the total body clearance is about 160 mL/min. The absolute bioavailability of octreotide acetate calculated after s.c. administration was rather variable, with values of about 100% for 100 ug and about 130% for 50 ug and 200 ug. There is no significant accumulation under conditions of repeated s.c. administration. The pharmacokinetic profile of octreotide after intramuscular of SANDOSTATIN * LAR * reflects the release profile from the polymer matrix and its biodegradation. Once released into the systemic circulation, octreotide distributes according to its known pharmacokinetic profile following administration of SANDOSTATIN * s.c. In patients with acromegaly, plateau octreotide concentrations after single doses of 10, 20 and 30 mg of SANDOSTATIN * LAR * are 358, 926 and 1710 pg/mL, respectively. Steady state octreotide concentrations reached after 3 injections at 4-week intervals are higher by a factor of approximately 1.6 to 1.8, reaching 1557 and 2384 pg/mL after multiple injections of 20 and 30 mg, respectively. No accumulation of octreotide beyond that expected from overlapping release profiles occurred over a period of up to 28 monthly SANDOSTATIN * LAR * injections. In patients with carcinoid tumours, the mean octreotide serum concentrations after six doses of 10 mg, 20 mg and 30 mg of SANDOSTATIN * LAR * administered by intramuscular injection every four weeks were 1231 pg/mL, 2620 pg/mL and 3928 pg/mL, respectively. Concentrations were dose proportional and steady-state concentrations were reached after two injections of 20 and 30 mg and after three injections of 10 mg.

Clinical Pharmacology

SANDOSTATIN * s.c. Ampoules and Multidose vials

Carcinoid Tumors

Patients with carcinoid tumors are the most responsive to therapy with approximately 70 to 90% achieving symptom control, characterized by a decrease in diarrhea and flushing. In many cases, this is accompanied by a fall in plasma serotonin and reduced urinary excretion of 5- hydroxyindole acetic acid (5-HIAA). In the event of no beneficial response to SANDOSTATIN * treatment, continuation of therapy beyond one week is not recommended, although in non-responders no serious sustained adverse drug effects have been reported.

VIPomas

The biochemical characteristic of these tumors is over-production of vasoactive intestinal peptide (VIP). In 70% of patients with VIPomas, administration of SANDOSTATIN * results in alleviation of the severe secretory diarrhea typical of this condition and consequent improvement in quality of life. This is accompanied by an improvement in associated electrolyte abnormalities, e.g. hypokalemia, enabling enteral and parenteral fluid and electrolyte supplementation to be withdrawn. Clinical improvement is usually accompanied by a reduction in plasma VIP levels, which may fall to the normal reference range.

Acromegaly

In acromegalic patients (including those who have failed to respond to surgery, irradiation of dopamine agonist treatment), SANDOSTATIN * lowers plasma levels of GH and/or somatomedin C. A clinically relevant GH reduction (by 50% or more) occurs in almost all patients, and normalization (plasma GH < 5 ng/mL) can be achieved in about half the cases. In most patients, SANDOSTATIN * markedly reduces the clinical symptoms of the disease such as headache, skin and soft tissue swelling, hyperhidrosis, arthralgia, paresthesia. In patients with a lare pituitary adenoma, SANDOSTATIN * treatment may result in some shrinkage of the tumor mass.

Prevention of complications following pancreatic surgery

Complications following high risk pancreatic surgery (such as peripancreatic fluid collection, abscess, leaking from the surgical anastomosis, fistula and subsequent sepsis and acute pancreatitis) are chiefly linked with pancreatic proenzyme secretion activated by surgical trauma. They are due to pancreatic juice leaking from the pancreatic remnant and reaching the peripancreatic region. The action of the activated digestive enzymes leads to severe inflammation and may cause autodestruction of peripancreatic and pancreatic tissue, including intestinal organs and major vessels. SANDOSTATIN * inhibits basal and stimulated exocrine pancreatic secretion and, when administered peri- and post-operatively, reduces the incidence of complications following pancreatic surgery.

Bleeding Gastro-oesophageal varices

The precise mode of action of SANDOSTATIN * on portal hypertension is still unclear. SANDOSTATIN * is thought to reduce splanchnic blood flow primarily by inhibiting vasoactive gastro-intestinal hormone secretion and exerting a direct vasomotor effect on splanchnic vessels, thus reducing portal blood flow. Using human sephanous veins, it has been shown that vasoconstriction is mediated by type 2 somatostatin receptors.

SANDOSTATIN * LAR * (Octreotide for Injectable Suspension)

Acromegaly

In patients with acromegaly, SANDOSTATIN * LAR * administered intramuscularly at 4-week intervals, delivers consistent and therapeutic octreotide serum concentrations thus consistently lowering GH and normalizing IGF 1 serum concentrations in the majority of patients. In most patients SANDOSTATIN * LAR * markedly reduces the clinical symptoms of the disease such as headache, perspiration, paresthesia, fatigue, osteoarthralgia and carpal tunnel syndrome. In individual patients with pituitary adenomas, SANDOSTATIN * LAR * was reported to lead to shrinkage of the tumour mass.

Carcinoid tumours and VIPomas

In patients with carcinoid tumours and VIPomas, administration of octreotide results in improvement of symptoms, particularly flushing and diarrhea.

TOXICOLOGY ACUTE TOXICOLOGY Single intravenous injections of SANDOSTATIN * (octreotide acetate) were administered to mice and rats. Animals were observed until death occurred or for a period of seven days following administration.

Octreotide acetate caused no unusual effects. Immediately after administration the following signs were observed: numbness, strained and sometimes slower breathing, jumping and roll and stretch cramps. The animals which died did so within one hour, the survivors were without signs after two days.

Subchronic and Chronic Toxicity

Chronic Toxicity Studies with SANDOSTATIN * LAR *

Special Toxicity Studies with SANDOSTATIN * LAR *: Local Tolerance

Teratological and reproductive studies

Rats and rabbits were treated intravenously with SANDOSTATIN * (octreotide acetate) 0.01, 0.1 or 1 mg/kg/day from day 6 to 15 or 6 to 18 post coitum. Dams and their fetuses were sacrificed at term and examined. In rats and rabbits the 0.01 mg/kg/day dose was well tolerated by the dams but the mid and high doses caused slight dose-dependent weight gain inhibition. No adverse effect on the reproduction data or fetal and placental weight was observed. Morphological findings in fetuses of both species gave no indication of a teratogenic potential of the drug.

In a peri- and post-natal study in rats treated subcutaneously with doses of 0.02, 0.1 or 1.0 mg/kg/day from day 15 post coitum until autopsy on day 21 post-partum, octreotide acetate was well tolerated by the F0 females of all treatment groups, although slightly lower weight gain during pregnancy was noted in the high dose group. The reduced growth observed in rat pups was most likely a direct consequence of the drug's main pharmacological action, i.e. growth hormone inhibition.

In a fertility and general reproduction performance study in female rats treated subcutaneously, once daily, with doses of 0.02, 0.1 or 1 mg/kg/day, octreotide acetate was well tolerated by the F0 dams of the lower and mid dose group. In the high dose group, body weight gain was slightly reduced during the 2 weeks preceding mating and there was localized hair loss at the site of injection. Reproduction performance was normal at all dose levels. Prenatal and post-natal development of F1 offspring was not affected except for some growth retardation. The reproduction performance of F1 animals as well as the development of the F2 offspring were also normal.

Animal studies do not indicate direct or indirect harmful effects with respect to pregnancy, embryonal/foetal development, parturition or postnatal development apart from some transient retardation of physiological growth.

Mutagenicity

In vitro mutagenicity was tested in Salmonella typhimurium strains TA1535, TA1537, TA1538, TA98 and TA100 in the presence and absence of a rat liver S9 homogenate (Ames test). No mutagenic effect was found.

In vivo

mutagenicity was investigated by means of the micronucleus test using adult CD mice (Charles River). Octreotide acetate was administered intravenously twice within 24 hours. Doses were 5, 16 or 50 mg/kg for each treatment. Controls received the vehicle only. Micronuclei were evaluated in bone marrow preparations made 48 or 72 hours after the first administration. Octreotide acetate was not mutagenic in this test system.

In a second in vivo mutagenicity test, damage to germ cell DNA was evaluated using the unscheduled DNA systhesis (UDS) technique. Male CD mice were injected intravenously with single doses of either 25 or 50 mg/kg. One hour after the administration of octreotide acetate, the mice received an intra-testicular injection of radioactive marked thymidine. Sperm were taken from the cauda epididymis at various time intervals, counted, and tested for radioactivity in a scintillation counter. In this test system octreotide acetate had no effect on the DNA of germ cells.

The SANDOSTATIN * LAR * microspheres were devoid of mutagenic potential when tested in a validated in vitro bacterial assay.

Oncogenicity Studies

The results of the oncogenicity studies in rats and mice do not indicate a direct carcinogenic effect of octreotide acetate and are not considered an impediment for human use

Page 45 of 57

REFERENCES

1. Anderson JV, Bloom SR. Long term therapy with a somatostatin derivative (SMS 201-995) in a series of patients with vasoactive intestinal peptide secreting pancreatic tumors. Can J Physiol Pharmacol 1986; 64 (suppl): 9, abstr no 119.

2. Bassi Cl, Falconi M, et al. Prophylaxis of Complications after Pancreatic Surgery: Results of a Multicentre trial in Italy. Digestion. 1994; 55 (Suppl. 1): 41-47.

3. Besson I, Ingrand P, et al. Sclerotherapy with or without octreotide for acute variceal bleeding. N. Engl. J. Med. 1995; 333: 555-560

4. Bloom SR, Greenwood C (ed. ). Proceedings of somatostatin '85: Chemical, Physiological and Clinical advances. Scand J, Gastroenterology 1986; 21(S119):1-274.

5. Brabant G, Muller MJ, Rotsch M, et al. Treatment of carcinoid syndrome and VIPoma with a long-acting somatostatin derivative (SMS 201-995). Scand J Gastroenterol 1986; 21 (suppl 119): 177-180.

6. Buchler M, Freiss H, et al. Role of Octreotide in the Prevention of Postoperative Complications Following Pancreatic Resection.. Am. J. Pancreatic Surgery. 1992; 163: 125- 131.

7. Clements D, Elias E. Regression of metastatic VIPoma with somatostatin derivative SMS 201-995. Lancet 1985; I (8433): 874-5.

8. Del Pozo E, Kutz K. SMS 201-995, a new somatostatin analog: pharmacological profile.

Neuroendocrinol Lett 1985; 7:111. Del Pozo E, Neufeld M, Schluter K, Tortosa F, Clarenbach P, Bieder E, Wendel L, Nuesch E, Marbach P, Cramer H, et al. Endocrine profile of a long-acting somatostatin derivative SMS 201-995. Study in normal volunteers following subcutaneous administration. ACTA Endocrinol (COPENH) 1986; III(4):433-9. Dimeck J, Feniuk W, et al. Somatostatin-induced contraction of human isolated saphenous vein involves sst2 receptor-mediated activation of L-type calcium channels. J Cardiovasc Pharmacol 1995; 26: 721-728. Edwards CA, Cann PA, Read NW, et al. Effect of somatostatin derivative SMS 201-995 on fluid and electrolyte transport in a patient with secretory diarrhea. Scand J Gastroenterol 1986; 21 (suppl 119): 259-261. Friess H, Klempa I, et al. Prophylaxis of Complications after Pancreatic Surgery: Results of a Multicentre trial in Germany. Digestion. 1994; 55(Suppl. 1): 35-40. Hwang SJ, Lin HC, et al. A randomized controlled trial comparing octreotide and vasopressin in the management of acute esophageal variceal bleeding. J Hepatology 1992, 16: 320-325. Juby LD, Burke DA, Axon ATR. Somatostatin derivative SMS 201-995 long term therapy for VIPoma. Postgrad Med J 1987; 63: 287-289. Kallivretakis N, Yotis A, del Pozo E, Marbach P, Mountokalakis T, Tolis G. Pharmacokinetics of SMS 201-995 in normal subjects and in patients with severe renal failure. Neuroendocrinol Lett 1985; 7:92:Be 3.2. Kraenzlin ME, Wood SM, Neufeld M, Adrian TE, Bloom SR. Effect of long acting somatostatin-derivative, SMS 201-995, on gut hormone secretion in normal subjects. Experientia (Basel) 1985; 41:738-40. Kraenzlin ME, Chang JLC, Wood SM, et al. Long-term treatment of a VIPoma with somatostatin derivative resulting in remission of symptoms and possible shrinkage of metastases. Gastroenterology 1985; 88: 185-187. Kvols LK, Moertel CE, O'Connel MJ, Schutt AL, Rubin, Hahn RG. Treatment of malignant carcinoid syndrome: evaluation of a long acting somatostatin derivative. New Engl J Med 1986; 315(II):663-6. Kvols LK, Martin JK, Marsh HM, Moertel CG. Rapid reversal of carcinoid crisis with a somatostatin derivative. New Engl J Med 1985; 313:1229-30. Long RG, Barnes AJ, Adrian TE, Mallinson CN, Brown MR, Vale W, Rivier JE, Christofides ND, Bloom SR. Suppression of pancreatic endocrine tumour secretion by long-acting somatostatin derivative. Lancet 1979; ii:764-7. Marsh HM, Martin JK, Kvols LK, et al. Carcinoid crisis during anesthesia: Successful treatment with somatostatin derivative. Anesthesiology 1987; 66: 89-91. Pederzoli P, Bassi C, et al. Efficacy of octreotide in the prevention of complications of elective pancreatic surgery. Br. J. Surgery. 1194; 81: 265-269. Pedretti G, Elia G, et al. Octreotide versus terlipressin in acute variceal hemorrhage in liver cirrhosis. Emergency control and prevention of early rebleeding. Clin. Invest. 1994; 72: 653- 659. Santagelo W, O'Dorisio T, Kim J, Severino G, Krejs G. VIPoma syndrome: effect of a somatostatin derivative on intestinal water and ion transport. Regul Pept 1985; S53. Souquet JC, Charvialle JA et al. Biological and clinical efficacy of a long-acting somatostatin analog (SMS 201-995) in secreting apudomas. Can J Physiol Pharmacol 1986; 64 (suppl): 64 (Abstr. No. 240). Stoeckmann F, Richter G, Conlon JM, et al. Effect of short- and long-term treatment with SMS 201-995 in patients with carcinoid tumors. Gastroenterology 1986; 90: 1650. Stoeckmann F, Creutzfeldt W. SMS 201-995 for treatment of patients with carcinoid tumors and Zollinger-Ellison syndrome. Regul Pept 1987; 18: 377. Stoeckmann F, Richter G, Lembcke B, et al. Long-term treatment of patients with endocrine gastrointestinal tumours with the somatostatin derivative SMS 201-995. Scand J Gastroenterol 1986; 21 (suppl 119); 230-237. Sung JJY, Chung S, et al. Octreotide infusion or emergency sclerotherapy for variceal haemorrhage. Lancet 1993; 342: 637-641. Sung JJY, Chung S, et al. Prospective randomized study of effect of octreotide on rebleeding from oesophageal varices after endoscopic ligation. Lancet 1995: 346: 1666-1669. Vinik AI, Tsai ST, Moattari AR, et al. Somatostatin derivative (SMS 201-995) in the management of gastroenteropancreatic tumors and diarrhea syndromes. Amer J Med 1986; 81 (suppl 6B); 23-40. Chanson P. et al. Octreotide Therapy for Thyroid-Stimulating Hormone Secreting Pituitary Adenomas. Ann. of Inter. Med. 1993, Vol. 119; p.236-240. Ginsburg J. Concensus Discussion and Conclusions. In Sandostatin and the Treatment of Acromegaly, Concensus Round Table, Amsterdam 1987 - Edit. : S. Lamberts. Publ. Springer Verlag Berlin, Heidelberg, New York, London, Paris, Tokyo 1988 p. 163-171. Papagrigoriou L. et al. Administration of Octreotide in Acromegaly. J. Endocr. Invest. 1993, Vol.16, Suppl.8, p.140, Abs. A 43). Roelen C. et al. High Affinity Growth Hormone Binding Protein in Plasma of Patients with Acromegaly and the Effect of Octreotide Treatment. Clin.Endocr. 1991, Vol.37, p.373-378. Schindel B. et al. Effect of Octreotide on 24-hour Growth Hormone and Prolactin Secretory Patterns in Acromegalies. Hormone Research 1991, Vol.36, p.209-215. IMPORTANT: PLEASE READ

PART III: CONSUMER INFORMATION

SANDOSTATIN *

(octreotide acetate injection)

This leaflet is part III of a three-part "Product Monograph" published when SANDOSTATIN * was approved for sale in Canada and is designed specifically for Consumers. This leaflet is a summary and will not tell you everything about SANDOSTATIN *. Contact your doctor or pharmacist if you have any questions about the drug.

ABOUT THIS MEDICATION

What is SANDOSTATIN * used for?

SANDOSTATIN * (octreotide acetate) is used:

• to control symptoms in patients with gastroenteropancreatic (GEP) endocrine tumors or with acromegaly.

• for the prevention of complications following pancreatic surgery.

• for the emergency treatment of bleeding varices (stretched veins) in the esophagus and stomach in

patients with liver disease and as protection from rebleeding.

What is a Gastroenteropancreatic (GEP) Endocrine Tumor?

GEP endocrine tumors are growths that have developed from

endocrine cells in the gastrointestinal tract (the stomach,

intestines, appendix) or the pancreas.

Some symptoms come about because GEP endocrine tumors produce and secrete chemical substances called peptides, i.e. small proteins in excess - overloading the system.

The over-secretion of peptides cause diarrhea and flushing. Carcinoid tumors (generally occurring in the esophagus,

stomach, intestines, appendix, and lungs) and VIPomas (almost always occurring in the pancreas) are the most common type of GEP endocrine tumor.

Diarrhea can cause dehydration, it is therefore very important to control it and replace the loss of water and electrolytes as quickly as possible.

What is Acromegaly?

Acromegaly is the result of an overproduction of growth hormone by the pituitary gland (a pea-sized gland located at the base of the brain). Uncontrolled disease may lead to arthritis, cardiac and neurologic problems. Approximately 20% to 30% of acromegalic patients also demonstrate high blood pressure.

What SANDOSTATIN * (octreotide acetate) Does?

GEP Endocrine Tumors:

SANDOSTATIN *works to help slow down the release of the peptides that cause diarrhea and flushing. It also stimulates water absorbption.

Acromegaly:

SANDOSTATIN * has been shown to lower the overproduction of growth hormone by the pituitary gland.

When it should not be used:

SANDOSTATIN * should not be used if you are allergic to the active ingredient octreotide or to any other ingredient of the formulation.

What the medicinal ingredient is:

octreotide acetate.

What the important nonmedicinal ingredients are:

The ampoules contain: lactic acid, sodium hydrogen carbonate and water for injection.

The multidose vials contain: lactic acid, sodium hydrogen carbonate, mannitol and water for injection.

What dosage forms it comes in:

SANDOSTATIN * (octreotide acetate) is a solution supplied in:

• 1 mL ampoules, each containing 50 ug, 100 ug or 500 ug of octreotide as acetate. SANDOSTATIN * is available in boxes of 5 ampoules.

and

5 mL multidose vials. Each vial contains 1000 ug of octreotide as acetate (200 ug/mL).

Acromegaly is a life-time, uncommon, debilitating disease characterized by changes in facial bone structure and specific hormonal abnormalities.

IMPORTANT: PLEASE READ

WARNINGS AND PRECAUTIONS

How to Prepare Your Injection of SANDOSTATIN *?

BEFORE you use SANDOSTATIN * talk to your doctor or pharmacist if you:

have high blood pressure (hypertension),

have problems with your blood sugar levels, either too high or too low (hypoglycaemia),

have gallstones or have had gallstones in the past, as prolonged use of SANDOSTATIN * may result in gallstone formation,

have problems with your liver (e.g. liver cirrhosis),

have problems with your kidneys and require dialysis,

are pregnant, suspect that you may be pregnant,

are breast feeding,

have heart problems.

If you receive long treatment with SANDOSTATIN * your doctor may wish to check your thyroid function periodically.

There is very little experience with the use of SANDOSTATIN * in children.

Women of child-bearing potential should use an effective contraceptive method during treatment.

INTERACTIONS WITH THIS MEDICATION

Drugs that may interact with SANDOSTATIN * include:

drugs to control blood pressure (e.g. beta blockers,

calcium channel blockers),

drugs to control blood sugar (e.g. sulfonylureas, insulin, and diazoxide),

cimetidine,

cyclosporine,

bromocriptine.

anti-diarrheal agents (affect fluid and electrolytes)

Please inform your doctor or pharmacist if you are taking or have recently taken any other drugs or herbal products, even those without a prescription.

SANDOSTATIN * is best injected between meals or on retiring to bed. This may reduce the gastrointestinal side effects of SANDOSTATIN *.

PROPER USE OF THIS MEDICATION

Usual dose:

Your doctor will tell you how much SANDOSTATIN * to take each day. SANDOSTATIN * is to be injected under your skin (subcutaneous injection). The doctor will also tell you how to divide your dosage through the day.

You will receive your supply of SANDOSTATIN * either in ampoules or multidose vials. The ampoules or multidose vials should be visually inspected and not used in the presence of floating particles or discoloration.

1. Ampoules

1. Before breaking open the ampoule, tap the neck portion so that any medication that may be trapped will flow down into the bottom portion of the ampoule.

2. Once the ampoule is opened, insert the needle and pull back the plunger to fill the syringe with the desired amount of drug. (Your doctor or nurse will tell you how to read the markings on your syringe so that you can fill it with the right amount of drug for your dose.) Discard any unused medication.

3. Check to see if there are any air bubbles in the syringe.

If bubbles do appear, hold the syringe upright (with the needle pointed up) and lightly tap the barrel. This should make the bubbles rise to the top of the syringe. Then gently press the plunger to push the bubbles out.

Multidose Vials

1. Peel off the aluminum seal.

2. Wipe the top of the vial with an alcohol swab.

3. Remove the cap from the needle and insert the needle into the vial through the rubber stopper.

4. Leave the needle in the bottle.

5. Turn the vial and the syringe upside down. Keep the needle tip within the liquid. Pull the plunger and carefully withdraw the prescribed amount of SANDOSTATIN * (your doctor or nurse will tell you how to read the markings on the syringe so that you fill it with the correct amount of drug for your dose).

6. Turn the bottle and syringe back upright.

7. Withdraw the needle from the vial.

8. Check to see if there are any air bubbles in the syringe. If bubbles do appear, hold the syringe upright (with the needle pointed up) and lightly tap the barrel. This should make the bubbles rise to the top of the syringe. Then gently press the plunger to push the bubbles out.

How to Inject Your Dose of SANDOSTATIN *

1. Choose the area of your hip, thigh, or abdomen where you want to make your injection.

IMPORTANT: PLEASE READ

Clean the site with a fresh alcohol wipe, and keep it nearby.

Hold the syringe like a pencil, and remove the needle cap.

Use the thumb and forefinger of your other hand to gently pinch up a fold of skin at the place you want to inject. This will lift the subcutaneous tissue away from the muscle underneath.

Hold the syringe at a 45o angle, and insert the entire length of the needle into the fold of skin in one quick motion.

Once the needle is inserted, let go of the skin.

Using your free hand, pull back on the plunger slightly to check whether you have placed the needle in a blood vessel. (You don't want to.) If any blood appears in the syringe, this is not a proper site for your injection. You will have to remove and discard the syringe and needle and start over.

Once the needle is inserted properly, slowly inject all of the medication.

When you are finished injecting the medicine, place your alcohol wipe where the needle enters the skin. Press lightly.

Withdraw the needle at the same angle it is inserted.

Gently hold the wipe on your skin for about five seconds.

Put the cap back on the needle and dispose of the syringe and needle safely. Do not reuse the syringe and needle. Single-use syringes and needles are used to reduce the chance of infection. Collect your used needles and syringes in a metal container, such as a coffee can, and then dispose of them in a covered garbage can. This will keep others (especially children) from injuring themselves.

Important Points to Remember

Pay close attention to the amount of drug you are taking into the syringe for injection. Make sure it is the amount your

doctor has prescribed for you.

Missed Dose:

If you forget to take a scheduled injectioncheck with your doctor. Do not double you dose at the next injection.

Overdose:

No life-threatening reactions have been reported after overdosage of SANDOSTATIN *.

If you think you have injected more SANDOSTATIN * than you should, contact your doctor or poison control center in your area.

SIDE EFFECTS AND WHAT TO DO ABOUT THEM

Like all medicines SANDOSTATIN * may cause some side effects. If you experience any of these, tell your doctor.

Some patients have experienced a burning sensation at the injection site. For most people, the burning lasts only a few moments. Injecting the drug at room temperature rather than cold from the refrigerator may alleviate the burning sensation.

Serious side effects

Gallstones, leading to sudden back pain.

Too much or too little sugar in the blood.

Underactive thyroid gland (hypothyroidism) causing changes in heart rate, appetite or weight; tiredness, feeling cold, or swelling at the front of the neck.

Changes in thyroid function tests.

Inflammation of the gallbladder (cholecystitis).

Impaired glucose tolerance.

Irregular heart beat (slow or fast).

Thirst, low urine output, dark urine, dry flushed skin.

Hypersensitivity (allergic) reactions including skin rash.

A type of an allergic reaction (anaphylaxis) which causes difficulty in breathing, swelling of the face or dizziness.

Acute inflammation of the pancreas gland causing severe stomach pain (pancreatitis).

Liver inflammation (hepatitis); symptoms may include yellowing of the skin and eyes (jaundice), nausea, vomiting, loss of appetite, generally feeling unwell, itching, light-coloured urine.

Other side effects

The side effects listed below are usually mild and tend to disappear as treatment progresses.

• nausea

• vomiting

• stomach pain

• diarrhea

• feeling of fullness in the stomach

• flatulence (wind)

• loss of appetite

• constipation

• headache

• stomach discomfort after meal

• fatty stools

• loose stools

• discoloration of faeces

• dizziness

IMPORTANT: PLEASE READ

• change in liver function tests

• hair loss

• shortness of breath.

Since gallstones may occasionally form during prolonged use of SANDOSTATIN *, your doctor may wish to check your gallbladder periodically.

This is not a complete list of side effects. For any unexpected effects while taking SANDOSTATIN *, contact your doctor or pharmacist.

IMPORTANT: PLEASE READ

REPORTING SUSPECTED SIDE EFFECTS

To monitor drug safety, Health Canada through the Canada Vigilance Program collects information on serious and unexpected side effects of drugs. If you suspect you have had a serious or unexpected reaction to this drug you may notify Canada Vigilance:

By toll-free telephone: 866-234-2345 By toll-free fax: 866-678-6789

Online: www.healthcanada.gc.ca/medeffect By email: CanadaVigilance @hc-sc.gc.ca

By regular mail:

Canada Vigilance National Office

Marketed Health Products Safety and Effectiveness Information Bureau

Marketed Health Products Directorate

Health Products and Food Branch, Health Canada Tunney's Pasture, AL 0701C

Ottawa ON K1A 0K9

NOTE: Should you require information related to the management of the side effect, please contact your health care provider before notifying Canada Vigilance. The Canada Vigilance Program does not provide medical advice.

HOW TO STORE IT

SANDOSTATIN * must be stored at 2deg to 8degC (in a refrigerator). However, you may leave your daily dose of SANDOSTATIN * (ampoules or multidose vials) out at a room temperature of up to 30degC for up to 2 weeks. The ampoules should be opened just prior to administration and any unused portion discarded.

Keep the container in the outer carton in order to protect from light. Do not freeze.

Do not use SANDOSTATIN * (ampoules or multidose vials) after the expiry date.

Keep in a safe place out of reach of children and pets.

MORE INFORMATION

This document plus the full product monograph, prepared for health professionals can be found at:

http://www.novartis.ca

or by contacting the sponsor, Novartis Pharmaceuticals Canada Inc., at:

1-800-363-8883

This leaflet was prepared by Novartis Pharmaceuticals Canada Inc.

Last revised: March 6, 2008

IMPORTANT: PLEASE READ

PART III: CONSUMER INFORMATION

SANDOSTATIN * LAR *

(octreotide acetate for injectable suspension)

This leaflet is part III of a three-part "Product Monograph" published when SANDOSTATIN * LAR * was approved for sale in Canada and is designed specifically for Consumers. This leaflet is a summary and will not tell you everything about SANDOSTATIN * LAR *. Contact your doctor or pharmacist if you have any questions about the drug.

ABOUT THIS MEDICATION

What is SANDOSTATIN * LAR * used for?

SANDOSTATIN * LAR * (octreotide acetate) is used to control symptoms associated with gastroenteropancreatic (GEP) endocrine tumors and acromegaly in patients who are adequately controlled with SANDOSTATIN *.

What is a Gastroenteropancreatic (GEP) Endocrine Tumor?

GEP endocrine tumors are growths that have developed from

endocrine cells in the gastrointestinal tract (the stomach, intestines, appendix) or the pancreas.

Some symptoms come about because GEP endocrine tumors produce and secrete chemical substances called peptides, i.e. small proteins in excess - overloading the system.

The over-secretion of peptides cause diarrhea and flushing. Carcinoid tumors (generally occurring in the esophagus,

stomach, intestines, appendix, and lungs) and VIPomas

(almost always occurring in the pancreas) are the most common type of GEP endocrine tumor.

Diarrhea can cause dehydration, it is therefore very important to control it and replace the loss of water and electrolytes as quickly as possible.

What is Acromegaly?

Acromegaly is a life-time, uncommon, debilitating disease characterized by changes in facial bone structure and specific hormonal abnormalities.

Acromegaly is the result of an overproduction of growth hormone by the pituitary gland (a pea-sized gland located at the base of the brain). Uncontrolled disease may lead to arthritis, cardiac and neurologic problems. Approximately 20% to 30% of acromegalic patients also demonstrate high blood pressure.

What SANDOSTATIN * (octreotide acetate) Does?

GEP Endocrine Tumors:

SANDOSTATIN *works to help slow down the release of the peptides that cause diarrhea and flushing. It also stimulates water absorbption.

Acromegaly:

SANDOSTATIN * LAR * has been shown to lower the overproduction of growth hormone by the pituitary gland

When it should not be used:

SANDOSTATIN * LAR * should not be given to anyone who is allergic to octreotide or any other ingredient of the formulation.

What the medicinal ingredient is:

octreotide acetate.

What the important nonmedicinal ingredients are:

The powder contains: poly (DL-lactide-co-glycolide) and mannitol.

The diluent conatins: sodium carboxymethylcellulose, mannitol and sterile water.

What dosage forms it comes in:

SANDOSTATIN * LAR * is available as powder in vials and is supplied in a kit which includes either:

• One vial containing either 10, 20, or 30 mg octreotide (as acetate) slow release;

• Two ampoules, each containing 2 mL of the diluent to be used for suspending the powder;

• An injection set containing one plastic 5 mL syringe and two needles [40 mm (1.5 inch) 19

gauge].

OR

One vial of SANDOSTATIN * LAR * containing either 10, 20 or 30 mg of octreotide (as acetate) slow release;

A pre-filled glass syringe containing 2.5 mL of

diluent to be used for suspending the powder ;

two needles [40 mm, 19 gauge];

an instruction booklet.

IMPORTANT: PLEASE READ

WARNINGS AND PRECAUTIONS

BEFORE you use SANDOSTATIN * LAR * talk to your doctor or pharmacist if you:

have high blood pressure (hypertension),

have problems with your blood sugar levels, either too high or too low (hypoglycaemia),

have gallstones or have had gallstones in the past, as prolonged use of SANDOSTATIN * LAR * may

result in gallstone formation,

have problems with your liver (e.g. liver cirrhosis),

have problems with your kidneys and require dialysis,

are pregnant or suspect that you may be pregnant,

are breast feeding.

have heart problems.

If you receive long treatment with SANDOSTATIN * LAR * your doctor may wish to check your thyroid function periodically.

There is very little experience with the use of SANDOSTATIN * in children.

Women of child-bearing potential should use an effective contraceptive method during treatment.

INTERACTIONS WITH THIS MEDICATION

Drugs that may interact with SANDOSTATIN * LAR * include:

drugs to control blood pressure (e.g. beta blockers, calcium channel blockers),

drugs to control blood sugar (e.g. sulfonylureas, insulin, and diazoxide),

cimetidine,

cyclosporine,

bromocriptine.

anti-diarrheal agents (affect fluid and electrolytes)

Please inform your doctor or pharmacist if you are taking or have recently taken any other drugs or herbal products, even those without a prescription.

PROPER USE OF THIS MEDICATION

SANDOSTATIN * LAR * is to be given to you by your doctor or nurse as an injection into the muscle of the buttocks. With repeated administration the left and right buttock should be used alternately.

Usual Dose:

Starting dose is usually 20 mg every 4 weeks. The dose may be changes later depending on your condition.

Missed Dose:

If you miss your injection, please contact your doctor as soon as possible.

Overdose:

No life-threatening reactions have been reported after overdose of SANDOSTATIN * LAR *.

If you think you have been given more SANDOSTATIN * LAR * than you should, talk to your doctor or nurse immediately.

SIDE EFFECTS AND WHAT TO DO ABOUT THEM

Like all medicines SANDOSTATIN * LAR * may cause some side effects. If you experience any of these, tell your doctor.

A few people experience pain at the injection site, which usually lasts for only a short time (usually about one hour), and sometimes swelling and rash.

Some side effects can be serious

Gallstones, leading to sudden back pain.

Too much or too little sugar in the blood.

Underactive thyroid gland (hypothyroidism) causing changes in heart rate, appetite or weight; tiredness, feeling cold, or swelling at the front of the neck.

Changes in thyroid function tests.

Inflammation of the gallbladder (cholecystitis).

Impaired glucose tolerance.

Irregular heart beat (slow or fast).

Thirst, low urine output, dark urine, dry flushed skin.

Hypersensitivity (allergic) reactions including skin rash.

A type of an allergic reaction (anaphylaxis) which causes difficulty in breathing, swelling of the face or dizziness.

Acute inflammation of the pancreas gland causing severe stomach pain (pancreatitis).

Liver inflammation (hepatitis); symptoms may include yellowing of the skin and eyes (jaundice), nausea, vomiting, loss of appetite, generally feeling unwell, itching, light-coloured urine.

IMPORTANT: PLEASE READ

Other side effects

The side effects listed below are usually mild and tend to disappear as treatment progresses.

• nausea

• vomiting

• stomach pain

• diarrhea

• feeling of fullness in the stomach

• flatulence (wind)

• loss of appetite

• constipation

• headache

• stomach discomfort after meal

• fatty stools

• discoloration of faeces

• dizziness

• change in liver function tests

• hair loss

• shortness of breath.

Since gallstones may occasionally form during prolonged use of SANDOSTATIN *, your doctor may wish to check your gallbladder periodically.

This is not a complete list of side effects. For any unexpected effects while taking SANDOSTATIN * LAR *, contact your doctor or pharmacist.

IMPORTANT: PLEASE READ

REPORTING SUSPECTED SIDE EFFECTS

To monitor drug safety, Health Canada through the Canada Vigilance Program collects information on serious and unexpected side effects of drugs. If you suspect you have had a serious or unexpected reaction to this drug you may notify Canada Vigilance:

By toll-free telephone: 866-234-2345 By toll-free fax: 866-678-6789

Online: www.healthcanada.gc.ca/medeffect By email: CanadaVigilance @hc-sc.gc.ca

By regular mail:

Canada Vigilance National Office

Marketed Health Products Safety and Effectiveness Information Bureau

Marketed Health Products Directorate

Health Products and Food Branch, Health Canada Tunney's Pasture, AL 0701C

Ottawa ON K1A 0K9

NOTE: Should you require information related to the management of the side effect, please contact your health care provider before notifying Canada Vigilance. The Canada Vigilance Program does not provide medical advice.

HOW TO STORE IT

The SANDOSTATIN * LAR * powder and diluent should be stored at 2deg to 8degC (in a refrigerator). Keep the vial in the outer carton in order to protect it from light. The vials should be allowed to reach room temperature on the day of the injection, but must be protected from light. However, prepare the suspension immediately before injection. Once removed from the refrigerator, the vials will usually reach room temperature within 30 to 60 minutes.

Do not use SANDOSTATIN * LAR * after the expiry date. Keep in a safe place out of reach of children and pets.

MORE INFORMATION

This document plus the full product monograph, prepared for health professionals can be found at:

http://www.novartis.ca

or by contacting the sponsor, Novartis Pharmaceuticals Canada Inc., at:

1-800-363-8883

This leaflet was prepared by

Novartis Pharmaceuticals Canada Inc. Dorval, Quebec

H9S 1A9

Last revised: March 6, 2008