Single-use vial (1 mL) - 50 :g/mL, 100 :g/mL, 500 :g/mL octreotide Multidose vial (5 mL), 200 :g/mL octreotide

CONTRAINDICATIONS

OCTREOTIDE ACETATE OMEGA (octreotide acetate) is contraindicated in patients with a hypersensitivity to octreotide or to any component of the formulation.

Single doses of octreotide acetate injection have been shown to inhibit gallbladder contractility and decrease bile secretion in normal volunteers. In clinical trials with octreotide acetate 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 octreotide acetate 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. 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 octreotide acetate 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 octreotide acetate be evaluated periodically (at about 6 to 12-month intervals) using ultrasound evaluations of the gallbladder and bile ducts.

Sudden escape from symptomatic control by octreotide acetate may occur infrequently, with rapid recurrence of severe symptoms. Dosage adjustment therefore may be required. As GH-secreting pituitary tumors may sometimes expand, causing serious complications (e.g. visual field defects), it is essential that all patients treated with octreotide acetate be carefully monitored. If evidence of tumor 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.

Octreotide acetate therapy is occasionally associated with mild transient hypo- or hyperglycemia due to alterations in the balance between the counter-regulatory hormones, insulin, glucagon and growth hormone. Patients should be closely observed on introduction of octreotide acetate 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 octreotide acetate. In non-diabetics and type II diabetics with partially intact insulin reserves, octreotide acetate administration can result in prandial increases in glycemia. Severe hyperglycemia, subsequent pneumonia, and death following initiation of octreotide acetate injection therapy was reported in one patient with no history of hyperglycemia. Predicting the effect of octreotide acetate on glucose tolerance in any given patient is not possible at this time. It is recommended that all acromegalic patient have their serum glucose carefully monitored during initiation and titration of therapy with octreotide acetate. 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.

Data on the effect of chronic therapy with octreotide acetate 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 :g of octreotide acetate daily. Therefore, baseline and periodic assessment of thyroid function (TSH, total and/or free T4) is advised during chronic therapy with octreotide acetate.

In both acromegalic and carcinoid syndrome patients, bradycardia, arrhythmias and conduction abnormalities have been reported during octreotide therapy. 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 PRECAUTIONS). Dose adjustments in drugs such as beta-blockers that have bradycardia effects may be necessary. In one acromegalic patient with severe congestive heart failure, initiation of octreotide acetate 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).

There is evidence that octreotide acetate 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 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. 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.

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

Baseline and periodic (at about 6 to 12-month intervals) ultrasonography is recommended during therapy with octreotide acetate to assess the presence of gallstones (see WARNINGS). If gallstones do occur, they are usually asymptomatic. Symptomatic gallstones should receive medical attention.

Careful instruction in sterile subcutaneous injection techniques should be given to the patients and to other persons who may administer octreotide acetate injection (see INFORMATION FOR THE PATIENT). 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.

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-I (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 octreotide acetate injection. Alternatively, a single measurement of IGF-I (somatomedin C) level may be made two weeks after initiation of octreotide acetate injection or dosage change. Baseline and periodic total and/or free T4 measurements should be performed during chronic therapy (see information under GENERAL PRECAUTIONS).

Many patients with carcinoid syndrome or VIPomas being treated with octreotide acetate 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 octreotide acetate therapy is added to other therapies used to control glycemic states, such as sulfonylureas, insulin and diazoxide, to beta 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 octreotide acetate. Adjustment of the dosage of drugs, such as insulin, affecting glucose metabolism may be required following initiation of octreotide acetate therapy in patients with diabetes. Since octreotide acetate 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. Octreotide acetate 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. Octreotide acetate 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).

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

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

Reproduction studies have been performed in rats and rabbits at doses up to 30 times the highest human dose and have revealed no evidence of impaired fertility or harm to the fetus due to octreotide acetate. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.

It is not known whether this drug is excreted in human milk. Because many drugs are excreted in milk, caution should be exercised when octreotide acetate is administered to a nursing woman.

Experience with octreotide acetate in the pediatric population is limited. Octreotide acetate 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 :g/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 octreotide acetate injection for more than 1 year; catch-up growth occurred after octreotide acetate 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 :g subcutaneous dose of octreotide acetate injection.

ADVERSE REACTIONS

The main side effects encountered with octreotide acetate administration are local (at the site of injection) and gastrointestinal.

Octreotide acetate Single-use & Multidose Vials in GEP and Acromegaly:

Composite Listing of Adverse Reactions in 196 GEP Endocrine Tumor Patients and 114 Acromegalic Patients Treated with octreotide acetate

Adverse Reaction Profile According to Body System	GEP Endocrine Tumor Patients (n=196) %	Acromegalic Patients (n=114) %
Gastrointestinal S.	6.6	57.9
Diarrhea	6.6	57.9
Abdominal discomfort	4.1	43.9
Stools loose	3.1	36.0
Nausea	8.7	29.8
Flatulence	0.5	13.2
Constipation	1.0	8.8
Abdominal distention	-	7.9
Stools abnormal	0.5	6.1
Cholelithiasis	< 1.0	4.4
Rectal gas	-	4.4
Vomiting	2.6	4.4
Fatty stools	3.6	-
GI bleeding	0.5	-
Rectal disorders	0.5	-
Hemorrhoids	-	1.8
Cholecystitis	-	1.8
Eructations	-	1.8
Integumentary S.
Pain at injection site	8.2	9.6
Acne	-	4.4
Bruise	0.5	4.4
Pruritus	-	4.4
Alopecia / Baldness / Hair loss	1.0	3.5
Musculoskeletal S.
Backache / pain	0.5	4.4
Joint pain	-	4.4
Arthritis	-	2.6
Arm/leg heavy-tired	-	2.6
Leg ache / pain	-	2.6
Osteoarthritis	-	1.8
Vertebral disk disorder	-	1.8
Twitching	-	1.8

Respiratory S.	0.5	2.6
Throat pain	0.5	2.6
Flu symptoms	-	6.1
Cold symptoms	-	6.1
Sinusitis	-	3.5
Nasal congestion	-	1.8
Cardiovascular S.	-	3.5
Leg cramps	-	3.5
Dyspnea	-	1.8
Epistaxis	-	1.8
Chest pain	0.5	-
Edema	1.0	2.6
Ischemic Attack	0.5	-
Hypertension	0.5	-
Thrombophlebitis	0.5	-
Cramps	-	2.6
Autonomic S.
Visual disturbances	0.5	2.6
Mouth dry / furry / xerostomia	0.5	1.8
Flushing	0.5	1.8
Numbness	-	1.8
Hot flash	-	1.8
Central nervous S.
Headache	1.5	18.4
Dizziness	1.5	14.9
Fatigue	1.0	9.6
Anxiety / Nervousness	0.5	2.6
Asthenia	0.5	-
Bell's palsy	0.5	-
Seizure	0.5	-
Depression	0.5	2.6
Sleepiness / insomnia	0.5	1.8
Weakness	1.0	-
Moody	-	2.6
Appetite loss	-	1.8
Irritability	-	1.8

Tinnitus Urogenital S.	- 1.8
Urinary tract infection	- 6.1
Pollakiuria	- 3.5
Vagina infection	- 2.6
Vagina itch	- 1.8
Breast lump	- 1.8
Dysuria	- 1.8
Kidneys, pain in	- 1.8
Polyuria	- 1.8
Prostatitis	- 1.8
Tumor breast	- 1.8
Hematologic Hematoma, injection site	- 9.6
Endocrine S. Hypoadrenalism	- 2.6
Hypothyroidism	- 1.8
Hypogonadism	- 1.8
Hypoglycemia	- 1.8
Miscellaneous
Foot pain	- 1.8
Fever	- 1.8
Otitis	- 1.8
Weight gain	- 1.8

Local reactions after S.C. administration of octreotide acetate include pain and sensations of stinging, tingling or burning at the site of injection, with redness and swelling. These rarely last more than fifteen minutes. Local discomfort may be reduced by allowing the solution to reach room temperature before injection and by slowly injecting octreotide acetate. In clinical trials, acromegalic patients had a higher incidence of diarrhea, abdominal pain/discomfort, nausea and loose stools than patients treated with octreotide acetate for other indications. It is believed that the primary reason for this observation is that patients who received octreotide acetate for carcinoid syndrome, VIPoma and other gastroenteropancreatic tumors had these gastrointestinal symptoms at baseline and would only report them as adverse events if they became more frequent or severe during octreotide acetate treatment. The adverse event rate for octreotide acetate during study B301 is presented in comparison to placebo. This comparison more accurately reflects the difference in adverse event rates between octreotide acetate and placebo.

Number % Patients in US Studies B301, B302, B303 with Adverse Events by Treatment and by Body System. Events Occurring in $ 3%
Specific Adverse Event by Body System	Placebo B301 (n=55) %	Octreotide acetate B301 (n=60 ) %	Octreotide acetate B301, B302 &B303 (n=114) %
Skin	2 (3.6)	5 (8.3)	11 (9.6)
Pain at injection site	2 (3.6)	5 (8.3)	11 (9.6)
Acne	-	2 (3.3)	5 (4.4)
Bruise	1 (1.1)	2 (3.3)	5 (4.4)
Pruritus	-	-	5 (4.4)
Alopecia/Baldness/Hair loss	-	-	4 (3.5)
Musculoskeletal
Back aches/pain	-	-	5 (4.4)
Joint pain	2 (3.6)	1 (1.7)	5 (4.4)
Respiratory
Flu symptoms	-	2 (3.3)	7 (6.1)
Cold symptoms	-	2 (3.3)	7 (6.1)
Sinusitis	-	-	4 (3.5)
Cardiovascular
Leg cramps	-	-	4 (3.5)
Hematologic
Hematoma, injection site	6 (10.9)	1 (1.7)	11 (9.6)
Gastrointestinal
Diarrhea	6 (10.9)	32 (53.3)	66 (57.9)
Abdominal discomfort	7 (12.7)	14 (23.3)	50 (43.9)
Stools loose	8 (14.5)	16 (26.7)	41 (36.0)
Nausea	6 (10.9)	17 (28.3)	34 (29.8)
Flatulence	2 (3.6)	6 (10.0)	15 (13.2)
Constipation	-	1 (1.7)	10 (8.8)
Abdominal distention	-	2 (3.3)	9 (7.9)
Stools abnormal	-	3 (5.0)	7 (6.1)
Cholelithiasis	-	-	5 (4.4)
Rectal gas	-	-	5 (4.4)
Vomiting	1 (1.8)	3 (5.0)	5 (4.4)
Urogenital Urinary tract infection	-	3 (5.0)	7 (6.1)
Pollakiuria	2 (3.6)	1 (1.7)	4 (3.5)
Central Nervous Headache	6 (10.9)	8 (13.3)	21 (18.4)
Dizziness	6 (10.9)	5 (8.3)	17 (14.9)
Fatigue	2 (3.6)	3 (5.0)	11 (9.6)

Gastrointestinal side effects include anorexia, nausea, vomiting, crampy abdominal pain, abdominal bloating, flatulence, loose stools, diarrhea and steatorrhea. Although measured fecal fat excretion may increase, there is no evidence to date that long-term treatment with octreotide acetate has led to nutritional deficiency due to malabsorption. In rare instances, gastrointestinal side effects may resemble acute intestinal obstruction with progressive abdominal distention, severe epigastric pain, abdominal tenderness and guarding. Occurrence of gastrointestinal side effects may be reduced by avoiding meals around the time of octreotide acetate administration, that is, by timing injections between meals or at bedtime.

Octreotide acetate Single-use & Multidose Vials in the Prevention of Complications Following Pancreatic Surgery Local reactions at the site of injection were the most frequently reported side effects in 247 patients undergoing pancreatic surgery treated with octreotide acetate for 7 consecutive days starting on the day of the operation, at least 1 hour before laparatomy. Pruritus, exanthema, vomiting, biliary sludge and fever were each reported in 0.4% of patients and flushes and rash occurred in 0.8% of patients.

Octreotide acetate Single-use & Multidose Vials in Bleeding Gastro-oesophageal Varices

Raised blood glucose levels were reported in 23 of 98 cirrhotic patients treated with octreotide acetate 25 :g/hour administered by I.V. infusion over 5 days for the emergency management of bleeding oesophageal varices. Diarrhea occurred in 5% of patients.

General

Prolonged use of octreotide acetate may result in gallstone formation (see PRECAUTIONS). Pancreatitis may develop in patients on long-term treatment with octreotide acetate who develop cholelithiasis. Because of its inhibitory action on growth hormone, glucagon and insulin, octreotide acetate may impair glucose regulation. Postprandial glucose tolerance may be impaired and in some instances, with chronic administration, a state of persistent hyperglycemia may be induced. Hypoglycemia has also been observed. Acute pancreatitis has been reported in rare instances. Generally, this effect is seen within the first hours or days of octreotide acetate treatment and resolves on withdrawal of the drug. Rarely, hair loss has been reported in patients receiving octreotide acetate treatment. Rarely, hypersensitivity reactions have been reported. Isolated reports of anaphylactic reactions. Octreotide acetate administered S.C. and to a much lesser degree by I.V. infusion, can lead to hypersensitivity reaction that may range from generalized pruritus to cardiovascular shock or bronchospasm, with one case of death having been reported. Isolated reports of bradycardia. In patients who are predisposed by having a relatively low pretreatment heart rates or whose cardiovascular system is already compromised, as in cirrhotic patients with bleeding esophageal varices, it is of importance that physicians be alerted to the possible undesirable effect of bradycardia. There have been isolated reports of hepatic dysfunctions associated with octreotide acetate administration. These consist of the following: acute hepatitis without cholestasis and normalization of transaminase values on withdrawal of octreotide acetate has occurred; the slow development of hyperbilirubinemia in association with elevation of alkaline phosphatase, gamma glutamyl transferase and, to a lesser extent, transaminases.

SYMPTOMS AND TREATMENT OF OVERDOSAGE

Octreotide acetate Single-use & Multidose Vials

No life-threatening reactions have been reported after acute overdosage. Doses of up to 2000 :g octreotide given as subcutaneous injection t.i.d. for several months have been well tolerated. The maximum I.V. single dose of octreotide acetate given to an adult to date has been 1000 :g by bolus injection. The observed signs and symptoms were a brief drop in heart rate, facial flushing, abdominal cramps, diarrhea, an empty feeling in the stomach and nausea, all of which resolved within twenty-four hours of drug administration. One patient received an accidental overdosage of octreotide acetate by continuous infusion (250 :g per hour for forty-eight hours instead of 25 :g per hour). He experienced no side effects. The management of overdosage is symptomatic.

DOSAGE AND ADMINISTRATION

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.

Octreotide acetate Single-use & Multidose Vials

Subcutaneous injection is the recommended route of administration of 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 :g, 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 tumor-produced hormones (in cases of carcinoid tumors 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 octreotide acetate during the first two weeks of therapy ranges from 100 to 600 :g per day in two to four divided doses (mean daily dosage is 300 :g). In the clinical studies, the median daily maintenance dosage was approximately 450 :g, but clinical and biochemical benefits were obtained in some patients with as little as 50 :g, while others required doses up to 1500 :g per day. However, experience with doses above 750 :g per day is limited.

VIPomas

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

Acromegaly

Daily dosages of 100 :g to 300 :g 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 :g per day. A maximum dose of 1500 :g 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 therapy with octreotide acetate, therapy should be discontinued.

Prevention of Complications Following Pancreatic Surgery

Daily dosage of 100 :g 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 octreotide acetate is 25 :g/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 single-use 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 octreotide acetate 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.

Do not use if cloudiness, particulate matter, precipitation, discolouration or leakage is evident.

Drug

Substance

PHARMACEUTICAL INFORMATION

Common Name:

Octreotide acetate

Chemical Name: D-Phenylalanyl-L-hemicystyl-L-phenylalanyl-D-tryptophyl-L-lysyl-L-threonyl-L- hemicystyl-L-threoninol cyclic (267) disulfide acetate

Structural Formula:

NH2 H O

N O

N H

O HN

N Ac

O N

H O

O O N H H H

NH2

HO HO

Molecular Formula: C49H66N10O10S2, x CH3COOH

Molecular Weight

: 1019.3 x 60.05

Description

: Octreotide acetate is a bridged octapeptide analogue of somatostatin. It is 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 25/C, the solubility of octreotide acetate is > 10 mg/mL in water; > 10 mg/mL in glacial acetic acid and > 10 mg/mL in methanol.

Composition of OCTREOTIDE ACETATE OMEGA Single-use Vials

COMPOSITION	CONCENTRATION 1 ( : g/mL)
Octreotide (free peptide *)	50	100	500
glacial Acetic acid	2000	2000	2000
Sodium acetate trihydrate	2000	2000	2000
Sodium chloride	7000	7000	7000

Water for Injection, q.s. 1.0 mL

Present as octreotide acetate

Sodium acetate trihydrate or glacial Acetic acid is added to provide a buffered solution pH 4.2 +- 0.2.

Composition of OCTREOTIDE ACETATE OMEGA Multidose Vials

COMPOSITION	CONCENTRATION 1 ( : g/mL)
Octreotide (free peptide *)	200
glacial Acetic acid	2000
Sodium acetate trihydrate	2000
Sodium chloride	7000
Phenol	5000

Water for Injection, q.s. 1.0 mL

Present as octreotide acetate Sodium acetate trihydrate or glacial Acetic acid is added to provide a buffered solution pH 4.2 +- 0.2.

STABILITY AND STORAGE REQUIREMENTS

OCTREOTIDE ACETATE OMEGA Single-use & Multidose Vials Single-use Vials: for prolonged storage, OCTREOTIDE ACETATE OMEGA single-use vials should be kept at temperatures of 2 to 8oC. Protect from light and from freezing.

Multidose Vials

: Store at 2 to 8/C. Protect from light and from freezing.

For day-to-day use, the single-use vials may be stored at room temperature for up to 2 weeks; they must be protected from light. The single-use vials should be opened just prior to administration and any unused portion discarded. For day-to-day use, the multidose vials (OCTREOTIDE ACETATE OMEGA 200 :g/mL) may be stored at room temperature for up to 2 weeks prior to initial puncture; they must be protected from light. After initial puncture, OCTREOTIDE ACETATE OMEGA 200 :g/mL multidose vials should be stored at temperatures of 2 to 8/C and should be used within 15 days. Solution for continuous I.V. infusion: Immediately prior to use, the contents of the single-use 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 octreotide acetate at a rate of 25 :g/hour. The following are examples of dilutions which may be used:

Octreotide acetate			Volume of physiological saline	Approximate available volume mL	Nominal concentration : g/mL	Infusion rate mL/h ( : g/h)
Concentration : g/mL	Size mL	Volume mL	Volume of physiological saline	Approximate available volume mL	Nominal concentration : g/mL	Infusion rate mL/h ( : g/h)
500	1	1	49	50	10	2.5 (25)
200	5	2.5	47.5	50	10	2.5 (25)
200	5	3	93	96	6.25	4 (25)

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. Do not use if cloudiness, particulate matter, precipitation, discolouration or leakage is evident. Octreotide acetate 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.

AVAILABILITY OF DOSAGE FORMS

OCTREOTIDE ACETATE OMEGA Single-use & Multidose Vials OCTREOTIDE ACETATE OMEGA is supplied in 2 mL single-use vials of 1 mL of solution, each containing 50 :g, 100 :g or 500 :g of octreotide as acetate. OCTREOTIDE ACETATE OMEGA is available in boxes of 5 vials. OCTREOTIDE ACETATE OMEGA is also available in 5 mL multidose vials. Each vial contains 1000 :g of octreotide as acetate (200 :g/mL).

INFORMATION FOR THE PATIENT

OCTREOTIDE ACETATE OMEGA Single-use & Multidose Vials

The information that follows is intended as a guide for patients who must self-administer octreotide acetate subcutaneously for the control of symptoms associated with carcinoid tumors, VIPomas or acromegaly.

What is a Gastroenteropancreatic (GEP) Endocrine Tumor?

GEP endocrine tumors are growths that have developed from endorine cells in the gastrointestinal tract (the stomach, intestines, appendix) or the pancreas. GEP endocrine tumors grow very slowly and are often silent - not letting you know that they are there. Sometimes, however, they produce symptoms that are very noticeable. Some of these symptoms come about because GEP endocrine tumors produce and secrete chemical substances called peptides, i.e. small proteins. These same peptides are normally produced in your body - but in very small amounts. In other words, enough to do the jobs they are meant to do. The peptides don't build up; they don't enter the body's circulatory system; they simply do their job, degrade, and pass out of the body causing no symptoms, causing no harm. The problem is that when GEP endocrine tumors produce and secrete these very same peptides, they often do it to excess - overloading the system. When that happens, the body cannot handle the extra amounts of peptide in a normal way. The oversupply of peptide gets into the circulatory system, travels through the body and causes a variety of abnormal reactions, including diarrhea and flushing. The particular peptide that is released by the tumor, as well as the location of the tumor, determine the reactions or symptoms you will experience.

Carcinoid tumors

Carcinoid tumors are the most common type of GEP endocrine tumor. These growths can occur in the esophagus, stomach, intestines, appendix, as well as the lungs. Most carcinoid tumors produce only a small amount of peptide, which generally goes unnoticed. In some cases, however, carcinoid cells from the tumor spread through the bloodstream to the liver, where they form new tumors. When this occurs, the peptide they produce and secrete has easy access to the body's circulatory system through the liver. As the excess peptide travels through the body, it may cause a number of reactions or symptoms. This group of symptoms is referred to as the carcinoid syndrome. The most common symptoms of the carcinoid syndrome are diarrhea and flushing. Other symptoms of carcinoid syndrome include: wheezing or other asthma-like symptoms; and symptoms of heart disease, such as breathlessness.

VIPomas

VIPomas are GEP endocrine tumors that secrete vasoactive intestinal peptide (VIP). They almost always occur in the pancreas, a large gland behind the stomach that produces insulin and other secretions used in digestion. Normal secretion of VIP helps to moisten the stool so that it can pass through the bowel more easily. VIPomas however, produce excessive amounts of VIP - allowing too much fluid to enter the intestines. This flooding of the intestines causes very watery diarrhea - producing as many as 15 or more bowel movements a day. The body cannot tolerate diarrhea of this volume for very long. The loss of so much fluid causes dehydration, with the body losing not only a significant part of its water supply but important chemicals (electrolytes), such as sodium and potassium, as well. It is very important to stop diarrhea and to 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. Signs and symptoms of acromegaly due to excessive hormonal secretion include oily skin, acne, excessive sweating, headache, depression, visual disturbances, joint pain, changes in facial bone structure, muscle weakness, menstrual disorders. Acromegalic patients may also experience increased activity of the thyroid, diabetes, respiratory problems and daytime somnolence. It is frequently associated with arthritis and cardiac and neurologic problems. Acromegaly is the result of an overproduction of growth hormone by the pituitary gland. This in turn results in overproduction of somatomedin C (IGF-1) by the liver. Approximately 20% to 30% of acromegalic patients also demonstrate high blood pressure.

What Does octreotide acetate do?

GEP Endocrine Tumors:

Somatostatin

is another peptide hormone that occurs naturally in the body. It acts as a modulator, helping to keep many of the body's peptides including the GEP endocrine peptides, the growth hormone and the IGF-1 (somatomedin C) - at their appropriate levels. Octreotide acetate is a synthetic peptide that was created to mimic the natural modulating effects of somatostatin. The advantage of octreotide acetate is that it is stronger and has a much longer duration of action than somatostatin, which makes it more useful in therapy. In fact, injection of octreotide acetate two or three times a day - which a patient can easily learn to do - offers symptom control for people with GEP endocrine tumors and acromegaly.

Octreotide acetate helps slow down the release of the peptides that cause the diarrhea and flushing. It stimulates fluid and electrolyte absorption, and it prolongs the transit time through the small intestine. These activities combine to dramatically curb diarrhea and the threat of dehydration. Bowel movements may decrease from 10 or 20 a day to two or three. For many people, flushing episodes nearly disappear. For others, the number and severity of episodes decrease substantially; and the duration of the attacks could decrease from hours to minutes a day.

Acromegaly

Octreotide acetate has been shown to lower the growth hormone and Somatomedin C levels in the blood. As these hormones are principally responsible for the clinical signs and symptoms of acromegaly, normalization of hormone levels improves the symptoms of headache, soft tissue swelling, joint pain, excessive perspiration, depression, fatigue, cystic acne and somnolence.

SOME GUIDELINES FOR USING OCTREOTIDE ACETATE

When should OCTREOTIDE ACETATE OMEGA not be used? OCTREOTIDE ACETATE OMEGA should not be given to anyone who is allergic to the active ingredient octreotide or to any other ingredient of the formulation. A list of ingredients in OCTREOTIDE ACETATE OMEGA is given in the section of this leaflet called "What is in OCTREOTIDE ACETATE OMEGA ? ". Tell your doctor if you suspect you have had an allergic reaction to any of these ingredients in the past.

Can OCTREOTIDE ACETATE OMEGA be used if you have any other medical problems? Tell your doctor: if you know that you have gallstones now, or have had them in the past, as prolonged use of octreotide acetate may result in gallstone formation. if you have problems with your blood sugar levels, either too high (diabetes) or too low (hypoglycemia)

Can OCTREOTIDE ACETATE OMEGA be used if you are taking other medicines? You can generally continue taking other medicines while on octreotide acetate. However, the blood levels of certain medicines such as cimetidine, cyclosporine, and bromocriptine have been reported to be affected by octreotide acetate. It is, therefore, important to tell your doctor or pharmacist about any other medicines you are taking before using octreotide acetate, including those you have bought without a prescription. If you are diabetic, your doctor may need to adjust your anti-diabetic treatment.

Can OCTREOTIDE ACETATE OMEGA be taken with food? Avoid meals around the time of administration of OCTREOTIDE ACETATE OMEGA. OCTREOTIDE ACETATE OMEGA is best injected between meals or on retiring to bed. This may reduce the gastrointestinal side effects of OCTREOTIDE ACETATE OMEGA.

Can octreotide acetate be given to the elderly?

Yes, experience with octreotide acetate has shown that there are no special requirements for elderly patients.

Can octreotide acetate be given to children?

There is very little experience with the use of octreotide acetate in children.

Can octreotide acetate be used if you are pregnant or breast feeding?

There is no experience with the use of octreotide acetate in pregnant women. Therefore, it should be used during pregnancy only if clearly needed. Tell your doctor if you are pregnant, or want to become pregnant. There is no experience with octreotide acetate in nursing mothers. Therefore, you should not breast-feed your child while you are on octreotide acetate.

What is the Dose of octreotide acetate?

Your doctor will tell you how much octreotide acetate to take each day. The dosage is prescribed to suit your particular needs. The doctor will also tell you how to divide your dosage through the day. For example, he or she might prescribe a total dosage of 450 micrograms per day, to be taken in three equal injections of 150 micrograms each. Very often patients start at a low dose for the first few days of treatment and then increase slowly to a higher dose.

How is OCTREOTIDE ACETATE OMEGA Taken? Currently, OCTREOTIDE ACETATE OMEGA is given by subcutaneous injection. That means that the drug is injected just under the skin. This is the same kind of injection procedure used by people who have diabetes and need insulin. It is easy to learn. It is easy to do. And preparing and taking the injections (usually two or three a day) will take very little time - probably only a total of 15 minutes a day.

How to Prepare your Injection of OCTREOTIDE ACETATE OMEGA? You will receive your supply of OCTREOTIDE ACETATE OMEGA either in single-use or in multidose vials.

Single-use & Multidose Vials

Peel off the aluminium seal.
Wipe the top of the vial with an alcohol swab.
Remove the cap from the needle and insert the needle into the vial through the rubber stopper.
Leave the needle in the bottle.
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 octreotide acetate (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).
Turn the bottle and syringe back upright.
Withdraw the needle from the vial.
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 OCTREOTIDE ACETATE OMEGA Choose the area of your hip, thigh, or abdomen where you want to make your injection. 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 45/ 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. If you forget to take a scheduled injection, most doctors will suggest that you take at the time you remember and then go on with your normal schedule. (Check with your doctor to see if this procedure is acceptable.) You will not be harmed by forgetting a dose; however, you may get some temporary breakthrough of the symptoms (eg, diarrhea or flushing) that you are treating. This will then correct itself as you proceed with your normal schedule.

What side effects can octreotide acetate have?

Some patients say that they experience a burning sensation at the site where they are injecting the drug. Others do not experience this sensation at all. It depends, in part, on the size of the dose they are taking. The reason for the burning is due to the formulation of the drug. For most people, the burning lasts only a few moments. They inject and then rub the spot gently and, in a few seconds, the stinging is gone. For those who find it uncomfortable and want to alleviate the burning sensation, you may want to try injecting the drug at room temperature rather than cold from the refrigerator. In other words, you can take the medication out of the refrigerator for 20 minutes before you intend to use it and let it warm a bit. But don't forget, OCTREOTIDE ACETATE OMEGA vials must be refrigerated, they cannot be heated without destroying the medication. Like all medicines octreotide acetate may cause some side effects. Side effects such as those 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

Other side effects which occur less frequently are changes in blood sugar levels and liver problems. Rarely, hypersensitivity (allergic reactions) which may lead to skin rash, difficulty in breathing, swelling of the face and dizziness, hair loss and acute pancreatitis (inflammation of the pancreas gland causing severe stomach pain) and very rarely, slowed heart beat have been reported. Since gallstones may occasionally form during prolonged use of octreotide acetate, your doctor may wish to check your gallbladder periodically.

When to Take Your Injection of OCTREOTIDE ACETATE OMEGA? Your doctor or nurse will help you plan how to divide your dosage through the day. Symptom control is best achieved when the doses are evenly distributed over a 24-hour period.

What Is in OCTREOTIDE ACETATE OMEGA? OCTREOTIDE ACETATE OMEGA contains the active ingredient octreotide (present as octreotide acetate). The single-use vials also contain some inactive ingredients: glacial acetic acid, sodium acetate trihydrate, sodium chloride and water for injection. The multidose vials also contain some inactive ingredients: glacial acetic acid, phenol, sodium acetate trihydrate, sodium chloride and water for injection.

Storage

For prolonged storage, OCTREOTIDE ACETATE OMEGA must be refrigerated at 2 to 8/C (36 to 46/F) - typical refrigerator temperatures. However, you may leave your daily dose of OCTREOTIDE ACETATE OMEGA single-use vials out at a room temperature of up to 30/C (86/F) for up to 2 weeks. If the drug is left out at room temperature for longer than 2 weeks, the medication may break down and become ineffective. The single-use vials should be opened just prior to the administration and any unused portion discarded. The multidose vial may be kept at room temperature for up to 2 weeks before you start using it. If the drug is left out at room temperature for more than 2 weeks the medication can break down and become ineffective. Once opened the multidose vial should be kept refrigerated (at 2 to 8/C) and should be used within 15 days. A supply of OCTREOTIDE ACETATE OMEGA can be kept refrigerated for up to two years without deteriorating (do not use after the expiry date). However, the drug should never be frozen. Because peptides are very delicate, freezing and thawing the drug can damage it and impair its effectiveness. OCTREOTIDE ACETATE OMEGA should be protected from light.

PHARMACOLOGY

Pharmacodynamics studies with 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 activities 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 studies have been performed in rats, dogs and rhesus monkeys after single and multiple doses. The bioavailability of octreotide acetate 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 "-disposition half-life of 0.3 to 0.4 hours and a $-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

:g and about130% for 50 :g and 200 :g. There is no significant accumulation under conditions of repeated S.C. administration.

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 octreotide acetate treatment, continuation of therapy beyond one week is not recommended, although in non-responders no serious sustained adverse drug effects have been reported.

The biochemical characteristic of these tumors is over-production of vasoactive intestinal peptide (VIP). In 70% of patients with VIPomas, administration of octreotide acetate 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.

In acromegalic patients (including those who have failed to respond to surgery, irradiation of dopamine agonist treatment), octreotide acetate 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, octreotide acetate markedly reduces the clinical symptoms of the disease such as headache, skin and soft tissue swelling, hyperhidrosis, arthralgia, paresthesia. In patients with a large pituitary adenoma, octreotide acetate treatment may result in some shrinkage of the tumor mass.

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. Octreotide acetate inhibits basal and stimulated exocrine pancreatic secretion and, when administered peri- and post-operatively, reduces the incidence of complications following pancreatic surgery.

The precise mode of action of octreotide acetate on portal hypertension is still unclear. Octreotide acetate 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 saphenous veins, it has been shown that vasoconstriction is mediated by type 2 somatostatin receptors.

TOXICOLOGY

Single intravenous injections of 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.

Rats and rabbits were treated intravenously with 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.

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

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 system.

In a second in vivo mutagenicity test, damage to germ cell DNA was evaluated using the unscheduled DNA synthesis (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 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

SELECTED BIBLIOGRAPHY

J. Med. 1995; 333: 555-560. Bloom SR, Greenwood C (ed. ). Proceedings of somatostatin '85: Chemical, Physiological and Clinical advances. Scand J, Gastroenterology 1986; 21 (S119):1-274. 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. 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. Clements D, Elias E. Regression of metastatic VIPomas with somatostatin derivative SMS 201-995. Lancet 1985; I (8433): 874-5. Del Pozo E, Kutz K. SMS 201-995, a new somatostatin analog: pharmaceutical 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; 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. Supression of pancreatic endocrine tumor 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 tumors 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 hemorrhage. 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. A43). 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.

Species	LD 50 , mg/kg
Mouse Rat	72 (64-82) 18 (15-21)

SUBCHRONIC AND CHRONIC TOXICITY
Species	Duration	Route	Dose (mg/kg/d)	Observations
Rats	4 weeks	I.P.	1.0, 4.0, 16.0	Low dose : Slightly 9 feed intake, slight 8 in serum alkaline phophatase (SAP) values Mid dose : 9 weight gain & feed intake, slight 8 in urine volume & SAP, 9 serum albumin High dose : Moderate 9 in weight gain and feed intake, 9 serum albumin, with slight 8 in " 2 -globulin, slight 9 in serum glucose, slight 8 in SGOT and SAP values, unilateral, small, soft testes in 2 M, inhibited spermiogenesis with atrophy of germinal epithelium of seminiferous tubules in 3 M. NOAEL: 4 mg/kg/day
Dogs	4 weeks	I.V.	0.2, 0.8, 3.2	Low dose : Sporadic diarrhea, occasional prolapse of nictitating membrane, hypersalivation Mid dose : Diarrhea, occasional prolapse of nictitating membrane, howling on injection, hyperemia of the skin of the head High dose : Frequent diarrhea, occasional prolapse of nictitating membrane, hypersalivation, hyperemia of the skin of the head, slight weight loss, slight 8 in urine specific gravity. NOAEL: 0.2 mg/kg/day
Rats	26 weeks	I.P.	0.02, 0.1, 1.0	Low dose : No significant findings Mid dose : No significant findings High dose : 9 feed intake & urine volume. 8 specific gravity of urine in F. NOAEL: 1 mg/kg/day
Dogs	26 weeks + 4 weeks recovery	I.V.	0.01, 0.05, 0.5	Low dose : Sporadic diarrhea, sporadic emesis. Scattered single cell necrosis of acidophils, pituitary gland in one F. Mid dose : Frequent diarrhea, sporadic emesis. Pituitary findings as above in 1 F High dose : Sporadic emesis. Pituitary findings as above in 1 F and 1 M All groups : Additional investigation concentrating on determining the nature of the affected pituitary cell showed that octreotide acetate-treated recovery dogs stained positively for prolactin and negatively for growth hormone. Furthermore, plasma levels of prolactin, growth hormone and 17 $ -estradiol were unaffected by octreotide acetate treatment.
Dogs	52 weeks	S.C.	0.24, 0.80, 1.25	Low and mid doses : 9 lactate dehydrogenase (M) High dose : 9 lactate dehydrogenase (M & F). 4 M died due to large tissue masses at the injection sites. All available information at present indicates that the findings are species- specific and have no significance to the use of octreotide acetate in humans. All groups : 9 body weight and body weight gain. Local irritation at the injection site (alopecia, encrustation and thickening/swelling of the skin). 9 creatinine kinase and aspartate amino transferase. 8 alkaline phosphatases (F) and glucose; 9 sodium levels; total protein, albumin and " -globulin; bilirubin and calcium (F). Urinalysis : 9 specific gravity and osmolarity; 8 volume and pH in F only. Microscopically : 8 incidence of inflammation and hemorrhage of the cutis/subcutis and skin - Abscesses. Sarcomas at the injection sites noted only at 1.25 mg/kg/day. This lesion is considered to be treatment-related. Since the development of sarcomas in sites after repeated injection over long periods of time in rats is a well known effect, these sarcomas are considered to be expression of a chronic irritant effect of the test article at the high dose level, rather than a direct oncogenic effect.
Dogs	52 weeks	S.C.	0.05, 0.15, 0.30	Low dose : Transient 9 in food intake in M at start of treatment. Mid dose : Transient 9 in food intake in M at start of treatment and 9 mean body weight gain in M & F; slight but persistent 9 in total protein levels (F at week 52). High dose : Transient 9 in food intake in M at start of treatment and 9 mean body weight gain in M & F; slight but persistent 9 in total protein levels (F); high incidence of diarrhea in one F (relationship with treatment not clearly established); 9 in pancreas weight in M (relationship with the treatment unclear). Mid & High doses : 9 in $ phase elimination half-life noted after prolonged administration. Finding may be related to the formation of antibodies to octreotide acetate. No such observations noted in single dose experiments.
Rats	104 weeks	S.C.	0.25, 0.80, 1.25	Control : Microscopically observed sarcomas of the skin/subcutis not as severe as treatment groups Low dose : 9 body weight gain from week 7 in F. Microscopically observed sarcomas of the skin/subcutis not as severe high dose group. Mid dose : 9 body weight & body weight gain and 8 relative food consumption in M. Microscopically observed sarcomas of the skin/subcutis not as severe high dose group. High dose : 9 body weight & body weight gain throughout study and 8 relative food consumption (more severe in M than F ). Microscopically observed sarcomas of the skin/subcutis. All groups (including control) : Signs of local irritation at injection site including alopecia, encrustations, scabs and thickening/swelling of skin. Microscopically observed 8 incidence of inflammation, fibrosis, necrosis and hemorrhage associated with S.C. masses.
ADDITIONAL TOXICITY STUDIES
Dogs	3 weeks	I.V.	0.1 (0.05 b.i.d.)	Treatment : Moderate to severe diarrhea, 9 body weight & feed intake. Little variation in basal levels of prolactin or growth hormone. Recovery (staggered recovery periods from 1 to 35 days) : Sections of the pituitary revealed development of proliferation foci and heaped nuclei reaching a maximum at 7 days recovery, no longer apparent at day 35 of recovery. Scattered degenerated cells apparent only on days 21 and 35 of recovery.
Monkey (Rhesus) -6F	3 weeks	I.V.	1.0 (0.5 b.i.d.)	Treatment and Recovery periods : No clinical findings attributable to treatment. No diarrhea, no alterations in basal values of plasma GH, PRL or glucose. Pituitary gland showed no morphological alterations. No treatment related findings in other organs. Electron microscopy revealed no treatment-related alterations in the pituitary.
Dogs	26 weeks	I.V.	0.5	Treatment : Diarrhea Recovery period (staggered from 6 hours to 12 weeks with 2 animals per period) : Focal proliferation and single cell necrosis of pituitary gland. Pituitary function test (dogs treated with an injection of pituitary releasing factor during 1, 8 and 16 weeks of recovery): significant inhibition of stimulated GH release from pituitary up to 8 th recovery week; by 14 th week, GH response similar to control values.

Species	Duration	Route	N/Dose	Dose (mg/kg/d)	Observations
Rats	116	S.C.	60 M	Placebo,	Mid & High dose : Marginal but statistically significant 8 in the relative
(KFM-	weeks		60 F	NaCl 0.9%	proportion of lymphocytes by 10 to 8% on average in M of mid & high dose
han				0.24, 0.80,	groups, and by 16% on average in F of high group, when compared with the
Wistar)				1.25	controls. Dose-related 9 in body weight gain in F
					All groups : No treatment-related differences in intercurrent mortality and food
					intake. Except for the 8 incidence of injection site nodule (high dose M in
					particular) and reproductive tract masses/nodules (high dose F), the
					macroscopic lesions findings did not distinguish treated from control rats. Fast-
					growing masses at injection sites, particularly in neck region of M. At 1.25
					mg/kg/day and 0.24 mg/kg/day, these masses were recorded earlier and at a
					higher frequency than in other groups of M. They were identified as
					subcutaneous sarcomata. Alopecia, crusts, sore spots and (scabbed) wounds at
					the injection sites of both sexes with a higher incidence in the mid & high dose
					groups. Dose related 8 in incidence of ovarian sections without corpora lutea.
					Within the uterus: dose related 8 in glandular dilatation and 8 incidence of
					luminal dilatation (particularly high dose group) when compared to controls.
					Endometritis observed in all of the treated groups (particularly high dose), but
					not the controls.
Mice	8 5 / 8 6	S.C.	60 M	Placebo,	0.4, 1.2 & 2 mg/kg/d : 8 incidence of duodenal mucosal hyperplasia (F)
(KFM-	weeks (F)		60 F	NaCl 0.9%	frequently associated with inflammation and duodenal dilatation.
han				0.1, 0.4,	All treated-groups : No effect in intercurrent mortality, on clinical signs or
NMRI)	9 8 / 9 9			1.2, 2.0	nodules and masses, food consumption and body weight development. No
	week (M)				change in differential blood count. No treatment related change in
					macroscopical findings. Non neoplastic lesions at the injection sites identical
					to those observed in control groups. Neoplastic lesions at the injection sites
					identical to these observed in control groups.

PRODUCT MONOGRAPH

THERAPEUTIC CLASSIFICATION