Page 1 of 60 PRODUCT MONOGRAPH Pr SANDOSTATIN ® (Octreotide acetate Injection) 50 μg/ mL, 100 μg/ mL, 200 μg/ mL, 500 μg/ mL Pr SANDOSTATIN ® LAR ® Octreotide (as acetate) for Injectable Suspension 10, 20 or 30 mg octreotide (as acetate) per vial SYNTHETIC OCTAPEPTIDE ANALOGUE OF SOMATOSTATIN Novartis Pharmaceuticals Canada Inc. Dorval, Quebec H9S 1A9 Date of Preparation: June 6, 1989 Date of Revision: August 11, 2014 Submission Control No: 171147 SANDOSTATIN and LAR are registered trademarks.
Transcript
Page 1 of 60
PRODUCT MONOGRAPH
Pr
SANDOSTATIN®
(Octreotide acetate Injection)
50 µg/ mL, 100 µg/ mL, 200 µg/ mL, 500 µg/ mL
Pr
SANDOSTATIN® LAR
®
Octreotide (as acetate) for Injectable Suspension
10, 20 or 30 mg octreotide (as acetate) per vial
SYNTHETIC OCTAPEPTIDE ANALOGUE OF SOMATOSTATIN
Novartis Pharmaceuticals Canada Inc.
Dorval, Quebec
H9S 1A9
Date of Preparation:
June 6, 1989
Date of Revision:
August 11, 2014
Submission Control No: 171147 SANDOSTATIN and LAR are registered trademarks.
Page 2 of 60
Table of Contents
PART I: HEALTH PROFESSIONAL INFORMATION .........................................................3 SUMMARY PRODUCT INFORMATION ........................................................................3
INDICATIONS AND CLINICAL USE ..............................................................................3
ACTION AND CLINICAL PHARMACOLOGY ............................................................31
STORAGE AND STABILITY ..........................................................................................33
DOSAGE FORMS, COMPOSITION AND PACKAGING .............................................34
PART II: SCIENTIFIC INFORMATION ...............................................................................36 PHARMACEUTICAL INFORMATION ..........................................................................36
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.
Page 21 of 60
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 μg, 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 μg per day in two to four divided doses (mean daily dosage is 300 μg). In the
clinical studies, the median daily maintenance dosage was approximately 450 μg, but clinical and
biochemical benefits were obtained in some patients with as little as 50 μg, while others required
doses up to 1500 μg per day. However, experience with doses above 750 μg per day is limited.
Page 22 of 60
VIPomas Daily dosages of 200 to 300 μg in two to four divided doses are recommended during the initial
2 weeks of therapy (range 150 to 750 μg) to control symptoms of the disease. On an individual
basis, dosage may be adjusted to achieve a therapeutic response, but usually doses above 450 μg
per day are not required.
Acromegaly Daily dosages of 100 µg to 300 µg 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 µg per day. A
maximum dose of 1500 µg 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 μg 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 μg/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 health care professional. 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
Page 23 of 60
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 μg/L) the
dose may be increased to 30 mg every four weeks.
For patients whose serum GH concentrations are consistently below 1 μg/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 μg/day in 2-4 divided doses (mean daily dose is 300 μg). Some patients may
require doses up to 1500 μg/day. The suggested daily dose for VIPomas is 200-300 μg in 2-4
divided doses (range 150-750 μg); dosage may be adjusted on an individual basis to control
symptoms but usually doses above 450 μg/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
Page 24 of 60
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 SANDOSTATIN® LAR
® (Octreotide [as acetate] for Injectable
Suspension):
SANDOSTATIN® LAR
® is supplied in kits containing:
a. One vial of SANDOSTATIN
® LAR
® 10 mg, 20 mg or 30 mg octreotide [as acetate] for
injectable suspension
b. One prefilled syringe containing the diluent (showing the peel-off outer syringe label)
c. One vial adapter for drug product reconstitution
Page 25 of 60
d. One 20G x 1.5” safety injection needle
e. One instruction booklet
f. The package insert
Follow the instructions below carefully to ensure proper reconstitution of SANDOSTATIN®
LAR® before deep intragluteal injection.
There are 3 critical steps in the reconstitution of SANDOSTATIN® LAR
®. Not following them
could result in failure to deliver the drug appropriately.
The kit must reach room temperature. Remove the kit from the fridge. Let the kit
stand at room temperature for a minimum of 30 minutes before reconstitution, but do not
exceed 24 hours.
After adding the diluent, let the vial stand for a minimum of 2 minutes (up to 5 min) to
ensure that the powder is fully saturated.
After saturation, shake the vial moderately in a horizontal direction for a minimum of
30 seconds until a uniform suspension is formed. The SANDOSTATIN®
LAR®
suspension must only be prepared immediately before administration. 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.
SANDOSTATIN® LAR
® should only be administered by a trained health care professional.
Page 26 of 60
Step 1
Remove the SANDOSTATIN®
LAR® kit from
refrigerated storage.
ATTENTION: It is essential to start the
reconstitution process only after the kit
reaches room temperature. Let the kit stand
at room temperature for a minimum of 30
minutes before reconstitution, but do not
exceed 24 hours.
Step 2
Remove the plastic cap from the vial and clean
the rubber stopper of the vial with an alcohol
wipe.
Remove the lid film of the vial adapter
packaging, but do NOT remove the vial adapter
from its packaging.
Holding the vial adapter packaging, position the
vial adapter on top of the vial and push it fully
down so that it snaps in place, confirmed by an
audible “click.”
Page 27 of 60
Lift the packaging off the vial adapter with a
vertical movement.
Step 3
Remove the cap from the syringe prefilled with
diluent and screw the syringe onto the vial
adapter
Slowly push the plunger all the way down to
transfer all the diluent into the vial.
Step 4
ATTENTION: It is essential to let the vial
stand for a minimum of 2 minutes (up to 5
minutes) to ensure that the diluent has fully
saturated the powder.
Note: It is normal if the plunger rod moves up
as there might be a slight overpressure in the
vial.
At this stage prepare the patient for injection.
Step 5
After the saturation period, make sure that the
Page 28 of 60
plunger is pushed all the way down in the
syringe.
ATTENTION: Keep the plunger pressed and
shake the vial moderately in a horizontal
direction for a minimum of 30 seconds so that
the powder is completely suspended (milky
uniform suspension). Repeat moderate
shaking for another 30 seconds if the powder
is not completely suspended.
Step 6
Turn syringe and vial upside down, slowly pull
the plunger back and draw the entire contents
from the vial into the syringe.
Unscrew the syringe from the vial adapter.
Step 7
The product in the syringe now consists of
reconstituted SANDOSTATIN®
LAR®
Octreotide (as acetate) for Injectable
Suspension.
To avoid confusion, peel off the outer syringe
label which corresponds only with the diluent.
It is no longer a correct representation of the
current contents of the syringe.
Page 29 of 60
Step 8
Screw the safety injection needle onto the
syringe.
Pull the protective cover straight off the needle.
To avoid sedimentation, you may gently shake
the syringe to maintain a milky uniform
suspension.
Gently tap the syringe to remove any visible
bubbles and expel them from the syringe
The reconstituted SANDOSTATIN® LAR
® is
now ready for immediate administration.
Step 9
SANDOSTATIN® LAR
® must be given only by
deep intragluteal injection, NEVER
intravenously.
Prepare the injection site with an alcohol wipe.
Insert the needle fully into the left or right
gluteus at a 90º angle to the skin.
Slowly pull back the plunger to check that no
blood vessel has been penetrated (reposition if a
Page 30 of 60
blood vessel has been penetrated).
Slowly depress the plunger until the syringe is
empty. Withdraw the needle from the injection
site and activate the safety guard (as shown in
Step 10).
Step 10
Activate the safety guard over the needle in one
of the 2 methods shown:
A. either press the hinged section of the
safety guard down onto a hard surface
(figure A)
B. or push the hinge forward with your
finger (figure B)
An audible “click” confirms the proper
activation.
Dispose of syringe immediately (in a sharps
container).
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).
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 μg/hour. The following are examples of dilutions which may
be used:
SANDOSTATIN® Volume of
physiological
saline
Approximate
available
volume mL
Nominal
concentration
µg/mL
Infusion
rate
mL/h
(µg/h)
Concentration
µg/mL
Size
mL
Volume
mL
500 1 1 49 50 10 2.5 (25)
200 5 2.5 47.5 50 10 2.5 (25)
Page 31 of 60
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.
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
Page 32 of 60
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 α and β 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.
Page 33 of 60
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.
Page 34 of 60
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.
Store the pre-filled syringe with 2 mL diluent at 2 to 8 ºC.
Do not freeze.
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.
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 μg 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 μg of
octreotide as acetate (200 μg/mL).
SANDOSTATIN® LAR
® is supplied in kits containing
One single dose 6 mL glass 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 mL of diluent.
One vial adapter for drug product reconstitution
One 20G x 1.5” safety injection needle
An instruction booklet.
Composition of SANDOSTATIN® Ampoules
Composition Concentration1 (μg/mL)
Page 35 of 60
Octreotide (free peptide*) 50 100 500
Lactic acid 3,400 3,400 3,400
Mannitol 45,000 45,000 45,000 1 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
Composition Concentration1 (μg/mL)
Octreotide (free peptide)* 200
Lactic acid 3,400
Phenol 5,000
Mannitol 45,000 1 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 pre-filled syringe (with diluent) for SANDOSTATIN® LAR
®
(Octreotide for Injectable Suspension)
Composition per syringe
Carboxymethylcellulose sodium 14 mg
Mannitol
Poloxamer 188
12 mg
4 mg
Water for Injection (q.s. ad) 2 mL
Composition of SANDOSTATIN® LAR
® (Octreotide for Injectable Suspension)
Composition Concentration (mg/vial)
10 mg*/ vial 20 mg*/vial 30 mg*/vial
Octreotide acetate 11.2 22.4 33.6
Poly (DL-lactide-co-glycolide) 188.8 377.6 566.4
Mannitol 41.0 81.9 122.9 * Octreotide as free peptide
Page 36 of 60
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
total protein, albumin and α globulin; bilirubin and calcium (F).
Urinalysis: ↓ specific gravity and osmolarity; ↑ volume and pH in F only.
Microscopically: ↑ 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 ↓ in food intake in M at start of treatment.
Mid dose: Transient ↓ in food intake in M at the start of treatment and↓ mean body
weight gain in M & F; slight but persistent↓ in total protein levels (F at week 52).
High dose: Transient ↓ in food intake in M at start of the treatment and ↓ mean body
weight gain in M & F; slight but persistent ↓ in total protein levels (F); high incidence of
diarrhea in one F (relationship with treatment not clearly established); ↓ in pancreas
weight in M (relationship with the treatment unclear).
Mid & high doses: ↓ in β 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.
Page 45 of 60
Rat 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: ↓ body weight gain from week 7 in F. Microscopically observed sarcomas of
the skin/subcutis not as severe high dose group.
Mid dose: ↓ body weight & body weight gain and ↑ relative food consumption in M.
Microscopically observed sarcomas of the skin/subcutis not as severe high dose group.
High dose: ↓ body weight & body weight gain throughout study and ↑ 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
↑incidence of inflammation, fibrosis, necrosis and hemorrhage associated with s.c.
masses.
Additional Toxicity Studies
Species Duration Route Dose (mg/kg/d) Observations
Dogs 3 weeks i.v. 0.1
(0.05 b.i.d.)
Treatment: Moderate to severe diarrhea, ↓ 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 & 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 8th
recovery week; by 14th week, GH response similar to control values.
Page 46 of 60
Chronic Toxicity Studies with SANDOSTATIN® LAR
®
Species Duration Route N/dose Dose Observations
Rat/CR-SD
26 weeks
17 weeks
(recovery)
i.m. bilateral
injection into
biceps femoris
muscles
15M/15F
15M (recovery)
0, 2.5 mg in
0.5 mL 0.5%
sodium CMC
every 4 weeks
All groups (including controls): No deaths and no drug related signs
or changes in clinical pathology parameters. Reversible
granulomatous myositis at injection sites. Benign hemangiomas at
injection site. This is related to the i.m. injection of the
Microspheres of SANDOSTATIN® LAR
®
Rat/CR-SD 24 weeks
39 weeks
(recovery)
i.m. 50M 0, 2.5 mg 2.5 mg group: ↓ body weights compared to controls. This finding
was not present at the end of recovery period.
All groups: No treatment related findings. No hyperplastic or
neoplastic findings and no hemangiomas at injection sites.
Special Toxicity Studies with SANDOSTATIN® LAR
®: Local Tolerance
Species Duration Route N/dose Dose Observations
Rat/CD Single dose i.m. bilateral
(gastrocnemius
muscle)
18M
9M (Control)
0, 20 mg in 0.2
mL 0.5%
sodium CMC
Animals sacrificed sequentially at 9 time points between day 2 and
day 92.
Microencapsulated octreotide acetate well tolerated with no treatment
related clinical signs or findings. No difference in response at
injection site between diluent control and drug loaded microspheres.
Rat
CR/CD
Single dose i.m. injection
(gastrocnemius
muscle)
7M Control (LAR®
microsphere
diluent); 2 mg
One animal per group sacrificed on days 5, 15, 30, 45, 60, 75 and 90.
No adverse histologic findings at injection sites and no difference in
muscle histopathology or pattern of microcapsule degradation.
Rabbit
NZW
Single dose i.m. bilateral
(sacrospinalis
muscles)
9M 0, 25 mg (in 2.0
mL 0.5%
sodium CMC)
Animals sacrificed sequentially at 9 time points between day 2 and
day 92.
Microencapsulated octreotide acetate well tolerated with no
treatment-related clinical signs or mortality. No difference in
response at injection site between diluent control and drug loaded
microspheres.
Rabbit
NZW
Single dose i.m. 7M Control (LAR®
microsphere
diluent), 25 mg
One animal per group sacrificed on days 5, 15, 30, 45, 60, 75 and 90.
No difference in response between diluent control and drug loaded
microspheres.
Page 47 of 60
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 diluent 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.
Page 48 of 60
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
Species Duration Route N/dose Dose
(mg/kg/d)
Observations
Rats (KFM-
han Wistar)
116 weeks s.c. 60M
60F
Placebo,
NaCl 0.9%,
0.24, 0.80,
1.25
Mid & high dose: Marginal but statistically significant ↑ in the relative
proportion of lymphocytes by 10 to 8% on average in M of mid & high dose
groups, and by 16% on average in F of high group, when compared with the
controls. Dose-related ↓ in body weight gain in F
All groups: No treatment-related differences in intercurrent mortality and food
intake.
Except for the ↑ 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 ↑ in incidence
of ovarian sections without corpora lutea. Within the uterus: dose related ↑ in
glandular dilatation and ↑ 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.
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