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SANDOSTATIN LAR 10 MG POWDER AND SOLVENT FOR SUSPENSION FOR INJECTION

Active substance(s): OCTREOTIDE ACETATE

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SUMMARY OF PRODUCT CHARACTERISTICS

1

NAME OF THE MEDICINAL PRODUCT
Sandostatin LAR 10 mg powder and solvent for suspension for injection

2

QUALITATIVE AND QUANTITATIVE COMPOSITION
One vial contains 10 mg octreotide (as octreotide acetate)
Excipients with known effect
Contains less than 1 mmol (23 mg) sodium per dose, i.e is essentially “sodium-free”.
For a full list of excipients, see section 6.1.

3

PHARMACEUTICAL FORM
Powder and solvent for suspension for injection.
Powder: White to white with yellowish tint.
Solvent: Clear, colourless to slightly yellow or brown solution.

4

CLINICAL PARTICULARS

4.1

Therapeutic indications
Treatment of patients with acromegaly in whom surgery is inappropriate or
ineffective, or in the interim period until radiotherapy becomes fully effective (see
section 4.2).
Treatment of patients with symptoms associated with functional
gastro-entero-pancreatic endocrine tumours e.g. carcinoid tumours with features of
the carcinoid syndrome (see section 5.1).

Treatment of patients with advanced neuroendocrine tumours of the midgut or of
unknown primary origin where non-midgut sites of origin have been excluded.
Treatment of TSH-secreting pituitary adenomas:
• when secretion has not normalised after surgery and/or radiotherapy;
• in patients in whom surgery is inappropriate;
• in irradiated patients, until radiotherapy is effective.

4.2.

Posology and method of administration
Posology
Acromegaly
Initially 0.05 to 0.1 mg by subcutaneous (s.c.) injection every 8 or 12 hours. Dosage
adjustment should be based on monthly assessment of GH and IGF-1 levels (target:
GH <2.5 ng/mL; IGF-1 within normal range) and clinical symptoms, and on
tolerability. In most patients, the optimal daily dose will be 0.3 mg. A maximum dose
of 1.5 mg per day should not be exceeded. For patients on a stable dose of
Sandostatin, assessment of GH and IGF-1 should be made every 6 months.
If no relevant reduction in GH levels and no improvement in clinical symptoms have
been achieved within 3 months of starting treatment with Sandostatin, therapy should
be discontinued.
Gastro-entero-pancreatic endocrine tumours
Initially 0.05 mg once or twice daily by s.c. injection. Depending on clinical response,
effect on levels of tumour-produced hormones (in cases of carcinoid tumours, on the
urinary excretion of 5-hydroxyindole acetic acid), and on tolerability, dosage can be
gradually increased to 0.1 to 0.2 mg 3 times daily. Under exceptional circumstances,
higher doses may be required. Maintenance doses have to be adjusted individually.
In carcinoid tumours, if there is no beneficial response within 1 week of treatment
with Sandostatin at the maximum tolerated dose, therapy should not be continued.
Complications following pancreatic surgery
0.1 mg 3 times daily by s.c. injection for 7 consecutive days, starting on the day of
surgery at least 1 hour before laparotomy.
Bleeding gastro-oesophageal varices
25 micrograms/hour for 5 days by continuous intravenous (i.v.) infusion. Sandostatin
can be used in dilution with physiological saline.
In cirrhotic patients with bleeding gastro-oesophageal varices, Sandostatin has been
well tolerated at continuous i.v. doses of up to 50 micrograms/hour for 5 days.
Treatment of TSH-secreting pituitary adenomas
The dosage most generally effective is 100 micrograms three times a day by s.c.
injection. The dose can be adjusted according to the responses of TSH and thyroid
hormones. At least 5 days of treatment will be needed to judge the efficacy.
Use in the elderly
There is no evidence of reduced tolerability or altered dosage requirements in elderly
patients treated with Sandostatin.

Use in children
Experience with Sandostatin in children is limited.
Use in patients with impaired liver function
In patients with liver cirrhosis, the half-life of the drug may be increased,
necessitating adjustment of the maintenance dosage.
Use in patients with impaired renal function
Impaired renal function did not affect the total exposure (AUC) to octreotide
administered as s.c. injection, therefore no dose adjustment of Sandostatin is
necessary.
Method of administration
Sandostatin may be administered directly by subcutaneous (s.c.) injection or by
intravenous (i.v.) infusion after dilution. For further instructions on handling and
instructions for dilution of the medicinal product, refer to section 6.6.

4.3.

Contraindications
Hypersensitivity to the active substance or to any of the excipients listed in section
6.1.

4.4.

Special warnings and precautions for use
General
As GH-secreting pituitary tumours may sometimes expand, causing serious
complications (e.g. visual field defects), it is essential that all patients be carefully
monitored. If evidence of tumour expansion appears, alternative procedures may be
advisable.
The therapeutic benefits of a reduction in growth hormone (GH) levels and
normalisation of insulin-like growth factor 1 (IGF-1) concentration in female
acromegalic patients could potentially restore fertility. Female patients of
childbearing potential should be advised to use adequate contraception if necessary
during treatment with octreotide (see section 4.6).
Thyroid function should be monitored in patients receiving prolonged treatment with
octreotide.
Hepatic function should be monitored during octreotide therapy.
Cardiovascular related events
Common cases of bradycardia have been reported. Dose adjustment of medicinal
products such as beta blockers, calcium channel blockers, or agents to control fluid
and electrolyte balance, may be necessary (see section 4.5).
Gallbladder and related events

Cholelithiasis is a very common event during Sandostatin treatment and may be
associated with cholecystitis and biliary duct dilatation (see section 4.8). Ultrasonic
examination of the gallbladder before and at about 6-monthly intervals during
Sandostatin LAR therapy is recommended.
Glucose metabolism
Because of its inhibitory action on growth hormone, glucagon, and insulin release,
Sandostatin LAR may affect glucose regulation. Post-prandial glucose tolerance may
be impaired. As reported for patients treated with s.c. Sandostatin, in some instances,
the state of persistent hyperglycaemia may be induced as a result of chronic
administration. Hypoglycaemia has also been reported.
In patients with concomitant Type I diabetes mellitus, Sandostatin LAR is likely to
affect glucose regulation, and insulin requirements may be reduced. In non-diabetics
and type II diabetics with partially intact insulin reserves, Sandostatin s.c.
administration may result in increases in post-prandial glycaemia. It is therefore
recommended to monitor glucose tolerance and antidiabetic treatment.
In patients with insulinomas, octreotide, because of its greater relative potency in
inhibiting the secretion of GH and glucagon than that of insulin, and because of the
shorter duration of its inhibitory action on insulin, may increase the depth and prolong
the duration of hypoglycaemia. These patients should be closely monitored.
Nutrition
Octreotide may alter absorption of dietary fats in some patients.
Depressed vitamin B12 levels and abnormal Schilling’s tests have been observed in
some patients receiving octreotide therapy. Monitoring of vitamin B12 levels is
recommended during therapy with Sandostatin LAR in patients who have a history of
vitamin B12 deprivation.
Sodium content
Sandostatin LAR contains less than 1 mmol (23 mg) sodium per dose, i.e is
essentially “sodium-free”.

4.5

Interaction with other medicinal products and other forms of interaction
Dose adjustment of medicinal products such as beta blockers, calcium channel
blockers, or agents to control fluid and electrolyte balance may be necessary when
Sandostatin LAR is administered concomitantly (see section 4.4).

Dose adjustments of insulin and antidiabetic medicinal products may be required
when Sandostatin LAR is administered concomitantly (see section 4.4).
Octreotide has been found to reduce the intestinal absorption of ciclosporin and to
delay that of cimetidine.
Concomitant administration of octreotide and bromocriptine increases the
bioavailability of bromocriptine.

Limited published data indicate that somatostatin analogues might decrease the
metabolic clearance of compounds known to be metabolised 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 metabolised by
CYP3A4 and which have a low therapeutic index (e.g. quinidine, terfenadine) should
therefore be used with caution.

4.6

Fertility, pregnancy and lactation
Pregnancy
There is a limited amount of data (less than 300 pregnancy outcomes) from the use of
octreotide in pregnant women, and in approximately one third of the cases the
pregnancy outcomes are unknown. The majority of reports were received after postmarketing use of octreotide and more than 50% of exposed pregnancies were reported
in patients with acromegaly. Most women were exposed to octreotide during the first
trimester of pregnancy at doses ranging from 100-1200 micrograms/day of
Sandostatin s.c. or 10-40 mg/month of Sandostatin LAR. Congenital anomalies were
reported in about 4% of pregnancy cases for which the outcome is known. No causal
relationship to octreotide is suspected for these cases.
Animal studies do not indicate direct or indirect harmful effects with respect to
reproductive toxicity (see section 5.3).
As a precautionary measure, it is preferable to avoid the use of Sandostatin LAR
during pregnancy (see section 4.4).
Breastfeeding
It is unknown whether octreotide is excreted in human breast milk. Animal studies
have shown excretion of octreotide in breast milk. Patients should not breast-feed
during Sandostatin LAR treatment.
Fertility
It is not known whether octreotide has an effect on human fertility. Late descent of
the testes was found for male offsprings of dams treated during pregnancy and
lactation. Octreotide, however, did not impair fertility in male and female rats at doses
of up to 1 mg/kg body weight per day (see section 5.3).

4.7

Effects on ability to drive and use machines
Sandostatin LAR has no or negligible influence on the ability to drive and use
machines. Patients should be advised to be cautious when driving or using machines
if they experience dizziness, asthenia/fatigue, or headache during treatment with
Sandostatin LAR.

4.8.

Undesirable effects

Summary of the safety profile
The most frequent adverse reactions reported during octreotide therapy include
gastrointestinal disorders, nervous system disorders, hepatobiliary disorders, and
metabolism and nutritional disorders.
The most commonly reported adverse reactions in clinical trials with octreotide
administration were diarrhoea, abdominal pain, nausea, flatulence, headache,
cholelithiasis, hyperglycaemia and constipation. Other commonly reported adverse
reactions were dizziness, localised pain, biliary sludge, thyroid dysfunction (e.g.,
decreased thyroid stimulating hormone [TSH], decreased total T4, and decreased free
T4), loose stools, impaired glucose tolerance, vomiting, asthenia, and hypoglycaemia.
Tabulated list of adverse reactions
The following adverse drug reactions, listed in Table 1, have been accumulated from
clinical studies with octreotide:
Adverse drug reactions (Table 1) are ranked under heading of frequency, the most
frequent first, using the following convention: very common (≥1/10); common
(≥1/100, <1/10); uncommon (≥1/1,000, <1/100); rare (≥1/10,000, <1/1,000) very rare
(<1/10,000), including isolated reports. Within each frequency grouping, adverse
reactions are ranked in order of decreasing seriousness.
Table 1

Adverse drug reactions reported in clinical studies

Gastrointestinal disorders
Very common:
Diarrhoea, abdominal pain, nausea, constipation, flatulence.
Common:
Dyspepsia, vomiting, abdominal bloating, steatorrhoea, loose
stools, discolouration of faeces.
Nervous system disorders
Very common:
Headache.
Common:
Dizziness.
Endocrine disorders
Common:
Hypothyroidism, thyroid disorder (e.g., decreased TSH,
decreased total T4, and decreased free T4).
Hepatobiliary disorders
Very common:
Cholelithiasis.
Common:
Cholecystitis, biliary sludge, hyperbilirubinaemia.
Metabolism and nutrition disorders
Very common:
Hyperglycaemia.
Common:
Hypoglycaemia, impaired glucose tolerance, anorexia.
Uncommon:
Dehydration.
General disorders and administration site conditions
Very common:
Injection site reactions.
Common:
Asthenia.
Investigations
Common:
Elevated transaminase levels.
Skin and subcutaneous tissue disorders
Common:
Pruritus, rash, alopecia.
Respiratory disorders
Common:
Dyspnoea.

Cardiac disorders
Common:
Uncommon:

Bradycardia.
Tachycardia.

Post-marketing
Spontaneously reported adverse reactions, presented in Table 2, are reported
voluntarily and it is not always possible to reliably establish frequency or a causal
relationship to drug exposure.
Table 2

Adverse drug reactions derived from spontaneous reports

Blood and lymphatic system disorders
Thrombocytopenia
Immune system disorders
Anaphylaxis, allergy/hypersensitivity reactions.
Skin and subcutaneous tissue disorders
Urticaria
Hepatobiliary disorders
Acute pancreatitis, acute hepatitis without cholestasis, cholestatic hepatitis, cholestasis,
jaundice, cholestatic jaundice.
Cardiac disorders
Arrhythmias.
Investigations
Increased alkaline phosphatase levels, increased gamma glutamyl transferase levels.
Description of selected adverse reactions
Gallbladder and related reactions
Somatostatin analogues have been shown to inhibit gallbladder contractility and
decrease bile secretion, which may lead to gallbladder abnormalities or sludge.
Development of gallstones has been reported in 15 to 30% of long-term recipients of
s.c. Sandostatin. The incidence in the general population (aged 40 to 60 years) is
about 5 to 20%. Long-term exposure to Sandostatin LAR of patients with acromegaly
or gastro-entero-pancreatic tumors suggests that treatment with Sandostatin LAR does
not increase the incidence of gallstone formation, compared with s.c. treatment. If
gallstones do occur, they are usually asymptomatic; symptomatic stones should be
treated either by dissolution therapy with bile acids or by surgery.
Gastrointestinal disorders
In rare instances, gastrointestinal side effects may resemble acute intestinal
obstruction, with progressive abdominal distension, severe epigastric pain, abdominal
tenderness and guarding.
The frequency of gastrointestinal adverse events is known to decrease over time with
continued treatment.
Hypersensitivity and anaphylactic reactions
Hypersensitivity and allergic reactions have been reported during post-marketing.
When these occur, they mostly affect the skin, rarely the mouth and airways. Isolated
cases of anaphylactic shock have been reported.
Injection site reactions
Injection site related reactions including pain, redness, haemorrhage, pruritus,
swelling or induration were commonly reported in patients receiving Sandostatin

LAR; however, these events did not require any clinical intervention in the majority
of the cases.
Metabolism and nutrition disorders
Although measured faecal fat excretion may increase, there is no evidence to date that
long-term treatment with octreotide has led to nutritional deficiency due to
malabsorption.
Pancreatic enzymes
In very rare instances, acute pancreatitis has been reported within the first hours or
days of Sandostatin s.c. treatment and resolved on withdrawal of the drug. In addition,
cholelithiasis-induced pancreatitis has been reported for patients on long-term
Sandostatin s.c. treatment.
Cardiac disorders
Bradycardia is a common adverse reaction with somatostatin analogues. In both
acromegalic and carcinoid syndrome patients, ECG changes were observed such as
QT prolongation, axis shifts, early repolarisation, 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 diseases (see section 4.4).
Thrombocytopenia
Thrombocytopenia has been reported during post-marketing experience, particularly
during treatment with Sandostatin (i.v.) in patients with cirrhosis of the liver, and
during treatment with Sandostatin LAR. This is reversible after discontinuation of
treatment.
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is
important. It allows continued monitoring of the benefit/risk balance of the medicinal
product. Healthcare professionals are asked to report any suspected adverse reactions
via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard.

4.9

Overdose
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.

5.1.

Pharmacodynamic properties

Pharmacotherapeutic group: Somatostatin and analogues, ATC code: H01CB02
Octreotide is a synthetic octapeptide derivative of naturally occurring somatostatin
with similar pharmacological effects, but with a considerably prolonged duration of
action. It inhibits pathologically increased secretion of growth hormone (GH) and of
peptides and serotonin produced within the GEP endocrine system.
In animals, octreotide is a more potent inhibitor of GH, glucagon and insulin release
than somatostatin is, with greater selectivity for GH and glucagon suppression.
In healthy subjects octreotide, like somatostatin, has been shown to inhibit:
• release of GH stimulated by arginine, exercise- and insulin-induced
hypoglycaemia,
• post-prandial 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).
Unlike somatostatin, octreotide inhibits GH secretion preferentially over insulin and
its administration is not followed by rebound hypersecretion of hormones (i.e. GH in
patients with acromegaly).
In patients with acromegaly, Sandostatin LAR, a galenical formulation of octreotide
suitable for repeated administration at intervals of 4 weeks, delivers consistent and
therapeutic octreotide serum concentrations thus consistently lowering GH and
normalising IGF 1 serum concentrations in the majority of patients. In most patients,
Sandostatin LAR markedly reduces the clinical symptoms of the disease, such as
headache, perspiration, paraesthesia, fatigue, osteoarthralgia and carpal tunnel
syndrome. In previously untreated acromegaly patients with GH-secreting pituitary
adenoma, Sandostatin LAR treatment resulted in a tumour volume reduction of >20%
in a significant proportion (50%) of patients.
In individual patients with GH-secreting pituitary adenoma, Sandostatin LAR was
reported to lead to shrinkage of the tumour (prior to surgery). However, surgery
should not be delayed.
For patients with functional tumours of the gastro-entero-pancreatic endocrine
system, treatment with Sandostatin LAR provides continuous control of symptoms
related to the underlying disease. The effect of octreotide in different types of gastroentero-pancreatic tumours are as follows:
Carcinoid tumours
Administration of octreotide may result in improvement of symptoms, particularly of
flushing and diarrhoea. In many cases, this is accompanied by a fall in plasma
serotonin and reduced urinary excretion of 5 hydroxyindole acetic acid.
VIPomas
The biochemical characteristic of these tumours is overproduction of vasoactive
intestinal peptide (VIP). In most cases, administration of octreotide results in
alleviation of the severe secretory diarrhoea typical of the condition, with consequent
improvement in quality of life. This is accompanied by an improvement in associated
electrolyte abnormalities, e.g. hypokalaemia, enabling enteral and parenteral fluid
and electrolyte supplementation to be withdrawn. In some patients, computed
tomography scanning suggests a slowing or arrest of progression of the tumour, or

even tumour shrinkage, particularly of hepatic metastases. Clinical improvement is
usually accompanied by a reduction in plasma VIP levels, which may fall into the
normal reference range.
Glucagonomas
Administration of octreotide results in most cases in substantial improvement of the
necrolytic migratory rash which is characteristic of the condition. The effect of
octreotide on the state of mild diabetes mellitus which frequently occurs is not
marked and, in general, does not result in a reduction of requirements for insulin or
oral hypoglycaemic agents. Octreotide produces improvement of diarrhoea, and
hence weight gain, in those patients affected. Although administration of octreotide
often leads to an immediate reduction in plasma glucagon levels, this decrease is
generally not maintained over a prolonged period of administration, despite continued
symptomatic improvement.
Gastrinomas/Zollinger-Ellison syndrome
Therapy with proton pump inhibitors or H2 receptor blocking agents generally
controls gastric acid hypersecretion. However, diarrhoea, which is also a prominent
symptom, may not be adequately alleviated by proton pump inhibitors or H2 receptor
blocking agents. Sandostatin LAR can help to further reduce gastric acid
hypersecretion and improve symptoms, including diarrhoea, as it provides
suppression of elevated gastrin levels, in some patients.
Insulinomas
Administration of octreotide produces a fall in circulating immunoreactive insulin. In
patients with operable tumours, octreotide may help to restore and maintain
normoglycemia pre-operatively. In patients with inoperative benign or malignant
tumours, glycaemic control may be improved even without concomitant sustained
reduction in circulating insulin levels.
Advanced neuroendocrine tumours of the midgut or of unknown primary origin
where non-midgut sites of origin have been excluded
A Phase III, randomised, double-blind, placebo-controlled study (PROMID)
demonstrated that Sandostatin LAR inhibits tumour growth in patients with advanced
neuroendocrine tumours of the midgut. 85 patients were randomised to receive
Sandostatin LAR 30 mg every 4 weeks (n=42) or placebo (n=43) for 18 months, or
until tumour progression or death.
Main inclusion criteria were: treatment naïve; histologically confirmed; locally
inoperable or metastatic well-differentiated; functionally active or inactive
neuroendocrine tumours/carcinomas; with primary tumour located in the midgut or
unknown origin believed to be of midgut origin if a primary within the pancreas,
chest, or elsewhere was excluded.
The primary endpoint was time to tumour progression or tumour-related death (TTP).
In the intent-to-treat analysis population (ITT) (all randomised patients), 26 and
41 progressions or tumour-related deaths were seen in the Sandostatin LAR and
placebo groups, respectively (HR = 0.32; 95% CI, 0.19 to 0.55; p-value =.000015).

In the conservative ITT (cITT) analysis population in which 3 patients were censored
at randomization, 26 and 40 progressions or tumour-related deaths were observed in
the Sandostatin LAR and placebo groups, respectively (HR=0.34; 95% CI, 0.20 to
0.59; p-value =.000072; Fig 1). Median time to tumour progression was 14.3 months
(95% CI, 11.0 to 28.8 months) in the Sandostatin LAR group and 6.0 months (95%
CI, 3.7 to 9.4 months) in the placebo group.
In the per-protocol analysis population (PP) in which additional patients were
censored at end study therapy, tumour progression or tumour-related death was
observed in 19 and 38 Sandostatin LAR and placebo recipients, respectively (HR =
0.24; 95% CI, 0.13 to 0.45; p-value =.0000036).
Figure 1
Kaplan-Meier estimates of TTP comparing Sandostatin LAR
with placebo (conservative ITT population)

Table 3

TTP results by analysis populations

TTP Events

ITT

Sandostatin
LAR
26

Median TTP months [95% C.I.]
Placebo
41

Sandostatin
LAR
NR

HR [95% C.I.]
p-value *

Placebo
NR

0.32
[95% CI, 0.19 to
0.55] P=0.000015
cITT
26
40
14.3
6.0
0.34
[95% CI, 11.0 [95% CI, 3.7 to
[95% CI, 0.20 to
to 28.8]
9.4]
0.59] P=0.000072
PP
19
38
NR
NR
0.24
[95% CI, 0.13 to
0.45] P=0.0000036
NR=not reported; HR=hazard ratio; TTP=time to tumour progression; ITT=intention to treat;
cITT=conservative ITT; PP=per protocol
*Logrank test stratified by functional activity
Treatment effect was similar in patients with functionally active (HR = 0.23; 95% CI,
0.09 to 0.57) and inactive tumours (HR = 0.25; 95% CI, 0.10 to 0.59).
After 6 months of treatment, stable disease was observed in 67% of patients in the
Sandostatin LAR group and 37% of patients in the placebo group.
Based on the significant clinical benefit of Sandostatin LAR observed in this preplanned interim analysis the recruitment was stopped.
The safety of Sandostatin LAR in this trial was consistent with its established safety
profile.
Treatment of TSH-secreting pituitary adenomas
Sandostatin LAR, one i.m. injection every 4 weeks, has been shown to suppress
elevated thyroid hormones, to normalise TSH and to improve the clinical signs and
symptoms of hyperthyroidism in patients with TSH-secreting adenomas. Treatment
effect of Sandostatin LAR reached statistical significance as compared to baseline
after 28 days and treatment benefit continued for up to 6 months.

5.2

Pharmacokinetic properties
After single i.m. injections of Sandostatin LAR, the serum octreotide concentration
reaches a transient initial peak within 1 hour after administration, followed by a
progressive decrease to a low undetectable octreotide level within 24 hours. After
this initial peak on day 1, octreotide remains at sub-therapeutic levels in the majority
of the patients for the following 7 days. Thereafter, octreotide concentrations
increase again, and reach plateau concentrations around day 14 and remain relatively
constant during the following 3 to 4 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,
concomitant with the terminal degradation phase of the polymer matrix of the dosage
form.

In patients with acromegaly, plateau octreotide concentrations after single doses of 10
mg, 20 mg and 30 mg Sandostatin LAR amount to 358 ng/L, 926 ng/L, and 1,710
ng/L, respectively. Steady-state octreotide serum concentrations, reached after 3
injections at 4 week intervals, are higher by a factor of approximately 1.6 to 1.8 and
amount to 1,557 ng/L and 2,384 ng/L after multiple injections of 20 mg and 30 mg
Sandostatin LAR, respectively.
In patients with carcinoid tumours, the mean (and median) steady-state serum
concentrations of octreotide after multiple injections of 10 mg, 20 mg and 30 mg of
Sandostatin LAR given at 4 week intervals also increased linearly with dose and were
1,231 (894) ng/L, 2,620 (2,270) ng/L and 3,928 (3,010) ng/L, respectively.
No accumulation of octreotide beyond that expected from overlapping release profiles
occurred over a duration of up to 28 monthly injections of Sandostatin LAR.
The pharmacokinetic profile of octreotide 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 for s.c. administration. The volume of
distribution of octreotide at steady-state is 0.27 L/kg and the total body clearance is
160 mL/min. Plasma protein binding amounts to 65% and essentially no drug is
bound to blood cells.
Pharmacokinetic data with limited blood sampling in pediatric patients with
hypothalamic obesity, aged 7–17 years, receiving Sandostatin LAR 40 mg once
monthly, showed mean octreotide trough plasma concentrations of 1,395 ng/L after
the first injection and of 2,973 ng/L at steady state. A high inter-subject variability is
observed.
Steady-state trough octreotide concentrations were not correlated with age and BMI,
but moderately correlated with body weight (52.3–133 kg) and was significantly
different between male and female patients, i.e. about 17% higher for female patients.

5.3

Preclinical safety data
Acute and repeated dose toxicology, genotoxicity, carcinogenicity and reproductive
toxicology studies in animals revealed no specific safety concerns for humans.
Reproduction studies in animals revealed no evidence of teratogenic, embryo/foetal or
other reproduction effects due to octreotide at parental doses of up to 1 mg/kg/day.
Some retardation of the physiological growth was noted in the offspring of rats which
was transient and attributable to GH inhibition brought about by excessive
pharmacodynamic activity (see section 4.6).
No specific studies were conducted in juvenile rats. In the pre- and post-natal
developmental studies, reduced growth and maturation was observed in the F1
offspring of dams given octreotide during the entire pregnancy and lactation period.
Delayed descent of the testes was observed for male F1 offsprings, but fertility of the
affected F1 male pups remained normal. Thus, the above mentioned observations
were transient and considered to be the consequence of GH inhibition.

6

PHARMACEUTICAL PARTICULARS

6.1

List of excipients
Powder (Vial):
Poly (DL-lactide-co-glycolide)
Mannitol (E421)
Solvent (Prefilled syringe):
Carmellose sodium
Mannitol (E421)
Poloxamer 188
Water for injections

6.2

Incompatibilities
In the absence of compatibility studies, this medicinal product must not be mixed
with other medicinal products.

6.3

Shelf life
3 years
The product must not be stored after reconstitution (must be used immediately).

6.4

Special precautions for storage
Store in the original package in order to protect from light.
Store in a refrigerator (2°C to 8°C). Do not freeze.
Sandostatin LAR may be stored below 25°C on the day of the injection.
.

6.5

Nature and contents of container
Unit packs containing one 6 mL glass vial with rubber stopper (bromobutyl rubber),
sealed with an aluminium flip-off seal, containing powder for suspension for injection
and one 3 mL colourless pre-filled glass syringe with front and plunger stopper
(chlorobutyl rubber) with 2 mL solvent, co-packaged in a sealed blister tray with one
vial adapter and one safety injection needle.
Multipacks of three unit packs, each unit pack containing: one 6 mL glass vial with
rubber stopper (bromobutyl rubber), sealed with an aluminium flip-off seal,

containing powder for suspension for injection and one 3 mL colourless pre-filled
glass syringe with front and plunger stopper (chlorobutyl rubber) with 2 mL solvent,
co-packaged in a sealed blister tray with one vial adapter and one safety injection
needle.
Not all pack sizes may be marketed

6.6.

Special precautions for disposal and other handling
Any unused medicinal product or waste material should be disposed of in accordance
with local requirements.
Instructions for preparation and intramuscular injection for Sandostatin LAR
FOR DEEP INTRAMUSCULAR INJECTION ONLY

Included in the injection kit:

a.
b.
c.
d.

One vial containing Sandostatin LAR powder,
One prefilled syringe containing the vehicle solution for reconstitution,
One vial adapter for drug product reconstitution,
One safety injection needle.

Follow the instructions below carefully to ensure proper reconstitution of Sandostatin LAR
before deep intramuscular injection.
There are 3 critical actions in the reconstitution of Sandostatin LAR. Not following them
could result in failure to deliver the drug appropriately.
• The injection kit must reach room temperature. Remove the injection kit from the
fridge and 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 solution, ensure that the powder is fully saturated by
letting the vial stand for 5 minutes.
• 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.
Sandostatin LAR should only be administered by a trained healthcare professional.

Step 1


Remove the Sandostatin LAR injection kit from
refrigerated storage.
ATTENTION: It is essential to start the reconstitution
process only after the injection 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.
Note: The injection kit can be re-refrigerated if needed.
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.”



Lift the packaging off the vial adapter with a vertical
movement.




Step 3
Remove the cap from the syringe prefilled with diluent
solution and screw the syringe onto the vial adapter.
Slowly push the plunger all the way down to transfer all
the diluent solution in the vial.

Step 4
ATTENTION: It is essential to let the vial stand for 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 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


Prepare injection site with an alcohol wipe.



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


Screw the safety injection needle onto the syringe.



Gently re-shake the syringe to ensure a milky uniform
suspension



Pull the protective cover straight off the needle.



Gently tap the syringe to remove any visible bubbles and
expel them from the syringe. Verify that injection site has
not been contaminated.



Proceed immediately to Step 8 for administration to the
patient. Any delay may result in sedimentation.

Step 8


Sandostatin LAR must be given only by
intramuscular injection, NEVER intravenously.



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 blood vessel has been
penetrated).



Depress the plunger with steady pressure until the syringe
is empty. Withdraw the needle from the injection site and
activate the safety guard (as shown in Step 9).

deep

Step 9


Activate the safety guard over the needle in one of the two
methods shown:
- either press the hinged section of the safety guard down
onto a hard surface (figure A)
- 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).

7.

MARKETING AUTHORISATION HOLDER
Novartis Pharmaceuticals UK Limited
Frimley Business Park
Frimley
Camberley
Surrey
GU16 7SR
United Kingdom

8

MARKETING AUTHORISATION NUMBER(S)
PL 00101/0511

9

DATE OF FIRST AUTHORISATION/RENEWAL OF THE
AUTHORISATION
29 April 1998

10

DATE OF REVISION OF THE TEXT
06/03/2018

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Further information

Always consult your healthcare provider to ensure the information displayed on this page applies to your personal circumstances.

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