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Novartis Pharmaceuticals UK Ltd

Frimley Business Park, Frimley, Camberley, Surrey, GU16 7SR
Telephone: +44 (0)1276 692 255
Fax: +44 (0)1276 698 449
Medical Information Direct Line: +44 (0)1276 698 370
Medical Information e-mail: medinfo.uk@novartis.com
Customer Care direct line: +44 (0)845 741 9442

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Summary of Product Characteristics last updated on the eMC: 23/04/2013
SPC Sandostatin LAR


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1. Name of the medicinal product

Sandostatin® LAR® 10 mg, 20 mg or 30 mg powder and solvent for suspension for injection


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2. Qualitative and quantitative composition

The active substance is octreotide* free peptide, 10 mg, 20 mg or 30 mg nominally 4.15% of fill weight equivalent to 4.65% of octreotide acetate.

Following suspension of the powder (microspheres) with the supplied vehicle solution, Sandostatin LAR suspension contains less than 1mmol (23mg) of sodium per dose, i.e. essentially “sodium-free”.

For a full list of excipients see section 6.1.

* INN rec.


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3. Pharmaceutical form

Powder and solvent for suspension for injection.

Powder: white to off-white powder.

Solvent for suspension for injection: clear, colourless solution.

Sandostatin LAR is a long-acting depot injection form of octreotide. Powder (microspheres for suspension for injection) to be suspended in a vehicle immediately prior to i.m. injection.


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4. Clinical particulars

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4.1 Therapeutic indications

Treatment of patients with acromegaly:

For symptomatic control and reduction of growth hormone and IGF-1 levels in patients with acromegaly

• who are adequately controlled on s.c. treatment with Sandostatin; in whom surgery or radiotherapy is inappropriate or ineffective, or in the interim period until radiotherapy becomes fully effective.

• in short term treatment (3-12 months) prior to pituitary surgery (see also Section 5.1 Pharmacological properties).

Treatment of patients with advanced neuroendocrine tumours of the midgut; or of unknown primary origin where non-midgut sites of origin have been excluded.

Relief of symptoms associated with functional gastroenteropancreatic endocrine tumours including:

• Carcinoid tumours with features of carcinoid syndrome

• VIPomas

• Glucagonomas

in patients whose symptoms are adequately controlled on s.c. treatment with Sandostatin.

Currently data does not support the use of Sandostatin as antitumour therapy in patients with pancreatic neuroendocrine tumours.


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4.2 Posology and method of administration

Sandostatin LAR may only be administered by deep intragluteal injection. The site of repeat intragluteal injections should be alternated between the left and right gluteal muscle (see 6.6 Instructions for use/handling).

Acromegaly

For patients who have not received prior treatment with subcutaneous Sandostatin, a test dose of s.c. Sandostatin (50-100mcg) is recommended to assess any adverse reaction to octreotide prior to initiating treatment with Sandostatin LAR.

For de novo patients who have received a test dose and for patients who are adequately controlled with s.c. Sandostatin, treatment should be started with 20mg Sandostatin LAR intramuscularly at 4-week intervals for 3 months. Treatment with Sandostatin LAR can be started on the day after the last dose of s.c. Sandostatin. Subsequent dosage adjustment should be based on serum growth hormone (GH) and insulin-like growth factor l (IGF 1)/somatomedin C concentrations and clinical symptoms.

For patients in whom clinical symptoms and biochemical parameters (GH; IGF 1) are not fully controlled (GH concentrations still above 2.5μg/L{5mU/L}), the dose may be increased to 30mg every 4 weeks.

For patients whose GH concentrations are consistently below 1μg/L (2mU/L), whose IGF 1 serum concentrations have normalised, and in whom most reversible signs/symptoms of acromegaly have disappeared after 3 months of treatment with 20mg, the dose may be reduced to 10mg every 4 weeks. However, in this group of patients serum GH and IGF 1 concentrations, and clinical signs/symptoms should be monitored particularly closely.

For patients on a stable dose of Sandostatin LAR, assessment of GH and IGF should be made every 12 months. Six-monthly monitoring may be necessary in those patients whose clinical and biochemical control is less adequate.

In order to permit successful endocrine testing of the completeness of tumour removal 5-6 weeks post surgery, the last injection of Sandostatin LAR should be administered at least 3-4 weeks prior to surgery.

Treatment of patients with advanced neuroendocrine tumours of the midgut; or of unknown primary origin where non-midgut sites of origin have been excluded

The recommended dose of Sandostatin LAR is 30mg administered every 4 weeks (see section 5.1 Pharmacodynamic properties). Treatment with Sandostatin LAR for tumour control should be continued in the absence of tumour progression.

Relief of symptoms associated with functional gastroenteropancreatic endocrine tumours

After adequate control has been established with Sandostatin s.c., treatment should be started with 20mg Sandostatin LAR intramuscularly at 4-week intervals. Treatment with Sandostatin s.c. should be continued at the previously effective dosage for 2 weeks after the first injection of Sandostatin LAR. Response should be assessed after 3 months of treatment.

For patients in whom symptoms are only partially controlled after 3 months of treatment, the dose may be increased to 30mg Sandostatin LAR every 4 weeks.

For patients in whom symptoms and biological markers are well controlled after 3 months of treatment, the dose may be reduced to 10mg Sandostatin LAR every 4 weeks.

For days when symptoms associated with gastroenteropancreatic tumours may increase during treatment with Sandostatin LAR, additional administration of s.c. Sandostatin is recommended at the dose used prior to the Sandostatin LAR treatment.

Use in patients with impaired renal function

Impaired renal function did not affect the total exposure (AUC; area under the curve) to octreotide when administered s.c. as Sandostatin. Therefore, no dose adjustment of Sandostatin LAR is necessary.

Use in patients with impaired hepatic function

In a study with Sandostatin administered s.c. and i.v. it was shown that the elimination capacity may be reduced in patients with liver cirrhosis, but not in patients with fatty liver disease. In certain cases patients with liver impairment may require dose adjustment.

Use in elderly patients

In a study with Sandostatin administered s.c., no dose adjustment was necessary in patients ≥ 65 years of age. Therefore, no dose adjustment is necessary in this group with Sandostatin LAR.

Use in children

There is very limited experience with use of Sandostatin LAR in children.


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4.3 Contraindications

Known hypersensitivity to octreotide or to any of the excipients.


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4.4 Special warnings and precautions for use

General

As GH-secreting pituitary tumours may sometimes expand, causing serious complications (eg. visual field defects), it is essential that all patients be carefully monitored. If evidence of tumour expansion appears, alternative procedures are 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 child-bearing potential should be advised to use adequate contraception if necessary during treatment with octreotide (see also section 4.6 Pregnancy and lactation).

Thyroid function (TSH and thyroid hormone levels) should be monitored in patients receiving prolonged treatment with octreotide.

Hepatic function should be monitored during octreotide therapy.

Cardiovascular related events

Uncommon cases of bradycardia have been reported. Dose adjustments of drugs such as beta-blockers, calcium channel blockers, or agents to control fluid and electrolyte balance, may be necessary.

Gallbladder and related events

The incidence of gallstone formation with Sandostatin treatment is estimated to be between 15-30%. Long term exposure to Sandostatin LAR of patients with acromegaly or gastroenteropancreatic tumours suggests that treatment with Sandostatin LAR does not increase the incidence of gallstone formation, compared with s.c. treatment. Ultrasonic examination of the gallbladder before and at about 6 monthly intervals during Sandostatin LAR therapy is however recommended. If gallstones do occur, they are usually asymptomatic; symptomatic stones should be treated either by dissolution therapy with bile acids or by surgery.

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 a state of persistent hyperglycaemia may be induced as a result of chronic administration. Hypoglycaemia has also been observed.

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 receiving Sandostatin LAR.

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 the 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.


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4.5 Interaction with other medicinal products and other forms of interaction

Octreotide has been found to reduce the intestinal absorption of cyclosporin and to delay that of 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, caution should be exercised during co-administration of octreotide and drugs mainly metabolized by CYP3A4, which have a low therapeutic index (e.g. carbamazepine, digoxin, warfarin and terfenadine).


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4.6. Pregnancy and lactation

Pregnancy

Sandostatin should only be prescribed to pregnant women under compelling circumstances (see also section 4.4 Special warnings and precautions for use).

There are no adequate and well-controlled studies in pregnant women. In the post-marketing experience, data on a limited number of exposed pregnancies have been reported in patients with acromegaly, however, in half of the cases the pregnancy outcomes are unknown. Most women were exposed to octreotide during the first trimester of pregnancy at doses ranging from 100-300 micrograms/day of Sandostatin s.c. or 20-30 mg/month of Sandostatin LAR. In approximately two-thirds of the cases with known outcome, the women elected to continue octreotide therapy during their pregnancies.

There were no cases of congenital anomalies or malformations due to octreotide usage in the cases that reported pregnancy outcomes.

Studies in animals showed transient growth retardation of offspring, possibly consequent upon the specific endocrine profiles of the species tested, but there was no evidence of foetotoxic, teratogenic or other reproduction effects.

Lactation

Patients should not breastfeed during Sandostatin treatment. It is unknown whether octreotide is excreted in human breast milk. Animal studies have shown excretion of octreotide in breast milk.


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4.7 Effects on ability to drive and use machines

No data exist on the effects of Sandostatin LAR on the ability to drive and use machines.


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4.8 Undesirable effects

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, bilary 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.

In rare instances, gastrointestinal side-effects may resemble acute intestinal obstruction, with progressive abdominal distension, severe epigastric pain, abdominal tenderness and guarding.

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.

In very rare instances, acute pancreatitis has been reported within the first hours or days of s.c. Sandostatin treatment and resolved on withdrawal of the drug. In addition, cholelithiasis-induced pancreatitis has been reported for patients on long-term s.c. Sandostatin treatment.

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 Special warnings and precautions for use).

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 trials

Endocrine disorders

 

Common:

Hypothyroidism, thyroid dysfunction (e.g., decreased TSH, decreased Total T4, and decreased Free T4).

Metabolism and nutrition disorders

 

Very common:

Common:

Uncommon:

Hyperglycaemia.

Hypoglycaemia, impaired glucose tolerance, anorexia.

Dehydration.

Cardiac disorders

 

Common:

Uncommon:

Bradycardia.

Tachycardia.

Respiratory disorders

 

Common:

Dyspnoea.

Gastrointestinal disorders

 

Very common:

Common:

Diarrhoea, abdominal pain, nausea, constipation, flatulence.

Dyspepsia, vomiting, abdominal bloating, steatorrhoea, loose stools, discolouration of faeces.

Nervous system disorders

 

Very common:

Common:

Headache.

Dizziness.

Hepatobiliary disorders

 

Very common:

Common:

Cholelithiasis.

Cholecystitis, biliary sludge, hyperbilirubinaemia.

Skin and subcutaneous tissue disorders

 

Common:

Pruritus, rash, alopecia.

General disorders and administration site

 

Very common:

Injection site localised pain.

Investigations

 

Common:

Elevated transaminase levels.

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

Immune 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.


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4.9 Overdose

A limited number of accidental overdoses of Sandostatin LAR have been reported. The doses ranged from 100mg to 163mg/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 90mg/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.


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5. Pharmacological properties

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5.1 Pharmacodynamic properties

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 GH and of peptides and serotonin produced within the gastroenteropancreatic (GEP) endocrine system.

In animals, octreotide is a more potent inhibitor of GH, glucagon and insulin release than somatostatin, 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 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 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 individual patients with GH-secreting pituitary adenoma, Sandostatin LAR was reported to lead to shrinkage of the tumour mass (prior to surgery). However, progression to surgery should not be delayed. Further tumour shrinkage cannot be expected as a feature of continued long term treatment.

For patients with functional tumours of the gastroenteropancreatic endocrine system, treatment with Sandostatin LAR provides continuous control of symptoms related to the underlying disease. The effect of octreotide in different types of gastroenteropancreatic 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 falling plasma serotonin and reduced urinary excretion of 5-hydroxyindole acetic acid.

VIPomas: The biochemical characteristics 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. 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.

Treatment of patients with 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 conservative ITT (cITT) analysis population reported by the PROMID study group (Rinke et al., 2009) 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 =0.000072; 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. 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 66 % of patients in the Sandostatin LAR group and 37 % of patients in the placebo group.

The observed TTP benefit was confirmed by a supportive post-hoc analysis performed by Novartis on the ITT analysis population based on 61 events of tumour progressions or tumour-related deaths (25, including one tumour related death, in the Sandostatin LAR arm and 36 in the placebo arm). Median TTP in this post-hoc ITT analysis was 11.3 months (95% CI, 6.7-14.3) in the Sandostatin LAR group and 5.6 months (95% CI, 3.5-6.2) in the placebo group, (HR 0.41, 95% CI, 0.24 to 0.70; p-value=0.0008). This significant delay of progression was consistently observed in the subsets according to functional status, with hazard ratios of 0.41 (95% CI, 0.18 to 0.95) and 0.41 (95% CI, 0.20 to 0.82) in functionally active and inactive tumours, respectively.

Figure 1 Kaplan-Meier estimates of TTP comparing Sandostatin LAR with placebo (conservative ITT population)

Table 1 TTP results by analysis populations

 

TTP Events

Median TTP months [95% C.I.]

HR [95% C.I.]

p-value *

Sandostatin LAR

Placebo

Sandostatin LAR

Placebo

cITT

26

40

14.3

[95% CI, 11.0 to 28.8]

6.0

[95% CI, 3.7 to 9.4]

0.34

[95% CI, 0.20 to 0.59]

P=0.000072

NVS ITT

25

36

11.3

[95% CI, 6.7 to 14.3]

5.6

[95% CI, 3.5 to 6.2]

0.41

[95% CI, 0.24 to 0.7]

P=0.0008

HR=hazard ratio; TTP=time to tumor progression; ITT=intention to treat;

cITT=conservative ITT; NVS ITT: supportive post-hoc analysis conducted by Novartis

*Logrank test stratified by functional activity

Based on the significant clinical benefit of Sandostatin LAR observed in this pre-planned interim analysis the recruitment was stopped.

The safety of Sandostatin LAR in this trial was consistent with its established safety profile.


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5.2 Pharmacokinetic properties

After single i.m. injections of Sandostatin LAR, the 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 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, reach plateau concentrations at 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, mean plateau octreotide concentrations after single doses of 10mg, 20mg and 30mg of Sandostatin LAR amount to 358ng/L, 926ng/L and 1710ng/L, respectively. Steady-state serum octreotide concentrations, reached after 3 injections at 4-week intervals, are higher by a factor of approximately 1.6 to 1.8 and amount to 1557ng/L, and 2384ng/L after multiple injections of 20mg and 30mg of Sandostatin LAR, respectively.

In patients with carcinoid tumours, the mean (and median) steady-state serum concentrations of octreotide after multiple injections of 10mg, 20mg and 30mg of Sandostatin LAR given a 4-week intervals also increase linearly with dose and were 1231 (894) ng/L, 2620 (2270) ng/L, and 3928 (3010) 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 1395 ng/l after the first injection and of 2973 ng/l at steady state. A high inter-subject variability was 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.


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5.3 Preclinical safety data

Acute toxicity

Acute toxicity studies of octreotide in mice revealed LD50 values of 72mg/kg by the i.v. route and of 470mg/kg by the s.c. route. The acute i.v. LD50 value of octreotide in rats was determined at 18mg/kg. Octreotide acetate was well tolerated by dogs receiving up to 1mg/kg body weight by i.v. bolus injection.

Repeated dose toxicity

In a repeat dose study performed in rats by i.m. injection of 2.5mg Sandostatin LAR in 50mg microspheres every 4 weeks for 21 weeks, with necropsy at 26 weeks, no drug-related necropsy findings were observed. The only histopathological findings considered to be of significance were at the injection site in treated and control animals, where the microspheres had provoked a reversible granulomatous myositis. After a single i.m. injection of Sandostatin LAR in rats and rabbits, biodegradation of microspheres was complete by day 75 after injection in both species.

Mutagenicity

Octreotide and/or its metabolites were devoid of mutagenic potential when investigated in vitro in validated bacterial and mammalian cell test systems. Increased frequencies of chromosomal changes were observed in V79 Chinese hamster cells in vitro, albeit at high and cytotoxic concentrations only. Chromosomal aberrations were however not increased in human lymphocytes incubated with octreotide acetate in vitro. In vivo, no clastogenic activity was observed in the bone marrow of mice treated with octreotide i.v. (micronucleus test) and no evidence of genotoxicity was obtained in male mice using a DNA repair assay of sperm heads. The microspheres were devoid of mutagenic potential when tested in a validated in vitro bacterial assay.

Carcinogenicity/chronic toxicity

In studies in rats in which s.c. Sandostatin at daily doses up to 1.25mg/kg body weight were administered, fibrosarcomas were observed, predominantly in a number of male animals, at the s.c. injection site after 52, 104 and 113/116 weeks. Local tumours occurred also in the control rats, however development of these tumours was attributed to disordered fibroplasia produced by sustained irritant effects at the injection sites, enhanced by the acidic lactic acid/mannitol vehicle. This non-specific tissue reaction appeared to be particular to rats.

Neoplastic lesions were observed neither in mice receiving daily s.c. injections of Sandostatin at doses up to 2mg/kg for 98 weeks, nor in dogs which were treated with daily s.c. doses of the drug for 52 weeks.

The 116-week carcinogenicity study in rats with s.c. Sandostatin also revealed uterine endometrial adenocarcinomas, their incidence reaching statistical significance at the highest s.c. dose level of 1.25mg/kg per day. The finding was associated with an increased incidence of endometritis, a decreased number of ovarian corpora lutea, a reduction in mammary adenomas and the presence of uterine glandular and luminal dilation, suggesting a state of hormonal imbalance. The available information clearly indicates that the findings of endocrine-mediated tumours in rats are species-specific and are not relevant for the use of the drug in humans.

Reproduction toxicity

Fertility as well as pre-, peri- and post-natal studies in female rats revealed no adverse effects on reproductive performance and development of the offspring, when s.c. doses up to 1mg/kg body weight per day were administered. Some retardation of the physiological growth noted in pups was transient and attributable to GH inhibition brought about by excessive pharmacodynamic activity.


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6. Pharmaceutical particulars

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6.1 List of excipients

Poly (DL-lactide-co-glycolide); mannitol.


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6.2 Incompatibilities

Sandostatin LAR microspheres for injection is to be used as a single dose container, without any dilution with other products. Therefore, no compatibility data with other products have been generated.


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6.3 Shelf life

36 months.


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6.4 Special precautions for storage

Store at 2 to 8°C, protect from light. Sandostatin LAR can remain at room temperature on the day of injection. However, the suspension must only be prepared immediately prior to i.m. injection.


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6.5 Nature and contents of container

The microspheres are packaged in 5ml glass vials (Type I, Ph Eur), with a PTFE-faced rubber stopper and sealed with an aluminium flip-off seal.


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6.6 Special precautions for disposal and other handling

Instructions for i.m. injection of Sandostatin LAR for deep intragluteal injection only

Remove the cap from vial containing Sandostatin LAR. Assure that the powder is settled at the bottom of the vial by lightly tapping the vial. Remove the cap from the vehicle syringe. Attach one of the supplied needles to the vehicle syringe.

Insert needle through centre of rubber stopper of the Sandostatin LAR vial.

Without disturbing the Sandostatin LAR powder, gently inject the vehicle into the vial by running the vehicle down the inside wall of the vial. Do not inject the vehicle directly into the powder. Withdraw any excess air present in the vial.

Do not disturb the vial until the vehicle has wetted the Sandostatin LAR powder for suspension. Once complete wetting (approximately 2-5 minutes) has occurred, the vial should be moderately swirled until a uniform suspension is achieved. Do not vigorously shake the vial.

Immediately draw 2ml of air into the syringe and re-insert the needle through the rubber stopper. Inject the 2ml of air into the vial and then, with the bevel down and the vial tipped at approximately 45 degree angle, slowly draw the entire contents of the vial containing the suspension into the syringe. Immediately change the needle (supplied).

Gently invert the syringe as needed to maintain a uniform suspension. Eliminate air from syringe and disinfect the injection site. Insert needle into right or left gluteus and draw back to ensure that no blood vessel has been penetrated. Immediately inject i.m. by deep intragluteal injection.

Sandostatin LAR must be given only by intragluteal injection, never i.v. If a blood vessel has been penetrated, select another injection site.

Special precautions for disposal

Any unused product or waste material should be disposed of in accordance with local requirements.


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7. Marketing authorisation holder

Novartis Pharmaceuticals UK Limited

(Trading as Sandoz Pharmaceuticals)

Frimley Business Park

Frimley

Camberley

Surrey

GU16 7SR

United Kingdom


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8. Marketing authorisation number(s)

Sandostatin LAR 10mg: PL 00101/0511

Sandostatin LAR 20mg: PL 00101/0512

Sandostatin LAR 30mg: PL 00101/0513


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9. Date of first authorisation/renewal of the authorisation

07 June 2007


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10. Date of revision of the text

18 April 2013


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Link to this document from your website: http://www.medicines.org.uk/emc/medicine/1321/SPC/


Active Ingredients/Generics