Novartis Pharmaceuticals UK Ltd

Thyroid function (TSH and thyroid hormone levels) should be monitored in patients receiving long-term Sandostatin therapy.

Hepatic function should be monitored during octreotide therapy.

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.  In most of the cases with known outcome, normal newborns were reported, but also several spontaneous abortions during the first trimester, and a few induced abortions.

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

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 (see section 5.3 Preclinical safety data).

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.

Octreotide Ampoules 50 mcg/ml solution for injection or concentrate for solution for infusion

Octreotide Ampoules 100 mcg/ml solution for injection or concentrate for solution for infusion

Octreotide Ampoules 500 mcg/ml solution for injection or concentrate for solution for infusion

Octreotide Multidose Vial 1mg/5ml solution for injection or concentrate for solution for infusion.

Section 4.4 Special Warnings and Precautions for Use

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General

As growth hormone 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.

Thyroid function should be monitored in patients receiving long-term Sandostatin therapy.

To:

General

As growth hormone 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 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 long-term Sandostatin therapy.

Section 4.6 Pregnancy and Lactation

Has been changed from:

Experience with octreotide in pregnant or nursing women is very limited, and they should therefore be given the drug only under compelling circumstances.

Women receiving treatment with Sandostatin should not breastfeed their infants.

To:

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.  In  most of the cases with known outcome, normal newborns were reported, but also several spontaneous abortions during the first trimester, and a few induced abortions.

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

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 (see section 5.3 Preclinical safety data).

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. 

Section 4.8 Undesirable Effects

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The main side-effects are local injection site reactions and gastrointestinal reactions.

The most commonly reported adverse reactions in clinical trials with Sandostatin administration were diarrhoea, abdominal pain, flatulence and local injection site pain or irritation.

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

Pain or a sensation of stinging, tingling or burning at the site of s.c. injection,

with redness and swelling, rarely lasting more than 15 minutes. Local discomfort may be reduced by allowing the solution to reach room temperature before injection.

The following adverse drug reactions, listed in Table 1, have been accumulated from clinical studies with octreotide and spontaneously reported adverse reactions:

Adverse reactions (Table 1) are ranked under heading of frequency, the most frequent first, using the following convention: very common (≥1/10); common (³ 1/100 to <1/10); uncommon (≥1/1,000 to ≤1/100); rare (≥1/10,000 to ≤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

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. 

Occurrence of gastrointestinal side-effects may be reduced by avoiding meals around the time of octreotide administration, that is, by injecting between meals or on retiring to bed.

In rare instances, acute pancreatitis has been reported; generally, this effect is seen within the first hours or days of Sandostatin treatment and resolves on withdrawal of the drug.  In addition, cholelithiasis-induced pancreatitis has been reported for patients on long-term Sandostatin treatment.

There have been isolated cases of biliary colic following the abrupt withdrawal of the drug in acromegalic patients in whom biliary sludge or gallstones had developed.

Post-marketing

The following adverse drug reactions have been observed during post-marketing experience.  On rare occasions thyroid dysfunction has been reported both under and over activity.  In some cases dyspepsic signs have been reported in patients receiving octreotide acetate.

Symptoms and episodes of arrhythmia have been reported in patients receiving octreotide acetate.  Other ECG changes such as QT prolongation, axis shifts, early repolarisation, low voltage, R/S transition, early R wave progression, and non-specific ST-T wave changes, have been reported during octreotide acetate therapy.  The relationship of these events to octreotide acetate is however not established because many acromegalic and carcinoid patients have underlying cardiac diseases (see section 4.4 Special warnings and precautions for use).

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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, 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.

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

Pain or a sensation of stinging, tingling or burning at the site of s.c. injection, with redness and swelling, rarely lasting more than 15 minutes. Local discomfort may be reduced by allowing the solution to reach room temperature before injection.

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. 

Occurrence of gastrointestinal side-effects may be reduced by avoiding meals around the time of octreotide administration, that is, by injecting between meals or on retiring to bed.

In rare instances, acute pancreatitis has been reported; generally, this effect is seen within the first hours or days of Sandostatin treatment and resolves on withdrawal of the drug.  In addition, cholelithiasis-induced pancreatitis has been reported for patients on long-term Sandostatin treatment.

There have been isolated cases of biliary colic following the abrupt withdrawal of the drug in acromegalic patients in whom biliary sludge or gallstones had developed.

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 (³ 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

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

10.       DATE OF (PARTIAL) REVISION OF THE TEXT

Changed from 23 Feb 09  to  05 June 2009

Section 4.9 has changed from:

4.9.      Overdose

Doses of up to 2000 microgrammes octreotide given as subcutaneous tid for several months have been well tolerated.

No life-threatening reactions have been reported after acute overdosage.  The maximum single dose so far given to an adult so far has been 1 mg by intravenous bolus injection.  The observed signs and symptoms were a brief drop in heart rate, facial flushing, abdominal cramps, diarrhoea, an empty feeling in the stomach and nausea, which resolved in 24 hours of drug administration.

One patient has been reported to have received an accidental overdosage of Sandostatin by continuous infusion (250 microgrammes per hour for forty eight hours instead of 25 microgrammes per hour).  He experienced no side-effects.

The management of overdosage is symptomatic.

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4.9.      Overdose

A limited number of accidental overdoses of Sandostatin in adults and children have been reported.  In adults, the doses ranged from 2400-6000 micrograms/day administered by continuous infusion (100-250 micrograms/hour) or subcutaneously (1500 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 50-3000 micrograms/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 3000-30,000 micrograms/day in divided doses subcutaneously.

The management of overdosage is symptomatic.

SECTION 2

The following text has been added:

Sandostatin solution for injection contains less than 1mmol (23mg) sodium per dose, i.e essentially “sodium-free”.

SECTION 3

The following text has been added:

The solution is clear and colourless.

SECTION 6.6

The following text has been added:

 
Special precautions for disposal

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

SECTION 10

Date of revision changed from 24 October 2007 to 06 May 2008