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SANDOSTATIN® LAR® SAFETY INFORMATION

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Contraindications

Known hypersensitivity to octreotide or to any of the excipients (see list of excipients).

Special warnings and precautions for use

General
Interaction with other medicinal products and other forms of interaction
Pregnancy, breastfeeding and fertility
Effects on ability to drive and use machines
Undesirable effects and adverse drug reactions
Overdose

General

As GH-secreting pituitary tumors may sometimes expand, causing serious complications (e.g., visual field defects), it is essential that all patients be carefully monitored. If evidence of tumor expansion appears, alternative procedures may be advisable.

The therapeutic benefits of a reduction in growth hormone (GH) levels and normalization 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 Pregnancy, breastfeeding and fertility).

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 Interaction with other medicinal products and other forms of interaction).

Gallbladder and related events

Octreotide inhibits secretion of cholecystokinin, resulting in reduced contractility of the gallbladder and an increased risk of sludge and stone formation. Development of gallstones has been reported in 15 to 30% of long-term recipients of s.c. Sandostatin®. The prevalence 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. 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, the state of persistent hyperglycemia may be induced as a result of chronic administration. Hypoglycemia 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 glycemia. 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 hypoglycemia. 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”.

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 Special warnings and precautions for use).

Dose adjustments of insulin and antidiabetic medicinal products may be required when Sandostatin® LAR® is administered concomitantly (see Special warnings and precautions for use).

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 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 CYP3A4 and which have a low therapeutic index (e.g., quinidine, terfenadine) should therefore be used with caution.

Pregnancy, breastfeeding and fertility

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 Preclinical safety data).

As a precautionary measure, it is preferable to avoid the use of Sandostatin® LAR® during pregnancy (see Special warnings and precautions for use).

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 breastfeed 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 Summary of Product Characteristics).

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®. 

Undesirable effects and adverse drug reactions

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 diarrhea, abdominal pain, nausea, flatulence, headache, cholelithiasis, hyperglycemia and constipation. Other commonly reported adverse reactions were dizziness, localized pain, biliary sludge, thyroid dysfunction (eg, decreased thyroid stimulating hormone [TSH], decreased total T4, and decreased free T4), loose stools, impaired glucose tolerance, vomiting, asthenia, and hypoglycemia.

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: Diarrhea, abdominal pain, nausea, constipation, flatulence.
Common: Dyspepsia, vomiting, abdominal bloating, steatorrhea, loose stools, discoloration of feces.
Nervous system disorders
Very common: Headache.
Common: Dizziness.
Endocrine disorders
Common: Hypothyroidism, thyroid dysfunction (eg, decreased TSH, decreased total T4, and decreased free T4).
Hepatobiliary disorders
Very common: Cholelithiasis.
Common: Cholecystitis, biliary sludge, hyperbilirubinemia.
Metabolism and nutrition disorders
Very common: Hyperglycemia.
Common: Hypoglycemia, 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: Dyspnea.
Cardiac disorders
Common: Bradycardia.
Uncommon: 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 

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

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.

Injection site reactions

Injection site related reactions including pain, burning, redness, hematoma, hemorrhage, pruritus or swelling 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 fecal 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

In both acromegalic and carcinoid syndrome patients, ECG changes were observed such as QT prolongation, axis shifts, early repolarization, low voltage, R/S transition, early R wave progression, and nonspecific 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 Special warnings and precautions).

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorization 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 national reporting system.

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.

List of excipients

Powder (Vial):
Poly(DL-lactide-co-glycolide)
Mannitol (E421)

Solvent (Prefilled syringe):
Carmellose sodium
Mannitol (E421)
Poloxamer 188
Water for injections

Pharmaceutical formulations may vary between countries.

Please see the Summary of Product Characteristics.