Adverse reactions : תופעות לוואי

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:                 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



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.
Any suspected adverse events should be reported to the Ministry of Health according to the National Regulation by using an online form https://sideeffects.health.gov.il/ Side effects can also be reported to Novartis using the following e-mail address: Safetydesk.israel@novartis.com