- 1. Name of the medicinal product
- 2. Qualitative and quantitative composition
- 3. Pharmaceutical form
- 4. Clinical particulars
- 4.1 Therapeutic indications
- 4.2 Posology and method of administration
- 4.3 Contraindications
- 4.4 Special warnings and precautions for use
- 4.5 Interaction with other medicinal products and other forms of interaction
- 4.6 Fertility, pregnancy and lactation
- 4.7 Effects on ability to drive and use machines
- 4.8 Undesirable effects
- 4.9 Overdose
- 5. Pharmacological properties
- 5.1 Pharmacodynamic properties
- 5.2 Pharmacokinetic properties
- 5.3 Preclinical safety data
- 6. Pharmaceutical particulars
- 6.1 List of excipients
- 6.2 Incompatibilities
- 6.3 Shelf life
- 6.4 Special precautions for storage
- 6.5 Nature and contents of container
- 6.6 Special precautions for disposal and other handling
- 7. Marketing authorisation holder
- 8. Marketing authorisation number(s)
- 9. Date of first authorisation/renewal of the authorisation
- 10. Date of revision of the text
- Legal category
Excipients with known effectContains less than 1 mmol (23 mg) sodium per dose, i.e is essentially sodium-free.For the full list of excipients, see section 6.1.
AcromegalyIt is recommended to start treatment with the administration of 20 mg Sandostatin LAR at 4-week intervals for 3 months. Patients on treatment with s.c. Sandostatin can start treatment with Sandostatin LAR 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 1/somatomedin C (IGF-1) concentrations and clinical symptoms.For patients in whom, within this 3-month period, clinical symptoms and biochemical parameters (GH; IGF-1) are not fully controlled (GH concentrations still above 2.5 microgram/L), the dose may be increased to 30 mg every 4 weeks. If after 3 months, GH, IGF-1, and/or symptoms are not adequately controlled at a dose of 30 mg, the dose may be increased to 40 mg every 4 weeks.For patients whose GH concentrations are consistently below 1 microgram/L, whose IGF-1 serum concentrations normalised, and in whom most reversible signs/symptoms of acromegaly have disappeared after 3 months of treatment with 20 mg, 10 mg Sandostatin LAR may be administered every 4 weeks. However, particularly in this group of patients, it is recommended to closely monitor adequate control of serum GH and IGF-1 concentrations, and clinical signs/symptoms at this low dose of Sandostatin LAR.For patients on a stable dose of Sandostatin LAR, assessment of GH and IGF-1 should be made every 6 months.
Gastro-entero-pancreatic endocrine tumours
Treatment of patients with symptoms associated with functional gastro-entero-pancreatic neuroendocrine tumoursIt is recommended to start treatment with the administration of 20 mg Sandostatin LAR at 4-week intervals. Patients on treatment with s.c. Sandostatin should continue at the previously effective dosage for 2 weeks after the first injection of Sandostatin LAR.For patients in whom symptoms and biological markers are well controlled after 3 months of treatment, the dose may be reduced to 10 mg Sandostatin LAR every 4 weeks.For patients in whom symptoms are only partially controlled after 3 months of treatment, the dose may be increased to 30 mg Sandostatin LAR every 4 weeks.For days when symptoms associated with gastro-entero-pancreatic 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. This may occur mainly in the first 2 months of treatment until therapeutic concentrations of octreotide are reached.
Treatment of patients with advanced neuroendocrine tumours of the midgut or of unknown primary origin where non-midgut sites of origin have been excludedThe recommended dose of Sandostatin LAR is 30 mg administered every 4 weeks (see section 5.1). Treatment with Sandostatin LAR for tumour control should be continued in the absence of tumour progression.
Treatment of TSH-secreting adenomasTreatment with Sandostatin LAR should be started at a dose of 20 mg at 4-weekly intervals for 3 months before considering dose adjustment. The dose is then adjusted on the basis of the TSH and thyroid hormone response.
Use in patients with impaired renal functionImpaired renal function did not affect the total exposure (AUC) to octreotide when administered s.c. as Sandostatin. Therefore, no dose adjustment of Sandostatin LAR is necessary.
Use in patients with impaired hepatic functionIn 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 impaired hepatic function may require dose adjustment.
Use in the elderlyIn a study with Sandostatin administered s.c., no dose adjustment was necessary in subjects ≥ 65 years of age. Therefore, no dose adjustment is necessary in this group of patients with Sandostatin LAR.
Use in childrenThere is limited experience with the use of Sandostatin LAR in children.
Method of administrationSandostatin LAR may only be administered by deep intramuscular injection. The site of repeat intramuscular injections should be alternated between the left and right gluteal muscle (see section 6.6).
GeneralAs 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 eventsCommon 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 eventsOctreotide 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 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 metabolismBecause 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.
NutritionOctreotide 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 contentSandostatin LAR contains less than 1 mmol (23 mg) sodium per dose, i.e is essentially sodium-free.
PregnancyThere 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 post-marketing 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).
BreastfeedingIt 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.
FertilityIt 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).
Summary of the safety profileThe 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 reactionsThe 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
|Very common:||Diarrhoea, abdominal pain, nausea, constipation, flatulence.|
|Common:||Dyspepsia, vomiting, abdominal bloating, steatorrhoea, loose stools, discolouration of faeces.|
|Nervous system disorders|
|Common:||Hypothyroidism, thyroid dysfunction (e.g., decreased TSH, decreased total T4, and decreased free T4).|
|Common:||Cholecystitis, biliary sludge, hyperbilirubinaemia.|
|Metabolism and nutrition disorders|
|Common:||Hypoglycaemia, impaired glucose tolerance, anorexia.|
|General disorders and administration site conditions|
|Very common:||Injection site reactions.|
|Common:||Elevated transaminase levels.|
|Skin and subcutaneous tissue disorders|
|Common:||Pruritus, rash, alopecia.|
Post-marketingSpontaneously 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|
|Acute pancreatitis, acute hepatitis without cholestasis, cholestatic hepatitis, cholestasis, jaundice, cholestatic jaundice.|
|Increased alkaline phosphatase levels, increased gamma glutamyl transferase levels.|
Description of selected adverse reactions
Gastrointestinal disordersIn 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 reactionsInjection site related reactions including pain, burning, redness, haematoma, haemorrhage, 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 disordersAlthough 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 enzymesIn 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 disordersIn 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).
Reporting of suspected adverse reactionsReporting 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.
Carcinoid tumoursAdministration 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.
VIPomasThe 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.
GlucagonomasAdministration 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 syndromeTherapy 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.
InsulinomasAdministration 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 excludedA 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||Median TTP months [95% C.I.]||HR [95% C.I.] p-value *|
|Sandostatin LAR||Placebo||Sandostatin LAR||Placebo|
|ITT||26||41||NR||NR||0.32 [95% CI, 0.19 to 0.55] P=0.000015|
|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|
|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 of TSH-secreting pituitary adenomasSandostatin 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.
Included in the injection kit:a. One vial containing Sandostatin LAR powder,b. One prefilled syringe containing the vehicle solution for reconstitution,c. One vial adapter for drug product reconstitution,d. 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 • 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.• If immediate administration is delayed, gently re-shake the syringe to ensure a milky uniform suspension • Prepare injection site with an alcohol wipe. • Pull the protective cover straight off the needle. • Gently tap the syringe to remove any visible bubbles and expel them from the syringe. • 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 deep intramuscular injection, NEVER intravenously. • Insert the needle fully into the left or right gluteus at a 90° 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).|
|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).|
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