Sandostatin LAR

Sandostatin LAR

octreotide

Manufacturer:

Novartis

Distributor:

Zuellig
/
Four Star
Full Prescribing Info
Contents
Octreotide acetate.
Description
Each vial contains octreotide microspheres free peptide 10, 20 or 30 mg nominally 4.15% of fill weight equivalent to 4.65% of octreotide acetate. It also contains poly (DL-lactide-co-glycolide) 78.35% of nominal fill weight; sterile mannitol 17% of nominal fill weight.
Without Vial Adapter/Safety Needle: One pre-filled syringe (solvent for parenteral use) containing sodium carboxymethylcellulose 12.5 mg, mannitol 15 mg and water for injection 2.5 mL plus 2 needles [40 mm (1.5 inch), 20 gauge].
With Vial Adapter and Safety Needle: One pre-filled syringe (solvent for parenteral use) containing sodium carbosymethylcellulose 14 mg, mannitol 12 mg, poloxamer 188 4 mg and water for injections.
Sandostatin LAR is a long-acting depot injection form of octreotide. Microspheres to be suspended in a vehicle immediately prior to IM injection.
Sandostatin LAR suspension contains <1 mmol (23 mg) of sodium per dose ie, essentially sodium-free.
Action
Anti-growth hormone.
Pharmacology: Pharmacodynamics: 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 hypoglycemia; postprandial 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 (ie, 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 eg, headache, perspiration, paraesthesia, fatigue, osteoarthralgia and carpal tunnel syndrome. In previously untreated acromegaly patients with GH-secreting pituitary adenoma, Sandostatin LAR treatment resulted in a tumor volume reduction of >20% in a significant proportion (50%) of patients.
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 fall in 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 eg, hypokalaemia, enabling enteral and parenteral fluid and electrolyte supplementation to be withdrawn. In some patients, computer 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.
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 as 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 of plasma glucagon levels, this decrease is generally not maintained over a prolonged period of administration, despite continued symptomatic improvement.
Gastrinomas/Zollinger-Ellison Syndrome: Although therapy with proton pump inhibitors or H2-receptor-blocking agents controls the recurrent peptic ulceration which results from chronic gastrin-stimulated hypersecretion of gastric acid, such control may be incomplete. Diarrhoea may also be a prominent symptom not alleviated in all patients by this therapy. Octreotide alone or in conjunction with proton pump inhibitors or H2-receptor antagonists may reduce gastric acid hypersecretion and improve symptoms, including diarrhoea. Other symptoms possibly due to peptide production by the tumour eg, flushing, may also be relieved. Plasma gastrin levels fall in some patients.
Insulinomas: Administration of octreotide produces a fall in circulating immunoreactive insulin. In patients with operable tumours, octreotide may help to restore and maintain normoglycaemia preoperatively. In patients with inoperative benign or malignant tumours, glycaemic control may be improved even without concomitant sustained reduction in circulating insulin levels.
GRFomas: These rare tumours are characterised by production of GH-releasing factor (GRF) alone or in conjunction with other active peptides. Octreotide produces improvement in the features and symptoms of the resultant acromegaly. This is probably due to inhibition of GRF and GH secretion, and a reduction in pituitary enlargement may follow.
Advanced Neuroendocrine Tumors of the Midgut or Unknown Primary Tumor Location: A phase III, randomized, double-blind, placebo-controlled study (PROMID) demonstrated that Sandostatin LAR inhibits tumor growth in patients with advanced neuroendocrine tumors of the midgut.
85 patients were randomized to receive Sandostatin LAR 30 mg every 4 weeks (n = 42) or placebo (n = 43) for 18 months, or until tumor progression or death.
Main inclusion criteria were: Treatment naive; histologically confirmed; locally inoperable or metastatic well-differentiated; functionally active or inactive neuroendocrine tumors/carcinomas; with primary tumor 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 tumor progression or tumor-related death (TTP).
In the intent-to-treat analysis population (ITT) (all randomized patients), 26 and 41 progressions or tumor-related deaths were seen in the Sandostatin LAR and placebo groups, respectively (HR = 0.32; 95% CI, 0.19-0.55; p-value =.000015).
In the conservative ITT (cITT) analysis population in which 3 patients were censored at randomization, 26 and 40 progressions or tumor-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 tumor progression was 14.3 months (95% CI, 11 to 28.8 months) in the Sandostatin LAR group and 6 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, tumor progression or tumor-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). (See figure and table.)

Click on icon to see table/diagram/image


Click on icon to see table/diagram/image

Treatment effect was similar in patients with functionally active (HR = 0.23; 95% CI, 0.09-0.57) and inactive tumors (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.
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.
Pharmacokinetics: After single IM injection of Sandostatin LAR, the serum octreotide concentration reaches a transient initial peak within 1 hr after administration, followed by a progressive decrease to a low undetectable octreotide level within 24 hrs. After this initial peak on day 1, octreotide remains at subtherapeutic levels in the majority of the patients in the following 7 days. Thereafter, octreotide concentrations increase again and reach plateau concentrations around day 14 and remain relatively constant during the following 3-4 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, plateau octreotide concentrations after single doses of 10, 20 and 30 mg Sandostatin LAR amount to 358, 926 and 1710 ng/L, respectively. Steady-state octreotide serum concentrations, reached after 3 injections at 4-week intervals, are higher by a factor of approximately 1.6-1.8 and amount to 1557 and 2384 ng/L after multiple injections of 20 and 30 mg Sandostatin LAR, respectively.
In patients with carcinoid tumours, the mean (and median) steady-state serum concentrations of octreotide after multiple injections of 10, 20 and 30 mg of Sandostatin LAR given at 4-week intervals also increased linearly with dose and were 1231 (894), 2620 (2270) 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 SC 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.
Toxicology: Preclinical Safety Data: Acute Toxicity: Acute toxicity studies of octreotide in mice revealed LD50 values of 72 mg/kg by the IV route and of 470 mg/kg by the SC route. The acute IV LD50 value of octreotide in rats was determined at 18 mg/kg. Octreotide acetate was well tolerated by dogs receiving up to 1 mg/kg BW by IV bolus injection.
Repeat-Dose Toxicity: In a repeat-dose study performed in rats by IM injection of 2.5 mg Sandostatin LAR in 50-mg 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 IM 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 IV (micronucleus test) and no evidence of genotoxicity was obtained in male mice using a DNA repair assay on 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 SC Sandostatin at daily doses up to 1.25 mg/kg body weight were administered, fibrosarcomas were observed, predominantly in a number of male animals, at the SC injection site after 52, 104 and 113/116 weeks. Local tumours also occurred 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 nonspecific tissue reaction appeared to be particular to rats.
Neoplastic lesions were observed neither in mice receiving daily SC injections of Sandostatin at doses up to 2 mg/kg for 98 weeks, nor in dogs which were treated with daily SC doses of the drug for 52 weeks.
The 116 week carcinogenicity study in rats with SC Sandostatin also revealed uterine endometrial adenocarcinomas, their incidence reaching statistical significance at the highest SC dose level of 1.25 mg/kg/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 postnatal studies in female rats revealed no adverse effects on reproductive performance and development of the offspring, when SC doses of up to 1 mg/kg body weight/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.
Indications/Uses
Treatment of patients with acromegaly who are adequately controlled on SC treatment with Sandostatin; patients in whom surgery, radiotherapy or dopamine agonist treatment is inappropriate or ineffective, or in the interim period until radiotherapy becomes fully effective (see Dosage & Administration).
Treatment of patients with symptoms associated with functional gastroenteropancreatic endocrine tumours in whom symptoms are adequately controlled on SC treatment with Sandostatin: Carcinoid tumours with features of the carcinoid syndrome; VIPomas; glucagonomas; gastrinomas/Zollinger-Ellison syndrome; insulinomas, for preoperative control of hypoglycaemia and for maintenance therapy; and GRFomas.
Treatment of patients with advanced neuroendocrine tumors of the midgut; or of unknown primary where non-midgut sites of origin have been excluded. Currently data does not support the use of Sandostatin as antitumor therapy in patients with pancreatic neuroendocrine tumours.
Dosage/Direction for Use
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 Instructions for IM Injection of Sandostatin LAR).
Acromegaly: For patients who are adequately controlled with SC Sandostatin, it is recommended to start treatment with the administration of 20 mg Sandostatin LAR at 4-week intervals for 3 months. Treatment with Sandostatin LAR can be started the day after the last dose of SC Sandostatin. Subsequent dosage adjustment should be based on serum growth hormone (GH) and insulin-like growth factor I/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 >2.5 mcg/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 <1 mcg/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.
For patients in whom surgery or radiotherapy is inappropriate or ineffective, or in the interim period until radiotherapy becomes fully effective, a short test dosing period of SC administration of Sandostatin is recommended to assess the response and systemic tolerability of octreotide prior to initiating treatment with Sandostatin LAR as described previously.
Gastroenteropancreatic Endocrine Tumours: Symptoms Associated with Functional Gastroenteropancreatic Neuroendocrine Tumors: For patients in whom symptoms are adequately controlled with SC Sandostatin, it is recommended to start treatment with the administration of Sandostatin LAR 20 mg at 4-week intervals. The treatment with SC Sandostatin should be continued at the previously effective dosage for 2 weeks after the 1st injection of Sandostatin LAR.
For patients who were not previously treated with SC Sandostatin, it is recommended to start with the administration of SC Sandostatin at a dosage of 0.1 mg 3 times daily for a short period (approximately 2 weeks) to assess the response and systemic tolerability of octreotide before initiating the treatment with Sandostatin LAR as described previously.
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 gastroenteropancreatic tumours may increase during treatment with Sandostatin LAR, additional administration of SC 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.
Advanced Neuroendocrine Tumors of the Midgut or Unknown Primary Tumor Location: The recommended dose of Sandostatin LAR is 30 mg administered every 4 weeks (see Actions: Pharmacodynamics). Treatment with Sandostatin LAR for tumor control should be continued in the absence of tumor progression.
Patients with Impaired Renal Function: Impaired renal function did not affect the total exposure (AUC) to octreotide when administered SC as Sandostatin. Therefore, no dose adjustment of Sandostatin LAR is necessary.
Patients with Impaired Hepatic Function: In a study with Sandostatin administered SC and IV, it was shown that the elimination capacity may be reduced in patients with liver cirrhosis, but not in patients with fatty liver disease. Due to the wide therapeutic window of octreotide, no dose adjustment of Sandostatin LAR is necessary in patients with liver cirrhosis.
Elderly: In a study with Sandostatin administered SC, no dose adjustment was necessary in patients ≥65 years. Therefore, no dosage adjustment is necessary in this group of patients with Sandostatin LAR.
Overdosage
A limited number of accidental overdoses of Sandostatin LAR have been reported. The doses ranged from 100-163 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.
Contraindications
Hypersensitivity to octreotide or any of the components of Sandostatin LAR.
Special Precautions
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 normalization 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 Use in pregnancy & lactations).
Thyroid function should be monitored in patients receiving prolonged treatment with octreotide.
Cardiovascular Related Events: Uncommon cases of bradycardia have been reported. Dose adjustments of drugs eg, β-blockers, calcium-channel blockers, or agents to control fluid and electrolyte balance, may be necessary.
Gallbladder and Related Events: Development of gallstones has been reported in 15-30% of long-term recipients of SC Sandostatin. The prevalence in the general population (aged 40-60 years) is about 5-20%. 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 SC 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 SC Sandostatin, in some instances, a state of persistent hyperglycemia may be induced as a result of chronic administration.
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 SC 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.
Guidelines for the Management of Patients During Sandostatin LAR Treatment with Respect to the Development of Gallstones: Patients should undergo a baseline ultrasound examination of the gallbladder prior to commencing octreotide treatment.
Periodic repeat ultrasound examination of the gallbladder should be performed, preferably at about 6-month intervals, throughout Sandostatin LAR treatment.
If stones are already present before the start of therapy, the potential benefit of Sandostatin LAR should be assessed against the potential risk associated with the gallstones. There is no evidence at present that Sandostatin LAR adversely affects the course or prognosis of preexisting gallstones.
Management of Patients Who Develop Gallstones in Association with Sandostatin LAR: Asymptomatic Gallstones: Sandostatin LAR may be continued depending on re-assessment of the benefit/risk ratio. Either way, no action is required except to continue monitoring with increased frequency if this is considered necessary.
Symptomatic Gallstones: Sandostatin LAR may be either stopped or continued depending on re-assessment of the benefit/risk ratio. Either way, the gallstones should be treated like any other symptomatic gallstones. Medically, this includes combined bile acid therapy (eg, chenodeoxycholic acid [CDCA] 7.5 mg/kg/day together with ursodeoxycholic acid [UDCA] 7.5 mg/kg/day) associated with ultrasound monitoring until the stones have completely disappeared.
Effects on the Ability to Drive or Operate Machinery: No data exist on the effects of Sandostatin LAR on the ability to drive and use machines.
Use in children: There is very limited experience with the use of Sandostatin LAR in children.
Use In Pregnancy & Lactation
Pregnancy: 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 1st trimester of pregnancy at doses ranging from 100-300 mcg/day of Sandostatin SC or 20-30 mg/month of Sandostatin LAR. In approximately ⅔ 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 1st 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/fetal development, parturition or postnatal development apart from some transient retardation of physiological growth (see Pharmacology: Toxicology under Actions).
Sandostatin should only be prescribed to pregnant women under compelling circumstances (see Precautions).
Lactation: 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 treatment.
Adverse Reactions
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.
In rare instances, gastrointestinal side effects may resemble acute intestinal obstruction, with progressive abdominal distension, severe epigastric pain, abdominal tenderness and guarding.
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.
In very rare instances, acute pancreatitis has been reported within the 1st hours or days of Sandostatin SC treatment and resolved on withdrawal of the drug. In addition, cholelithiasis-induced pancreatitis has been reported for patients on long-term Sandostatin SC treatment.
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 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 Precautions).
The following adverse drug reactions, have been accumulated from clinical studies with octreotide:
Adverse drug reactions 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.
Gastrointestinal Disorders: Very common: Diarrhea, abdominal pain, nausea, constipation, flatulence. Common: Dyspepsia, vomiting, abdominal bloating, steatorrhoea, loose stools, discoloration of faeces.
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: Very common: Injection site localized pain.
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 are reported voluntarily and it is not always possible to reliably establish frequency or a causal relationship to drug exposure.
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.
Drug Interactions
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 P-450 enzymes, which may be due to 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 (eg, quinidine, terfenadine) should therefore be used with caution.
Incompatibilities: Sandostatin LAR 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.
Caution For Usage
Instructions for intramuscular injection of Sandostatin LAR without vial adapter/safety needle:
Follow the instructions carefully to ensure complete saturation of the powder and its uniform suspension before intramuscular (IM) injection.
Sandostatin LAR suspension must only be prepared immediately before administration. Sandostatin LAR should only be administered by a trained health professional.
Allow the Sandostatin LAR vial and the vehicle syringe to reach room temperature.
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.
Disinfect the rubber stopper of the vial with an alcohol swab. Insert the needle through the centre of the rubber stopper of the Sandostatin LAR vial.
Without disturbing the Sandostatin LAR powder, gently inject all 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 the needle from the vial.
Do not disturb the vial until the vehicle has totally wetted the Sandostatin LAR powder (between 2-5 min). Without inverting the vial check the powder on the walls and bottom of the vial. If dry spots exist, allow undisturbed wetting to continue. At this stage, prepare the patient for injection.
Once complete wetting has occurred, the vial should be moderately swirled for about 30-60 seconds until a uniform milky suspension is achieved. Do not vigorously shake the vial as this may cause the suspension to flocculate, making it unusable.
Immediately re-insert the needle through the rubber stopper and then, with the bevel down and the vial tipped at approximately 45  degree angle, slowly draw the contents of the vial into the syringe. Do not invert the vial when filling the syringe as this may affect the amount withdrawn.
It is normal for a small amount of suspension to remain on the walls and bottom of the vial. This is a calculated overfill.
Immediately change the needle (supplied).
Administration must occur immediately after the suspension has been prepared. Gently invert the syringe as needed to maintain a uniform suspension. Eliminate air from syringe.
Disinfect the injection site with an alcohol swab.
Insert needle into right or left gluteus and draw back to ensure that no blood vessel has been penetrated. Inject slowly IM by deep intragluteal injection with steady pressure. If the needle blocks, attach a new needle of the same diameter (1.1 mm, 19 gauge).
Sandostatin LAR must be given only by deep intragluteal injection, never intravenously If a blood vessel has been penetrated, attach a new needle and select another injection site.
Instructions for Intramuscular Injection of Sandostatin LAR with Vial Adapter/Safety Needle:
Step 1. Take the Sandostatin LAR injection kit out of the refrigerated storage in order to ensure it reaches room temperature. Plan approximately 30-60 min for acclimatization but do not exceed 24 hrs.
Wash your hands with soap and hot water. Place the package on a clean and flat surface. Peel off the lid film from the blister tray containing the injection kit.
Take the vial containing the Sandostatin LAR powder and detach the flip off cap.
Step 2. Clean the rubber stopper of the vial with an alcohol swab.
Note: Do not touch the rubber stopper after it has been cleaned.
Peel off the lid film of the blister tray containing the vial adapter. Do not remove the vial adapter from the blister tray.
Holding the blister tray, position the vial adapter on top of the vial and push it fully down so that it snaps in place onto the vial, confirmed by an audible “click”.
Hold the blister tray by the top and with a vertical movement lift the blister tray off the vial adapter.
Step 3. Pull-off the cap from the prefilled syringe containing the vehicle solution and screw the syringe onto the vial adapter.
Slowly push the plunger all the way down to transfer all the vehicle solution in the vial.
Step 4. Let the vial stand until the vehicle has wetted the powder (between 2-5 min). At this stage, prepare the patient for injection.
Note: It is normal if the plunger rod moves up as there might be a slight overpressure in the vial.
Step 5. After the wetting period, press the plunger all the way back in the syringe.
Keep the plunger pressed and shake the vial moderately in a horizontal direction for about 30 seconds.
Check visually that the powder is completely suspended in the vehicle (uniform milky suspension). Repeat shaking for further 30 seconds if the powder is not completely suspended.
Step 6. Turn syringe and vial upside down, slowly pull the plunger out and draw the entire content from the vial into the syringe.
Unscrew the syringe from the vial adapter.
Administration must occur immediately after reconstitution.
Step 7. Screw the safety injection needle onto the syringe.
Pull the protective cover straight off the needle.
Gently invert the syringe to maintain a uniform suspension.
Gently tap the syringe to remove any visible bubbles and expel them from the syringe.
The reconstituted Sandostatin LAR is now ready for immediate administration.
Step 8. Sandostatin LAR must be given only by deep intragluteal injection, never IV.
Clean the injection site with an alcohol swab.
Insert the needle fully into the right or left gluteus.
Slowly draw back the plunger rod to check that no blood vessel has been penetrated, otherwise change the needle position.
Using a steady pressure, slowly depress the plunger rod to inject the entire dose. After completing the injection, 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, using a single handed technique:
Either by pressing the hinged section of the safety guard down onto a rigid surface; eg, table or by pushing the hinge forward with your forefinger making sure always to keep all fingers behind the needle tip.
An audible "click" confirms the proper activation of the safety mechanism.
Dispose of the vial and the syringe with needle immediately in a sharps container or other rigid closed disposal container.
Special precautions for disposal: Any unused product or waste material should be disposed of in accordance with local requirements.
Note: Sandostatin LAR must be kept out of the reach and sight of children.
Storage
Store at 2-8°C (in a refrigerator). Keep the vial in the outer carton in order to protect it from light. Sandostatin LAR can remain below 25°C on the day of injection. However, the suspension must only be prepared immediately prior to IM injection.
Shelf-Life: 24 months.
ATC Classification
H01CB02 - octreotide ; Belongs to the class of antigrowth hormone. Used in hypothalamic hormone preparations.
Presentation/Packing
Powd for inj (vial, without vial adapter: white to off-white powder clear; colourless solution; with vial adapter: white to white with yellowish tint powder; clear, colourless to slightly yellow or brown solution) 10 mg x 1's. 20 mg x 1's. 30 mg x 1's.
Exclusive offer for doctors
Register for a MIMS account and receive free medical publications worth $768 a year.
Sign up for free
Already a member? Sign in