Sandostatin/Sandostatin LAR

Sandostatin/Sandostatin LAR

octreotide

Manufacturer:

Novartis

Distributor:

Zuellig Pharma
Full Prescribing Info
Contents
Octreotide acetate.
Description
Sandostatin: Each Sandostatin ampoule also contains lactic acid, mannitol, sodium hydrogen carbonate and water for injection.
Each Sandostatin multidose vial also contains the following excipients: Lactic acid, phenol, mannitol, sodium hydrogen carbonate and water for injection.
Sandostatin LAR: Sandostatin LAR contains octreotide free peptide 20 or 30 mg nominally 4.15% of fill weight equivalent to 4.65% of octreotide acetate. Each Sandostatin LAR vial also contains the following excipients: Poly (DL-lactide-co-glycolide) 78.35% of nominal fill weight and sterile mannitol 17% of nominal fill weight.
Each Sandostatin LAR pre-filled syringe (solvent for parenteral use) contains sodium carboxymethylcellulose 12.5 mg, mannitol 15 mg and water for injection to make 2.5 mL.
Sandostatin LAR is a long-acting depot injection form of octreotide. Microspheres to be suspended in a vehicle immediately prior to IM injection.
Action
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 growth hormone (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 has been shown to inhibit release of GH stimulated by arginine, exercise-induced and insulin-induced hypoglycaemia; 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 secretion preferentially over insulin and its administration is not followed by rebound hypersecretion of hormones (ie, GH in patients with acromegaly).
Acromegalic Patients: Sandostatin lowers plasma levels of GH and insulin-like growth factor 1/somatomedin C (IGF-1). A GH reduction by ≥50% occurs in up to 90% patients and a reduction of serum GH to <5 ng/mL can be achieved in about half of the cases. In most patients, Sandostatin markedly reduces the clinical symptoms of the disease eg, headache, skin and soft tissue swelling, hyperhidrosis, arthralgia and paraesthesia. In patients with a large pituitary adenoma, Sandostatin treatment may result in some shrinkage of the tumour mass.
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 tumour volume reduction of >20% in a significant proportion (50%) of patients.
In patients with functional tumours of the GEP endocrine system, Sandostatin, because of its diverse endocrine effects, modifies a number of clinical features. Clinical improvement and symptomatic benefit occur in patients who still have symptoms related to their tumours despite previous therapies, which may include surgery, hepatic artery embolization and various chemotherapies eg, streptozotocin and 5-fluorouracil.
For patients with functional tumours of the GEP endocrine system, treatment with Sandostatin LAR provides continuous control of symptoms related to the underlying disease.
Effects of Sandostatin/Sandostatin LAR in the different tumour types of GEP tumours are as follows: Carcinoid Tumours: Administration of Sandostatin/Sandostatin LAR 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 characteristic of these tumours is overproduction of vasoactive intestinal peptide (VIP). In most cases, administration of Sandostatin/Sandostatin LAR 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 Sandostatin/Sandostatin LAR 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 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, which may, however, be of short duration (about 2 hrs). In patients with operable tumours, octreotide may help to restore and maintain normoglycaemia preoperatively. In patients with inoperable 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.
Sandostatin: In patients with acquired immune deficiency syndrome (AIDS)-related refractory diarrhoea, Sandostatin produces partial or complete control of stool output in about 1/3 of patients with diarrhoea unresponsive to conventional anti-infective and/or antidiarrhoeal agents.
For patients undergoing pancreatic surgery, the peri- and postoperative administration of Sandostatin reduces the incidence of typical postoperative complications (eg, pancreatic fistula, abscess and subsequent sepsis, postoperative acute pancreatitis).
In patients presenting with bleeding gastroesophageal varices due to underlying cirrhosis, Sandostatin administration in combination with specific treatment (eg, sclerotherapy) is associated with better control of bleeding and early rebleeding, reduced transfusion requirements and improved 5-day survival. While the precise mode of action of Sandostatin is not fully elucidated, it is postulated that Sandostatin reduces splanchnic blood flow through inhibition of vasoactive hormones (eg, VIP, glucagon).
Pharmacokinetics: Sandostatin: Absorption: After SC injection, Sandostatin is rapidly and completely absorbed. Peak plasma concentrations are reached within 30 min.
Distribution: The volume of distribution is 0.27 L/kg and the total body clearance 160 mL/min. Plasma protein-binding amounts to 65%. The amount of Sandostatin bound to blood cells is negligible.
Elimination: The elimination half-life after SC administration is 100 min. After IV injection, the elimination is biphasic, with half-lives of 10 and 90 min, respectively. Most of the peptide is eliminated via the faeces, while approximately 32% is excreted unchanged into the urine.
Special Patient Population: Impaired renal function did not affect the total exposure (AUC) to octreotide administered as SC injection.
The elimination capacity may be reduced in patients with liver cirrhosis but not in patients with fatty liver disease.
Sandostatin LAR: After single IM injections 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 for 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 Sandostatin LAR 10, 20 and 30 mg 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 Sandostatin LAR 20 and 30 mg, respectively.
In patients with carcinoid tumours, the mean (and median) steady-state serum concentrations of octreotide after multiple injections of Sandostatin LAR 10, 20 and 30 mg 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 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 body weight by IV bolus injection.
Repeat-Dose Toxicity: Sandostatin: A 26-week IV toxicity study in dogs carried out at dose levels of up to 0.5 mg/kg twice daily revealed progressive changes in acidophil prolactin-containing cells in the pituitary. Further investigations showed this to be within physiological range, apparently without relationship to the exogenously administered somatostatin. There were no significant alterations in plasma hormone levels. Female Rhesus monkeys receiving the same dose level of 0.5 mg/kg twice daily for 3 weeks failed to reveal pituitary changes, and there were no alterations of basal levels of plasma GH, prolactin or glucose.
Whereas the acidic vehicle produced inflammation and fibroplasia upon repeated SC injection in rats, there was no evidence that octreotide acetate causes delayed type hypersensitivity reactions when injected intradermally in guinea pigs in 0.1% solution in 0.9% sterile saline.
Sandostatin LAR: In a repeat-dose study performed in rats by IM injection of Sandostatin LAR 2.5 mg 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 clinical 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, biodegration of microspheres was complete by day 75 after injection in both species.
Carcinogenicity, Mutagenicity & Impairment of Fertility: In rats receiving octreotide acetate at daily doses up to 1.25 mg/kg body weight, fibrosarcomas were observed, predominantly in a number of male animals, at the SC injection site after 52, 104 and 113/116 weeks. Local tumours occurred also 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 octreotide at doses up to 2 mg/kg for 98 weeks, nor in dogs which were treated with daily SC doses of octreotide for 52 weeks.
The 116-week carcinogenicity study in rats with SC octreotide 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 octreotide in humans.
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 IV octreotide (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.
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/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
Sandostatin: Symptomatic control and reduction of growth hormone (GH) and insulin-like growth factor 1/somatomedin C (IGF-1) plasma levels in patients with acromegaly who are inadequately controlled by surgery or radiotherapy. Sandostatin treatment is also indicated for acromegalic patients unfit or unwilling to undergo surgery, or in the interim period until radiotherapy becomes fully effective.
Relief of symptoms associated with functional gastroenteropancreatic (GEP) endocrine tumours: Carcinoid tumours with features of the carcinoid syndrome; VIPomas; glucagonomas; gastrinomas/Zollinger-Ellison syndrome, usually in conjunction with proton-pump inhibitors or H2-antagonist therapy; insulinomas, for preoperative control of hypoglycaemia and for maintenance therapy; GRFomas.
Sandostatin is not an antitumour therapy and is not curative in these patients.
Control of refractory diarrhoea associated with AIDS.
Prevention of complications following pancreatic surgery.
Emergency management to stop bleeding and to protect from rebleeding owing to gastroesophageal varices in patients with cirrhosis. Sandostatin is to be used in association with specific treatment eg, endoscopic sclerotherapy.
Sandostatin LAR: Treatment of patients with acromegaly who are adequately controlled on SC treatment with Sandostatin; in whom surgery or radiotherapy 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 (GEP) 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; GRFomas.
Treatment of patients with advanced neuroendocrine tumour of the midgut or unknown primary tumour location.
Dosage/Direction for Use
Sandostatin: Acromegaly: Initially, 0.05-0.1 mg by SC injection every 8 or 12 hrs. Dosage adjustment should be based on monthly assessment of GH and IGF-1 levels (target: GH <2.5 ng/mL; IGF-1 within normal range), and clinical symptoms and on tolerability. In most patients, the optimal daily dose will be 0.3 mg. A maximum dose of 1.5 mg/day should not be exceeded. For patients on a stable dose of Sandostatin, assessment of GH should be made every 6 months.
If no relevant reduction of GH levels and no improvement of clinical symptoms have been achieved within 3 months of starting treatment with Sandostatin, therapy should be discontinued.
Gastroenteropancreatic (GEP) Endocrine Tumours: Initially, 0.05 mg once or twice daily by SC injection. Depending on clinical response, effect on levels of tumour-produced hormones (in cases of carcinoid tumours, on the urinary excretion of 5-hydroxyindole-acetic acid) and on tolerability, dosage can be gradually increased to 0.1-0.2 mg 3 times daily. Under exceptional circumstances, higher doses may be required. Maintenance doses have to be adjusted individually.
In carcinoid tumours, if there is no beneficial response within 1 week of treatment with Sandostatin at the maximum tolerated dose, therapy should not be continued.
AIDS-Related Refractory Diarrhoea: The data suggest that 0.1 mg 3 times daily by SC injection is the optimal starting dose. If diarrhoea is not controlled after 1 week of treatment, the dose should be titrated on an individual basis up to 0.25 mg 3 times daily. Dose adjustment should be based on assessment of stool output and on tolerability.
If within 1 week of treatment with Sandostatin at a dose of 0.25 mg 3 times daily and no improvement is achieved, therapy should be discontinued.
Complications following Pancreatic Surgery: 0.1 mg 3 times daily by SC injection for 7 consecutive days, starting on the day of operation at least 1 hr before laparotomy.
Bleeding Gastroesophageal Varices: 25 mcg/hr for 5 days by continuous IV infusion. Sandostatin can be used in dilution with physiological saline.
In cirrhotic patients with bleeding gastroesophageal varices, Sandostatin has been well tolerated at continuous IV doses of up to 50 mcg/hr for 5 days.
Sandostatin LAR: 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 Cautions for Usage: Instructions for Use/Handling).
Acromegaly: For patients who are adequately controlled with SC Sandostatin, it is recommended to start treatment with the administration of Sandostatin LAR 20 mg 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 GH and 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.
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, Sandostatin LAR 10 mg 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 (GEP) Endocrine Tumours: 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 Sandostatin LAR 10 mg every 4 weeks.
For patients in whom symptoms are only partially controlled after 3 months of treatment, the dose may be increased to Sandostatin LAR 30 mg every 4 weeks.
For days when symptoms associated with GEP 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 Tumours of the Midgut or Unknown Primary Tumour Location: Recommended Dose: 30 mg administered every 4 weeks. Treatment with Sandostatin LAR for tumour control should be continued in the absence of tumour progression.
Impaired Renal Function: Impaired renal function did not affect the AUC to octreotide administered as SC injection; therefore, no dose adjustment of Sandostatin/Sandostatin LAR is necessary.
Impaired Hepatic Function: In patients with liver cirrhosis, the half-life of octreotide may be increased, necessitating adjustment of the maintenance dosage.
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.
Children: Experience with Sandostatin/Sandostatin LAR in children is limited.
Elderly: There is no evidence of reduced tolerability or altered dosage requirements in elderly patients treated with Sandostatin.
In a study with Sandostatin administered SC, no dose adjustment was necessary in patients (≥65 years). Therefore, no dose adjustment is necessary in this group of patients with Sandostatin LAR.
Administration: Instructions for Use and Handling: Sandostatin: SC Administration: Patients who are to self-administer Sandostatin by SC injection must receive precise directions from the physician or the nurse.
To reduce local discomfort, it is recommended that the solution should be at room temperature before injection. Multiple injections at short intervals at the same site should be avoided.
Ampoules should be opened just prior to administration and any used portion discarded.
To prevent contamination, it is recommended that the cap of multidose vials should be punctured not more than 10 times.
IV Infusion: Parenteral drug products should be inspected visually for discoloration and particulate matter prior to administration.
Sandostatin is physically and chemically stable for 24 hrs in sterile physiological saline solutions or sterile solutions of dextrose (glucose) 5% in water. However, because Sandostatin can affect glucose homeostasis, it is recommended that physiological saline solutions be used other than dextrose. The diluted solutions are physically and chemically stable for at least 24 hrs <25°C.
From a microbiological point of view, the diluted solution should preferably be used immediately. If the solution is not used immediately, storage prior to use is the responsibility of the user and should be at 2-8°C. Before administration, the solution has to be brought to room temperature again.
The cumulated time between reconstitution, dilution with infusion media, storage in a refrigerator and end of administration must not be longer than 24 hrs.
In cases where Sandostatin is to be administered by IV infusion, the contents of one 0.5-mg ampoule should normally be dissolved in 60 mL physiological saline, and the resulting solution should be infused by means of an infusion pump. This should be repeated as often as necessary until the prescribed duration of treatment is reached. Sandostatin has also been infused in lower concentrations.
Sandostatin LAR: IM Injection: For deep intragluteal injection only.
Follow the instructions as follows carefully to ensure complete saturation of the powder and its uniform suspension before 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 center 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 (at least 2-5 min). Without inverting the vial, check the powder on the walls and bottom of the vial. If dry spots exist, allow the 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 sec 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 reinsert 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, gauge 19).
Sandostatin LAR must be given only by deep intragluteal injection, never IV. If a blood vessel has been penetrated, attach a new and select another injection site.
Any unused product or waste material should be disposed of in accordance with local requirements.
Overdosage
Doses of up to Sandostatin 2000 mcg given as SC injection 3 times daily for several months have been well tolerated.
The maximum IV single dose so far given to an adult has been 1 mg by bolus injection. The signs and symptoms observed were a brief drop in heart rate, facial flushing, abdominal cramps, diarrhoea, an empty feeling in the stomach and nausea, all of which resolved within 24 hrs of drug administration.
One patient has been reported to have received an accidental overdosage of Sandostatin by continuous infusion (0.25 mg/hr for 48 hrs instead of 0.025 mg/hr). He experienced no side effects.
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.
No life-threatening reactions have been reported after acute overdosage.
Treatment: The management of overdosage is symptomatic.
Contraindications
Hypersensitivity to octreotide or to any the excipients of Sandostatin/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 GH levels and normalization of 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 Use in pregnancy & lactation as follows).
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 GEP 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 6- to 12-monthly intervals during Sandostatin therapy 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.
Recommendations 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 repetition of ultrasound examination of the gallbladder should be performed, preferably at 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 risks 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 reassessment 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 reassessment of the benefit/risk ratio. Either way, the gallstones should be treated like any other symptomatic gallstones. Medically, this may include combined bile acid therapy [eg, chenodeoxycholic acid (CDCA) together with ursodeoxycholic acid (UDCA)] or monotherapy with UDCA associated with ultrasound monitoring until the stones have completely disappeared. For posology and treatment duration, consult locally approved prescribing information for CDCA and/or UDCA.
Gastroenteropancreatic Endocrine Tumours: During the treatment of GEP endocrine tumours, there may be rare instances of sudden escape from symptomatic control by Sandostatin, with rapid recurrence of severe symptoms.
Glucose Metabolism: Because of its inhibitory action on GH, glucagon and insulin release, Sandostatin/Sandostatin LAR may affect glucose regulation. Postprandial glucose tolerance may be impaired and, in some instances, the state of persistent hyperglycaemia may be induced as a result of chronic administration.
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 observed during initiation of Sandostatin therapy and at each change of dosage. Marked fluctuations of blood glucose concentration may possibly be reduced by smaller, more frequently administered doses.
In patients with concomitant type I diabetes mellitus, Sandostatin LAR is likely to affect glucose regulation and insulin requirements may be reduced by the administration of Sandostatin/Sandostatin LAR. In nondiabetics and type II diabetics with partially intact insulin reserves, Sandostatin/Sandostatin LAR administration may result in increases in prandial or postprandial glycaemia. It is therefore recommended to monitor glucose tolerance and antidiabetic treatment.
Oesophageal Varices: Since, following bleeding episodes from oesophageal varices, there is an increased risk for the development of insulin-dependent diabetes or for changes in insulin requirement in patients with preexisting diabetes, an appropriate monitoring of blood glucose levels is mandatory.
Local Site Reactions: In a 52-week toxicity study in rats, predominantly in males, sarcomas were noted at the SC injection site only at the highest dose (about 40 times the maximum human dose). No hyperplastic or neoplastic lesions occurred at the SC injection site in a 52-week dog toxicity study. There have been no reports of tumour formation at the injection sites in patients treated with Sandostatin for up to 15 years. All the information available at present indicates that the findings in rats are species specific and have no significance for the use of the Sandostatin in humans.
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/Sandostatin LAR in patients who have a history of vitamin B12 deprivation.
Effects on the Ability to Drive or Operate Machinery: No data exist on the effects of Sandostatin/Sandostatin LAR on the ability to drive and use machines.
Use in 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 these 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 SC Sandostatin or 20-30 mg/month of Sandostatin LAR. In approximately 2/3 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/foetal development, parturition or postnatal development apart from some transient retardation of physiological growth (see Toxicology under Actions).
Sandostatin should only be prescribed to pregnant women under compelling circumstances.
Use in 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.
Use in Children: There is very limited experience with the use of Sandostatin/Sandostatin LAR in children.
Use In Pregnancy & Lactation
Use in 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 these 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 SC Sandostatin or 20-30 mg/month of Sandostatin LAR. In approximately 2/3 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/foetal development, parturition or postnatal development apart from some transient retardation of physiological growth (see Toxicology under Actions).
Sandostatin should only be prescribed to pregnant women under compelling circumstances.
Use in 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 main adverse effects encountered with Sandostatin/Sandostatin LAR administration include gastrointestinal (GI), nervous system, hepatobiliary, metabolism and nutritional disorders and local injection site reactions (Sandostatin).
The most commonly reported adverse reactions in clinical trials with octreotide administration were diarrhoea, abdominal pain, flatulence, headache, cholelithiasis, hyperglycaemia, constipation and local injection site pain or irritation.
Intermittent GI adverse effects can occur in about 10% of patients, but usually decline with continued treatment. In rare instances, GI adverse effects may resemble acute intestinal obstruction, with progressive abdominal distention, severe epigastric pain, abdominal tenderness and guarding.
Pain or sensation of stinging, tingling or burning at the site of SC injection, with redness and swelling, rarely lasting >15 min. Local discomfort may be reduced by allowing the solution to reach room temperature before injection, or by injecting a smaller volume using a more concentrated solution.
Other commonly reported adverse reactions were dizziness, localized pain, biliary sludge, thyroid dysfunction [eg, decreased thyroid stimulating hormone (TSH), total and free T4], loose stools, impaired glucose tolerance, vomiting, asthenia and hypoglycaemia. In rare instances, GI side effects may resemble acute intestinal obstruction, with progressive abdominal distention, severe epigastric pain, abdominal tenderness and guarding.
The following adverse drug reactions, have been accumulated from clinical studies with octreotide and spontaneously reported adverse reactions.
Adverse 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 (≥1/1000, <1/100); rare (≥1/10,000, <1/1000); very rare (<1/10,000), including isolated reports. Within each frequency grouping, adverse reactions are ranked in order of decreasing seriousness.
Sandostatin: Immune System Disorders: Rare: Hypersensitivity, rash. Very Rare: Anaphylaxis.
Endocrine Disorders: Very Rare: Hypoglycaemia, hyperglycaemia.
Cardiac Disorders: Uncommon: Bradycardia, tachycardia.
Respiratory Disorders: Very Rare: Dyspnoea.
Gastrointestinal Disorders: Common: Diarrhoea, crampy abdominal pain, constipation, flatulence. Rare: Steatorrhoea, nausea, vomiting, abdominal bloating. Very Rare: Acute pancreatitis, anorexia, loose stools.
Hepatobiliary Disorders: Uncommon: Cholecystitis. Rare: Gallstones. Very Rare: Acute hepatitis without cholestasis, hyperbilirubinaemia, elevated alkaline phosphatase, γ-glutamyl transferase and transaminases.
Skin and Subcutaneous Tissue Disorders: Uncommon: Transient hair loss.
General Disorders and Administration Site Conditions: Common: Local injection site pain, swelling and irritation.
Sandostatin LAR: Immune System Disorders: Rare: Hypersensitivity, rash. Very Rare: Anaphylaxis.
Endocrine Disorders: Common: Hypothyroidism, thyroid dysfunction (eg, decreased TSH, total T4 and free T4).
Cardiac Disorders: Uncommon: Bradycardia, tachycardia.
Respiratory Disorders: Very Rare: Dyspnoea.
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.
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.
Skin and Subcutaneous Disorders: Common: Pruritus, rash, alopecia.
General Disorders and Administration Site Conditions: Very Common: Localized injection site pain.
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 GI adverse effects may be reduced by avoiding meals around the time of Sandostatin administration ie, by injecting between meals or on retiring to bed.
In very rare instances, acute pancreatitis has been reported; generally, this effect is seen within the first hrs or days of Sandostatin/Sandostatin LAR treatment and resolved on withdrawal of the drug. In addition, cholelithiasis-induced pancreatitis has been reported for patients on long-term Sandostatin/Sandostatin LAR treatment.
Post-Marketing: Sandostatin: 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 instances, 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 eg, QT prolongation, axis shifts, early repolarisation, low voltage, R/S transition, early R wave progression, and nonspecific 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 Precautions).
Sandostatin LAR: Spontaneously reported adverse reactions (listed as follows) are reported voluntarily and it is not always possible to reliably establish frequency or a causal relationship to drug exposure.
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 and γ-glutamyl transferase levels.
Drug Interactions
Octreotide has been found to reduce the intestinal absorption of cyclosporin 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 the suppression of GH. 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: Octreotide acetate is not stable in total parenteral nutrition (TPN) solutions.
Sandostatin LAR microspheres for injection 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.
Storage
Sandostatin: Ampoules: For prolonged storage, store at 2-8°C. Do not freeze. For day to day use, store at temperature not above 30°C for up to 2 weeks.
Multidose Vial: For prolonged storage, store at 2-8°C. For day to day use, multidose vials may be stored at temperatures not above 25°C for up to 2 weeks.
Sandostatin LAR: Store at 2-8°C (refrigerator). Protect 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.
ATC Classification
H01CB02 - octreotide ; Belongs to the class of antigrowth hormone. Used in hypothalamic hormone preparations.
Presentation/Packing
Sandostatin: Inj (amp) 0.1 mg/mL x 5's. Multidose vial 0.2 mg/mL x 5 mL x 1's.
Sandostatin LAR: Powd for inj (vial, white to off-white microsphere for susp for inj), (with pre-filled syringe) 20 mg x 1's. 30 mg x 1's.
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