Sandostatin

DESCRIPTION

Octreotide is the acetate salt of a cyclic octapeptide. It is a long-acting octapeptide with pharmacologic properties mimicking those of the natural hormonesomatostatin. Octreotide is known chemically as LCysteinamide, D-phenylalanyl-L-cysteinyl-L-phenylalanyl-D-tryptophyl-L-lysyl-L-threonyl-N-[2-hydroxy-1- (hydroxy-methyl) propyl]-, cyclic (2→7)-disulfide; [R-(R*,R*)].

The molecular weight of octreotide is 1019.3 (freepeptide, C₄₉H₆₆N₁₀O₁₀S₂) and itsamino acidsequence is:

Sandostatin LAR Depot is available in a vial containing the sterile drug product, which when mixed with diluent, becomes a suspension that is given as a monthly intragluteal injection. The octreotide is uniformly distributed within the microspheres which are made of a biodegradable glucose star polymer, D,L-lactic and glycolic acids copolymer. Sterile mannitol is added to the microspheres to improve suspendability.

Sandostatin LAR Depot is available as: sterile 6-mL vials in 3 strengths delivering 10 mg, 20 mg, or 30 mg octreotide-free peptide. Each vial of Sandostatin LAR Depot delivers:

Name of Ingredient	10 mg	20 mg	30 mg
octreotide acetate	11.2 mg*	22.4 mg*	33.6 mg*
D,L-lactic and glycolic acids co polymer	18 8.8 mg	377.6 mg	566.4 mg
mannitol	41.0 mg	81.9 mg	122.9 mg
*Equivalent to 10/20/30 mg octreotide base.

Each syringe of diluent contains:
carboxymethylcellulose sodium	14.0 mg
mannitol	12.0 mg
poloxamer 188	4.0 mg
water for injection	2.0 mL

INDICATIONS

Acromegaly

Sandostatin®(10月reotide acetate) is indicated to reduce blood levels ofgrowth hormoneand IGF-I (somatomedin C) inacromegalypatients who have had inadequate response to or cannot be treated with surgicalresection,pituitaryirradiation, and bromocriptine mesylate at maximally tolerated doses. The goal is to achieve normalization of growth hormone and IGF-I (somatomedin C) levels (seeDOSAGE AND ADMINISTRATION). In patients with acromegaly, Sandostatin reduces growth hormone to within normal ranges in 50% of patients and reduces IGF-I (somatomedin C) to within normal ranges in 50%-60% of patients. Since the effects of pituitary irradiation may not become maximal for several years, adjunctive therapy with Sandostatin to reduce blood levels of growth hormone and IGF-I (somatomedin C) offers potential benefit before the effects of irradiation are manifested.

Improvement in clinical signs and symptoms, or reduction in tumor size or rate of growth, were not shown in clinical trials performed with Sandostatin; these trials were not optimally designed to detect such effects.

Carcinoid Tumors

Sandostatin is indicated for thesymptomatic treatmentof patients with metastatic carcinoid tumors where it suppresses or inhibits the severe diarrhea and flushing episodes associated with the disease.

Sandostatin studies were not designed to show an effect on the size, rate of growth or development of metastases.

Vasoactive Intestinal Peptide Tumors (VIPomas)

Sandostatin is indicated for the treatment of the profuse watery diarrhea associated with VIP-secreting tumors. Sandostatin studies were not designed to show an effect on the size, rate of growth or development of metastases.

DOSAGE AND ADMINISTRATION

Sandostatin®(10月reotide acetate) may be administered subcutaneously or intravenously. Subcutaneous injection is the usual route of administration of Sandostatin for control of symptoms. Pain with subcutaneous administration may be reduced by using the smallest volume that will deliver the desired dose. Multiple subcutaneous injections at the same site within short periods of time should be avoided. Sites should be rotated in a systematic manner.

Parenteraldrug products should be inspected visually for particulate matter and discoloration prior to administration.Do not use if particulates and/or discoloration are observed.应该使用适当的无菌技术在前paration of parenteral admixtures to minimize the possibility of microbial contamination.Sandostatin is not compatible in Total Parenteral Nutrition (TPN) solutions because of the formation of a glycosyl octreotide conjugate which may decrease the efficacy of the product.

Sandostatin is stable in sterile isotonicsalinesolutions or sterile solutions of dextrose 5% in water for 24 hours. It may be diluted in volumes of 50-200 mL and infused intravenously over 15-30 minutes or administered by IV push over 3 minutes. In emergency situations (e.g., carcinoid crisis), it may be given by rapid bolus.

The initial dosage is usually 50 mcg administered twice or three times daily. Upward dose titration is frequently required. Dosage information for patients with specific tumors follows.

Acromegaly

Dosage may be initiated at 50 mcg three times a day. Beginning with this low dose may permit adaptation to adversegastrointestinaleffects for patients who will require higher doses. IGF-I (somatomedin C) levels every 2 weeks can be used to guide titration. Alternatively, multiple growth hormone levels at 0-8 hours after Sandostatin® (octreotide acetate) administration permit more rapid titration of dose. The goal is to achieve growth hormone levels less than 5 ng/mL or IGF-I (somatomedin C) levels less than 1.9 unit/mL in males and less than 2.2 unit/mL in females. The dose most commonly found to be effective is 100 mcg three times a day, but some patients require up to 500 mcg three times a day for maximum effectiveness. Doses greater than 300 mcg/day seldom result in additionalbiochemicalbenefit, and if an increase in dose fails to provide additional benefit, the dose should be reduced. IGF-I (somatomedin C) or growth hormone levels should be reevaluated at 6-month intervals.

Sandostatin should be withdrawn yearly for approximately 4 weeks from patients who have received irradiation to assess disease activity. If growth hormone or IGF-I (somatomedin C) levels increase and signs and symptoms recur, Sandostatin therapy may be resumed.

Carcinoid Tumors

The suggested daily dosage of Sandostatin during the first 2 weeks of therapy ranges from 100600 mcg/day in 2-4 divided doses (mean daily dosage is 300 mcg). In the clinical studies, the median daily maintenance dosage was approximately 450 mcg, but clinical and biochemical benefits were obtained in some patients with as little as 50 mcg, while others required doses up to 1500 mcg/day. However, experience with doses above 750 mcg/day is limited.

VIPomas

Daily dosages of 200-300 mcg in 2-4 divided doses are recommended during the initial 2 weeks of therapy (range: 150-750 mcg) to control symptoms of the disease. On an individual basis, dosage may be adjusted to achieve a therapeutic response, but usually doses above 450 mcg/day are not required.

HOW SUPPLIED

Sandostatin®(10月reotide acetate) Injection is available in 1 mL ampuls and 5-mL multi-dose vials as follows:

Ampuls

50 mcg/mL Octreotide (as acetate)

Package of 10 ampuls ..........NDC0078-0180-01

100 mcg/mL Octreotide (as acetate)

Package of 10 ampuls ..........NDC0078-0181-01

500 mcg/mL Octreotide (as acetate)

Package of 10 ampuls ..........NDC0078-0182-01

Multi-Dose Vials

200 mcg/mL Octreotide (as acetate)

Box of one ..........NDC0078-0183-25

1000微克/毫升Octreotide(醋酸)

Box of one ..........NDC0078-0184-25

Storage

For prolonged storage, Sandostatin ampuls and multi-dose vials should be stored at refrigerated temperatures 2°C-8°C (36°F-46°F) and store in outer carton in order to protect from light. At room temperature (20°C-30°C or 70°F-86°F), Sandostatin is stable for 14 days if protected from light. The solution can be allowed to come to room temperature prior to administration. Do not warm artificially. After initial use, multiple-dose vials should be discarded within 14 days. Ampuls should be opened just prior to administration and the unused portion discarded. Dispose unused product or waste properly.

Distributed by: Novartis Pharmaceuticals Corporation East Hanover, NJ 07936. Revised: Apr 2019

SIDE EFFECTS

Gallbladder Abnormalities

Gallbladderabnormalities, especially stones and/orbiliary sludge, frequently develop in patients on chronic Sandostatin® (octreotide acetate) therapy (see警告).

Cardiac

In acromegalics,sinus bradycardia(< 50 bpm) developed in 25%; conduction abnormalities occurred in 10% and arrhythmias developed in 9% of patients during Sandostatin therapy (seePRECAUTIONS-General).

Gastrointestinal

Diarrhea, loose stools, nausea and abdominal discomfort were each seen in 34%-61% of acromegalic patients in U.S. studies although only 2.6% of the patients discontinued therapy due to these symptoms. These symptoms were seen in 5%-10% of patients with other disorders.

The frequency of these symptoms was not dose-related, but diarrhea and abdominal discomfort generally resolved more quickly in patients treated with 300 mcg/day than in those treated with 750 mcg/day. Vomiting,flatulence, abnormal stools, abdominaldistention, and constipation were each seen in less than 10% of patients.

In rare instances, gastrointestinal side effects may resemble acuteintestinal obstruction, with progressive abdominal distension, severe epigastric pain, abdominal tenderness and guarding.

Hypo/Hyperglycemia

Hypoglycemiaandhyperglycemiaoccurred in 3% and 16% of acromegalic patients, respectively, but only in about 1.5% of other patients. Symptoms of hypoglycemia were noted in approximately 2% of patients.

Hypothyroidism

In acromegalics, biochemicalhypothyroidismalone occurred in 12% whilegoiteroccurred in 6% during Sandostatin therapy (seePRECAUTIONS-General). In patients without acromegaly, hypothyroidism has only been reported in several isolated patients and goiter has not been reported.

Other Adverse Events

Pain on injection was reported in 7.7%, headache in 6% and dizziness in 5%.Pancreatitiswas also observed (see警告ANDPRECAUTIONS).

Other Adverse Events 1%-4%

Other events (relationship to drug not established), each observed in 1%-4% of patients, included fatigue, weakness,pruritus, joint pain, backache,urinary tract infection, cold symptoms, flu symptoms, injection sitehematoma, bruise, edema, flushing, blurred vision, pollakiuria, fatmalabsorption, hair loss, visual disturbance and depression.

Other Adverse Events < 1%

Events reported in less than 1% of patients and for which relationship to drug is not established are listed: Gastrointestinal:hepatitis,jaundice, increase in liver enzymes,GIbleeding,hemorrhoids,appendicitis,gastric/peptic ulcer, gallbladderpolyp;

Integumentary:rash,cellulitis,petechiae,urticaria,basal cell carcinoma;

Musculoskeletal:arthritis, jointeffusion, muscle pain,Raynaud's phenomenon;

Cardiovascular:chest pain, shortness of breath,thrombophlebitis,ischemia,congestive heart failure,hypertension,hypertensivereaction,palpitations, orthostatic BP decrease,tachycardia;

CNS:anxiety,libidodecrease,syncope,tremor,seizure,vertigo,Bell's Palsy, paranoia, pituitaryapoplexy, increasedintraocular pressure,amnesia, hearing loss, neuritis;

Respiratory:pneumonia, pulmonarynodule, status asthmaticus;

Endocrine:galactorrhea, hypoadrenalism,diabetesinsipidus,gynecomastia,amenorrhea, polymenorrhea,oligomenorrhea,vaginitis;

Urogenital:nephrolithiasis,hematuria;

Hematologic:anemia, iron deficiency,epistaxis;

Miscellaneous:otitis, allergic reaction, increased CK, weight loss.

Evaluation of 20 patients treated for at least 6 months has failed to demonstrate titers of antibodies exceeding background levels. However, antibody titers to Sandostatin were subsequently reported in three patients and resulted in prolonged duration of drug action in two patients. Anaphylactoid reactions, includinganaphylactic shock, have been reported in several patients receiving Sandostatin.

Postmarketing Experience

以下不良反应identified during the postapproval use of Sandostatin. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Hepatobiliary:cholelithiasis,cholecystitis,cholangitis和胰腺炎,有时再保险quiredcholecystectomy

Gastrointestinal:intestinal obstruction

Hematologic:thrombocytopenia

DRUG INTERACTIONS

Sandostatin has been associated with alterations in nutrient absorption, so it may have an effect on absorption of orally administered drugs. Concomitant administration of Sandostatin with cyclosporine may decrease blood levels of cyclosporine and result in transplant rejection.

Patients receivinginsulin, oralhypoglycemicagents, beta blockers, calcium channel blockers, or agents to control fluid andelectrolytebalance, may require dose adjustments of these therapeutic agents.

Concomitant administration of octreotide and bromocriptine increases the availability of bromocriptine. Limited published data indicate that somatostatin analogs might decrease the metabolic clearance of compounds known to be metabolized by cytochrome P450 enzymes, which may be due to the suppression of growth hormones. Since it cannot be excluded that octreotide may have this effect, other drugs mainly metabolized by CYP3A4 and which have a low therapeutic index (e.g., quinidine, terfenadine) should therefore be used with caution.

Drug/Laboratory Test Interactions

No known interference exists with clinical laboratory tests, includingamineor peptide determinations.

Drug Abuse And Dependence

There is no indication that Sandostatin has potential for drug abuse or dependence. Sandostatin levels in thecentral nervous systemare negligible, even after doses up to 30,000 mcg.

警告

Single doses of Sandostatin® (octreotide acetate) have been shown to inhibit gallbladder contractility and decreasebilesecretion in normal volunteers. In clinical trials (primarily patients with acromegaly orpsoriasis), the incidence ofbiliarytract abnormalities was 63% (27%gallstones, 24% sludge without stones, 12% biliaryductdilatation). The incidence of stones or sludge in patients who received Sandostatin for 12 months or longer was 52%. Less than 2% of patients treated with Sandostatin for 1 month or less developed gallstones. The incidence of gallstones did not appear related to age, sex or dose. Like patients without gallbladder abnormalities, the majority of patients developing gallbladder abnormalities on ultrasound had gastrointestinal symptoms. The symptoms were not specific for gallbladder disease. A few patients developed acute cholecystitis, ascending cholangitis, biliary obstruction, cholestatic hepatitis, or pancreatitis during Sandostatin therapy or following its withdrawal. One patient developed ascending cholangitis during Sandostatin therapy and died. There have been postmarketing reports of cholelithiasis (gallstones) resulting in complications requiring cholecystectomy.

If complications of cholelithiasis are suspected, discontinue Sandostatin and treat appropriately.

PRECAUTIONS

General

Sandostatin®(10月reotide acetate) alters the balance between the counter-regulatory hormones, insulin, glucagon and growth hormone, which may result in hypoglycemia or hyperglycemia. Sandostatin also suppresses secretion ofthyroid stimulating hormone, which may result in hypothyroidism. Cardiac conduction abnormalities have also occurred during treatment with Sandostatin. However, the incidence of these adverse events during long-term therapy was determined vigorously only in acromegaly patients who, due to their underlying disease and/or the subsequent treatment they receive, are at an increased risk for the development ofdiabetes mellitus, hypothyroidism, andcardiovascular disease. Although the degree to which these abnormalities are related to Sandostatin therapy is not clear, new abnormalities of glycemic control,thyroidfunction andECGdeveloped during Sandostatin therapy as described below.

Risk Of Pregnancy With Normalization Of IGF-1 And GH

Although acromegaly may lead toinfertility, there are reports of pregnancy in acromegalic women. In women with active acromegaly who have been unable to become pregnant, normalization of GH and IGF-1 may restore fertility. Female patients of childbearing potential should be advised to use adequate contraception during treatment with octreotide.

The hypoglycemia or hyperglycemia which occurs during Sandostatin therapy is usually mild, but may result in overt diabetes mellitus or necessitate dose changes in insulin or other hypoglycemic agents. Hypoglycemia and hyperglycemia occurred on Sandostatin in 3% and 16% of acromegalic patients, respectively. Severe hyperglycemia, subsequent pneumonia, and death following initiation of Sandostatin therapy was reported in one patient with no history of hyperglycemia.

In patients with concomitant Type I diabetes mellitus, Sandostatin Injection and Sandostatin LAR® Depot (octreotide acetate for injectable suspension) are likely to affect glucose regulation, and insulin requirements may be reduced. Symptomatic hypoglycemia, which may be severe, has been reported in these patients. In non-diabetics and Type II diabetics with partially intact insulin reserves, Sandostatin Injection or Sandostatin LAR Depot administration may result in decreases in plasma insulin levels and hyperglycemia. It is therefore recommended that glucose tolerance and antidiabetic treatment be periodically monitored during therapy with these drugs.

In acromegalic patients, 12% developed biochemical hypothyroidism only, 8% developed goiter, and 4% required initiation of thyroid replacement therapy while receiving Sandostatin. Baseline and periodic assessment of thyroid function (TSH, total and/or free T4) is recommended during chronic therapy.

In acromegalics,bradycardia(< 50 bpm) developed in 25%; conduction abnormalities

occurred in 10% and arrhythmias occurred in 9% of patients during Sandostatin therapy. Other EKG changes observed included QT prolongation,axisshifts, early repolarization, low voltage, R/S transition, and early R wave progression. These ECG changes are not uncommon in acromegalic patients. Dose adjustments in drugs such as beta-blockers that have bradycardia effects may be necessary. In one acromegalic patient with severe congestive heart failure, initiation of Sandostatin therapy resulted in worsening ofCHFwith improvement when drug was discontinued. Confirmation of a drug effect was obtained with a positive rechallenge.

Several cases of pancreatitis have been reported in patients receiving Sandostatin therapy. Sandostatin may alter absorption of dietaryfatsin some patients.

In patients with severe renal failure requiringdialysis, the half-life of Sandostatin may be increased, necessitating adjustment of the maintenance dosage.

Depressedvitamin B12levels and abnormal Schilling's tests have been observed in some patients receiving Sandostatin therapy, and monitoring of vitamin B12 levels is recommended during chronic Sandostatin therapy.

Laboratory Tests

这可能是有用的作为加压实验室测试l markers in determining and following patient response depend on the specific tumor. Based on diagnosis, measurement of the following substances may be useful in monitoring the progress of therapy:

Acromegaly

Growth Hormone, IGF-I (somatomedin C) Responsiveness to Sandostatin may be evaluated by determining growth hormone levels at 1-4 hour intervals for 8-12 hours post dose. Alternatively, a single measurement of IGF-I (somatomedin C) level may be made two weeks after drug initiation or dosage change.

Carcinoid

5-HIAA (urinary 5-hydroxyindoleacetic acid), plasmaserotonin, plasma Substance P

VIPoma

VIP (plasma vasoactive intestinal peptide)

Baseline and periodic total and/or free T4 measurements should be performed during chronic therapy (seePRECAUTIONS-General).

Carcinogenesis, Mutagenesis, Impairment Of Fertility

Studies in laboratory animals have demonstrated no mutagenic potential of Sandostatin.

Nocarcinogenic可能是在老鼠subcuta治疗neously for 85-99 weeks at doses up to 2000 mcg/kg/day (8 x the human exposure based on body surface area). In a 116week subcutaneous study in rats, a 27% and 12% incidence of injection site sarcomas or squamous cell carcinomas was observed in males and females, respectively, at the highest dose level of 1250 mcg/kg/day (10 x the human exposure based on body surface area) compared to an incidence of 8%-10% in the vehicle-control groups. The increased incidence of injection site tumors was most probably caused by irritation and the high sensitivity of the rat to repeated subcutaneous injections at the same site. Rotating injection sites would prevent chronic irritation in humans. There have been no reports of injection site tumors in patients treated with Sandostatin for up to 5 years. There was also a 15% incidence of uterine adenocarcinomas in the 1250 mcg/kg/day females compared to 7% in the saline-control females and 0% in the vehicle-control females. The presence ofendometritiscoupled with the absence of corpora lutea, the reduction in mammary fibroadenomas, and the presence of uterine dilatation suggest that the uterine tumors were associated withestrogendominance in the aged female rats which does not occur in humans.

Sandostatin did not impair fertility in rats at doses up to 1000 mcg/kg/day, which represents 7x the human exposure based on body surface area.

There are no adequate and well-controlled studies of octreotide use in pregnant women. Reproduction studies have been performed in rats and rabbits at doses up to 16 times the highest recommended human dose based on body surface area and revealed no evidence of harm to the fetus due to octreotide. However, because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.

In postmarketing data, a limited number of exposed pregnancies have been reported in patients with acromegaly. Most women were exposed to octreotide during the first trimester of pregnancy at doses ranging from 100-300 mcg/day of Sandostatin s.c. or 20-30 mg/month of Sandostatin LAR, however some women elected to continue octreotide therapy throughout pregnancy. In cases with a known outcome, nocongenitalmalformations were reported.

Nursing Mothers

It is not known whether octreotide is excreted into human milk. Because many drugs are excreted in human milk, caution should be exercised when octreotide is administered to a nursing woman.

Pediatric Use

Safety and efficacy of Sandostatin Injection in the pediatric population have not been demonstrated.

No formal controlled clinical trials have been performed to evaluate the safety and effectiveness of Sandostatin in pediatric patients under age 6 years. In post-marketing reports, serious adverse events, includinghypoxia,坏死性小肠结肠炎,和死亡reported with Sandostatin use in children, most notably in children under 2 years of age. The relationship of these events to octreotide has not been established as the majority of these pediatric patients had serious underlyingco-morbidconditions.

The efficacy and safety of Sandostatin using the Sandostatin LAR Depot formulation was examined in a single randomized, double-blind, placebo-controlled, six month pharmacokinetics study in 60 pediatric patient's age 6-17 years with hypothalamicobesityresulting fromcranialinsult. The mean octreotide concentration after 6 doses of 40 mg Sandostatin LAR Depot administered by IM injection every four weeks was approximately 3 ng/ml. Steady-state concentrations was achieved after 3 injections of a 40 mg dose. MeanBMIincreased 0.1 kg/m² in Sandostatin LAR Depot-treated subjects compared to 0.0 kg/m² in saline control-treated subjects. Efficacy was not demonstrated. Diarrhea occurred in 11 of 30 (37%) patients treated with Sandostatin LAR Depot. No unexpected adverse events were observed. However, with Sandostatin LAR Depot 40 mg once a month, the incidence of new cholelithiasis in this pediatric population (33%) was higher than that seen in other adults indications such as acromegaly (22%) ormalignantcarcinoid syndrome(24%), where Sandostatin LAR Depot was 10 to 30 mg once a month.

Geriatric Use

Clinical studies of Sandostatin did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

OVERDOSE

A limited number of accidental overdoses of Sandostatin® in adults have been reported. In adults, the doses ranged from 2,400–6,000 mcg/day administered by continuous infusion (100250 mcg/hour) or subcutaneously (1,500 mcg three times a day). Adverse events in some patients includedarrhythmia,hypotension, cardiac arrest, brain hypoxia, pancreatitis, hepatitis steatosis,hepatomegaly,lactic acidosis, flushing, diarrhea,lethargy, weakness, and weight loss.

Sandostatin Injection given in intravenous boluses of 1 mg (1000 mcg) to healthy volunteers did not result in serious ill effects, nor did doses of 30 mg (30,000 mcg) given intravenously over 20 minutes and of 120 mg (120,000 mcg) given intravenously over 8 hours to research patients.

If overdose occurs, symptomatic management is indicated. Up-to-date information about the treatment of overdose can often be obtained from the National Poison Control Center at 1800-222-1222.

CONTRAINDICATIONS

Sensitivity to this drug or any of its components.

CLINICAL PHARMACOLOGY

Sandostatin®(10月reotide acetate) exerts pharmacologic actions similar to the natural hormone, somatostatin. It is an even more potent inhibitor of growth hormone, glucagon, and insulin than somatostatin. Like somatostatin, it also suppresses LH response to GnRH, decreases splanchnic blood flow, and inhibits release of serotonin, gastrin, vasoactive intestinal peptide,secretin, motilin, and pancreaticpolypeptide.

By virtue of these pharmacological actions, Sandostatin has been used to treat the symptoms associated with metastatic carcinoid tumors (flushing and diarrhea), and Vasoactive Intestinal Peptide (VIP) secreting adenomas (watery diarrhea).

Sandostatin substantially reduces growth hormone and/or IGF-I (somatomedin C) levels in patients with acromegaly.

Single doses of Sandostatin have been shown to inhibit gallbladder contractility and to decrease bile secretion in normal volunteers. In controlled clinical trials, the incidence of gallstone or biliary sludge formation was markedly increased (see警告).

Sandostatin suppresses secretion of thyroid stimulating hormone (TSH).

Pharmacokinetics

After subcutaneous injection, octreotide is absorbed rapidly and completely from the injection site. Peak concentrations of 5.2 ng/mL (100-mcg dose) were reached 0.4 hours after dosing. Using a specificradioimmunoassay, intravenous and subcutaneous doses were found to be bioequivalent. Peak concentrations and area under the curve (AUC) values were dose proportional after intravenous single doses up to 200 mcg and subcutaneous single doses up to 500 mcg and after subcutaneous multiple doses up to 500 mcg three times a day (1500 mcg/day).

In healthy volunteers, the distribution of octreotide from plasma was rapid (tα½ = 0.2 h), the volume of distribution (Vdss) was estimated to be 13.6 L, and the total body clearance ranged from 7 L/hr to 10 L/hr. In blood, the distribution into the erythrocytes was found to be negligible and about 65% was bound in the plasma in a concentration-independent manner. Binding was mainly tolipoproteinand, to a lesser extent, toalbumin.

The elimination of octreotide from plasma had an apparent half-life of 1.7 to 1.9 hours compared with 1-3 minutes with the natural hormone. The duration of action of Sandostatin is variable but extends up to 12 hours depending upon the type of tumor. About 32% of the dose is excreted unchanged into the urine. In an elderly population, dose adjustments may be necessary due to a significant increase in the half-life (46%) and a significant decrease in the clearance (26%) of the drug.

In patients with acromegaly, the pharmacokinetics differs somewhat from those in healthy volunteers. A mean peak concentration of 2.8 ng/mL (100-mcg dose) was reached in 0.7 hours after subcutaneous dosing. The volume of distribution (Vdss) was estimated to be 21.6 ± 8.5 L, and the total body clearance was increased to 18 L/h. The mean percent of the drug bound was 41.2%. The disposition and elimination half-lives were similar to normals.

In patients with renal impairment, the elimination of octreotide from plasma was prolonged and total body clearance reduced. In mild renal impairment (CLCR 40-60 mL/min), octreotide t½ was 2.4 hours and total body clearance was 8.8 L/hr, in moderate impairment (CLCR 10-39 mL/min) t½ was 3.0 hours and total body clearance 7.3 L/hr, and in severely renally impaired patients not requiring dialysis (CLCR < 10 mL/min) t½ was 3.1 hours and total body clearance was 7.6 L/hr. In patients with severe renal failure requiring dialysis, total body clearance was reduced to about half that found in healthy subjects (from approximately 10 L/hr to 4.5 L/hr).

Patients with livercirrhosisshowed prolonged elimination of drug, with octreotide t½ increasing to 3.7 hr and total body clearance decreasing to 5.9 L/hr, whereas patients with fattyliver diseaseshowed t½ increased to 3.4 hr and total body clearance of 8.2 L/hr.

PATIENT INFORMATION

Careful instruction in sterile subcutaneous injection technique should be given to the patients and to other persons who may administer Sandostatin Injection. Inform patients that cholelithiasis has been reported with the use of Sandostatin. Advise patients to contact their healthcare provider if they experience signs or symptoms of gallstones (cholelithiasis) or complications of gallstones (e.g., cholecystitis, cholangitis, and pancreatitis).