OCTREOTIDE BIOINDUSTRIA L.I.M

Injection, a cyclic octapeptide prepared as a clear sterile solution of octreotide, acetate salt, in a buffered lactic acid solution for administration by deep subcutaneous or intravenous injection.

Octreotide acetate, known chemically as L-Cysteinamide, D-phenylalanyl-L-cysteinyl-L-phenylalanyl-D-tryptophyl-L-lysyl-L-threonyl-N-[2-hydroxy-1-(hydroxymethyl)propyl]-,cyclic (2 → 7)-disulfide; [R-(R, R)] acetate salt, is a long-acting octapeptide with pharmacologic actions mimicking those of the natural hormone somatostatin.

Injection is available as sterile 1-mL vials in 3 strengths, containing 50 mcg, 100 mcg, or 500 mcg octreotide (as acetate).

Each vial also contains glacial acetic acid, USP (2 mg), mannitol, USP (45 mg), sodium acetate trihydrate, USP (2 mg), water for injection, USP (quantity sufficient to 1 mL).

Glacial acetic acid, USP and sodium acetate trihydrate, USP are added to provide a buffered solution, pH to 4.2 ± 0.5.

The molecular weight of octreotide acetate is 1019.3 g/mol (free peptide, C 49 H 66 N 10 O 10 S 2 ) and its amino acid sequence is: Structural image.

Octreotide Acetate Injection is a somatostatin analogue indicated: Acromegaly: To reduce blood levels of growth hormone (GH) and insulin growth factor-1 (IGF-1; somatomedin C) in acromegaly patients who have had inadequate response to or cannot be treated with surgical resection, pituitary irradiation, and bromocriptine mesylate at maximally tolerated doses.

For the symptomatic treatment of patients with metastatic carcinoid tumors where it suppresses or inhibits the severe diarrhea and flushing episodes associated with the disease.

Tumors (VIPomas) : For the treatment of profuse watery diarrhea associated with VIP-secreting tumors.

Improvement in clinical signs and symptoms, or reduction in tumor size or rate of growth, were not shown in clinical trials performed with Octreotide Acetate Injection; these trials were not optimally designed to detect such effects. 1.1 Acromegaly Octreotide Acetate Injection is indicated to reduce blood levels of growth hormone (GH) and insulin growth factor-1 (IGF-1; somatomedin C) in acromegaly patients who have had inadequate response to or cannot be treated with surgical resection, pituitary irradiation, and bromocriptine mesylate at maximally tolerated doses. 1.2 Carcinoid Tumors Octreotide Acetate Injection is indicated for treatment of severe diarrhea and flushing episodes associated with metastatic carcinoid tumors. 1.3 Vasoactive Intestinal Peptide Tumors Octreotide Acetate Injection is indicated for the treatment of the profuse watery diarrhea associated with vasoactive intestinal peptide tumors (VIPomas)-secreting tumors. 1.4 Important Limitations of Use Improvement in clinical signs and symptoms, or reduction in tumor size or rate of growth, were not shown in clinical trials performed with Octreotide Acetate Injection; these trials were not optimally designed to detect such effects.

B12 deficiency, history (de) Liver Circhrosis Diabetes Child under 15 years of age Female likely to be pregnant Insulinoma Extended treatment.

Octreotide acetate injection exerts pharmacologic actions similar to the natural hormone, somatostatin.

It is an even more potent inhibitor of GH, glucagon, and insulin than somatostatin.

Like somatostatin, it also suppresses luteinizing hormone (LH) response to gonadotropin releasing hormone (GnRH), decreases splanchnic blood flow, and inhibits release of serotonin, gastrin, VIP, secretin, motilin, and pancreatic polypeptide.

By virtue of these pharmacological actions, octreotide has been used to treat the symptoms associated with metastatic carcinoid tumors (flushing and diarrhea), and VIP secreting adenomas (watery diarrhea). 12.2 Pharmacodynamics Octreotide substantially reduces GH and/or IGF-1 (somatomedin C) levels in patients with acromegaly.

Single doses of octreotide 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.

Octreotide suppresses secretion of

TSH. 12.3 Pharmacokinetics Absorption 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 specific radioimmunoassay, IV and subcutaneous doses were found to be bioequivalent.

Peak concentrations and area under the curve (AUC) values were dose proportional after IV single doses up to 200 mcg and subcutaneous single doses up to 500 mcg and after subcutaneous multiple doses up to 500 mcg 3 times a day (1,500 mcg/day).

In patients with acromegaly, a mean peak concentration of 2.8 ng/mL (100-mcg dose) was reached in 0.7 hours after subcutaneous dosing.

In healthy volunteers, the distribution of octreotide from plasma was rapid (tα½ = 0.2 h), the volume of distribution (V dss ) 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 to lipoprotein and, to a lesser extent, to albumin.

In patients with acromegaly, the volume of distribution (V dss ) 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 elimination of octreotide from plasma had an apparent half-life of 1.7 to 1.9 hours compared with to 3 minutes with the natural hormone.

The duration of action of octreotide acetate injection 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 disposition and elimination half-lives were similar to normal subjects.

In patients with mild renal impairment (CL CR to 60 mL/min), octreotide t 1/2 was 2.4 hours and total body clearance was 8.8 L/hr, in moderate impairment (CL CR to 39 mL/min) t 1/2 was 3.0 hours and total body clearance 7.3 L/hr. In patients with severe renal impairment not requiring dialysis (CL CR < 10 mL/min), octreotide t 1/2 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 liver cirrhosis showed prolonged elimination of drug, with octreotide t 1/2 increasing to 3.7 hr and total body clearance decreasing to 5.9 L/hr, whereas patients with fatty liver disease showed t 1/2 increased to 3.4 hr and total body clearance of 8.2 L/hr. 12.6 Immunogenicity Evaluation of 20 patients treated for at least 6 months has failed to demonstrate titers of antibodies exceeding background levels.

However, antibody titers to octreotide acetate injection were subsequently reported in 3 patients and resulted in prolonged duration of drug action in 2 patients.

Mechanism of action

Octreotide is a synthetic octapeptide derived from natural somatostatin, with the same pharmacological effects and a clearly prolonged duration of action.

It inhibits the pathological increase in growth hormone (GH) secretion, peptides and serotonin produced by the gastroenteropancreatic endocrine system (GEP).

In animals, octreotide is a more potent inhibitor of GH, glucagon, and insulin secretion compared to somatostatin, with greater selectivity for inhibition of GH and glucagon.

In healthy subjects, it was found that l的octreotide inhibited: the release of GH stimulated by arginine, exercise, or insulin-induced hypoglycaemia; postprandial release of insulin, glucagon, sonotent-like insulin, sonotent-like-depletion of the same pathogene as the other peptides-induced pathogene and the other peptides-induced patho-depletion of the sothreotin; the other peptides-induced-deplentin-de-resin; and the other peptidesthegot.

• Hyperglycaemia (Very common)
• Transaminases (increase) (Common)
• Hyperbilirubinaemia (Common)
• Hypoglycaemia (Common)
• Free thyroxine decreased Alkaline phosphates (increase)
• Gamma GT (increase)
• TSH (decrease)
• T4 (decrease)
• Alopecia (Common)
• Pruritus (Common)
• Rash (Common)
• Urticaria Asthenia (Common)
• Hypothyroidism (Common)
• Dysthyroidism (Common)
• Thrombocytopenia Cholecystitis (Common)
• Bile lithiasis (Very common)
• Bile mud (Common) gallbladder disorder Acute hepatitis Cholestatic Ictery Cholestasis
• Abnormal biliary flow Ictery Cholestatic hepatitis Anaphylactic shock (Isolated cases)
• Anaphylactic reaction Hypersensitivity Injection site reaction (Very common)
• Injection site tingling
• Swelling at the injection site Erythema at the injection site Pain at injection site
• Burning sensation at the injection site Dehydration (Uncommon)
• Anorexia (Common)
• Glucose tolerance (Common)
• Feeling dizzy (Common)
• Bradycardia (Common)
• Tachycardia (Uncommon)
• ST segment abnormal with electrocardiogram ST-T segment anomaly QT space extension
• Decreased progression of the R wave to the electrocardiogram Arrhythmia Electrocardiogram anomaly
• QRS (longening)
• Repolarization disorder Constipation (Very common)
• Soft stool (Common)
• Discoloration of stools (Common)
• Vomiting (Common)
• Ball-down (Common)
• Dyspepsia (Common)
• Flatulence (Very common)
• Nausea (Very common)
• Diarrhoea (Very common)
• Abdominal pain (Very common)
• Steatorrhoea (Common)
• Sensitive abdominal Pancreatitis Abdominal distension Feeling abdominal discomfort
• Fatty stool Epigastric pain Digestive disorder Intestinal occlusion Acute Pancreatitis
• Headache (Very common)
• Dyspnoea (Common).

limited number of accidental overdoses of octreotide acetate injection in adults have been reported.

In adults, the doses ranged from to 6,000 mcg/day administered by continuous infusion (100 to 250 mcg/hour) or subcutaneously (1,500 mcg 3 times a day).

Adverse events in some patients included arrhythmia, complete atrioventricular block, hypotension, cardiac arrest, brain hypoxia, pancreatitis, hepatitis steatosis, hepatomegaly, lactic acidosis, flushing, diarrhea, lethargy, weakness, and weight loss.

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 1-800-222-1222.

Sensitivity to this drug or any of its components.

Acetate injection may be administered subcutaneously or intravenously.

Recommended initial Octreotide Acetate injection dosage is 50 mcg three times daily during the initial 2 weeks of therapy.

Maintenance dose 100 mcg to 500 mcg three times daily.

Recommended dosage range of 100 mcg to 600 mcg daily in two to four divided doses during the initial 2 weeks of therapy.

Recommended dosage range of 200 mcg to 300 mcg daily in two to four divided doses during the initial 2 weeks of therapy. 2.1 Dosage and Administration Overview Octreotide Acetate injection may be administered subcutaneously or intravenously.

Pain with subcutaneous administration may be reduced by using the smallest volume that will deliver the desired dose.

Sites should be rotated in a systematic manner.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration.

Do not use if particulates and/or discoloration are observed.

Octreotide Acetate injection is not compatible in Total Parenteral Nutrition solutions because of the formation of a glycosyl octreotide conjugate which may decrease the efficacy of the product.

Acetate injection may be diluted in volumes of 50 mL to 200 mL and infused intravenously over to 30 minutes or administered by intravenous (IV) push over 3 minutes.

In emergency situations (e.g., carcinoid crisis), it may be given by rapid bolus.

Assess total and/or free T4 levels at baseline and periodically during chronic octreotide acetate therapy. 2.2 Recommended Dosage and Monitoring for Acromegaly The recommended initial dosage of octreotide acetate is 50 mcg three times daily to be administered subcutaneously.

Increase octreotide acetate dose based upon GH or IGF-1 levels.

The goal is to achieve

GH levels less than 5 ng/mL or IGF-1 levels within normal range.

Monitor GH or

IGF-1 every two weeks after initiating octreotide acetate therapy or with dosage change, and to guide titration.

The most common dosage is 100 mcg three times daily, but some patients require up to 500 mcg three times daily for maximum effectiveness.

Doses greater than 300 mcg/day seldom result in additional biochemical benefit, and if an increase in dose fails to provide additional benefit, the dose should be reduced.

Acetate injection should be withdrawn yearly for approximately 4 weeks from patients who have received irradiation to assess disease activity.

If GH or

IGF-1 levels increase and signs and symptoms recur, Octreotide Acetate injection therapy may be resumed. 2.3 Recommended Dosage and Monitoring for Carcinoid Tumors The recommended daily dosage of Octreotide Acetate injection during the first 2 weeks of therapy ranges from to 600 mcg/day in two to four divided doses given subcutaneously (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.

Measurement of urinary 5-hydroxyindole acetic acid, plasma serotonin, plasma Substance P may be useful in monitoring the progress of therapy. 2.4 Recommended Dosage and Monitoring for Vasoactive Intestinal Peptide Tumors Daily dosages of 200 mcg to 300 mcg in two to four divided doses given subcutaneously are recommended during the initial 2 weeks of therapy (range, 150 mcg to 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.

Measurement of

Plasma vasoactive intestinal peptide (VIP) may be useful in monitoring the progress of therapy.

Discard unused portion.

Injection is available in 1 mL single-dose vials as follows: NDC Octreotide Acetate Injection Package Factor 71288.

• 566 -02 50 mcg per mL Single-Dose Vial 10 vials per carton 71288.

• 567 -02 100 mcg per mL Single-Dose Vial 10 vials per carton 71288.

• 568 -02 500 mcg per mL Single-Dose Vial 10 vials per carton Storage and Handling For prolonged storage, Octreotide Acetate Injection single-dose vials should be stored at refrigerated temperatures 2°C to 8°C (36°F to 46°F) and store in outer carton in order to protect from light.

At room temperature (20°C to 30°C or 70°F to 86°F), Octreotide Acetate Injection 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.

Vials should be opened just prior to administration and the unused portion discarded.

Dispose unused product or waste properly.

Injection is stable in sterile isotonic saline solutions or sterile solutions of dextrose 5% in water for 24 hours.

The container closure is not made with natural rubber latex.

The limited data with octreotide acetate injection in pregnant women are insufficient to inform a drug-associated risk for major birth defects and miscarriage.

In animal reproduction studies, no adverse developmental-effects were observed with IV administration of octreotide to pregnant rats and rabbits during organogenesis at doses 7.

• and 13-times, respectively the maximum recommended human dose (MRHD) of 1.5 mg/day based on body surface area (BSA).

Transient growth retardation, with no impact on postnatal development, was observed in rat offspring from a pre.

• and post-natal study of octreotide at IV doses below the MRHD based on BSA.

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown.

In the

U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

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 to 300 mcg/day of octreotide acetate injection or 20 mg to 30 mg once a month of octreotide acetate for injectable suspension, however some women elected to continue octreotide therapy throughout pregnancy.

In cases with a known outcome, no congenital malformations were reported.

In embryo-fetal development studies in rats and rabbits, pregnant animals received IV doses of octreotide up to 1 mg/kg/day during the period of organogenesis.

A slight reduction in body weight gain was noted in pregnant rats at 0.1 and 1 mg/kg/day. There were no maternal effects in rabbits or embryo-fetal effects in either species up to the maximum dose tested.

At 1 mg/kg/day in rats and rabbits, the dose multiple was approximately 7.

• and 13-times, respectively, at the highest recommended human dose of 1.5 mg/day based on BSA.

In a pre.

• and post-natal development rat study at IV doses of 0.02-1 mg/kg/day, a transient growth retardation of the offspring was observed at all doses which was possibly a consequence of GH inhibition by octreotide.

The doses attributed to the delayed growth are below the human dose of 1.5 mg/day, based on BSA.

Safety and efficacy of octreotide acetate injection in the pediatric population have not been demonstrated.

No formal controlled clinical trials have been performed to evaluate the safety and effectiveness of octreotide acetate injection in pediatric patients under age 6 years.

In postmarketing reports, serious adverse events, including hypoxia, necrotizing enterocolitis, and death, have been reported with octreotide acetate injection 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 underlying co-morbid conditions.

The efficacy and safety of octreotide acetate injection using the octreotide acetate for injectable suspension formulation was examined in a single randomized, double-blind, placebo-controlled, 6 month pharmacokinetics study in 60 pediatric patients age to 17 years with hypothalamic obesity resulting from cranial insult.

The mean octreotide concentration after 6 doses of 40 mg octreotide acetate for injectable suspension administered by intramuscular (IM) injection every 4 weeks was approximately 3 ng/mL.

Steady-state concentrations was achieved after 3 injections of a 40-mg dose.

Mean body mass index (BMI) increased 0.1 kg/m in octreotide acetate for injectable suspension-treated subjects compared to 0.0 kg/m in saline control-treated subjects.

Efficacy was not demonstrated.

Diarrhea occurred in of 30 (37%) patients treated with octreotide acetate for injectable suspension.

No unexpected adverse events were observed.

However, with octreotide acetate for injectable suspension at 40 mg once a month, the incidence of new cholelithiasis in this pediatric population (33%) was higher than that seen in other adult indications such as acromegaly (22%) or malignant carcinoid syndrome (24%), where octreotide acetate for injectable suspension was 10 mg to 30 mg once a month.

Clinical studies of octreotide acetate injection did not include sufficient numbers of subjects aged 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.