Octrea

Octreotide acetate.

Each mL solution contains Octreotide acetate equivalent to Octreotide 100 μg (=0.1 mg).
Each prefilled syringe of 1 mL contains Octreotide acetate equivalent to Octreotide 100 μg (=0.1 mg).
Excipients/Inactive Ingredients: Lactic acid, Mannitol, Sodium bicarbonate, Water for injection.

Pharmacotherapeutic group: Antigrowth hormones. ATC code: H01BC02.
Pharmacology: Pharmacodynamics: Mechanism of action: Octreotide is a synthetic octapeptide analogue of naturally occurring somatostatin (growth hormone [somatropin] release inhibiting factor). Its pharmacological effects are similar to somatostatin by inhibiting some anterior pituitary hormones release (i.e. GH, IGF-1), inhibiting serotonin release, and the secretion of gastrin, vasoactive intestinal peptide (VIP), insulin, glucagon, secretin, motilin and pancreatic polypeptide hormones related to GEP.
Also suppresses LH response to GnRH, secretion of thyroid-stimulating hormone (TSH) and decreases splanchnic blood flow. Octreotide has longer plasma half-life and duration of action as compared to endogenous somatostatin.
Because of its inhibitory effects on the secretion of serotonin and various gastroenteropancreatic peptides (e.g. gastrin, VIP, insulin, glucagon, secretin, motilin, pancreatic polypeptide), administration of octreotide may result in improvement of symptoms associated with metastatic carcinoid tumors, particularly flushing and diarrhea associated with carcinoid syndrome, watery diarrhea associated with VIP-secreting tumors.
In patients with VIPomas, the biochemical characteristic is overproduction of vasoactive intestinal peptide (VIP). Therapy with octreotide results in decreasing plasma VIP level, stool volume, and electrolyte loss (e.g. hypokalemia), with consequent improvement in quality of life.
In patients with acromegaly, octreotide consistently decreases GH and normalizes IGF-1 plasma levels in the majority of patients.
Pharmacokinetics: Absorption: Octreotide is rapidly and completely absorbed from the injection site (s.c.). Peak plasma concentration is reached about 25 to 40 minutes after dosing, and is distributed to body tissues.
Distribution: The volume of distribution is 0.27 L/kg, the total body clearance 160 mL/min. Plasma protein binding is approximately 65%. The distribution into the blood cell was negligible.
Elimination: The half-life after subcutaneous administration is 1.7 to 1.9 hours; prolonged in elderly patients; liver cirrhosis; renal impairment. Renal impairment did not affect the total exposure (AUC) to octreotide. Most of the peptide is eliminated via the feces, while approximately 32% of the dose is excreted unchanged into the urine.

Octreotide is indicated for symptomatic control and reduction growth hormone (GH) and IGF-1 plasma level in patient with acromegaly who are inadequately controlled by surgery or radiotherapy. Octerotide treatment is also indicated for acromegalic patients unfit or unwilling to undergo surgery, or in the interim period until radiotherapy becomes fully effective.
Octreotide is indicated for relief of symptoms associated with functional gastro-entero-pancreatic (GEP) endocrine tumors such as: Carcinoid Tumors: Octreotide is indicated 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.
Vasoactive intestinal peptide tumors (VIPomas): Octreotide is indicated for the treatment of profuse watery diarrhea associated with VIP-secreting tumors.
Gastrinoma (Zollinger-Ellison syndrome) usually use in conjunction with proton pump inhibitors.
Insulinomas: Octreotide is indicated for pre-operative control of hypoglycemia and for maintenance therapy.
GRFomas (growth hormone-releasing factor-secreting tumor): Octreotide is not anti-tumor therapy and is not curative in these patients.
It is also indicated for the prevention of complications following pancreatic surgery, and for the emergency management to stop bleeding gastroesophageal varices in patients with cirrhosis, endoscopic sclerotherapy and may be used in treatment of other disorders such as HIV-associated diarrhea, pancreatic endocrine tumors (especially islet cell tumors).

Symptoms associated with Carcinoid Tumors with features of carcinoid syndrome, VIPomas, Glucagonomas, Gastro-entero-pancreatic endocrine tumors: Adult: initial 50 micrograms (0.05 mg) subcutaneous injection 1-2 times a day, adjusted according to response; increase to 200 micrograms 3 times a day, higher dose may be required exceptionally; maintenance dose are variable; in carcinoid tumors, discontinue after 1 week if no effect.
If rapid response required, initial dose may be given by intravenous injection (with ECG monitoring and after dilution).
Acromegaly, short term treatment before pituitary surgery or long-term treatment in those inadequately controlled by other treatment or by radiotherapy or until radiotherapy become fully effective: By subcutaneous injection,
Adults: 100-200 micrograms 3 times a day, discontinue if no response within 3 months.
Prevention of complication following pancreatic surgery: By subcutaneous injection,
Adults: 100 microgram 3 times daily for 7 consecutive days, starting on the day of operation at least 1 hour before laparotomy.
Bleeding gastro-esophageal varices: 25 micrograms/hour for 5 days by continuous i.v. infusion. Octreotide can be used in dilution with 0.9% normal saline solution. In cirrhotic patients with bleeding gastro-esophageal varices, Octreotide has been well tolerated at continuous i.v. doses of up to 50 micrograms/hour for 5 days.
HIV-associated diarrhea: Initial dosage: 100 microgram, 3 times/day given subcutaneously, the dose may be titrated to 250 mcg 3 times/day if diarrhoea is not controlled after 1 week. Dose adjustment should be based on assessment of stool output and on tolerability.
If this is not effective after 1 further week at a dose 250 microgram, 3 times/day, then the treatment should be stopped.
Special populations: Use in the elderly (> 65 years): Clearance and the elimination half-life of octreotide may be prolonged in elderly patients, dosage adjustments may be necessary.
Pregnancy: Limited information of using Octreotide in pregnancy. Possible effect on fetal growth in animal. Use Octreotide only if potential benefit outweighs risk.
Breast feeding: Limited information of breast feeding in human. Avoid using in breast feeding.
Use in children (< 18 years): Experience with Octreotide in children is limited. Risk and benefit of using octreotide should be evaluated.
Use in patients with liver function impairment: In patients with liver cirrhosis, the half-life of the drug may be increased, adjustment of the maintenance dosage may be necessary.
Use in patients with renal function impairment: Half-life of octreotide may be increased in patients with renal failure requiring dialysis, and adjustment of octreotide dosage may be necessary.
Direction for administration: For intravenous injection or intravenous infusion, dilute with 0.9 % sodium chloride to a concentration of 10-50%. The diluted solution are physically and chemically stable for 24 hours below 25°C. From a microbiological point of view, the diluted solution should preferably be used immediately. Storage should be at 2-8°C.
Single dose prefilled syringes are for single use only. The package should be opened only immediately prior to use.
The solution should be inspected visually for changes of color or solid particles prior to administration.
To reduce local discomfort, let the solution reach room temperature before injection. Avoid multiple injections at short intervals at the same site.

Number of accidental overdoses reports of octreotide in adults and children has been limited.
In adults, the doses ranged from 2,400-6,000 microgram/day administered by continuous infusion (100-250 microgram/hour) or subcutaneously (1,500 micrograms, 3 times/day). The adverse events reported were arrhythmia, hypotension, cardiac arrest, brain hypoxia, pancreatitis, hepatitis steatosis, diarrhea, weakness, lethargy, weight loss, hepatomegaly, and lactic acidosis.
In children, the doses ranged from 50-3,000 microgram/day administered by continuous infusion (2.1-500 microgram/hour) or subcutaneously (50-100 microgram). The only adverse event reported was mild hyperglycemia.
No unexpected adverse events have been reported in cancer patients receiving Octreotide at doses of 3,000-30,000 microgram/day in divided doses subcutaneously.
The management of overdose is symptomatic.

Known hypersensitivity to Octreotide or to any of excipients.

General: As growth hormone (GH) secreting pituitary tumors may sometimes expand, causing serious complications (e.g. visual field defect), it is essential that all patients be carefully monitored. If evidence of tumor expansion appears, alternative procedures should be considered.
The therapeutic benefits of a reduction in GH levels and normalisation of insulin like growth factor -1 (IGF-1) concentration in female acromegalic patients could potentially restore fertility. Contraception is recommended for acromegaly female patients (if necessary).
Because Octreotide suppresses secretion of TSH which may result in hypothyroidism. Thyroid function (TSH, total and/or free thyroxine [T4]) should be monitored in patients receiving long-term therapy with octreotide.
Cardiovascular related events: Cardiovascular effects occurring in less than 1% of patients receiving octreotide injection. Cardiovascular effects include hypertension, thrombophlebitis, ischemia, congestive heart failure, palpitation, orthostatic decrease in blood pressure, syncope and chest pain.
Sinus bradycardia has been reported 25% of patients with acromegaly treated with octreotide injection and 19% in patients with carcinoid syndrome treated with octreotide. Dose adjustment of Beta blocker, calcium channel blocker or agent to control fluid and electrolyte balance are necessary.
Gallbladder: Cholelithiasis is a very common event during Octreotide treatment and may be associated with cholecystitis and biliary duct dilatation. Ultrasonic examination of the gallbladder before, and at about 6-12 month intervals during Octreotide therapy is therefore recommended.
GEP endocrine tumors: During the treatment of Gastroenterohepatic (GEP) endocrine tumors, there may be rare instances of sudden escape from symptomatic control by octreotide, with rapid recurrence of severe symptoms.
Glucose metabolism: Because of octreotide-induced alterations in various hormones involved in glucose homeostasis, patients should be observed closely for symptomatic evidence of hypoglycemia or hyperglycemia whenever octreotide therapy is initiated or dosage is adjusted. Post-prandial hyperglycemia may occur in nondiabetic patients as result of chronic administration. Hypoglycemia has also been found.
Insulinoma, insulin requirement may be reduced in patients with type 1 diabetes mellitus during octreotide therapy.
Esophageal varices: Since, following bleeding episodes from esophageal varices, there is an increased risk for the development of insulin-dependent diabetes or for changes in insulin requirement in patients with pre-existing diabetes, an appropriate monitoring of blood glucose levels is mandatory.
Local site reactions: Pain and/or burning at the subcutaneous injection site occur frequently in patients receiving octreotide, (about 7.7% of patients with various conditions), but usually persist for only about 15 minutes after injection and may diminish in frequency and severity with continued use. It has been suggested that adverse local effects result principally from the injection volume and acidity (pH of approximately 4.2).
Nutrition: Octreotide may alter absorption of dietary fats in some patients. Depressed vitamin B₁₂ levels and abnormal Schilling tests have been observed in some patients receiving octreotide therapy. Monitoring of vitamin B₁₂ levels is recommended during therapy with octreotide in patients who have a history of vitamin B₁₂ deprivation.

Adverse drug reactions are listed by Medra system organ class. The adverse drug reactions are ranked by frequency, with the most frequency first, using the following convention: very common (≥ 1/10) common (≥ 1/100, < 1/10); uncommon (≥ 1/1000); rare (≥ 1/10,000, < 1/1000) very rare (< 1/10,000).
Common adverse effects of octreotide include GI discomfort e.g. diarrhea, loose stools, abdominal discomfort, bloating, constipation, nausea and vomiting were each seen in 34% to 61% of acromegaly patient in US studies, although only 2.6% of the patients discontinued therapy. These symptoms were seen in 5% to 10% of patient with other order.
In general, GI effects of octreotide injection develop during the first days to weeks of therapy and diminish with time. GI effects may be minimized by avoiding meals around the time of octreotide administration.
Cardiac disorders: In acromegalic patient, bradycardia (25%) and arrhythmias developed during octreotide therapy (9%). Chest pain, congestive heart failure, hypertensive reaction, ischemia, orthostatic blood pressure decrease, palpitation, shortness of breath, tachycardia, thrombophlebitis were reported less than 1%.
Hepatobiliary disorders: Hepatitis, increased liver enzyme, and jaundice has been uncommonly reported.
In very rare instances, acute pancreatitis has been reported within the first hours or days of octreotide (s.c.) treatment and resolved on withdrawal of the drug.
Dermatologic effects: Bruising, hair loss, pruritus is common in patient receiving octreotide. Rash and urticaria were also reported.
Central nervous system disorders: Fatigue, headache, malaise, and dizziness are commonly reported. Anxiety, seizures, drowsiness, vertigo, hyperesthesia, head pounding, insomnia, irritability, forgetfulness, malaise, nervousness, shakiness, tremor, numbness or Bell's palsy has been uncommonly reported.
Hypersensitivity: Anaphylactic reactions, including anaphylactic shock have been reported in patients receiving octreotide.
Endocrine disorders: Hypoglycemia and hyperglycemia occurred in patients receiving octreotide. In patient treated with octreotide, hypothyroidism or goiter was reported.
Respiratory disorders: Pneumonia, pulmonary nodule, status asthmaticus are uncommonly reported. Dyspnea reported very rare.
Other adverse effects: Common: flu-like symptoms, pollakiuria, visual disturbance.
Uncommon: shortness of breath, weight loss, and increased creatine kinase (CK, creatine phosphokinase, CPK).

Octreotide has been associated with alteration in nutrient absorption and may have effect the oral absorption of other drugs.
Dose adjustment of medicinal products may be necessary when octreotide is administered concomitantly such as beta blockers, calcium channel blockers, or agents to control fluid and electrolyte balance, cyclosporine, cimetidine, insulin and antidiabetic medicinal products, and bromocriptine.
The caution is advised if octreotide is used concomitantly with drugs with a low therapeutic index that are primarily metabolised by CYP3A4 (e.g. quinidine, terfenadine).

Do not use if particulates and/or discoloration are observed.
The solution can be allowed to come to room temperature prior to administration.
Octreotide 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.
In case where Octreotide administered by i.v. infusion the content of 0.5 mg should normally be dissolved in 60 ml physiological saline (0.9% Normal saline) and the resulting solution should be infused by an infusion pump. This should be repeated as often as necessary until the prescribed duration of treatment is reached.

Store at temperature between 2°C to 8°C.
Do not freeze. Protect from light.

Other Gastrointestinal Drugs / Trophic Hormones & Related Synthetic Drugs

H01CB02 - octreotide ; Belongs to the class of antigrowth hormone. Used in hypothalamic hormone preparations.

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