Octreotide

Octreotide is an Octapeptide analogue belonging to Antidiarrheal.

Octreotide is a peptide drug used to treat acromegaly as well as diarrhea associated with metastatic carcinoid tumors and vasoactive intestinal peptide-secreting tumors.

After a subcutaneous dose, octreotide is absorbed completely upon administration. After the administration of an oral delayed-release capsule, peak concentrations were found to be 33% lower than after subcutaneous administration. The Cmax was attained at 1.67–2.5 hours after oral administration versus 30 minutes for the subcutaneous route. At 20 mg twice a day in patients with acromegaly, peak concentration was 2.5 mg/nL versus 5.30 ng/mL at 40 mg twice a day. AUC increases in proportion with the dose, regardless of the route. Approximately 65% of the dose is bound in the plasma to lipoproteins and albumin. Octreotide has been reported to be heavily metabolized in the liver. About 32% of an oral octreotide dose is excreted into the urine and 30-40% is excreted by the liver into the feces. About 11% of the unchanged parent drug is found in the urine, and 2% of the unchanged parent drug can be recovered in the feces.

Octreotide shows side effects like Diarrhea, nausea, vomiting, stomach discomfort, pain, or swelling, heartburn, gas, joint or back pain, sweating, swelling in hands, feet, ankles, or lower legs, tiredness, and dizziness.

Octreotide is available in the form of Oral Capsules and Injectable solution.

Octreotide is available in India, the US, Canada, China, France, Italy, Russia, Spain, and Australia.

Octreotide belongs to the Antidiarrheal Agent and acts as an Octapeptide analogue.

Octreotide binds to somatostatin receptors coupled to phospholipase C through G proteins and leads to smooth muscle contraction in the blood vessels. Downstream effects that stimulate phospholipase C, the production of 1, 4,5-inositol triphosphate, and action on the L-type calcium channels lead to the inhibition of growth hormone, treating the various growth-hormone and metabolic effects of acromegaly. Octreotide's suppression of luteinizing hormone (LH), reduction in splanchnic blood flow, and inhibition of serotonin, gastrin, vasoactive intestinal peptide, secretin, motilin, and pancreatic polypeptide provide relief for the gastrointestinal and flushing symptoms of carcinoid and/or VIPoma tumors.

The Onset of action of Octreotide is about 30 minutes (via injectable solution).

The Duration of action of Octreotide is about 12 hours.

The Tmax of Octreotide is 0.4-1 hours.

Octreotide is a synthetic protein like a hormone in the human body called somatostatin. It is used for the treatment of acromegaly, a hormonal disorder in which the pituitary gland produces an excess of growth hormone. It is also used for the treatment of severe watery diarrhea associated with certain cancers.

Octreotide is approved for use in the following clinical indications

• Acromegaly
• Vasoactive Intestinal Peptide Tumor
• Carcinoid Tumor

• Acromegaly

Initial dose: 50 mcg, IV or subcutaneously, 3 times a day

Maintenance dose: Usually 100 mcg, 3 times a day

Maximum dose: 500 mcg, 3 times a day

• Vasoactive Intestinal Peptide Tumor

Initial dose: 200 to 300 mcg per day, IV or subcutaneously, in 2 to 4 divided doses

Maintenance dose: 150 to 750 mcg per day

• Carcinoid Tumor

Initial dose: 100 to 600 mcg per day, IV or subcutaneously, in 2 to 4 divided doses

Octreotide is available in various strengths as 50 mcg/mL; 100 mcg/mL; 500 mcg/mL; 200 mcg/mL; 1000 mcg/mL; 10 mg; 20 mg; 30 mg; 2500 mcg/mL.

Octreotide is available in the form of Oral Capsule and Injectable solution.

• Dosage Adjustment in Kidney Patient

Injectable formulations: No adjustment is recommended.

Delayed release oral capsules: End-stage renal disease: Initiate dose at 20 mg orally once daily.

Octreotide is contraindicated in patients with

• Hypersensitivity to octreotide or any component of the formulation

• Abnormal Schillings test

Chronic treatment has been associated with abnormal Schillings test; monitor vitamin B₁₂ levels.

• Cardiovascular events

Complete atrioventricular block has been reported in patients receiving IV therapy during surgical procedures; most causes occurred with continuous IV infusion at higher than recommended doses. The safety of continuous IV infusion has not been established in patients receiving octreotide for approved indications.

• Hypothyroidism

Suppresses secretion of TSH; monitors for hypothyroidism.

• Cardiovascular disease

Use with caution in patients with heart failure or concomitant medications that alter heart rate or rhythm; bradycardia, conduction abnormalities, and arrhythmia have been observed in acromegalic and carcinoid syndrome patients. Cardiovascular medication requirements may change.

• Excessive GI fluid loss

In patients with conditions associated with excessive GI fluid loss receiving TPN, concomitant use of octreotide may reverse fluid losses and cause increases in serum zinc; monitor zinc levels (manufacturer's labeling).

• Hepatic impairment

Use caution in patients with hepatic impairment; dosage adjustment may be required in patients with established cirrhosis.

• Neuroendocrine tumors

Prophylactic cholecystectomy is recommended in patients with GI or pancreatic neuroendocrine tumors undergoing abdominal surgery if octreotide treatment is planned.

• Renal impairment

Use with caution in patients with renal impairment; dosage adjustment may be required in patients receiving dialysis.

• QTc-prolonging agents

Octreotide may enhance the adverse/toxic effects of other QTc-prolonging agents.

• LAR depot suspension

Mild to moderate injection-site pain (usually lasting 1 hour) may occur with the LAR depot suspension. Do not use LAR depot suspension formulation for the treatment of sulfonylurea-induced hypoglycemia

• A vehicle used in LAR depot suspension (polylactide-co-glycolide microspheres)

Has rarely been associated with retinal artery occlusion in patients with abnormal arteriovenous anastomosis (eg, patent foramen ovale).

• Older adult

Dosage adjustment may be necessary; significant increases in elimination half-life have been observed in older adults.

• Pediatric

Post marketing cases of serious and fatal events, including hypoxia and necrotizing enterocolitis, have been reported with octreotide use in children (usually with serious underlying conditions), particularly in children <2 years of age. In studies with octreotide LAR depot suspension, the incidence of cholelithiasis in children is higher than the reported incidences for adults and efficacy was not demonstrated.

• Appropriate use

Use of octreotide for the treatment of delayed and/or prolonged hypoglycemia due to sulfonylurea overdose: The onset of hypoglycemia typically occurs within 8 to 12 hours of a sulfonylurea overdose (Boyle 1993; Dougherty 2010; Lung 2011; Spiller 1997; Spiller 2006); however, the onset may be delayed for up to 24 hours. In rare cases, hypoglycemia may develop >24 hours after ingestion. Episodes of prolonged hypoglycemia (>13 hours) have been reported following sulfonylurea overdosage; adequate duration of monitoring and treatment must be provided when octreotide is used for this indication.

• Radiolabeled diagnostic evaluations:

Therapy with the octreotide injection solution formulation should be withheld 24 hours prior to administration of radiolabeled somatostatin analogs; the LAR depot suspension formulation should be withheld at least 2 months before administration of radiolabeled somatostatin analogs (Oberg 2004).

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.

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 post-marketing 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 Octreotide s.c. or 20-30 mg/month of Octreotide LAR, however, some women elected to continue octreotide therapy throughout pregnancy. In cases with a known outcome, no congenital malformations were reported.

Take on an empty stomach. The Oral capsules should be taken on an empty stomach. Food reduces oral octreotide absorption by 90%.

Common

● Bradycardia, cardiac arrhythmia, cardiac conduction disturbance, including prolonged QT interval on ECG and ST segment changes), edema, flushing, tachycardia, Pruritus, Decreased free T4, diabetes mellitus, goiter, hypoglycemia, increased thyroid stimulating hormone level, Abdominal distention, dyspepsia, fecal discoloration, gastritis, gastroesophageal reflux disease, gastrointestinal motility disorder, hemorrhoids, malabsorption, steatorrhea, tenesmus, xerostomia, Pollakiuria, urinary tract infection, Bruise, Cold symptoms, influenza, Hematoma at injection site, Depression, Back pain, Blurred vision, visual disturbance Respiratory: Nasopharyngitis, upper respiratory tract infection, Chest pain, heart failure, hypertensive crisis, ischemia, orthostatic hypotension, palpitations, Raynaud's disease, syncope, thrombophlebitis, Cellulitis, skin rash, urticaria, Adrenocortical insufficiency, amenorrhea, decreased libido, diabetes insipidus, galactorrhea not associated with childbirth, gynecomastia, infrequent uterine bleeding, iron deficiency, menstrual disease (polymenorrhea), pituitary apoplexy, weight loss, Appendicitis, gastric ulcer, gastrointestinal hemorrhage, intestinal obstruction, intestinal polyps, peptic ulcer, Hematuria, vaginitis, Basal cell carcinoma of skin, petechia, polyp (gallbladder), Hepatitis, increased liver enzymes, Hypersensitivity reaction, Amnesia, anxiety, Bell's palsy, neuritis, paranoid ideation, seizure, vertigo, Arthritis, increased creatine phosphokinase in blood specimen, joint effusion, myalgia, tremor, Increased intraocular pressure, Hearing loss, otitis, Nephrolithiasis, Dyspnea, epistaxis, pneumonia, status asthmaticus, Nodule (pulmonary).

Rare

● Acute myocardial infarction, aneurysm, arterial thrombosis (arm), atrial fibrillation, facial edema, Vitamin B₁₂ deficiency, Abdominal swelling, necrotizing enterocolitis, Breast carcinoma, pancytopenia, thrombocytopenia, Liver steatosis, Anaphylactic shock, nonimmune anaphylaxis, Aphasia, hemiparesis, intracranial hemorrhage, migraine, paresis, suicidal tendencies, Glaucoma, retinal thrombosis, scotoma, Deafness, Increased serum creatinine, renal failure syndrome, renal insufficiency, Pneumothorax (aggravated), pulmonary hypertension.

• Cyclosporine

Concomitant administration of octreotide injection with cyclosporine may decrease blood levels of cyclosporine and result in transplant rejection.

• Insulin and Oral Hypoglycemic Drugs

Octreotide inhibits the secretion of insulin and glucagon. Therefore, blood glucose levels should be monitored when Sandostatin LAR treatment is initiated or when the dose is altered and antidiabetic treatment should be adjusted accordingly.

• Bromocriptine

Concomitant administration of octreotide and bromocriptine increases the availability of bromocriptine.

• Other Concomitant Drug Therapy

Concomitant administration of bradycardia-inducing drugs (e.g., beta-blockers) may have an additive effect on the reduction of heart rate associated with octreotide. Dose adjustments of concomitant medication may be necessary. Octreotide has been associated with alterations in nutrient absorption, so it may have an effect on the absorption of orally administered drugs.

• Drug Metabolism Interactions

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

The common side effects of Octreotide include the following

Common side effects

● Diarrhea, Nausea, Vomiting, Stomach discomfort, pain, or swelling, Heartburn, Gas, Joint or back pain, Sweating, Swelling in hands, Feet, Ankles, or lower legs, Tiredness, Dizziness.

Rare side effects

● Pain in the upper right part of the stomach, Center of the stomach, Back, or Shoulder; Yellowing of skin or whites of eyes; Fever with chills; or Nausea, Fever, Cough, Stuffy or runny nose, Sneezing, Pain during urination, or other infection symptoms, Sluggishness, Sensitivity to cold pale, Dry skin, and brittle fingernails and hair, Swelling of your tongue, Throat, Lips, Eyes or face, Difficulty swallowing or breathing, Rash, Itching, Feeling faint, Chest pain, Rapid heartbeat.

• Pregnancy

Pregnancy Category B

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 post marketing 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 Octreotide s.c. or 20-30 mg/month of Octreotide LAR, however some women elected to continue octreotide therapy throughout pregnancy. In cases with a known outcome, no congenital malformations 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 Octreotide Injection in the pediatric population have not been demonstrated.

• Geriatric Use

Clinical studies of Octreotide did not include enough 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.

Symptoms: Weakness, Lethargy, Diarrhoea, Weight loss, Hot flushes, Hypotension, Arrhythmia, Pancreatitis, Hepatic steatosis, Hepatomegaly, Lactic acidosis, Brain hypoxia, and Cardiac arrest.

Management: Symptomatic treatment.

Pharmacodynamic

Octreotide mimics the naturally occurring hormone known as somatostatin. Like somatostatin, it demonstrates activity against growth hormone and glucagon, treating the disordered tissue growth and insulin regulation in patients with acromegaly. In addition, octreotide relieves the flushing and diarrhea associated with gastrointestinal tumors by reducing splanchnic blood flow and various gastrointestinal hormones associated with diarrhea.

Pharmacokinetics

• Absorption

After a subcutaneous dose, octreotide is absorbed completely upon administration. After the administration of an oral delayed-release capsule, peak concentrations were found to be 33% lower than after subcutaneous administration. The Cmax was attained at 1.67–2.5 hours after oral administration versus 30 minutes for the subcutaneous route. At 20 mg twice a day in patients with acromegaly, peak concentration was 2.5 mg/nL versus 5.30 ng/mL at 40 mg twice a day. AUC increases in proportion with the dose, regardless of the route.

• Distribution

In a pharmacokinetic study, the volume of distribution was 13.6 L in healthy volunteers.One pharmacokinetic study revealed a volume of distribution ranging from 18.1-30.4L after intravenous administration in healthy volunteers.

Approximately 65% of the dose is bound in the plasma to lipoproteins and albumin.

• Metabolism and Excretion

Octreotide has been reported to be heavily metabolized in the liver.

About 32% of an oral octreotide dose is excreted into the urine and 30-40% is excreted by the liver into the feces. About 11% of the unchanged parent drug is found in the urine, and 2% of the unchanged parent drug can be recovered in the feces.

• https://www.accessdata.fda.gov/drugsatfda_docs/label/2010/019667s058,021008s023lbl.pdf
• https://www.uptodate.com/contents/octreotide-drug-information?search=octreotide&source=panel_search_result&selectedTitle=1~148&usage_type=panel&kp_tab=drug_general&display_rank=1
• https://medlineplus.gov/druginfo/meds/a620051.html
• https://reference.medscape.com/drug/sandostatin-lar-octreotide-342836
• https://www.drugs.com/pregnancy/octreotide.html
• https://go.drugbank.com/drugs/DB00104
• https://www.mims.com/india/drug/info/octreotide?type=full&mtype=generic
• https://www.rxlist.com/sandostatin-drug.htm#clinpharm