Octreotide

H01C - Hypothalamic hormones ATC H01CB02 Protein approved 1988 Oral Parenteral Natural product Orphan

JFDA label: Sandostatin LAR Vial

Mechanism of Action

Mimics natural somatostatin by inhibiting serotonin release, and the secretion of gastrin, VIP, insulin, glucagon, secretin, motilin, and pancreatic polypeptide. Decreases growth hormone and IGF-1 in acromegaly. Octreotide provides more potent inhibition of growth hormone, glucagon, and insulin as compared to endogenous somatostatin. Also suppresses LH response to GnRH, secretion of thyroid-stimulating hormone and decreases splanchnic blood flow.

Indications

Approved

Acromegaly
Carcinoid tumors
Injection solution
LAR depot suspension
Vasoactive intestinal peptide-secreting tumors

Off-label

AIDS-associated diarrhea (including Cryptosporidiosis)
Carcinoid crisis (prevention)
Congenital hyperinsulinism
Cushing's syndrome (ectopic)
Diarrhea (refractory or persistent) associated with chemotherapy
Diarrhea associated with graft-versus-host disease (GVHD)
Gastroenteropancreatic neuroendocrine tumors (metastatic)
Gastroesophageal variceal hemorrhage
Hepatorenal syndrome
Hypothalamic obesity
Malignant bowel obstruction
Postgastrectomy dumping syndrome
Small bowel fistulas
Sulfonylurea-induced hypoglycemia
Thymoma/thymic malignancies (advanced)
Zollinger-Ellison syndrome

Contraindications

Source: Lexicomp

Hypersensitivity to octreotide or any component of the formulation Absolute

Adverse Reactions

Very Common >10%Common 1–10%Uncommon 0.1–1% Rare 0.01–0.1%Very Rare <0.01%Not Known

Cardiac disorders (12)

Very Common chest pain · hypertension · palpitations · peripheral edema · Sinus bradycardia

Common angina pectoris · cardiac arrhythmia · Cardiac conduction disturbance · cardiac failure · edema · flushing · phlebitis

Nervous system disorders (22)

Very Common anxiety · confusion · dizziness · Fatigue · headache · hypoesthesia · insomnia · malaise · pain · paresthesia · rigors

Common Abnormal gait · amnesia · depression · drowsiness · hallucination · hypertonia · nervousness · neuralgia · neuropathy · vertigo · voice disorder

Renal and urinary disorders (6)

Very Common Nephrolithiasis

Common Impotence · mastalgia · pollakiuria · urinary incontinence · urinary tract infection

Blood and lymphatic system disorders (4)

Very Common Anemia

Common Bruise · hematoma · hypoproteinemia

Immune system disorders (1)

Very Common Antibody development

Metabolism and nutrition disorders (8)

Very Common Hyperglycemia · hypothyroidism

Common albuminuria · cachexia · Goiter · gout · hypoglycemia · hypokalemia

Gastrointestinal disorders (28)

Very Common abdominal cramps · abdominal pain · anorexia · biliary obstruction · cholelithiasis · constipation · Diarrhea · flatulence · gallbladder sludge · loose stools · nausea · vomiting

Common colitis · diverticulitis · dysgeusia · Dyspepsia · dysphagia · fecal discoloration · gastritis · gastroenteritis · gingivitis · glossitis · malabsorption · melena · steatorrhea · stomatitis · tenesmus · xerostomia

Skin and subcutaneous tissue disorders (6)

Very Common alopecia · diaphoresis · Pruritus · skin rash

Common Acne vulgaris · cellulitis

Musculoskeletal and connective tissue disorders (7)

Very Common arthralgia · arthropathy · Back pain · myalgia · weakness

Common Hyperkinesia · tremor

Eye disorders (2)

Common Blurred vision · visual disturbance

Ear and labyrinth disorders (2)

Very Common Otalgia

Common Tinnitus

Infections and infestations (4)

Common Abscess · bacterial infection · candidiasis · cold symptoms

General disorders and administration site conditions (3)

Very Common Fever · Pain at injection site

Common Hematoma at injection site

Respiratory, thoracic and mediastinal disorders (9)

Very Common cough · dyspnea · flu-like symptoms · pharyngitis · rhinitis · sinusitis · Upper respiratory tract infection

Common Bronchitis · epistaxis

Dosing

Source: Lexicomp

Acromegaly: SubQ, IV: Initial: 50 mcg 3 times/day; titrate to achieve growth hormone levels Note: Should be withdrawn yearly for a 4-week interval (8 weeks for depot injection) in patients who have received irradiation. Resume if levels increase and signs/symptoms recur. IM depot injection: Patients must be stabilized on subcutaneous octreotide for at least 2 weeks before switching to the long-acting depot. Upon switch: 20 mg IM intragluteally every 4 weeks for 3 months, then the dose may be modified based upon response. Dosage adjustment for acromegaly: After 3 months of depot injections, the dosage may be continued or modified as follows: GH ≤1 ng/mL, IGF-1 normal, and symptoms controlled: Reduce octreotide depot to 10 mg IM every 4 weeks GH ≤2.5 ng/mL, IGF-1 normal, and symptoms controlled: Maintain octreotide depot at 20 mg IM every 4 weeks GH >2.5 ng/mL, IGF-1 elevated, and/or symptoms uncontrolled: Increase octreotide depot to 30 mg IM every 4 weeks Note: Patients not adequately controlled at a dose of 30 mg may increase dose to 40 mg every 4 weeks. Dosages >40 mg are not recommended. Carcinoid tumors: SubQ, IV: Initial 2 weeks: 100 to 600 mcg/day in 2 to 4 divided doses; usual range: 50 to 750 mcg/day (some patients may require up to 1,500 mcg/day); experience with doses above 750 mcg/day is limited. IM depot injection: Patients must be stabilized on subcutaneous octreotide for at least 2 weeks before switching to the long-acting depot. Upon switch: 20 mg IM intragluteally every 4 weeks for 2 months, then the dose may be modified based upon response. Note: Patients should continue to receive their SubQ injections for the first 2 weeks at the same dose in order to maintain therapeutic levels (some patients may require 3 to 4 weeks of continued SubQ injections). Patients who experience periodic exacerbations of symptoms may require temporary SubQ injections in addition to depot injections (at their previous SubQ dosing regimen) until symptoms have resolved. Dosage adjustment for carcinoid tumors: After 2 months of depot injections, the dosage may be continued or modified as follows: Increase to 30 mg IM every 4 weeks if symptoms are inadequately controlled Decrease to 10 mg IM every 4 weeks, for a trial period, if initially responsive to 20 mg dose Dosage >30 mg is not recommended Vasoactive intestinal peptide tumors (VIPomas): SubQ, IV: Initial 2 weeks: 200 to 300 mcg/day in 2 to 4 divided doses; titrate dose based on response/tolerance. Range: 150 to 750 mcg/day (doses >450 mcg/day are rarely required) IM depot injection: Patients must be stabilized on subcutaneous octreotide for at least 2 weeks before switching to the long-acting depot. Upon switch: 20 mg IM intragluteally every 4 weeks for 2 months, then the dose may be modified based upon response. Note: Patients receiving depot injection should continue to receive their SubQ injections for the first 2 weeks at the same dose in order to maintain therapeutic levels (some patients may re

(For additional information see "Octreotide: Pediatric drug information") Infants and Children: Congenital hyperinsulinism (off-label use): SubQ: Initial: 2 to 10 mcg/kg/day; up to 40 mcg/kg/day have been used (Stanley 1997). Secretory diarrhea (off-label use): IV, SubQ: Doses of 1 to 10 mcg/kg every 12 hours have been used in children beginning at the low end of the range and increasing by 0.3 mcg/kg/dose at 3-day intervals. Suppression of growth hormone (animal data) is of concern when used as long-term therapy. Sulfonylurea-induced hypoglycemia (off-label use): Note: Although octreotide use has been advocated as a first line therapy, indications and dosing for octreotide are not firmly established (Glatstein 2012). Octreotide may reduce the incidence of recurrent hypoglycemia seen with dextrose-alone therapy (Fasano 2008). In addition, although subcutaneous administration is the preferred route, administration via intravenous bolus and intravenous infusion have also been described in the literature (Barkin 2013; Braatvedt 1997; Carr 2002; Crawford 2004; Dougherty 2010; Dougherty 2013; Fasano 2008; Graudins 1997; Green 2003; Hung 1997; McLaughlin 2000; Mordel 1998). Optimal care decisions should be made based upon patient-specific details. Repeat dosing, dose escalation, or initiation of a continuous infusion may be required in patients who experience recurrent hypoglycemia. Duration of treatment may exceed 24 hours. SubQ: 1 to 1.25 mcg/kg; repeat in 6 hours as needed based upon blood glucose concentrations (Howland 2011). Children generally need only a single dose (Dougherty 2013).

Refer to adult dosing. Elimination half-life is increased by 46% and clearance is decreased by 26%; dose adjustment may be required. Dosing should generally begin at the lower end of dosing range.

Regular injection (solution): Mild to severe impairment: There are no dosage adjustments provided in the manufacturer’s labeling. Severe impairment requiring dialysis: There are no specific dosage adjustments provided in the manufacturer’s labeling; however, a dosage adjustment may be needed since clearance is reduced by ~50%. Depot injection: Mild to severe impairment: No initial dosage adjustment necessary. Severe impairment requiring dialysis: Initial dose: 10 mg IM every 4 weeks; titrate based upon response (clearance is reduced by ~50%)

Regular injection (solution): There are no dosage adjustments provided in the manufacturer’s labeling. Half-life is prolonged and total body clearance is decreased in patients with cirrhosis and fatty liver disease. Depot injection: Patients with established cirrhosis of the liver: Initial dose: 10 mg IM every 4 weeks; titrate based upon response.

Warnings & Precautions

Source: Lexicomp

Abnormal Schillings test

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

Cholelithiasis

May impair gallbladder function (inhibits gallbladder contractility and decreases bile secretion); monitor patients for cholelithiasis. The incidence of gallbladder stone or biliary sludge increases with a duration of therapy of ≥12 months. Prophylactic cholecystectomy is recommended in patients with gastrointestinal or pancreatic neuroendocrine tumors undergoing abdominal surgery if octreotide treatment is planned (Oberg 2004).

Glucose regulation

Somatostatin analogs may affect glucose regulation. In type I diabetes, severe hypoglycemia may occur; in type II diabetes or patients without diabetes, hyperglycemia may occur. Insulin and other hypoglycemic medication requirements may change. Octreotide may worsen hypoglycemia in patients with insulinomas; use with caution.

Local reactions

Mild to moderate injection-site pain (usually lasting 1 hour) may occur with the depot formulation.

Hypothyroidism

Suppresses secretion of TSH; monitor for hypothyroidism.

Pancreatitis

May alter absorption of dietary fats; monitor for pancreatitis. Disease-related concerns:

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 fluid loss

May reduce excessive fluid loss in patients with conditions that cause such a loss; periodic monitoring for elevations in zinc levels is recommended in such patients that are maintained on total parenteral nutrition (TPN).

Hepatic impairment

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

Renal impairment

Use with caution in patients with renal impairment; dosage adjustment may be required in patients receiving dialysis. Concurrent drug therapy issues:

Drug-drug interactions

Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

QTc-prolonging agents

Octreotide may enhance the adverse/toxic effects of other QTc-prolonging agents. Dosage form specific issues:

Depot formulation

Do not use depot formulation for the treatment of sulfonylurea-induced hypoglycemia (Dougherty 2010).

Vehicle used in depot injection (polylactide-co-glycolide microspheres)

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

Elderly

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

Females

Therapy may restore fertility; females of childbearing potential should use adequate contraception.

Pediatric

Postmarketing 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 Other warnings/precautions:

Radiolabeled diagnostic evaluations

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

Pregnancy & Lactation

Pregnancy

FDA category B

Adverse events have not been observed in animal reproduction studies. Octreotide crosses the placenta and can be detected in the newborn at delivery (Caron 1995; Fassnacht 2001; Maffei 2010); data concerning use in pregnancy is limited. In case reports of acromegalic women who received normal doses of octreotide during pregnancy, no congenital malformations were reported. Because normalization of IGF-1 and GH may restore fertility in women with acromegaly, women of childbearing potential should use adequate contraception during treatment. Long-acting formulations should be discontinued ~2 months prior to a planned pregnancy; use short acting octreotide as needed until conception. Octreotide therapy may be considered in pregnant women with worsening symptoms if needed. Monitoring of IGF-1 and/or GH is not recommended during pregnancy (Katznelson 2014).

Lactation

Octreotide is excreted in breast milk. In a case report, a woman was taking octreotide SubQ in doses up to 2,400 mcg/day prior to and throughout pregnancy. Octreotide was measurable in the colostrum in concentrations similar to those in the maternal serum (Maffei 2010); however, oral absorption of octreotide is considered to be poor (Battershill 1989). The manufacturer recommends that caution be exercised when administering octreotide to nursing women.

Monitoring

Clinical pearl	Acromegaly: Growth hormone, somatomedin C (IGF-1) Carcinoid: 5-HIAA, plasma serotonin and plasma substance P VIPomas: Vasoactive intestinal peptide Chronic therapy: Thyroid function (baseline and periodic), vitamin B12 level, blood glucose, glycemic control and antidiabetic regimen (patients with diabetes mellitus), cardiac function (heart rate, ECG), zinc level (patients with excessive fluid loss maintained on TPN)

Clinical pearl

Acromegaly: Growth hormone, somatomedin C (IGF-1) Carcinoid: 5-HIAA, plasma serotonin and plasma substance P VIPomas: Vasoactive intestinal peptide Chronic therapy: Thyroid function (baseline and periodic), vitamin B12 level, blood glucose, glycemic control and antidiabetic regimen (patients with diabetes mellitus), cardiac function (heart rate, ECG), zinc level (patients with excessive fluid loss maintained on TPN)

Chemistry & Properties

Formula	C49H66N10O10S2
Molecular weight	1019.26 g/mol
IUPAC name	(4R,7S,10S,13R,16S,19R)-10-(4-aminobutyl)-19-[[(2R)-2-amino-3-phenylpropanoyl]amino]-16-benzyl-N-[(2R,3R)-1,3-dihydroxybutan-2-yl]-7-[(1R)-1-hydroxyethyl]-13-(1H-indol-3-ylmethyl)-6,9,12,15,18-pentaoxo-1,2-dithia-5,8,11,14,17-pentazacycloicosane-4-carboxamide
CAS	83150-76-9
PubChem CID	448601
InChIKey	`DEQANNDTNATYII-OULOTJBUSA-N`

SMILES

C[C@@H](O)[C@@H]1NC(=O)[C@H](CCCCN)NC(=O)[C@@H](Cc2c[nH]c3ccccc23)NC(=O)[C@H](Cc2ccccc2)NC(=O)[C@@H](NC(=O)[C@H](N)Cc2ccccc2)CSSC[C@@H](C(=O)N[C@H](CO)[C@@H](C)O)NC1=O

Biology & Pharmacokinetics

Pharmacokinetics predicted

Bioavailability	70.0%
Half-life	2.011 h
Volume of distribution	0.432 L/kg
Protein binding	19.6%
BBB penetrant	No

Enzyme interactions

Enzyme	Role	Detail
CYP2D6	Substrate	—

Receptor binding (top 6)

Target	Action	Affinity
SOMATOSTATIN SST2 (SSTR2)	Binding	pKi 9.2
SOMATOSTATIN SST5 (SSTR5)	Binding	pKi 8.1
SOMATOSTATIN SST3 (SSTR3)	Binding	pKi 8.0
OPIATE Mu (OPRM1)	Binding	pKi 7.9
SOMATOSTATIN SST4 (SSTR4)	Binding	pKi 6.3
SOMATOSTATIN SST1 (SSTR1)	Binding	pKi 6.3

Transporters

BCRP (Inhibitor)BSEP (Inhibitor)BSEP (Inhibitor)MRP1 (Inhibitor)MRP2 (Inhibitor)MRP3 (Inhibitor)MRP4 (Inhibitor)OATP1B1 (Inhibitor)OATP1B1 (Inhibitor)OATP1B3 (Inhibitor)P-gp (Inhibitor)MDR1 (Substrate)MRP2 (Substrate)P-gp (Substrate)

Drug–drug interactions (100+, DDInter)

Interacting drug	Severity	Management
Bexarotene	major
Copper oxodotreotide Cu-64	major
Lonafarnib	major
Pexidartinib	major
Telotristat ethyl	major
Acalabrutinib	moderate
Acarbose	moderate
Acebutolol	moderate
Acetohexamide	moderate
Adenosine	moderate
Albiglutide	moderate
Alogliptin	moderate
Amiodarone	moderate
Amlodipine	moderate
Atenolol	moderate
Avapritinib	moderate
Bepridil	moderate
Betaxolol	moderate
Betaxolol (ophthalmic)	moderate
Bisoprolol	moderate
Bromocriptine	moderate
Canagliflozin	moderate
Carteolol	moderate
Carteolol (ophthalmic)	moderate
Carvedilol	moderate
Chlorpropamide	moderate
Cyclosporine	moderate
Dapagliflozin	moderate
Digitoxin	moderate
Digoxin	moderate
Dihydroergotamine	moderate
Diltiazem	moderate
Disopyramide	moderate
Dofetilide	moderate
Dotatate	moderate
Dronedarone	moderate
Dulaglutide	moderate
Duvelisib	moderate
Empagliflozin	moderate
Entrectinib	moderate

Showing 40 of 100+.

Registered Products (7)

Brand	Form / strength	Pack	Agent	Citizen (JOD)
Octride	Ampoule 100 mcg/ml	1 ampoule	Reda Jardaneh Drug Store	2.540
Sandostatin 100 mcg/ml Solution for Injection	Injection 100 mcg/ml	5 amp	The Jordan Drugstore Co	23.940
Jintrotide	Vial 0.1 mg	10 vial	Reda Jardaneh Drug Store	28.770
Syngro	Pre-filled Syringe 10 mg	1 vial	Hikma Pharmaceuticals Co.Ltd/Jordan	132.680
Sandostatin LAR Vial	Vial 20 mg	1 PFS	The Jordan Drugstore Co	—
Syngro	Pre-filled Syringe (as acetate) 30 mg	1 vial	Hikma Pharmaceuticals Co.Ltd/Jordan	—
Syngro	Pre-filled Syringe (as actetate) 20 mg	1 vial	/ HIKMA PHARMACEUTICALS.IND/JORDAN / General / / HIKMA PHARMACEUTICALS.IND/JORDAN / General / Genera	—