OVERVIEW

PRODUCT INFORMATION

CHEMICAL FORMULAS AND STRUCTURES

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DRUG	CAS REGISTRY NO.	MOLECULAR FORMULA	STRUCTURE
Lanreotide	108736-35-2	C54-H69-N11-O10-S2
Octreotide	83150-76-9	C49-H66-N10-O10-S2
Pasireotide	396091-73-9	C58-H66-N10-O9
Somatostatin	51110-01-1	Protein	Not Available

ANNOTATED BIBLIOGRAPHY

References updated: 30 March 2016

• Zimmerman HJ. Hepatic injury from the treatment of infectious and parasitic diseases. In, Zimmerman HJ. Hepatotoxicity: the adverse effects of drugs and other chemicals on the liver. 2nd ed. Philadelphia: Lippincott, 1999, pp. 589-637.

  (Expert review of hepatotoxicity published in 1999, mentions that octreotide has been implicated in several cases of acute hepatocellular injury which subsided after drug withdrawal).
• Kaplowitz N, DeLeve LD, eds. Drug-induced Liver Disease. 3rd edition. Amsterdam: Elsevier, 2013.

  (Multiauthored text book on drug induced liver injury; does not discuss octreotide).
• Sharkey KA, Wallace JL. Treatment of disorders of bowel motility and water flux: anti-emetics; agents used in biliary and pancreatic disease. In, Brunton LL, Chabner BA, Knollman BC, eds. Goodman & Gilman’s the pharmacological basis of therapeutics. 12th ed. New York: McGraw-Hill, 2011, pp. 1323-49.

  (Textbook of pharmacology and therapeutics).
• Kvols LK, Moertel CG, O'Connell MJ, Schutt AJ, Rubin J, Hahn RG. Treatment of the malignant carcinoid syndrome. Evaluation of a long-acting somatostatin analogue. N Engl J Med 1986; 315: 663-6. [PubMed: 2427948]

  (Among 25 patients with metastatic carcinoid tumors treated with octreotide for 2 to 18 months, tolerance was “excellent” and “no evidence of …hepatic... toxicity was found”).
• Arosio M, Bazzoni N, Ambrosi B, Faglia G. Acute hepatitis after treatment of acromegaly with octreotide. Lancet 1988; 2 (8626-8627): 1498. [PubMed: 2904619]

  (50 year old man with acromegaly developed abnormal liver tests without symptoms 5 months after starting octreotide [ALT 143 U/L, Alk P 1269 U/L, bilirubin not given], which resolved within 3 weeks of stopping and arose again with jaundice 3 months after restarting [bilirubin 12.8 mg/dL, ALT 2140 U/L, Alk P 1324 U/L], resolving again within 2 months of stopping).
• Ho KY, Weissberger AJ, Marbach P, Lazarus L. Therapeutic efficacy of the somatostatin analog SMS 201-995 (octreotide) in acromegaly. Effects of dose and frequency and long-term safety. Ann Intern Med 1990; 112: 173-81. [PubMed: 2404445]

  (Among 18 patients with acromegaly treated with octreotide for at least one year, 9 [50%] developed gallstones, which were “small and numerous” and 2 [11%] developed symptoms and underwent cholecystectomy).
• Daughaday WH. Octreotide is effective in acromegaly but often results in cholelithiasis. Ann Intern Med 1990; 112: 159-60. [PubMed: 2404444]

  (Editorial in response to Ho [1990] on the safety of octreotide in acromegaly recommends that it be limited to cases refractory to surgery).
• Minocha A, Dean HA Jr. Octreotide-induced acute hepatic toxicity. Am J Gastroenterol 1991; 86: 525. [PubMed: 2012056]

  (53 year old man with cirrhosis and variceal hemorrhage developed serum enzyme elevations within 12 hours of starting infusions of octreotide [bilirubin levels not given, ALT rising from 59 to 1190 U/L, Alk P 81-151 U/L], enzymes decreasing rapidly upon stopping).
• Catnach SM, Anderson JV, Fairclough PD, Trembath RC, Wilson PA, Parker E, Besser GM, Wass JA. Effect of octreotide on gall stone prevalence and gall bladder motility in acromegaly. Gut 1993; 34: 270-3. [PMC free article: PMC1373983] [PubMed: 8432484]

  (Gallstones were found by ultrasound in 34% of 39 acromegalic patients who had received octreotide vs 16% of 38 patients who had not).
• Hussaini SH, Pereira SP, Murphy GM, Kennedy C, Wass JA, Besser GM, Dowling RH. Composition of gall bladder stones associated with octreotide: response to oral ursodeoxycholic acid. Gut 1995; 36: 126-32. [PMC free article: PMC1382366] [PubMed: 7890216]

  (Among 14 patients with acromegaly who were treated with octreotide and had gall bladder stones, chemical analysis in 2 showed cholesterol-rich stones; gall bladder bile in 6 was supersaturated with cholesterol; and ursodiol therapy resulted in partial or complete stone dissolution in 5 of 9 subjects).
• González-Martín JA, Donnay S, Morillas J, Gómez-Aparicio C, Garcia-Cano J, Pérez-Vigara G, Roldán A. Acute liver injury and octreotide. Am J Gastroenterol 1996; 91: 2434-5. [PubMed: 8931436]

  (54 year old woman with acromegaly developed marked ALT elevations within a day of starting octreotide [ALT 538 U/L, GGT 133 U/L, bilirubin normal], which resolved within 2 weeks of stopping and recurred on rechallenge with a single dose [ALT 673 U/L]).
• Radetti G, Gentili L, Paganini C, Messner H. Cholelithiasis in a newborn following treatment with the somatostatin analogue octreotide. Eur J Pediatr 2000; 159: 550. [PubMed: 10923237]

  (Newborn with congenital hyperinsulinemia developed jaundice 5 weeks after starting octreotide [bilirubin direct 3.6 and total 3.9 mg/dL, ALT 152 U/L, GGT 187 U/L], ultrasound showed stones in gall bladder and common duct, and abnormalities resolved within 6 weeks of lowering the octreotide dose and starting ursodiol).
• Sheehan MT, Nippoldt TB. Hepatolithiasis (intrahepatic stone) during octreotide therapy for acromegaly: a case report. Pituitary 2000; 3: 227-30. [PubMed: 11788010]

  (27 year old man with acromegaly developed symptomatic cholelithiasis 5 years after starting octreotide and 2 years after cholecystectomyand presented later with recurrent painful intrahepatic stone disease [bilirubin 4.1 mg/dL, ALT 614 U/L, Alk P 192 U/L], ultimately requiring surgery).
• Crook MA, Steger A. Abnormal liver function tests in a patient fed with total parenteral nutrition and treated with octreotide. Nutrition 2001; 17: 152-4. [PubMed: 11240342]

  (54 year old woman with complications after cholecystectomy developed modest rises in liver tests on octreotide which worsened on parenteral nutrition [peak bilirubin 2.1 mg/dL, ALT 183 U/L, Alk P 199 U/L], resolving completely only when both were stopped).
• Thomas LA, Veysey MJ, Murphy GM, Russell-Jones D, French GL, Wass JA, Dowling RH. Octreotide induced prolongation of colonic transit increases faecal anaerobic bacteria, bile acid metabolising enzymes, and serum deoxycholic acid in patients with acromegaly. Gut 2005; 54: 630-5. [PMC free article: PMC1774470] [PubMed: 15831907]

  (Octreotide caused increases in colonic transit times which affected deoxycholic acid levels in stool and serum, changes which might result in an increased risk for gallstones).
• Feenstra J, van Aken MO, de Herder WW, Feelders RA, van der Lely AJ. Drug-induced hepatitis in an acromegalic patient during combined treatment with pegvisomant and octreotide long-acting repeatable attributed to the use of pegvisomant. Eur J Endocrinol 2006; 154: 805-6. [PubMed: 16728538]

  (45 year old man with acromegaly developed abnormal liver tests 5 months after pegvisomant [growth hormone receptor antagonist] was added to octreotide therapy [ALT 1148 U/L, Alk P 149 U/L, bilirubin not given], which decreased when pegvisomant was stopped and recurred when it was restarted alone without octreotide).
• Reuben A, Koch DG, Lee WM; Acute Liver Failure Study Group. Drug-induced acute liver failure: results of a U.S. multicenter, prospective study. Hepatology 2010; 52: 2065-76. [PMC free article: PMC3992250] [PubMed: 20949552]

  (Among 1198 patients with acute liver failure enrolled in a US prospective study between 1998 and 2007, 133 were attributed to drug induced liver injury, but none were due to octreotide).
• Avatapalle B, Padidela R, Randell T, Banerjee I. Drug-induced hepatitis following use of octreotide for long-term treatment of congenital hyperinsulinism. BMJ Case Rep 2012; 2012. [PMC free article: PMC4543377] [PubMed: 22850563]

  (Baby girl with refractory congenital hyperinsulinemia developed rising ALT on high doses of octreotide [peak ALT 1061 U/L with normal Alk P and bilirubin], with “normal” liver biopsy and rapid resolution on stopping octreotide).
• Ben-Ari J, Greenberg M, Nemet D, Edelstein E, Eliakim A. Octreotide-induced hepatitis in a child with persistent hyperinsulinemia hypoglycemia of infancy. J Pediatr Endocrinol Metab 2013; 26: 179-82. [PubMed: 23327813]

  (8 month old boy with congenital hyperinsulinemia developed liver test abnormalities on high doses of octreotide [ALT 535 U/L, AST 1065 U/L, with normal Alk P and bilirubin], liver biopsy showing portal inflammation and “hydropic degeneration”, resolving within 4 days of stopping).
• Koren I, Riskin A, Barthlen W, Gillis D. Hepatitis in an infant treated with octreotide for congenital hyperinsulinism. J Pediatr Endocrinol Metab 2013; 26: 183-5. [PubMed: 23327817]

  (9 month old girl with congenital hyperinsulinemia developed abnormal liver tests 4 months after starting high doses of octreotide [peak ALT >1000 U/L with minimal increases in Alk P and GGT and normal bilirubin], falling to normal within 1 month of stopping).
• Björnsson ES, Bergmann OM, Björnsson HK, Kvaran RB, Olafsson S. Incidence, presentation and outcomes in patients with drug-induced liver injury in the general population of Iceland. Gastroenterology 2013; 144: 1419-25. [PubMed: 23419359]

  (Systematic review of literature of drug induced liver injury in Latin American countries published from 1996 to 2012 identified 176 cases, the most common implicated agents being nimesulide [n=53: 30%], cyproterone [n=18] and nitrofurantoin [n=17]; no case was attributed to octreotide).
• Levy-Khademi F, Irina S, Avnon-Ziv C, Levmore-Tamir M, Leder O. Octreotide-associated cholestasis and hepatitis in an infant with congenital hyperinsulinism. J Pediatr Endocrinol Metab 2015; 28: 449-51. [PubMed: 25324442]

  (3 month of boy with congenital hyperinsulinemia had fluctuating liver test abnormalities on octreotide therapy [bilirubin rising to 20.1 mg/dL, direct 17 mg/dL, ALT 538 U/L, Alk P normal] and rapid recovery upon stopping).
• Visentin M, Stieger B, Merz M, Kullak-Ublick GA. Octreotide inhibits the bilirubin carriers organic anion transporting polypeptides 1B1 and 1B3 and the multidrug resistance-associated protein 2. J Pharmacol Exp Ther 2015; 355: 145-51. [PubMed: 26330539]

  (Studies using cell lines and membrane vesicles showed that octreotide inhibited several membrane transport proteins which are involved in bilirubin uptake and secretion).
• Melmed S, Popovic V, Bidlingmaier M, Mercado M, van der Lely AJ, Biermasz N, Bolanowski M, et al. Safety and efficacy of oral octreotide in acromegaly: results of a multicenter phase III trial. J Clin Endocrinol Metab 2015; 100: 1699-708. [PubMed: 25664604]

  (Among 155 patients with acromegaly switched from injectable therapy to oral octreotide, the majority had a durable beneficial effect and side effects were those typical of octreotide, 18 [12%] had a “hepatobiliary” disorder and 12 [8%] developed gallstones; while “clinically meaningful alterations were not observed in laboratory safety parameters”, although 2 patients are described who developed ALT elevations and jaundice).
• Chalasani N, Bonkovsky HL, Fontana R, Lee W, Stolz A, Talwalkar J, Reddy KR, et al.; United States Drug Induced Liver Injury Network. Features and outcomes of 899 patients with drug-induced liver injury: The DILIN Prospective Study. Gastroenterology 2015; 148: 1340-52.e7. [PMC free article: PMC4446235] [PubMed: 25754159]

  (Among 899 cases of drug induced liver injury enrolled in a US prospective study between 2004 and 2013, one case was judged probably due to octreotide, a 67 year old woman with severe heart disease, diabetes and gastrointestinal bleeding developed marked cholestasis [peak bilirubin 49.3 mg/dL, ALT 533 U/L, Alk P 1482 U/L] while in the intensive care unit receiving octreotide and multiple other medications).