Octreotide


Article Author:
Dipanjan Debnath


Article Editor:
Pramil Cheriyath


Editors In Chief:
Kranthi Sitammagari
Mayank Singhal


Managing Editors:
Avais Raja
Orawan Chaigasame
Carrie Smith
Abdul Waheed
Khalid Alsayouri
Trevor Nezwek
Radia Jamil
Erin Hughes
Patrick Le
Anoosh Zafar Gondal
Saad Nazir
William Gossman
Hassam Zulfiqar
Hussain Sajjad
Steve Bhimji
Muhammad Hashmi
John Shell
Matthew Varacallo
Heba Mahdy
Ahmad Malik
Sarosh Vaqar
Mark Pellegrini
James Hughes
Beata Beatty
Beenish Sohail
Nazia Sadiq
Hajira Basit
Phillip Hynes


Updated:
7/6/2019 11:11:54 AM

Indications

The primary FDA-approved indications of octreotide, seen by clinical studies, are for the treatment of acromegaly and thyrotrophinomas. In patients with acromegaly, octreotide has been documented to be clinically more effective than bromocriptine, through multiple clinical trials comparing both drugs. In the management of carcinoid syndrome, octreotide has been found to be more beneficial over the current treatment options, especially in cases of carcinoid crises, where it has shown to provide improved clinical outcomes. Additionally, in patients with tumors producing increased vasoactive intestinal peptide, such as VIPoma, especially those which have already metastasized and have become refractory to traditional symptomatic therapy, octreotide could be the drug of choice as evidenced by few clinical trials. Despite limited research, octreotide has been proven to be a first line therapy for stool or fistula output reduction in patients with high-output secretory diarrhea, such as those caused by cryptosporidium, especially seen in AIDS patients and those with small intestinal fistulas. Initial studies regarding the use of octreotide have provided positive outcomes in various conditions such as hyperinsulinemia induced neonatal hypoglycemia, insulin-dependent diabetes mellitus, reactive pancreatitis, dumping syndrome, and postprandial hypotension, however,  further studies are required to identify and document the utility of octreotide in the above diseases, before being incorporated in treatment guidelines.[1]

Octreotide is also used off-label, not approved by FDA, in diarrhea which is refractory or persistent, that associated with chemotherapy and with graft-versus-host disease and AIDS-associated diarrhea caused by cryptosporidiosis.[2] Also, octreotide has found use in metastatic gastroenteropancreatic neuroendocrine tumors,[3] advanced thymoma and other thymic malignancies, prevention of carcinoid crisis, hepatorenal syndrome, hypoglycemia due to sulfonylurea, congenital hyperinsulinism,  ectopic  Cushing syndrome, hypothalamic obesity, Zollinger-Ellison syndrome, dumping syndrome after gastrectomy, and small intestinal fistulas.

USE OF OCTREOTIDE IN PREGNANT AND LACTATING PATIENTS           

Octreotide is a category B medication, as per FDA, which indicates that no documentation exists of identifiable fetal risk in animal reproduction studies and studies involving pregnant women are inadequate and ill-defined presently.[2]

Although studies regarding octreotide use during breastfeeding are few,[4] in various case reports with patients receiving the subcutaneous form octreotide, there was a significant level of the drug found in breast milk, almost at similar concentrations found in serum.[5] However, further studies showed that the oral absorption of octreotide was not very efficient.[1]

USE OF OCTREOTIDE IN PEDIATRIC POPULATION                                                         

In pediatric patients, especially those under the age of 6 years, evaluation of the efficacy and safety of octreotide remains undetermined due to a lack of well documented randomized controlled clinical trials. In multiple clinical trials and reports regarding octreotide use in the pediatric age group, especially in children less than 2 years of age serious adverse events, including and not limited to hypoxia, necrotizing enterocolitis, and fatal outcomes, have been documented. No well-established relationship between the adverse events and octreotide yet exists as most of the patients in the pediatric age group had clinically significant comorbid conditions.

USE OF OCTREOTIDE IN GERIATRIC POPULATION                                                           

Clinical studies involving octreotide have not included sufficient numbers of subjects aged 65 and older; hence, it has been challenging to establish the response of the geriatric population to octreotide compared to younger adults. However, extreme caution needs to be exercised during dose selection for the geriatric population, with initial lower doses and careful titration thereafter, considering the higher frequency of decreased cardiac, hepatic, and renal function, and of other comorbid diseases or other drug therapies.[2]

Mechanism of Action

Octreotide is an analog of the polypeptide hormone, somatostatin.[1] Octreotide acts on the somatostatin receptors, which couple to phospholipase C via inhibitory G proteins, and causes vascular smooth muscle contraction. The alpha and beta-gamma subunits of the G proteins inhibit adenyl cyclase and stimulate phospholipase C, respectively. At a cellular level, like somatostatin, octreotide induces an increase in calcium entry via L-type calcium channels, which leads to increased calcium-induced calcium release via ryanodine receptor calcium release channels from the sarcoplasmic reticulum in the smooth muscle cells, thus, activating myosin light-chain kinase, via its interaction with calcium-calmodulin, and therefore, initiating the contraction cycle. In addition, the release of calcium from the sarcoplasmic reticulum is also due to the formation of 1, 4,5-inositol triphosphate, potentiated by phospholipase C[6] Hence, octreotide, similar to the action of endogenous somatostatin, inhibits the release of hormones from the anterior pituitary gland, including thyroid-stimulating hormone and growth hormone, and hormones of the gastroenteropancreatic endocrine system such as insulin and glucagon[1]

Administration

There are no oral formulations available for octreotide. Octreotide administration may be through a subcutaneous or intravenous route.  It is usually administered as an octreotide acetate injection, either as a subcutaneous or a long-acting release form. Compared to subcutaneous octreotide, the bioavailability of the long-acting release form is relatively low at about 60%. The subcutaneous form is available either as sterile 1-mL ampules in three strengths;  50 mg, 100 mg a, d  500 mg, or a  sterile 5-mL multidose vials in two strengths; 200 mg/mL and 1000 mg/mL. They are usually dosed at three-times-daily, whereas the long-acting release form is a depot formulation containing 10- to 30-mg dose of octreotide, and is available in three strengths;  10 mg per 6 mL,  20 mg per 6 mL and  30 mg per 6 mL, which is usually administered intramuscularly every 28 days[2][7]

Adverse Effects

  1. Gastrointestinal abnormalities (34% to 61%) are transient and mild to moderate and include diarrhea, nausea, abdominal discomfort, gallbladder abnormalities, such as cholelithiasis and microlithiasis, biliary sediment and sludge due to alteration of fat absorption and possibly by decreasing motility of the gallbladder.[7]
  2. [7]Bradycardia occurs in 25% of patients with acromegaly, conduction abnormalities (10%) and arrhythmias (9%).
  3. Hypoglycemia (3%) and hyperglycemia (16%) occur due to alteration in glucose metabolism; usually mild in severity.
  4. Hypothyroidism: In patients with acromegaly, subclinical hypothyroidism occurred in 12% and goiter occurred in 6% during treatment with octreotide acetate. In patients without acromegaly, isolated cases of hypothyroidism have been reported. However, there was no incidence of goiter in this subset of patients.
  5. Dermatologic: Itching (18%).[2]
  6. Pain at the injection site (7.7%).[1]
  7. Headache and dizziness (6%).
  8. Other side effects, documented in less than 4% of patients on octreotide, include cold and flu symptoms, weakness, fatigue, depression, blurred vision, pruritus, hair loss, vision disturbance, flushing of the skin, arthralgia, lower back pain, increased urinary frequency especially during waking hours, and urinary tract infection, edema, bruising and hematoma formation at the injection site, and malabsorption of fat and other nutrients.[2]

Contraindications

Hypersensitivity reaction on administration, due to octreotide or any of its components is the main contraindication to its future use. Octreotide should also be used very cautiously in patients with insulinoma and type 2 diabetes mellitus who require intensive blood glucose monitoring and control because it can lower glucose levels dramatically and reduce the insulin requirements in these patients by up to 50%. Therefore, serum glucose concentrations should be monitored carefully during octreotide therapy.  Octreotide also increases the bioavailability of bromocriptine by up to 40%, which is a matter of concern because octreotide and bromocriptine are used in the treatment of acromegaly.  Octreotide may also lead to bradycardia, arrhythmias, or conduction defects and, therefore, should be used with caution in the at-risk groups of patients.[2]

Monitoring

Octreotide, being a somatostatin analog, requires close monitoring because of the numerous physiological actions of somatostatin in the body. Additionally, various markers are specific indicators of the therapeutic effect of octreotide and response of our body to drug therapy.

In the treatment of acromegaly, serum growth hormone (GH) and insulin-like growth factor (IGF) require monitoring. However, the frequency of monitoring differs by the formulation of octreotide administered. Use of the short-acting formulation requires measurement of serum IGF-1 only once, around 14 days after initiating octreotide therapy or after any change in dose, or a GH assay after every 1 to -4 hours for 8 to 12 hours after administration of every dose. The use of octreotide’s newer long-acting formulation needs less intensive monitoring in the form of a serum GH assay and a serum IGF-1assay around 3 months before administration of the subsequent dose. The maintenance phase in the treatment of acromegaly also requires monitoring to detect delayed adverse effects. Hence, serum GH and serum IGF-1 levels should be obtained every 3 to 6 months.

During the management of carcinoid syndrome, the measurement of 5-hydroxyindole-acetic acid, serotonin, and substance P levels are necessary.

Octreotide treatment for VIPomas requires periodic measurement of the vasoactive intestinal peptide, to monitor tumor burden and risk of relapse.

In addition to the above, patients on long term octreotide therapy require monitoring of various clinical parameters, both at baseline and periodically, for prevention and early detection of adverse effects. These effects include blood glucose levels, including monitoring of glycemic control in patients with type 2 diabetes mellitus, cardiac function with periodic electrocardiograms, thyroid function tests, plasma vitamin B and zinc, especially in patients receiving total parenteral nutrition who are at risk of  excessive fluid loss, and abdominal ultrasound to look for abnormalities of the gall bladder in the presence of clinical findings.[8]

Toxicity

Limited studies have assessed octreotide toxicity. However, isolated studies have shown a mild degree of bone marrow suppression and impairment in spermatogenesis due to inhibition of serum inhibin B and concomitant increase in FSH in supratherapeutic doses. There is a need to conduct significantly larger studies and trials to define and establish the therapeutic index of octreotide and identify its toxic effects and its management.[9]

Enhancing Healthcare Team Outcomes

Although it has been a few decades since the synthesis of octreotide,[10] its use has limitations to a few indications. However, in recent times, octreotide has found utility in various other previously unexplored therapeutic modalities. Although the understanding of octreotide is increasing due to the numerous studies and clinical trials, however, further reviews and trials are required for a better understanding of the pharmacokinetics and pharmacodynamics of the drug to recognize better and control the adverse effects of octreotide. Also, there is a need for coordination amongst the members of the healthcare team to enhance evidence-based outcomes for patients on octreotide therapy.

 Octreotide therapy requires an interprofessional team approach, including physicians, specialists, specialty-trained nurses, and pharmacists, all collaborating across disciplines to achieve optimal patient results. [Level V]


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Octreotide - Questions

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Which is a treatment for endocrine tumors that secrete vasoactive intestinal peptide or growth hormone?



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Which of the following is not an effect of octreotide?



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In what percentage of patients does octreotide causes cholecystitis?



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A 65-year-old man is brought to the emergency department for a 1-day history of mild nausea and dyspepsia that is worse with fasting and improves after eating. He has also had a 12-hour history of weakness and frequent black stools. He does not drink alcohol. He has no history of gastrointestinal bleeding, bleeding disorders, chronic liver disease, cardiovascular disease, or malignancy. On physical examination, the temperature is 37.0 C (98.6 F), blood pressure is 110/60 mmHg, pulse rate is 96/min, respiration rate is 16/min, and BMI is 35. Abdominal examination reveals tenderness in the epigastrium without guarding or rebound. Rectal examination shows the presence of blood in stools. Laboratory studies revealed a hemoglobin level of 7.4 g/dL. He is admitted to the hospital and is resuscitated with intravenous fluids and given IV pantoprazole. On Upper GI endoscopy, a 1.5-cm clean-based gastric ulcer is identified, with several lower esophageal varices. Which of the following is the most appropriate next step in management?



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A 65-year-old woman is hospitalized for altered mental status. She has alcoholic cirrhosis complicated by ascites. There is no history of fever, hematemesis, hematochezia, or melena. Her medications include lactulose, furosemide, and spironolactone. On physical examination, the temperature is 36.4 C (97.5 F), blood pressure is 142/94 mmHg, pulse rate is 73/min, respiration rate is 17/min, and BMI is 26 kg/m2. She is disoriented to time, place and person. Scleral icterus, multiple spider angiomata, and asterixis are present. The mucous membranes are dry. The abdominal examination confirms ascites. Laboratory studies show bilirubin 3.5 mg/dL (59.9 µmol/L), albumin 2.6 g/dL (26 g/L), INR 1.4 (normal range, 0.8-1.2), blood urea nitrogen (BUN) 38 mg/dL (13.6 mmol/L), and creatinine 2.5 mg/dL (221 µmol/L). The urinalysis is normal. Her diuretics and lactulose were discontinued. She was given an albumin challenge, however, she did not improve. Which of the following is the most appropriate treatment in this patient?



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A 65-year-old woman with advanced serous epithelial carcinoma of the ovary presents to the emergency department with a 2-day history of nausea, vomiting, and abdominal pain. On physical examination, the temperature is 39.1 C (102.4 F), blood pressure is 110/75 mmHg, pulse rate is 92/min, and respiration rate is 16/min. She has diffuse abdominal pain with tenderness, guarding, and rebound phenomena. The chest is clear to auscultation and percussion. There are no heart murmurs, and no palpable lymphadenopathy is noted. She underwent an erect abdominal X-ray which showed multiple air-fluid levels. A supine abdominal X-ray showed dilated bowel loops. Which of the following treatments is most likely to improve her symptoms?

Attributed To: Contributed by Michael Schick DO, MA



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A 65-year-old male with acromegaly presented to his healthcare provider with vision disturbance. Imaging was done which revealed a growth hormone secreting macroadenoma. He underwent trans-sphenoidal pituitary resection. Five months after the surgery, his insulin-like growth factor type I (IGF-I) concentration is elevated. A magnetic resonance imaging (MRI) of the brain reveals a residual and inoperable tumor confined to the right cavernous sinus. Which of the following is the most appropriate management?



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A 65-year-old woman is evaluated for a 3-day history of fever, nausea, vomiting and abdominal pain localized to the right lower quadrant. Her past medical history is unremarkable, and she takes no medications. On physical examination, the temperature is 39.1 C (102.4 F), blood pressure is 112/72 mm Hg, pulse rate is 94/min, and respiration rate is 18/min. There is right lower quadrant abdominal pain with tenderness, guarding, and rebound phenomena. The chest is clear to auscultation with no heart murmurs. No lymphadenopathy is present. Contrast-enhanced CT scan of the abdomen and pelvis shows acute appendicitis. No other abnormalities are seen. The patient undergoes a laparoscopic appendectomy. Histologic examination shows acute appendicitis with a well-differentiated tumor, 1 cm in diameter. On further evaluation, it is determined that this tumor has a neuroendocrine cell origin. Which of the following is the most appropriate management?

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  • Image 1707 Not availableImage 1707 Not available
    Contributed by Scott Dulebohn, MD
Attributed To: Contributed by Scott Dulebohn, MD



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Octreotide - References

References

Battershill PE,Clissold SP, Octreotide. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic potential in conditions associated with excessive peptide secretion. Drugs. 1989 Nov;     [PubMed]
Borna RM,Jahr JS,Kmiecik S,Mancuso KF,Kaye AD, Pharmacology of Octreotide: Clinical Implications for Anesthesiologists and Associated Risks. Anesthesiology clinics. 2017 Jun;     [PubMed]
Sanyal AJ, Octreotide and its effects on portal circulation. Gastroenterology. 2001 Jan;     [PubMed]
McKeage K,Cheer S,Wagstaff AJ, Octreotide long-acting release (LAR): a review of its use in the management of acromegaly. Drugs. 2003;     [PubMed]
Maffei P,Tamagno G,Nardelli GB,Videau C,Menegazzo C,Milan G,Calcagno A,Martini C,Vettor R,Epelbaum J,Sicolo N, Effects of octreotide exposure during pregnancy in acromegaly. Clinical endocrinology. 2010 May;     [PubMed]
Colao A,Merola B,Ferone D,Lombardi G, Acromegaly. The Journal of clinical endocrinology and metabolism. 1997 Sep;     [PubMed]
Katznelson L,Laws ER Jr,Melmed S,Molitch ME,Murad MH,Utz A,Wass JA, Acromegaly: an endocrine society clinical practice guideline. The Journal of clinical endocrinology and metabolism. 2014 Nov;     [PubMed]
Valkema R,De Jong M,Bakker WH,Breeman WA,Kooij PP,Lugtenburg PJ,De Jong FH,Christiansen A,Kam BL,De Herder WW,Stridsberg M,Lindemans J,Ensing G,Krenning EP, Phase I study of peptide receptor radionuclide therapy with [In-DTPA]octreotide: the Rotterdam experience. Seminars in nuclear medicine. 2002 Apr;     [PubMed]
Bauer W,Briner U,Doepfner W,Haller R,Huguenin R,Marbach P,Petcher TJ,Pless, SMS 201-995: a very potent and selective octapeptide analogue of somatostatin with prolonged action. Life sciences. 1982 Sep 13;     [PubMed]
Wolin EM, The expanding role of somatostatin analogs in the management of neuroendocrine tumors. Gastrointestinal cancer research : GCR. 2012 Sep;     [PubMed]

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