Octreotide

Article Author:
Dipanjan Debnath
Article Editor:
Pramil Cheriyath
Updated:
7/6/2019 11:11:54 AM
PubMed Link:
Octreotide

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]


References

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[2] 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 PMID: 28526153]
[3] Wolin EM, The expanding role of somatostatin analogs in the management of neuroendocrine tumors. Gastrointestinal cancer research : GCR. 2012 Sep;     [PubMed PMID: 23112884]
[4] Colao A,Merola B,Ferone D,Lombardi G, Acromegaly. The Journal of clinical endocrinology and metabolism. 1997 Sep;     [PubMed PMID: 9284694]
[5] 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 PMID: 19769624]
[6] Sanyal AJ, Octreotide and its effects on portal circulation. Gastroenterology. 2001 Jan;     [PubMed PMID: 11208741]
[7] McKeage K,Cheer S,Wagstaff AJ, Octreotide long-acting release (LAR): a review of its use in the management of acromegaly. Drugs. 2003;     [PubMed PMID: 14609359]
[8] 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 PMID: 25356808]
[9] 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 PMID: 11965606]
[10] 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 PMID: 6128648]