Octreotide

Octreotide is a metabolically stabilised eight-residue mimic of native somatostatin-14, with high affinity for SSTR2, moderate affinity for SSTR5 and little for SSTR1, SSTR3 or SSTR4. Receptor binding is Gi-coupled: it lowers cyclic AMP, closes voltage-gated calcium channels and opens potassium channels, which shuts down hormone exocytosis from pituitary somatotrophs, pancreatic islets and neuroendocrine tumour cells. In acromegaly this reduces GH and downstream IGF-1; in carcinoid and VIPoma it reduces serotonin and vasoactive intestinal peptide release. Antiproliferative effects on neuroendocrine tumours through SSTR2-mediated phosphatase signalling are established well enough that the drug is used for tumour control, not only symptom control.

Targets: SSTR2, SSTR5, Growth hormone secretion, Serotonin and VIP release

• · Usual maintenance is 100 mcg three times daily; doses above 300 mcg per day rarely add benefit.
• · Label range is 100 to 600 mcg per day; a few patients need up to 1500 mcg per day.
• · 10, 20 or 30 mg every 4 weeks. Immediate-release cover is continued for the first two weeks after the first depot dose.
• · Start 20 mg twice daily, maximum 40 mg twice daily. Food dramatically reduces absorption.

Work out your exact syringe units →

• very commonDiarrhoea, abdominal cramping and flatulence— Worst in the first two weeks and usually settles.
• very commonGallstones and biliary sludge— Roughly half of patients on long-term therapy develop them; most stay asymptomatic but some need cholecystectomy.
• commonHyperglycaemia or hypoglycaemia— Suppresses insulin and glucagon together, so glucose can move in either direction.
• commonInjection-site pain and induration— More pronounced with the depot.
• uncommonBradycardia and conduction changes— Relevant in patients already on rate-limiting drugs.
• uncommonVitamin B12 malabsorption— Worth checking on multi-year therapy.

• Known hypersensitivity to octreotide
• Uncontrolled symptomatic cholelithiasis without a plan to manage it
• Caution in insulin-treated diabetes, where insulin requirements usually fall

• cautioninsulin-icodec — Octreotide suppresses insulin secretion and alters glucose handling; insulin doses frequently need reduction.
• synergypegvisomant — Combined somatostatin analogue plus GH receptor antagonist is a standard second-line acromegaly regimen.
• redundantpasireotide — Same receptor family; they are alternatives, not a stack.

• · IGF-1 and random GH every 3 to 6 months in acromegaly
• · Gallbladder ultrasound at baseline and every 6 to 12 months
• · Fasting glucose and HbA1c
• · Thyroid function and vitamin B12 on long-term therapy

Prescription drug approved in the US, EU and most other markets. Generic injectable octreotide is widely available.

• Sandostatin and Sandostatin LAR Depot FDA prescribing information (label)
• Rinke et al. 2009, PROMID placebo-controlled trial of octreotide LAR in midgut neuroendocrine tumours (trial)
• Endocrine Society clinical practice guideline on acromegaly (guideline)

Native somatostatin-14 presents a Phe7-Trp8-Lys9-Thr10 turn to the receptor and everything else in the 14-residue ring is scaffolding. Octreotide keeps the turn, discards the scaffolding, and stabilises what is left with D-amino acids and a shorter disulfide. Once bound, SSTR2 signals through Gi and Go: adenylate cyclase is inhibited so cyclic AMP falls, inwardly rectifying potassium channels open and hyperpolarise the cell, and voltage-gated L-type calcium channels close. Hormone exocytosis is calcium-triggered, so removing the calcium transient removes the secretory event. That is why suppression of secretion is fast and near-complete and does not depend on any change in gene expression. The antiproliferative arm is separate and slower: SSTR2 recruits the tyrosine phosphatase SHP-1, which dephosphorylates growth-factor receptor signalling and drives p27kip1-mediated cell-cycle arrest, while SSTR3 engagement can trigger p53-dependent apoptosis. That is the arm PROMID was testing, and it is why the drug is given for tumour control at doses that already saturate the secretory effect. The gallstone problem is mechanism, not idiosyncrasy: SSTR2 on gallbladder smooth muscle blunts postprandial contraction and cholecystokinin release falls, so bile sits. The glucose unpredictability is mechanism too, because insulin, glucagon and GLP-1 are suppressed at once and which one dominates varies by patient.

The two-week gap after the first LAR injection is where people come unstuck. The microspheres take about two weeks to start releasing, so stopping the immediate-release injections on the day of the first depot brings carcinoid symptoms roaring back and the patient concludes the depot does not work. Second, gallstones: about half of long-term users form them, most stay silent, and the ones that do not usually present during a treatment break or a period of rapid weight loss, so anyone facing elective abdominal surgery should have the gallbladder imaged first. Third, the two-directional glucose swing catches insulin users out because requirements typically fall and nobody warned them. Fourth, the LAR kit is unforgiving: room temperature, supplied diluent only, injected within minutes or it sets in the needle, and bacteriostatic water is not a substitute. Fifth, injecting the depot subcutaneously instead of deep intramuscular gluteal gives erratic release and a painful nodule.

1. 50 mcgWeeks 1-2 — 50 mcg subcutaneously three times daily. This period exists to prove tolerance and confirm responsiveness before committing to a depot.
2. 100 mcgWeeks 3-12 — 100 mcg three times daily is the usual maintenance immediate-release dose in acromegaly.
3. 20 mgMonth 1 onward — Switch to Sandostatin LAR 20 mg intramuscularly every 4 weeks, continuing the immediate-release injections for the first 2 weeks because the microspheres release almost nothing in that window.
4. 30 mgMonth 4 — If IGF-1 is still elevated after three LAR injections, step up to 30 mg every 4 weeks.
5. 10 mgMonth 7 — If IGF-1 and GH are fully suppressed, step down to 10 mg every 4 weeks. Well-controlled patients are sometimes extended to every 6 or 8 weeks instead of reducing the milligrams.

• SSTR2 — Sub-nanomolar and dominant. Published IC50 values sit near 0.4 nM but I did not resolve a primary source this session.

  Gi-coupled inhibition of adenylate cyclase, potassium channel opening and calcium channel closure. Shuts down GH release from somatotrophs, serotonin from enterochromaffin cells and VIP from VIPoma. Also carries the antiproliferative SHP-1 signal.

• SSTR5 — Moderate, roughly an order of magnitude weaker than SSTR2

  Contributes to GH suppression and to insulin suppression from pancreatic beta cells.

• SSTR3 — Weak

  Minor contribution; in other analogues SSTR3 engagement is linked to apoptotic signalling.

• SSTR1 and SSTR4 — Negligible

  Essentially unbound, which is the main pharmacological difference from pasireotide.

• PROMID Phase 3, placebo-controlled, double-blind · 2009

  Time to tumour progression in metastatic well-differentiated midgut neuroendocrine tumours. Octreotide LAR 30 mg monthly markedly prolonged median time to progression versus placebo, establishing an antiproliferative effect rather than symptom control alone.

Flushing and diarrhoea in carcinoid syndrome often improve within hours of the first subcutaneous injection, which is one of the more dramatic responses in endocrinology. GH falls within an hour of each injection, but IGF-1, which is what you actually measure, takes weeks to reset. Expect a meaningful IGF-1 read at 3 months, not 3 weeks. LAR plateaus after roughly three monthly injections, so dose decisions before that are premature. Antiproliferative benefit is measured in months of progression-free survival and is invisible to the patient.

The only combination with real evidence is octreotide plus pegvisomant in acromegaly, and it works because the two act at completely different points: octreotide reduces GH output from the adenoma, pegvisomant blocks whatever GH still escapes from reaching the liver. In partial responders that normalises IGF-1 in the large majority, and it usually needs less pegvisomant than monotherapy, which matters at that drug's price. Do not stack octreotide with lanreotide or pasireotide; they compete for the same receptors and you pay twice for one effect. Cabergoline is a cheap third agent worth trying before pegvisomant when IGF-1 excess is modest, particularly with co-secreted prolactin. If the patient is on insulin or a sulfonylurea, treat that as part of the stack and expect to change the dose in the first fortnight.

Against lanreotide: pharmacologically near-identical, so the choice is delivery. Lanreotide autogel is a deep subcutaneous prefilled syringe a partner or the patient can give at home; octreotide LAR is an intramuscular microsphere suspension needing a clinician and a careful mixing ritual. If home administration matters, lanreotide wins on practicality alone. Against pasireotide: octreotide is the SSTR2 drug, pasireotide is the SSTR5 drug. Pasireotide controls more acromegaly patients and is the only one that works in Cushing's disease, but it causes hyperglycaemia in roughly three quarters of users. Start with octreotide or lanreotide and escalate only when SSTR2 selectivity has failed. Against pegvisomant: pegvisomant normalises IGF-1 more reliably than any somatostatin analogue but does nothing to the tumour, so it controls the disease rather than treating it.

$200–$8000/month. Unverified order-of-magnitude estimate, not sourced in this session. Generic immediate-release subcutaneous octreotide sits at the low end in the US; Sandostatin LAR runs into the thousands per monthly injection and oral Mycapssa is more expensive still.

• ?No primary source resolved this session for octreotide's numerical SSTR subtype IC50 values, so the affinity fields are qualitative. The Signifor LAR label carries a binding table but only for somatostatin-14 and pasireotide.
• ?Time to steady state on LAR is conventionally three injections, roughly 84 days, but I did not fetch the Sandostatin LAR label to confirm it, so the field is null.
• ?Oral Mycapssa bioavailability is not given numerically because I did not resolve that label; the food effect is well established but the number is not.
• ?PROMID enrolled roughly 85 patients but I did not confirm the exact figure, so participants is null.
• ?Cost figures are unverified estimates.

• Placebo-controlled, double-blind, prospective, randomized study on the effect of octreotide LAR in the control of tumor growth in patients with metastatic neuroendocrine midgut tumors: a report from the PROMID Study Group Rinke A, et al., Journal of Clinical Oncology, 2009 · PMID 19704057

  The trial that turned octreotide from a symptom drug into a tumour drug.

• SANDOSTATIN (octreotide acetate) injection, solution - FDA prescribing information Novartis Pharmaceuticals Corporation, DailyMed

  Source of every pharmacokinetic number here: Vdss 13.6 L, clearance 7-10 L/h, 65 percent protein binding, 32 percent urinary excretion unchanged, tmax 0.4 h.