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lanreotide
Lanreotide is a synthetic analogue of somatostatin, an endogenous peptide with high affinity for somatostatin type 2 and type 5 receptors found in the pituitary gland, pancreas and growth hormone-secreting pituitary tumours. Somatostatin analogues inhibit cell proliferation via direct anti-tumour effects from activation of somatostatin receptors on tumour cells and indirect effects via inhibition of mitogenic growth factors, such as insulin-like growth factor and inhibition of tumour angiogenesis.
Population pharmacokinetics in patients with neuroendocrine tumours showed rapid initial release of lanreotide within the first day after injection. Steady state concentrations were reached after 4 to 5 injections of 120 mg every 4 weeks and were sustained up to 96 weeks after the first injection.
Intravenous administration shows limited extravascular distribution.
| PPB |
79-83% |
Extensive metabolism in the GI tract after biliary excretion.
| Urine |
< 1% after a single dose of 3 mg SC |
| Feces |
< 0.5% of administered dose over 24 hrs at steady state |
| Half-life |
mean terminal in patients with neuroendocrine tumours: 50 +/- 28 days |
- For the treatment of enteropancreatic neuroendocrine tumours in adult patients with grade 1 or a subset of grade 2 (equivalent to Ki67 < 10%) unresectable, locally advanced or metastatic disease
- Treatment of adult patients with carcinoid syndrome; when used, lanreotide reduces the administration frequency of short-acting somatostatin analog rescue therapy
Notes:
Approval on enteropancreatic neuroendocrine tumours was based on a progression-free survival benefit in a placebo controlled phase III study. No overall survival benefit was noted. Data on hindgut tumour was limited.
Refer to the product monograph for non-oncologic indications.
Emetogenic Potential:
Extravasation Potential: None
The following adverse effects includes those reported with a frequency ≥ 5% in clinical trials in enteropancreatic NETs patients administered lanreotide every 4 weeks, where the incidence was greater than placebo by ≥ 2%, as well severe or life-threatening events from other trials.
| ORGAN SITE | SIDE EFFECT* (%) | ONSET** | |||
|---|---|---|---|---|---|
| Auditory | Hearing impaired (1- <5%, permanent; carcinoid patients) | E D | |||
| Cardiovascular | Bradycardia (rare) | E | |||
| Hypertension (13%) | E | ||||
| Dermatological | Rash (5%) | E | |||
| Gastrointestinal | Abdominal pain (24%) | E | |||
| Dehydration (5%) | E | ||||
| Nausea, vomiting (19%) | I E | ||||
| General | Fatigue (8%) | E | |||
| Hematological | Anemia (1 to <5%; carcinoid patients) | D | |||
| Hepatobiliary | Biliary tract disorders (14%) (cholelithiasis; rare - cholecystitis) | E D | |||
| Hepatic failure (rare) | E D | ||||
| Other (6%) (pancreatic insufficiency - 6%) | E | ||||
| Pancreatitis (rare) | D | ||||
| Hypersensitivity | Hypersensitivity / anaphylaxis | I | |||
| Injection site | Injection site reaction (8%) (pain) | I E | |||
| Metabolic / Endocrine | Hyperglycemia (7%) /diabetes | E | |||
| Hypoglycemia (rare) | E | ||||
| Hypothyroidism (rare) | E D | ||||
| Musculoskeletal | Musculoskeletal pain (10%) | E | |||
| Nervous System | Dizziness (9%) | E | |||
| Headache (16%) | E | ||||
| Syncope (rare) | E | ||||
| Respiratory | Cough, dyspnea (6%) | E | |||
* "Incidence" may refer to an absolute value or the higher value from a reported range.
"Rare"
may refer to events with < 1% incidence, reported in post-marketing, phase 1 studies,
isolated data or anecdotal
reports.
** I = immediate (onset in hours to days)
E = early (days to weeks)
D = delayed (weeks to months)
L = late (months to years)
The most common side effects for lanreotide include abdominal pain, nausea, vomiting, headache, biliary tract disorders, hypertension, musculoskeletal pain, dizziness, fatigue, hyperglycemia and ↓ pancreatic enzymes.
Patients with cardiac disorders may experience sinus bradycardia; heart rate should be monitored.
Lanreotide inhibits the secretion of insulin and glucagon and may result in changes to blood glucose levels, including hypo or hyperglycemia. Blood glucose levels should be monitored, especially in diabetic patients.
Lanreotide may reduce gallbladder motility leading to cholelithiasis.
Refer to protocol by which patient is being treated.
If patients are being treated with lanreotide for enteropancreatic NETs, do not give an additional dose for the treatment of carcinoid syndrome.
No dosage adjustment required. The drug should be discontinued in the case of disease progression or severe adverse events.
In acromegaly patients, lanreotide clearance is reduced by 30% in patients with moderate to severe hepatic impairment. Patients with neuroendocrine tumours or carcinoid tumours and hepatic impairment have not been studied.
Suggested dosage adjustment:
| Hepatic impairment | Lanreotide starting dose |
| Mild (Child-Pugh A) | Use with caution as no data |
| Moderate to severe (Child-Pugh B or C) | Use with caution as no data* |
*in acromegaly, a dose of 60 mg is recommended.
Lanreotide clearance was not affected in patients with neuroendocrine tumours and mild or moderate renal impairment. Patients with carcinoid syndrome and renal impairment have not been studied.
Suggested dosage adjustment:
| Renal impairment (CrCl in ml/min) | Enteropancreatic NET starting dose (mg) | Carcinoid syndrome starting dose (mg) |
| Mild to moderate (CrCl ≥ 30) | 120 | Use with caution as no data |
| Severe (CrCl < 30) | Use with caution as no data* | Use with caution as no data* |
*in acromegaly, a dose of 60 mg is recommended.
Increases in half-life and mean residence time were observed in healthy subjects over 65 years of age, with no change in either AUC or Cmax. No effect of age on clearance and volume of distribution was observed in pharmacokinetics analysis with NET patients aged 65-85 years. Clinical studies did not include sufficient patients to evaluate the impact of age.
Dosage adjustment is not necessary.
Lanreotide has not been studied in pediatric patients.
- Lanreotide should be injected by deep subcutaneous route in the superior external quadrant of the buttock
- In the case of self-administration (with appropriate training), the injection may be given in the upper outer thigh
- The injection site should be alternated between right and left sides
- If a dose is missed, the next dose should be administered as soon as possible
- The drug should be stored under refrigeration (2-8oC) in its original package
- Patients who are hypersensitive to this drug or any ingredients in the formulation
- Patients who are hypersensitive to somatostatin or related peptides
- Patients with complicated, untreated lithiasis of the bile ducts
- Use with caution and monitor blood glucose closely in patients with diabetes
- Exercise caution when driving or operating machinery while on treatment, as headache and dizziness were most commonly reported.
Other Drug Properties:
-
Carcinogenicity:
Documented in animals
An increased incidence of subcutaneous tumours at injection sites was observed in animals given daily injections. These findings are unlikely to be clinically relevant in humans receiving monthly injections.
-
Fetotoxicity:
Yes
-
Teratogenicity:
Unlikely
Lanreotide is not recommended for use in pregnancy given limited clinical experience. Adequate contraception should be used by both sexes during treatment, and for at least 6 months after the last dose.
-
Excretion into breast milk:
Unknown
Breastfeeding is not recommended.
-
Fertility effects:
Unlikely
Lanreotide is extensively metabolized in the GI tract after biliary excretion and may reduce intestinal absorption of co-administered drugs.
Limited data indicate that somatostatin analogues may decrease metabolic clearance of drugs metabolized by CYP450 enzymes.
| AGENT | EFFECT | MECHANISM | MANAGEMENT |
|---|---|---|---|
| Bradycardia-inducing drugs (e.g. beta-blockers) | ↓ heart rate | Additive | Dose adjustment of concomitant drugs may be necessary |
| Cyclosporine (oral) | ↓ cyclosporine serum levels | Delayed intestinal absorption of cyclosporine | Monitor serum levels of cyclosporine and adjust the cyclosporine dose as needed or switch to IV cyclosporine |
| Bromocriptine | ↑ bioavailability of bromocriptine | altered bromocriptine absorption | Caution and monitor for bromocriptine toxicity |
| Hypoglycemic agents (e.g. insulin, sulfonylureas) | ↑ risk of hypoglycemia | Additive | Caution, monitor and adjust dose of hypoglycemic agent as required |
| CYP3A4 substrates (e.g. cyclosporine, pimozide, tacrolimus, triazolo-benzodiazepines, dihydropyridine calcium-channel blockers, certain HMG-CoA reductase inhibitors) | ↑ substrate exposure | lanreotide may reduce clearance (theoretical) | Caution & monitor with drugs that have a low therapeutic index |
Treating physicians may decide to monitor more or less frequently for individual patients but should always consider recommendations from the product monograph.
| Monitor Type | Monitor Frequency |
|---|---|
Blood glucose |
Baseline and at each visit; more frequent in diabetic patients |
Heart rate |
Baseline and at each visit; more frequent in patients with cardiac disorders |
Gallbladder ultrasound |
Baseline and periodic |
Thyroid function |
As clinically indicated |
Clinical toxicity assessment for GI effects, injection site reactions, CNS effects, hypertension |
At each visit |
Grade toxicity using the current NCI-CTCAE (Common Terminology Criteria for Adverse Events) version
Caplin ME, Pavel M, Ćwikła JB, et al; CLARINET Investigators. Lanreotide in metastatic enteropancreatic neuroendocrine tumors. N Engl J Med. 2014 Jul 17;371(3):224-33.
Lanreotide: Drug information. Lexicomp. Accessed June 12, 2017.
Somatuline autogel (lanreotide injection) product monograph. Ipsen Biopharmaceuticals Canada Inc. February 1, 2018.
June 2019 Updated emetic risk category.
Refer to the New Drug Funding Program or Ontario Public Drug Programs websites for the most up-to-date public funding information.
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