Somatuline Autogel

Lanreotide.

Somatuline Autogel 60 mg, 90 mg and 120 mg is a prolonged-release solution for injection in a pre-filled syringe containing 60 mg, 90 mg and 120 mg of lanreotide acetate respectively.
Somatuline Autogel 60 mg: Each pre-filled syringe contains a supersaturated solution of lanreotide acetate corresponding to 0.246 mg of lanreotide base/mg of solution, which ensures an actual injection dose of 60 mg.
Somatuline Autogel 90 mg: Each pre-filled syringe contains a supersaturated solution of lanreotide acetate corresponding to 0.246 mg of lanreotide base/mg of solution, which ensures an actual injection dose of 90 mg.
Somatuline Autogel 120 mg: Each pre-filled syringe contains a supersaturated solution of lanreotide acetate corresponding to 0.246 mg of lanreotide base/mg of solution, which ensures an actual injection dose of 120 mg.
Excipients/Inactive Ingredients: Water for injections, acetic acid (for pH adjustment).

Pharmacotherapeutic group: Pituitary and hypothalamic hormones and analogues; Somatostatin and analogues. ATC code: H01C B03.
Pharmacology: Pharmacodynamics: Mechanism of action: Lanreotide in an octapeptide analogue of natural somatostatin. Like somatostatin, lanreotide is an inhibitor of various endocrine, neuroendocrine, exocrine and paracrine functions. Lanreotide has a high affinity for human somatostatin receptors (SSTR) 2, 3 and 5, and reduced affinity for human SSTR 1, 3 and 4. Activity at human SSTR 2 and 5 is the primary mechanism considered to be responsible for GH inhibition. Lanreotide is more active than natural somatostatin and shows a longer duration of action. Its marked selectivity for the secretion of growth hormone compared to that of insulin, makes this a product suited to the treatment of acromegaly.
Lanreotide, exhibits a general exocrine anti-secretory action. It inhibits the basal secretion of motilin, gastric inhibitory peptide and pancreatic polypeptide, but has no significant effect on fasting secretin or gastrin secretion. Additionally, it decreases the levels of plasma chromogranin A and urinary 5-HIAA (5 Hydroxyindolacetic acid) in patients with GEP-NETs and elevated levels of these tumour markers.
Lanreotide inhibits meal-induced increases in superior mesenteric artery blood flow and portal venous blood flow.
Lanreotide reduces prostaglandin E1-stimulated jejunal hydroelectrolytic secretion (water, sodium potassium and chloride).
Lanreotide reduces prolactin levels in acromegalic patients treated long term.
Clinical studies: In an open-label study, Somatuline Autogel 120 mg was administered every 28 days for 48 weeks in 90 previously untreated acromegalic patients diagnosed with pituitary macroadenoma. At week 48, 63% of the patients showed a clinically relevant reduction in tumor volume of ≥20% (which was the primary efficacy endpoint) although statistical significance was not reached (95% CI: 52% - 73%).
The mean percentage reduction of tumour volume was 26.8%, GH levels were below 2.5 μg/L in 77.8% of the patients and IGF-1 levels normalised in 50%. Normalised IGF-1 levels combined with GH levels below 2.5 μg/L were observed in 43.5% of the patients.
Patients reported a relief of acromegaly symptoms such as fatigue (56.5%), excess perspiration (66.1%), arthralgia (59.7%), soft tissue swelling (66.1%) and headache (38.7%).
A reduction in tumor volume and concentrations of GH and IGF-1 was shown from week 12 and was maintained for 48 weeks.
The study excluded patients who were expected to require pituitary surgery or radiotherapy during the study period.
The inhibitory action of lanreotide on intestinal exocrine secretion, digestive hormones and cellular proliferation mechanisms is particularly interesting for its application in the treatment of the symptoms of endocrine digestive tumours, especially carcinoids.
A phase III, 96-week, fixed duration, randomized, double-blind, multi-centre, placebo-controlled trial was conducted in patients with gastroenteropancreatic neuroendocrine tumours to assess the antiproliferative effect of lanreotide.
Patients were randomized 1:1 to receive either Somatuline Autogel 120 mg every 28 days (n=101) or placebo (n=103). Randomization was stratified by previous therapy at entry and the presence/absence of progression at baseline as assessed by RECIST 1.0 (Response Evaluation Criteria in Solid Tumours) during a 3 to 6 months screening phase.
Patients had metastatic and/or locally advanced inoperable disease with histologically confirmed well or moderately well differentiated tumours primarily localized in the pancreas (44.6% patients), midgut (35.8%), hindgut (6.9%) or of other/unknown primary location 12.7%).
69% of patients with GEP-NETs had tumour grade 1 (G1), defined by either a proliferation index Ki67 ≤2% (50.5% of the overall patient population) or a mitotic index <2 mitosis/10 HPF (18.5% of the overall patient population) and 30% of patients with GEP-NETs had tumours in the lower range of grade 2 (G2) (defined by a Ki67 index >2% - ≤10%). Grade was not available in 1% of the patients.
The study excluded patients with G2 GEP-NETs with a higher cellular proliferation index (Ki67 >10% - ≤20%) and G3 GEP neuroendocrine carcinomas (Ki67 index >20%).
Overall, 52.5% of the patients had an hepatic tumour load ≤10%, 14.5% had an hepatic tumour load >10 and ≤25% and 33% had an hepatic tumour load >25%.
The primary endpoint was progression-free survival (PFS) measured as time to either disease progression by RECIST 1.0 or death within 96 weeks after first treatment administration. Analysis of PFS utilized independent centrally-reviewed radiological assessment of progression. (See Table 1 and Figure 1.)

Click on icon to see table/diagram/image


Click on icon to see table/diagram/image

The beneficial effect of lanreotide in reducing the risk of progression or death was consistent regardless of the location of primary tumour, hepatic tumour load, previous chemotherapy, baseline Ki67, tumour grade or other pre-specified characteristics as shown in Figure 2.
A clinically relevant benefit of treatment with Somatuline Autogel was seen in patients with tumours of pancreatic, midgut and other/unknown origin as in the overall study population. The limited number of patients with hindgut tumours (14/204) contributed to difficulty in interpreting the results in this subgroup. The available data suggested no benefit of lanreotide in these patients. (See Figure 2.)

Click on icon to see table/diagram/image

Crossover from placebo to open-label Somatuline Autogel, in the extension study, occurred in 45.6% (47/103) of the patients.
Paediatric population: The European Medicines Agency has waived the obligation to submit the results of studies with Somatuline Autogel in all subsets of the paediatric population in acromegaly and pituitary gigantism (see Dosage & Administration for information on paediatric use). The European Medicines Agency has listed gastroenteropancreatic neuroendocrine tumours (excluding neuroblastoma, neuroganglioblastoma, phaeochromocytoma) on the list of class waivers.
Pharmacokinetics: Intrinsic pharmacokinetic parameters of lanreotide after intravenous administration in healthy volunteers indicated limited extravascular distribution, with a steady-state volume of distribution of 16.1 L. Total clearance was 23.7 L/h, terminal half-life was 1.24 hours and mean residence time of 0.68 hours. In studies evaluating excretion, less than 5% of lanreotide were excreted in urine and less than 0.5% were recovered unchanged in faeces, indicating some biliary excretion.
After a deep subcutaneous injection of Somatuline Autogel 60 mg, 90 mg and 120 mg to healthy volunteers, lanreotide concentrations increase to achieve average maximum serum concentrations of 4.25, 8.39 and 6.79 ng/ml. These values of C_max are achieved during the first day after the administration at 8, 12 and 7 hours (median values). From the peak serum levels of lanreotide concentrations decrease slowly following a first order kinetics with a terminal elimination half-life of 23.3, 27.4 and 30.1 days respectively and 4 weeks after the administration mean lanreotide serum levels were 0.9, 1.11 and 1.69 ng/ml respectively. Absolute bioavailability was 73.4, 69.0 and 78.4%.
After deep subcutaneous administration of Somatuline Autogel 60 mg, 90 mg and 120 mg to acromegalic patients, lanreotide concentrations increase to achieve average maximum serum concentrations of 1.6, 3.5 and 3.1 ng/ml. These values of C_max are achieved during the first day after the administration at 6, 6 and 24 hours. From the peak serum levels of lanreotide concentrations decrease slowly following first order kinetics and 4 weeks after the administration mean lanreotide serum levels were 0.7, 1.0 and 1.4 ng/ml, respectively.
Steady state serum levels of lanreotide were reached, on average, after 4 injections every 4 weeks. After repeated dose administration every 4 weeks the average values of C_max at steady state were 3.8, 5.7 and 7.7 ng/ml for 60, 90 and 120 mg respectively, the average C_min values obtained being 1.8, 2.5 and 3.8 ng/ml. The peak through fluctuation index was moderate ranging from 81 to 108%.
Linear pharmacokinetic release profiles were observed after deep subcutaneous administration of Somatuline Autogel 60 mg, 90 mg and 120 mg in acromegalic patients.
In a population PK analysis in 290 GEP-NET patients receiving Somatuline Autogel 120 mg, rapid initial release was seen with mean C_max values of 7.49 ± 7.58 ng/mL reached within the first day after a single injection. Steady-state concentrations were reached after 5 injections of Somatuline Autogel 120 mg every 28 days and were sustained up to the last assessment (up to 96 weeks after the first injection). At steady-state the mean C_max values were 13.9 ± 7.44 ng/mL and the mean trough serum levels were 6.56 ± 1.99 ng/mL. The mean apparent terminal half-life was 49.8 ± 28.0 days.
Renal/Hepatic impairment: Subjects with severe renal impairment show an approximately 2-fold decrease in total serum clearance of lanreotide, with a consequent increase in half-life and AUC. In subjects with moderate to severe hepatic impairment, a reduction in clearance was observed (30%). Volume of distribution and mean residence time increased in subjects with all degrees of hepatic insufficiency.
It is not necessary to alter the starting dose in patients with renal or hepatic impairment, as lanreotide serum concentrations in these populations are expected to be well within the range of serum concentrations safely tolerated in healthy subjects.
No effect on clearance of lanreotide was observed in a population PK analysis of GEP-NET patients including 165 with mild and moderate renal impairment (106 and 59 respectively) treated with Somatuline Autogel. GEP-NET patients with severely impaired renal function were not studied.
No GEP-NET patients with hepatic impairment (as per Child-Pugh score) were studied.
Elderly patients: Elderly subjects show an increase in half-life and mean residence time compared with healthy young subjects. It is not necessary to alter the starting dose in elderly patients, as lanreotide serum concentrations in this population are expected to be well within the range of serum concentrations safely tolerated in healthy subjects.
In a population PK analysis of GEP-NET patients including 122 aged 65 to 85 years, no effect of age on clearance and volume of distribution of lanreotide was observed.
Toxicology: Preclinical safety data: Effects in non-clinical studies were observed only at exposures considered sufficiently in excess of the maximum human exposure indicating little relevance to clinical use.
In carcinogenic bioassay studies conducted in rats and mice, no systemic neoplastic changes were observed at doses in excess of those achieved in humans at therapeutic doses. Increased incidence of subcutaneous tumours were observed at the injection sites likely due to the increased dose frequency in animals (daily) compared to monthly dosing in humans and therefore may not be clinically relevant.
In in vitro and in vivo standard battery tests, lanreotide did not show any genotoxic potential.

Somatuline Autogel 60 mg & 90 mg: Treatment of acromegaly when secretion of Growth Hormone (GH) and Insulin-like Growth Factor-1 (IGF-1) remain abnormal after surgery and/or radiotherapy.
Treatment of the clinical syndrome associated with acromegaly.
Treatment of the clinical symptoms of neuroendocrine (particularly carcinoid) tumours.
Somatuline Autogel 120 mg: Treatment of acromegaly when secretion of Growth Hormone (GH) and Insulin-like Growth Factor-1 (IGF-1) remain abnormal after surgery and/or radiotherapy.
Treatment of the clinical syndrome associated with acromegaly.
Treatment of the clinical symptoms of neuroendocrine (particularly carcinoid) tumours.
Treatment of grade 1 and a subset of grade 2 (Ki67 index up to 10%) gastroenteropancreatic neuroendocrine tumours (GEP-NETs) of midgut, pancreatic or unknown origin where hindgut sites of origin have been excluded, in adult patients with unresectable locally advanced or metastatic disease.

Initiation of treatment: Acromegaly: The recommended starting dose is 60 mg to 120 mg administered every 28 days.
For example: In patients previously treated with SOMATULINE P.R. 30 mg powder and solvent for prolonged-release suspension for injection (I.M.) every 14 days, the initial dose of Somatuline Autogel should be 60 mg every 28 days.
In patients previously treated with SOMATULINE P.R. 30 mg powder and solvent for prolonged-release suspension for injection (I.M.) every 10 days, the initial dose of Somatuline Autogel should be 90 mg every 28 days.
In patients previously treated with SOMATULINE P.R. 30 mg powder and solvent for prolonged-release suspension for injection (I.M.) every 7 days, the initial dose of Somatuline Autogel should be 120 mg every 28 days.
Neuroendocrine tumors: The recommended dose is 60 mg to 120 mg administered every 28 days. The dose should be adjusted according to the degree of symptomatic relief obtained.
Adaptation of treatment: The treatment should be adjusted for each patient in a specialized unit.
The dose should be individualized according to the response which is evaluated by monitoring plasma GH and IGF-1 levels and by assessing changes in symptoms.
Acromegaly: It is recommended: To reduce the dose when the concentrations are normalized GH <1 ng/ml and normalized IGF-1 and/or disappearance of clinical symptoms; To maintain the dose when the concentrations of the GH are between 2.5 ng/ml and 1 ng/ml; To increase the dose when the concentrations of GH are higher than 2.5 ng/ml.
Patients well controlled on a somatostatin analogue can be treated with Somatuline Autogel 120 mg every 42 or 56 days.
Treatment of clinical symptoms associated with carcinoid tumours: In case of insufficient response judged by clinical symptom (flushes and soft stools), the dose may be increased to 120 mg every 28 days (4 weeks).
In case of sufficient response judged by clinical symptom (flushes and soft stools), the dose may be decreased to 60 mg every 28 days (4 weeks).
Treatment of grade 1 and a subset of grade 2 (Ki67 index up to 10%) gastroenteropancreatic neuroendocrine tumours of midgut, pancreatic or unknown origin where hindgut sites of origin have been excluded, in adult patients with unresectable locally advanced or metastatic disease: The recommended dose is one injection of Somatuline Autogel 120 mg administered every 28 days. The treatment should be continued for as long as needed for tumour control.
Renal and/or hepatic impairment: In patients with impaired renal or hepatic function, no dosage adjustment is necessary due to the wide therapeutic window of lanreotide.
Elderly patients: In elderly patients, no dosage adjustment is necessary.
Paediatric population: The safety and efficacy of Somatuline Autogel in children and adolescents has not been established.
Method of administration: The solution should be injected via the deep subcutaneous route in the superior external quadrant of the buttock.
The injection is made by healthcare professional. However, for patients receiving stable dose of Somatuline Autogel the product may be administered either by the patient or by a person around him after appropriate training by a healthcare professional. In case of self-injection, the injection should be given in the upper outer thigh.
The decision to allow administration by the patient or a trained person should be made by the healthcare professional.
Regardless of the site of injection, the skin should not be folded and the needle should be inserted rapidly to its full length, perpendicularly to the skin. The injection site should alternate between the right and left side.

If overdosage occurs, symptomatic management is indicated.

Hypersensitivity to the active substance, somatostatin or related peptides or to any of the excipients listed.

Pharmacological studies in animals and humans show that lanreotide, like somatostatin and its analogues, inhibits secretion of insulin and glucagon. Hence patient treated with lanreotide may experience hypoglycaemia or hyperglycaemia. Blood glucose levels should be monitored when lanreotide treatment is initiated, or when the dose is altered. Any diabetic treatment should be adjusted accordingly. In insulin-treated diabetic patients, the insulin doses will initially be reduced by 25% then adapted to the blood glucose level, which must be carefully controlled in these patients when starting the treatment.
Lanreotide may reduce gallbladder motility and lead to gallstone formation. Therefore, patients may need to be monitored periodically. It is advised, during prolonged treatment, to perform treatment and every 6 months, an echography of the gallbladder. There have been postmarketing reports of gallstones, including cholecystitis, cholangitis, and pancreatitis, requiring cholecystectomy in patients taking lanreotide. If complications of cholelithiasis are suspected, discontinue lanreotide and treat appropriately.
Slight decreases in thyroid function have been seen during treatment with lanreotide in acromegalic patients, though clinical hypothyroidism is rare. Thyroid function tests are recommended where clinically indicated.
In acromegalic patients and patients presenting with primitive thyrotropic adenoma, use of lanreotide is not exempt from the monitoring of the volume of the pituitary tumour.
In patients without underlying cardiac problems, lanreotide may lead to a decrease of heart rate without necessarily reaching the threshold of bradycardia. In patients suffering from pre-existing cardiac disorders, sinus bradycardia may occur. Caution should be taken when initiating treatment with lanreotide in patients with bradycardia.
The appearance of a significant and lasting increase of steatorrhoea justifies the complementary prescription of pancreatic extracts.
Effects on ability to drive and use machines: While no effect on the ability to drive and use machines has been established, dizziness has been reported with Somatuline Autogel. If a patient is affected, he/she should not drive or operate machinery.

Pregnancy: There is a limited amount of data (less than 300 pregnancy outcomes) from the use of lanreotide in pregnant women.
Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity. As a precautionary measure, it is preferable to avoid the use of lanreotide during pregnancy.
Breast-feeding: It is not known whether Somatuline Autogel is excreted in human milk.
A risk to the newborns/infants cannot be excluded.
Somatuline Autogel should not be used during breast-feeding.
Fertility: Reduced fertility was observed in female rats due to the inhibition of GH secretion at doses in excess of those achieved in humans at therapeutic doses.

Undesirable effects reported by patients suffering from acromegaly and GEP-NETs treated with lanreotide in clinical trials are listed under the corresponding body organ systems according to the following classification: Very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); not known (cannot be estimated from the available data).
The most common adverse drug reactions following treatment with lanreotide are gastrointestinal disorders (most commonly reported are diarrhoea and abdominal pain, usually mild or moderate and transient), cholelithiasis (often asymptomatic) and injection site reactions (pain, nodule and induration).
The profile of undesirable effects is similar for all indications. (See Table 2.)

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Combination requiring precautions for use: Cyclosporin (oral use): Decrease in cyclosporin blood levels (decrease in the intestinal cyclosporin absorption). Increase the cyclosporin dose under the control of circulating blood levels and reduce of doses after stopping lanreotide treatment.
Insulin, glitazones, repaglinide, sulphonylureas: Risk of hypoglycaemia or hyperglycaemia: decrease in the needs of antidiabetic treatment following the decrease or increase in endogen glucagon secretion. The glycemic self-monitoring must be reinforced and the posology of antidiabetic treatment during treatment by lanreotide should be adapted as required.
Concomitant administration of bradycardia inducing drugs (e.g. beta blockers) may have an additive effect on the slight reduction of heart rate associated with lanreotide. Dose adjustments of such concomitant medications may be necessary.
The limited published data available indicate that somatostatin analogues may decrease the metabolic clearance of compounds known to be metabolised by cytochrome P450 enzymes, which may be due to the suppression of growth hormone. Since it cannot be excluded that lanreotide may have this effect, other drugs mainly metabolized by CYP3A4 and which have a low therapeutic index (e.g. quinidine) should therefore be used with caution.
Other information: Interactions with highly plasma bound drugs are unlikely in view of the moderate binding of lanreotide to serum proteins.

Incompatibilities: Not applicable.
Instructions for use and handling: The Somatuline Autogel prolonged-release solution for injection in a pre-filled syringe is a ready-to use supersaturated lanreotide that forms a whitish, translucent autogel.
For immediate and single use following first opening.
It is important that the injection of the product is performed exactly according to the instruction in the package leaflet.
Do not use if the laminated pouch is damaged or opened.
Any unused product or waste material should be disposed of in accordance with local requirements.
The following instructions explain how to inject Somatuline Autogel.
Instructions for Administration of the Product: Attention: Read all the instructions carefully before starting the injection. The injection is a deep subcutaneous injection that requires a specific technique different to normal subcutaneous injections.
The following instructions explain how to inject Somatuline Autogel.
Somatuline Autogel is supplied in a ready to use pre-filled syringe fitted with an automatic safety system. The needle will retract that automatically locks in place following the full administration of the product, to help prevent needle stick injury.
1. Remove Somatuline Autogel from the refrigerator 30 minutes prior to administration. Injection of cold medication may be painful. Keep laminated pouch sealed until just prior to injection.
2. Attention: Before opening the pouch, check that it is intact and that the medication has not expired.
Do not use the pre-filled syringe: If the patient drops or damages the pre-filled syringe or if the pre-filled syringe or pouch appear damaged in any way.
If the product has expired; the expiry date is printed on the outer carton and the pouch.
If any of the previously mentioned apply the patient should contact the doctor or pharmacist.
3. Wash hands with soap.
4. Tear-open the pouch along the dotted line and take out the pre-filled syringe. The content of the pre-filled syringe is a semi-solid phase having a gel-like appearance, with viscous characteristics and a colour varying from white to pale yellow. The supersaturated solution can also contain micro bubbles that can clear up during injection. These differences are normal and do not interfere with the quality of the product.
After opening the protective laminated pouch, the product should be administered immediately.
5. Select an injection site: 5a. If a healthcare professional (HCP) or someone else like a trained family member or friend is doing the injection: use the superior external (upper, outer) quadrant of the buttock (for injection by healthcare professional (HCP) or someone else like a trained family member or friend).
5b. If the patient is injecting himself/herself: use the upper outer part of the thigh (if the patient is the one injecting).
Alternate the injection site between the right and left side each time the patient receives an injection of Somatuline Autogel. Avoid areas with moles, scar tissues, reddened skin, or skin that feels bumpy.
6. Clean the injection.
7. Before injecting, remove the pre-filled syringe from its tray. Discard the tray.
8. Remove the needle cap by pulling off and discard it.
9. Flatten injection area using the thumb and index finger of the hand not holding the pre-filled syringe to stretch the skin. Do not pinch the skin. Use a strong, straight dart-like motion to quickly insert the needle perpendicular to the skin (90 degree angle), all the way into the skin.
It is very important that the patient inserts the needle completely. The patient should not see any needle once it is fully inserted.
Do not aspirate (do not draw back).
10. Release inject site that has been flattened by the hand. Push plunger with steady very firm pressure. The medication is thicker and harder to push than the patient might expect. Typically, 20 seconds are needed. Inject the full dose and give a final push to make sure the patient cannot depress it any further.
Note: maintain pressure on the plunger with the thumb to avoid activation of the automatic safety system.
11. Without releasing the pressure on the plunger, withdraw the needle from the injection site.
12. Then release pressure on the plunger. The needle will automatically retract into the needle guard where it will be locked permanently.
13. Apply gentle pressure to the injection site with a dry cotton ball or sterile gauze to prevent any bleeding. Do not rub or massage the injection site after administration.
14. Dispose of the used syringe as instructed by the doctor or healthcare provider. Do not dispose of the device in the general household rubbish.

Store at +2°C to 8°C (refrigerator). Store in original package in order to protect from light.
Once removed from the refrigerator, product left in its sealed pouch may be returned to the refrigerator (the number of temperature excursions must not exceed three times) for continued storage and later use, provided it has been stored for no longer than a total of 24 hours at below 40°C.
Shelf life: 2 years.
After opening the protective laminated pouch, the product should be administered immediately.

Trophic Hormones & Related Synthetic Drugs

H01CB03 - lanreotide ; Belongs to the class of antigrowth hormone. Used in hypothalamic hormone preparations.

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