Treatment of acromegaly when the circulating levels of growth Hormone (GH) and of IGF-1 remain abnormal after surgery and/or radiotherapy or for whom surgery and/or radiotherapy is not an option.

Treatment of the clinical symptoms associated with acromegaly.

Treatment of clinical symptoms associated with 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 (see section 5.1). 

Posology

SOMATULINE Autogel prolonged-release solution for injection presents as 3 different dosages: 60 mg, 90 mg and 120 mg.

 Acromegaly and treatment of clinical symptoms associated with carcinoid tumours Initiation of treatment

Acromegaly

The recommended dose is 60 to 120 mg administered every 28 days.

For example:

-                  in patients previously treated with SOMATULINE Autogel 30 mg powder and solvent for prolonged-release suspension for injection (I.M.) every 14 days, the initial dose of SOMATULINE Autogel is 60 mg every 28 days;

-                  in patients previously treated with SOMATULINE Autogel 30 mg powder and solvent for prolonged-release suspension for injection (I.M.) every 10 days, the initial dose of SOMATULINE Autogel is 90 mg every 28 days;

-                  in patients previously treated with SOMATULINE Autogel 30 mg powder and solvent for prolonged-release suspension for injection (I.M.) every 7 days, the initial dose of SOMATULINE Autogel is 120 mg every 28 days.

Treatment of clinical symptoms associated with carcinoid tumours

The recommended starting dose is 90 mg every 28 days (4 weeks) during 2 months.

Adaptation of treatment

The treatment should be adjusted for each patient in a specialised unit.

The dose should be individualised according to the response which is evaluated by monitoring plasma GH and IGF-1 levels and by assessing changes in clinical symptoms.

Acromegaly

It is recommended:

-        to reduce the dose when the concentrations are normalised (GH < 1 ng/ml and normalised IGF-1 and/or disappearance of clinical symptoms),

-        to maintain the dose when the concentrations of 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 an insufficient response judged by clinical symptoms (flushes and soft stools), the dose may be increased to 120 mg every 28 days (4 weeks).

In case of a sufficient response judged by clinical symptoms (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 (see section 5.2).

Elderly patients

In elderly patients, no dosage adjustment is necessary (see section 5.2).

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 sub-cutaneous route in the superior external quadrant of the buttock or in the upper outer thigh.

The injection is made by healthcare professional. However, for patients who receive a 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 made in the upper outer thigh.

The decision of administration by the patient or another trained person should be taken 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.

▪ 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 before treatment and every 6 months, an echography of the gallbladder (cf. section 4.8).

▪ Pharmacological studies in animals and humans showed that lanreotide, like somatostatin and other somatostatin analogues, inhibits secretion of insulin and glucagon. Hence, patients 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 antidiabetic 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.

▪ 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 preexisting cardiac disorders, sinus bradycardia may occur. Caution should be taken when initiating treatment with lanreotide in patients with bradycardia (see section 4.5).

▪ The appearance of a significant and lasting increase of steatorrhoea justifies the complementary prescription of pancreatic extracts.

Decrease in cyclosporine blood levels (decrease in the intestinal cyclosporine absorption). Increase the cyclosporine 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 decrease or increase in endogen glucagon secretion. 

The glycaemic self monitoring must be reinforced and the posology of antidiabetic treatment during treatment by lanreotide should be adapted as required.

Limited published data indicate that concomitant administration of somatostatin analogues and bromocriptine may increase the availability of bromocriptine.

▪ 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 (see section 4.4).

▪ 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.

Category: B

Studies in animals showed no evidence of teratogenic effects associated with lanreotide during organogenesis.

The number of pregnancies exposed to lanreotide is very limited. Therefore, lanreotide should be administered to pregnant women only if clearly needed.

Breast-feeding

It is not known whether this drug is excreted in human milk.  

Because many drugs are excreted in human milk, caution should be exercised when lanreotide is administered during lactation.

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.

Somatuline Autogel has minor or moderate influence on the ability to drive and use machines.  However, dizziness has been reported with Somatuline Autogel 90 mg (see section 4.8). If a patient is affected, he/she should not drive or operate machinery

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.

* based on a pool of studies conducted in acromegalic patients 

** based on a pool of studies conducted in patients with GEP-NETs

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions to: Agence nationale de sécurité du médicament et des produits de santé (ANSM) et réseau des Centres Régionaux de Pharmacovigilance – Web site: www.ansm.sante.fr

To report any side effect(s): 

• Saudi Arabia: 

The National Pharmacovigilance and Drug Safety Center (NPC) 

Fax: +966-11-205-7662 

Call NPC at +966-11-2038222, Exts: 2317-2356-2340 

Toll free phone: 8002490000 

E-mail: npc.drug@sfda.gov.sa 

Website: www.sfda.gov.sa/npc

If overdose occurs, symptomatic management is indicated.

Pharmacotherapeutic group: Pituitary and hypothalamic hormones and analogues; Somatostatin and analogues.

ATC code: H01C B03. 

Mechanism of action

Lanreotide is 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 and 5 and a reduced binding affinity for human SSTR1, 3, and 4. Activity at human SSTR 2 and 5 is the primary mechanism believed 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, like somatostatin, 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 significantly reduces prostaglandin E1-stimulated jejunal hydroelectrolytic secretion (water, sodium, potassium and chloride). Lanreotide reduces prolactin levels in acromegalic patients treated long term.

In an open-label study, Lanreotide LP 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 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 heachache (38.7%).

A reduction in tumor volume and concentrations of GH and IGF-1was 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, placebocontrolled trial was conducted in patients with gastroenteropancreatic neuroendocrine tumours to assess the antiproliferative effect of lanreotide. 

Patients were randomized 1:1 to receive either lanréotide LP 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 month 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 (Ki 67 >10% - ≤ 20%) and G3 GEP neuroendocrine carcinomas (Ki 67 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. 

Table 1: Efficacy results of the phase III study

Figure 1: Kaplan-Meier Progression Free Survival Curves

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. 

Figure 2 – Results of the Cox Proportional Hazards Covariates Analysis of PFS

Crossover from placebo to open-label lanréotide LP, 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 lanréotide LP in all subsets of the paediatric population in acromegaly and pituitary gigantism (see section 4.2 for information on paediatric use). The European Medicines Agency has listed gastroenteropancreatic neuroendocrine tumours (excluding neuroblastoma, neuroganglioblastoma, phaechromocytoma) on the list of class waivers.

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 1.14 hours and mean residence time was 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 deep subcutaneous administration of SOMATULINE Autogel 60, 90 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 Cmax 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, 90 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 Cmax 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 Cmax at steady state were 3.8, 5.7 and 7.7 ng/ml for 60, 90 and 120 mg respectively, the average Cmin 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, 90 and 120 mg in acromegalic patients.

Trough lanreotide serum levels obtained after three deep subcutaneous injections of SOMATULINE Autogel 60, 90 or 120 mg given every 28 days are similar to the steady-state trough lanreotide serum levels obtained in acromegalic patients previously treated with intramuscular administrations of SOMATULINE Autogel 30 mg every 14, 10 or 7 days respectively.

In a population PK analysis in 290 GEP-NET patients receiving lanréotide LP 120 mg, rapid initial release was seen with mean Cmax 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 lanréotide LP 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 Cmax 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 halflife 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 lanréotide LP. 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.

▪ 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 bioassays 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.

Water for injections, acetic acid (for pH adjustment).

Not applicable.

Store in a refrigerator (2°C - 8°C). 

Store in the 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.

SOMATULINE Autogel is supplied in a pre-filled syringe (polypropylene) fitted with an automatic safety system with a plunger stopper (bromobutyl rubber), and a needle (stainless steel) covered by a plastic cap.

Each ready to use pre-filled syringe is placed into a plastic tray and packed in a laminated pouch and a cardboard box.

Box of one 0.5 ml pre-filled syringe and one needle (1.2 mm x 20 mm). 

The SOMATULINE Autogel 90 mg prolonged-release solution for injection in a pre-filled syringe is a ready-for use supersaturated lanreotide solution that forms a whitish, translucent PR.

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.