Treatment of acromegaly  when the circulating levels of Growth Hormone (GH) and of IGF-1 remains 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.

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

Initiation of treatment

Acromegaly

The recommended starting dose is 60 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 P.R. 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 P.R. 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 P.R. should be 120 mg every 28 days;

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 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 LP 120 mg every 42 or 56 days.

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).

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

SOMATULINE PR is not recommended for use in children and adolescents due to a lack of data on safety and efficacy.

Method of administration:

The solution should be injected via the deep sub-cutaneous route in the superior external quadrant of the buttock.

The injection is made by healthcare professional. However, for patients who receive stable dose of SOMATULINE 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 of administration by the patient or a trained person should be taken by 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 show 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 as soon as treatment begins.

▪ 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 adenomas, 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.  Care should be taken when initiating treatment with lanreotide in patients with bradycardia (see section 4.5).

▪ In carcinoid tumours, lanreotide must not be prescribed before having eliminated the presence of an obstructive intestinal tumour.

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

Associations requiring precautions for use

Cyclosporine (oral use) : decrease in cyclosporine blood levels (decrease in the intestinal cyclosporine absorption). Increase the cyclosporine dose under the control of circulating blood levels and reduction 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.

▪ 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.    

Pregnancy

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.

Lactation

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.

While no effect on the ability to drive and use machines has been established, dizziness has been reported with SOMATULINE PR 60 mg.  If a patient is affected, he/she should not drive or operate machinery. 

Undesirable effects reported by patients suffering from acromegaly 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).

The most commonly expected 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, nodules and induration).

The profile of undesirable effects is similar for other indications.

▪ Investigations:

Common: ALAT increased, ASAT abnormal, ALAT abnormal, blood bilirubin increased, blood glucose increased, glycosylated haemoglobin increased, weight decreased 

Uncommon: ASAT increased, blood alkaline phosphatase increased, blood bilirubin abnormal , blood sodium decreased

▪ Cardiac disorders

Common:  Sinus bradycardia

▪ Nervous system disorders

Common:  Dizziness, headache

▪ Gastrointestinal disorders

Very common:  Diarrhoea, loose stools, abdominal pain

Common:  Nausea, vomiting, constipation, flatulence, abdominal distension, abdominal discomfort, dyspepsia

Uncommon: Faeces discoloured

▪ Skin and subcutaneous tissue disorders Common:  Alopecia, hypotrichosis

▪ Metabolism and nutrition disorders

Common:  Hypoglycaemia

Uncommon: Diabetes mellitus, hyperglycaemia

▪ Vascular disorders:

Uncommon: Hot flush

▪ General disorders and administration site conditions:

Common:  Fatigue, injection site reactions (pain, mass, induration, nodule, pruritus) Uncommon: Asthenia

▪ Hepatobiliary disorders

Very common:  Cholelithiasis Common:  Biliary dilatation

▪ Psychiatric disorders:

Uncommon: Insomnia

Post-marketing safety experience:

Post-marketing safety experience has not identified any other relevant information other than occasional reports of pancreatitis.

If overdose occurs, symptomatic management is indicated.

Pharmacotherapeutic group: Antigrowth hormones, ATC code: H01C B03. 

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.

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. Lanreotide markedly inhibits mealinduced 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.

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.

Lanreotide is clearly more active than natural somatostatin and shows a much longer duration of action.

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 feces, indicating some biliary excretion.

After deep subcutaneous administration of SOMATULINE L.P. 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 L.P. 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 L.P. 60, 90 and 120 mg in acromegalic patients.

Trough lanreotide serum levels obtained after three deep subcutaneous injections of SOMATULINE P.R  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 P.R  30 mg every 14, 10 or 7 days respectively.

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. 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 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.

To be stored at a temperature between + 2° C and + 8° C (refrigerator). Store in its original primary packaging.

Somatuline LP 60 mg is supplied in a pre-filled syringe (clear polypropylene), fitted with an automatic safety system, a needle (stainless steel), a plastic needle sheat (LDPE) and a plunger stopper (bromobutyl rubber).

Each    pre-filled          syringe            is         packed            in         a          laminated pouch (polyethylene teraphtalate/aluminium/polyethylene laminate) and a card box.

Box of one 0.5 ml pre-filled syringe with an automatic safety system and one needle (1.2 x 20 mm).

The SOMATULINE P.R. 60 mg prolonged-release solution for injection in a pre-filled syringe is a ready-for use supersaturated lanreotide solution 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.