Somatuline^® Autogel^® 60mg, solution for injection in a pre-filled syringe.

Somatuline^® Autogel^® 90mg, solution for injection in a pre-filled syringe.

Somatuline^® Autogel^® 120mg, solution for injection in a pre-filled syringe.

Lanreotide (I.N.N.), 60mg, 90mg or 120mg (as acetate).

Each pre-filled syringe contains a supersaturated solution of lanreotide acetate corresponding to 0.246mg lanreotide base/mg of solution, which ensures an actual injection dose of 60mg, 90mg or 120mg respectively, of lanreotide.

For excipients, see 6.1.

Solution for injection in a pre-filled syringe.

White to pale yellow semi-solid formulation.

Somatuline Autogel is indicated for the treatment of individuals with acromegaly when the circulating levels of Growth Hormone (GH) and/or Insulin-like Growth Factor-1 (IGF-1) remain abnormal after surgery and/or radiotherapy, or in patients who otherwise require medical treatment. The goal of treatment in acromegaly is to reduce GH and IGF-1 levels and where possible to normalise these values.

Somatuline Autogel is also indicated for the treatment of symptoms associated with neuroendocrine (particularly carcinoid) tumours.

Posology

Acromegaly

In patients receiving a somatostatin analogue for the first time, the recommended starting dose is 60mg of Somatuline Autogel administered every 28 days.

In patients previously treated with Somatuline LA 30mg once every 14 days, the initial dose of Somatuline Autogel should be 60mg every 28 days; in patients previously treated with Somatuline LA 30mg once every 10 days, the initial dose of Somatuline Autogel should be 90mg every 28 days; and in patients treated with Somatuline LA 30mg once every 7 days, the initial dose of Somatuline Autogel should be 120mg every 28 days.

Thereafter, for all patients, the dose should be individualised according to the response of the patient (as judged by a reduction in symptoms and/or a reduction in GH and/or IGF-1 levels).

If the desired response is not obtained, the dose may be increased.

For patients whose GH concentrations are below 1ng/mL (approx 2mU/L), whose IGF-1 serum concentrations have normalised, and in whom most reversible signs of acromegaly have disappeared the monthly dose should be decreased. If appropriate, this may be achieved by giving Somatuline Autogel 120mg at increased intervals of 42-56 days.

For patients on Somatuline Autogel 60mg or 90mg every 28 days who are well controlled (GH concentrations less than 2.5ng/mL (approx 5 mU/L) but above 1ng/mL (approx 2mU/L) and normalised IGF-1 levels) the dose should be maintained, or alternatively Somatuline Autogel 120mg may be given at increased intervals of 56 or 42 days respectively.

For patients in whom clinical symptoms and biochemical parameters are not adequately controlled (GH concentrations still above 2.5ng/mL (approx 5mU/L) or IGF-1 greater than (age matched) normal) the dose of Somatuline Autogel may be increased to a maximum of 120mg at 28 day intervals.

Long term monitoring of symptoms, GH and IGF-1 levels should be routinely carried out in all patients.

Neuroendocrine tumours:

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

The dose should be adjusted according to the degree of symptomatic relief obtained.

Paediatric population:

Somatuline Autogel is not recommended for use in children and adolescents due to lack of data on safety and efficacy.

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 (see section 5.2).

Elderly patients:

In elderly patients, no dosage adjustment is necessary due to the wide therapeutic window of lanreotide (see section 5.2).

Method of Administration:

Somatuline Autogel should be injected, via the deep subcutaneous route, into the superior, external quadrant of the buttock.

The injection may be given by a healthcare professional or, for patients considered by their healthcare professional to be stabilised on their treatment with Somatuline Autogel, by an appropriately trained friend or relative of the patient (see section 5.1). Alternatively, such patients may self-administer the product after appropriate training. In this case the injection should be given in the upper, outer thigh.

Regardless of the site of administration, the skin should be stretched prior to injection. The needle should be inserted rapidly to its full length, perpendicularly to the skin.

The injection site should be alternated between the right and left sides.

Hypersensitivity to lanreotide or related peptides or any of the excipients

Lanreotide may reduce gall bladder motility and lead to gallstone formation. Therefore, patients may need to be monitored periodically.

Pharmacological studies in animals and humans show that lanreotide, like somatostatin and other somatostatin analogues, inhibits the 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 and any anti-diabetic treatment should be adjusted accordingly.

Slight decreases in thyroid function have been seen during treatment with lanreotide in patients with acromegaly, although clinical hypothyroidism is rare (<1%). Tests of thyroid function should be done where clinically indicated.

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 cardiac disorders prior to lanreotide treatment, sinus bradycardia may occur. Care should be taken when initiating treatment with lanreotide in patients with bradycardia (see section 4.5).

In patients with carcinoid tumours, lanreotide must not be prescribed before excluding the presence of an obstructive intestinal tumour.

The pharmacological gastrointestinal effects of lanreotide may reduce the intestinal absorption of co-administered drugs including ciclosporin. Concomitant administration of ciclosporin with lanreotide may decrease the relative bioavailability of ciclosporin and therefore may necessitate the adjustment of ciclosporin dose to maintain therapeutic levels.

Interactions with highly plasma bound drugs are unlikely in view of the moderate binding of lanreotide to serum proteins.

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 medicines may be necessary.

The limited published data available indicate the 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 metabolised by CYP3A4 and which have a low therapeutic index (e.g. quinidine, terfenadine) should therefore be used with caution.

Non-clinical data

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

Clinical data:

Data on a limited number of exposed pregnancies indicate no adverse effects of lanreotide on pregnancy or on the health of the foetus/newborn child. To date, no other relevant epidemiological data are available.

Because animal studies are not always predictive of human responses, 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.

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.

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 indurations).

The profile of undesirable effects is similar for other indications.

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 high binding affinity for human somatostatin receptors (SSTR) 2 and 5, and a reduced binding affinity for human SSTR 1, 3 and 4. Activity at SSTR 2 and 5 is the primary mechanism considered to be responsible for GH inhibition.

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 meal-induced increases in superior mesenteric artery blood flow and portal venous blood flow. Lanreotide significantly reduces prostaglandin E1-stimulated jejunal secretion of water, sodium, potassium and chloride. Lanreotide reduces prolactin levels in patients with acromegaly treated long term.

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

During an open label, controlled study involving patients with acromegaly treated with a stable dose of Somatuline Autogel for at least 4 months, 93% of the patients who received self or partner administered injections of Somatuline Autogel after appropriate training were considered competent to perform unsupervised injections (maintenance of GH and IGF-1 levels).

Intrinsic pharmacokinetic parameters of lanreotide after intravenous administration in healthy volunteers indicated limited extravascular distribution, with a steady-state volume of distribution of 16.1L. Total clearance was 23.7L/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 was excreted in urine and less than 0.5% was recovered unchanged in faeces indicating some biliary excretion.

After deep subcutaneous administration of Somatuline Autogel 60, 90 and 120mg to healthy volunteers, lanreotide concentrations increase to achieve average maximum serum concentrations of 4.25, 8.39 and 6.79ng/mL, respectively. 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 first-order kinetics with a terminal elimination half-life of 23.3, 27.4 and 30.1 days, respectively. 4 weeks after the administration mean lanreotide serum levels were 0.9, 1.11 and 1.69ng/mL, respectively. Absolute bioavailability was 73.4, 69.0 and 78.4%, respectively.

After deep subcutaneous administration of Somatuline Autogel 60, 90 and 120mg to patients with acromegaly, lanreotide concentrations increase to achieve average maximum serum concentrations of 1.6, 3.5 and 3.1ng/mL, respectively. 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 1.4ng/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 7.7ng/mL for 60, 90 and 120mg, respectively, the average Cmin values obtained being 1.8, 2.5 and 3.8ng/mL. The peak trough 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 120mg in patients with acromegaly.

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

Lanreotide serum levels of 1ng/mL are able to suppress GH to < 5ng/mL in more than 60% of patients studied. Lanreotide serum levels of 2.5ng/mL are able to suppress GH to < 5ng/mL in more than 90% of patients studied.

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%). The 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 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.

Water for injections.

Not applicable.

2 years.

After opening the protective laminated pack, the product should be administered immediately.

Store in a refrigerator between 2°C to 8°C in the original package. Do not freeze.

Somatuline Autogel is supplied in a clear polypropylene pre-filled syringe with a stainless steel needle and a plunger stopper made from bromobutyl rubber coated with silicone.

Each pre-filled syringe is packed in a nylon/polyethylene/aluminium laminated bag.

Box of one individual 60mg dose in a 0.3mL syringe with a needle (1.2mm x 20mm).

Box of one individual 90mg dose in a 0.3mL syringe with a needle (1.2mm x 20mm).

Box of one individual 120mg dose in a 0.5mL syringe with a needle (1.4mm x 20mm).

The solution for injection in a pre-filled syringe is ready for use.

For immediate and single use following first opening.

Ipsen Limited

190 Bath Road

Slough, Berkshire

SL1 3XE, UK

PL 34926/0005 (Somatuline^® Autogel^® 60mg)

PL 34926/0006 (Somatuline^® Autogel^® 90mg)

PL 34926/0007 (Somatuline^® Autogel^® 120mg)

16^th October 2001

14^th September 2011