Somatuline LA 30mg, powder for suspension for injection.

Each vial contains 30mg of lanreotide, presented as lanreotide acetate.

After reconstitution with the solvent, 1mL of suspension contains 15mg lanreotide as lanreotide acetate.

For a full list of excipients, see section 6.1.

Powder for suspension for injection.

Powder = a practically white friable cake.

Acromegaly:

Somatuline LA is indicated for the treatment of 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.

Thyrotropic Adenomas:

Somatuline LA is indicated for the treatment of thyrotrophic adenomas when the circulating level of thyroid stimulating hormone remains inappropriately high after surgery and/or radiotherapy.

Neuroendocrine Tumours:

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

Acromegaly and Neuroendocrine Tumours:

Initially, one intramuscular injection should be given every 14 days. The frequency of subsequent injections may be varied in accordance with the individual patient's response (as judged by a reduction in symptoms and/or a reduction in GH and/or IGF-1 levels) such that injections can be given every 7 to 10 days as necessary.

Thyroid tumours:

Treatment should only be initiated and maintained by physicians experienced in the management of this condition.

Initially, one intra-muscular injection should be given every 14 days. In the case of an insufficient response, as judged by the levels of thyroid hormone and TSH, the frequency of injection may be increased to one every 10 days. Continued treatment should be guided by periodic measurement of thyroid hormone and TSH.

Elderly:

No dose modification is required in elderly patients.

Children:

As there is no experience of the use of the product in children, the use of Somatuline LA in children cannot be advised.

Hypersensitivity to lanreotide or related peptides or any of the excipients.

Somatuline LA may reduce gallbladder motility and lead to gallstone formation. Therefore patients may need to be monitored periodically.

Pharmacological studies in animals and humans show that Somatuline LA, like somatostatin and its analogues, inhibits secretion of insulin and glucagon. Hence, patients treated with Somatuline LA may experience hypoglycaemia or hyperglycaemia. Blood glucose levels should be monitored when Somatuline treatment is initiated, or when the dose is altered and any antidiabetic treatment should be adjusted accordingly.

Slight decrease in thyroid function have been seen during treatment with Somatuline LA in acromegalic patients, though clinical hypothyroidism is rare. Thyroid function tests are recommended where clinically indicated.

In patients without underlying cardiac problems Somatuline LA may lead to a decrease of heart rate without necessarily reaching the threshold of bradycardia. In patients suffering from cardiac disorders prior to Somatuline LA treatment, sinus bradycardia may occur. Care should be taken when initiating treatment with Somatuline in patients with bradycardia ( see section 4.5).

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

The pharmacological gastrointestinal effects of Somatuline LA may reduce the intestinal absorption of co-administered drugs including ciclosporin.

Concomitant administration of ciclosporin with Somatuline LA 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 Somatuline LA 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 Somatuline LA. 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 Somatuline may have this effect, other drugs mainly metabolized by CYP3A4 and which have a low therapeutic index (e.g. quinidine, terfenadine) should therefore be used with caution.

Pregnancy:

Non-clinical data:

Studies in animals showed no evidence of teratogenic effects associated with Somatuline LA 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 Somatuline on pregnancy or on the health of the foetus/new born child. To date, no other relevant epidemiological data are available.

Because animal studies are not always predictive of human responses, Somatuline LA 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 Somatuline is administered during lactation.

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

Undesirable effects reported by patients suffering from acromegaly treated with Somatuline 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 Somatuline 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.

▪ 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 system 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.

Somatuline LA is an octapeptide analogue of natural somatostatin. Like somatostatin, Somatuline LA 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.

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

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

Intrinsic pharmacokinetic parameters of Somatuline LA 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 Somatuline LA was excreted in urine and less than 0.5% was recovered unchanged in faeces, indicating some biliary excretion.

The plasma profile of a single dose of Somatuline LA 30mg administered intramuscularly in healthy volunteers is characterised by an initial rapid release phase, corresponding to the release of peptide bound to the surface of the microspheres, and then by a second release phase, followed by a very slow decrease induced by the prolonged release of the active substance captured in the microparticles constituting the drug product.

After an initial serum concentration peak of 8.5 ± 4.7 ng/mL obtained between 1 and 2 h after drug administration, serum levels decrease during 1-3 days and then rise from day 3 to 5 until day 14-21 showing a “pseudo plateau” with most of the serum levels around 1ng/mL during this period of time.

This prolonged release behaviour is described by a mean residence time of 15.0 ± 1.6 days and a half-life of 5.0 ± 2.3 days.

The pharmacokinetic profile in acromegalic patients after a single administration of Somatuline LA is comparable to that obtained in healthy volunteers.

Pharmacokinetic profile after repeated administration has also been studied in acromegalic patients. Steady state levels is obtained after the 4th consecutive dose presenting a peak of 10.9 ± 4.4 ng/mL around 2 hours after administration and then a “pseudo plateau” followed by a first order kinetics. The mean minimum and average serum concentrations at steady state is 2.2 ± 0.7 and 2.8 ± 0.8 ng/mL respectively and a no relevant accumulation is observed (Rac = 2.2).

Renal/Hepatic impairment

Subjects with severe renal impairment show an approximately 2-fold decrease in total serum clearance of Somatuline LA, 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 Somatuline LA 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 Somatuline LA 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, Somatuline LA did not show any genotoxic potential.

Resorption of micropheres is completed in 45 – 60 days.

Lactide glycolide copolymer,

Lactic glycolic copolymer,

Mannitol (E421),

Carmellose sodium (E466),

Polysorbate 80 (E433)

This medicinal product must not be mixed with other medicinal products except those mentioned in section 6.6.

2 years

After reconstitution, the suspension should be used immediately.

Store in a refrigerator (2°C to 8°C) in the original package

For storage conditions of reconstituted medicinal product, see section 6.3.

Powder in a vial (type I glass), with a rubber stopper (halogenobutyl) and cap (aluminium) and 2mL solvent in an ampoule (type I glass).

Box of 1 vial, 1 ampoule, 1 syringe and 2 needles.

Box of 2 vials, 2 ampoules, 2 syringes and 4 needles.

Box of 6 vials, 6 ampoules, 6 syringes and 12 needles.

Not all pack sizes may be marketed.

The powder should be reconstituted with the solvent immediately before injection. Keeping the vial upright, shake from side to side until a homogenous suspension is formed.

It is important that injection of this product is performed according to the instructions in the package leaflet.

For single use only.

Do not use if the kit is damaged or opened.

Any unused product or waste material should be disposed of in a sharps bin.

Ipsen Limited

190 Bath Road

Slough, Berkshire

SL1 3XE, UK

Somatuline LA PL number: 06958 / 0018

26 January 1998

20 July 2010