Somatuline LA 30 mg, powder for suspension for injection.

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

After reconstitution with the solvent, 1 mL of suspension contains 15 mg 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 thyrotropic adenomas when the circulating level of thyroid stimulating hormone remains inappropriately high after surgery and/or radiotherapy.

Neuroendocrine Tumours:

Somatuline LA is 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.

Thyrotropic Adenomas:

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 patients:

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

Paediatric population:

Somatuline LA 30 mg is not recommended for use in children and adolescents due to a 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).

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 LA treatment is initiated, or when the dose is altered and any antidiabetic treatment should be adjusted accordingly.

Slight decrease in thyroid function has been seen during treatment with lanreotide 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 lanreotide 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 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 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 following treatment with Somatuline LA.

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.

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.

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 LA. 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.

Post-marketing safety experience:

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

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 via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard.

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.

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 acromegalic patients treated long term.

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

A randomised, placebo controlled study has investigated the effects of lanreotide LA 30 mg administration every 10 days in 80 patients with inoperable upper intestinal obstruction of malignant origin due to confirmed peritoneal carcinomatosis. The primary objective was to assess the proportion of responders 7 days after a single injection of lanreotide LA 30 mg versus placebo. Treatment response was defined as 1 or less vomiting episode per day for at least 3 consecutive days, or no vomiting recurrence for at least 3 consecutive days for subjects in whom a nasogastric tube had been removed.

In the Intent-to-Treat [ITT] population (43 in the lanreotide group and 37 in the placebo group), when based on subject diary record cards (DRC) assessed at day 7, the responders rate was more favourable for lanreotide than placebo, although not statistically significant (41.9% [18/43] versus 29.7% [11/37], odds ratio=1.75 [95% CI 0.68 - 4.49, p=0.24]). When based on investigators assessment, there was a statistically significant difference in the responders rate in favour of lanreotide versus placebo in this population (50.0% [19/38] and 28.6% [10/35], respectively [odds ratio=2.82, 95% CI 1.00 - 7.86, p=0.048]).

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 eva luating excretion, less than 5% of lanreotide 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 30 mg 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 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.

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 2 mL 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

PL 34926/0004

26 January 1998/20 May 2004

04 November 2014