Ipsen Pharmaceuticals Ltd

Somatuline Autogel 90mg, solution for injection.

Lanreotide (I.N.N.), presented as lanreotide acetate 90 mg

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

For a full list of excipients, see section 6.1.

Solution for injection.

White to off-white, translucent and viscous supersaturated solution in a pre-filled syringe, ready for use.

SOMATULINE AUTOGEL is indicated for the long term 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 indicated for the relief of symptoms associated with acromegaly.

SOMATULINE AUTOGEL is also indicated for the treatment of symptoms associated with carcinoid tumours.

Posology

Acromegaly

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

For example, in patients previously treated with Somatuline LA 30 mg with a dose every 14 days, the initial dose of SOMATULINE AUTOGEL should be 60 mg every 28 days, and in patients previously treated with Somatuline LA 30 mg with a dose every 10 days, the initial dose of SOMATULINE AUTOGEL should be 90 mg every 28 days.

Thereafter 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 IGF1 levels).

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

If complete control is obtained (based on GH levels under 1 ng/ml, normalised IGF1 levels and/or disappearance of symptoms), the dose may be decreased, or alternatively, 120mg can be given at increased intervals of 42-56 days.

Long term monitoring of symptoms, GH and IGF1 levels should be undertaken as clinically indicated.

Neuroendocrine tumours:

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

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

Method of Administration:

SOMATULINE AUTOGEL should be injected, via the deep sub-cutaneous route, into the superior, external quadrant of the buttock.

The injection may be given by a healthcare professional or, for patients who are receiving a stable dose of SOMATULINE AUTOGEL, by an appropriately trained friend or relative of the patient. Alternatively, patients who have received appropriate training may self-administer the product. 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.

Currently there is no experience of administration of SOMATULINE AUTOGEL in children, therefore use of SOMATULINE AUTOGEL in children cannot be recommended.

Hypersensitivity to lanreotide or related peptides.

Pharmacological studies in animals and humans show that lanreotide, like somatostatin and its analogues, may produce a transient inhibition of the secretion of insulin and glucagon. Hence, diabetic patients treated by SOMATULINE AUTOGEL may experience a slight transient change in blood glucose levels. Blood glucose levels should be checked in order to determine whether anti-diabetic treatment needs to be adjusted.

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

Lanreotide may reduce gall bladder motility and therefore, gall bladder echography may be advisable at the start of treatment and as clinically indicated thereafter. If gallstones do occur, they are generally asymptomatic. Symptomatic stones should be treated as medically indicated.

Hepatic/renal 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 hepatic impairment, an increase in volume of distribution and mean residence time are observed, but there is no difference in total clearance or AUC. Elderly subjects show an increase in half-life and mean residence time compared with healthy young subjects. Due to the wide therapeutic window of lanreotide, it is not necessary to alter the dose in these circumstances.

Concomitant administration of lanreotide injection with cyclosporin may decrease blood levels of cyclosporin, hence blood levels of cyclosporin should be monitored.

Interactions with highly plasma bound drugs are unlikely in view of the moderate binding of lanreotide to serum proteins (78 % mean serum binding).

Reproductive studies in rats and rabbits at doses up to 33 times the human dose have failed to demonstrate a risk to the foetus; however there are no adequate and well-controlled studies in pregnant women. Because animal reproductive studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.

Six pregnancies and one suspected pregnancy have been reported in patients who were being treated with lanreotide. Four pregnancies resulted in healthy, full term infants. One acromegalic patient delivered prematurely due to maternal complications. One patient with acromegaly had a first trimester miscarriage. One additional patient with acromegaly had a suspected first trimester miscarriage. No causal effect can be established between lanreotide and these data.

There is no information available on the presence of lanreotide in human breast milk. SOMATULINE AUTOGEL should be used in pregnancy or lactation only if clearly needed.

Therapy with SOMATULINE AUTOGEL is unlikely to impair patients' ability to drive or use machines.

Clinical tolerance

The adverse reactions related to SOMATULINE AUTOGEL during clinical trials are consistent with those seen with other prolonged release formulations of lanreotide, and are predominantly gastrointestinal. In clinical trials of SOMATULINE AUTOGEL in acromegalic patients, 80% of patients experienced at least 1 adverse event. More than 50% of these adverse events were classified as gastrointestinal system disorders. The most commonly reported adverse reactions are diarrhoea, abdominal pain and nausea. These reactions are usually mild and transient.

Very common adverse reactions: the following adverse reactions occurred in more than 10% of patients: Diarrhoea, abdominal pain, nausea.

Common adverse reactions: the following adverse reactions occurred in greater than 5% but less than 10% of patients: constipation, flatulence, cholelithiasis, gall bladder sludge.

Less common adverse reactions: the following adverse reactions occurred in between 1 and 5% of patients: asthenia, fatigue, increased bilirubin.

Uncommon adverse reactions: the following adverse reactions occurred in less than 1% of patients. Injection site pain, skin nodule, hot flushes, leg pain, malaise, headache, tenesmus, vomiting, abnormal glucose tolerance, hyperglycaemia, decreased libido, somnolence, pruritus, increased sweating, skin disorder (not specified).

Local tolerance

Reactions at the injection site may occur after the deep subcutaneous injection of SOMATULINE AUTOGEL in the buttock. When specific enquiry was made, pain, redness, itching and induration were reported at the injection site 30 minutes after dosing in up to 8%, 5%, 5% and 19% of patients respectively. After 3 dosing intervals, these symptoms or signs were reduced to 6%, 2% 3% and 9% of patients or fewer. In all cases, the symptoms were described as mild.

In clinical trials, lanreotide has been administered in doses up to 15 mg per day without serious adverse events related to the treatment. Human experience of overdose of prolonged release forms of lanreotide is limited to one unconfirmed case report of overdose where a patient was reported to have taken one intramuscular injection of the 30 mg prolonged release formulation daily for two months (instead of 1 injection every 7 to 14 days). One week after stopping therapy the 52 year-old man with a history of acromegaly, diabetes mellitus and arterial hypertension suffered a fatal cardiac infarction.

If overdosage 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. It shows high binding affinity for human somatostatin receptors (SSTR) 2, 3 and 5, and reduced affinity for human SSTR 1 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 acromegalic patients treated long term.

Pharmacokinetic parameters of lanreotide after intravenous administration in healthy volunteers indicated limited extravascular distribution, with a steady-state volume of distribution of 13 l. Total clearance was 20 l/h, terminal half-life was 2.5 hours and mean residence time was 0.68 hours.

After a single subcutaneous injection of SOMATULINE AUTOGEL 60 mg in healthy volunteers, a maximum serum concentration (Cmax) of 5.8 ± 4 ng/ml was reached after 6 hours, followed by a slow decrease (mean residence time: 30 ± 6 days, apparent half-life: 33 ± 14 days). The absolute bioavailability was 63 ± 10%.

After a single intramuscular injection of SOMATULINE AUTOGEL 60 mg in healthy volunteers, a maximum serum concentration (Cmax) of 6.8 ± 3 ng/ml was reached after 15 hours, followed by a slow decrease (mean residence time: 23 ± 11 days, apparent half-life: 23 ± 9 days). The absolute bioavailability was 79 ± 10%.

Therefore the route of administration (subcutaneous or intramuscular) does not show any marked influence on the lanreotide pharmacokinetic profile.

After a single intramuscular injection of SOMATULINE AUTOGEL 90 mg in healthy volunteers, a maximum serum concentration (Cmax) of 9.8 ± 5 ng/ml was reached after 10 hours, followed by a slow decrease (mean residence time: 26 ± 4 days, apparent half-life: 31 ± 16 days). The absolute bioavailability was 58 ± 10%.

After a single intramuscular injection of SOMATULINE AUTOGEL 120 mg in healthy volunteers, a maximum serum concentration (Cmax) of 12.8 ± 7 ng/ml was reached after 16 hours, followed by a slow decrease (mean residence time: 29 ± 3 days, apparent half-life: 28 ± 6 days). The absolute bioavailability was 55 ± 10%.

Therefore lanreotide serum concentration after intramuscular administration of SOMATULINE AUTOGEL 60, 90 and 120 mg shows an almost log-linear first order lanreotide release profile.

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 lanreotide 30 mg prolonged release microparticles (Somatuline LA) every 14, 10 or 7 days respectively.

In vitro and animal toxicology studies have not shown any specific toxic potential for lanreotide. The observed effects are related to the pharmacological properties of lanreotide on the endocrine system.

Water for injections

Not applicable.

Unopened : 2 years

Once opened, use immediately.

Store in a refrigerator between +2°C and +8°C in its original package. Do not freeze.

SOMATULINE AUTOGEL is supplied in a clear polypropylene pre-filled syringe with a stainless steel needle. Each pre-filled syringe is packed in a nylon / polyethylene / aluminium laminated bag.

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

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

For immediate and single use following first opening.

For single use only.

Ipsen Pharmaceuticals Ltd

7 Upper Lesson Street

Dublin 4

Ireland

Trading as:

Ipsen Pharmaceuticals

PA869/4/3

22^nd February 2002

October 2007