Somatuline Autogel 60 mg, 90 mg and 120 mg solution for injection in a pre-filled syringe

Section 2 has been updated with text under "Warnings and precautions" to talk to doctor or pharmacist if there are symptoms of lanreotide effect on pancreatic enzymes secretion.

Section 4 has been updated with text under 'Not known: frequency cannot be estimated from the available data' on decrease in pancreatic enzymes.

Section 4.4 'Special warnings and precautions for use' has been updated with text on pancreatic exocrine insufficiency (PEI).

Section 4.8 'Undesirable effects' has been updated to add 'pancreatic exocrine insufficiency (PEI)' as an ADR and 'injection site abscess' ADR has been moved under "General disorders and administration site conditions' column.

PIL

5 How to store Somatuline Autogel

The temperature excursion has been changed from 24 hours to 72 hours.

6 Contents of the pack and other information

The description of the box containing the needle has been amended to state with an attached needle instead of one needle. 

Following changes were made to the SmPC:

6.3 Shelf-life

The shelf life has been changed from 2 years to 3 years.

6.4 Special precautions for storage

The temperature excursion has been changed from 24 hours to 72 hours.

6.5 Nature and content of container

The description of the box containing the needle has been amended to state with an attached needle instead of one needle. 

The following changes have been made to the SmPC:

-Section 4.2: An updated statement regarding the monitoring of GH and IGF-1 levels has been added under the posology section for Acromegaly.

-Section 4.3: The statement regarding hypersensitivity to the active substance has been updated.

- Section 4.6: Section 4.6 has been amended to include updated information the use of lanreotide during pregnancy and lactation.

- Section 4.8: Section 4.8 has been updated to add a footnote regarding the Gastrointestinal disorder “abdominal discomfort”.

- Section 5.3: Additional information related to reproductive studies has been added.

To update SmPC section 4.4 to include ‘complications of cholelithiasis’, to update section 4.8 to add a new ADR ‘cholangitis’

Update to section 4.8 of SPC to add new ADRs.

Added "Patients well controlled on a somatostatin analogue can be treated with Somatuline Autogel 120 mg every 42-56 days." to section 4.2 under 'Treatment of symptoms associated with neuroendocrine tumours'

Treatment of grade 1 and a subset of grade 2 (Ki67 index up to 10%) gastroenteropancreatic neuroendocrine tumours of midgut, pancreatic or unknown origin where hindgut sites of origin have been excluded, in adult patients with unresectable locally advanced or metastatic disease

The recommended dose is one injection of Somatuline Autogel 120 mg administered every 28 days. The treatment with Somatuline Autogel should be continued for as long as needed for tumour control.

SUMMARY OF PRODUCT CHARACTERISTICS

1.                  NAME OF THE MEDICINAL PRODUCT

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

2.         QUALITATIVE AND QUANTITATIVE COMPOSITION

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 60 mg of lanreotide.

For a full list of excipients, see 6.1.

3.         PHARMACEUTICAL FORM

Solution for injection in a pre-filled syringe.

White to pale yellow semi solid formulation.

4.         CLINICAL PARTICULARS

            4.1       Therapeutic Indications

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.

4.2       Posology and Method of Administration

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.

4.3       Contraindications

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

4.4       Special Warnings and Special Precautions for Use

Somatuline Autogel 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 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 and any ant diabetic treatment should be adjusted accordingly.

Slight decreases in thyroid function have been seen during treatment with lanreotide in acromegalic patients, although clinical hypothyroidism is rare. Thyroid function test 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.

4.5  Interactions with Other Medicaments and Other Forms of Interaction

The pharmacological gastrointestinal effects of lanreotide may reduce the intestinal absorption of co-administered drugs including cyclosporin.
Concomitant administration of cyclosporine with lanreotide may decrease the relative bioavailability of cyclosporine and therefore may necessitate the adjustment of cyclosporine 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 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 lanreotide 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.

4.6       Fertility, pregnancy and lactation

Pregnancy

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/new-born 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.

4.7       Effects on Ability to Drive and Use Machines

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

4.8       Undesirable Effects

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 > 10%; common > 1% to < 10%; uncommon >0.1% to <1%.

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.

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.

            4.9       Overdose

If overdose occurs, symptomatic management is indicated.

5.         PHARMACOLOGICAL PROPERTIES

5.1       Pharmacodynamic Properties

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, 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.

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

5.2       Pharmacokinetic Properties

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 1.14hours 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 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 Autogel 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 Autogel 60, 90 and 120 mg in acromegalic patients.

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.

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.

5.3       Preclinical Safety Data

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.

6.         PHARMACEUTICAL PARTICULARS

6.1       List of Excipients

Water for injections

Glacial acetic acid (for pH adjustment)

6.2       Incompatibilities

Not applicable.

6.3       Shelf Life

2 years.

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

            6.4       Special Precautions for Storage

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

6.5       Nature and Contents of Container

SOMATULINE AUTOGEL is supplied in a pre-filled syringe (clear polypropylene) fitted with an automatic safety system, a needle (stainless steel), a plastic needle sheath (LDPE) and a plunger stopper (bromobutyl rubber).

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

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

6.6       Special precautions for disposal of a used medicinal product or waste material as derived from such medicinal products and other handling of the product

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

For immediate and single use following first opening.

It is important that the injection of the product is performed exactly according to the instructions 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.

7.         MARKETING AUTHORISATION HOLDER

Ipsen Pharmaceuticals Ltd

7 Upper Leeson Street

Dublin 4

Ireland

Trading as:

Ipsen Pharmaceuticals

8.         MARKETING AUTHORISATION NUMBER

PA869/4/2

9.         DATE OF FIRST AUTHORISATION/RENEWAL OF AUTHORISATION

Date of first authorisaton:22 February 2002

Date of last renewal: 22 February 2007

10.       DATE OF REVISION OF THE TEXT

December 2010

4.2 Posology and method of administration

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.