SOMATULINE AUTOGEL 120 MG SOLUTION FOR INJECTION - summary of medicine characteristics

1 NAME OF THE MEDICINAL PRODUCT

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

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Lanreotide (I.N.N.), 120 mg (as acetate)

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

For 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 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.

The treatment of grade 1 and a subset of grade 2 (Ki67 index up to 10%) gastroenteropan­creatic neuroendocrine tumours (GEP-NETs) of midgut, pancreatic or unknown origin where hindgut sites of origin have been excluded, in adult patients with unresectable locally advanced or metastatic disease (see section 5.1).

The treatment of symptoms associated with neuroendocrine (particularly carcinoid) tumours.

4.2 Posology and method of administration

Posology

Acromegaly

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

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

Patients well controlled on a somatostatin analogue can alternatively be treated with Somatuline Autogel 120 mg every 42 – 56 days (6 to 8 weeks).

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

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.

Treatment of symptoms associated with 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.

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).

Paediatric population

The safety and efficacy of Somatuline Autogel in children and adolescents has not been established.

Method of Administration

Somatuline Autogel is administered by deep subcutaneous injection in the superior external quadrant of the buttock or in the upper outer thigh.

For patients who receive a stable dose of Somatuline Autogel, and after appropriate training, the product may be administered either by the patient or by a trained person. In case of self-injection the injection should be given in the upper outer thigh.

The decision regarding administration by the patient or a trained person should be taken by a healthcare professional.

Regardless of the injection site, the skin should not be folded and the needle should be inserted rapidly and to its full length, perpendicularly to the skin.

The injection site should alternate between the right and left side.

4.3 Contraindi­cations

Hypersensitivity to the active substance, somatostatin or related peptides or to any of the excipients listed in section 6.1.

4.4 Special warnings and precautions for use

Lanreotide may reduce gallbladder motility and lead to gallstone formation. Therefore, patients may need to be monitored periodically. There have been post-marketing reports of gallstones resulting in complications, including cholecystitis, cholangitis, and pancreatitis, requiring cholecystectomy in patients taking lanreotide. If complications of cholelithiasis are suspected, discontinue lanreotide and treat appropriately.

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 antidiabetic 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%). Thyroid function tests 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).

4.5 Interaction with other medicinal products and other forms of interaction The pharmacological gastrointestinal effects of lanreotide may result in the reduction of 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 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 metabolised 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

There is a limited amount of data (less than 300 pregnancy outcomes) from the use of lanreotide in pregnant women.

Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity.

As a precautionary measure, it is preferable to avoid the use of lanreotide during pregnancy.

Breast-feeding

It is not known whether Somatuline Autogel is excreted in human milk.

A risk to the newborns/infants cannot be excluded.

Somatuline Autogel should not be used during breast-feeding.

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.

4.7 Effects on ability to drive and use machines

Somatuline Autogel has minor or moderate influence on the ability to drive and use machines. No studies on the effects on the ability to drive and use machines have been performed.

However, dizziness has been reported with Somatuline Autogel (see section 4.8). 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 and GEP-NETs 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), not known (cannot be estimated from the available data).

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 all indications.

* based on a pool of studies conducted in acromegalic patients

** based on a pool of studies conducted in patients with GEP-NETs

Reporting of suspected adverse reactions

Reporting of 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. Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9 Overdose

If overdose occurs, symptomatic management is indicated.

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Pituitary and hypothalamic hormones and analogues;

Somatostatin and analogues

ATC code: H01C B03.

Mechanism of action

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 SSTR 1, 3 and 4. Activity at human SSTR 2 and 5 is the primary mechanism considered to be responsible for GH inhibition. Lanreotide is more active than natural somatostatin and shows a longer duration of action.

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. Additionally, it decreases the levels of plasma chromogranin A and urinary 5-HIAA (5 Hydroxyindo­lacetic acid) in patients with GEP-NETs and elevated levels of these tumour markers. Lanreotide markedly inhibits meal-induced increases in superior mesenteric artery blood flow and portal venous blood flow. Lanreotide significantly reduces prostaglandin El-stimulated jejunal secretion of water, sodium, potassium and chloride. Lanreotide reduces prolactin levels in patients with acromegaly patients treated long term.

In an open-label study, Somatuline Autogel 120 mg was administered every 28 days for 48 weeks in 90 previously untreated acromegalic patients diagnosed with pituitary macroadenoma. Patients expected to require pituitary surgery or radiotherapy during the study period were excluded.

At week 48, 63% of the patients showed a reduction in tumour volume of > 20% (which was the primary efficacy endpoint) although statistical significance was not reached (95% CI: 52%-73%). A less than 20% reduction was obtained in 24 patients (27%) and an increase in tumour volume was observed in 9 patients (10%).

The mean percentage reduction of tumour volume was 26.8%, GH levels were below 2.5 jrg/L in 77.8% of the patients and IGF-1 levels normalised in 50%. Normalised IGF-1 levels combined with GH levels below 2.5 jrg/L were observed in 43.5% of the patients.

Patients reported a relief of acromegaly symptoms such as fatigue (56.5%), excess perspiration (66.1%), arthralgia (59.7%) and soft tissue swelling (66.1%). Less patients had relief of headache (38.7) %.

A reduction in tumour volume and concentrations of GH and IGF-1 was shown from week 12 and was maintained for 48 weeks).

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).

A phase III, 96-week, fixed duration, randomised, double-blind, multi-centre, placebo-controlled trial of Somatuline Autogel was conducted in patients with gastroenteropan­creatic neuroendocrine tumours to assess the antiproliferative effect of lanreotide.

Patients were randomised 1:1 to receive either Somatuline Autogel 120 mg every 28 days (n=101) or placebo (n=103). Randomisation was stratified by previous therapy at entry and the presence/absence of progression at baseline as assessed by RECIST 1.0 (Response Evaluation Criteria in Solid Tumours) during a 3 to 6 month screening phase.

Patients had metastatic and/or locally advanced inoperable disease with histologically confirmed well or moderately well differentiated tumours primarily localised in the pancreas (44.6% patients), midgut (35.8%), hindgut (6.9%) or of other/unknown primary location (12.7%).

69% of patients with GEP-NETs had tumour grade 1 (G1), defined by either a proliferation index Ki67 < 2% (50.5% of the overall patient population) or a mitotic index < 2 mitosis/10 HPF (18.5% of the overall patient population) and 30% of patients with GEP-NETs had tumours in the lower range of grade 2 (G2) (defined by a Ki67 index > 2% – < 10%). Grade was not available in 1% of the patients. The study excluded patients with G2 GEP-NETs with a higher cellular proliferation index (Ki 67 >10% – < 20%) and G3 GEP neuroendocrine carcinomas (Ki 67 index > 20%). Overall, 52.5% of the patients had a hepatic tumour load < 10%, 14.5% had a hepatic tumour load > 10 and < 25% and 33% had a hepatic tumour load > 25%.

The primary endpoint was progression-free survival (PFS) measured as time to either disease progression by RECIST 1.0 or death within 96 weeks after first treatment administration. Analysis of PFS utilised independent centrally-reviewed radiological assessment of progression.

Table 1: Efficacy results of the phase III study

Figure 1: Kaplan-Meier Progression Free Survival Curves

The beneficial effect of lanreotide in reducing the risk of progression or death was consistent regardless of the location of primary tumour, hepatic tumour load, previous chemotherapy, baseline Ki67, tumour grade or other pre-specified characteristics as shown in Figure 2.

A clinically-relevant benefit of treatment with Somatuline Autogel was seen in patients with tumours of pancreatic, midgut and other/unknown origin as in the overall study population. The limited number of patients with hindgut tumours (14/204) contributed to difficulty in interpreting the results in this subgroup. The available data suggested no benefit of lanreotide in these patients.

Figure 2 – Results of the Cox Proportional Hazards Covariates Analysis of PFS

Age

Baseline chromogranin A

Baseline Ki67

Body mass index

Grade of tumor

Hepatic tumor ioad

Location of primary tumor

Previous chemotherapy

Previous surgery for primary tumor

Race

Sex

Time since diagnosis

Hazard Ratio (95% Cl)

Note: All HRs are the relative hazard for lanreotide Autogel vs placebo.The resultsfor covariates are derived from separate Cox PH models with terms for treatment, progression at baseline, previous therapy at entry, and the term labeled on the vertical axis.

Crossover from placebo to open-label Somatuline Autogel, in the extension study, occurred in 45.6% (47/103) of the patients.

Paediatric population

The European Medicines Agency has waived the obligation to submit the results of studies with Somatuline Autogel in all subsets of the paediatric population in acromegaly and pituitary gigantism (see section 4.2 for information on paediatric use). The European Medicines Agency has listed gastroenteropan­creatic neuroendocrine tumours (excluding neuroblastoma, neuroganglioblas­toma, phaechromocytoma) on the list of class waivers.

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 1.14 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 120 mg to healthy volunteers, lanreotide concentrations increase to achieve average maximum serum concentrations of 4.25, 8.39 and 6.79 ng/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 1.69 ng/ml respectively. Absolute bioavailability was 73.4, 69.0 and 78.4%, respectively.

After deep subcutaneous administration of Somatuline Autogel 60, 90 and 120 mg to patients with acromegaly, lanreotide concentrations increase to achieve average maximum serum concentrations of 1.6, 3.5 and 3.1 ng/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 1.4 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 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 120 mg in patients with acromegaly.

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

In a population PK analysis in 290 GEP-NET patients receiving Somatuline Autogel 120 mg, rapid initial release was seen with mean Cmax values of 7.49 ± 7.58 ng/ml reached within the first day after a single injection. Steady-state concentrations were reached after 5 injections of Somatuline Autogel 120 mg every 28 days and were sustained up to the last assessment (up to 96 weeks after the first injection). At steadystate the mean Cmax values were 13.9 ± 7.44 ng/ml and the mean trough serum levels were 6.56 ± 1.99 ng/ml. The mean apparent terminal half-life was 49.8 ± 28.0 days.

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.

No effect on clearance of lanreotide was observed in a population PK analysis of GEP-NET patients including 165 with mild and moderate renal impairment (106 and 59 respectively) treated with Somatuline Autogel. GEP-NET patients with severely impaired renal function were not studied.

No GEP-NET patients with hepatic impairment (as per Child-Pugh score) were studied.

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 a population PK analysis of GEP-NET patients including 122 aged 65 to 85 years, no effect of age on clearance and volume of distribution of lanreotide was observed.

5.3 Preclinical safety data

6   PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Water for injection

Glacial acetic acid (for pH adjustment).

6.2 Incompatibilities

Not applicable

6.3 Shelf life

2 years.

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

6.4 Special precautions for storage

Store in a refrigerator between 2°C – 8°C. Store in the original package in order to protect from light.

Once removed from the refrigerator, product left in its sealed pouch may be returned to the refrigerator (the number of temperature excursions must not exceed three times) for continued storage and later use, provided it has been stored for no longer than a total of 24 hours at below 40°C.

6.5 Nature and contents of container

Somatuline Autogel is supplied in a pre-filled syringe (polypropylene) fitted with an automatic safety system with a plunger stopper (bromobutyl rubber) and a needle (stainless steel) covered by a plastic cap.

Each ready to use pre-filled syringe is placed into a plastic tray and packed in a laminated pouch and a cardboard box.

Box of one 0.5 ml pre-filled syringe with one needle (1.2 mm x 20 mm).

6.6 Special precautions for disposal

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.

The used injection device should be disposed of in a designated sharps container.

7 MARKETING AUTHORISATION HOLDER

Ipsen Limited

190 Bath Road

Slough, Berkshire

SL1 3XE, UK

8 MARKETING AUTHORISATION NUMBER(S)

PL 34926/0007

DATE OF FIRST AUTHORISATION/RE­NEWAL OF THE

AUTHORISATION

Date of first authorisation: 16 October 2001

Date of latest renewal: 07 April 2009