SOMATULINE AUTOGEL 60MG SOLUTION FOR INJECTION

Active substance: LANREOTIDE

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SUMMARY OF PRODUCT CHARACTERISTICS

1

NAME OF THE MEDICINAL PRODUCT
Somatuline® Autogel® 60mg, solution for injection in a prefilled syringe.

2

QUALITATIVE AND QUANTITATIVE COMPOSITION
Lanreotide (I.N.N.), 60mg (as acetate)
Each prefilled syringe contains a supersaturated solution of lanreotide acetate
corresponding to 0.246mg lanreotide base/mg of solution, which ensures an
actual injection dose of 60mg of lanreotide.
For excipients, see 6.1.

3

PHARMACEUTICAL FORM
Solution for injection in a prefilled 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.
SOMATULINE AUTOGEL is also indicated for the treatment of symptoms
associated with neuroendocrine (particularly carcinoid) tumours.

4.2

Posology and method of administration
Posology
Acromegaly
In patients receiving a somatostatin analogue for the first time, the

recommended starting dose is 60mg of Somatuline Autogel administered
every 28 days.
In patients previously treated with Somatuline LA 30mg once every 14 days,
the initial dose of Somatuline Autogel should be 60mg every 28 days, in
patients previously treated with Somatuline LA 30mg once every 10 days, the
initial dose of Somatuline Autogel should be 90mg every 28 days; and in
patients treated with Somatuline LA 30mg once every 7 days, the initial dose
of Somatuline Autogel should be 120mg every 28 days.
Thereafter, for all patients, 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).
If the desired response is not obtained, the dose may be increased.
For patients whose GH concentrations are below 1ng/mL (approx 2mU/L),
whose IGF-1 serum concentrations have normalised, and in whom most
reversible signs of acromegaly have disappeared the monthly dose should be
decreased. If appropriate, this may be achieved by giving Somatuline Autogel
120mg at increased intervals of 42-56 days.
For patients on Somatuline Autogel 60mg or 90mg every 28 days who are well
controlled (GH concentrations less than 2.5ng/mL (approx 5 mU/L) but above
1ng/mL (approx 2mU/L) and normalised IGF-1 levels) the dose should be
maintained, or alternatively Somatuline Autogel 120mg may be given at
increased intervals of 56 or 42 days respectively.
For patients in whom clinical symptoms and biochemical parameters are not
adequately controlled (GH concentrations still above 2.5ng/mL (approx 5
mU/L) or IGF-1 greater than (age matched) normal) the dose of Somatuline
Autogel may be increased to a maximum of 120mg at 28 day intervals.
Long term monitoring of symptoms, GH and IGF-1 levels should be routinely
carried out in all patients.
Neuroendocrine tumours:
The recommended starting dose is 60 to 120mg administered every 28 days.
The dose should be adjusted according to the degree of symptomatic relief
obtained.
Paediatric population:
Somatuline Autogel is not recommended for use in children and adolescents
due to 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).
Elderly patients:

In elderly patients, no dosage adjustment is necessary due to the wide
therapeutic window of lanreotide ( see section 5.2).
Method of Administration:
Somatuline Autogel should be injected, via the deep subcutaneous route, into
the superior, external quadrant of the buttock.
The injection may be given by a healthcare professional or, for patients
considered by their healthcare professional to be stabilised on their treatment
with Somatuline Autogel, by an appropriately trained friend or relative of the
patient (see section 5.1). Alternatively, such patients may self-administer the
product after appropriate training. 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.

4.3

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

4.4

Special warnings and precautions for use
Lanreotide may reduce gall bladder 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 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%). Tests of thyroid function 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

Interaction with other medicinal products and other forms of interaction
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 lanreotide. Dose adjustments of such concomitant medicines may be
necessary.
The limited published data available indicate the 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

Pregnancy and lactation
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/newborn 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 Somatuline 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 (≥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 indurations).
The profile of undesirable effects is similar for other indications.

System organ class

Very common
(≥1/10)

common (≥1/100 to uncommon
<1/10)
(≥1/1,000 to
<1/100)

Investigations

ALAT increased,
ASAT abnormal,
ALAT abnormal,
blood bilirubin
increased, blood
glucose increased,
glycosylated
haemoglobin
increased, weight
decreased

Cardiac disorders

Sinus bradycardia

Nervous system
disorders

Dizziness,
headache

Gastrointestinal
disorders

Diarrhoea, loose
stools, abdominal
pain

Nausea, vomiting,
constipation,
flatulence,
abdominal
distension,
abdominal
discomfort,
dyspepsia

ASAT increased,
blood alkaline
phosphatase
increased, blood
bilirubin abnormal ,
blood sodium
decreased

Faeces discoloured

Skin and
subcutaneous tissue
disorders

Alopecia,
hypotrichosis

Metabolism and
nutrition disorders

Hypoglycaemia

Vascular disorders

Hot flush

General disorders
and administration
site conditions
Hepatobiliary
disorders

Diabetes mellitus,
hyperglycaemia

Fatigue, injection
site reactions (pain,
mass, induration,
nodule, pruritus)
Cholelithiasis

Asthenia

Biliary dilatation

Psychiatric
disorders

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 and 5, and a reduced binding affinity for human SSTR 1, 3 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 patients with acromegaly treated long
term.

Lanreotide is clearly more active than natural somatostatin and shows a much longer
duration of action.
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).
Somatostatin analogues are reported to have an anti-proliferative effect. This has
been evidenced for lanreotide by stabilisation of tumour growth similar to that seen
with octreotide in two small uncontrolled studies. This effect is relevant for those
patients with well differentiated advanced neuroendocrine tumours of the midgut.

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 16.1L. Total
clearance was 23.7L/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
bilary excretion.
After deep subcutaneous administration of Somatuline Autogel 60, 90 and
120mg to healthy volunteers, lanreotide concentrations increase to achieve
average maximum serum concentrations of 4.25, 8.39 and 6.79ng/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 1.69ng/mL respectively. Absolute bioavailability was 73.4,
69.0 and 78.4%, respectively.
After deep subcutaneous administration of Somatuline Autogel 60, 90 and
120mg to patients with acromegaly, lanreotide concentrations increase to
achieve average maximum serum concentrations of 1.6, 3.5 and 3.1ng/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 1.4ng/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 7.7ng/mL for 60,
90 and 120mg respectively, the average Cmin values obtained being 1.8, 2.5
and 3.8ng/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 120mg in

patients with acromegaly.
Trough lanreotide serum levels obtained after three deep subcutaneous
injections of Somatuline Autogel 60, 90 or 120mg given every 28 days are
similar to the steady-state trough lanreotide serum levels obtained in patients
with acromegaly previously treated with intramuscular administrations of
lanreotide 30mg prolonged release microparticles (Somatuline LA) every 14,
10 or 7 days, respectively.
Lanreotide serum levels of 1ng/mL are able to suppress GH to < 5ng/mL in
more than 60% of patients studied. Lanreotide serum levels of 2.5ng/mL are
able to suppress GH to < 5ng/mL in more than 90% of patients studied.
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%). The 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 bioassay 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 pack, the product should be
administered immediately.

6.4

Special precautions for storage
Store in refrigerator between +2°C and +8°C in its 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
terephthalate / 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 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.

7

MARKETING AUTHORISATION HOLDER
Ipsen Limited
190 Bath Road
Slough, Berkshire
SL1 3XE, UK

8

MARKETING AUTHORISATION NUMBER(S)
PL 34926/0005

9

DATE OF FIRST AUTHORISATION/RENEWAL OF THE
AUTHORISATION
16 October 2001

10

DATE OF REVISION OF THE TEXT
18/10/2013

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Source: Medicines and Healthcare Products Regulatory Agency

Disclaimer: Every effort has been made to ensure that the information provided here is accurate, up-to-date and complete, but no guarantee is made to that effect. Drug information contained herein may be time sensitive. This information has been compiled for use by healthcare practitioners and consumers in the United States. The absence of a warning for a given drug or combination thereof in no way should be construed to indicate that the drug or combination is safe, effective or appropriate for any given patient. If you have questions about the substances you are taking, check with your doctor, nurse or pharmacist.

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