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SOMATULINE AUTOGEL 90MG SOLUTION FOR INJECTION

Active substance(s): LANREOTIDE / LANREOTIDE ACETATE

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SUMMARY OF PRODUCT CHARACTERISTICS

1

NAME OF THE MEDICINAL PRODUCT
Somatuline® Autogel® 90mg, solution for injection in a prefilled syringe.

2

QUALITATIVE AND QUANTITATIVE COMPOSITION
Lanreotide (I.N.N.), 90mg (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 90mg 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.
• 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 60mg to 120mg 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 2.5ng/mL (approx 5mU/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 120mg 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
Somatuline Autogel is not recommended for use in children and adolescents due to
lack of data on safety and efficacy.
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 lanreotide or related peptides or any of the excipients listed in
section 6.1.

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 anti-diabetic 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).

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
Studies in animals showed no evidence of teratogenic effects associated with
lanreotide during organogenesis.
Data on a limited number of pregnant women exposed to lanreotide 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.
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).
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.

System organ
class

Very
common
(≥1/10)

Investigations

Post-marketing
safety
experience
(frequency not
known)

Insomnia*

Psychiatric
disorders
Nervous system
disorders

Hepatobiliary
disorders
Musculoskeletal
and connective
tissue disorders
Skin and
subcutaneous
tissue disorders
General
disorders and
administration
site conditions

Uncommon
(≥1/1,000 to
<1/100)

Hypoglycaemia,
decreased
appetite**,
hyperglycaemia,
diabetes mellitus

Metabolism and
nutrition
disorders

Cardiac
disorders
Vascular
disorders
Gastrointestinal
disorders

Common (≥1/100
to <1/10)

Dizziness,
headache,
lethargy**
Sinus
bradycardia*
Hot flushes*
Diarrhoea,
loose stools*,
abdominal
pain

Cholelithiasis

Nausea, vomiting,
constipation,
flatulence,
abdominal
distension,
abdominal
discomfort,
dyspepsia,
steatorrhoea**
Biliary dilatation*

Faeces
discoloured*

Musculoskeletal
pain**,
myalgia**
Alopecia,
hypotrichosis*
Asthenia, fatigue,
injection site
reactions (pain,
mass, induration,
nodule, pruritus)
ALAT
increased*, ASAT
abnormal*,
ALAT
abnormal*, blood
bilirubin
increased*, blood
glucose
increased*,
glycosylated
haemoglobin
increased*,
weight decreased,

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

Pancreatitis

pancreatic
enzymes
decreased**
Immune system
disorders

Allergic
reactions
(including
angioedema,
anaphylaxis,
hypersensitivity)

* 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 authorization 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.

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 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 E1-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 120mg 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 μg/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 μg/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, randomized, 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 randomized 1:1 to receive either Somatuline Autogel 120 mg every 28
days (n=101) or placebo (n=103). Randomization 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 localized 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 an hepatic tumour load ≤10%, 14.5% had
an hepatic tumour load > 10 and ≤25% and 33% had an 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 utilized independent centrallyreviewed radiological assessment of progression.
Table 1: Efficacy results of the phase III study
Median Progression free survival
(weeks)
Somatuline Autogel
(n=101 )

Placebo
(n=103 )

> 96 weeks

72.00 weeks
(95% CI : 48.57, 96.00)

Hazard Ratio
(95% CI)

Reduction
in risk of
progression
or death

0.470
(0.304, 0.729)

53%

p-value

0.0002

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 prespecified 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

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 16.1L. 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 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 1.69ng/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 3.1ng/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 1.4 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 7.7ng/mL for 60, 90 and 120 mg
respectively, the average Cmin values obtained being 1.8, 2.5 and 3.8ng/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.
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 steadystate trough lanreotide serum levels obtained in patients with acromegaly previously
treated with intramuscular administrations of lanreotide 30 mg 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.
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
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 34926/0006

9

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

10

DATE OF REVISION OF THE TEXT
06/05/2017

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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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