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CLIPPER 5MG GASTRORESISTANT PROLONGED RELEASE TABLETS

Active substance: BECLOMETASONE DIPROPIONATE

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SUMMARY OF PRODUCT CHARACTERISTICS

1

NAME OF THE MEDICINAL PRODUCT
Clipper 5 mg gastro-resistant prolonged release tablets ▼

2.

QUALITATIVE AND QUANTITATIVE COMPOSITION
Each tablet contains 5 mg of beclometasone dipropionate
For excipients, see 6.1

3.

PHARMACEUTICAL FORM
Gastro-resistant prolonged release tablets
Each ivory white, coated tablet is round and convex

4.

CLINICAL PARTICULARS

4.1

Therapeutic indications
The tablets are indicated for the treatment of mild or moderate ulcerative
colitis in active phase, as add-on therapy to 5-ASA containing drugs in
patients who are non-responders to 5-ASA therapy in active phase.

4.2

Posology and method of administration

Method of Administration
Tablets must be swallowed whole with a little liquid. The tablets should not be
broken or chewed.
Dosage Recommendations
Adults
One Clipper 5 mg tablet a day to be taken in the morning before or after a light
breakfast.
Therapy cycles of not more than four weeks are recommended.
Elderly

No special dose adjustment is recommended. However, experience with Clipper in
the elderly is limited.
Children
There is no experience with Clipper tablets in children. Clipper is not recommended
for use in children.

4.3

Contraindications

Clipper 5 mg gastro-resistant prolonged release tablets are contraindicated in patients
with :
-

hypersensitivity to beclometasone dipropionate or to any of the excipients
tubercular, local mycotic and viral infections

4.4

Special warnings and precautions for use
As there are no data in patients with severe hepatic impairment, treatment with
Clipper in these patients is not recommended.
There are no data in patients with hepatic or renal insufficiency, so these patients
should only be treated with caution.
Use with caution in patients with tuberculosis, diabetes mellitus, gastro-duodenal
ulcer, serious arterial hypertension, osteoporosis, hypoadrenalism, glaucoma and
cataract.
In case of pre-existing intestinal infection, or where such infection arises during
treatment, appropriate antibiotic therapy must be instituted immediately.
Clinical safety data on treatment duration of more than four weeks are not available,
therefore, the use of the product for longer periods is not recommended.
After four weeks of treatment a reduction of the plasmatic levels of corticosteroids
has been observed in up to 25 % of patients treated with Clipper 5 mg per day. This
percentage is much lower if compared to the percentage of patients treated with oral
systemic corticosteroids, such as prednisolone at a dose of 40 mg per day, showing
plasma cortisol levels below the normal range (76 % after eight weeks of treatment,
published data). This is due to the low systemic availability of the active metabolite,
beclometasone-17-monopropionate (B-17-MP), after administration of Clipper 5 mg
per day, which is approximately 20 % compared to the intravenous dose. The effect
on HPA–axis could be considered as transient and a recovery of HPA function is
expected to occur after withdrawal of the drug. However, due to the lack of follow up
data after the usual treatment period, careful supervision of patients’ clinical
symptoms is recommended.
In case of prolonged treatment, possible adverse effects related to the suppression of
HPA-axis may occur (see section 4.8). The suppression of the HPA-axis can reduce

the stress response. Where patients are subject to surgery or other stresses,
supplementary glucocorticoids treatment is recommended.
This medicinal product contains lactose. Patients with rare hereditary problems of
galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption
should not take this medicine.
Patients and/or carers should be warned that potentially severe psychiatric adverse
reactions may occur with systemic steroids (see section 4.8). Symptoms typically
emerge within a few days or weeks of starting the treatment. Risks may be higher
with high doses/systemic exposure (see also section 4.5 pharmacokinetic interactions
that can increase the risk of side effects), although dose levels do not allow prediction
of the onset, type, severity or duration of reactions. Most reactions recover after either
dose reduction or withdrawal, although specific treatment may be necessary.
Patients/carers should be encouraged to seek medical advice if worrying
psychological symptoms develop, especially if depressed mood or suicidal ideation is
suspected. Patients/carers should also be alert to possible psychiatric disturbances
that may occur either during or immediately after dose tapering/withdrawal of
systemic steroids, although such reactions have been reported infrequently.
Particular care is required when considering the use of systemic corticosteroids in
patients with existing or previous history of severe affective disorders in themselves
or in their first degree relatives. These would include depression or manic-depressive
illness and previous steroid psychosis.

4.5
Interactions with other medicinal products and other forms of
interactions
No specific studies on possible interactions have been performed with Clipper.
As beclometasone dipropionate undergoes a very rapid metabolism via esterases
enzymes without involvement of cytochrome P450, a metabolic interaction with drugs
inhibiting the P450 isoenzymes is unlikely.
Clipper in clinical studies has been used in conjunction with oral or rectal treatment
with mesalazine. Even if no specific pharmacodynamic interactions have been
studied, clinical trials did not evidence any increase of adverse events severity due to
the association of BDP with 5-ASA products. In addition, according to the different
pharmacokinetic pathway of the two drugs, metabolic interactions are not expected to
occur

4.6

Pregnancy and lactation
Pregnancy
Data on a large number of exposed pregnancies indicate no adverse effects of
1 mg per day beclometasone dipropionate ( after inhalation ), on pregnancy or
on the health of the newborn child. To date, no other relevant epidemiological
data on oral administration of 5 mg beclometasone dipropionate are available.
High doses of systemic corticosteroids for longer periods may cause
intrauterine growth retardation.

Studies in animals have shown reproductive toxicity ( see section 5.3 ).
Clipper should not be used in pregnancy, unless strictly indicated after a
careful risk / benefit evaluation. Foetal growth should be monitored.
Lactation
It is not known whether beclometasone dipropionate is excreted in breast milk.
Due to the lack of data, the administration of Clipper during lactation is not
recommended unless strictly indicated after a careful risk / benefit evaluation.

4.7

Effects on ability to drive and use machines

Clipper has no or negligible influence on the ability to drive and use machines.

4.8

Undesirable effects
A wide range of psychiatric reactions including affective disorders (such as irritable,
euphoric, depressed and labile mood, and suicidal thoughts), psychotic reactions
(including mania, delusions, hallucinations, and aggravation of schizophrenia),
behavioural disturbances, irritability, anxiety, sleep disturbances, and cognitive
dysfunction including confusion and amnesia have been reported with systemic
corticosteroids. Reactions are common and may occur in both adults and children. In
adults, the frequency of severe reactions has been estimated at 5-6%.
Psychological effects have been reported on withdrawal of corticosteroids; the
frequency is unknown.
The adverse reactions found during clinical studies in patients treated with 5 mg of
Clipper were all classified as mild or moderate and were all uncommon (≤ 1/100 >
1/1000):
SYSTEM ORGAN CLASS

UNDESIRABLE EFFECT

Psychiatric disorders

anxiety

Nervous system disorders

headache, somnolence

Gastrointestinal disorders

nausea, constipation, abdominal pain

Musculoskeletal and connective tissue disorders muscle cramps
Reproductive system and breast disorders

menorrhagia

General disorders and administration site
conditions

influenza like illness, pyrexia

During clinical trials carried out with Clipper 5 mg tablets a reduction of plasma
cortisol levels at the end of four weeks treatment has been observed in up to 25 % of
patients, however, clinical symptoms associated with adrenal suppression have not
been reported.

Particularly at high doses of systemic corticosteroids taken for long periods, rare (≤
1/1000 > 1/10000) systemic adverse events may occur.
These may include:
SYSTEM ORGAN CLASS
Infections and infestations

oropharyngeal candidiasis

Blood and the lymphatic system disorders

lymphopenia, monocytopenia,
granulocytosis

Endocrine disorders

adrenal suppression, cushingoid

Metabolism and nutrition disorders

obesity

Nervous system disorders

headache, benign intracranial
hypertension

Eye disorders

cataract, glaucoma

Skin and subcutaneous tissue disorders

lipohypertrophy, rosacea

Musculoskeletal and connective tissue disorders

4.9

UNDESIRABLE EFFECT

osteoporosis

Overdose

No cases of overdose have so far been reported. However, in case of acute or chronic
intake exceeding the therapeutic dose, the following measures should be taken :
Acute
Ingestion of the drug in doses in excess of those recommended may lead to temporary
suppression of adrenal function. This does not require emergency action.
Chronic
Monitoring of adrenal reserve may be indicated. Treatment should be continued at a
dose sufficient to control the ulcerative colitis and no more.

5.

PHARMACOLOGICAL PROPERTIES

5.1

Pharmacodynamic properties
Pharmacotherapeutic Group : Corticosteroids for local use
ATC Code : A07E A07
Clipper tablets contain beclometasone dipropionate ( BDP ), a pro-drug with
weak glucocorticoid receptor binding affinity. BDP is hydrolysed via esterase
enzymes to the active metabolite, beclometasone-17-monopropionate ( B-17MP ), which has high topical anti-inflammatory activity ( approximately thirty
times the potency of BDP ).

Scintigraphic study in healthy volunteers with Clipper demonstrated that
tablets’ integrity was maintained whilst the preparation resided within the
stomach. Once in the small intestine, the tablets remained intact for a
considerable period of time ( 57 to 118 minutes ), before showing initial signs
of disintegration. The prolonged release tablets core gradually eroded and a
complete disintegration was achieved within 4 to 5 hours in the proximal colon
and small intestine.
Effects on the pituitary-adrenal axis were evaluated in four clinical studies as
well as in clinical pharmacology study conducted in ulcerative colitis patients.
Even if serum morning cortisol level was influenced by the administration of
Clipper Tablets, which lead to a suppression of the endogenous cortisol level
at the end of treatment in a maximum of 25 % of patients, no corticosteroidrelated adverse drug reaction was reported during the limited treatment period
of the clinical trials.
As treatment with Clipper Tablets lasts for no more than four weeks, the effect
on HPA–axis could be considered as transient and a recovery of HPA
function is expected to occur after withdrawal of the drug.

5.2

Pharmacokinetic properties
Beclometasone dipropionate ( BDP ), is very rapidly hydrolysed to its active
metabolite ( B-17-MP ), via esterase enzymes found mostly in liver and lung
tissues. In human serum and intestinal juices, B-17-MP is probably formed by
pancreatine. Minor inactive metabolites, beclometasone-21-monopropionate (
B-21-MP ), and beclometasone ( BOH ), are also formed. The hydrolysis of
BDP in the intestinal fluids was confirmed during a study aimed to quantitate
BDP and its metabolites in ileostomy effluents of patients who had a terminal
ileostom. Following intravenous dosing, the disposition of BDP and B-17-MP
are characterised by high plasma clearance (150 L per hour and 120 L per
hour, respectively ), with a small volume of distribution at steady state for
BDP ( 20 L ) and larger tissue distribution for B-17-MP ( 424 L ). The
terminal elimination half-lives are 0.5 hour and 2.7 hours for BDP and B-17MP, respectively. Plasma protein binding is moderately high. The renal
excretion of BDP and its metabolites is negligible. Faecal excretion is the
major route of BDP elimination mainly as polar metabolites.
The pharmacokinetics of BDP and its active metabolite, B-17-MP after single
and repeated oral administrations of Clipper was evaluated in ulcerative colitis
disease patients. BDP levels were always under the limit of quantitation ( < 20
µg per ml ). The maximum plasma concentration of B-17-MP obtained after
two weeks treatment with Clipper 5 mg, once daily, appeared to be similar, ie.,
approximately 1 ng per ml, to the Cmax observed with a 1 mg dose of BDP
administered by inhalation. The systemic availability of B-17-MP evaluated
in comparison with an intravenous dose was about 20 %.

5.3

Preclinical safety data
Chronic toxicity studies with beclometasone dipropionate resulted in dose
dependent effects typical of glucocorticoids.
Beclometasone dipropionate is non-genotoxic and no evidence of
carcinogenicity was observed in rats.
Reproduction toxicity studies in animals have revealed teratogenic and
embryo-foetal effects in mice and rabbits and an increased abortion rate and
retarded uterine growth in monkeys.

6.

PHARMACEUTICAL PARTICULARS

6.1

List of excipients
In Tablet Core
Lactose monohydrate
Hypromellose ( E. 464 )
Microcrystalline cellulose
Maize starch
Magnesium stearate
In Tablet Coat
Macrogol 4000
Methacrylic acid-methyl methacrylate copolymer ( 1:1 )
Titanium dioxide ( E. 171 )
Talc

6.2

Incompatibilities
Not applicable

6.3.

Shelf life
3 years

6.4

Special precautions for storage

No special precautions for storage.

6.5

Nature and contents of the container
PVC/PVDC/Al/PVDC blister.
Package of 10 or 30 tablets

6.5

Nature and contents of container
PVC / PVDC / Al / PVDC blister
Packs of 10 or 30 tablets
Not all pack sizes may be marketed.

6.6

Instruction for use and handling
No special requirements.

7.

8.

MARKETING AUTHORISATION HOLDER
Chiesi Limited,
Cheadle Royal Business Park,
Highfield,
Cheadle,
SK8 3GY,
UK.

MARKETING AUTHORISATION NUMBER(S)
PL 08829/0153

9

DATE OF FIRST AUTHORISATION/RENEWAL OF THE
AUTHORISATION
03/10/2008

10

DATE OF REVISION OF THE TEXT
22/12/2008

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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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