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PENTASA SACHET 4 G PROLONGED RELEASE GRANULES

Active substance(s): MESALAZINE

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SUMMARY OF PRODUCT CHARACTERISTICS

1

NAME OF THE MEDICINAL PRODUCT
PENTASA Sachet 4g prolonged release granules

2

QUALITATIVE AND QUANTITATIVE COMPOSITION
Each sachet contains mesalazine 4 g
For a full list of excipients, see section 6.1.

3

PHARMACEUTICAL FORM
Prolonged release granules
White-grey to pale white-brown granules

4

CLINICAL PARTICULARS

4.1

Therapeutic indications
Mild to moderate ulcerative colitis

4.2

Posology and method of administration
Posology
Ulcerative colitis
Adults
Active disease
Individual dosage, up to 4 g mesalazine once daily or divided into 2-4 doses.
Maintenance treatment
Individual dosage. Recommended dosage, 2 g mesalazine once daily.

Paediatric population:
The safety and efficacy in children below 6 years of age have not been
established.
There is only limited documentation for an effect in children (age 6-18 years).
Children 6 years of age and older:
Active disease: To be determined individually, starting with 30-50 mg/kg/day
in divided doses. Maximum dose: 75 mg/kg/day in divided doses. The total
dose should not exceed 4 g/day (maximum adult dose).
Maintenance treatment: To be determined individually, starting with 15-30
mg/kg/day in divided doses. The total dose should not exceed 2 g/day
(recommended adult dose).
It is generally recommended that half the adult dose may be given to children
up to a body weight of 40 kg; and the normal adult dose to those above 40 kg.
Method of administration
Oral use
The granules must not be chewed.
The contents of the sachet should be emptied onto the tongue and washed
down with some water or orange juice.
4.3

Contraindications
Hypersensitivity to mesalazine, any of the excipients listed in section 6.1, or
salicylates.
Severe liver and/or renal impairment.

4.4

Special warnings and precautions for use
Caution is recommended when treating patients allergic to sulphasalazine (risk
of allergy to salicylates). In case of acute symptoms of intolerance, i.e.
abdominal cramps, abdominal pain, fever, severe headache and rash, the
treatment should be discontinued immediately.
Caution is recommended in patients with impaired liver function. Liver
function parameters like ALT or AST should be assessed prior to and during
treatment, at the discretion of the treating physician.
The drug is not recommended for use in patients with impaired renal function
and in patients with haemorrhagic diathesis. The renal function should be
regularly monitored (e.g. serum creatinine), especially during the initial phase

of treatment. Urinary status (dip sticks) should be determined prior to and
during treatment at the discretion of the treating physician. Mesalazine
induced nephrotoxicity should be suspected in patients developing renal
dysfunction during treatment. The concurrent use of other known nephrotoxic
agents, such as NSAIDs and azathioprine, may increase the risk of renal
reactions.
Caution is recommended in patients with active peptic ulcer.
Patients with pulmonary disease, in particular asthma, should be very carefully
monitored during a course of treatment.
Mesalazine-induced cardiac hypersensitivity reactions (myo- and pericarditis)
have been reported rarely. Serious blood dyscrasias have been reported very
rarely with mesalazine (see section 4.5). Blood tests for differential blood
counts is recommended prior to and during treatment, at the discretion of the
treating physician. Treatment should be discontinued on suspicion or evidence
of these adverse reactions.
As a guideline, follow-up tests are recommended 14 days after commencement
of treatment, then a further two to three tests at intervals of 4 weeks. If the
findings are normal, follow-up tests should be carried out every three months.
If additional symptoms occur, these tests should be performed immediately.

4.5

Interaction with other medicinal products and other forms of interaction
No interaction studies have been performed. Combination therapy with
Pentasa and azathioprine or 6-mercaptopurine or thioguanine have shown a
higher frequency of myelosuppressive effects, and an interaction cannot be
ruled out, however, the mechanism behind the interaction is not established.
Regular monitoring of white blood cells is recommended and the dosage
regimen of thiopurine should be adjusted accordingly.
There is weak evidence that mesalazine might decrease the anticoagulant
effect of warfarin.

4.6

Fertility, pregnancy and lactation

Pentasa Sachet should not be used during pregnancy and lactation except when
the potential benefits of the treatment outweigh the possible hazards in the
opinion of the physician. The underlying condition itself (Inflammatory bowel
disease (IBD)) may increase risks for adverse pregnancy outcome.

Pregnancy: Mesalazine is known to cross the placental barrier and its
concentration in umbilical cord plasma is lower than the concentration in
maternal plasma. The metabolite acetyl-mesalazine is found at similar
concentrations in umbilical cord and maternal plasma. Animal studies on oral
mesalazine do not indicate direct or indirect harmful effects with respect to
pregnancy, embryo/foetal development, parturition or postnatal development.
There are no adequate and well controlled studies of Pentasa use in pregnant
women. Limited published human data on mesalazine show no increase in the
overall rate of congenital malformations. Some data show an increased rate of
preterm birth, stillbirth, and low birth weight; however, these adverse
pregnancy outcomes are also associated with active inflammatory bowel
disease.
Blood disorders (leucopenia, thrombocytopenia, anaemia) have been reported
in new-borns of mothers being treated with Pentasa Sachet.
In one single case after long-term use of a high dose of mesalazine (2-4g,
orally) during pregnancy, renal failure in a neonate was reported.

Breast-feeding: Mesalazine is excreted in breast milk. The mesalazine
concentration in breast milk is lower than in maternal blood, whereas the
metabolite - acetyl-mesalazine - appears in similar or increased concentrations.
No controlled studies with Pentasa Sachet during breast-feeding have been
carried out. Only limited experience during lactation in women after oral
application is available to date. Hypersensitivity reactions like diarrhoea
cannot be excluded. If the infant develops diarrhoea, breast-feeding should be
discontinued.
Fertility: Animal data on Mesalazine show no effect on male and female
fertility
4.7

Effects on ability to drive and use machines
Pentasa Sachet has no or negligible influence on the ability to drive or use
machines.

4.8

Undesirable effects

The most frequent adverse reactions seen in clinical trials are diarrhoea, nausea,
abdominal pain, headache, vomiting, and rash. Hypersensitivity reactions and drug
fever may occasionally occur.
Frequency of adverse effects, based on clinical trials and reports from post-marketing
surveillance
SOC

Common
≥1/100 to <1/10

Rare
≥1/10,000 to ≤1/1,000

Very rare
≤1/10,000

Blood and the
lymphatic
system disorders

Blood disorders such as:
Anaemia, aplastic
anaemia, agranulocytosis,
neutropenia, leukopenia
(incl. granulocytopenia),
pancytopenia,
thrombocytopenia, and
eosinophilia (as part of an
allergic reaction.

Immune system
disorders

Hypersensitivity reaction
including allergic
exanthema, anaphylactic
reaction, Drug Reaction
with Eosinophilia and
Systemic Symptoms
(DRESS)

Nervous system
disorders

Headache

Cardiac
disorders
Respiratory,
thoracic and
mediastinal
disorders

Gastrointestinal
disorders

Hepato-biliary
disorders

Dizziness

Myocarditis*
Pericarditis*

Diarrhoea
Abdominal pain
Nausea
Vomiting
Flatulence

Acute pancreatitis*
Increased amylase
(blood and/or urine)

Drug Fever
Peripheral neuropathy
Benign intracranial
hypertension in
adolescents
Pericardial effusion
Allergic alveolitis,
allergic and fibrotic lung
reactions (incl. dyspnoea,
coughing,
bronchospasm),
pulmonary eosinophilia,
interstitial lung disease,
pulmonary infiltration,
pneumonitis)
Pancolitis

Increased liver enzymes,
cholestasis parameters
and bilirubin,
hepatotoxicity (incl.

SOC

Common
≥1/100 to <1/10

Rare
≥1/10,000 to ≤1/1,000

Very rare
≤1/10,000
hepatitis*, cholestatic
hepatitis, cirrhosis,
hepatic
failure)

Skin and
subcutaneous
tissue disorders

Musculoskeletal
and connective
tissue disorders
Renal and
urinary
disorders

Rash (incl.
urticaria,
erythematous
rash)

(Reversible) alopecia
Quincke’s oedema,
Erythema multiforme
Stevens-Johnson
Syndrome (SJS)
Myalgia
Arthralgia
Lupus erythematosus-like
reactions
Renal function
impairment
(incl. interstitial
nephritis* (acute and
chronic), nephrotic
syndrome, renal
insufficiency
acute/chronic)
Urine discolouration.

Reproductive
system and
breast disorders

Oligospermia (reversible)

(*) The mechanism of mesalazine-induced myo- and pericarditis, pancreatitis,
nephritis and hepatitis is unknown, but it might be of allergic origin.
It is important to note that several of these disorders can also be attributed to the
inflammatory bowel disease itself.

Reporting of suspected adverse reactions
Reporting 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.
4.9

Overdose
Acute experience in animals: A single intravenous dose of mesalazine in rats
of 920 mg/kg and single oral doses of mesalazine in pigs up to 5 g/kg were not
lethal.

Human experience: There is limited clinical experience with overdose of
Pentasa sachet which does not indicate renal or hepatic toxicity. Since Pentasa
is an amino salicylate, symptoms of salicylate toxicity may occur. Symptoms
of salicylate over dosage are well described in the literature.
There have been reports of patients taking oral daily doses of 8 grams for a
month without any adverse events
There is no specific antidote and treatment is symptomatic and supportive. The
treatment at hospital includes close monitoring of renal function.

5

PHARMACOLOGICAL PROPERTIES

5.1

Pharmacodynamic properties
Pharmacotherapeutic groups: Intestinal anti-inflammatory agents,
aminosalicylic acid and similar agents
ATC code: A07E C02
Mesalazine is the active component of sulfasalazine, which has been used for a
long time in the treatment of ulcerative colitis and Crohn’s disease.
The therapeutic value of mesalazine appears to be due to local effect on the
inflamed intestinal tissue, rather than to systemic effect. There is information
suggesting that severity of colonic inflammation in ulcerative colitis patients
treated with mesalazine is inversely correlated with mucosal concentrations of
mesalazine.
Increased leukocyte migration, abnormal cytokine production, increased
production of arachidonic acid metabolites, particularly leukotriene B4, and
increased free radical formation in the inflamed intestinal tissue are all present
in patients with inflammatory bowel disease. The mechanism of action of
mesalazine is not fully understood although mechanisms such as activation of
the γ-form of peroxisome proliferator-activated receptors (PPAR-γ) and
inhibition of nuclear factor-kappa B (NF-κB) in the intestinal mucosa have
been implicated. Mesalazine has in-vitro and in-vivo pharmacological effects
that inhibit leukocyte chemotaxis, decrease cytokine and leukotriene
production and scavenge for free radicals. It is currently unknown which, if
any, of these mechanisms play a predominant role in the clinical efficacy of
mesalazine.
The risk of colorectal cancer (CRC) is slightly increased in ulcerative colitis.
Observed effects of mesalazine in experimental models and patient biopsies
support the role of mesalazine in prevention of colitis-associated CRC, with
down regulation of both inflammation dependent and non-inflammation
dependent signalling pathways involved in the development of colitisassociated CRC. However data from meta-analyses, including both referral
and non-referral populations, provide inconsistent clinical information
regarding the benefit of mesalazine in the carcinogenesis risk associated with

ulcerative colitis.

5.2

Pharmacokinetic properties
General Characteristics of the Active Substance
Disposition and local availability: The therapeutic activity of mesalazine most likely
depends on a local contact of the drug with the diseased area of the intestinal mucosa.
Pentasa Sachet prolonged release granules consist of ethylcellulose coated
microgranules of mesalazine. The coated microgranules enter the duodenum within
an hour of administration, independent of food co-administration. Mesalazine is
continuously released from the coated microgranules throughout the gastrointestinal
tract in any enteral pH conditions.
Absorption: Bioavailability of Pentasa after oral administration can be estimated to
approx. 30%, based on urine recovery data in healthy volunteers. Maximum plasma
concentrations are seen 1-6 hours post-dose. A once-daily dosing regimen of
mesalazine (1 × 4 g/d) and a twice-daily dosage (2 × 2 g/d) results in a comparable
systemic exposure (AUC) over 24 hours and indicate a continuous release of
mesalazine from the formulation over the treatment period. Steady-state is reached
after a treatment period of 5 days following oral administration.
Single dose
Cmax (ng/mL)

AUC 0-24
(h·ng/mL)

Steady state
Cmax (ng/mL)

Mesalazine
2 g BID
5103.51
36,456
6803.70
4 g OD
8561.36
35,657
9742.51
Molecular weight of mesalazine: 153.13 g/moL; Ac-mesalazine: 195.17 g/moL.

AUC 0-24
(h·ng/mL)
57,519
50,742

The transit and release of mesalazine after oral administration are independent of food
co-administration, whereas the systemic exposure may be increased.
Distribution: Mesalazine and acetyl-mesalazine do not cross the blood-brain barrier.
Protein binding of mesalazine is approximately 50% and of acetyl-mesalazine about
80%.
Metabolism: Mesalazine is metabolised both pre-systemically by the intestinal
mucosa and systemically in the liver to N-acetyl-mesalazine (acetyl-mesalazine)
principally by NAT-1. Some acetylation also occurs through the action of colonic
bacteria. The acetylation seems to be independent of the acetylator phenotype of the
patient. The metabolic ratio of acetyl-mesalazine to mesalazine in plasma after oral
administration ranges from 3.5 to 1.3 after daily doses of 500 mg×3 and 2 g×3,
respectively, implying a dose-dependent acetylation which may be subject to
saturation.
Elimination: Due to the continuous release of mesalazine throughout the
gastrointestinal tract, the elimination half-life cannot be determined after oral
administration. However, once the formulation is not present in the GI tract
elimination will follow the plasma half-life of orally or IV administered uncoated

mesalazine, which is approximately 40 minutes and for acetyl-mesalazine
approximately 70 minutes.
Characteristics in Patients
Pathophysiologic changes such as diarrhoea and increased bowel acidity observed
during active inflammatory bowel disease have only a minor impact on the delivery
of mesalazine to the intestinal mucosa after oral administration. A urine excretion 2025% of the daily dose has been observed in patients with accelerated intestinal transit.
Likewise, a corresponding increase in faecal excretion has been seen.

5.3

Preclinical safety data
Toxic renal effects have been demonstrated in all species tested. Rat and
monkey dosages and plasma concentrations at the No Observed Adverse
Effect Levels (NOAELs) exceed those used in humans by a factor of 2-7.2.
In vitro test systems and in-vivo studies showed no evidence of mutagenic
effects. Studies on the tumourigenic potential carried out in rats showed no
evidence of any substance-related increase in the incidence of tumours.
Animal studies on oral mesalazine do not indicate direct or indirect harmful
effects with respect to fertility, pregnancy, embryo-foetal development,
parturition or postnatal development.

6

PHARMACEUTICAL PARTICULARS

6.1

List of excipients
Ethylcellulose
Povidone

6.2

Incompatibilities
Not applicable

6.3

Shelf life
2 years
The granules should be used immediately after first opening of the sachet.

6.4

Special precautions for storage
This medicinal product does not require any special storage conditions.

6.5

Nature and contents of container
Polyester/Aluminium/LD polyethylene sachet.
Pack sizes:
1 x 20 sachets
1 x 30 sachets
1 x 50 sachets
1 x 100 sachets
Not all pack sizes may be marketed

6.6

Special precautions for disposal
Any unused product or waste material should be disposed of in accordance
with local requirements.

7

MARKETING AUTHORISATION HOLDER
Ferring Pharmaceuticals Ltd
Drayton Hall
Church Road
West Drayton
UB7 7PS
United Kingdom

8

MARKETING AUTHORISATION NUMBER(S)
PL 03194/0117

9

DATE OF FIRST AUTHORISATION/RENEWAL OF THE
AUTHORISATION

03/11/2014

10

DATE OF REVISION OF THE TEXT
23/08/2016

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Source: Medicines and Healthcare Products Regulatory Agency

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