This information is intended for use by health professionals

1. Name of the medicinal product

PENTASA® Suppositories 1g

2. Qualitative and quantitative composition

Each suppository contains mesalazine 1g

3. Pharmaceutical form

Suppositories

Oblong, compressed white to light tan, speckled suppositories

4. Clinical particulars
4.1 Therapeutic indications

PENTASA Suppositories are indicated for the treatment of ulcerative proctitis.

4.2 Posology and method of administration

Ulcerative Proctitis:

Usual adult dose: Acute treatment: 1 suppository daily for 2 to 4 weeks.

Maintenance treatment: 1 suppository daily.

Children: Not recommended. There is little experience and only limited documentation for an effect in children.

Elderly Patients: The usual adult dose applies.

4.3 Contraindications

PENTASA is contraindicated in:

- patients with known hypersensitivity to salicylates or any of the excipients

- patients with severe liver and/or renal impairment

4.4 Special warnings and precautions for use

Blood tests (differential blood count; liver function parameters such as ALT or AST; serum creatinine) and urinary status (dip sticks) should be determined prior to and during treatment, at the discretion of the treating physician. 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.

Caution is recommended in patients with impaired hepatic function.

PENTASA should not be used in patients with impaired renal function. Mesalazine-induced renal toxicity should be considered, if renal function deteriorates during treatment.

Patients with pulmonary disease, in particular asthma, should be very carefully monitored during a course of treatment with PENTASA.

Patients with a history of adverse drug reactions to preparations containing sulphasalazine (risk of allergy to salicylates), should be kept under close medical surveillance on commencement of a course of treatment with PENTASA. Should PENTASA cause acute intolerance reactions such as abdominal cramps, acute abdominal pain, fever, severe headache and rash, the treatment should be discontinued immediately.

If a patient develops dehydration while on treatment with mesalazine, normal electrolyte levels and fluid balance should be restored as soon as possible.

Mesalazine-induced cardiac hypersensitivity reactions (myo- and pericarditis) have been reported rarely. Treatment should be discontinued on suspicion or evidence of these reactions.

4.5 Interaction with other medicinal products and other forms of interaction

In patients who are concomitantly treated with azathioprine, or 6-mercaptopurine, or thioguanine, a possible increase in the myelosuppressive effects of azathioprine, or 6-mercaptopurine, or thioguanine should be taken into account.

There is weak evidence that mesalazine might decrease the anticoagulant effect of warfarin.

4.6 Pregnancy and lactation

PENTASA should be used with caution during pregnancy and lactation and only if the potential benefit outweighs the possible risks in the opinion of the physician.

Pregnancy

Mesalazine is known to cross the placental barrier. There is no adequate data on the use of PENTASA in pregnant women. However, data on a limited number of exposed pregnancies indicate no adverse effect of mesalazine on the pregnancy or on the health of the fetus/newborn child. To date no other relevant epidemiologic data are available.

In one single case after long-term use of a high dose of mesalazine (2-4 g, orally) during pregnancy, renal failure in a neonate was reported.

Animal studies on oral mesalazine do not indicate direct or indirect harmful effects with respect to pregnancy, embryonic/fetal development, parturition or postnatal development.

Blood disorders (leucopenia, thrombocytopenia, anaemia) have been reported in new-borns of mothers being treated with PENTASA.

PENTASA should only be used during pregnancy if the potential benefit outweighs the possible risk.

Breast-feeding

N-acetyl-5-aminosalicylic acid and to a lesser degree 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. There is limited experience of the use of oral mesalazine in lactating women available to date. No controlled studies with PENTASA during breast-feeding have been carried out. Hypersensitivity reactions such as diarrhoea in the infant cannot be excluded. Therefore, PENTASA should only be used during breast-feeding, if the potential benefit outweighs the possible risk. If the infant develops diarrhoea, breast-feeding should be discontinued.

4.7 Effects on ability to drive and use machines

No effects on the ability to drive and use machines have been observed.

4.8 Undesirable effects

Table 1: Undesirable effects

Following rectal administration local reactions such as pruritus, rectal discomfort and urge may 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

Altered blood counts (aplastic anaemia, anaemia, agranulocytosis, pancytopenia, neutropenia, leukopenia, thrombocytopenia), and eosinophilia (as part of an allergic reaction).

Nervous system disorders

Headache, dizziness

Peripheral neuropathy

Cardiac disorders

Myocarditis*

Pericarditis*

Respiratory, thoracic and mediastinal disorders

Allergic and fibrotic lung reactions (including dyspnoea, cough, bronchospasm, alveolitis pulmonary eosinophilia, lung infiltration, pneumonitis)

Gastrointestinal disorders

Abdominal pain, diarrhoea, flatulence, nausea, vomiting, increased amylase

Acute pancreatitis*

Renal and urinary disorders

Impairment of renal function***

including acute and chronic interstitial nephritis*, nephrotic syndrome, urine discolouration and renal insufficiency

Skin and subcutaneous tissue disorders

Rash (incl. urticaria, erythematous rash)

Photosensitivity**

Alopecia (reversible)

Erythema multiforme, and Stevens-Johnson Syndrome (SJS)

Musculoskeletal and connective tissue disorders

Myalgia, arthralgia

Immune system disorders

Hypersensitivity reaction such as allergic exanthema, drug fever, lupus erythematosus syndrome, pancolitis

Hepato-biliary disorders

Changes in liver function parameters (increase in transaminases, and cholestasis parameters), hepatitis*, cholestatic hepatitis, cirrhosis, hepatic failure

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.

(**) Photosensitivity: More severe reactions are reported in patients with pre-existing skin conditions such as atopic dermatitis and atopic eczema.

(***) Renal failure has been reported. Mesalazine-induced nephrotoxicity should be suspected in patients developing renal dysfunction during treatment.

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, or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9 Overdose

Acute experience in animals:

Single oral doses of mesalazine of up to 5g/kg in pigs or a single intravenous dose of mesalazine at 920mg/kg in rats were not lethal.

Human experience:

There are rare data on overdosage (e.g. intended suicide with high oral doses of mesalazine), which do not indicate renal or hepatic toxicity.

Management of overdose:

There is no specific antidote and the treatment is symptomatic and supportive. The treatment at hospital includes close monitoring of renal function.

5. Pharmacological properties
5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Intestinal anti-inflammatory agents.

Mechanism of action and pharmacodynamic effects:

Mesalazine is recognised as the active moiety of sulphasalazine in the treatment of ulcerative colitis. It is thought to act locally on the gut wall in inflammatory bowel disease, although its precise mechanism of action has not been fully elucidated.

Increased leucocyte 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. Mesalazine has in-vitro and in-vivo pharmacological effects that inhibit leucocyte 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.

5.2 Pharmacokinetic properties

General characteristics of the active substance:

Disposition and local availability:

PENTASA suppositories are designed to provide the distal part of the intestinal tract with high concentrations of mesalazine and a low systemic absorption. They are used to treat the rectum.

Biotransformation:

Mesalazine is metabolised both pre-systemically by the intestinal mucosa and systemically in the liver to N-acetyl mesalazine (acetyl mesalazine). The acetylation seems to be independent of the acetylator phenotype of the patient. Some acetylation also occurs through the action of colonic bacteria.

Acetyl mesalazine is thought to be clinically as well as toxicologically inactive, although this remains to be confirmed.

Absorption:

The absorption following rectal administration is low, but depends on the dose, the formulation and the extent of spread. Based on urine recoveries in healthy volunteers under steady-state conditions given a daily dose of 2g (1g x 2), approximately 10% of the dose is absorbed after administration of suppositories.

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%.

Elimination:

The plasma half-life of pure mesalazine is approximately 40 minutes and for acetyl mesalazine approximately 70 minutes. Both substances are excreted in urine and faeces. The urinary excretion consists mainly of acetyl mesalazine.

Characteristics in patients:

In patients with impaired liver and kidney functions, the resultant decrease in the rate of elimination and increased systemic concentration of mesalazine may constitute an increased risk of nephrotoxic adverse reactions.

5.3 Preclinical safety data

There are no pre-clinical data of relevance to the prescriber which are additional to that already included in other sections of the SPC.

6. Pharmaceutical particulars
6.1 List of excipients

Povidone Ph. Eur.

Macrogol 6000 Ph. Eur.

Magnesium stearate Ph. Eur.

Talc Ph. Eur.

6.2 Incompatibilities

None known

6.3 Shelf life

36 months

6.4 Special precautions for storage

Do not store above 25°C. Store in the original package.

6.5 Nature and contents of container

Double aluminium foil blister strips of 7 suppositories each.

Pack size: 28

6.6 Special precautions for disposal and other handling

None

Administrative Data

7. Marketing authorisation holder

Ferring Pharmaceuticals Ltd.

Drayton Hall

Church Road

West Drayton

UB7 7PS

United Kingdom

8. Marketing authorisation number(s)

PL 3194/0045

9. Date of first authorisation/renewal of the authorisation

19th April 2011

10. Date of revision of the text

January 2018