Summary of medicine characteristics - PENTASA MESALAZINE ENEMA 1G
1. NAME OF THE MEDICINAL PRODUCT
Pentasa® Mesalazine Enema.
2. QUALITATIVE AND QUANTITATIVE COMPOSITION
Each enema bottle contains mesalazine 1g in 100ml.
3. PHARMACEUTICAL FORM
3. PHARMACEUTICAL FORMRectal suspension.
Each bottle contains 100ml of a colourless to faint yellow suspension containing 1g mesalazine.
4. CLINICAL PARTICULARS
4.1. Therapeutic indications
Pentasa Mesalazine Enema is indicated for the treatment of ulcerative colitis affecting the distal colon and rectum.
4.2. Posology and method of administration
Adults: The recommended dosage is one enema at bedtime.
Chlldren: Not recommended.
Pentasa Mesalazine Enemas are for rectal administration
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. Severe cutaneous adverse reactions, including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), have been reported in association with mesalazine treatment. Should PENTASA cause acute intolerance reactions such as abdominal cramps, acute abdominal pain, fever and severe headache, and/or the first appearance of signs and symptoms of severe skin reactions, such as skin rash, mucosal lesions, or any other signs of hypersensitivity, the treatment should be discontinued immediately.
If a patient develops dehydration while on treatment with meclizine, 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.
Cases of nephrolithiasis have been reported with the use of mesalazine including stones with a 100% mesalazine content. It is recommended to ensure adequate fluid intake during treatment.
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 Fertility, 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
Severe cutaneous adverse reactions, including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), have been reported in association with mesalazine treatment (see section 4.4).
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 postmarketing surveillance
| SOC | Common >1/100 to <1/10 | Rare >1/10,000 to <1/1,000 | Very rare <1/10,000 | Not known (cannot be estimated from the available data). |
| Blood and the lymphatic system disorders | Altered blood counts (aplastic 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, | Acute pancreatitis* |
| SOC | Common >1/100 to <1/10 | Rare >1/10,000 to <1/1,000 | Very rare <1/10,000 | Not known (cannot be estimated from the available data). |
| nausea, vomiting, increased amylase | ||||
| Renal and urinary disorders | Impairment of renal function**** including acute and chronic interstitial nephritis*, nephrotic syndrome, urine discolouration and renal insufficiency | Nephrolithias is*** | ||
| Skin and subcutaneous tissue disorders | Rash (incl. urticaria, erythematous rash) | Photosensitivity
| Alopecia (reversible) Erythema multiforme, and | Stevens-Johnson Syndrome (SJS)/Toxic epidermal necrolysis (TEN) |
| 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 | Oligospermia |
| SOC | Common >1/100 to <1/10 | Rare >1/10,000 to <1/1,000 | Very rare <1/10,000 | Not known (cannot be estimated from the available data). |
| system and breast disorders | (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 preexisting skin conditions such as atopic dermatitis and atopic eczema.
(** *) Nephrolithiasis: see section 4.4 for further information.
(** **) 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
4.9 OverdoseAcute 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 invivo 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® enemas are designed to provide the distal part of the intestinal tract with high concentrations of mesalazine and a low systemic absorption. The enemas have been shown to reach and cover the descending colon.
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), about 15–20% of the dose is absorbed after administration of enemas.
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:
The systemic absorption following administration of Pentasa® enemas has been shown to be significantly decreased in patients with active ulcerative colitis compared to those in remission.
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
5.3. Preclinical safety dataThere 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
Disodium Edetate
Sodium Metabisulphite
Sodium Acetate
Hydrochloric Acid, concentrated
Purified Water
6.2. Incompatibilities
None known.
6.3 Shelf life
36 months
6.4. Special precautions for storage
6.4. Special precautions for storageDo not store above 25°C. Keep bottle in outer carton.
6.5. Nature and contents of container
Polyethylene enema bottles fitted with a tip and valve for rectal application, supplied in nitrogen-filled aluminium-foil bags. Presented in cartons containing 7 × 100ml bottles individually foil-wrapped.
6.6.
Instructions for use, handling and disposal
None.
7 MARKETING AUTHORISATION HOLDER
7 MARKETING AUTHORISATION HOLDERFerring Pharmaceuticals Ltd
Drayton Hall Church Road West Drayton UB7 7PS
UK
8. MARKETING AUTHORISATION NUMBER
PL 03194/0027
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION15th November 1988 / 4th February 1999