Pentasa Sachets 2 g Prolonged release granules.

PENTASA u00ae SACHETS is indicated in adults and children age 6 years and over for:

• The treatment of mild to moderate ulcerative colitis and the maintenance of remission in ulcerative colitis.
• The treatment of mild to moderate Crohnu2019s disease (CDAI score 200 to 400).

Posology

Ulcerative colitis:

Treatment of active disease:

Adults: Individual dosage, up to 4 g mesalazine once daily or in divided doses.

Maintenance treatment: Adults: Individual dosage, recommended dosage, 2 g mesalazine once daily. Can also be taken in divided doses.

Crohnu2019s disease:

Active and maintenance treatment for adults: Individual dosage, up to 4 g mesalazine daily in divided doses.

Paediatric population

There is only limited documentation for an effect in children (age 6-18 years).

Ulcerative colitis:

Treatment of active disease: Children 6 years of age and older: 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: Children 6 years of age and older: 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 with a body weight of up to 40 kg; and the normal adult dose to those above 40 kg.

Crohnu2019s disease:

Treatment of active disease: Children 6 years of age and older: 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: Children 6 years of age and older: To be determined individually, starting with 15 - 30 mg/kg/day in divided doses. The total dose should not exceed 4 g/day (recommended adult dose). It is generally recommended that half the adult dose may be given to children with a body weight of up to 40 kg; and the normal adult dose to those above 40 kg.

Method of administration

PENTASA u00ae granules must not be chewed. The contents of the sachet should be emptied on the tongue and swallowed with water or juice. Alternatively, the entire content of the sachet can be taken with yogurt and consumed immediately.

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

Caution is recommended in patients allergic to sulfasalazine (risk of allergy to salicylates). Severe cutaneous adverse reactions (SCARs), including Drug reaction with eosinophilia and systemic symptoms (DRESS), Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), have been reported in association with mesalazine treatment such as PENTASA u00ae SACHETS. In case of acute symptoms of intolerance i.e., abdominal cramps, acute abdominal pain, fever, 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.

Caution is recommended in patients with impaired liver function. Liver function parameters such as ALT or AST should be assessed prior to and during treatment, at the discretion of the treating doctor. (See section 4.3). PENTASA u00ae SACHETS is not recommended for use in patients with renal impairment. Renal function should be monitored regularly (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 doctor. PENTASA u00ae SACHETS induced nephrotoxicity should be suspected in patients developing renal dysfunction during treatment. With concurrent use of other known nephrotoxic medicines, such as NSAIDs and azathioprine, renal function should be monitored more frequently. Caution is recommended in patients with active peptic ulcer. Patients with pulmonary disease, in particular asthma, should be carefully monitored during a course of treatment; please refer to section 4.8. Mesalazine-induced cardiac hypersensitivity reactions (myo- and pericarditis) have been reported. Serious blood dyscrasias have been reported with PENTASA u00ae SACHETS (see section 4.5). Blood test for differential blood count is recommended prior to and during treatment, at the discretion of the treating doctor. Treatment should be discontinued on suspicion or evidence of these adverse reactions. Symptoms can include bleeding, bruises, sore throat and fever or, in case of myocarditis and pericarditis, fever and chest pain accompanied by shortness of breath.

Idiopathic intracranial hypertension

Idiopathic intracranial hypertension (pseudotumor cerebri) has been reported in patients receiving mesalazine. Patients should be warned for signs and symptoms of idiopathic intracranial hypertension, including severe or recurrent headache, visual disturbances or tinnitus. If idiopathic intracranial hypertension occurs, discontinuation of mesalazine (as contained in PENTASA u00ae SACHETS) should be considered. Cases of nephrolithiasis have been reported with the use of mesalazine (as contained in PENTASA u00ae SACHETS) including stones with a 100 % mesalazine content. It is recommended to ensure adequate fluid intake during treatment. 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. PENTASA u00ae SACHETS should be used with caution in the elderly. Mesalazine (as contained in PENTASA u00ae SACHETS) may produce red-brown urine discoloration after contact with sodium hypochlorite bleach (e.g. in toilets cleaned with sodium hypochlorite contained in certain bleaches).

Combination therapy with 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 dosage regime of thiopurines should be adjusted accordingly. PENTASA u00ae SACHETS might decrease the anticoagulant effect of warfarin. The concurrent use of other known nephrotoxic medicines such as NSAIDs and azathioprine may increase the risk of renal reactions (see 4.4 Special warnings and precautions for use).

PENTASA u00ae SACHETS should be used with caution during pregnancy or by women who are breastfeeding their infants. The underlying condition itself (Inflammatory bowel disease (IBD)) may increase risks for adverse pregnancy outcome.

Pregnancy

Mesalazine as contained in PENTASA u00ae SACHETS 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. There are no adequate and well-controlled studies of PENTASA u00ae SACHETS 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. 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, embryo-foetal development, parturition or postnatal development. Blood disorders (pancytopenia, leukopenia, thrombocytopenia, anaemia) have been reported in new-borns of mothers being treated with PENTASA u00ae SACHETS.

Breastfeeding

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. No controlled studies with PENTASA u00ae SACHETS during breastfeeding have been carried out. Hypersensitivity reactions like diarrhoea in the infant cannot be excluded. If the infant develops diarrhoea, breastfeeding should be discontinued.

Fertility

Animal data on mesalazine show no effect on male and female fertility.

Treatment with PENTASA u00ae SACHETS is unlikely to affect the ability to drive and/or use machines.

The most frequent side effects seen in clinical trials were diarrhoea, nausea, abdominal pain, headache, vomiting and rash. Hypersensitivity reactions and drug fever may occur. Severe cutaneous adverse reactions (SCARs), including Drug reaction with eosinophilia and systemic symptoms (DRESS), Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), have been reported in association with mesalazine treatment such as PENTASA u00ae SACHETS (see section 4.4).

Frequency of adverse effects, based on clinical trials and reports from post-marketing surveillance:

System Organ Class (SOC)

Common ( u2265 1/100 to < 1/10)

Rare ( u2265 1/10 000 to < 1/1 000)

Very rare (< 1/10 0000)

Not known (cannot be estimated from the available data)

Blood and lymphatic system disorders

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

Immune system disorders

Hypersensitivity reaction including anaphylactic reaction

Nervous system disorders

Headache

Dizziness

Peripheral neuropathy, idiopathic intracranial hypertension (see section 4.4)

Cardiac disorders

Myocarditis*, pericarditis*

Pericardial effusion

Respiratory, thoracic and mediastinal disorders

Allergic and fibrotic lung reactions (including dyspnoea, coughing, bronchospasm, allergic alveolitis, pulmonary eosinophilia, interstitial lung disease, pulmonary infiltration, pneumonitis)

Gastrointestinal disorders

Diarrhoea, abdominal pain, Increased amylase, acute pancreatitis*

Pancolitis

Nausea, vomiting, flatulence

Hepato-biliary disorders

Increase in transaminases, cholestasis parameters (e.g., alkaline phosphatase, gamma-glutamyl transferase and bilirubin), hepatotoxicity (including hepatitis*, cholestatic hepatitis, cirrhosis, hepatic failure)

Skin and subcutaneous tissue disorders

Rash (including urticaria, erythematous rash)

Photosensitivity**

Alopecia (reversible), Quinckeu2019s oedema, dermatitis allergic, erythema multiforme, Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) Stevens-Johnson Syndrome (SJS), toxic epidermal necrolysis (TEN)

Musculoskeletal and connective tissue disorders

Myalgia, arthralgia, lupus erythematosus- like syndrome (systemic lupus erythematosus)

Renal and urinary disorders

Renal function impairment (including Nephrolithiasis*** acute and chronic interstitial nephritis*, nephrotic syndrome, renal insufficiency), urine discolouration***

Reproductive system and breast disorders

Oligospermia (reversible)

General disorders

Drug fever

(*) 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.

(***) See section 4.4 for further information. 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 medicine is important. It allows continued monitoring of the benefit/risk balance of the medicine. Healthcare providers are asked to report any suspected adverse drug reactions to SAHPRA via the Med Safety APP (Medsafety X SAHPRA) and eReporting platform (who-umc.org) found on SAHPRA website.

There is limited clinical experience with overdose of PENTASA u00ae SACHETS which does not indicate renal or hepatic toxicity. Since PENTASA u00ae SACHETS is an amino salicylate, symptoms of salicylate toxicity, such as acid-base balance disorder, hyperventilation, pulmonary oedema, vomiting, dehydration and hypoglycaemia, may occur. Symptoms of salicylate overdosage 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.