Salofalk

Tablet: Each tablet contains mesalazine (5-aminosalicylic acid) 500 mg.
Granules: Stick-formed or round, greyish white granules.
Each sachet of Salofalk 1.5 g granules contains 1.5 g mesalazine.
Excipients w/ known effect: Each sachet of Salofalk 1.5 g granules contains 3.0 mg aspartame and 0.12 mg sucrose.
Excipients/Inactive Ingredients: Tablet: Calcium stearate, croscarmellose sodium, basic butylated methylacrylate copolymer (=Eudragit E), methacrylic acid-methyl methacrylate copolymer (1:1) (=Eudragit L), glycine, colloidal silica anhydrous, hypromellose, macrogol 6000, microcrystalline cellulose, sodium carbonate anhydrous, povidone K25, talc, coloring agents: titanium dioxide (E 171), iron oxide hydrate (E 172).
Granules: Aspartame (E 951), Carmellose sodium, Citric acid, Colloidal anhydrous silica, Hypromellose, Magnesium stearate, Methacrylic acid-methyl methacrylate copolymer (1:1) (MW: approx. 135,000) (Eudragit L 100), Methylcellulose, Microcrystalline cellulose, Polyacrylate dispersion 40% (Eudragit NE 40 D containing 2% Nonoxynol 100), Povidone K 25, Simeticone, Sorbic acid (Ph.Eur.), Talc, Titanium dioxide (E 171), Triethyl citrate, Vanilla custard flavouring (containing sucrose).

Pharmacotherapeutic Group: Granules: Intestinal anti-inflammatory agents; Aminosalicylic acid and similar agents.
Pharmacology: Pharmacodynamics: Mechanism of Action: Granules: The mechanism of the anti-inflammatory action is unknown. The results of in vitro studies indicate that inhibition of lipoxygenase may play a role.
Effects on prostaglandin concentrations in the intestinal mucosa have also been demonstrated. Mesalazine (5-aminosalicylic acid/5-ASA) may also function as a radical scavenger of reactive oxygen compounds.
Pharmacodynamic effects: Mesalazine, orally administered, acts predominantly locally at the gut mucosa and in the submucosal tissue from the luminal side of the intestine. It is important, therefore, that mesalazine is available at the regions of inflammation. Systemic bioavailability/plasma concentrations of mesalazine are therefore of no relevance for therapeutic efficacy, but rather a factor for safety. In order to realise this, Salofalk granules are gastric juice resistant and release mesalazine in a pH dependent manner, due to Eudragit L coating, and prolonged manner, due to the matrix granule structure.
Pharmacokinetics: Tablet: General aspects of mesalazine: Absorption: Mesalazine absorption is highest in the proximal regions and lowest in the distal regions of the intestine.
Biotransformation: Mesalazine is metabolised pre-systemically to the pharmacologically inactive N-acetyl-5-aminosalicylic acid (N-Ac-5-ASA) in both the intestinal mucosa and the liver. Acetylation appears to be independent of the patient's acetylator phenotype. Some of the mesalazine is also acetylated by the bacteria of the large intestine. 43% of mesalazine and 78% of N-Ac-5-ASA are protein-bound.
Elimination/excretion: Mesalazine and its metabolite N-Ac-5-ASA, are excreted in the faeces (major fraction), renally (the amount varies between 20% and 50%, depending on the method of administration, the pharmaceutical form and the associated mode of release of mesalazine) and via the biliary route (minor fraction). Renal excretion is mainly in the form of N-Ac-5-ASA. Approximately 1% of the orally administered mesalazine dose passes into breast milk, mainly as N-Ac-5-ASA.
Specific aspects of Salofalk 500 mg: Distribution: A combined pharmacoscintigraphic/pharmacokinetic study has shown that in fasting patients, Salofalk 500 mg, gastro-resistant tablets reach the ileocoecal region within approximately 3-4 hours and the ascending colon within approximately 4-5 hours. In the colon, the total transit time is around 17 hours.
Absorption: Release of mesalazine from Salofalk 500 mg, gastro-resistant tablets, begins after a lag-phase of approximately 3-4 hours. Peak plasma concentrations are reached after approximately 5 hours (ileocoecal region), and are 3.0±1.6 μg/mL for mesalazine and 3.4±1.6 μg/mL for the N-Ac-5-ASA metabolite following administration of 3 x 500 mg mesalazine/day under steady-state conditions.
Elimination: With multiple dosing (3 x 1 Salofalk 500 mg, gastro-resistant tablets taken over 2 days; 1 gastro-resistant tablet on the third day = day of investigation), the total renal elimination rate of mesalazine and N-Ac-5-ASA over 24 hours was approximately 60%. When administered orally, the non-metabolised mesalazine fraction was approximately 10%.
Granules: General considerations of mesalazine: Absorption: Mesalazine absorption is highest in proximal and lowest in distal gut areas.
Biotransformation: Mesalazine is metabolised both pre-systemically by the intestinal mucosa and the liver to the pharmacologically inactive N-acetyl-5-aminosalicylic acid (N-Ac-5-ASA). The acetylation seems to be independent of the acetylator phenotype of the patient. Some acetylation also occurs through the action of colonic bacteria. Protein binding of mesalazine and N-Ac-5-ASA is 43% and 78%, respectively.
Elimination: Mesalazine and its metabolite N-Ac-5-ASA are eliminated via the faeces (major part), renally (varies between 20 and 50%, depending on the kind of application, pharmaceutical preparation and route of mesalazine release, respectively), and biliary (minor part). Renal excretion predominantly occurs as N-Ac-5-ASA. About 1% of the total orally administered mesalazine dose is excreted into the breast milk mainly as N-Ac-5-ASA.
Salofalk Granules specific: Distribution: Owing to the granule size of approx. 1 mm, transit from the stomach to the small intestine is fast.
A combined pharmacoscintigraphic/pharmacokinetic study showed that the compound reaches the ileocaecal region within approx. 3 hours and the ascending colon within approx. 4 hours. The total transit time in the colon amounts to about 20 hours.
Approximately 80% of an administered oral dose is estimated to be available in the colon, sigmoid colon and rectum.
Absorption: Mesalazine release from Salofalk granules starts after a lag phase of about 2-3 hours. Peak plasma concentrations are reached at about 4-5 hours. The systemic bioavailability of mesalazine after oral administration is estimated to be approximately 15-25%.
Food intake delays absorption by 1 to 2 hours but does not change the rate and extent of absorption.
Elimination: From a 3 x 500 mg daily mesalazine dose in long-term therapy, a total renal elimination of mesalazine and N-Ac-5-ASA under steady state conditions was calculated to be about 25%. The unmetabolised excreted mesalazine part was less than 1% of the oral dose. The terminal elimination half-life observed after single dose administration of 3 * 500 mg or 3 * 1000 mg Salofalk granules was 10.5 hours.
Toxicology: Preclinical safety data: Granules: Preclinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, genotoxicity, carcinogenicity (rat) or toxicity to reproduction.
Kidney toxicity (renal papillary necrosis and epithelial damage in the proximal convoluted tubule or the whole nephron) has been seen in repeat-dose toxicity studies with high oral doses of mesalazine. The clinical relevance of this finding is unknown.

Tablet: Salofalk is used for the treatment of: Ulcerative colitis and proctitis (treatment of acute attack or to prevent relapse); Crohn's disease (treatment of acute attack).
Granules: For the treatment of acute episodes and the maintenance of remission of mild to moderate ulcerative colitis.

Tablet: Take one tablet in the morning, at midday and in the evening one (1) hour before meals which should be swallowed whole with sufficient liquid.
The duration of therapy is determined by the physician.
In patients with bowel resection of the ileocoecal region with resection of the ileocoecal valve, in rare cases it was observed that Salofalk 500 mg Enteric-coated tablets were excreted undissolved with the faeces due to the too fast intestinal passage. In case of this observation, please contact the physician.
Granules: Dosage: Adults and the elderly: For the treatment of acute episodes of ulcerative colitis: Once daily, 1-2 sachets of Salofalk (equivalent to 1.5-3.0 g mesalazine daily) preferably to be taken in the morning according to the individual clinical requirement.
For the maintenance of remission of ulcerative colitis: The standard treatment is 0.5 g mesalazine 3 times daily (in the morning, at midday and in the evening) corresponding to a total dose of 1.5 g mesalazine per day.
For patients known to be at increased risk for relapse for medical reasons or due to difficulties to adhere to application of three daily doses, the dosing schedule can be adapted to 3.0 g mesalazine given as a single daily dose, preferably in the morning.
Paediatric population: 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 bw/day once daily preferably in the morning or in divided doses. Maximum dose: 75 mg/kg bw/day. The total dose should not exceed the maximum adult dose.
Maintenance treatment: To be determined individually, starting with 15-30 mg/kg bw/day in divided doses. The total dose should not exceed the 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: Granules: The contents of the sachets of Salofalk granules should not be chewed. The granules should be taken on the tongue and swallowed, without chewing, with plenty of liquid. Both in the treatment of acute inflammatory episodes and during long term treatment, Salofalk granules should be used on a regular basis and consistently in order to achieve the desired therapeutic effects.
The treatment of acute episodes of ulcerative colitis usually lasts 8 weeks. The duration of use is determined by the physician.

Granules: There are rare data on overdosage (e.g. intended suicide with high oral doses of mesalazine), which do not indicate renal or hepatic toxicity. There is no specific antidote and treatment is symptomatic and supportive.

Tablet: Hypersensitivity to salicylic acid, salicylates and its derivatives or any of the ingredients.
Severe liver and kidney function disturbances.
Granules: Salofalk granules are contraindicated in patients with: hypersensitivity to the active substance, to salicylates or to any of the excipients; Severe impairment of hepatic or renal function.

Tablet: Blood tests (differential blood count; liver function parameters such as transaminases; serum creatinine) and urine status (dip sticks/sediments) should be checked before and during treatment, at the discretion of the doctor. As a guideline, controls are recommended 14 days after starting treatment, then a further two to three times at intervals of 4 weeks.
If the findings are normal, follow-up tests are required every three months. If additional symptoms develop, tests must be performed immediately. The recommended kidney function tests are serum urea (BUN) and creatinine assay as well as urine sediment test.
Caution is recommended in patients with impaired hepatic function.
Salofalk 500 mg enteric coated tablets should not be used in patients with impaired renal function. Mesalazine-induced renal toxicity should be considered, if renal function deteriorates during treatment.
In patients with pulmonary function disturbances, in particular asthma, close medical supervision is necessary during treatment with drugs containing mesalazine.
Treatment with Salofalk 500 mg Enteric-coated tablet should only be started under medical supervision in patients with known hypersensitivity to preparations containing sulphasalazine. If acute signs of intolerability e.g. cramps, acute abdominal pain, fever, severe headache and skin rash occur, treatment must be withdrawn immediately.
Granules: 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.
Mesalazine should not be used in patients with impaired renal function. Mesalazine-induced renal toxicity should be considered if renal function deteriorates during treatment. If this is the case, Salofalk granules should be discontinued immediately.
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.
Mesalazine may produce red-brown urine discoloration after contact with sodium hypochlorite bleach (e.g. in toilets cleaned with sodium hypochlorite contained in certain bleaches).
Serious blood dyscrasias have been reported very rarely with mesalazine.
Hematological investigations should be performed if patients suffer from unexplained haemorrhages, bruises, purpura, anaemia, fever or pharyngolaryngeal pain. Salofalk granules should be discontinued in case of suspected or confirmed blood dyscrasia.
Cardiac hypersensitivity reactions (myocarditis, and pericarditis) induced by mesalazine have been rarely reported. Salofalk granules must then be discontinued immediately.
Patients with pulmonary disease, in particular asthma, should be very carefully monitored during a course of treatment with mesalazine.
Severe cutaneous adverse reactions: 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.
Mesalazine should be discontinued, at the first appearance of signs and symptoms of severe skin reactions, such as skin rash, mucosal lesions, or any other sign of hypersensitivity.
Patients with a history of adverse drug reactions to preparations containing sulfasalazine should be kept under close medical surveillance on commencement of a course of treatment with mesalazine. Should Salofalk granules cause acute intolerance reactions, such as abdominal cramps, acute abdominal pain, fever, severe headache and rash, therapy should be discontinued immediately.
This medicine contains 3 mg aspartame in each sachet of Salofalk 1.5 g granules. Aspartame is a source of phenylalanine. It may be harmful in patients with phenylketonuria (PKU).
Salofalk 1.5 g granules contain sucrose. Patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption or sucrase-isomaltase insufficiency should not take this medicine.
This medicine contains less than 1 mmol sodium (23 mg) per sachet, that is to say essentially 'sodium-free'.
Effects on ability to drive and use machines: Mesalazine has no influence or negligible influence on the ability to drive and use machines.

Pregnancy: Tablet: There are no adequate data on the use of Salofalk 500 mg enteric coated tablets in pregnant women. However, data on a limited number of exposed pregnancies indicate no adverse effect of mesalazine on pregnancy or on the health of the foetus/newborn child. To date no other relevant epidemiologic data are available. In one single case after long-term use of a high dose mesalazine (2-4 g, orally) during pregnancy, renal failure in a neonate was reported. Salofalk 500 mg Enteric-coated tablet should only be used during pregnancy on medical advise since only the doctor can undertake the necessary assessment of likely benefits versus the potential risks.
Granules: There are no adequate data on the use of mesalazine in pregnant women. However, data on a limited number of exposed pregnancies indicate no adverse effect of mesalazine on pregnancy or on the health of the foetus/newborn child. To date no other relevant epidemiologic data are available. In one single case after long-term use of high dose 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/foetal development, parturition or postnatal development.
Salofalk granules should only be used during pregnancy if the potential benefit outweighs the possible risk.
Breast-feeding: Tablet: Only limited experience is available on the use of mesalazine-containing drugs during breast-feeding. The active substance is excreted in small amount into breast milk. Therefore, hypersensitivity reactions in the infant cannot be ruled out. To date, these have merely consisted of single cases of diarrhea. If the baby develops diarrhea during the use of Salofalk while breast-feeding, breast-feeding should be discontinued.
The patient should only use Salofalk 500 mg enteric coated tablets during breast-feeding, if the doctor tells the patient to since only the doctor can undertake the necessary assessment of likely benefits versus the potential risks.
Granules: N-acetyl-5-aminosalicylic acid and to a lesser degree mesalazine are excreted in breast milk. Only limited experience during lactation in women is available to date. Hypersensitivity reactions, like diarrhoea in the infant, cannot be excluded. Therefore, Salofalk granules should only be used during breastfeeding if the potential benefit outweighs the possible risk. If the infant develops diarrhoea, the breastfeeding should be discontinued.

Tablet: Gastrointestinal tract side effects: Abdominal pain, diarrhea, flatulence, nausea, vomiting.
Central nervous system side effects: Headache, dizziness, peripheral neuropathy.
Side effects on the kidney: Impairment of renal function including acute and chronic interstitial nephritis and renal insufficiency.
Hypersensitivity reactions: Allergic skin rash (exanthema), drug fever, spasmodic contraction of the airways (bronchospasm), inflammation of the heart sac and heart muscle (peri- and myocarditis), acute inflammation of the pancreas (pancreatitis), allergic and fibrotic lung reactions (including dyspnoea, cough, alveolitis, pulmonary eosinophilia, lung infiltration, pneumonitis), butterfly rash (lupus erythematosus syndrome), inflammation of the entire large bowel (pancolitis).
Musculoskeletal disorders: Muscle and joint pain (myalgia, arthralgia).
Blood and lymphatic system disorders: Changes in the blood counts (aplastic anaemia, agranulocytosis, pancytopenia, neutropenia, leucopenia, thrombocytopenia).
Disorders of the liver and gall bladder: Changes in liver function tests (raised transaminase and parameters of cholestasis), inflammation of the liver (hepatitis), inflammation of the liver associated with cholestasis (cholestatic hepatitis).
Disorders of the skin and appendages: Hair loss (alopecia) and the development of baldness.
Disorders of the reproductive system: Oligospermia (reversible).
Note: Salofalk 500 mg enteric-coated tablets should be taken under medical supervision.
Granules: See table.

Click on icon to see table/diagram/image

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

Tablet: Specific interaction studies have not been performed.
In patients who are concomitantly treated with azathioprine, 6-mercaptopurine or thioguanine, a possible increase in the myelosuppressive effects of azathioprine, 6-mercaptopurine or thioguanine should be taken into account.
There is weak evidence that mesalazine might decrease the anticoagulant effect of warfarin.
Granules: Specific interaction studies have not been performed.
Lactulose or similar preparations which lower stool pH: Possible reduction of mesalazine release from granules due to decreased pH caused by bacterial metabolism of lactulose.
In patients who are concomitantly treated with azathioprine, 6-mercaptopurine or thioguanine, a possible increase in the myelosuppressive effects of azathioprine, 6-mercaptopurine or thioguanine should be taken into account.
There is weak evidence that mesalazine might decrease the anticoagulant effect of warfarin.

Shelf-life: 48 months.
Tablet: Store at temperatures not exceeding 25°C.
Granules: Store at temperatures not exceeding 30°C.

GIT Regulators, Antiflatulents & Anti-Inflammatories

A07EC02 - mesalazine ; Belongs to the class of aminosalicylic acid and similar antiinflammatory. Used in the treatment of intestinal inflammation.

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