Salofalk

Mesalazine.

Gastro-resistant tablet: Each gastro-resistant tablet contains 500 mg mesalazine.
PR granules: Each sachet of Salofalk 1.5g granules contains 1.5 g mesalazine.
Suppository: 1 Salofalk 500 mg suppository contains: Mesalazine (5-aminosalicylic acid) 500 mg.
Enema: Salofalk 2g/30ml enemas: 1 Salofalk 2g/30ml enema (= 30 g rectal suspension) contains 2 g mesalazine.
Excipients with known effect: Gastro-resistant tablet: sodium carbonate and croscarmellose sodium.
PR granules: Each sachet of Salofalk 1.5g granules contains 3.0 mg aspartame.
Suppository: Hard fat, docusate sodium, cetyl alcohol.
Enema: One Salofalk 2g/30ml enema contains 140.4 mg potassium metabisulphite and 30 mg sodium benzoate.
Excipients/Inactive Ingredients: Gastro-resistant tablet: Basic butylated methylacrylate copolymer (Ph.Eur.) (rel. molar mass: approx. 150000 (= Eudragit E)), Calcium stearate (Ph.Eur.) [herbal], Croscarmellose sodium, Iron oxide yellow (E 172), Glycine, Colloidal anhydrous silica, Hypromellose, Macrogol 6000, Methacrylic acid methyl methacrylate copolymer (1:1) (Ph.Eur.) (rel. molar mass: approx. 135000 (= Eudragit L)), Microcrystalline cellulose, Sodium carbonate, Povidone K25, Talc, Titanium dioxide (E 171).
PR granules: Aspartame (E 951), Carmellose sodium, Citric acid, Colloidal anhydrous silica, Hypromellose, Magnesium stearate, Methacrylic acid-methyl methacrylate copolymer (1:1) ((MW approx. 135000)) (Eudragit L 100), Methylcellulose, Microcrystalline Cellulose, Polyacrylate dispersion 40% (Eudragit NE 40 D containing 2% Nonoxynol 100), Povidone K 25, Simeticone, Sorbic acid, Talc, Titanium dioxide (E 171), Triethyl citrate, Vanilla custard flavouring, Ethanol (only present as residue in the final product, up to 1.25 %).
Enema: Salofalk 2g/30ml enemas: Carbomer 35 000, potassium acetate, potassium metabisulphite (max. 0.14 g, equivalent to max. 0.08 g SO₂), sodium benzoate, Disodium edetate, purified water, xanthan gum.

Pharmacotherapeutic group: Aminosalicylic acid and similar agents. ATC code: A07EC02.
Pharmacology: Pharmacodynamics: Gastro-resistant tablet, PR granules and Enema: 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.
Gastro-resistant tablet, PR granules: Mesalazine, orally administered, acts predominantly locally at the gut mucosa and in the submucous 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.
Gastro-resistant tablet: In order to fulfill these criteria, Salofalk 500mg tablets are coated with Eudragit L; they are thus gastro-resistant and release of mesalazine is pH-dependent.
PR granules: In order to realise this, Salofalk granules are gastric juice resistant and release mesalazine in a pH dependent manner, due to an Eudragit L coating, and prolonged manner, due to the matrix granule structure.
Enema: On reaching the intestinal lumen, rectally administered mesalazine has largely local effects on the intestinal mucosa and submucosal tissue.
Pharmacokinetics: General considerations of mesalazine: Gastro-resistant tablet and Enema: Absorption: Mesalazine absorption is highest in proximal gut regions 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%, dependent on 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 500mg tablets specific: Distribution: A combined pharmacoscintigraphic/pharmacokinetic study showed that Salofalk 500mg tablets reach the ileocoecal region after approximately 3-4 hours in fasting subjects and reach the ascending colon within approximately 4-5 hours. The total transit time in the colon is approximately 17 hours.
Absorption: Release of mesalazine from Salofalk 500mg tablets, begins after a lag-phase of approximately 3-4 hours. Peak plasma concentrations are reached after approximately 5 hours (ileocoecal region) and, at 3 x 500 mg mesalazine/day under steady-state conditions, are 3.0 ± 1.6 μg/ml for mesalazine and 3.4 ± 1.6 μg/ml for the metabolite, N-Ac-5-ASA.
Elimination: The total renal elimination rate for mesalazine and N-Ac-5-ASA over 24 hours during multiple intake (3 x 1 Salofalk 500mg tablets, for 2 days; 1 tablet on the third day=examination day) was approximately 60%. The non-metabolised mesalazine fraction after oral administration was approximately 10%.
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 elimination half-life in this study was 4.4 hours.
Salofalk 2g/30ml enemas specific: Distribution: An imaging study in patients with mild-to-moderate acute ulcerative colitis showed that the rectal suspension at the start of treatment and at remission after 12 weeks is distributed mainly in the rectum and sigmoid colon and to a lesser extent in the descending colon.
Absorption and elimination: No specific pharmacological studies on Salofalk 2g/30ml enemas are available.
In a study on Salofalk 4g/60ml enemas in ulcerative colitis patients in remission, peak plasma concentrations of 0.92 μg/ml 5-ASA and 1.62 μg/ml N-Ac-5-ASA were achieved after approximately 11-12 hours under steady-state conditions. The elimination rate was approximately 13% (45-hour value), with most (approximately 85%) being eliminated in the form of the metabolite, N-Ac-5-ASA.
The steady-state plasma concentrations of 5-ASA and N-Ac-5-ASA in children with chronic inflammatory bowel disease under treatment with Salofalk 2g/30ml enemas were 0.2-1.0 μg/ml and 0.4-2.0 μg/ml respectively.
Toxicology: Preclinical safety data: Gastro-resistant tablet, PR granules and Enema: 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.

Gastro-resistant tablet and PR granules: For the treatment of acute episodes and the maintenance of remission of ulcerative colitis.
Gastro-resistant tablet: For the treatment of acute episodes of Crohn's disease.
Suppository: Ulcerative colitis, proctitis and inflammation of the anal canal.
Enema: Mild and moderate attacks of ulcerative colitis (a chronic inflammatory disease of the large bowl) limited to the rectum and the sigmoid colon.

Posology: Gastro-resistant tablet: Adults and elderly: Depending upon the clinical requirements in the individual case, the following daily dosages are recommended: (See Table 1.)

Click on icon to see table/diagram/image

Gastro-resistant tablet and PR granules: Children: 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. The total dose should not exceed the maximum adult dose.
Maintenance treatment (ulcerative colitis): To be determined individually, starting with 15-30 mg/kg/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.
PR granules: Adults and the elderly: For the treatment of acute episodes of ulcerative colitis: Once daily, 1 sachet of Salofalk 3g granules, 1-2 sachets of Salofalk 1.5g granules, 3 sachets of Salofalk 1000mg granules or 3 sachets of Salofalk 500mg granules (equivalent to 1.5-3.0 g mesalazine daily) preferably to be taken in the morning according to the individual clinical requirement.
It is also possible to take the prescribed daily dose in three divided doses (1 sachet of Salofalk 500mg granules 3 times daily or 1 sachet of Salofalk 1000mg granules 3 times daily) if this is more convenient to the patient.
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.
Suppository: Insert 1 Salofalk 500 mg suppository into the anus in the morning, at midday and in the evening when acute signs of inflammation are present.
As soon as remission occurs, the dose should be reduced to 1 suppository of Salofalk 250 mg 3 times daily to avoid recurrences.
Treatment with Salofalk 500 mg suppositories demands reliability and consistency from the side of the patient to enable therapeutic success.
The duration of therapy is determined by the physician.
Enema: (Salofalk 2g/30ml enemas): Adults and elderly: In patients with symptoms of acute inflammation, the content of two enema bottles (2 x 30 g suspension) is instilled in the rectum as an enema once daily at bedtime.
Children: There is little experience and only limited documentation for an effect in children.
If there are problems to retain the large quantity of liquid, the Salofalk 2g/30ml enemas may also be applicated in two doses, e.g. during the night (after a bowel movement which discharges the first doses) or early in the morning.
Treatment with Salofalk enemas must be administered regularly and consistently, because only in this way can healing be successfully achieved.
Method of administration: The duration of use is determined by the physician.
Gastro-resistant tablet: Salofalk 500mg tablets should be taken in the morning, at midday and in the evening, 1 hour before meals. They should be swallowed whole, not chewed, and taken with plenty of fluid.
Treatment with Salofalk 500mg tablets should be administered regularly and consistently, both in the acute inflammatory stage and during maintenance therapy in order to achieve the desired therapeutic effect.
For maintenance of remission in ulcerative colitis, the dose can usually be reduced to 1.5 g mesalazine/day (adults and adolescents with a body weight over 40 kg) and 0.75 g mesalazine/day (children/adolescents).
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.
This product is not interchangeable with other brand or dosage form of products containing mesalazine.
Enema: Rectal use.
The best results are achieved if the bowel is emptied before administration of the Salofalk enemas.
Preparation: The bottle should be shaken for 30 seconds.
Then the protective cap of the applicator removed.
The bottle should be held at the top and the bottom.
The correct position for administration is as follows: The patient should lie down on his/her left side with his/her left leg stretched out and right leg bent. This makes it easier for the rectal suspension to be administered and for the enema to be effective.
Administration of the rectal suspension: The tip of the applicator should be inserted deep into the rectum.
The bottle should be tipped downwards slightly and then squeezed slowly.
Once the bottle is empty, the applicator tip should be slowly withdrawn from the rectum.
The patient should remain lying down in this position for at least 30 minutes to allow the contents of the enema to spread throughout the rectum.
If possible, the rectal suspension should be allowed to exert its effects all night.

Gastro-resistant tablet, PR granules and Enema: 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.
Suppository: Symptom and treatment of overdosage: Owing to the biopharmaceutical properties of Salofalk 500 mg suppository and the substance-specific pharmacokinetic properties of mesalazine, only small amounts of the active principle are available for systemic action. For this reason signs of intoxication are thus not to be reckoned with even when very high doses are taken. In principle, similar symptoms would have to occur to those which are familiar in salicylate intoxications: mixed acidosis-alkalosis, hyperventilation, pulmonary oedema, dehydration by sweating and vomiting, hypoglycaemia.
Therapy of intoxications: In mixed acidosis-alkalosis: restoration of the acid-base equilibrium in accordance with the situation, electrolyte substitution.
In dehydration by sweating and vomiting: fluid administration.
In hypoglycaemia: glucose administration.

Salofalk 500mg tablets/suppositories/enemas are contraindicated in patients with: known hypersensitivity to salicylates or any of the excipients under Description; severe impairment of hepatic or renal function.
Suppository: Salofalk 500 mg suppositories must not be taken in: gastric and duodenal ulcers; haemorrhagic diathesis (predisposition to bleeding).
Salofalk 500 mg suppositories should not be used to treat infants and small children because of insufficient experience with this age group.
Use in pregnancy and lactation: In the first three months of pregnancy mesalazine should only be used if strictly indicated. Wherever possible, women wishing to have children should wait for a phase when as little as possible or no medication is required before beginning pregnancy. If the individual's condition allows, treatment should be interrupted in the last 2 - 4 weeks of pregnancy. As yet there is insufficient experience with the medicament during breast-feeding. If treatment becomes necessary during lactation, the child should be weaned.

Granules: Unsuitable for phenyketonurics.

Tablet/Enema: 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 3 months. If additional symptoms occur, these tests should be performed immediately.
Caution is recommended in patients with impaired hepatic function.
Salofalk 500mg tablets/enemas 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 Salofalk 500mg tablets/enemas.
Patients with a history of adverse drug reactions to preparations containing sulphasalazine should be kept under close medical surveillance on commencement of a course of treatment with Salofalk 500mg tablets/enemas. Should Salofalk 500mg tablets/enemas cause acute intolerance reactions such as abdominal cramps, acute abdominal pain, fever, severe headache and rash, therapy should be discontinued immediately.
Tablet/Granules: Photosensitivity: More severe reactions are reported in patients with pre-existing skin conditions such as atopic dermatitis and atopic eczema.
Tablet: 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.
Note: In rare cases, in patients who have undergone bowel resection/bowel surgery in the ileocoecal region with removal of the ileocoecal valve, it has been observed that Salofalk 500 mg tablets were excreted undissolved in the stool, due to an excessively rapid intestinal passage.
This medicinal product contains 49 mg sodium per tablet, equivalent to 2.5% of the WHO recommended maximum daily intake for sodium. The maximum daily dose of this product is equivalent to 22% of the WHO recommended maximum daily intake for sodium. Salofalk 500 mg tablets are considered high in sodium. This should be particularly taken into account for those on a low salt diet.
Granules: In patients with phenylketonuria, it should be kept in mind that Salofalk granules contain aspartame as a sweetening agent, equivalent to 0.56 mg (Salofalk 500mg granules), 1.12 mg (Salofalk 1000mg granules), 1.68 mg (Salofalk 1.5g granules) and 3.36 mg (Salofalk 3g granules) phenylalanine.
Enema: Due to their potassium metabisulphite content, Salofalk enemas can provoke allergic reactions with anaphylactic symptoms and bronchial constriction (bronchospasm) in sensitive patients, particularly in those with asthma or a history of allergies.
Because the product contains sodium benzoate, it may provoke hypersensitivity reactions in suitably predisposed patients in the form of irritation of the skin, eyes and mucous membranes.
Effects on ability to drive and use machines: No effects on the ability to drive and use machines have been observed.

Pregnancy: Tablet/Enema: There are no adequate data from the use of Salofalk 500mg tablets/enemas 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.
Animal studies on oral mesalazine do not indicate direct or indirect harmful effects with respect to pregnancy, embryonal/fetal development, parturition or postnatal development. Salofalk 500mg tablets/enemas should only be used during pregnancy if the potential benefit outweighs the possible risk.
Breastfeeding: Tablet/Enema: 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 such as diarrhoea in the infant, cannot be excluded. Therefore, Salofalk 500mg/enemas should only be used during breast-feeding if the potential benefit outweighs the possible risk. If the infant develops diarrhoea, the breast-feeding should be discontinued.

Tablet: The following undesirable effects have been observed after administration of mesalazine: (See Table 2.)
Suppository: Gastrointestinal side effects: Abdominal discomfort, diarrhoea, flatulence, nausea and vomiting have been reported rarely.
Central nervous system side effects: In isolated cases under treatment with mesalazine central nervous phenomena such as headache and dizziness have been observed.
Hypersensitivity reactions: Hypersensitivity reactions that are not dose-dependent and are common to salicylic acid and its derivatives such as allergic rush, drug fever, bronchospasm, peri- and myocarditis, acute pancreatitis and interstitial nephritis are possible in rare cases.
Sporadic cases of allergic alveolitis have been observed during treatment with mesalazine. In isolated cases pancolitis may occur.
Under certain conditions, some drugs with a similar chemical structure to mesalazine may cause a lupus erythematosus-like syndrome. Thus, the onset of this syndrome cannot be ruled out under treatment with Salofalk 500 mg suppositories.
Other side effects: Myalgia and arthralgia have been observed rarely.
Elevated methaemoglobin levels cannot be excluded on account of the chemical structure of the active constituent.
In isolated cases changes in the blood count (aplastic anemia, agranulocytosis, pancytopenia, neutropenia, leucopenia, thrombocytopenia) have been reported after the use of drugs containing mesalazine.
There have been occasional reports of inflammation of the liver (hepatitis), in rare cases changes in liver function parameters (elevated transaminase levels) occur.
Note: Salofalk 500 mg suppositories should be taken under medical supervision. A blood count and urine status should be performed at the attending physician's discretion during treatment. As a general guideline we recommend tests 14 days after beginning treatment, and then another 2 to 3 times at 4-weekly intervals.
If the findings are normal, follow-up tests are required every three months or if additional signs of illness occur. The recommended kidney function tests are serum urea (BUN) and creatinine assays as well as urine sediment tests.
Patients should be monitored for elevated methaemoglobin values.
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 suppositories 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.
Enema: The following undesirable effects have been observed ater administration of mesalazine: (See Table 3.)

Click on icon to see table/diagram/image

There is weak evidence that mesalazine might decrease the anticoagulant effect of warfarin.
Tablet/Enema: 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.
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.
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.
Suppository: Interactions may occur if the following drugs are given at the same time as Salofalk: Anticoagulants: possible potentiation of the anticoagulative action (increased risk of bleeding in the gastrointestinal tract).
Glucocorticoids: possible increase in gastric side effects.
Sulphonylureas: possible potentiation of the hypoglycaemic effect.
Methotrexate: possible increase of the methotrexate toxicity.
Probenicid/sulphinpyrazone: possible reduction in uricosuric effects.
Spironolactone/furosemide: possible reduction in diuretic effects.
Rifampicin: possible reduction in tuberculostatic effects.

Incompatibilities: Tablet/Enema: Not applicable.
Special precautions for disposal and other handling: Tablet/Enema: No special requirements.

Tablet/Granules: Store below 30°C.
Suppository: Do not store above 30°C (86°F) and protect from light.
Enema: Store below 30°C and protect from light.
Shelf life: Tablet/Enema: 2 years.
Granules: 4 years.

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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