PRODUCT INFORMATION SALOFALK Tablets NAME OF...

Product Information Salofalk® Tablets

PRODUCT INFORMATION SALOFALK® Tablets

NAME OF DRUG Mesalazine Proper name: 5-Aminosalicylic Acid

Chemical name: 2-hydroxy-5-aminobenzoic acid, also referred to as 5-amino salicylic acid or 5-ASA C7H7NO3 = 153.1

CAS number- 89-57-6 DESCRIPTION Mesalazine is a white to greyish, voluminous powder, slightly pink in colour. It is practically insoluble in ethanol (90%), methanol (70%), water, ether, and chloroform, soluble in HCl (warmed 10% solution); soluble in NaOH (10% solution, with salt formation). Salofalk tablets have a functional coating, which ensures gastro-resistance to allow a reliable distribution and pH-dependent release of the active ingredient, mesalazine, at the intended site of action starting in the ileocoecal region. SALOFALK tablets contain mesalazine, anhydrous sodium carbonate, glycine, povidone, microcrystalline cellulose, croscarmellose sodium, anhydrous colloidal silica, calcium stearate, hypromellose, methacrylic acid copolymer, purified talc, titanium dioxide, iron oxide yellow, macrogol 6000, Eudragit E100. PHARMACOLOGY Pharmacodynamic properties Mesalazine has been identified as the active component of sulfasalazine in inflammatory bowel disease and is thought to have a topical action. The mechanism of action by which mesalazine protects the mucosa in chronic inflammatory bowel disease is not yet fully known. Mesalazine seems to act in multiple ways against several inflammatory mediators and principles. The results of in vitro investigations indicate that inhibition of lipoxygenase may play a role. Effects on prostaglandin concentrations in the intestinal mucosa have also been demonstrated, as has an influence on leukotriene production. Mesalazine may also function as a radical scavenger of reactive oxygen compounds.

Page 1


Pharmacokinetic Properties General considerations: The efficacy of mesalazine (5-ASA) appears to be determined not by the systemic but the local availability of the substance at the target site. Metabolism of mesalazine occurs mainly in the intestinal mucosa and, to a lesser extent, in the liver. The main metabolite is N-acetyl-5-aminosalicylic acid, which is – like 5-ASA – predominantly eliminated by the renal and faecal routes. It appears to have no therapeutic activity or specific toxic effects. The acetylation step appears irreversible. As metabolism occurs mainly in the intestinal mucosa, it has not been possible to differentiate between a rapid and slow acetylation form as in the case of sulfasalazine/sulfapyridine. The plasma protein binding of mesalazine and acetylated mesalazine is 43% and 78%, respectively. Absorption of mesalazine decreases in the intestinal tract from proximal to distal. Because of low absorption rates from oral delayed release preparations or rectal applications forms, the main elimination route is via faeces. Absorbed mesalazine and N-acetyl-5-ASA are eliminated mainly via kidneys. Less than 1% 5-ASA and about 24% N-acetyl-5-ASA based on the administered 5-ASA dose are excreted in the urine. Biliary excretion is a minor route of elimination. There is no pharmacokinetic data in the elderly using SALOFALK granules or tablets. SALOFALK tablets: SALOFALK tablets are gastric juice resistant and release mesalazine in the terminal ileal region in a pH dependent manner due to the Eudragit-L coating. Under starved condition the tablet transit time from the stomach to the small intestine is (0.79 ± 0.7 hours). It is recommended that tablets are taken about 1 hour before a meal to avoid dose-dumping.

Page 2


Pharmacokinetic data are summarised in the following table for SALOFALK granules and tablets (granules: 3 x 500 mg mesalazine/day, tablets: 3 x 2 (250mg) mesalazine/day, steady state conditions, 24 healthy volunteers):

Granules Tablets Pharmacokinetic Parameters

Mesalazine/5-ASA

N-Acetyl-5-ASA Mesalazine/5-ASA

N-Acetyl-5-ASA

tlag [h] 2.4 ± 0.8 2.4 ± 0.8 3.4 ± 1.0 3.5 ± 0.9 tmax [h] 4.3 ± 0.6 4.5 ± 0.9 4.4 ± 0.9 4.6 ± 0.9 t 1/2 [h] 4.4 ± 3.9 8.2 ± 6.0 2.8 ± 1.9 5.0 ± 2.4 Cmax [µg/mL] 0.8 ± 0.4 1.8 ± 0.7 2.0 ± 1.5 2.6 ± 1.4 AUC0-24h [µg x h/mL] 7.7 ± 3.3 29.0 ± 7.5 12.2 ± 6.4 34 ± 10.7 Ae urine [mmol] 0.286 ± 0.28 9.4 ± 2.4 1.48 ± 1.0 10.98 ± 2.8 Ae urine [%] 0.72 ± 0.7 24.03 ± 6.2 3.77 ± 2.5 28.02 ± 7.0 ∑ Ae 5-ASA + Ac-5-ASA [mmol]

9.7 ± 2.6

12.5 ± 3.4

∑ Ae 5-ASA + Ac-5-ASA [%] 24.8 ± 6.5 31.8 ± 8.8

The total quantity of mesalazine and N-acetyl-5-ASA eliminated by the renal pathway over 24 hours is equivalent to about 25% to 32% respectively of the administered dose of SALOFALK granules and tablets. About 30% of this amount is absorbed in the ileocoecal area and about 90% in total in the ileocoecal and ascending colon regions. Therefore about 80-90% 5-ASA of administered dose is available in the descending colon, sigmoid and rectum where absorption of mesalazine is low. Granule and tablet preparations radio-labelled with 153Sm (Samarium) showed the following gastrointestinal distribution (means ± S.D.): Granules Tablets Gastric emptying 0.94 ± 0.70 h 0.56 ± 0.71 h Appearance in small bowel 0.65 ± 0.40 h 0.79 ± 0.71 h Transit time in small bowel 3.07 ± 0.88 h 3.00 ± 0.84 h Disappearance from small bowel 3.71 ± 1.08 h 3.79 ± 1.17 h Ileocoecal region: appearance 3.31 ± 1.03 h 3.83 ± 0.89 h Ileocoecal region: disappearance 6.15 ± 2.48 h 5.56 ± 1.57 h Ascending colon: appearance 4.08 ± 1.39 h 4.74 ± 1.15 h Ascending colon: disappearance 13.57 ± 4.45 h 10.88 ± 1.48 h Overall transit time in colon 19.92 ± 1.39 h 17.37 ± 4.80 h

Page 3


Plasma Cmax values of 5-ASA and Ac-5-ASA during steady-state were about 1.4 and 1.2 fold higher after once daily dosing (o.d.) when compared to values obtained after dosing three times daily (t.i.d.) dosing of the same daily dose Plasma trough levels at the end of the dosing interval were only slightly (0.3 and 0.4 times, 5-ASA and Ac-5-ASA respectively) lower after o.d. dosing when compared to that after t.i.d. dosing. There is no indication of systemic drug accumulation, when given o.d. The administration of a single oral dose of SALOFALK granules, 20 mg/kg body weight, in 13 children with active colonic inflammatory bowel disease (IBD) (age range: 5.9 to 15.8 years) showed that the pharmacokinetics of systemic exposure in children corresponds with those in adults. SALOFALK was safe and well tolerated. CLINICAL TRIALS Ulcerative colitis The criteria used to evaluate the efficacy of the substance in the therapy of ulcerative colitis are frequency of bowel movements, rectal haemorrhage, abdominal pain, general well-being, temperature, extraintestinal manifestations, ESR, and haemoglobin. These criteria have been summarised in the clinical activity index (CAI) to evaluate the efficacy of treatment for ulcerative colitis. The safety and efficacy of SALOFALK granules (1.5 g to 3 g 5-ASA/day) was compared against mesalazine tablets (SALOFALK 500 mg tablets, 1.5 g to 3.0 g 5-ASA/day) in a double-blind randomised multi-centre study in 233 patients with mild to moderately active ulcerative colitis over a period of 8 weeks. The primary efficacy criterion, complete response rate (per protocol analysis, PP) was very similar in the granules (68%) and the tablets (70%) groups. The efficacy analysis (PP) showed that more patients treated with mesalazine tablets (47%) had to increase the dose from 1.5 g mesalazine/day to 3.0 g mesalazine/day compared to patients treated with granules (38%). Similar results were obtained by the ITT (intention-to-treat) analysis: 39% of the granules group, 45% of the tablets group, i.e., more patients came into remission (49%) with the 1.5 g 5-ASA/day from granules than from tablets (43%). Granules, therefore, in total were as efficacious and as well tolerated as the tablets at the same dose. Subgroup analyses showed that the response rates to granules were higher in patients with high baseline disease activity (CAI>8) and with 1 or more extraintestinal manifestations than the tablets: Parameters Granules Tablets CAI ≤8 67% 74% CAI >8 65% 44% Extraintestinal Manifestation: -none 69% 72% -1 or more 53% 36% In another study, the efficacy and safety of SALOFALK granules of different dosages (1.5 g, 3.0 g, 4.5 g/day) were compared in 321 patients with mild to moderately active ulcerative colitis in a double-blind manner for a treatment period of 8 weeks. Complete response (CAI ≤ 4) was obtained by 50% in the 1.5 g dose group, by 66% in the 3.0 g group (in comparison to 1.5 g: p = 0.014) and by 55% in the 4.5 g group (in comparison to 1.5 g: not significant, p = 0.318). The 3.0 g/day dose appears to be the optimal dose.

Page 4


In a double-blind, randomised comparative study, the efficacy and tolerability of once daily (o.d.) 3.0 g SALOFALK granules was compared with three time daily (t.i.d.) 1.0 g SALOFALK granules in 380 patients with active ulcerative colitis over a period of eight weeks. The data show that for SALOFALK granules, a daily dose of 3 g mesalazine given o.d. is therapeutically equivalent to the conventional t.i.d. dosage regimen for the induction of remission (CAI ≤ 4) in patients with mild-to-moderate ulcerative colitis. The clinical remission rate in the PP analysis set (primary analysis) was 84.4% in the o.d. group and 81.3% in the t.i.d. group. The resulting p-value for the non-inferiority test (pre-defined margin: -15%) was 0.0007 with a 95% CI of [-11.4%, 17.6%]. With the achieved lower boundary of the derived 95% CI of 3.1%, an even narrower margin for the non-inferiority was kept. Remission rates in ITT analysis set were very similar, 80.8% in the o.d. group and 77.4% in the t.i.d. group. ITT test result (p = 0.0007) and 95% CI (-11.4%, 18.1%) agreed with the PP analysis. Once daily dosing of SALOFALK granules was as safe and well tolerated as three times daily dosing of SALOFALK granules. Crohn’s ileitis and colitis The clinical pattern of symptoms and complications of Crohn’s disease is more varied than that of ulcerative colitis. The criteria used to evaluate the efficacy of the substance in the therapy of Crohn’s disease are summarised in the Crohn’s disease Activity Index (CDAI) and consist of stool frequency, abdominal pain rating, well-being scale ratings, use of loperamide or codeine to control diarrhoea, body weight, haematocrit, presence of abdominal masses and physicians’ assessment of patients’ wellbeing. Four controlled studies ranging in duration from 8 to 12 weeks have been performed to investigate the efficacy of Salofalk in comparison to standard therapies such as glucocorticosteroids and the combination glucocorticosteroids/sulfasalazine in the treatment of Crohn’s disease. In a randomised controlled trial of 3 month duration, there was no difference in efficacy between the group taking 3g/d Salofalk (3 x 2 Salofalk 500 mg tablets), in comparison with the group taking a combination of sulphasalazine (3g) and methylprednisolone (initial 40 mg, then weekly reduction by 4 mg). Clinical remission could be observed in 83% of the mesalazine group in comparison to 88% of the sulphasalazine group. There was no statistically significant difference between the groups. In another randomised controlled multicentre trial of 3 month duration, following the administration of 3g mesalazine (3 x 4 tablets Salofalk 250 mg) or prednisone (initially 40 mg, then weekly reduction by 4 mg) to Crohn’s disease patients, the reduction and maintenance of reduction in CDAI scores were similar in the two groups. There was no statistically significant (p≥0.05) difference between treatments in the reduction in CDAI score at week 12. In a further study, high-dose Salofalk (3x3 Salofalk 500 mg = 4.5g) was compared with 6-methylprednisolone (initially 48 mg, weekly tapering for 8 weeks to 8 mg per day) in the therapy of Crohn’s disease. Following 8 weeks of therapy, 40% of the patients in the 5-ASA group and 56.3% of the patients in the 6-methylprednisolone group were in remission (CDAI<150 and a decrease of at least 60 points, p=0.5867). The fourth trial (n=40) comparing the efficacy and safety of mesalazine 1.5 g/day with sulphasalazine 3g/day provides supportive evidence that Salofalk is as effective as standard therapy. The fall in CDAI from baseline to 8 weeks was statistically significant for both treatments, while the mean reduction in CDAI score was greater with mesalazine than with sulphasalazine (196.477 vs 139.0).

Page 5


Four placebo-controlled studies investigated the efficacy of mesalazine in the maintenance of remission of Crohn’s disease. The dosages varied from 1 to 3 g/d mesalazine with a follow up period ranging from 1 to 1.5 years. The patients in the trials had either medically or surgically induced remission. All trials showed a significant improvement in the use of mesalazine when compared to placebo. In one of these trials involving 59 Crohn’s patients on a treatment dosage of 1g/d mesalazine and one year follow up, the recurrence rate in the mesalazine group was 27% compared with 55% in the placebo group (p<0.05). In another multi-centre study involving 163 patients receiving prophylactic treatment with 3 g mesalazine/day for up to 72 months, the symptomatic recurrence rate in the mesalazine group was significantly reduced in comparison with the placebo group (31% vs. 41%, p=0.031). In the third placebo controlled study, including 206 patients, treated with 1.5g/day mesalazine for up to 12 months, the relapse estimate was significantly lower in patients with ileal disease (8.3% on 5-ASA vs. 31% on placebo, p=0.0535) and in patients with previous bowel resection (14.2% vs. 47%, p=0.0435). The fourth study, including 66 patients, showed that patients with Crohn’s ileocolitis appeared to respond best to mesalazine (p=0.09). Results of the various studies show that oral delayed release SALOFALK tablets are well tolerated in patients with ulcerative colitis and Crohn’s ileitis and colitis. INDICATIONS SALOFALK tablets are indicated in the treatment of acute episodes and maintenance of remission of: i. Mild to moderate ulcerative colitis; and ii. Crohn’s ileitis and colitis CONTRAINDICATIONS SALOFALK tablets are contraindicated in patients with the following: • hypersensitivity to salicylic acid, salicylic acid derivatives, e.g. mesalazine/5-ASA. • hypersensitivity to any other ingredients in Salofalk • severe impairment of hepatic and renal function PRECAUTIONS SALOFALK should be given/used under medical supervision. SALOFALK is not recommended in patients with impaired renal function. The blood and renal status should be determined prior to and during treatment, at the discretion of the treating physician. As a guideline, checks are recommended 14 days after commencement of treatment, then a further 2 to 3 times at 4-weekly intervals. If the findings are normal, follow-up tests should be conducted every three months or immediately if additional signs of the disorder occur. To check renal function, it is recommended that levels of serum urea (BUN) and creatinine be determined as well as urine sediment examined. Mesalazine-induced renal toxicity should be considered if renal function deteriorates during treatment. As mesalazine might cause blood dyscrasias, although rarely reported, and hepatic impairment due to hypersensitivity reactions, blood parameters, like blood counts and

Page 6


liver function and cholestasis parameters (e.g. ALT, AST, alkaline phosphatase, γGT) may be monitored like the renal parameters. Epigastric pain, also commonly associated with inflammatory bowel disease and prednisone or sulfasalazine therapy, should be investigated in order to exclude pericarditis, hepatitis and pancreatitis either as adverse drug reactions to 5-ASA or secondary manifestations of inflammatory bowel disease. SALOFALK should be used/given with caution in patients with pulmonary function impairment, particularly asthma and in patients with known hypersensitivity to sulfasalazine containing preparations. Treatment in the latter patients should be instituted with careful medical supervision. Treatment should be discontinued immediately if symptoms of acute intolerance, e.g. cramps, acute abdominal pain, fever, severe headache and skin rash, occur. SALOFALK is not expected to affect the ability of patients to drive or operate machinery. Effects on fertility Fertility and reproductive performance were not impaired in rats treated orally with mesalazine prior to and during mating (both sexes) and throughout gestation and lactation (females) at doses up to 320 mg/kg/day, which is about the same as the maximal recommended clinical dose of Salofalk granules on a body surface area basis. Use in pregnancy (Category C) There was no evidence of embryotoxicity or teratogenicity in rats and rabbits treated orally with mesalazine during the period of organogenesis at respective doses of up to 320 and 495 mg/kg/day representing about the same, and 3.5 times, the maximal recommended clinical dose of Salofalk granules on a body surface area basis. Oral mesalazine does not show direct or indirect harmful effects with respect to parturition or postnatal development in animals. Human data on use during pregnancy are limited. No adverse effect of mesalazine on pregnancy or on the health of the foetus/newborn child was shown. To date no other relevant epidemiologic data are available. In one single case after oral use of 2-4 g mesalazine per day during the 3rd and 5th months of pregnancy, renal failure in a neonate was reported. Salofalk tablets should only be used during pregnancy if the potential benefit outweighs the possible risk. Use in lactation In rats, there were no adverse effects on dams or offspring from oral administration of mesalazine during late gestation and throughout lactation at doses up to 320 mg/kg/day which is about the same as the maximal recommended clinical dose of Salofalk granules on a body surface area basis. There has been a report of a patient receiving mesalazine suppositories during the lactation period. Twelve hours after the initial dose, the infant developed watery diarrhoea that disappeared on discontinuation of the mesalazine therapy but reappeared on rechallenge. There have been reports of mesalazine and of its metabolite N-acetyl-5-ASA found in breast milk. There is no experience with

Page 7


SALOFALK granules in lactating women. Salofalk should not be used during lactation unless the likely benefit of treatment outweighs the potential hazard. Paediatric use SALOFALK tablets should not be used in children below 6 years of age for the treatment of acute episodes and maintenance of remission of mild to moderate ulcerative colitis, as there is very limited experience with this age group. SALOFALK tablets should not be used in children below 12 years of age for the treatment of Crohn’s ileitis and colitis, as there is very limited experience with this age group. Use in the elderly Specific clinical data in only elderly patients for mesalazine are not available, but have been used in patients up to 75 years of age in clinical trials. Carcinogenicity There was no evidence of carcinogenicity in rats treated with mesalazine in the diet for 127 weeks at doses up to 320 mg/kg/day, associated with plasma concentrations of mesalazine and N-acetyl-5-ASA of 1 and 6 fold the respective clinical plasma concentrations associated with a 1500 mg dose of the granules and 4g/60 mL enema. Genotoxicity There was no evidence of genotoxic potential with mesalazine in bacterial gene mutation assays, of chromosomal damage in mouse haematopoietic cells following a single oral dose, or of increases in sister chromatid exchange frequencies in Chinese hamster bone marrow following a single intraperitoneal dose. Interactions with other medicines Studies to evaluate the potential interaction between SALOFALK and other drugs have not been performed. In common with other salicylates, interactions may occur during concomitant administration of mesalazine and the following drugs: •Coumarin-type anticoagulants: possible potentiation of the anticoagulant

effect action (increasing the risk of gastrointestinal haemorrhage)

• Glucocorticoids possible increase in undesirable gastric effects • Sulphonylureas: possible increase in the blood glucose-lowering

effects • Methotrexate: possible increase in toxic potential of

methotrexate • Probenecid/sulphinpyrazone: possible attenuation of the uricosuric effects • Spironolactone/frusemide: possible attenuation of the diuretic effects • Rifampicin possible attenuation of the tuberculostatic

effects • Lactulose or similar preparations, which lower stool pH:

Page 8


possible reduction of mesalazine release from tablets due to decreased pH caused by bacterial metabolism

In patients who are concomitantly treated with azathioprine or 6-mercaptopurine, possible enhanced myelosuppressive effects of azathioprine or 6-mercaptopurine should be taken into account. Effects on laboratory tests Not known to interfere with laboratory tests or physical diagnostic agents. ADVERSE EFFECTS The most frequent adverse reactions seen in clinical trials are headache (3%), abdominal pain (4%), exacerbation of ulcerative colitis (2%), abnormal hepatic function (2%) and upper respiratory tract infection (1%). In two clinical trials involving 550 patients with acute ulcerative colitis, tolerability was good. The table below shows the adverse events that occurred in at least 5% of patients in the clinical trials:

Adverse event

SAG-2/UCA SAG-15/UCA Salofalk 0.5 g tds

(n = 102)

Salofalk 1 g tds

(n = 108)

Salofalk 1.5 g tds

(n = 108)

Salofalk 0.5 – 1 g tds

granules (n = 114)


tablets (n=118)

AE/ Potential

ADR

AE/ Potential

ADR

AE/ Potential

ADR

AE/ Potential

ADR

AE/ Potential

ADR Headache 24%/3% 23%/12% 21%/4% 6%/3% 7%/3% Abdominal pain 5%/1% 7%/4% 7%/4% - - Ulcerative colitis aggravated

15%/2% 6%/1% 7%/0 5%/1% 8%/1%

Hepatic function abnormal

1%/1% 3%/2% 5%/5% - -

Upper resp tract infection

3%/0 4%/1% 7%/1% - -

Influenza like symptoms

- - - 3%/0 6%/0

The following adverse events presented by body system have been reported in international post marketing surveillance of SALOFALK preparations including enemas and tablets. In many cases, the relationship to SALOFALK has not been established.

Page 9


The common: (≥1% - <10%) adverse events were as follows: Body as a whole – General Disorders Headache Gastrointestinal System Disorders Abdominal pain, diarrhoea, nausea and vomiting, flatulence, exacerbation of ulcerative colitis Skin and Appendages Disorder Rash including pruritus, urticaria The following additional adverse events were uncommon and reported by < 1% of patients: Body as a Whole – General Disorders Fever, allergic reaction Central and Peripheral Nervous Systems Disorders Dizziness, paraesthesia, peripheral neuropathy Collagen disorders Lupus erythematosus syndrome (as observed for preparations with a similar chemical structure Gastrointestinal System Disorders Acute pancreatitis, pancolitis, neonate diarrhoea Liver and Biliary System Disorders Hepatitis, increased liver enzyme values (transaminase activity), intrahepatic cholestasis, increased bilirubin Musculo-skeletal System Disorders Arthralgia, myalgia, myositis Myo-, Endo-, Pericardial and Valve Disorders Pericarditis, myocarditis, pericardial effusion Platelet, Bleeding and Clotting Disorders Thrombocytopenia Red Blood Cell Disorders Aplastic anaemia, haemolytic anaemia Reproductive System Disorders Oligospermia (reversible) Respiratory System Disorders Bronchospasm, pleural effusion, alveolitis Skin and Appendages Disorders Alopecia, allergic exanthema, increased sweating

Page 10


Urinary System Disorders Acute or chronic interstitial nephritis, renal insufficiency, renal failure, nephrotoxicity White Cell and RES Disorders Agranulocytosis, leukopenia, neutropenia, pancytopenia DOSAGE AND ADMINISTRATION Unless otherwise prescribed, the recommended doses given in one to three divided doses for adults and the elderly are as follows -:

For acute treatment of: Ulcerative colitis - 1.5 g to 3 g per day Crohn’s ileitis and colitis - 3 to 4.5 g per day

For maintenance of remission and/or long term treatment of:

Ulcerative colitis - 1.5 g per day Crohn’s ileitis and colitis - 1.5 g to 3 g per day

Depending on disease severity in children older than 6 years of age, the recommended doses, given in one to three divided doses, for the treatment of ulcerative colitis are as follows -:

For acute treatment: 30-50 mg mesalazine/kg/day. For maintenance of remission and/or long term treatment: 15-30 mg mesalazine/kg per day.

It is generally recommended that half the adult dose may be given to patients up to a body weight of 40 kg; and the normal adult dose to those above 40 kg. SALOFALK tablets should not be used in children below 6 years of age for the treatment of acute episodes and maintenance of remission of mild to moderate ulcerative colitis, as there is very limited experience with this age group. SALOFALK tablets should not be used in children below 12 years of age for the treatment of Crohn’s ileitis and colitis, as there is very limited experience with this age group. SALOFALK tablets should be swallowed without chewing with sufficient fluid. The tablets should be taken at least 1 hour before a meal in order to allow for gastric emptying. SALOFALK should be used on a regular basis and consistently, in the treatment of acute inflammatory episode, in order to achieve the desired therapeutic effect. In general, an acute episode of ulcerative colitis or Crohn’s ileitis and colitis usually subsides by 8 weeks. In rare cases of patients who have undergone intestinal resection or bowel surgery of the ileocaecal region with removal of the ileocaecal valve, undissolved tablets of Salofalk 500 mg have been eliminated with the stools due to an excessively rapid intestinal passage.

Page 11


Page 12

OVERDOSAGE No overdosage has been reported to date. Possible symptoms may include nausea, vomiting and diarrhoea, and symptoms similar to salicylate overdose. There is no specific antidote. General supportive and symptomatic measures are recommended. For advice on the management of overdosage, please contact the Poisons Information Centre (telephone 13 11 26). PRESENTATION SALOFALK enteric coated tablets are presented as butter-yellow to ochre colour, lustreless with a smooth surface. They are supplied as a 500 mg dose of mesalazine in orange blister strips of aluminium foil backing packed in cardboard. Cartons of 100 tablets are available. STORAGE CONDITIONS Store below 25˚C. Store in a dry place and protect from light. NAME AND ADDRESS OF THE SPONSOR Orphan Australia Pty. Ltd. 300 Frankston-Dandenong road Dandenong Victoria 3175 Australia. Website: www.orphan.com.au POISON SCHEDULE OF THE MEDICINE S4 DATE OF APPROVAL This Product Information was approved by the TGA on: 6 May 2010 SALOFALK is a registered trademark of Dr. Falk Pharma GmbH, Germany, used under licence by Orphan Australia Pty. Ltd.

Product Information Salofalk® Granules

PRODUCT INFORMATION

SALOFALK® Granules NAME OF DRUG Mesalazine Proper name: 5-Aminosalicylic Acid


CAS number- 89-57-6 DESCRIPTION Mesalazine is a white to greyish, voluminous powder, slightly pink in colour. It is practically insoluble in ethanol (90%), methanol (70%), water, ether, and chloroform, soluble in HCl (warmed 10% solution); soluble in NaOH (10% solution, with salt formation). SALOFALK granules have a functional coating on the particles, which ensures gastro-resistance to allow a reliable distribution and pH-dependent release of the active ingredient, mesalazine, at the intended site of action starting in the ileocoecal region. The granules also contain a matrix system inside the particle core, which releases mesalazine independently of pH. SALOFALK granules contain mesalazine, microcrystalline cellulose, hypromellose, anhydrous colloidal silica, methacrylic acid copolymer, nonoxinol 100, magnesium stearate, simethicone emulsion (containing sorbic acid and methylcellulose), triethyl citrate, purified talc, carmellose sodium, aspartame, anhydrous citric acid, vanilla custard flavour 75016-32 (containing propylene glycol), povidone, titanium dioxide. PHARMACOLOGY Pharmacodynamic properties Mesalazine has been identified as the active component of sulfasalazine in inflammatory bowel disease and is thought to have a topical action. The mechanism of action by which mesalazine protects the mucosa in chronic inflammatory bowel disease is not yet fully known. Mesalazine seems to act in multiple ways against several inflammatory mediators and principles. The results of in vitro investigations indicate that inhibition of lipoxygenase may play a role. Effects on prostaglandin concentrations in the intestinal mucosa have also been demonstrated, as has an influence on leukotriene production. Mesalazine may also function as a radical scavenger of reactive oxygen compounds.

Page 1


Pharmacokinetic Properties General considerations: The efficacy of mesalazine (5-ASA) appears to be determined not by the systemic but the local availability of the substance at the target site. Metabolism of mesalazine occurs mainly in the intestinal mucosa and, to a lesser extent, in the liver. The main metabolite is N-acetyl-5-aminosalicylic acid, which is – like 5-ASA – predominantly eliminated by the renal and faecal routes. It appears to have no therapeutic activity or specific toxic effects. The acetylation step appears irreversible. As metabolism occurs mainly in the intestinal mucosa, it has not been possible to differentiate between a rapid and slow acetylation form as in the case of sulfasalazine/sulfapyridine. The plasma protein binding of mesalazine and acetylated mesalazine is 43% and 78%, respectively. Absorption of mesalazine decreases in the intestinal tract from proximal to distal. Because of low absorption rates from oral delayed release preparations or rectal applications forms, the main elimination route is via faeces. Absorbed mesalazine and N-acetyl-5-ASA are eliminated mainly via kidneys. Less than 1% 5-ASA and about 24% N-acetyl-5-ASA based on the administered 5-ASA dose are excreted in the urine. Biliary excretion is a minor route of elimination. There is no pharmacokinetic data in the elderly using SALOFALK granules or tablets. SALOFALK granules: SALOFALK granules are gastric juice resistant and release mesalazine in the terminal ileal region in a pH dependent manner due to the Eudragit-L coating. The release of mesalazine from the granules is prolonged due to the matrix granule structure. Owing to the granule size, under starved condition transit from the stomach to the small intestine is fast (0.65 + 0.40 hours). For the granules food intake may cause a shift of 1 to 2 hours to a longer tlag value (lag time after which mesalazine concentrations are first detectable in blood plasma) and a longer tmax value, but does not cause dose-dumping due to the small granule size. Food does cause a slight increase in Cmax and AUC values.

Page 2


Pharmacokinetic data are summarised in the following table for SALOFALK granules and tablets (granules: 3 x 500 mg mesalazine/day, tablets: 3 x 2 (250mg) mesalazine/day, steady state conditions, 24 healthy volunteers):

Granules Tablets Pharmacokinetic Parameters

Mesalazine/5-ASA N-Acetyl-5-ASA Mesalazine/5-ASA

N-Acetyl-5-ASA

tlag [h] 2.4 ± 0.8 2.4 ± 0.8 3.4 ± 1.0 3.5 ± 0.9 tmax [h] 4.3 ± 0.6 4.5 ± 0.9 4.4 ± 0.9 4.6 ± 0.9 t 1/2 [h] 4.4 ± 3.9 8.2 ± 6.0 2.8 ± 1.9 5.0 ± 2.4 Cmax [µg/mL] 0.8 ± 0.4 1.8 ± 0.7 2.0 ± 1.5 2.6 ± 1.4 AUC0-24h [µg x h/mL] 7.7 ± 3.3 29.0 ± 7.5 12.2 ± 6.4 34 ± 10.7 Ae urine [mmol] 0.286 ± 0.28 9.4 ± 2.4 1.48 ± 1.0 10.98 ± 2.8 Ae urine [%] 0.72 ± 0.7 24.03 ± 6.2 3.77 ± 2.5 28.02 ± 7.0 ∑ Ae 5-ASA + Ac-5-ASA [mmol] 9.7 ± 2.6

12.5 ± 3.4

∑ Ae 5-ASA + Ac-5-ASA [%] 24.8 ± 6.5 31.8 ± 8.8

The total quantity of mesalazine and N-acetyl-5-ASA eliminated by the renal pathway over 24 hours is equivalent to about 25% to 32% respectively of the administered dose of SALOFALK granules and tablets. About 30% of this amount is absorbed in the ileocoecal area and about 90% in total in the ileocoecal and ascending colon regions. Therefore about 80-90% 5-ASA of administered dose is available in the descending colon, sigmoid and rectum where absorption of mesalazine is low. Granule and tablet preparations radio-labelled with 153Sm (Samarium) showed the following gastrointestinal distribution (means ± S.D.): Granules Tablets Gastric emptying 0.94 ± 0.70 h 0.56 ± 0.71 h Appearance in small bowel 0.65 ± 0.40 h 0.79 ± 0.71 h Transit time in small bowel 3.07 ± 0.88 h 3.00 ± 0.84 h Disappearance from small bowel 3.71 ± 1.08 h 3.79 ± 1.17 h Ileocoecal region: appearance 3.31 ± 1.03 h 3.83 ± 0.89 h Ileocoecal region: disappearance 6.15 ± 2.48 h 5.56 ± 1.57 h Ascending colon: appearance 4.08 ± 1.39 h 4.74 ± 1.15 h Ascending colon: disappearance 13.57 ± 4.45 h 10.88 ± 1.48 h Overall transit time in colon 19.92 ± 1.39 h 17.37 ± 4.80 h Plasma Cmax values of 5-ASA and Ac-5-ASA during steady-state were about 1.4 and 1.2 fold higher after once daily dosing (o.d.) when compared to values obtained after dosing three times daily (t.i.d.) dosing of the same daily dose. Plasma trough levels at the end of the dosing interval were only slightly (0.3 and 0.4 times, 5-ASA and Ac-5-ASA respectively) lower after o.d. dosing when compared to that after t.i.d. dosing. There is no indication of systemic drug accumulation, when given o.d.

Page 3


The administration of a single oral dose of SALOFALK granules, 20 mg/kg body weight, in 13 children with active colonic inflammatory bowel disease (IBD) (age range: 5.9 to 15.8 years) showed that the pharmacokinetics of systemic exposure in children corresponds with those in adults. SALOFALK was safe and well tolerated. CLINICAL TRIALS The criteria used to evaluate the efficacy of the substance in the therapy of ulcerative colitis are frequency of bowel movements, rectal haemorrhage, abdominal pain, general well-being, temperature, extraintestinal manifestations, ESR, and haemoglobin. These criteria have been summarised in the clinical activity index (CAI) to evaluate the efficacy of treatment for ulcerative colitis. The safety and efficacy of SALOFALK granules (1.5 g to 3 g 5-ASA/day) was compared against mesalazine tablets (SALOFALK 500 mg tablets, 1.5 g to 3.0 g 5-ASA/day) in a double-blind randomised multi-centre study in 233 patients with mild to moderately active ulcerative colitis over a period of 8 weeks. The primary efficacy criterion, complete response rate (per protocol analysis, PP) was very similar in the granules (68%) and the tablets (70%) groups. The efficacy analysis (PP) showed that more patients treated with mesalazine tablets (47%) had to increase the dose from 1.5 g mesalazine/day to 3.0 g mesalazine/day compared to patients treated with granules (38%). Similar results were obtained by the ITT (intention-to-treat) analysis: 39% of the granules group, 45% of the tablets group, i.e., more patients came into remission (49%) with the 1.5 g 5-ASA/day from granules than from tablets (43%). Granules, therefore, in total were as efficacious and as well tolerated as the tablets at the same dose. Subgroup analyses showed that the response rates to granules were higher in patients with high baseline disease activity (CAI>8) and with 1 or more extraintestinal manifestations than the tablets: Parameters Granules Tablets CAI ≤8 67% 74% CAI >8 65% 44% Extraintestinal Manifestation: -none 69% 72% -1 or more 53% 36% In another study, the efficacy and safety of SALOFALK granules of different dosages (1.5 g, 3.0 g, 4.5 g/day) were compared in 321 patients with mild to moderately active ulcerative colitis in a double-blind manner for a treatment period of 8 weeks. Complete response (CAI ≤ 4) was obtained by 50% in the 1.5 g dose group, by 66% in the 3.0 g group (in comparison to 1.5 g: p = 0.014) and by 55% in the 4.5 g group (in comparison to 1.5 g: not significant, p=0.318). The 3.0 g/day dose appears to be the optimal dose. In a double-blind, randomised comparative study, the efficacy and tolerability of once daily (o.d.) 3.0 g SALOFALK granules was compared with three time daily (t.i.d.) 1.0 g SALOFALK granules in 380 patients with active ulcerative colitis over a period of eight weeks. The data show that for SALOFALK granules, a daily dose of 3 g mesalazine given o.d. is therapeutically equivalent to the conventional t.i.d. dosage regimen for the induction of remission (CAI ≤ 4) in patients with mild-to-moderate ulcerative colitis. The clinical remission rate in the PP analysis set (primary analysis) was 84.4% in the o.d. group and 81.3% in the t.i.d. group. The resulting p-value for

Page 4


the non-inferiority test (pre-defined margin: -15%) was 0.0007 with a 95% CI of [-11.4%, 17.6%]. With the achieved lower boundary of the derived 95% CI of 3.1%, an even narrower margin for the non-inferiority was kept. Remission rates in ITT analysis set were very similar, 80.8% in the o.d. group and 77.4% in the t.i.d. group. ITT test result (p = 0.0007) and 95% CI (-11.4%, 18.1%) agreed with the PP analysis. Once daily dosing of SALOFALK granules was as safe and well tolerated as three times daily dosing of SALOFALK granules. Results of the various studies show that oral delayed release SALOFALK granules are well tolerated in patients with ulcerative colitis. INDICATIONS SALOFALK granules are indicated in the treatment of acute ulcerative colitis of mild to moderate severity, and for the maintenance of remission and/or the long term treatment of ulcerative colitis. CONTRAINDICATIONS SALOFALK granules and tablets are contraindicated in patients with the following: • hypersensitivity to salicylic acid, salicylic acid derivatives, e.g. mesalazine/5-ASA

or to any of the other ingredients • severe impairment of hepatic and renal function PRECAUTIONS SALOFALK should be given/used under medical supervision. SALOFALK is not recommended in patients with impaired renal function. The blood and renal status should be determined prior to and during treatment, at the discretion of the treating physician. As a guideline, checks are recommended 14 days after commencement of treatment, then a further 2 to 3 times at 4-weekly intervals. If the findings are normal, follow-up tests should be conducted every three months or immediately if additional signs of the disorder occur. To check renal function, it is recommended that levels of serum urea (BUN) and creatinine be determined as well as urine sediment examined. Mesalazine-induced renal toxicity should be considered if renal function deteriorates during treatment. As mesalazine might cause blood dyscrasias, although rarely reported, and hepatic impairment due to hypersensitivity reactions, blood parameters, like blood counts and liver function and cholestasis parameters (e.g. ALT, AST, alkaline phosphatase, γGT) may be monitored like the renal parameters. Epigastric pain, also commonly associated with inflammatory bowel disease and prednisone or sulfasalazine therapy, should be investigated in order to exclude pericarditis, hepatitis and pancreatitis either as adverse drug reactions to 5-ASA or secondary manifestations of inflammatory bowel disease. SALOFALK should be used/given with caution in patients with pulmonary function impairment, particularly asthma and in patients with known hypersensitivity to sulfasalazine containing preparations. Treatment in the latter patients should be instituted with careful medical supervision. Treatment should be discontinued

Page 5


immediately if symptoms of acute intolerance, e.g. cramps, acute abdominal pain, fever, severe headache and skin rash, occur. In the case of phenylketonuria, it should be borne in mind that SALOFALK granules contain aspartame as a sweetening agent, equivalent to the following quantities of phenylalanine: SALOFALK granules equivalent to: Aspartame equivalent to the following Quantity of phenylalanine: 500 mg mesalazine 0.56 mg 1 g mesalazine 1.12 mg 1.5 g mesalazine 1.68 mg 3 g mesalazine 3.36 mg SALOFALK is not expected to affect the ability of patients to drive or operate machinery. Effects on fertility Fertility and reproductive performance were not impaired in rats treated orally with mesalazine prior to and during mating (both sexes) and throughout gestation and lactation (females) at doses up to 320 mg/kg/day, which is about the same as the maximal recommended clinical dose of Salofalk granules on a body surface area basis. Use in pregnancy (Category C) There was no evidence of embryotoxicity or teratogenicity in rats and rabbits treated orally with mesalazine during the period of organogenesis at respective doses of up to 320 and 495 mg/kg/day representing about the same, and 3.5 times, the maximal recommended clinical dose of Salofalk granules on a body surface area basis. Oral mesalazine does not show direct or indirect harmful effects with respect to parturition or postnatal development in animals. Human data on use during pregnancy are limited. No adverse effect of mesalazine on pregnancy or on the health of the foetus/newborn child was shown. To date no other relevant epidemiologic data are available. In one single case after oral use of 2-4 g mesalazine per day during the 3rd and 5th months of pregnancy, renal failure in a neonate was reported. Salofalk granules should only be used during pregnancy if the potential benefit outweighs the possible risk. Use in lactation In rats, there were no adverse effects on dams or offspring from oral administration of mesalazine during late gestation and throughout lactation at doses up to 320 mg/kg/day which is about the same as the maximal recommended clinical dose of Salofalk granules on a body surface area basis. There has been a report of a patient receiving mesalazine suppositories during the lactation period. Twelve hours after the initial dose, the infant developed watery diarrhoea that disappeared on discontinuation of the mesalazine therapy but reappeared on rechallenge. There have been reports of mesalazine and of its metabolite N-acetyl-5-ASA found in breast milk. There is no experience with

Page 6


SALOFALK granules in lactating women. Salofalk should not be used during lactation unless the likely benefit of treatment outweighs the potential hazard. Paediatric use SALOFALK should not be used in children below 6 years of age, as there is very limited experience with this age group. Use in the elderly Specific clinical data in only elderly patients for mesalazine are not available, but have been used in patients up to 75 years of age in clinical trials. Carcinogenicity There was no evidence of carcinogenicity in rats treated with mesalazine in the diet for 127 weeks at doses up to 320 mg/kg/day, associated with plasma concentrations of mesalazine and N-acetyl-5-ASA of 1 and 6 fold the respective clinical plasma concentrations associated with a 1500 mg dose of the granules and 4g/60 mL enema. Genotoxicity There was no evidence of genotoxic potential with mesalazine in bacterial gene mutation assays, of chromosomal damage in mouse haematopoietic cells following a single oral dose, or of increases in sister chromatid exchange frequencies in Chinese hamster bone marrow following a single intraperitoneal dose. Interactions with other medicines Studies to evaluate the potential interaction between SALOFALK and other drugs have not been performed. In common with other salicylates, interactions may occur during concomitant administration of mesalazine and the following drugs: •Coumarin-type anticoagulants: possible potentiation of the anticoagulant





effects • 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 or 6-mercaptopurine, possible enhanced myelosuppressive effects of azathioprine or 6-mercaptopurine should be taken into account.

Page 7


Effects on laboratory tests Not known to interfere with laboratory tests or physical diagnostic agents. ADVERSE EFFECTS The most frequent adverse reactions seen in clinical trials are headache (3%), abdominal pain (4%), exacerbation of ulcerative colitis (2%), abnormal hepatic function (2%) and upper respiratory tract infection (1%). In two clinical trials involving 550 patients with acute ulcerative colitis, tolerability was good. The table below shows the adverse events that occurred in at least 5% of patients in the clinical trials:

Adverse event

SAG-2/UCA SAG-15/UCA Salofalk 0.5 g tds

(n = 102)

Salofalk 1 g tds

(n = 108)

Salofalk 1.5 g tds

(n = 108)


granules (n = 114)


tablets (n=118)

AE/ Potential

ADR

AE/ Potential

ADR

AE/ Potential

ADR

AE/ Potential

ADR

AE/ Potential

ADR Headache 24%/3% 23%/12% 21%/4% 6%/3% 7%/3% Abdominal pain 5%/1% 7%/4% 7%/4% - - Ulcerative colitis aggravated

15%/2% 6%/1% 7%/0 5%/1% 8%/1%

Hepatic function abnormal

1%/1% 3%/2% 5%/5% - -

Upper resp tract infection

3%/0 4%/1% 7%/1% - -

Influenza like symptoms

- - - 3%/0 6%/0

The following adverse events presented by body system have been reported in international post marketing surveillance of SALOFALK preparations including enemas and tablets. In many cases, the relationship to SALOFALK has not been established. The common: (≥1% - <10%) adverse events were as follows: Body as a whole – General Disorders Headache Gastrointestinal System Disorders Abdominal pain, diarrhoea, nausea and vomiting, flatulence, exacerbation of ulcerative colitis Skin and Appendages Disorder Rash including pruritus, urticaria

Page 8


The following additional adverse events were uncommon and reported by < 1% of patients: Body as a Whole – General Disorders Fever, allergic reaction Central and Peripheral Nervous Systems Disorders Dizziness, paraesthesia, peripheral neuropathy Collagen disorders Lupus erythematosus syndrome (as observed for preparations with a similar chemical structure) Gastrointestinal System Disorders Acute pancreatitis, pancolitis, neonate diarrhoea Liver and Biliary System Disorders Hepatitis, increased liver enzyme values (transaminase activity), intrahepatic cholestasis, increased bilirubin Musculo-skeletal System Disorders Arthralgia, myalgia, myositis Myo-, Endo-, Pericardial and Valve Disorders Pericarditis, myocarditis, pericardial effusion Platelet, Bleeding and Clotting Disorders Thrombocytopenia Red Blood Cell Disorders Aplastic anaemia, haemolytic anaemia Reproductive System Disorders Oligospermia (reversible) Respiratory System Disorders Bronchospasm, pleural effusion, alveolitis Skin and Appendages Disorders Alopecia, allergic exanthema, increased sweating Urinary System Disorders Acute or chronic interstitial nephritis, renal insufficiency, renal failure, nephrotoxicity White Cell and RES Disorders Agranulocytosis, leukopenia, neutropenia, pancytopenia DOSAGE AND ADMINISTRATION For adults and the elderly: Unless otherwise prescribed, the recommended dose for acute ulcerative colitis is 1.5 g to 3 g per day. For maintenance of remission and/or long term treatment of ulcerative colitis, the recommended dose is 1.5 g per day.

Page 9


For children older than 6 years of age: The recommended dose for acute ulcerative colitis, depending on disease severity, is 30-50 mg mesalazine/kg/day. For maintenance of remission and/or long term treatment of ulcerative colitis, the recommended dose is 15-30 mg mesalazine/kg/day. Doses may be given in one to three divided doses. It is generally recommended that half the adult dose may be given to patients up to a body weight of 40 kg; and the normal adult dose to those above 40 kg. SALOFALK should not be used in children below 6 years of age, as there is very limited experience with this age group. SALOFALK granules should be swallowed without chewing with sufficient fluid. If granules are taken together with meals the gastric passage might be delayed for 1-2 hours, but does not influence the release profile and plasma concentrations. SALOFALK should be used on a regular basis and consistently, in the treatment of acute inflammatory episode, in order to achieve the desired therapeutic effect. In general, an acute episode of ulcerative colitis usually subsides by 8 weeks. OVERDOSAGE No overdosage has been reported to date. Possible symptoms may include nausea, vomiting and diarrhoea, and symptoms similar to salicylate overdose. There is no specific antidote. General supportive and symptomatic measures are recommended. For advice on the management of overdosage, please contact the Poisons Information Centre (telephone 13 11 26). PRESENTATION SALOFALK granules are presented as greyish white cylindrical or round particles. They are available in aluminium sachets of 500 mg, 1 g or 1.5 g doses of mesalazine. 500 mg sachets are available in packs of 50*, 100, or 300* sachets. 1 g sachets are available in packs of 50*, 100, or 150* sachets. 1.5 g sachets are available in packs of 60 or 100* sachets. (*currently not available) STORAGE CONDITIONS Store below 25˚C.

Page 10


Page 11

NAME AND ADDRESS OF THE SPONSOR Orphan Australia Pty. Ltd. 300 Frankston-Dandenong road Dandenong Victoria 3175 Australia. Website: www.orphan.com.au POISON SCHEDULE OF THE MEDICINE S4 DATE OF APPROVAL This Product Information was approved by the TGA on: 6 May 2010 SALOFALK® is a registered trademark of Dr. Falk Pharma GmbH, Germany, used under licence by Orphan Australia Pty. Ltd.

Product Information SALOFALK® enemas

Page 1

PRODUCT INFORMATION SALOFALK® Enemas



CAS number- 89-57-6

DESCRIPTION Mesalazine is a white to greyish, voluminous powder, slightly pink in colour. It is practically insoluble in ethanol (90%), methanol (70%), water, ether, and chloroform, soluble in HCl (warmed 10% solution); soluble in NaOH (10% solution, with salt formation). SALOFALK enemas contain, mesalazine, carbomer 934, disodium edetate, potassium acetate, potassium metabisulfite, purified water, sodium benzoate and xanthan gum. The disposable unit consists of an applicator tip protected by a polyethylene cover and lubricated with white petrolatum. The unit has a one-way valve to prevent back flow of the dispensed product. PHARMACOLOGY Pharmacodynamic properties Mesalazine has been identified as the active component of sulfasalazine in inflammatory bowel disease and is thought to have a topical action. The mechanism of action by which mesalazine protects the mucosa in chronic inflammatory bowel disease is not yet fully known. Mesalazine seems to act in multiple ways against several inflammatory mediators and principles. The results of in vitro investigations indicate that inhibition of lipoxygenase may play a role. Effects on prostaglandin concentrations in the intestinal mucosa have also been demonstrated, as has an influence on leukotriene production. Mesalazine may also function as a radical scavenger of reactive oxygen compounds. Pharmacokinetic Properties General considerations: The efficacy of mesalazine (5-ASA) appears to be determined not by the systemic but the local availability of the substance at the target site. Metabolism of mesalazine occurs mainly in the intestinal mucosa and, to a lesser extent, in the liver. The main metabolite is N-acetyl-5-aminosalicylic acid, which is – like 5-ASA – predominantly eliminated by the renal and faecal routes. It appears to have no therapeutic activity or specific toxic effects. The acetylation step appears irreversible. As metabolism occurs mainly in the intestinal mucosa, it has not been possible to differentiate between a rapid and slow acetylation form as in the case of sulfasalazine/sulfapyridine. The plasma protein binding of mesalazine and acetylated mesalazine is 43% and 78%, respectively. Absorption of mesalazine decreases in the intestinal tract from proximal to distal. Because of low absorption rates from oral delayed release preparations or rectal applications forms, the


Page 2

main elimination route is via faeces. Absorbed mesalazine and N-acetyl-5-ASA are eliminated mainly via kidneys. Biliary excretion is a minor route of elimination. There is little pharmacokinetic data available for rectal administered mesalazine in children. There is no pharmacokinetic data in the elderly using SALOFALK enemas. SALOFALK enemas: 4g/60 mL enema in patients with ulcerative colitis in remission show a median Cmax value of 0.92 µg/mL for 5-ASA at tmax of 11 hours, and for N-acetyl-5-ASA a median Cmax of 1.62 µg/mL at a tmax of 12 hours. The median urinary recovery was 13% during 45 hours, indicating a low absorption. The administration of high doses of mesalazine enema (2xSALOFALK 4g/60 mL daily) in patients with severely active ulcerative colitis, instilled into the caecum, showed the following Cmax values in plasma for 5-ASA at tmax of 1.5 h and for N-acetyl-5-ASA at tmax of 2.8 h. Application Day 5-ASA [µg/mL] N-acetyl-5-ASA [µg/mL] 1 1.4 1.9 2 2.5 3.6 Total urinary recovery on day 1 was 10.5% and on day 3 (steady state) 18.6% with 22% of that being 5-ASA, demonstrating, like with the oral application of SALOFALK granules, a low absorption rate. The serum elimination half-life on day 1 was 4.2h, therefore comparable with that of the SALOFALK granules (4.4h). In children with ulcerative colitis, SALOFALK enemas showed the following steady state plasma concentrations: SALOFALK enema 5-ASA [µg/mL] Ac-5-ASA [µg/mL] 2g/30 mL 0.2 - 1.0 0.4 - 2.0 4g/60 mL 0.5 - 2.8 0.9 - 4.1 Scintigraphic evaluation of (99Tc) technecium-sulphur colloid-labelled SALOFALK 2g /30 mL and SALOFALK 4 g/60 mL enema showed the following distribution in patients with mild to moderate active ulcerative colitis at the beginning of therapy (time: 0 week) and at time of remission after 12 weeks of treatment (median and range):

Distribution Region SALOFALK 2g/30 mL SALOFALK 4g/60 mL 0 week

[% ] 12 week [% ]

0 week [% ]

12 week [% ]

Rectum 1 (0-76) 0 (0-21) 9 (0-77) 3 (0-51) Sigmoid 99 (13-100) 100 (51-100) 61 (23-100) 85 (47-100) Descending colon 0 (0-47) 0 (0-35) 13 (0-68) 0 (0-51) Transverse colon 0 (0-39) 0 (0-5) 0 (0-0) 0 (0-0) Ascending colon 0 (0-0) 0 (0-0) 0 (0-0) 0 (0-0)

CLINICAL TRIALS The criteria used to evaluate the efficacy of the substance in the therapy of ulcerative colitis are frequency of bowel movements, rectal haemorrhage, mucosal appearance on endoscopy, and severity of the disease as evaluated by a physician. These criteria have been summarised in the disease activity index (DAI) to evaluate the efficacy of treatment for ulcerative colitis. In a multi-centre, randomised, double-blind, placebo-controlled study involving 153 patients, the efficacy of SALOFALK 4g/60 mL enemas in the therapy of


Page 3

ulcerative colitis was significantly better than that of placebo at 6 weeks. The study showed an endoscopic improvement of 70% vs. 37% of placebo (p=0.001). It also showed a 63% improvement by the physician global assessment (PGA) in the mesalazine group vs. 29% in the placebo group (p<0.001) while evaluation by the DAI showed a 55% decline (7.42 to 3.37) in the 5-ASA group vs. 22% (7.7 to 5.83) in the placebo group (p=0.0001). All components of the DAI were significantly lower for the treatment group than the placebo group, see table below.

Primary Efficacy Criteria, 4g/60 mL Enema Vs Placebo Efficacy Parameter

Treatment group

Mean Observation Change from Baseline to Endpoint

Baseline Day 22 Day 43 Endpoint

Overall Disease Activity Index

5-ASA Placebo

7.42 7.70

4.05** 6.03

2.67*** 5.07

3.37*** 5.83

-55.07%+*** -21.53%

a) Stool Frequency Index

5-ASA Placebo

1.53 1.92

1.11* 1.47

0.94* 1.31

1.01** 1.50

-0.57 -0.41

b) Rectal Bleeding Index

5-ASA Placebo

1.82 1.73

0.59*** 1.21

0.34*** 0.87

0.51*** 1.11

-1.30*** -0.61

c) Mucosal Appearance Index

5-ASA Placebo

2.17 2.13

1.22** 1.74

0.79*** 1.44

0.96*** 1.61

-1.21*** -0.56

d) Physician Assessment of Disease Severity

5-ASA Placebo

1.86 1.87

1.13*** 1.62

0.70*** 1.39

0.88*** 1.55

-0.97*** -0.30

+ Percent change for overall DAI only * Significant 5-ASA / Placebo difference, p<0.05 ** Significant 5-ASA / Placebo difference, p<0.01 *** Significant 5-ASA / Placebo difference, p<0.001

On completing the above study, patients were randomised to receive once daily SALOFALK 4g/60 mL or 2g/60 mL. This open study, showed the DAI score decreased by 62-75 % after 6 months of therapy, and there was no significant difference in the degree of improvement between the groups. A dose-dependent relationship with mesalazine does not seem to be evident in the maintenance of remission. INDICATIONS SALOFALK enemas are indicated in the treatment of acute ulcerative colitis of mild to moderate severity and for the maintenance treatment of ulcerative colitis. CONTRAINDICATIONS SALOFALK enema is contraindicated in patients with the following:

• hypersensitivity to salicylic acid, salicylic acid derivatives, e.g. mesalazine/5-ASA, sulfites and benzoates or to any of the other ingredients

• severe impairment of hepatic and renal function

SALOFALK enemas should be used with caution in patients with bronchial asthma. They contain sulfite which may cause hypersensitivity reactions.


Page 4

PRECAUTIONS SALOFALK should be given/used under medical supervision. SALOFALK is not recommended in patients with impaired renal function. The blood and renal status should be determined prior to and during treatment, at the discretion of the treating physician. As a guideline, checks are recommended 14 days after commencement of treatment, then a further 2 to 3 times at 4-weekly intervals. If the findings are normal, follow-up tests should be conducted every three months or immediately if additional signs of the disorder occur. To check renal function, it is recommended that levels of serum urea (BUN) and creatinine be determined as well as urine sediment examined. Mesalazine-induced renal toxicity should be considered if renal function deteriorates during treatment. As mesalazine might cause blood dyscrasias, although rarely reported, and hepatic impairment due to hypersensitivity reactions, blood parameters, like blood counts and liver function and cholestasis parameters (e.g. ALT, AST, alkaline phosphatase, γGT) may be monitored like the renal parameters. Epigastric pain, also commonly associated with inflammatory bowel disease and prednisone or sulfasalazine therapy, should be investigated in order to exclude pericarditis, hepatitis and pancreatitis either as adverse drug reactions to 5-ASA or secondary manifestations of inflammatory bowel disease. SALOFALK should be used/given with caution in patients with pulmonary function impairment, particularly asthma and in patients with known hypersensitivity to sulfasalazine containing preparations. Treatment in the latter patients should be instituted with careful medical supervision. Treatment should be discontinued immediately if symptoms of acute intolerance, e.g. cramps, acute abdominal pain, fever, severe headache and skin rash, occur. SALOFALK is not expected to affect the ability of patients to drive or operate machinery. Effects on fertility Fertility and reproductive performance were not impaired in rats treated orally with mesalazine prior to and during mating (both sexes) and throughout gestation and lactation (females) at doses up to 320 mg/kg/day, which is less than the maximal recommended clinical dose of SALOFALK enemas on a body surface area basis. Use in pregnancy (Category C) There was no evidence of embryotoxicity or teratogenicity in rats and rabbits treated orally with mesalazine during the period of organogenesis at respective doses of up to 320 and 495 mg/kg/day, representing less than, and about twice, the maximal recommended clinical dose of SALOFALK enemas on a body surface area basis. Oral mesalazine does not show direct or indirect harmful effects with respect to parturition or postnatal development in animals. Human data on use during pregnancy are limited. No adverse effect of mesalazine on pregnancy or on the health of the foetus/newborn child was shown. To date no other relevant epidemiologic data are available. In one single case after oral use of 2-4 g mesalazine per day during the 3rd and 5th months of pregnancy, renal failure in a neonate was reported. SALOFALK enemas should only be used during pregnancy if the potential benefit outweighs the possible risk.


Page 5

Use in lactation In rats, there were no adverse effects on dams or offspring from oral administration of mesalazine during late gestation and throughout lactation at doses up to 320 mg/kg/day, which is less than the maximal recommended clinical dose of SALOFALK enemas on a body surface area basis. There has been a report of a patient receiving mesalazine suppositories during the lactation period. Twelve hours after the initial dose, the infant developed watery diarrhoea that disappeared on discontinuation of the mesalazine therapy but reappeared on rechallenge. There have been reports of mesalazine and of its metabolite N-acetyl-5-ASA found in breast milk. But, there is no experience with SALOFALK enemas in lactating women. SALOFALK enemas should not be used during lactation unless the likely benefit of treatment outweighs the potential hazard. Paediatric use SALOFALK enemas should not be used in children 12 years old and under, as there is little experience with this age group. Use in the elderly Specific clinical data in only elderly patients for mesalazine are not available, but have been used in patients up to 75 years of age in clinical trials. Carcinogenicity There was no evidence of carcinogenicity in rats treated with mesalazine in the diet for 127 weeks at doses up to 320 mg/kg/day, associated with plasma concentrations of mesalazine and N-acetyl-5-ASA of 1 and 6 fold the respective clinical plasma concentrations associated with a 1500 mg dose of the granules and the 4 g/60mL enema. Genotoxicity There was no evidence of genotoxic potential with mesalazine in bacterial gene mutation assays, of chromosomal damage in mouse haematopoietic cells following a single oral dose, or of increases in sister chromatid exchange frequencies in Chinese hamster bone marrow following a single intraperitoneal dose. There is growing information that 5-ASA/mesalazine protects patients with ulcerative colitis from colo-rectal cancer.


Page 6

Interactions with other medicines Studies to evaluate the potential interaction between SALOFALK and other drugs have not been performed. In common with other salicylates, interactions may occur during concomitant administration of mesalazine and the following drugs:

•Coumarin-type anticoagulants: possible potentiation of the anticoagulant effect action (increasing the risk of gastrointestinal haemorrhage)

• Glucocorticoids possible increase in undesirable gastric effects

• Sulphonylureas: possible increase in the blood glucose-lowering effects

• Methotrexate: possible increase in toxic potential of methotrexate

• Probenecid/sulphinpyrazone: possible attenuation of the uricosuric effects

• Spironolactone/frusemide: possible attenuation of the diuretic effects

• Rifampicin possible attenuation of the tuberculostatic effects

In patients who are concomitantly treated with azathioprine or 6-mercaptopurine, possible enhanced myelosuppressive effects of azathioprine or 6-mercaptopurine should be taken into account. Effects on laboratory tests Not known to interfere with laboratory tests or physical diagnostic agents. ADVERSE EFFECTS The most common adverse events seen in clinical study are headache, hair loss, abdominal pain, diarrhoea and rash. In a placebo controlled clinical trial involving 153 patients, adverse events occurred in 25% and 40% of patients in the mesalazine and placebo enema groups respectively. Events reported by at least 2 patients in this trial are shown in Table I below.


Page 7

Table I System/reaction Salofalk 4g/60mL enema (n=76) Placebo (n=77) Body as a whole-General Disorders Headache Cold Fatigue Hair loss

11.8% 1.3% 2.6% 2.6%

7.8% 9.1% 6.5% 0%

Gastrointestinal Nausea Bloating Constipation Diarrhoea Cramps

0% 2.6% 1.3% 2.6% 1.3%

6.5% 2.6% 2.6% 1.3% 3.9%

Skin and Appendages Disorder Rash

2.6%

5.2%

Cardiovascular Dizziness

0%

2.6%

Genitourinary Urinary tract infection

0%

2.6%

Psychiatric Insomnia

1.3%

2.6%

The following adverse events presented by body system have been reported in international post marketing surveillance of SALOFALK preparations including enemas and tablets. In many cases, the relationship to SALOFALK has not been established. The common: (≥1% - <10%) adverse events were as follows: Body as a whole – General Disorders Headache Gastrointestinal System Disorders Abdominal pain, diarrhoea, nausea and vomiting, flatulence, exacerbation of ulcerative colitis, Skin and Appendages Disorder Rash including pruritus, urticaria The following additional adverse events were uncommon and reported by < 1% of patients: Body as a Whole – General Disorders Fever, allergic reaction Central and Peripheral Nervous Systems Disorders Dizziness, paraesthesia, peripheral neuropathy Collagen disorders Lupus erythematosus syndrome (as observed for preparations with a similar chemical structure). Gastrointestinal System Disorders Acute pancreatitis, pancolitis, neonate diarrhoea Liver and Biliary System Disorders Hepatitis, increased liver enzyme values


Page 8

(transaminase activity), intrahepatic cholestasis, increased bilirubin Musculo-skeletal System Disorders Arthralgia, myalgia, myositis Myo-, Endo-, Pericardial and Valve Disorders Pericarditis, myocarditis, pericardial effusion Platelet, Bleeding and Clotting Disorders Thrombocytopenia Red Blood Cell Disorders Aplastic anaemia, haemolytic anaemia Reproductive System Disorders Oligospermia (reversible) Respiratory System Disorders Bronchospasm, pleural effusion, alveolitis (In isolated cases hypersensitivity reactions, principally in the form of respiratory problems, may be experienced by non-asthmatics due to the content of potassium bisulfite in enemas.) Skin and Appendages Disorders Alopecia, allergic exanthema, increased sweating Urinary System Disorders Acute or chronic interstitial nephritis, renal insufficiency, renal failure, nephrotoxicity White Cell and RES Disorders Agranulocytosis, leukopenia, neutropenia, pancytopenia DOSAGE AND ADMINISTRATION Unless otherwise advised a dose of 2g or 4g mesalazine as SALOFALK enema once a day is used for the treatment of acute ulcerative colitis or maintenance of remission. The content of one enema bottle (2 g/30 mL, 2 g/60 mL, or 4 g/60 mL) is instilled in the rectum once every evening prior to going to bed. The best results are achieved if the bowels are evacuated prior to instillation of SALOFALK enema. The action of SALOFALK is enhanced if the patient lies on the left side when introducing the enema. The dosage should be adjusted to suit the progress of the condition. Discontinuation of treatment should be under supervision of the physician. Due to the considerable variation in the severity of the ulcerative colitis and the extent of the affected area it is not possible to recommend a uniform dose of mesalazine which will provide optimal effects. In clinical trials, rectal doses of 2-4 g mesalazine/day as enemas have been used in the therapy of both acute ulcerative colitis and maintenance of remission. Use in Children SALOFALK enemas should not be used in children 12 years old and under, as there is little experience with this age group.


Page 9

OVERDOSAGE No overdosage has been reported to date. Possible symptoms may include nausea, vomiting and diarrhoea, and symptoms similar to salicylate overdose. There is no specific antidote. General supportive and symptomatic measures are recommended. For advice on the management of overdosage, please contact the Poisons Information Centre (telephone 13 11 26). PRESENTATION SALOFALK enemas, 2 g/30 mL, 2 g/ 60 mL and 4 g/60 mL, are presented as a very light tan to brown, homogeneous suspension. They are supplied in opaque low-density concertina shaped polyethylene squeeze bottles with a low-density polyethylene applicator nozzle in cardboard cartons. Each carton contains 7 enemas in individual blister packs. STORAGE CONDITIONS Store below 25˚C. Protect from light. NAME AND ADDRESS OF THE SPONSOR Orphan Australia Pty. Ltd. 300 Frankston-Dandenong Road Dandenong Victoria 3175 Australia. POISON SCHEDULE OF THE MEDICINE S4 DATE OF APPROVAL This Product Information was approved by the TGA on: 6 May 2010 SALOFALK® is a registered trademark of Dr. Falk Pharma GmbH, Germany, used under licence by Orphan Australia Pty. Ltd.

Product Information SALOFALK® foam enemas

PRODUCT INFORMATION

SALOFALK® foam enemas



CAS number- 89-57-6 DESCRIPTION Mesalazine is a white to greyish, voluminous powder, slightly pink in colour. It is practically insoluble in ethanol (90%), methanol (70%), water, ether, and chloroform, soluble in HCl (warmed 10% solution); soluble in NaOH (10% solution, with salt formation). SALOFALK foam enemas contain, mesalazine, sodium metabisulfite, polysorbate 60, cetostearyl alcohol, disodium edetate, propylene glycol, propane, n-butane and isobutane. PHARMACOLOGY Pharmacodynamic properties Mesalazine has been identified as the active component of sulfasalazine in inflammatory bowel disease and is thought to have a topical action. The mechanism of action by which mesalazine protects the mucosa in chronic inflammatory bowel disease is not yet fully known. Mesalazine seems to act in multiple ways against several inflammatory mediators and principles. The results of in vitro investigations indicate that inhibition of lipoxygenase may play a role. Effects on prostaglandin concentrations in the intestinal mucosa have also been demonstrated, as has an influence on leukotriene production. Mesalazine may also function as a radical scavenger of reactive oxygen compounds. Pharmacokinetic Properties General considerations: The efficacy of mesalazine (5-ASA) appears to be determined not by the systemic but the local availability of the substance at the target site. Metabolism of mesalazine occurs mainly in the intestinal mucosa and, to a lesser extent, in the liver. The main metabolite is N-acetyl-5-aminosalicylic acid, which is – like 5-ASA – predominantly eliminated by the renal and faecal routes. It appears to

Page 1


have no therapeutic activity or specific toxic effects. The acetylation step appears irreversible. As metabolism occurs mainly in the intestinal mucosa, it has not been possible to differentiate between a rapid and slow acetylation form as in the case of sulfasalazine/sulfapyridine. The plasma protein binding of mesalazine and acetylated mesalazine is 43% and 78%, respectively. Absorption of mesalazine decreases in the intestinal tract from proximal to distal. Because of low absorption rates from oral delayed release preparations or rectal applications forms, the main elimination route is via faeces. Absorbed mesalazine and N-acetyl-5-ASA are eliminated mainly via kidneys. Biliary excretion is a minor route of elimination. In an open, randomised, cross-over study, healthy volunteers were given 7 doses of SALOFALK foam enema each dose consisting of 2 applicatorfuls equivalent to 2g mesalazine per day. The Cmax values after the first and last dose (steady state, 7 doses) are 985.1 ng/mL at tmax of 2.3 h and 774.9 ng/mL at tmax of 2.4 h, respectively. A summary of the pharmacokinetic data is presented below:

Pharmacokinetic parameters in healthy subjects

Salofalk foam enema (single dose of 2 applicatorfuls per day) Mesalazine Mean [SD]

N-Acetyl-5-ASA Mean [SD]

After Dose 1 Cmax [ng/mL] 985.1 [682.4] 1216.1 [649.1]

tmax [hr] 2.3 [1.3] 2.9 [1.0]

t1/2 [hr] 2.4 [2.0] 4.3 [3.2]

AUC(0-∞) [hr*ng/mL] 3794.3 [2568.2] 8462.1 [6025.8]

Ae0-48h [mg] 2.1 [1.8] 136.7 [121.0] After Dose 7

(Steady State) Cmax [ng/mL] 774.9 [434.5] 955.0 [365.4]

tmax [hr] 2.4 [1.1] 3.1 [1.7]

t1/2 [hr] 5.5 [4.8] 3.6 [1.9]

AUC(0-∞) [hr*ng/mL] 3541.0 [2730.4] 6738.3 [3938.0]

Ae0-48h [mg] 4.7 [6.5] 138.8 [111.2] In an open, non-randomised, single dose study, patients with active ulcerative proctitis or proctosigmoiditis were administered a single dose of foam enema consisting of 2 applicatorfuls, equivalent to 2 g mesalazine. Results showed a Cmax value of 1661.3 ng/mL for 5-ASA at tmax of 1.3 hour, and for N-acetyl-5-ASA a median Cmax of 1579.3 ng/mL at a tmax of 2.4 hours. The urinary recovery of 5-ASA + N-acetyl-5-ASA within 48 hours after single dose application of 2g mesalazine was 5.5%. Pharmacokinetic data for SALOFALK foam enema in patients with active ulcerative proctitis or protosigmoiditis are summarised in the following table:

Page 2


Pharmacokinetic parameters in patients

Salofalk foam enema (single dose of 2 applicatorfuls)

Mesalazine Mean [SD]

N-Acetyl-5-ASA Mean [SD]

Cmax [ng/mL] 1661.3 [1238.4] 1579.3 [948.3]

tmax [hr] 1.3 [1.0] 2.4 [0.9]

t1/2 [hr] 1.6 [1.1] 2.6 [1.6]

AUC(0-∞) [hr*ng/mL] 5285.1 [3325.9] 7967.0 [4412.4]

Ae0-48h [µMol] 79.3 [105.2] 812.3 [465.6] There is little pharmacokinetic data available for rectal administered mesalazine in children. There is no pharmacokinetic data in the elderly using SALOFALK foam enemas. Scintigraphic evaluation of samarium(153Sm) labelled SALOFALK foam versus SALOFALK enema showed that there is no significant difference in the rectal spread and intestinal distribution between the two dosage forms. The tables below show the rectal and intestinal distribution of SALOFALK foam enema versus SALOFALK enema in patients with left-sided ulcerative colitis and healthy subjects. The rectal and intestinal distribution of SALOFALK foam enema and SALOFALK enema in healthy subjects: Distribution Region Salofalk foam enema

2g dose Salofalk enema

2g/60 mL 5 min

[% of total dose]

12 hours [% of total

dose]

5 min [% of total

dose]


dose] Ascending colon 0 0 0 0 Transverse colon 0 0 0 0 Descending colon 0 7.00 0 8.50 Sigmoid 28.50 28.50 18.17 29.83 Rectum 46.25 39.50 81.83 28.33

Page 3


The rectal and intestinal distribution of SALOFALK foam enema and SALOFALK enema in patients with left-sided ulcerative colitis: Distribution Region Salofalk foam enema

2g dose Salofalk enema

2g/60 mL 5 min

[% of total dose]


dose]

5 min [% of total

dose]


dose] Ascending colon 0 0 0 0 Transverse colon 0 0 0 0 Descending colon 0 5.00 0 5.17 Sigmoid 33.60 22.20 30.00 11.67 Rectum 66.40 52.80 70.00 66.50

CLINICAL TRIALS The criteria used to evaluate the efficacy of the substance in the therapy of ulcerative colitis are frequency of bowel movements, rectal haemorrhage, abdominal pain, general well being, temperature, extra intestinal manifestations, ESR, and haemoglobin. These criteria have been summarised in the clinical activity index (CAI) to evaluate the efficacy of treatment for ulcerative colitis. In a multi-centre, randomised, double blind, placebo-controlled study (SAF-4/UCA) involving 111 patients, the efficacy of SALOFALK 2g/60 mL foam in the therapy of ulcerative colitis was significantly better than that of placebo at 6 weeks. The response rate was 64.8% vs. 40.4% placebo (p=0.0082). The study showed an endoscopic improvement of 70.4 vs. 45.6 % in the placebo group. Results of the studies and post marketing reports show that SALOFALK foam is well tolerated in patients with ulcerative colitis. INDICATIONS SALOFALK foam enemas are indicated in the treatment of acute ulcerative colitis of mild to moderate severity and for the maintenance treatment of ulcerative colitis. CONTRAINDICATIONS SALOFALK foam enemas are contraindicated in patients with the following: • hypersensitivity to salicylic acid, salicylic acid derivatives, e.g. mesalazine/5-

ASA and sulfites or to any of the other ingredients • severe impairment of hepatic and renal function SALOFALK foam enemas should be used with caution in patients with bronchial asthma. They contain sulfite which may cause hypersensitivity reactions.

Page 4


PRECAUTIONS SALOFALK should be given/used under medical supervision. SALOFALK is not recommended in patients with impaired renal function. The blood and renal status should be determined prior to and during treatment, at the discretion of the treating physician. As a guideline, checks are recommended 14 days after commencement of treatment, then a further 2 to 3 times at 4-weekly intervals. If the findings are normal, follow-up tests should be conducted every three months or immediately if additional signs of the disorder occur. To check renal function, it is recommended that levels of serum urea (BUN) and creatinine be determined as well as urine sediment examined. Mesalazine-induced renal toxicity should be considered if renal function deteriorates during treatment. As mesalazine might cause blood dyscrasias, although rarely reported, and hepatic impairment due to hypersensitivity reactions, blood parameters, like blood counts and liver function and cholestasis parameters (e.g. ALT, AST, alkaline phosphatase, γGT) may be monitored like the renal parameters. Epigastric pain, also commonly associated with inflammatory bowel disease and prednisone or sulfasalazine therapy, should be investigated in order to exclude pericarditis, hepatitis and pancreatitis either as adverse drug reactions to 5-ASA or secondary manifestations of inflammatory bowel disease. SALOFALK should be used/given with caution in patients with pulmonary function impairment, particularly asthma and in patients with known hypersensitivity to sulfasalazine containing preparations. Treatment in the latter patients should be instituted with careful medical supervision. Treatment should be discontinued immediately if symptoms of acute intolerance, e.g. cramps, acute abdominal pain, fever, severe headache and skin rash, occur. This medicine contains propylene glycol that may cause lactic acidosis, hyperosmolality, haemolysis and CNS depression. Care should be taken when administering SALOFALK foam to patients with diminished renal function. Slight to mild skin irritation due to propylene glycol may occur. SALOFALK foam enema is generally not expected to affect the ability of patients to drive or operate machinery. However, as Salofalk may cause dizziness, patients should be cautioned about their ability to drive a car and operate machinery. Effects on fertility Fertility and reproductive performance were not impaired in rats treated orally with mesalazine prior to and during mating (both sexes) and throughout gestation and lactation (females) at doses up to 320 mg/kg/day, which is less than the maximal recommended clinical dose of SALOFALK enemas on a body surface area basis. Use in pregnancy (Category C) There was no evidence of embryotoxicity or teratogenicity in rats and rabbits treated orally with mesalazine during the period of organogenesis at respective doses of up to 320 and 495 mg/kg/day, representing less than, and about twice, the maximal recommended clinical dose of SALOFALK enemas on a body surface area basis. Oral mesalazine does not show direct or indirect harmful effects with respect to parturition or postnatal development in animals. Human data on use during pregnancy are limited. No adverse effect of mesalazine on pregnancy or on the health of the foetus/newborn child was shown. To date no Page 5


other relevant epidemiologic data are available. In one single case after oral use of 2-4 g mesalazine per day during the 3rd and 5th months of pregnancy, renal failure in the neonate was reported. SALOFALK enemas should only be used during pregnancy if the potential benefit outweighs the possible risk. Use in lactation In rats, there were no adverse effects on dams or offspring from oral administration of mesalazine during late gestation and throughout lactation at doses up to 320 mg/kg/day, which is less than the maximal recommended clinical dose of SALOFALK foam enemas on a body surface area basis. There has been a report of a patient receiving mesalazine suppositories during the lactation period. Twelve hours after the initial dose, the infant developed watery diarrhoea that disappeared on discontinuation of the mesalazine therapy but reappeared on rechallenge. There have been reports of mesalazine and of its metabolite N-acetyl-5-ASA found in breast milk. But, there is no experience with SALOFALK foam enemas in lactating women. SALOFALK should not be used during lactation unless the likely benefit of treatment outweighs the potential hazard. Paediatric use SALOFALK foam enemas should not be used in children 12 years old and under, as there is little experience with this age group. Use in the elderly Specific clinical data in only elderly patients for mesalazine are not available, but have been used in patients up to 75 years of age in clinical trials. Carcinogenicity There was no evidence of carcinogenicity in rats treated with mesalazine in the diet for 127 weeks at doses up to 320 mg/kg/day, associated with plasma concentrations of mesalazine and N-acetyl-5-ASA of 1 and 6 fold the respective clinical plasma concentrations associated with a 1500 mg dose of the granules and the 4 g/60mL enema. Genotoxicity There was no evidence of genotoxic potential with mesalazine in bacterial gene mutation assays, of chromosomal damage in mouse haematopoietic cells following a single oral dose, or of increases in sister chromatid exchange frequencies in Chinese hamster bone marrow following a single intraperitoneal dose.

Page 6


Interactions with other medicines Studies to evaluate the potential interaction between SALOFALK and other drugs have not been performed. In common with other salicylates, interactions may occur during concomitant administration of mesalazine and the following drugs: •Coumarin-type anticoagulants: possible potentiation of the anticoagulant


• Glucocorticoids: possible increase in undesirable gastric effects • Sulphonylureas: possible increase in the blood glucose-lowering


methotrexate • Probenecid/sulphinpyrazone: possible attenuation of the uricosuric effects • Spironolactone/frusemide: possible attenuation of the diuretic effects • Rifampicin: possible attenuation of the tuberculostatic

effects In patients who are concomitantly treated with azathioprine or 6-mercaptopurine, possible enhanced myelosuppressive effects of azathioprine or 6-mercaptopurine should be taken into account. Effects on laboratory tests Not known to interfere with laboratory tests or physical diagnostic agents. ADVERSE EFFECTS The most common adverse events seen in clinical study are headache, hair loss, abdominal pain, diarrhoea and rash. In a placebo controlled clinical trial involving 111 patients, the rate of patients reporting at least 1 adverse event is 29.6% and 42.1% in the mesalazine and placebo foam enema groups respectively. The absolute and relative frequencies of patients with adverse events by Body System are shown in Table I below.

Page 7


Table I System/reaction Salofalk 2g/ day

foam enema (n=54)

Placebo (n=57)

Gastrointestinal system 6 (1.1%) 14 (24.6%)

Respiratory system 4 (7.4%) 5 (8.8%)

Body as a whole-General disorders 3 (5.6%) 6 (10.5%)

Central and peripheral nervous system 5 (9.3%) 4 (7.0%)

Haematologic/Lymphatic system 2 (3.7%) 8 (14.0 %)

Reproductive, female 1 (1.9%) 1 (1.8%)

Metabolic and nutritional - 2 (3.5%)

Skin and appendages - 1 (1.8%)

Musculo-skeletal system - 1 (1.8%)

Application site disorders - 1 (1.8%)

The following adverse events presented by body system have been reported in international post marketing surveillance of SALOFALK preparations including enemas and tablets. In many cases, the relationship to SALOFALK has not been established. The common: (≥1% - <10%) adverse events were as follows: Body as a whole – General Disorders Headache Gastrointestinal System Disorders Abdominal pain, diarrhoea, nausea and vomiting, flatulence, exacerbation of ulcerative colitis Skin and Appendages Disorder Rash including pruritus, urticaria The following additional adverse reactions were uncommon and reported by < 1% of patients: Body as a Whole – General Disorders Fever, allergic reaction, Central and Peripheral Nervous Systems Disorders Dizziness, paraesthesia, peripheral neuropathy Collagen disorders Lupus erythematosus syndrome (as observed for preparations with a similar chemical structure).

Page 8


Gastrointestinal System Disorders Acute pancreatitis, pancolitis, neonate diarrhoea Liver and Biliary System Disorders Hepatitis, increased liver enzyme values (transaminase activity), intrahepatic cholestasis, increased bilirubin Musculo-skeletal System Disorders Arthralgia, myalgia, myositis Myo-, Endo-, Pericardial and Valve Disorders Pericarditis, myocarditis, pericardial effusion Platelet, Bleeding and Clotting Disorders Thrombocytopenia Red Blood Cell Disorders aplastic anaemia, haemolytic anaemia Reproductive System Disorders Oligospermia (reversible) Respiratory System Disorders Bronchospasm, pleural effusion, alveolitis (In isolated cases hypersensitivity reactions, principally in the form of respiratory problems, may be experienced by non-asthmatics due to the content of sodium metabisulfite in enemas.) Skin and Appendages Disorders Alopecia, allergic exanthema, increased sweating Urinary System Disorders Acute or chronic interstitial nephritis, renal insufficiency, renal failure, nephrotoxicity White Cell and RES Disorders Agranulocytosis, leukopenia, neutropenia, pancytopenia DOSAGE AND ADMINISTRATION Unless otherwise advised a dose of 2g or 4g mesalazine as SALOFALK foam enema once a day is used for the treatment of acute ulcerative colitis or maintenance of remission. A dose of 2g SALOFALK foam is equivalent to 2 applications. The canister is first fitted with an applicator and then shaken for about 15 seconds before the applicator is inserted into the rectum as far as comfortable. To administer a dose of SALOFALK foam, the pump dome is fully pushed down and released. Note the spray can will only work properly when held with the pump dome pointing down. Following the second activation, the applicator should be held in position for 10-15 seconds before being withdrawn from the rectum. The best results are achieved if the bowels are evacuated prior to instillation of SALOFALK foam enema. The dosage should be adjusted to suit the progress of the condition. Discontinuation of treatment should be under supervision of the physician. Due to the considerable variation in the severity of the ulcerative colitis and the extent of the affected area it is not possible to recommend a uniform dose of

Page 9


mesalazine which will provide optimal effects. In clinical trials, rectal doses of 2-4 g mesalazine/day as enemas have been used in the therapy of both acute ulcerative colitis and maintenance of remission. Use in Children SALOFALK foam enemas should not be used in children 12 years old and under, as there is little experience with this age group. OVERDOSAGE No overdosage has been reported to date. Possible symptoms may include nausea, vomiting and diarrhoea, and symptoms similar to salicylate overdose. There is no specific antidote. General supportive and symptomatic measures are recommended. For advice on the management of overdosage, please contact the Poisons Information Centre (telephone 13 11 26). PRESENTATION SALOFALK foam enemas are available in an aluminium pressurised container with a metering valve containing 80 g of foam and 7disposable applicators for the administration of the foam. The disposable unit consists of an applicator tip protected by a polyethylene cover and lubricated with white petrolatum. The unit has a one-way valve to prevent back flow of the dispensed product. Each can contains sufficient foam for 14 applications (equivalent to 7 doses of 2g mesalazine). SALOFALK foam is presented as a white greyish to slightly reddish violet, creamy firm foam. STORAGE CONDITIONS Store below 25˚C. Do not refrigerate or freeze. This is a pressurised container, containing 3.75% by mass of flammable propellant. It should be kept away from any flames or sparks, including cigarettes. It should be protected from direct sunlight and must not be pierced or burnt even when empty. Do not refrigerate or freeze. Actuated containers should be used up within 12 weeks. NAME AND ADDRESS OF THE SPONSOR Orphan Australia Pty. Ltd. 300 Frankston-Dandenong Road Dandenong Victoria 3175 Australia. POISON SCHEDULE OF THE MEDICINE S4

Page 10


Page 11

DATE OF APPROVAL This Product Information was approved by the TGA on: 6 May 2010 SALOFALK® is a registered trademark of Dr. Falk Pharma GmbH, Germany, used under licence by Orphan Australia Pty. Ltd.

Product Information Salofalk® Suppositories

PRODUCT INFORMATION

SALOFALK® Suppositories



CAS number- 89-57-6 DESCRIPTION Mesalazine is a white to greyish, voluminous powder, slightly pink in colour. It is practically insoluble in ethanol (90%), methanol (70%), water, ether, and chloroform, soluble in HCl (warmed 10% solution); soluble in NaOH (10% solution, with salt formation). SALOFALK suppositories contain mesalazine and hard fat. PHARMACOLOGY Pharmacodynamic properties Mesalazine has been identified as the active component of sulfasalazine in inflammatory bowel disease and is thought to have a topical action. The mechanism of action by which mesalazine protects the mucosa in chronic inflammatory bowel disease is not yet fully known. Mesalazine seems to act in multiple ways against several inflammatory mediators and principles. The results of in vitro investigations indicate that inhibition of lipoxygenase may play a role. Effects on prostaglandin concentrations in the intestinal mucosa have also been demonstrated, as has an influence on leukotriene production. Mesalazine may also function as a radical scavenger of reactive oxygen compounds. Pharmacokinetic Properties General considerations: The efficacy of mesalazine (5-ASA) appears to be determined not by the systemic but the local availability of the substance at the target site. Metabolism of mesalazine occurs mainly in the intestinal mucosa and, to a lesser extent, in the liver. The main metabolite is N-acetyl-5-aminosalicylic acid, which is – like 5-ASA – predominantly eliminated by the renal and faecal routes. It appears to have no therapeutic activity or specific toxic effects. The acetylation step appears

Page 1


irreversible. As metabolism occurs mainly in the intestinal mucosa, it has not been possible to differentiate between a rapid and slow acetylation form as in the case of sulfasalazine/sulfapyridine. The plasma protein binding of mesalazine and acetylated mesalazine is 43% and 78%, respectively. Absorption of mesalazine decreases in the intestinal tract from proximal to distal. Because of low absorption rates from oral delayed release preparations or rectal applications forms, the main elimination route is via faeces. Absorbed mesalazine and N-acetyl-5-ASA are eliminated mainly via kidneys. Biliary excretion is a minor route of elimination. There is little pharmacokinetic data available for rectal administered mesalazine in children. There is no pharmacokinetic data in the elderly using SALOFALK suppositories. SALOFALK suppositories The mean peak plasma concentrations of mesalazine after a single rectal dose of 1 g mesalazine (SALOFALK 1 g suppository) were 192 ± 125 ng/mL (range 19 – 557 ng/mL), those of the main metabolite N-Acetyl-5-ASA were 402 ± 211 ng/mL (range 57 – 1070 ng/mL). Time to reach the peak plasma concentration of mesalazine was 7.1 ± 4.9 hr (range 0.3 – 24 hr). The plasma levels following rectal administration are lower than those following oral administration. Pharmacokinetic data are summarised in the following table for SALOFALK 1 g suppositories once daily in 48 healthy subjects:

Pharmacokinetic Parameters

Salofalk 1 g suppositories Mesalazine Mean* [SD]

N-Acetyl-5-ASA Mean* [SD]

Cmax [ng/mL] 192.36 [125.33] 401.58 [210.81]

tmax [hr] 7.06 [4.86] 8.81 [5.64]

t1/2 [hr] 8.27 [9.86] 10.80 [13.19]

AUC(0-24) [hr*ng/mL] 1933.71 [1765.42] 4893.33 [3767.03]

Ae0-24h [mg] 1.20 [1.07] 94.00 [69.21]

Ae0-48h [mg] 1.43 [1.27] 111.32 [83.82] * Arithmetic means After a single rectal dose of 1 g mesalazine (SALOFALK 1 g suppository) approximately 14% (sum of mesalazine and its metabolite N-acetyl-5-ASA) of the administered mesalazine dose was recovered in the urine during 48 hours. Scintigraphic studies of technetium-labelled mesalazine 500 mg suppositories showed peak spread of the suppository that had melted due to body temperature occurred after 2-3 hours. The spread was limited primarily to the rectum and rectosigmoid junction.

Page 2


CLINICAL TRIALS The criteria used to evaluate the efficacy of the substance in the therapy of ulcerative colitis are frequency of bowel movements, rectal haemorrhage, abdominal pain, general well-being, temperature, extraintestinal manifestations, erythrocyte sedimentation rate (ESR), and haemoglobin. These criteria have been summarised in the clinical activity index (CAI) to evaluate the efficacy of treatment for ulcerative colitis. In a multi-centre, randomised, investigator blinded study (SAS-6/UCA) involving 403 patients over 6 weeks, the efficacy and safety of SALOFALK 1 g suppository once daily at bedtime in the therapy of acute ulcerative proctitis was demonstrated to be therapeutically equivalent to that of SALOFALK 500 mg suppository three times daily. The primary efficacy variable was clinical remission, defined as Disease Activity Index (DAI) < 4 at the final visit. DAI is defined as the sum of the scores of four parameters: weekly stool frequency, weekly rectal bleeding, mucosal appearance and physician’s rating of disease activity.

Clinical remission results

Number (%) of patients with clinical remission at the final/withdrawal

examination

Difference between proportions a

[95% CI]

Shifted asymptotic χ2 test for com-

paring two rates b

Salofalk 1 g Suppository OD

Salofalk 0.5 g Suppository TID

Analysis PP 160/182 (87.9%) 156/172 (90.7%) –2.8% [–9.2%, 3.6%] 3.463 c ITT 168/200 (84.0%) 172/203 (84.7%) –0.7% [–7.8%, 6.4%] 3.790 c

OD, once daily; TID, three times daily a Difference between proportions [Salofalk 1 g suppository OD – Salofalk 500 mg suppository TID];

asymptotic confidence interval (CI). b ‘Effect’ = difference between proportions [Salofalk 1 g suppository OD – Salofalk 500 mg suppository

TID] + 0.15). c Inverse normal.

Overview of number (%) of patients in PP population with a change in DAI, CAI, and EI from baseline to last observation carried forward (LOCF)

DAI 1 a CAI EI b

Change

Salofalk 1 g Suppository

Salofalk 0.5 g

Suppository Salofalk 1 g Suppository

Salofalk 0.5 g

Suppository

Salofalk 1 g Suppository

Salofalk 0.5 g

Suppository OD

n = 182 TID

n = 172 OD

n = 182 TID

n = 172 OD

n = 176 TID

n = 164 Remission 160 (87.9%) 156 (90.7%) 160 (87.9%) 159 (92.4%) 149 (84.7%) 147 (89.6%)Improvement 17 (9.3%) 12 (7.0%) 172 (94.5%) 161 (93.6%) 19 (10.8%) 10 (6.1%)

OD, once daily; TID, three times daily; DAI, disease activity index; CAI, clinical activity index; EI, endoscopic index a Patients with (DAI) > 3 at baseline. b Patients with EI ≥ 4 at baseline. DAI=Remission: (DAI) < 4 at LOCF CAI=Remission: CAI ≤ 4 at LOCF (= clinical remission). EI=Remission: EI < 4 at final examination.

Page 3


Results of the studies show that SALOFALK suppositories are well tolerated in patients with ulcerative proctitis. INDICATIONS SALOFALK suppositories are indicated in the treatment of ulcerative proctitis. CONTRAINDICATIONS SALOFALK suppositories are contraindicated in patients with the following:

• hypersensitivity to salicylic acid, salicylic acid derivatives, e.g. mesalazine/5-ASA

• hypersensitivity to any other ingredients in SALOFALK suppository • severe impairment of hepatic and renal function

PRECAUTIONS SALOFALK should be given/used under medical supervision. SALOFALK is not recommended in patients with impaired renal function. The blood and renal status should be determined prior to and during treatment, at the discretion of the treating physician. As a guideline, checks are recommended 14 days after commencement of treatment, then a further 2 to 3 times at 4-weekly intervals. If the findings are normal, follow-up tests should be conducted every three months or immediately if additional signs of the disorder occur. To check renal function, it is recommended that levels of serum urea (BUN) and creatinine be determined as well as urine sediment examined. Mesalazine-induced renal toxicity should be considered if renal function deteriorates during treatment. As mesalazine might cause blood dyscrasias, although rarely reported, and hepatic impairment due to hypersensitivity reactions, blood parameters, like blood counts and liver function and cholestasis parameters (e.g. ALT, AST, alkaline phosphatase, γGT) may be monitored like the renal parameters. Epigastric pain, also commonly associated with inflammatory bowel disease and prednisone or sulfasalazine therapy, should be investigated in order to exclude pericarditis, hepatitis and pancreatitis either as adverse drug reactions to 5-ASA or secondary manifestations of inflammatory bowel disease. SALOFALK should be used/given with caution in patients with pulmonary function impairment, particularly asthma and in patients with known hypersensitivity to sulfasalazine containing preparations. Treatment in the latter patients should be instituted with careful medical supervision. Treatment should be discontinued immediately if symptoms of acute intolerance, e.g. cramps, acute abdominal pain, fever, severe headache and skin rash, occur. SALOFALK suppositories are generally not expected to affect the ability of patients to drive or operate machinery. Effects on fertility Fertility and reproductive performance were not impaired in rats treated orally with mesalazine prior to and during mating (both sexes) and throughout gestation and lactation (females) at doses up to 320 mg/kg/day. This dose is less than the maximal Page 4


recommended clinical dose of SALOFALK tablets, and about the same as the maximal recommended clinical dose of SALOFLK granules, on a body surface area basis. Use in pregnancy (Category C) There was no evidence of embryotoxicity or teratogenicity in rats and rabbits treated orally with mesalazine during the period of organogenesis at respective doses of up to 320 and 495 mg/kg/day. On a body surface area basis, these doses are about 0.5-2.5 times the maximal recommended clinical dose of SALOFALK tablets, and about 1.0-3.5 times the maximal recommended clinical dose of SALOFALK granules. Oral mesalazine does not indicate direct or indirect harmful effects with respect to parturition or postnatal development in animals. Human data on use during pregnancy are limited. No adverse effect of mesalazine on pregnancy or on the health of the foetus/newborn child was shown. To date no other relevant epidemiologic data are available. In one single case after oral use of 2-4 g mesalazine per day during the 3rd and 5th months of pregnancy, renal failure in the neonate was reported. SALOFALK suppositories should only be used during pregnancy if the potential benefit outweighs the possible risk. Use in lactation In rats, there were no adverse effects on dams or offspring from oral administration of mesalazine during late gestation and throughout lactation at doses up to 320 mg/kg/day. This dose is less than the maximal recommended clinical dose of SALOFALK tablets, and about the same as the maximal recommended clinical dose of SALOFALK granules, on a body surface area basis. There has been a report of a patient receiving mesalazine suppositories during the lactation period. Twelve hours after the initial dose, the infant developed watery diarrhoea that disappeared on discontinuation of the mesalazine therapy but reappeared on rechallenge. There have been reports of mesalazine and of its metabolite N-acetyl-5-ASA found in breast milk. But, there is no experience with SALOFALK suppositories in lactating women. SALOFALK should not be used during lactation unless the likely benefit of treatment outweighs the potential hazard. Paediatric use SALOFALK 1 g suppositories should not be used in children 12 years old and under, as there is little experience with this age group. Use in the elderly Specific clinical data in only elderly patients for mesalazine are not available, but have been used in patients up to 75 years of age in clinical trials. Carcinogenicity There was no evidence of carcinogenicity in rats treated with mesalazine in the diet for 127 weeks at doses up to 320 mg/kg/day, associated with plasma concentrations of mesalazine and N-acetyl-5-ASA of at least 15 fold the respective clinical plasma Cmax concentrations associated with a 1 g dose of SALOFALK suppository.

Page 5


Genotoxicity There was no evidence of genotoxic potential with mesalazine in bacterial gene mutation assays, of chromosomal damage in mouse haematopoietic cells following a single oral dose, or of increases in sister chromatid exchange frequencies in Chinese hamster bone marrow following a single intraperitoneal dose. Interactions with other drugs Studies to evaluate the potential interaction between SALOFALK and other drugs have not been performed. In common with other salicylates, interactions may occur during concomitant administration of mesalazine and the following drugs: •Coumarin-type anticoagulants: possible potentiation of the anticoagulant





effects In patients who are concomitantly treated with azathioprine or 6-mercaptopurine, possible enhanced myelosuppressive effects of azathioprine or 6-mercaptopurine should be taken into account. Effects on laboratory tests Not known to interfere with laboratory tests or physical diagnostic agents. ADVERSE EFFECTS In a multi-centre, randomised, investigator blinded study (SAS-6/UCA) involving 403 patients with active ulcerative proctitis, the rate of patients reporting at least 1 adverse event is 2.5% and 3.4% in the 1 g and 500 mg suppository groups respectively. The adverse events reported are shown in Table I below.

Page 6


Table I

Adverse Event Salofalk 1 g

suppositories (n=200)

Salofalk 500 mg suppositories

(n=203) Constipation 2 (1.0%) 1 (0.5%)

Lipase increased 1 (0.5%) 1 (0.5%)

Platelet count decreased 1 (0.5%) 1 (0.5%)

Pruritus - 2 (1.0%)

Abdominal pain 1 (0.5%) -

Anal discomfort - 1 (0.5%)

Back pain - 1 (0.5%)

Defaecation urgency - 1 (0.5%)

Flatulence - 1 (0.5%)

Nausea 1 (0.5%) - The following adverse events presented by body system have been reported in international post marketing surveillance of all SALOFALK preparations. In many cases, the relationship to SALOFALK has not been established. The common: (≥1% - <10%) adverse events were as follows: Body as a whole – General Disorders Headache Gastrointestinal Abdominal pain, diarrhoea, nausea and vomiting, flatulence, exacerbation of ulcerative colitis Skin and Appendages Disorder Rash including pruritus, urticaria The following additional adverse reactions were uncommon and reported by < 1% of patients: Body as a Whole – General Disorders Fever, allergic reaction Central and Peripheral Nervous Systems Disorders Dizziness, paraesthesia, peripheral neuropathy Collagen disorders Lupus erythematosus syndrome (as observed for preparations with a similar chemical structure).

Page 7


Gastrointestinal System Disorders Acute pancreatitis, pancolitis, neonate diarrhoea Liver and Biliary System Disorders Hepatitis, increased liver enzyme values (transaminase activity), intrahepatic cholestasis, increased bilirubin Musculo-skeletal System Disorders Arthralgia, myalgia, myositis Myo-, Endo-, Pericardial and Valve Disorders Pericarditis, myocarditis, pericardial effusion Platelet, Bleeding and Clotting Disorders Thrombocytopenia Red Blood Cell Disorders Aplastic anaemia, haemolytic anaemia Reproductive System Disorders Oligospermia (reversible) Respiratory System Disorders Bronchospasm, pleural effusion, alveolitis (In isolated cases hypersensitivity reactions, principally in the form of respiratory problems, may be experienced by non-asthmatics due to the content of sodium metabisulfite in enemas.) Skin and Appendages Disorders Alopecia, allergic exanthema, increased sweating Urinary System Disorders Acute or chronic interstitial nephritis, renal insufficiency, renal failure, nephrotoxicity White Cell and RES Disorders Agranulocytosis, leukopenia, neutropenia, pancytopenia DOSAGE AND ADMINISTRATION One SALOFALK 1 g suppository should be inserted into the rectum once daily at bedtime. The best results are achieved if the bowels are evacuated prior to insertion of SALOFALK suppository. Use in Children SALOFALK enemas should not be used in children 12 years old and under, as there is little experience with this age group.

Page 8


Page 9

OVERDOSAGE No overdosage has been reported to date. Possible symptoms may include nausea, vomiting and diarrhoea, and symptoms similar to salicylate overdose. There is no specific antidote. General supportive and symptomatic measures are recommended. For advice on the management of overdosage, please contact the Poisons Information Centre (telephone 13 11 26). PRESENTATION SALOFALK moulded suppositories are presented as light beige coloured, torpedo-shaped suppositories in white plastic strip packs. Each SALOFALK 1 g suppository contains 1 g of mesalazine. Cartons of 10* and 30 suppositories are available. (*currently not available) STORAGE CONDITIONS Store below 25˚C. Protect from light. NAME AND ADDRESS OF THE SPONSOR Orphan Australia Pty. Ltd. 300 Frankston-Dandenong Road Dandenong Victoria 3175 Australia. POISON SCHEDULE OF THE MEDICINE S4 DATE OF APPROVAL This Product Information was approved by the TGA on: 6 May 2010 SALOFALK® is a registered trademark of Dr. Falk Pharma GmbH, Germany, used under licence by Orphan Australia Pty. Ltd.

Date post:	24-Jan-2021
Category:	Documents
Upload:	others
View:	0 times
Download:	0 times

PRODUCT INFORMATION SALOFALK Tablets NAME OF...

Documents