Saloflak - Product Information
|Condition:||Crohn's Disease, Maintenance, Crohn's Disease, Inflammatory Bowel Disease, Ulcerative Colitis, Ulcerative Colitis, Active, Ulcerative Colitis, Maintenance, Ulcerative Proctitis|
|Ingredients:||mesalamine, carnauba wax, colloidal silicon dioxide, glycine, hydroxypropyl methylcellulose, iron oxide, magnesium stearate, methacrylic acid copolymer, microcrystalline cellulose, polydimethyl siloxane, polysorbate, povidone, sodium carbonate, sodium hydroxide, talc, titanium dioxide, triethyl citrate|
Summary Product Information
|Dosage Form /
|Clinically Relevant Non-medicinal
|Oral||Delayed release tablets
For a complete listing see Dosage Forms,
Composition and Packaging Section
Indications and Clinical Use
SALOFALK (mesalamine delayed release tablets) are indicated for adult patients for:
- treatment of acute ulcerative colitis
- prevention of relapse of Crohn’s disease in patients following bowel resection
Clinical studies with SALOFALK tablets have not been performed in the geriatric population.
Clinical studies with SALOFALK tablets have not been performed in the pediatric population.
SALOFALK (mesalamine delayed release tablets) is contraindicated in:
- patients with severe renal impairment (GFR<30ml/min/1.73m2) and/or severe hepatic impairment (see Warnings and Precautions).
- patients who are hypersensitive to this drug or to any ingredient in the formulation or component of the container. For a complete listing, see the Dosage Forms, Composition and Packaging section of the product monograph.
- cases of existing gastric or duodenal ulcer.
- patients with urinary tract obstructions.
- infants under two years of age.
- patients unable to swallow the intact tablets.
Patients who are hypersensitive to salicylates including acetylsalicylic acid (e.g. Aspirin), may also be hypersensitive to this medication.
Warnings and Precautions
There have been reports of hepatic failure and increased liver enzymes in patients with preexisting liver disease when treated with 5-ASA/Mesalazine products. Therefore, SALOFALK (mesalamine delayed release tablets) is contraindicated in patients with severe hepatic impairment (see CONTRAINDICATIONS). In patients with mild to moderate liver function impairment, caution should be exercised and SALOFALK (mesalamine delayed release tablets) should only be used if the expected benefit clearly outweighs the risks to the patients.
SALOFALK (mesalamine delayed release tablets) should be used only if the benefits clearly outweigh the risks in patients with underlying bleeding or clotting disorders as well as during pregnancy and lactation.
Patients with renal dysfunction, or elevated Blood Urea Nitrogen (BUN), or elevated serum creatinine, or with proteinuria, should be carefully monitored while receiving SALOFALK.
Concomitant treatment with mesalamine can increase the risk of myelosuppression in patients receiving azathioprine or 6-mercaptopurine
Effects on Ability to Drive and Use Machinery
There are no data available on the effects of mesalamine on ability to drive and use machines.
Carcinogenesis and Mutagenesis
Carcinogenicity studies in animals and mutagenicity tests were negative (see TOXICOLOGY).
Cardiac side effects, including pericarditis and myocarditis have been uncommonly reported with the use of mesalamine.
Cases of pericarditis have also been reported as manifestation of inflammatory bowel disease. Discontinuation of mesalamine may be warranted in some cases, but rechallenge with mesalamine can be performed under careful clinical observation should the continued therapeutic need for mesalamine be present.
Epigastric pain, also commonly associated with inflammatory bowel disease and prednisone or sulfasalazine (SAS) therapy (18%,), should be investigated in order to exclude pericarditis and pancreatitis either as adverse drug reactions to mesalamine or secondary manifestations of inflammatory bowel disease.
Patients with pyloric stenosis may have prolonged gastric retention of SALOFALK tablets which could delay release of mesalamine in the colon.
Reports of renal impairment, including minimal change nephropathy, and acute or chronic interstitial nephritis have been associated with mesalamine products and pro-drugs of mesalamine. SALOFALK (mesalamine delayed release tablets) is contraindicated in patients with severe renal impairment (see Contraindications). In patients with mild to moderate renal dysfunction, caution should be exercised and SALOFALK (mesalamine delayed release tablets) should be used only if the benefits outweigh the risks.
Patients on mesalamine, especially those with pre-existing renal disease, should be carefully monitored with urinalysis, and BUN and creatinine testing. Initial assessment and periodic monitoring of the renal function is recommended since mesalamine is substantially excreted by the kidney, and prolonged mesalamine therapy may damage the kidneys.
Because elderly patients are more likely to have decreased renal function, closer monitoring of the renal function may be needed.
Caution should be exercised when mesalamine (5-ASA) is initially used in patients known to be allergic to sulfasalazine. These patients should be instructed to discontinue therapy if signs of rash or pyrexia become apparent. In case of an allergic reaction, appropriate measures (standard of care) should be taken.
Acute Intolerance Syndrome
Mesalamine has been implicated in the production of an acute intolerance syndrome characterized by cramping, acute abdominal pain and bloody diarrhoea, sometimes fever, headache and a rash; in such cases prompt withdrawal is required. The patient’s history of sulfasalazine intolerance, if any, should be re-evaluated. If a rechallenge is performed later in order to validate the hypersensitivity, it should be carried out under close supervision and only if clearly needed, giving consideration to reduced dosage. The possibility of increased absorption of mesalamine and concomitant renal tubular damage as noted in the preclinical studies must be kept in mind. Patients on concurrent mesalamine products which contain or release mesalamine and those with pre-existing renal disease, should be carefully monitored with urinalysis, and BUN and creatinine testing.
SALOFALK should be used during pregnancy only if the benefits clearly outweigh the risks to the foetus. 5-ASA is known to cross the placental barrier, and no clinical studies have been performed in pregnant women
Animal studies did not show evidence of impaired fertility or harm to the foetus due to mesalamine (see TOXICOLOGY), however, because animal reproduction studies are not always predictive of human response, SALOFALK should be used during pregnancy only if clearly needed.
There are no clinical trial studies in nursing women. SALOFALK should be used in nursing women only if the benefits to the mother clearly outweigh the risks to the child. Mesalamine and its main metabolite N-acetyl-5-ASA are excreted in breast milk. The concentration of mesalamine is much lower than in maternal blood, but the metabolite Nacetyl-5-ASA appears in similar concentrations.
When mesalamine is used in nursing women, infants should be monitored for changes in stool consistency as hypersensitivity reactions manifested as diarrhoea in the infants have been reported.
Safety and effectiveness of SALOFALK therapy in pediatric patients have not been established.
SALOFALK should not be used in infants/toddlers aged less than 24 months.
Clinical studies of mesalamine did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac function or concomitant disease or other drug therapy.
Mesalamine is substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, it may be useful to monitor renal function.
Adverse Drug Reaction Overview
Hypersensitivity reactions have been reported in a sub-group of patients known to be allergic to sulfasalazine including rash, pyrexia, and dizziness with reactions occurring at the onset of therapy and resolving promptly following discontinuation
Other manifestations of hypersensitivity reported with mesalamine include acute pancreatitis, hepatitis, pericarditis, interstitial nephritis, interstitial pneumonia and pleural effusion. Interstitial pneumonia, pancreatitis and pericarditis have also been reported as manifestations of inflammatory bowel disease.
As with all 5-ASA products, exacerbations of ulcerative colitis characterized by cramping, acute abdominal pain and diarrhoea have been reported with mesalamine.
Other reported side effects include headache, flatulence, nausea, and hair loss, but do not appear to be common. Retreatment is not always associated with repeated hair loss. Aplastic anaemia has been reported in the literature with unspecified formulations of mesalamine.
Clinical Trial Adverse Drug Reactions
Because clinical trials are conducted under very specific conditions the adverse reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse drug reaction information from clinical trials is useful for identifying drug-related adverse events and for approximating rates.
|General Disorders and Administration Site
|Administration site reaction||1.3||0.5|
|Infections and Infestations|
|Urinary tract infection||0.5||2.2|
|Upper respiratory tract infection||0.1||0.5|
|Musculoskeletal, Connective Tissue and Bone
|Nervous System Disorders|
|Respiratory, Thoracic and Mediastinal Disorders|
|Skin and Subcutaneous Tissue Disorders|
Post-Market Adverse Drug Reactions
Adverse Reactions Reported With the Use of SALOFALK Tablets
The following adverse reactions have been identified during the post-approval use of SALOFALK tablets. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Abdominal discomfort, Abdominal pain (upper, lower), Diarrhoea, Faeces discoloured, Flatulence, Glossodynia, Nausea, Tongue discoloration, Tongue oedema
General Disorders And Administrative Site Disorders
Fatigue, Medication residue, Pyrexia
Sperm count decreased
Musculoskeletal And Connective Tissue Disorders
Back pain, Neck pain
Nervous System Disorders
Renal And Urinary Disorders
Chromaturia, Nephritis interstitial, Nephrolithiasis
Respiratory, Thoracic And Mediastinal Disorders
Lung infiltration, Interstitial pneumonia
Skin And Subcutaneous Tissue Disorders
Acute febrile neutrophilic dermatosis, Alopecia, Erythema, Pruritus, Rash, Urticaria
Interaction between azathioprine, 6-mercaptopurine and aminosalicylates (including mesalamine) can increase the risk of leucopenia. Other potential interactions with a number of drugs could occur (see Drug-Drug Interactions).
Interaction between azathioprine, 6-mercaptopurine and aminosalicylates including mesalamine, has been reported with oral mesalamine. Concomitant treatment with mesalamine can increase the risk of myelosuppression in patients receiving azathioprine or 6-mercaptopurine. An increase in whole blood 6-thioguanine nucleotide (6-TGN) concentrations has been reported although the mechanism of this interaction remains unclear.
Mesalamine could also increase renal and hematologic toxicity of methotrexate by additive effect and diminished absorption of folic acid.
The hypoglycemic effect of sulfonylureas may be enhanced. Interactions with coumarin, methotrexate, probenecid, sulfinpyrazone, spironolactone, furosemide and rifampicin cannot be excluded. Potentiation of undesirable glucocorticoid effects on the stomach is possible.
A theoretical interaction of salicylates with Varicella Virus Vaccine (chicken pox vaccine) might increase the risk of Reye’s syndrome; as a result, the use of salicylates (including mesalamine) is discouraged for six weeks following Varicella vaccination.
Drug-food, drug-herb, or drug-laboratory interactions have not been studied.
Drug-Laboratory Test Interactions
Several reports of possible interference with measurements, by liquid chromatography, of urinary normetanephrine causing a false-positive test result have been observed in patients exposed to sulfasalazine or its metabolite, mesalamine/mesalazine
Dosage and Administration
In the acute ulcerative colitis inflammatory stage, and in the prevention of recurrence of Crohn’s disease in adults, SALOFALK (mesalamine delayed release tablets) must be taken reliably and consistently by the patient in order to ensure therapeutic success. Tablets should be swallowed whole before meals with plenty of fluid. Do not crush.
Recommended Dose and Dosage adjustment
For the treatment of acute ulcerative colitis, two 500 mg SALOFALK tablets, three or four times per day (total adult dose: 3 g/day – 4 g/day). Prolonged treatment may be required.
For the prevention of recurrence of Crohn’s disease in patients following bowel resection, the total adult dose is 3 g/day in divided doses. Prolonged treatment is required.
If a dose of SALOFALK is missed, it should be used as soon as possible, unless it is almost time for the next dose. A patient should not take two SALOFALK® doses at the same time to make up for a missed dose.
Tablets should be taken consistently by the patient in order to ensure therapeutic success.
Tablets should be swallowed whole before meals with liquid. Do not crush. Abrupt discontinuation is not recommended. Prolonged treatment may be required.
There has been no clinical experience with mesalamine overdosage. However, because mesalamine is an aminosalicylate, the symptoms of overdose may mimic the symptoms of salicylate overdose; therefore, measures used to treat salicylate overdose may be applied to mesalamine overdose. Under ordinary circumstances, local mesalamine absorption from the colon is limited. There is no specific antidote and treatment is symptomatic and supportive.
|For management of a suspected drug overdose, contact your regional Poison Control Centre.|
Action and Clinical Pharmacology
Mechanism of Action
The mechanism of action of mesalamine (5-aminosalicylic acid, 5-ASA) is not fully understood, but appears to be topical rather than systemic. Inflammatory intestinal disease is often accompanied by diffuse tissue reactions including ulceration and cellular infiltration of lymphocytes, plasma cells, eosinophils, polymorphonuclear cells and activated phagocytic cells.
The interference of mesalamine with either leukotriene or prostaglandin metabolism may play a major role in suppressing the inflammatory response mechanism. 5-ASA prevents accumulation of thromboxane B2 and 6-keto-prostaglandin F1. Both 5-ASA and SAS reverse H2O, and Cl-secretion and increase Na+ secretion in experimentally-induced colitis in guinea pigs. SAS and 5-ASA are known to inhibit polymorphonuclear cell migration possibly via lipoxygenase inhibition at concentrations lower than those required to inhibit prostaglandin synthesis. It is thus possible that both SAS and 5-ASA are capable of inhibiting both pathways via lipoxygenase inhibition.
Intestinal secretion is stimulated not only by prostaglandins but also by the metabolites of arachidonic acid generated via the lipoxygenase pathway. Upon phagocytic activation and arachidonic acid metabolism activation, reactive oxygen metabolites are generated. 5-ASA acts as a dose dependent35 antioxidant which scavenges oxygen derived free radicals produced by activated phagocytes. In addition, 5-ASA associates with the membrane surface, allowing chain breaking anti-oxidant activity when peroxidation is initiated within the membrane. 5-ASA is able to block initiation of oxidation from solution as well as propagation within the membrane. 5-ASA also inhibits the formation of both eicosanoids and cytokines.
SALOFALK tablets contains mesalamine (5-aminosalicylic acid, 5-ASA), the active principle of the prodrug sulfasalazine. Although the 5-ASA mode of action is not clear, it appears to be multi-factorial. 5-ASA is thought to affect the inflammatory process through its ability to inhibit prostaglandin synthesis, interfere with leukotriene synthesis and consequent leukocyte migration as well as act as a potent scavenger of free radicals. Regardless of the mode of action, 5-ASA appears to be active mainly topically rather than systemically.
Oral administration of mesalamine enteric-coated tablets allows passage through the stomach intact, despite an average gastric dwell time of close to 3 hours in non-fasting patients and delivery, at pH of 6.0, to sites of topical action in the lower astrointestinal tract. Disintegration of mesalamine enteric-coated tablets usually occurs in the terminal ileum and proximal colon, allowing patients with ileal involvement to benefit from the drug. At the same time, most side effects attributed to the sulfapyridine moiety of SAS are avoided.
In a cross-over study to determine gastrointestinal transit and disintegration characteristics in the fed and fasted state in healthy subjects (n=8), gastric emptying of mesalamine entericcoated tablets was delayed by the presence of food. The tablets tended to disintegrate about five hours after leaving the stomach. Although the time between dosing and tablet disintegration was longer in fed subjects, there was no significant difference in disintegration times between the fasted and fed subjects once the tablet left the stomach. The enteric coating appeared to be unaffected by gastric retention time. Site of disintegration was affected by the rate of intestinal transit. In three of four subjects showing the slowest intestinal transit, disintegration occurred in the ileum. In eight instances (50%; 5 fed/3 fasted subjects), disintegration occurred in the ascending colon. In three instances, disintegration occurred beyond the ascending colon (1 fed/2 fasted). In the remaining two instances, the precise point of disintegration could not be accurately determined.
In a study of 13 patients with inflammatory bowel disease six with ulcerative colitis, one with total colectomy, seven with Crohn's disease, two with right hemi-colectomy), the tablets disintegrated with a mean time of 3.2 hours after leaving the stomach. For nine of the 11 patients for whom disintegration time could be accurately determined, this occurred within one hour of the mean time. Overall, tablet disintegration occurred in the small intestine in over 60% of the patients. Subsequently, the tablet became finally dispersed and remained in the colon for many hours.
Bioavailability has further been confirmed by measurement of 5-aminosalicylic acid in the ileostomy effluent of patients with or without small bowel resection receiving mesalamine enteric-coated tablets. Approximately 53% of mesalamine thus administered could be recovered in the effluent.
Pharmacokinetic data suggest that oral 5-ASA (mesalamine) is partially absorbed, excreted rapidly (range t1/2 = 0.4-2.4 hours), and partially recovered unchanged in the faeces.
In patients with active ulcerative colitis of Crohn’s disease receiving 500 mg of oral 5-ASA t.i.d., mean steady state plasma levels of 5-ASA and N-acetyl-5-ASA averaged 0.7 and 1.2 μg/mL respectively and were reached within 4-6 hours after administration. Treatment with a smaller dose (250 mg t.i.d.) achieved levels of 0.4 and 1.0 μg/mL, respectively.
5-ASA is metabolized by acetylation. The only major metabolite of 5-ASA identified in man is N-acetyl-5-aminosalicylic acid (N-Ac-5-ASA). The site of metabolism has not been elucidated. 5-ASA and its major metabolite N-acetyl-5-aminosalicylic acid are short lived in serum being excreted rapidly. N-acetyl-5-ASA exhibits a half life-reported at 5-10 hours. The elimination half life of 5-ASA appears to be dose dependent (1.4 ± 0.6 hours at 500 mg t.i.d. vs. 0.6 ± 0.2 hours at 250 mg t.i.d.).
The influence of renal and hepatic impairment on pharmacokinetics of mesalamine has not been evaluated.
The kidneys excrete both free 5-ASA and acetylated forms (N-Ac-5-ASA) into the urine. Urinary clearance of absorbed drug occurs rapidly, mainly as the acetylated metabolite. The mean recovery rate in urine following oral administration of 5-ASA has been estimated at approximately 44%. A fecal recovery rate of 35% consisted of both unabsorbed drug and the acetylated metabolite.
Storage and Stability
SALOFALK (mesalamine delayed release tablets) should be stored at controlled room temperature (15°-30°C). Protect from exposure to light.
Dosage Forms, Composition and Packaging
Each ochre colored, oblong, biconvex SALOFALK tablet contains: mesalamine 500 mg.
Non-medicinal ingredients: carnauba wax, colloidal silicon dioxide, glycine, hydroxypropyl methylcellulose, iron oxide, magnesium stearate, methacrylic acid copolymer, microcrystalline cellulose, polydimethyl siloxane, polysorbate, povidone, sodium carbonate, sodium hydroxide, talc, titanium dioxide, triethyl citrate. SALOFALK (mesalamine delayed release tablets) are gluten-free and phthalate-free.
SALOFALK tablets are supplied in bottles of 150 and 500 tablets.