Salofalk Rectal Suspension: Indications, Dosage, Precautions, Adverse Effects
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Salofalk Rectal Suspension - Product Information

Manufacture: Actavis
Country: Canada
Condition: Crohn's Disease, Maintenance, Crohn's Disease, Inflammatory Bowel Disease, Ulcerative Colitis, Ulcerative Colitis, Active, Ulcerative Colitis, Maintenance, Ulcerative Proctitis
Class: 5-aminosalicylates
Form: Liquid solution, Rectal
Ingredients: mesalamine, carbomer, edetate disodium, potassium acetate, potassium metabisulfite, purified water, sodium benzoate, xanthan gum

Summary Product Information

Route of
Administration
Dosage Form /
Strength
Clinically Relevant Non-medicinal
Ingredients
RectalSuspension 2 g/60 g
and 4 g/60 g
potassium metabisulfite
For a complete listing see DOSAGE FORMS,
COMPOSITION AND PACKAGING section.

Indications and Clinical Use

SALOFALK (mesalamine rectal suspension) 4 g/60 g is indicated:

  • in the management of distal ulcerative colitis (DUC) extending to the splenic flexure including refractory DUC defined to include patients who are difficult to manage with conventional therapies and patients who are allergic to sulfasalazine (SAS).
  • as adjunctive therapy in more extensive disease as well as for the prevention of relapse in distal ulcerative colitis.

SALOFALK rectal suspension, 2 g/60 g is indicated:

  • for the prevention of relapse in distal ulcerative colitis.

Geriatrics

Clinical studies with SALOFALK rectal suspension, 2 g/60 g and 4 g/60 g, have not been performed in the geriatric population.

Pediatrics

Information on the safety and efficacy of SALOFALK rectal suspension, 2 g and 4 g, in children is limited. Use of the drug should be limited to situations where a clear benefit is expected. SALOFALK rectal suspension should not be used in infants under two years of age.

Contraindications

SALOFALK (mesalamine rectal suspension) 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 hypersensitive to salicylates, including acetylsalicylic acid (e.g. Aspirin), may also be hypersensitive to this medication.

Warnings and Precautions

General

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 rectal suspension) 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 rectal suspension) should only be used if the expected benefit clearly outweighs the risks to the patients.

SALOFALK (mesalamine rectal suspension) 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).

Cardiovascular

Cardiac side effects, including pericarditis and myocarditis have been uncommonly reported with the use of mesalamine.

Cases of pericarditis have also been reported as manifestations 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.

Gastrointestinal

Epigastric pain, also commonly associated with inflammatory bowel disease and prednisone or 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.

Renal

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 rectal suspension) 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 rectal suspension) 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.

Sensitivity/Resistance

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.

Special Populations

Pregnant Women

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.

Nursing Women

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 N-acetyl-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.

Pediatrics

Information on the safety and efficacy of SALOFALK 2 g and 4 g rectal suspensions in children is limited. Use of the drug should be limited to situations where a clear benefit is expected.

SALOFALK should not be used in infants/toddlers aged less than 24 months.

Geriatrics

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 Reactions

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.

Table 1: Clinical Trial Adverse Events Reported in > 0.1% of Patients
SYSTEM ORGAN CLASS
Preferred Term
SALOFALK
N=841
%
Placebo
N=176
%
Cardiac Disorders
Pericarditis0.10.0
Gastrointestinal Disorders
Abdominal pain7.97.9
Flatulence6.04.5
Nausea5.66.8
Diarrhoea2.13.9
Abdominal distension1.41.1
Haemorrhoids1.30.0
Proctalgia1.10.0
Constipation0.92.2
Anorectal discomfort0.51.7
Pancreatitis0.10.0
Condition aggravated0.10.0
General Disorders and Administration Site
Conditions
Fatigue3.34.5
Pyrexia3.00.0
Administration site reaction1.30.5
Oedema peripheral0.56.2
Asthenia0.12.2
Infections and Infestations
Influenza5.20.5
Urinary tract infection0.52.2
Upper respiratory tract infection0.10.5
Musculoskeletal, Connective Tissue and Bone
Disorders
Arthralgia2.01.1
Back pain1.30.5
Nervous System Disorders
Headache6.711.3
Dizziness1.72.8
Insomnia0.11.7
Respiratory, Thoracic and Mediastinal Disorders
Pharyngolaryngeal pain2.02.8
Skin and Subcutaneous Tissue Disorders
Rash2.82.2
Spots2.25.1
Pruritus1.10.5
Alopecia0.81.1

Post-Market Adverse Drug Reactions

The following adverse reactions have been identified during the post-approval use of SALOFALK rectal suspension. 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.

Cardiac Disorders

Myocarditis

Gastrointestinal Disorders

Abdominal pain (upper, lower), Abdominal cramps, Abdominal discomfort, Constipation, Diarrhoea, Faeces discoloured (pale), Flatulence, Rectal tenesmus

General Disorders and Administrative Site Disorders

Fatigue, Medication residue, Pyrexia

Musculoskeletal and Connective Tissue Disorders

Back pain, Neck pain

Nervous System Disorders

Dizziness, Headache

Renal and Urinary Disorders

Chromaturia

Skin and Subcutaneous Tissue Disorders

Acute febrile neutrophilic dermatosis, Pruritus, Rash (erythematous, papular), Urticaria

Drug Interactions

Overview

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).

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

Dosing Considerations

Information on the safety and efficacy of SALOFALK (mesalamine rectal suspension) 2 g/60 g and 4 g/60 g in children is limited. Use of the drug should be limited to situations where a clear benefit is expected.

Recommended Dose and Dosage adjustment

Acute episodes

SALOFALK rectal suspension 4 g/60 g is self-administered on a daily basis during acute episodes of disease. Usually one unit-dose rectal suspension (4 g 5-ASA) is taken upon retiring and retained during the entire rest period. Best results are expected with prolonged retention.

The usual course of therapy for an adult is one unit of 4 g/60 g daily at bedtime. Response to treatment and adjustment in dosing frequency should be determined by periodic examination, including endoscopy and the assessment of symptomatology including rectal bleeding, stool frequency, and general well-being.

Daily dosing is continued until a significant response is achieved or the patient achieves remission.

Prevention of relapses

SALOFALK rectal suspension, 2 g/60 g is self-administered in the same manner on a daily basis to prevent relapse.

If, alternatively, the 4 g/60 g preparation is used to prevent relapse, the dose can usually be reduced to alternate days or every third day, depending upon disease activity. Abrupt discontinuation of 5-ASA is not recommended. Dose tapering is recommended and each patient should be titrated to meet individual needs. Maintenance therapy is recommended to assure continued remission. However, should symptoms of diarrhoea and rectal bleeding recur, dosage should be increased to 4 g/60 g/day.

Missed Dose

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 use two SALOFALK® doses at the same time to make up for a missed dose.

Administration

SALOFALK rectal suspension, 4 g/60 g is self-administered on a daily basis during acute episodes of disease.

SALOFALK rectal suspension, 2 g/60 g is self-administered in the same manner on a daily basis to prevent relapse.

Overdosage

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 generated35. 5-ASA acts as a dose dependent 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.

Pharmacodynamics

SALOFALK rectal suspension 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.

Pharmacokinetics

Absorption

Systemic absorption of rectally administered 5-ASA (mesalamine) is low as shown by urinary recoveries which range from 5 % to 35% of the amount given. In contrast, oral administration of free 5-ASA leads to high systemic absorption with rapid absorption from the small intestine; however, this route of administration provides for a reduced chance of topical effectiveness in the distal bowel. Rectally administered 5-ASA thus acts locally on the rectosigmoidal colon. Satisfactory dosages (4 g mesalamine rectal suspension) have reached the splenic flexure.

Distribution

Rectal administration allows for direct targeting of free 5-ASA to the sites of inflammation along the mucosal lumen of the rectum, sigmoid and distal large bowel. Free intraluminal 5-ASA is taken up by mucosal cells, where it is acetylated and inactivated as N-Ac-5-ASA. Following rectal dosing, both free 5-ASA and its inactive metabolite, N-Ac-5-ASA, can be found within 1-2 hours post administration in plasma.

Metabolism

5-ASA metabolism is metabolised by acetylation. The only major metabolite of 5-ASA identified in man is N-acetyl-5-aminosalicylic acid (N-Ac-5-ASA). Following rectal dosing, both free and acetylated forms can be found in plasma within 1-2 hours post administration. Usually plasma concentrations are low and do not exceed a maximum serum level of about 10 μg/mL at rectal daily doses of up to 4 grams. Peak plasma levels of rectally administered 5-ASA (4 g rectal suspension) are reached within 3 to 6 hours, with a value of 2.6 ± 2.3 μg/mL. Plasma levels are therefore negligible approximately 24 hours after dosing17. Following mucosal absorption, passage through the liver results in further acetylation46. These results are consistent with pharmacokinetic parameters as measured for 5-ASA and its metabolites determined in studies with solid oral dosage forms. In solid oral dosage studies, it has been determined that 5-ASA and its metabolite N-Ac-5-ASA are short lived in the serum with a half-life reported between 0.5-1.5 hours and 5-10 hours, respectively; 5-ASA is partially absorbed, excreted rapidly (t1/2 = 0.4 - 2.4 hours), and partially recovered unchanged in the faeces.

The influence of renal and hepatic impairment on pharmacokinetics of mesalamine has not been evaluated.

Excretion

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 recovery rate in urine varies between 8 and 17 percent of the administered rectal dose. Unabsorbed drug is excreted as the free and acetylated forms via faeces.

Storage and Stability

SALOFALK (mesalamine rectal suspension) is packaged in aluminum foil and should be stored at room temperature preferably under 25°C. Product expiration date and lot number are printed on the bottle base.

Special Handling Instructions

SALOFALK (mesalamine rectal suspension) will cause staining of direct contact surfaces, including but not limited to fabrics, flooring, painted surfaces, marble, granite, vinyl, and enamel.

Dosage Forms, Composition and Packaging

SALOFALK (mesalamine rectal suspension) 2 g/60 g and 4 g/60 g are available as a unit of use rectal suspension. Non-medicinal ingredients include: carbomer, edetate disodium, potassium acetate, potassium metabisulfite, purified water, sodium benzoate and xanthan gum. SALOFALK (mesalamine rectal suspension) is gluten- free and phthalate-free.

Each unit consists of a rectal dosing package designed for self-administration and disposal. A removable protective sheath covers the pre-lubricated suspension nozzle until ready for use. A one-way valve allows the suspension to flow from the bottle through the applicator nozzle and into the rectal vault as the patient squeezes the thin-walled collapsible bottle.