Salofalk Suppositories: Indications, Dosage, Precautions, Adverse Effects
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Salofalk Suppositories - 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: Rectal
Ingredients: mesalamine, witepsol H-15 (suppository wax base), gluten-free, phthalate-free

Summary Product Information

Route of
Administration
Dosage Form /
Strength
Clinically Relevant Non-medicinal
Ingredients
RectalSuppositories
500, 1000 mg
None
For a complete listing see Dosage Forms,
Composition and Packaging Section

Indications and Clinical Use

SALOFALK (mesalamine suppositories) 500 and 1000 mg are indicated:

  • in the management of ulcerative proctitis.
  • as adjunctive therapy in more extensive distal ulcerative colitis (DUC).

Geriatrics

Clinical studies with SALOFALK suppositories, 500 mg and 1000 mg have not been performed in the geriatric population.

Pediatrics

Information on the safety and efficacy of SALOFALK suppositories in children is limited. Therefore, use should be limited to situations where a clear benefit is expected. SALOFALK suppositories should not be used in infants under two years of age.

Contraindications

SALOFALK (mesalamine suppositories) 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 suppositories) 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 suppositories) should only be used if the expected benefit clearly outweighs the risks to the patients.

SALOFALK (mesalamine suppositories) 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 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.

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 suppositories) 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 suppositories) 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 sign 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 suppositories in children is limited.

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

Geriatrics

Clinical studies of mesalamine did not include sufficient number 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, and of 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 Trials

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, Pericarditis

Eye Disorders

Eye swelling

Gastrointestinal Disorders

Abdominal pain (upper, lower), Abdominal cramps, Abdominal distension, Abnormal faeces, Anal pruritus, Anorectal discomfort, Constipation, Diarrhoea, Faeces discoloured, Flatulence, Frequent bowel movements, Mucus stools, Nausea, Painful defecation, Pancreatitis, Proctalgia, Rectal discharge, Rectal tenesmus, Stomach discomfort, Vomiting

General Disorders and Administrative Site Disorders

Fatigue, Medication residue, Pyrexia.

Nervous System Disorders

Burning sensation, Dizziness, Headache

Respiratory, Thoracic And Mediastinal Disorders

Dyspnoea

Skin and Subcutaneous Tissue Disorder

Alopecia, Erythema, Pruritus, Rash, 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 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

Recommended Dose and Dosage Adjustment

One 500 mg SALOFALK rectal suppository is self-administered on a twice a day or three times a day basis. One 1000 mg SALOFALK rectal suppository is self-administered on a once daily basis, at bedtime. The usual adult dose is 1.0 - 1.5 g/day and dosing is continued until a significant response is achieved or until the patient achieves remission. Dose tapering is recommended. Abrupt discontinuation is not recommended. Best results are expected with prolonged retention.

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 suppositories are self-administered, one 500 mg suppository 2 or 3 times/day, and one 1000 mg suppository 1 time daily at bedtime. The suppository should be retained for 1 to 3 hours or longer to achieve the maximum benefit. While the effect of the suppositories may be seen within 3 to 21 days, the usual course of therapy would be from 3 to 6 weeks depending on symptoms and sigmoidoscopic findings.

Patient Instructions

  1. Detach one suppository from the strip of suppositories.
  2. Hold suppository upright and carefully remove the plastic wrapper.
  3. Avoid excessive handling of suppository, which is designed to melt at body temperature.
  4. Insert suppository completely into rectum with gentle pressure, pointed end first.
  5. A small amount of lubricating gel may be used on the tip of the suppository to assist insertion.

In children, information on the safety and efficacy of mesalamine suppositories is limited.

Therefore, use should be limited to situations where a clear benefit is expected.

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 olon 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-aminosalisylic 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 inhibition32 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.

Pharmacodynamics

SALOFALK suppositories contain mesalamine (5-aminosalisylic 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. Rectal administration as 500 or 1000 mg suppositories of mesalamine (5-aminosalicylic acid) 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.

Pharmacokinetics

Absorption

Mesalamine (5-ASA) administered as a rectal suppository is variably absorbed. Systemic absorption of rectally administered 5-ASA is low as shown by urinary recoveries which range from 5% to 35% of the daily dose adminstered. In patients with ulcerative colitis treated with mesalamine 500 mg rectal suppositories, administered once every eight hours for six days, the mean mesalamine peak plasma concentration (Cmax) was 353 ng/mL (CV=55%) following the initial dose and 361 ng/mL (CV=67%) at steady state. The mean minimum steady state plasma concentration (Cmin) was 89 ng/mL (CV=89%). Absorbed mesalamine does not accumulate in the plasma.

Distribution

Mesalamine administered as rectal suppositories distributes in rectal tissue to some extent. In patients with ulcerative proctitis treated with mesalamine 1000 mg rectal suppositories, rectal tissue concentrations for 5-ASA and N-acetyl-5-ASA have not been rigorously quantified.

Metabolism

Mesalamine is extensively 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. In patients with ulcerative colitis treated with one 500 mg mesalamine rectal suppository every eight hours for 6 days, peak concentrations (Cmax) of N-acetyl-5-ASA ranged from 467 ng/mL to 1399 ng/mL following the initial dose and from 193 ng/mL to 1304 ng/mL at steady state.

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

Excretion

Mesalamine is eliminated from plasma mainly by urinary excretion, predominantly as N-acetyl-5-ASA. In patients with ulcerative proctitis treated with one mesalamine 500 mg rectal suppository every eight hours for six days, ≤ 12% of the dose was eliminated in urine as unchanged 5-ASA and 8-77% as N-acetyl-5-ASA following the initial dose. At steady state, ≤ 11% of the dose was eliminated as unchanged 5-ASA and 3-35% as N-acetyl-5-ASA. The mean elimination half-life was five hours (CV=73%) for 5-ASA and six hours (CV=63%) for Nacetyl-5-ASA following the initial dose. At steady state, the mean elimination half-life was seven hours for both 5-ASA and N-acetyl-5-ASA (CV=102% for 5-ASA and 82% for N-acetyl-5-ASA).

Storage and Stability

SALOFALK (mesalamine, 5-aminosalicylic acid, 5-ASA) suppositories must be stored below 25°C (77oF). Can be refrigerated. Keep away from direct heat, light and humidity.

Special Handling Instructions

SALOFALK (mesalamine suppositories) 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

Each smooth light tan to grey, bullet-shaped SALOFALK suppository contains 500 mg or 1000 mg mesalamine (5-aminosalicylic acid) that are available in strips of 6 suppositories; boxes of 30 suppositories. Non-medicinal ingredients: Witepsol H-15 (suppository wax base). SALOFALK (mesalamine suppositories) are gluten-free and phthalate-free.