Salofalk (R) 5-ASA Suppositories - 250mg Product Monograph

ACTIONS AND CLINICAL PHARMACOLOGY

SALOFALK7 suppositories contain mesalamine (5-aminosalicylic acid, 5-ASA), the active principle of the prodrug sulfasalazine (SAS)^{1, 5, 6, 14}. Although its mode of action is not clear, 5-ASA is thought to affect the inflammatory process through its ability to inhibit prostaglandin synthesis^{37, 38}, interfere with leukotriene synthesis and consequent leukocyte migration^16-18 as well as act as a potent scavenger of free radicals⁵⁰. Regardless of the mode of action, 5-ASA appears to be active only topically. SALOFALK7 suppositories are inserted into the rectum thus providing topical application to the affected area.

Rectal administration, either as 250, 500 or 1000 mg suppositories or as 4g/60g or

2g/60g rectal suspension 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. Systemic absorption of rectally administered

5-ASA is low as shown by urinary and rectal recoveries which range from 5 to 35% of the amount given^19,24,33. Rectally administered 5-ASA with minimal systemic absorption thus acts locally on the recto-sigmoidal colon. Plasma concentrations are low, peaking at about 10µg/mL for daily rectal dosing of 4 grams²⁵ and are negligible

24 hours after administration²⁶.

5-ASA and its major metabolite N-acetyl-5-aminosalicylic acid (N-Ac-5-ASA) are short

lived in the serum with a half-life reported at between 5-10 hours⁴² and 24 hours^{29, 43,}

1. 47.

   N-acetyl-5-ASA exhibits a half life reported at 5-10 hours⁴² and 24 hours^29,43-47.

   In patients with active ulcerative colitis or Crohn=s disease receiving 500 mg of 5-ASA t.i.d. orally, 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. The elimination half life thus appears to be dose dependent (1.4 "

0.6 hour at 500 mg t.i.d. vs 0.6" 0.2 hour at 250 mg t.i.d.⁴²).

Regardless of the mode of administration, 5-aminosalicylic acid appears to be only effective topically.

INDICATIONS AND CLINICAL USE

SALOFALK7 mesalamine (5-aminosalicylic acid) suppositories, 250, 500 or 1000 mg are indicated in the management of ulcer-ative proctitis and as adjunctive therapy in more extensive distal ulcerative colitis (DUC).

CONTRAINDICATIONS

SALOFALK7 mesalamine (5-aminosalicylic acid) is contraindicated in patients with urinary tract obstructions and in infants under two years of age. Patients hypersensitive to salicylates including Aspirin7 may also be hypersensitive to this medication.

WARNINGS

Mesalamine (5-aminosalicylic acid, 5-ASA) should be used only

after critical appraisal of the risk to benefit ratio in patients with underlying liver of kidney disease, bleeding or clotting disorders as well as during pregnancy and lactation. Caution should be exercised in patients with elevated BUN.

PRECAUTIONS

Periodic urinalysis to assess kidney function is recommended since prolonged

mesalamine (5-aminosalicylic acid) therapy may damage the kidneys. Caution should be exercised when mesalamine is first used in patients known to be allergic to

sulfasalazine(SAS). These patients should be instructed to discontinue therapy at the first sign of rash or fever.

Epigastric pain, also commonly associated with I.B.D. and prednisone or SAS therapy (18%, Singleton et al N.C.D.S., 1983), should be investigated in order to exclude pericarditis and pancreatitis or hepatitis either as adverse drug reactions to 5-ASA or secondary manifestations or inflammatory bowel disease.

Drug Interactions:

No known drug interactions exist. The hypoglycemic effect of sulfonylureas may be enhanced. Interactions with coumarins, methotrexate, probenicid, sulfapyrazone, spironolactone, furosemide and rifampicin can not be excluded.

ADVERSE REACTIONS

Hypersensitivity reactions have been reported in a sub-group of patients known to be allergic to SAS including rash, fever, and dizziness. The apparent frequency is estimated at 3-4%^15-51, with

reactions occurring at the onset of therapy and resolving promptly following discontinuation.

In rare cases, following mesalamine (5-aminosalicylic acid) administration,

exacerbation of ulcerative colitis characterized by cramping, acute abdominal pain and diarrhea has been reported. Acute pancreatitis, hepatitis and pleural effusion have also been reported in association both with mesalamine and SAS, as have rare instances of pericarditis. Both pancreatitis and pericarditis have also been reported as manifestations of inflammatory bowel disease. Finally, acute or chronic interstitial nephritis has been reported in association with orally-administered mesalamine.

Other reported side effects include headache, flatulence, nausea, and alopecia, but do not appear to be common. During controlled clinical trials involving the administration of either rectal mesalamine or placebo, the following adverse reactions were reported in more than 0.1% of cases:

SYMPTOMS AND TREATMENT OF OVERDOSE

There is no experience with acute overdosage in humans. The drug is not metabolized to salicylate. There is no specific antidote and treatment is symptomatic and supportive.

DOSAGE AND ADMINISTRATION

Two 250 mg or one 500 mg SALOFALK7 mesalamine (5-aminosalicylic acid) suppositories are self-administered on a daily t.i.d. or b.i.d. basis. One 1000 mg SALOFALK7 suppository is self-administered on a once daily basis. The usual adult dose is 1.0 - 1.5 g/day²⁹ 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.

In children between the ages of 2 and 12, information on the safety and efficacy of SALOFALK7 suppositories is limited. Therefore, use should be limited to situations where a clear benefit is expected.

PHARMACEUTICAL INFORMATION

DRUG SUBSTANCE:

Chemical name: 5-aminosalicylic acid (5-ASA)

Proper name: mesalamine (USP, USAN)

Other name: mesalazine (INN, BAN)

Structural formula:

Molecular formula: C₇H₇NO₃ Molecular weight: 153.14 Description: 5-aminosalicylic acid is a light tan, needle shaped, crystalline powder. It is slightly soluble water and 10% HCl solution. It is very slightly soluble in methanol and is practically insoluble in chloroform, ethylene oxide, and ethanol. It is soluble in 10% NaOH solution.

The melting range is 272-280EC.

COMPOSITION:

In addition to the active ingredient mesalamine (5-aminosalicylic acid), SALOFALK7

suppositories contain the following non-medicinal ingredients: Witepsol H-15 (suppository wax base).

STORAGE:

SALOFALK7 mesalamine (5-aminosalicylic acid) suppositories must be stored in a cool place, preferably between 20E and 25EC.

AVAILABILITY

SALOFALK7 mesalamine (5-aminosalicylic acid) suppositories 250,

500, or 1000 mg are available in strips of 5 suppositories; boxes of 30 suppositories.

PHARMACOLOGY

5-ASA is the active metabolite of the prodrug SAS which acts to suppress

inflammatory bowel disease. Pharmacologic tests were conducted on 5-ASA by R.C.C., Itingen, Switzerland. Most used the oral route of administration at a dose of 500 mg/kg in order to simulate practice-relevant conditions.

No adverse effect of 5-ASA on the following parameters or in the following tests could be established: tremorine antagonism, hexobarbital sleep time, motor activity, anticonvulsant action (metrazol and electric shock), blood pressure, heart rate, respiratory rate (up to 10 mg/kg, i.v.), tocolysis (antispasmodic assay), local anaesthesia, antihyperthermal and antipyretic effects. In the paw-edema test with carrageen injection, 200 mg/kg administered orally proved ineffective, but 500 mg/kg 5-ASA administered orally exhibited mild antiphlogistic action.

In the renal function tests (natriuresis and diuresis), no biologically relevant effects of 200 mg/kg administered orally were demonstrated. After 600 mg/kg, marked functional changes were observed: increases in both total urinary output, natriuresis and proteinuria. The urinary sediment contained increased numbers of erythrocytes and epithelial cells. Both potassium elimination and specific weight were reduced. It can be concluded from these experiments that even high doses of 5-ASA have no effect on vital parameters. Disturbances in renal function are to be expected only at dosages equivalent to a single dose at least 8 to 10 times the daily dose in man. Mode of action: The mode of action of 5-ASA is still under investigation with several biochemical mechanisms being

proposed. At present, the action of 5-ASA in treating inflammatory bowel disease appears to be associated with the metabolism of arachidonic acid. Studies suggest that interference of 5-ASA with either leukotriene or prostaglandin metabolism response mechanism^16-18. Since prostaglandins definitely play a decisive role in inflammatory ulcerative intestinal disease, interference with the metabolism of prostanoids has long been postulated as the possible mechanism of action^34-36. Inflammatory intestinal disease is often accompanied by diffuse tissue reactions including ulceration and cellular infiltration of lymphocytes, plasma cells, eosinophils and polymorphonuclear cells. For example, prostaglandin synthetase activity of the mucosa³⁷ as well as 6-keto-prostaglandin F1 and thromboxane B2 also increase during active disease. In addition, increased prostaglandin³⁸ stimulate active ion secretion which in turn contributes to the diarrhea associated with the disease. 5-ASA prevents

accumulation of thromboxane B2 and 6-keto-prostaglandin F1³⁸. In addition, both 5-ASA and SAS reverse H₂O and Cl-secretion and increase Na+ secretion in experimentally-induced colitis in guinea pigs³⁹. Mush et al.⁴⁰ demonstrated that intestinal secretion is stimulated not only by prostaglandins but also by the

metabolites of arachidonic acid generated via the lipoxigenase pathway. Both SAS and 5-ASA are known to inhibit polymorphonuclear cell migration possibly via lipoxygenase inhibition⁴¹ 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.

TOXICOLOGY

A full battery of animal toxicology studies was conducted, including additional long-term carcinogenicity and chronic toxicity studies and three studies aimed at satisfying the special requirements for rectal dosage forms of 5-ASA, thereby providing safety data additional to the rectal tolerance study in dogs.

Brief summary of findings to date:

Animal studies to date show the kidney to be the only significant target organ for 5-ASA toxicity in rats and dogs. At high doses, the lesions produced consisted of papillary necrosis and multifocal proximal tubular injury. In rats, the no-effect levels were 160 mg/kg/day for females and 40 mg/kg/day for males (minimal and

reversible tubular lesions seen) after 13 weeks of oral administration. In dogs, the "no-effect" level in both males and females was 40 mg/kg/day after six months of oral administration. Aside from gastric and heart lesions, as well as bone marrow depression seen in some of the rats at the 640 mg/kg level and considered

secondary effects of the kidney damage, no other signs of systemic toxicity were noted at daily doses up to 160 mg/kg in rats and 120 mg/kg in dogs for 13 weeks and six months, respectively.

During up to 127 weeks of administration in rats of doses of 0, 50, 100 and 320 mg/kg/day, no significant differences were noted in unscheduled deaths, clinical signs, nodules or masses, between groups. Ophthalmoscopic investigations revealed no treatment-related changes. Treatment with SALOFALK7 was not associated with oncogenic changes or an increased tumor risk. The assessment of hematology, clinical biochemistry and urinalysis indicated no changes of

toxicological significance at 13, 26 and 52 weeks of treatment.

After 127 weeks, analysis of the lesions indicated slight substance-related and dose-dependent toxic changes as degenerative kidney damage and hyalinization of the tubular basement membrane and Bowman's capsule in the 100 mg and 320 mg/kg/day groups. Ulceration of the gastric mucosa and atrophy of the seminal vesicles were also more frequent in the 320 mg/kg/day group.

The battery of tests completed to date shows also that 5-ASA is devoid of embryotoxicity and teratogenicity in rats and rabbits; that it does not affect male rat fertility after five weeks of oral administration at 296 mg/kg/day; that it lacks the potential to affect late pregnancy, delivery, lactation or pup development in rats; and that it is without mutagenic properties in a standard series of tests.

Nephrotoxic potential of 5-aminosalicylic acid:

Owing to its structural relationship both to phenacetin, the aminophenols and salicylates, 5-ASA was included in a series of compounds studied following identification of antipyretic-analgesic nephropathy in humans. Calder et al. (Brit. Med. J., Nov. 27, 1971; Brit. Med. J., Jan. 15, 1972; Xenobiot Vol. 5, 1975) reported that, in rats, in addition to the proximal tubule necrosis seen with

acetyl-salicylic acid and phenacetin derivatives, 5-ASA produced papillary necrosis, following single intravenous doses ranging from 150 mg/kg to 872 mg/kg^{27, 28}.

Diener et al.²⁷ have shown that oral doses of 5-ASA of 30 mg/kg and 200 mg/kg daily for four weeks failed to produce any adverse effects on kidney function or histology in rat.

In a 13-week rat study, there were no renal lesions after four weeks in the animals receiving up to 160 mg/kg orally per day, but severe papillary necrosis and proximal tubular injury were

seen in most animals receiving 640 mg/kg orally per day. At 13 weeks, the female animals were free of pathology up to 160 mg/kg; minimal and reversible lesions in the tubules occurred in a few males (with no changes in renal function) at the 40 mg/kg level. After six months of oral administration in dogs, no toxicity was seen in the 40 mg/kg/day group. At 80 mg/kg/day, two of eight treated dogs showed slight to moderate renal papillary necrosis. These two dogs as well as two others showed minimal to moderate tubular lesions. At 120 mg/kg/day, two females had slight papillary necrosis. These and two others showed minimal to moderate tubule injury.

Thus, the animal toxicity data suggest that 5-ASA has a nephrotoxic potential comparable to acetyl-salicylic acid; on the other hand, extensive investigations of the problem of analgesic nephropathy have led to a current consensus that it is the combination products that provide the greatest hazard, and that single-ingredient antipyretic analgesics such as acetyl-salicylic acid are safe when taken in

reasonable doses. See Emkey (Amer. J. Med., June 24, 1983) and Editorial (Amer. Pharm., May 1984).

It is important to note, that despite 40 years of use of SAS world-wide for

treatment and long-term prophylaxis of ulcerative colitis and Crohn's disease, there has been no report of kidney disease directly attributable to the drug or to the diseases being treated. The fact that SAS results in therapeutic levels of sulfapyridine might have led to kidney disease mistaken as a systemic complication of inflammatory bowel disease, but we are aware of no report listing kidney disease as a complication either of ulcerative colitis or of Crohn's disease.

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