Salofalk Rectal Suspension
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Salofalk Rectal Suspension - Scientific 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

Pharmaceutical Information

Drug Substance

Proper name:5-aminosalicylic acid, mesalamine
Chemical name:5-aminosalicylic acid (5-ASA)
Molecular formula and molecular mass:C7H7NO3 153.14
Structural formula:


Physicochemical properties:
Description:5-aminosalicylic acid is a light tan to pink, needle shaped,
crystalline powder.
Solubility:Slightly soluble in water, very slightly soluble in methanol and
practically insoluble in chloroform; soluble in diluted HCl and
diluted alkali hydroxides.
Melting Range:272°-280°C

Clinical Trials

In a 6-week, randomized, placebo-controlled, double-blind trial in 59 patients with ulcerative colitis, Sutherland et al, demonstrated the safety and efficacy of 4 g mesalamine rectal suspension. Twenty-nine (29) patients received the treatment drug and 30 patients received placebo. There was a significant improvement in disease symptoms in the treatment group (p<0.0001) compared to the placebo group after 6 weeks of treatment. The mean disease activity index (DAI) decreased by 75% in the treatment group compared to 32% for placebo (p<0.05). The rectal suspension was well tolerated with few and insignificant side effects.

In a separate study, the efficacy and safety of mesalamine rectal suspension 2g/60g and 4g/60g in the maintenance of remission were evaluated in a 6-month, randomized, double-blind trial in 29 patients who had ulcerative colitis. Before admission to the study, patients had participated in a placebo-controlled mesalamine rectal suspension study and had achieved a significant improvement in their disease activity or were in remission. Further significant declines in DAI were demonstrated for both dose groups during the first 3 months of therapy (p<0.001). There was no significant difference in DAI scores between 3 and 6 months, or between the 2g/60g/day and 4g/60g/day doses. Two patients in the 2g/60g dose group and 3 patients in the 4g/60g dose group relapsed during the 6 month study period. Relapse rates did not differ significantly.

Detailed Pharmacology

Animal Studies

5-ASA (mesalamine) is the active moiety of the prodrug sulfasalazine which acts to suppress inflammatory bowel disease. Animal pharmacology tests were conducted on 5-ASA using the oral route of administration for most tests, 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 animal pharmacology 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 per os proved ineffective, but 500 mg/kg 5-ASA per os exhibited mild antiphlogistic action.

In the animal renal function tests (natriuresis and diuresis), no biologically relevant effects of 200 mg/kg per os were demonstrated. After 600 mg/kg, marked functional changes were observed: increases in total urinary output, natriuresis and proteinuria. The urinary sediment contained an increased number of erythrocytes and epithelial cells. Both potassium elimination and specify 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.

Human Studies

See Action and Clinical Pharmacology.

Toxicology

Long-term Toxicity

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 6 months of oral administration. In this six-month oral toxicity study in dogs, doses of 80 mg/kg/day (about 1.4 times the recommended human intra-rectal dose, based on body surface area) and higher, caused renal pathology similar to that described for the rat. In a rectal toxicity study of mesalamine suppositories in dogs, a dose of 166.6 mg/kg (about 3.0 times the recommended human intra-rectal dose, based on body surface area) produced chronic nephritis and pyelitis. Aside from gastric lesions, heart lesions and bone marrow depression seen in some of the rats at the 640 mg/kg level and considered secondary effects of 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.

In the 12-month oral toxicity study in dogs, keratoconjunctivitis sicca (KCS) occurred at oral doses of 40 mg/kg/day (about 0.72 times the recommended human intra-rectal dose, based on body surface area) and above.

Carcinogenicity

Administration of doses of 0, 50, 100 and 320 mg/kg/day for 127 weeks in rats did not result in significant differences in unscheduled deaths, clinical signs, nodules or masses, between groups. Ophthalmoscopic investigations revealed no treatment-related changes. Treatment with SALOFALK 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 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.

Mutagenicity

5-ASA was not mutagenic in the Ames test, E. coli reverse mutation assay, mouse micronucleus test, sister chromatid exchange assay, or in a chromosomal aberrations assay. In contrast, sulfapyridine, which is the other primary metabolite of salicylazosulfapyridine, has tested positive in certain mutagenicity tests.

Reproduction Studies

Teratology studies with 5-ASA have been performed in rats at oral doses up to 320 mg/kg/day and in rabbits at oral doses up to 495 mg/kg/day (about 1.7 and 5.4 times the recommended human intra-rectal dose, respectively). The battery of tests completed to date has shown 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; and that it lacks the potential to affect late pregnancy, delivery, lactation or pup development in rats.

Other Studies

Nephrotoxic potential of 5-aminosalicylic acid

Owing to its structural relationship 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. has reported in rats that in addition to the roximal tubule necrosis seen with acetylsalicylic acid (e.g. Aspirin) and phenacetin derivatives, 5-ASA produced papillary necrosis, following single intravenous doses ranging from 150 mg/kg to 872 mg/kg.

Diener et al 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/day 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 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.

5-ASA rectal irritation challenge in dogs

A rectal mucosa irritation study was designed and conducted to determine if 5-ASA rectal suspension causes any mucosal tissue stress either histologically or macroscopically. The test was carried out blind against placebo, administering one rectal suspension per day.

Treated dogs (n = 10) received 2.0 g of 5-ASA which was retained for an average of 5.5 hours over the 27-day study. The placebo group (n = 6) received suspensions of the same vehicle composition, but without 5-ASA. Calcium carbonate and food colouring were used in place of 5-ASA to mimic its appearance in the suspension formula. The rectal suspension control group (n = 2) received physiological saline enemas of equivalent volume daily. Seven days prior to dosing and after Days 15 and 30, all animals were given a proctologic examination with rectal biopsy. The histopathology data revealed no signs of significant irritation in either the treated or the control group. There was an increased incidence of edema of the lamina propria of the rectum in both the treated and control groups. These lesions represent the mildest form of inflammation normally expected in the rectum. This mucosal inflammation is a completely reversible alteration and is probably the result of mild superficial irritation. There was no significant difference in the incidence and or severity of these changes between the treated and control groups.

The anorectal examination data revealed no signs of irritation in either treated or control group animals. The amount of mucus present in the rectum increased with time in all dogs, but did not exceed minimal severity. There was no significant difference between treated and control groups in the incidence and/or degree of severity of anorectal examination.

In conclusion, these data indicated no significant rectal mucosal tissue irritation in dogs related to the daily rectal administration of 2 g of 5-aminosalicylic acid rectal suspension over a period of 27 days.