Asacol®

5-ASA

Lower Gastrointestinal Anti-inflammatory

Procter & Gamble Pharmaceuticals

http://www.pg.com/en_US/index.jhtml

Asacol Monograph PDF download here.

 

CPS:PIS_m067800

Date of Preparation: June 11, 1985

 

 

Pharmacology

The active ingredient in Asacol, mesalamine (5-aminosalicylic acid, also referred to as 5-ASA), is the major active component of sulfasalazine for the treatment of inflammatory bowel disease. The available evidence suggests that mesalamine has a topical anti-inflammatory effect on the colon, where it inhibits prostaglandin and leukotriene synthesis.

     Asacol tablets have a special acrylic-based resin coating which does not allow the drug to be released below pH 7. The coating delays release of mesalamine until the tablets reach the terminal ileum and colon. Once released in the colon, mesalamine is minimally absorbed and plasma levels are similar to those found following rectal administration of mesalamine. Approximately 20% of the administered dose released in the colon is absorbed, the remainder is available for colon therapeutic activity and excretion in the feces. Absorption of mesalamine is similar in fasted and fed subjects. The absorbed mesalamine is rapidly acetylated through the gut mucosal wall and by the liver. It is mainly excreted by the kidney, as N-acetyl-5-aminosalicylic acid.

 

Pharmacokinetics

Mesalamine release from Asacol is delayed until the terminal ileum as reflected by t_max's of about 7 hours for mesalamine and its metabolite, N-acetyl-5-aminosalicylic acid. The t½_elim.'s were about 3 hours for mesalamine and 10 hours for N-acetyl-5-aminosalicylic acid.

     Human studies conducted using radiological and serum markers showed that the Asacol coating delayed release of mesalamine until the terminal ileum was reached. Other studies compared mesalamine absorption when administered as an enema (a readily available dosage form) and when released for absorption in the stomach, small intestine, and colon relative to an i.v. dose. Once released in the colon, mesalamine was minimally absorbed and plasma levels were similar to those found following rectal administration. Approximately 20% of the administered dose released was absorbed, with about 80% available for topical activity in the colon. The absorbed mesalamine was rapidly acetylated through the gut mucosal wall and by the liver. It was mainly excreted by the kidney as N-acetyl-5-aminosalicylic acid.

     Serum levels and urinary excretion of mesalamine and N-acetyl-5-aminosalicylic acid following single and multiple equimolar Asacol and sulfasalazine doses to healthy subjects and to patients were compared. There was no consistent trend for greater serum mesalamine or metabolite levels following Asacol dosage. Based on urinary dose recoveries, the extent of mesalamine absorption for Asacol was no greater than that for sulfasalazine. Overall, there were no meaningful differences in the extents of mesalamine absorption following equimolar Asacol and sulfasalazine doses.

     In another study, there was a dose response in serum mesalamine and metabolite levels at Asacol doses of 1.2 and 2.4 g/day. In other studies when Asacol was administered at higher or lower doses than 1.2 and 2.4 g/day, serum mesalamine and N-acetyl-5-ASA concentrations differed from those for the 1.2 and 2.4 g/day doses as would be expected following a linear dose response relationship. The effects of coadministration of Asacol with cimetidine, an antacid containing activated simethicone and aluminum hydroxide, and antacid with a high fat meal were addressed in another study. There were no significant in vivo effects on mesalamine release or the extent of drug absorption from Asacol by any of the three treatments.

Clinical Trials: Mildly to Moderately Active Ulcerative Colitis: In a randomized, double-blind, placebo controlled clinical trial it was shown that Asacol (4.8 g/day of mesalamine in divided doses) was highly effective in inducing remission in ulcerative colitis patients with active disease.

Maintenance of Remission of Ulcerative Colitis: A 6-month, randomized, double-blind, placebo-controlled, multicentre study involved 264 patients treated with Asacol 0.8 g/day (n=90), 1.6 g/day (n=87), or placebo (n=87). The proportion of patients treated with 0.8 g/day who maintained endoscopic remission was not statistically significant compared to placebo. In the ITT analysis of patients treated with Asacol 1.6 g/day, Asacol maintained endoscopic remission of ulcerative colitis in 61 of 87 (70.1%) of patients, compared to 42 of 87 (48.3%) of placebo recipients (p=0.005).

     A pooled efficacy analysis of 4 maintenance trials compared Asacol (0.8 to 2.8 g/day) with sulfasalazine (2 to 4 g/day). Treatment success was 58 of 98 (59%) for Asacol and 70 of 102 (69%) for sulfasalazine, a nonsignificant difference.

     Additional double-blind clinical trials of 16-, 24-, and 52-weeks' duration have shown Asacol, in doses ranging from 0.8 to 4.4 g/day to be as effective as sulfasalazine for maintenance of remission. It is particularly noteworthy that most patients intolerant or allergic to sulfasalazine can be effectively maintained in remission on Asacol, as demonstrated in open-labeled clinical trials. In addition, male infertility resulting from sulfasalazine therapy has been shown to be reversible upon treatment with Asacol.

 

Indications

For the treatment of mild to moderate active ulcerative colitis, and for the maintenance of remission of mild to moderate ulcerative colitis. Asacol at the dosage tested of 1.6 g/day may not be effective for the maintenance of remission when the underlying disease is severe. Abrupt discontinuation may result in relapse.

 

Contraindications

In patients with a history of sensitivity to salicylates; sensitivity to any of the Asacol tablet components; existing gastric or duodenal ulcer; urinary tract obstruction; and in infants under 2 years of age.

 

Warnings

If toxic or hypersensitivity reactions occur, the drug should be discontinued. In assessing liver and joint complications, it should be kept in mind that these are frequently associated with ulcerative colitis.

     Renal impairment, including minimal change nephropathy, and acute and chronic interstitial nephritis, has been reported in patients taking Asacol tablets as well as in patients taking other mesalamine products.

     Caution should be exercised when using Asacol (or other compounds which contain or are converted to mesalamine or its metabolites) in patients with  hepatic dysfunction or history of renal disease. Asacol is not recommended for use in patients with renal impairment. It is recommended that all patients have an evaluation of renal function prior to initiation of Asacol tablets and periodically while on Asacol therapy (see Precautions).

 

Precautions

 

General

Patients with pyloric stenosis may have prolonged gastric retention of Asacol tablets which could delay release of mesalamine in the colon.

     Exacerbation of the symptoms of colitis, thought to have been caused by mesalamine or sulfasalazine has been reported in 3% of patients in controlled clinical trials. This acute reaction, characterized by cramping, abdominal pain, bloody diarrhea, and occasionally by fever, headache, malaise, pruritus, rash, and conjunctivitis, has been reported after the initiation of Asacol tablets as well as other mesalamine products. Symptoms usually abate when Asacol tablets are discontinued.

     Asacol and other mesalamine-containing products have differences in formulation and release characteristics that may lead to differences in concentrations of mesalamine delivered to the colon. If it is deemed necessary to switch from one mesalamine-containing product to another mesalamine-containing product, the prescriber should carefully assess the overall benefit-risk analysis based on the patient's clinical conditions and on all available information for the various mesalamine-containing products.

 

Drug Interactions

There are no known drug interactions. The effects of coadministration of Asacol with cimetidine, with an antacid containing activated dimethicone and aluminum hydroxide, or with an antacid accompanied by a high fat meal were addressed in a clinical study. There were no significant in vivo effects on mesalamine release or the extent of drug absorption from Asacol by any of the 3 treatments. It has been reported that simultaneous administration of famotidine, a potent H₂-antagonist, and Asacol does not influence the absorption and urinary excretion of mesalamine.

     Asacol should not be administered with preparations which lower the stool pH, such as lactulose.

     Interactions similar to ASA cannot be excluded.

 

Pregnancy

In reproduction studies, mesalamine was administered orally at a dosage of 480 mg/kg/day to pregnant rats and rabbits. No evidence of impaired female fertility or harm to the fetus due to therapy with Asacol was observed. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.

 

Lactation

It has been reported that small amounts of 5-ASA and higher concentrations of acetyl-5-ASA are found in breast milk. While the clinical significance of this has not been determined, caution should be exercised when Asacol is administered to a nursing woman.

 

Children

Safety and effectiveness of Asacol therapy in children have not been established.

Information to Be Provided to the Patient

1. Swallow tablets whole, taking care not to break the outer coating. The outer coating is designed to remain intact, to protect the active ingredient until it reaches the terminal ileum, where the tablet coating dissolves and the contents of the tablet are released into the terminal ileum and colon.

2. Take Asacol tablets only as prescribed. Do not change the number or frequency of tablets ingested without first consulting your physician.

3. What appears to be intact or partially intact tablets may infrequently appear in the stool. If this occurs repeatedly, consult your physician.

 

     Patients with ulcerative colitis should be made aware that ulcerative colitis rarely remits completely. Thus, it is important for patients to closely comply with the maintenance dosage prescribed by their doctors. By doing so, the risk of relapse can be substantially reduced.

 

Adverse Effects

Asacol is generally well tolerated. Adverse events seen in clinical trials with Asacol tablets have generally been mild and reversible, and have seldom resulted in discontinuation of treatment. Because Asacol does not contain a sulfa moiety, sulfa-related side effects are avoided. Many patients with a history of sulfasalazine intolerance are able to tolerate Asacol as demonstrated in open-label clinical trials. However, some patients who have experienced a hypersensitivity reaction to sulfasalazine may have a similar reaction to Asacol tablets or to other compounds which contain or are converted to mesalamine.

     In 2 short-term (6 weeks), double-blind, placebo-controlled clinical studies involving 245 patients, 155 of whom were randomized to Asacol tablets, 5 (3.2%) of the Asacol patients discontinued Asacol therapy because of adverse events as compared to 2 (2.2%) of the placebo patients. Adverse reactions leading to withdrawal from Asacol tablets include (each in 1 patient): diarrhea and colitis flare; dizziness, nausea, joint pain, and headache; rash, lethargy and constipation; dry mouth, malaise, lower back discomfort, mild disorientation, mild indigestion and cramping; headache, nausea, malaise, aching, vomiting, muscle cramps, a stuffy head, plugged ears, and fever.

     Adverse events occurring at a frequency of greater than 2% in these clinical trials are listed below. Overall, the incidence of adverse events seen with Asacol tablets was similar to placebo.

     Headache, abdominal pain, eructation, pain, nausea, pharyngitis, dizziness, asthenia, diarrhea, back pain, fever, rash, dyspepsia, rhinitis, arthralgia, vomiting, constipation, hypertonia, flatulence, flu syndrome, chills, colitis exacerbation, chest pain, peripheral edema, myalgia, pruritus, sweating, dysmenorrhea.

     Of these adverse events, only rash showed a consistently higher frequency with increasing Asacol dose in these studies.

     The following adverse reactions were seen in 2% of the patients in the controlled studies: malaise, arthritis, insomnia, increased cough, acne, and conjunctivitis.

     In a 6-month placebo-controlled maintenance trial involving 264 patients, 177 of whom were randomized to Asacol tablets, 6 (3.4%) of the Asacol patients discontinued Asacol therapy because of adverse events, as compared to 4 (4.6%) of the placebo patients. Adverse reactions leading to withdrawal from Asacol tablets included (each in 1 patient): anxiety; headache; pruritus, decreased libido; rheumatoid arthritis; and stomatitis and asthenia.

     In the 6-month placebo-controlled maintenance trial, the incidence of adverse events seen with Asacol tablets was similar to that seen with placebo. Adverse events occurring in Asacol 1.6 g/day group at a frequency of 2% or greater are listed in  Table 1.

CPS:Asacol_t1Click here for Table 1

Table 1: Asacol

Frequency (%) of Adverse Events Reported in the Long-term (6 months) Double-blind Controlled Study

 

Event	Placebo (n=87)	Asacol 0.8 g/day (n=90)	Asacol 1.6 g/day (n=87)
Headache	49	52	47
Rhinitis	36	43	40
Diarrhea	49	30	40
Abdominal Pain	44	30	33
Flatulence	30	21	28
Pain	11	19	23
Pharyngitis	15	22	21
Asthenia	16	10	20
Nausea	15	19	17
Fever	13	12	14
Constipation	13	4	13
Back Pain	11	21	10
Flu Syndrome	20	14	10
Colitis Flare	8	8	10
Gastrointestinal Bleeding	8	8	10
Stool Abnormality	8	7	10
Infection	3	7	9
Dizziness	7	8	8
Chest Pain	6	8	8
Arthralgia	9	7	8
Myalgia	5	7	8
Increased Cough	16	12	7
Sinusitis	6	7	7
Tenesmus	5	6	7
Rectal Disorder	2	1	7
Vomiting	7	6	6
Nervousness	2	6	6
Dyspepsia	9	9	5
Insomnia	5	4	5
Hypertonia	3	4	5
Gastroenteritis	1	2	5
Malaise	3	1	5
Dysmenorrhea	2	1	5
Paresthesia	5	0	5
Pruritus	7	2	3
Joint Disorder	0	2	3
Increased Urination	0	2	3
Vision Abnormality	0	1	3
Hematuria	1	0	3
Lung Disorder	0	0	3
Rectal Bleeding	5	4	2
Anxiety	2	3	2
Bronchitis	2	3	2
Abdomen Enlargement	0	3	2
Arthritis	2	1	2
Dysuria	1	1	2
Monilia Vagina	1	1	2
Amblyopia	0	1	2
Dry Mouth	0	1	2
Epistaxis	0	1	2
Lacrimation Disorder	0	1	2
Prostate Disorder	0	1	2
Somnolence	3	0	2
Urticaria	1	0	2
Asthma	0	0	2
Cystitis	0	0	2
Deaf	0	0	2
Vaginitis	0	0	2

 

     In addition, the following adverse reactions were seen in 1% of patients receiving Asacol 1.6 g/day in the maintenance study: migraine, ear disorder, rash, vasodilation, allergic reaction, dyspnea, chills, pneumonia, urine abnormality, peripheral edema, palpitations, anorexia, depression, urinary tract infection, leg cramps, alopecia and sweating.

     In uncontrolled clinical studies, the following adverse events occured at a frequency of 5% or greater and appeared to increase in frequency with increasing dose: asthenia, flu syndrome, back pain, arthralgia, and rhinitis.

     In addition to the adverse events listed above, the following adverse events have also been reported in controlled clinical trials, open-label studies, literature reports, or foreign and domestic marketing experience. Because many of these events were reported voluntarily from a population of unknown size, estimates of frequency cannot be made. The relationship of the reported events to Asacol is unclear in many cases, some, including anorexia, joint pain, pyoderma gangrenosum, oral ulcers, and anemia are sometimes part of the clinical presentation of ulcerative colitis.

 

Body as a Whole

neck pain, abdominal enlargement, facial edema, edema, lupus-like syndrome.

 

Cardiovascular

pericarditis (rare), myocarditis (rare), vasodilation, migraine.

 

Digestive

anorexia, hepatitis (rare), pancreatitis, gastroenteritis, gastritis, increased appetite, cholecystitis, dry mouth, oral ulcers, perforated peptic ulcer (rare), bloody diarrhea, tenesmus.

 

Hematologic

agranulocytosis (rare), aplastic anemia (rare), thrombocytopenia, eosinophilia, leukopenia, anemia, lymphadenopathy.

 

Musculoskeletal

gout.

 

Nervous

anxiety, depression, somnolence, emotional lability, hyperesthesia, vertigo, nervousness, confusion, paresthesia, tremor, peripheral neuropathy (rare), Guillain-Barré syndrome (rare), and transverse myelitis (rare).

 

Respiratory/Pulmonary

sinusitis, eosinophilic pneumonia, interstitial pneumonitis, asthma exacerbation, pleuritis.

 

Skin

alopecia, psoriasis (rare), pyoderma gangrenosum (rare), dry skin, erythema nodosum, urticaria.

Special Senses

ear pain, eye pain, taste perversion, blurred vision, tinnitus.

 

Urogenital

interstitial nephritis (see also Warnings), minimal change nephropathy (see also Warnings), dysuria, urinary urgency, hematuria, epididymitis, menorrhagia.

Laboratory Abnormalities

elevated AST or ALT, elevated alkaline phosphatase, elevated serum creatinine and BUN.

Hepatic

Asymptomatic elevations of liver function tests have occurred in patients taking Asacol tablets. These elevations usually resolve during continued therapy or with discontinuation of Asacol. When any elevations in liver enzymes are assessed, it should be kept in mind that hepatic complications are frequently associated with inflammatory bowel disease.

 

Overdose

 

     Two cases of pediatric overdosage have been reported. A 3-year-old male ingested 2 g of Asacol tablets. He was treated with ipecac and activated charcoal. No adverse events occurred. Another 3-year-old male, approximately 16 kg, ingested an unknown amount of a maximum of 24 g of Asacol crushed in solution (i.e., uncoated mesalamine). He was treated with orange juice and activated charcoal and experienced no adverse events.

 

 

Treatment

Mesalamine is not metabolized to salicylate. If the amount ingested is considered dangerous or excessive, induce vomiting with ipecac syrup unless the patient is convulsing, comatose, or has lost the gag reflex, in which case perform gastric lavage using a large bore tube. If indicated, follow with activated charcoal and a saline cathartic. There is no specific antidote and treatment is symptomatic and supportive.

 

Dosage

For the treatment of mildly to moderately active ulcerative colitis: Usual daily adult dose is 2 to 8 Asacol 400 mg tablets, taken orally in divided doses. In patients with severe active disease, the dose may be increased to 12 tablets daily.

For the maintenance of remission of ulcerative colitis: The recommended dosage in adults is 4 tablets, taken orally in divided doses. The treatment duration in a well-controlled clinical trial was 6 months.

     Abrupt discontinuation is not recommended.

     Patients with ulcerative colitis should be made aware that ulcerative colitis rarely remits completely. Thus, it is important for patients to closely comply with the maintenance dosage prescribed by their doctors. By doing so, the risk of relapse can be substantially reduced.

 

Supplied

Each brown-red, capsule-shaped, enteric-coated tablet, printed in black ink with “ASACOL NE”, contains: 5-ASA 400 mg (mesalamine), coated with a special acrylic-based resin, Eudragit S (methacrylic acid copolymer Type B [USP]), which delays release of the 5-ASA until the tablet reaches the terminal ileum. Nonmedicinal ingredients: dibutyl phthalate, Eudragit S (methacrylic acid copolymer Type B [USP]), iron oxide red, iron oxide yellow, lactose, magnesium stearate, polyethylene glycol, polyvinylpyrrolidone, sodium starch glycolate and talc. Bottles of 180. Store at controlled room temperature (15 to 30°C).