Asacol

Unless your doctor tells you otherwise, continue your normal diet.

Included as part of the PRECAUTIONS section.

Mechanism Of Action

The mechanism of action of mesalamine is unknown, but appears to be topical rather than systemic. Mucosal production of arachidonic acid metabolites, both through the cyclooxygenase pathways, that is, prostanoids, and through the lipoxygenase pathways, that is, leukotrienes and hydroxyeicosatetraenoic acids, is increased in patients with chronic ulcerative colitis, and it is possible that mesalamine diminishes inflammation by blocking cyclooxygenase and inhibiting prostaglandin production in the colon.

Pharmacokinetics

Approximately 28 percent of mesalamine in Asacol tablets is absorbed after oral ingestion. Absorption of mesalamine is similar in fasted and fed subjects. The T max for mesalamine and its metabolite, is usually delayed, reflecting the delayed-release, and ranges from 4 to 16 hours.

The absorbed mesalamine is rapidly acetylated in the gut mucosal wall and by the liver to N-acetyl-5aminosalicylic acid.

Absorbed mesalamine is excreted mainly by the kidney as N-acetyl-5-aminosalicylic acid. Unabsorbed mesalamine is excreted in feces.

After intravenous administration, the elimination half-life of mesalamine is reported to be approximately 40 minutes. After oral dosing, the terminal t½ values for mesalamine and N-acetyl-5-aminosalicylic acid are usually about 12 hours, but are variable, ranging from 2 to 15 hours. There is a large inter-subject and intra-subject variability in the plasma concentrations of mesalamine and N-acetyl-5aminosalicylic acid and in their elimination half-lives following administration of Asacol.

Specific Populations

In a dose-ranging PK study evaluating 30, 60 and 90 mg/kg/day doses of Asacol administered twice daily for four weeks, the mean Cavg values of mesalamine in pediatric ulcerative colitis patients ranged from approximately 400 ng/mL to 2100 ng/mL based on data from all dose levels.

In a study in pediatric ulcerative colitis patients (Study 3), mean plasma concentrations of mesalamine (based on sparse sampling) were 820 to 988 ng/mL at the low dose level (that is, 1.2, 2.0 or 2.4 g/day based on body weight strata of 17 to greater than 33 kg, 33 to less than 54 kg, and 54 to less than 90 kg, respectively).

Animal Toxicology And/Or Pharmacology

In animal studies (rats, mice, dogs), the kidney was the principal organ for toxicity. (In the following, comparisons of animal dosing to recommended human dosing are based on body surface area and a 2.4 g/day dose for a 60 kg person.)

Mesalamine causes renal papillary necrosis in rats at single doses of approximately 750 mg/kg to 1000 mg/kg (approximately 3 to 4 times the recommended human dose based on body surface area). Doses of 170 and 360 mg/kg/day (about 0.7 and 1.5 times the recommended human dose based on body surface area) given to rats for six months produced papillary necrosis, papillary edema, tubular degeneration, tubular mineralization, and urothelial hyperplasia.

In mice, oral doses of 4000 mg/kg/day mesalamine (approximately 8 times the recommended human dose based on body surface area) for three months produced tubular nephrosis, multifocal/diffuse tubulo-interstitial inflammation, and multifocal/diffuse papillary necrosis.

In dogs, single doses of 6000 mg (approximately 8 times the recommended human dose based on body surface area) of delayed-release mesalamine tablets resulted in renal papillary necrosis but were not fatal. Renal changes have occurred in dogs given chronic administration of mesalamine at doses of 80 mg/kg/day (1.1 times the recommended human dose based on body surface area).

Clinical Studies

Treatment Of Mildly To Moderately Active Ulcerative Colitis

Two placebo-controlled studies (Studies 1 and 2) have demonstrated the efficacy of Asacol tablets in patients with mildly to moderately active ulcerative colitis.

In one randomized, double-blind, multi-center trial of 158 patients (Study 1), Asacol doses of 1.6 g/day and 2.4 g/day for 6 weeks were compared to placebo. The scoring system for determination of treatment efficacy included assessment of stool frequency, rectal bleeding, sigmoidoscopic findings, patient's functional assessment, and physician global assessment. At the dose of 2.4 g/day, 21 of 43 (49 percent) patients using Asacol tablets showed an improvement in sigmoidoscopic appearance of the bowel compared to 12 of 44 (27 percent) patients using placebo (p = 0.048). In addition, significantly more patients in the Asacol tablets 2.4 g/day group showed improvement in rectal bleeding and stool frequency. The 1.6 g/day dose did not produce consistent evidence of effectiveness.

In a second randomized, double-blind, placebo-controlled clinical trial of 6 weeks duration in 87 patients (Study 2), Asacol tablets, at a dose of 4.8 g/day, for 6 weeks, resulted in sigmoidoscopic improvement in 28 of 38 (74 percent) patients compared to 10 of 38 (26 percent) placebo patients (p less than 0.001). Also, more patients in the Asacol tablets 4.8 g/day group than the placebo group showed improvement in overall symptoms.

The 4.8 g/day dose is not an approved dosage for the treatment of mildly to moderately active ulcerative colitis.

The safety and effectiveness of Asacol in pediatric patients 5 to 17 years of age for treatment of mildly to moderately active ulcerative colitis are supported by evidence from adequate and well controlled studies of Asacol in adults and a single study in pediatric patients.

A randomized, double-blind, 6-week study of 2 dose levels of Asacol (Study 3) was conducted in 82 pediatric patients 5 to 17 years of age with mildly or moderately active ulcerative colitis. All patients were divided by weight category (17 to less than 33 kg, 33 to less than 54 kg, and 54 to 90 kg) and randomly assigned to receive a low dose (1.2, 2.0, and 2.4 g/day for the respective weight category) or a high dose (2.0, 3.6, and 4.8 g/day). Doses were administered every 12 hours.

The proportion of patients who achieved success based on the Truncated Mayo Score (TM-Mayo) (based on the stool frequency and rectal bleeding subscores of the Mayo Score) and based on the Pediatric Ulcerative Colitis Activity Index (PUCAI) (which included assessment of abdominal pain, rectal bleeding, stool consistency and frequency, presence of nocturnal bowel movement and level of activity) was measured after 6 weeks of treatment. Success based on TM-Mayo was defined as either partial response (improvement from baseline in stool frequency or rectal bleeding subscores with no worsening in the other) or complete response (both stool frequency and rectal bleeding subscores equal 0). Success based on PUCAI was defined as either partial response (PUCAI reduction of greater than or equal to 20 points from Baseline to Week 6 with Week 6 score greater than or equal to 10) or complete response (PUCAI less than 10 at Week 6).

There were 41 patients in the low dose group and 41 patients in the high dose group who received at least one dose of Asacol; 36 patients in each dose group completed the study. Patients were considered treatment failures if they did not achieve success or dropped out due to adverse reaction or lack of efficacy.

At Week 6, 73.2 percent of the patients in the low dose group, and 70.0 percent of the patients in the high dose group achieved success based on the TM-Mayo; 34.1 percent of the patients in the low dose group and 42.5 percent of the patients in the high dose group achieved complete response. At Week 6, 56.1 percent of the patients in the low dose group, and 55.0 percent of the patients in the high dose group achieved success based on the PUCAI; 46.3 percent of the patients in the low dose group and 42.5 percent of the patients in the high dose group achieved complete response.

The high dose was not more effective than the low dose and is not an approved dosage [see DOSAGE AND ADMINISTRATION].

Maintenance Of Remission Of Ulcerative Colitis In Adults

A 6-month, randomized, double-blind, placebo-controlled, multi-center study (Study 4) involved 264 patients treated with Asacol tablets 0.8 g/day (n = 90), 1.6 g/day (n = 87), or placebo (n = 87). In the 0.8 g/day arm, patients were dosed twice daily; in the 1.6 g/day arm, patients were dosed four times daily. The proportion of patients treated with 0.8 g/day who maintained endoscopic remission was not statistically significant compared to placebo. The proportion of patients using Asacol tablets 1.6 g/day who maintained endoscopic remission of ulcerative colitis was in 61 of 87 (70.1 percent) compared with 42 of 87 (48.3 percent) of placebo patients (p = 0.005).

A pooled efficacy analysis of 4 maintenance trials compared Asacol tablets, at doses of 0.8 g/day to 2.8 g/day, in divided doses ranging from twice daily to four times per day, with sulfasalazine, at doses of 2 g/day to 4 g/day. Treatment success was seen in 59 of 98 (59 percent) patients using Asacol tablets and 70 of 102 (69 percent) of patients using sulfasalazine, a non-significant difference.

Tell your doctor about all the medicines you take including prescription and non-prescription medicines, vitamins, and herbal supplements. Especially tell your doctor if you take:

• medicines that can damage the kidneys, including non-steroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen (Advil) and aspirin (Ecotrin)
• azathioprine (Imuran)
• 6-mercaptopurine (Purinethol)
• antacids such as Maalox, Mylanta, Mag-Ox, Caltrate, Tums, or Rolaids

This is not a complete list of Asacol drug interactions.  Ask your doctor or pharmacist for more information.

Take Asacol exactly as prescribed. Do not change the dose or stop taking Asacol without talking to your doctor.

Asacol comes in delayed-release tablets and are usually taken 3 times a day, with or without food.

Asacol also comes in a high dose delayed-release tablet (Asacol HD). It is taken 3 times a day, with or without food.

Swallow tablets whole (do not chew, crush, or split).

• If you have an allergy to mesalamine, salicylates, sulfasalazine, or any other part of Asacol (mesalamine tablets).
• If you are allergic to any drugs like this one, any other drugs, foods, or other substances. Tell your doctor about the allergy and what signs you had, like rash; hives; itching; shortness of breath; wheezing; cough; swelling of face, lips, tongue, or throat; or any other signs.
• If you have any of these health problems: Kidney disease or liver disease.
• If you have had the varicella vaccine in the past 6 weeks.

This is not a list of all drugs or health problems that interact with this medicine.

Tell your doctor and pharmacist about all of your drugs (prescription or OTC, natural products, vitamins) and health problems. You must check to make sure that it is safe for you to take Asacol with all of your drugs and health problems. Do not start, stop, or change the dose of any drug without checking with your doctor.

• If your symptoms or health problems do not get better or if they become worse, call your doctor.
• Do not share your drugs with others and do not take anyone else's drugs.
• Keep a list of all your drugs (prescription, natural products, vitamins, OTC) with you. Give this list to your doctor.
• Talk with the doctor before starting any new drug, including prescription or OTC, natural products, or vitamins.
• Some drugs may have another patient information leaflet. Check with your pharmacist. If you have any questions about Asacol (mesalamine tablets), please talk with your doctor, nurse, pharmacist, or other health care provider.
• If you think there has been an overdose, call your poison control center or get medical care right away. Be ready to tell or show what was taken, how much, and when it happened.

This information should not be used to decide whether or not to take this medicine or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a brief summary of general information about Asacol. It does NOT include all information about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this medicine. This information is not specific medical advice and does not replace information you receive from the healthcare provider. You must talk with the healthcare provider for complete information about the risks and benefits of using Asacol.

Review Date: October 4, 2017

1.1 Treatment of Mildly to Moderately Active Ulcerative Colitis

Asacol® is indicated for the treatment of mildly to moderately active ulcerative colitis in patients 5 years of age and older.

1.2 Maintenance of Remission of Mildly to Moderately Active Ulcerative Colitis

Asacol is indicated for the maintenance of remission of mildly to moderately active ulcerative colitis in adults.

The most serious adverse reactions seen in Asacol clinical trials or with other products that contain mesalamine or are metabolized to mesalamine are:

• Renal Impairment [see Warnings and Precautions (5.1)]
  
• Mesalamine-Induced Acute Intolerance Syndrome [see Warnings and Precautions (5.2)] 
  
• Hypersensitivity Reactions [see Warnings and Precautions (5.3)]
  
• Hepatic Failure [see Warnings and Precautions (5.4)]

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug, and may not reflect the rates observed in practice.

In total, Asacol tablets have been evaluated in 2,690 patients with ulcerative colitis in controlled and open-label trials.

Clinical studies supporting Asacol use for the treatment of mildly to moderately active ulcerative colitis included two 6-week, placebo-controlled, randomized, double-blind studies in adults with mildly to moderately active ulcerative colitis (Studies 1 and 2), and one 6-week, randomized, double-blind, study of 2 dosage levels in children with mildly to moderately active ulcerative colitis (Study 3). Clinical studies supporting the use of Asacol tablets in the maintenance of remission of mildly to moderately active ulcerative colitis included a 6-month, randomized, double-blind, placebo-controlled, multi-center study (Study 4) and four active-controlled maintenance trials comparing Asacol tablets with sulfasalazine. Asacol has been evaluated in 427 adults and 82 children with ulcerative colitis in these controlled studies.

Treatment of Mildly to Moderately Active Ulcerative Colitis

Adults

In a 6-week placebo-controlled clinical study (Study 1) involving 105 patients, 53 of whom were randomized to Asacol 2.4 grams/day [see Clinical Studies (14.1)], 4% of the Asacol-treated patients in 2.4 grams/day group discontinued therapy because of adverse reactions as compared to 0% of the placebo-treated patients. The average age of patients was 41 years and 49% of patients were male. Adverse reactions leading to withdrawal from Asacol included (each in one patient): diarrhea and colitis flare; dizziness, nausea, joint pain, and headache.

The most common adverse reactions in patients treated with Asacol 2.4 grams/day in Study 1 are listed in Table 2 below.

* At Least 2% of Patients in the Asacol Group and at a Rate Greater than Placebo

Pediatric Patients 5 to 17 Years Old

A randomized, double-blind, 6-week study of 2 dosage levels of Asacol (Study 3) was conducted in 82 pediatric patients 5 to 17 years of age with mildly to moderately active ulcerative colitis. All patients were divided by body weight category (17 to less than 33 kg, 33 to less than 54 kg, and 54 to 90 kg) and randomly assigned to receive a low dosage (1.2, 2, and 2.4 grams/day for the respective body weight category) or a high dosage (2, 3.6, and 4.8 grams/day).

The high dosage regimen is not recommended because it was not found to be more effective than the recommended low dosage regimen [see Dosage and Administration (2.1) and Clinical Studies (14.1)].

Duration of exposure to Asacol among the 82 patients in the study ranged from 12 to 50 days (mean of 40 days in each dosage group). The majority (88%) of patients in each group were treated for more than 5 weeks. Table 3 provides a summary of the specific reported adverse reactions.

* At Least 5% of Patients in the low dosage or high dosage group

Twelve percent of the patients in the low dosage group (5 patients) and 2% of the patients in the high dosage group (1 patient) had serious adverse reactions. The serious adverse reactions consisted of sinusitis, adenovirus infection, and pancreatitis in one patient each in the low dosage group. Abdominal pain and decreased body mass index occurred in one patient and bloody diarrhea and sclerosing cholangitis also occurred in one patient in the low dosage group. Anemia and syncope occurred in one patient in the high dosage group.

Five patients were withdrawn from the study due to adverse reactions: 3 (7%) in the low dosage group (1 patient each with adenovirus infection, sclerosing cholangitis, and pancreatitis) and 2 patients (5%) in the high dosage group (1 patient with increased amylase and increased lipase, and 1 patient with upper abdominal pain).  

In general, the nature and severity of reactions in the pediatric population was similar to those reported in adult populations of patients with ulcerative colitis.

Maintenance of Remission of Mildly to Moderately Active Ulcerative Colitis

Clinical studies supporting the use of Asacol tablets in the maintenance of remission of mildly to moderately active ulcerative colitis in adults included a randomized, double-blind, multi-center, placebo-controlled clinical trial of 6 months’ duration in 264 patients (Study 4 [see Clinical Studies (14.2)].

In Study 4, a randomized, double-blind, multi-center, placebo-controlled clinical trial of 6 months’ duration, 87 patients were randomized to receive Asacol 1.6 grams/day compared to 87 patients randomized to placebo. The average age of patients in Study 4 was 42 years and 55 % of patients were male. Adverse reactions leading to study withdrawal in patients using Asacol included (each in one patient): anxiety, stomatitis and asthenia.

In addition to the adverse reactions listed in Table 2, the following occurred at a frequency of 2% or greater in patients who received Asacol in Study 4: abdominal enlargement, gastroenteritis, gastrointestinal hemorrhage, infection, joint disorder, nervousness, paresthesia, hemorrhoids, tenesmus, urinary frequency, and vision abnormalities.

6.2 Postmarketing Experience

In addition to the adverse reactions reported above in clinical trials involving Asacol, the adverse reactions listed below have been identified during post-approval use of Asacol and other mesalamine-containing products. 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.

Body as a Whole: Neck pain, facial edema, edema, lupus-like syndrome, drug fever.

Cardiovascular: Pericarditis, myocarditis [see Warnings and Precautions (5.3)].

Gastrointestinal: Anorexia, pancreatitis, gastritis, increased appetite, cholecystitis, dry mouth, oral ulcers, perforated peptic ulcer, bloody diarrhea.

Hematologic: Agranulocytosis aplastic anemia, thrombocytopenia, eosinophilia, leukopenia, anemia, lymphadenopathy.

Musculoskeletal: Gout.

Nervous: Depression, somnolence, emotional lability, hyperesthesia, vertigo, confusion, tremor, peripheral neuropathy, transverse myelitis, Guillain-Barré syndrome.

Renal: Renal failure, interstitial nephritis, minimal change nephropathy [see Warnings and Precautions (5.1)].

Respiratory/Pulmonary: Eosinophilic pneumonia, interstitial pneumonitis, asthma exacerbation, pleuritis.

Skin: Alopecia, psoriasis, pyoderma gangrenosus, dry skin, erythema nodosum, urticaria.

Special Senses: Eye pain, taste perversion, blurred vision, tinnitus.

Urogenital: Dysuria, urinary urgency, hematuria, epididymitis, menorrhagia, reversible oligospermia.

Laboratory Abnormalities: Elevated AST (SGOT) or ALT (SGPT), elevated alkaline phosphatase, elevated GGT, elevated LDH, elevated bilirubin, elevated serum creatinine and BUN.

You should not use Asacol if you are allergic to mesalamine, aspirin, sulfasalazine, or salicylates (such as Nuprin Backache Caplet, Kaopectate, KneeRelief, Pamprin Cramp Formula, Pepto-Bismol, Tricosal, Trilisate, and others).

To make sure Asacol is safe for you, tell your doctor if you have:

• a stomach condition called pyloric stenosis;

• heart disease;

• kidney disease;

• liver disease; or

• a history of blockage in your digestive tract (stomach or intestines).

It is not known whether Asacol will harm an unborn baby. Tell your doctor if you are pregnant or plan to become pregnant.

Mesalamine can pass into breast milk and may harm a nursing baby. Tell your doctor if you are breast-feeding a baby.

Do not give this medicine to a child without medical advice.

Seek emergency medical attention or call the Poison Help line at 1-800-222-1222.