Canasa

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

• Renal Impairment [see WARNINGS AND PRECAUTIONS]
• Mesalamine-Induced Acute Intolerance Syndrome [see WARNINGS AND PRECAUTIONS]
• Hypersensitivity Reactions [see WARNINGS AND PRECAUTIONS]
• Hepatic Failure [see WARNINGS AND PRECAUTIONS]

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.

The most common adverse reactions in adult patients with mildly to moderately active ulcerative proctitis in double-blind, placebo-controlled trials are summarized in the Table 1 below.

Table 1: Adverse Reactions Occurring In More Than 1% of Mesalamine Suppository Treated Patients (Comparison to Placebo)

In a multicenter, open-label, randomized, parallel group study in 99 patients comparing the CANASA 1000 mg suppository administered nightly to that of the mesalamine 500 mg suppository twice daily. The most common adverse reactions in both groups were headache (14%), flatulence (5%), abdominal pain (5%), diarrhea (3%), and nausea (3%). Three (3) patients discontinued medication because of an adverse reaction; one of these adverse reactions (headache) was deemed possibly related to study medication. The recommended dosage of CANASA is 1000 mg administered rectally once daily at bedtime [see DOSAGE AND ADMINISTRATION].

Postmarketing Experience

In addition to the adverse reactions reported above in clinical trials involving CANASA, the adverse reactions listed below have been identified during post-approval use of CANASA 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: drug fever, fatigue, lupus-like syndrome, medication residue
• Cardiac Disorders: myocarditis, pericarditis, pericardial effusion [see WARNINGS AND PRECAUTIONS]
• Eye disorders: eye swelling
• Gastrointestinal Disorders: abdominal cramps, abdominal distension, anal pruritus, anorectal discomfort, constipation, feces discolored, flatulence, frequent bowel movements, gastrointestinal bleeding, mucus stools, nausea, painful defecation, pancreatitis, proctalgia, rectal discharge, rectal tenesmus, stomach discomfort, vomiting
• Hepatic Disorders: cholestatic jaundice, hepatitis, jaundice, Kawasaki-like syndrome including changes in liver enzymes, liver necrosis, liver failure
• Hematologic Disorders: agranulocytosis, aplastic anemia, thrombocytopenia
• Neurological/Psychiatric Disorders: Guillain-Barre syndrome, peripheral neuropathy, transverse myelitis
• Renal Disorders: interstitial nephritis, renal failure, minimal change nephropathy [see WARNINGS AND PRECAUTIONS]
• Respiratory, Thoracic and Mediastinal Disorders: hypersensitivity pneumonitis (including allergic alveolitis, eosinophilic pneumonitis, interstitial pneumonitis)
• Skin and Subcutaneous Tissue Disorder: alopecia, erythema, erythema nodosum, pruritus, psoriasis, pyoderma gangrenosum, urticaria
• Urogenital: reversible oligospermia

There have been no documented reports of serious toxicity in man resulting from massive overdosing with mesalamine suppository. Under ordinary circumstances, mesalamine absorption from the colon is limited.

Mechanism Of Action

The mechanism of action of mesalamine is not fully understood, but appears to be topical rather than systemic. Although the pathology of inflammatory bowel disease is uncertain, both prostaglandins and leukotrienes have been implicated as mediators of mucosal injury and inflammation.

Pharmacokinetics

Mesalamine (5-ASA) administered as a rectal suppository is variably absorbed. 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.

Mesalamine administered as a rectal suppository distributes in rectal tissue to some extent.

In patients with ulcerative proctitis treated with mesalamine 500 mg as a rectal suppository every 8 hours for 6 days, the mean elimination half-life was 5 hours (CV=73%) for 5-ASA and 5 hours (CV=63%) for N-acetyl-5-ASA, the active metabolite, following the initial dose. At steady state, the mean elimination half-life was 7 hours for both 5-ASA and N-acetyl-5-ASA (CV=102% for 5ASA and 82% for N-acetyl-5-ASA).

Metabolism

The absorbed mesalamine is extensively metabolized, mainly to N-acetyl-5-ASA in the liver and in the gut mucosal wall. In patients with ulcerative colitis treated with one mesalamine 500 mg rectal suppository every eight hours for six days, the peak concentration (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.

Excretion

Mesalamine is eliminated from plasma mainly by urinary excretion, predominantly as N-acetyl-5-ASA. In patients with ulcerative proctitis treated with mesalamine 500 mg as a rectal suppository every 8 hours for 6 days, 12% or less of the dose was eliminated in urine as unchanged 5-ASA and 8% to 77% was eliminated as N-acetyl-5-ASA following the initial dose. At steady state, 11% or less of the dose was eliminated in the urine as unchanged 5-ASA and 3% to 35% was eliminated as N-acetyl-5-ASA.

Animal Toxicology And/Or Pharmacology

Toxicology studies of mesalamine were conducted in rats, mice, rabbits and dogs, and the kidney was the main target organ of toxicity. In rats, adverse renal effects were observed at a single oral dose of 600 mg/kg (about 3.2 times the recommended human intra-rectal dose of CANASA, based on body surface area) and at intravenous doses of >214 mg/kg (about 1.2 times the recommended human intra-rectal dose of CANASA, based on body surface area). In a 13-week oral gavage toxicity study in rats, papillary necrosis and/or multifocal tubular injury were observed in males receiving 160 mg/kg (about 0.86 times the recommended human intra-rectal dose of CANASA, based on body surface area) and in both males and females at 640 mg/kg (about 3.5 times the recommended human intra-rectal dose of CANASA, based on body surface area). In a combined 52-week toxicity and 127-week carcinogenicity study in rats, degeneration of the kidneys and hyalinization of basement membranes and Bowman’s capsule were observed at oral doses of 100 mg/kg/day (about 0.54 times the recommended human intra-rectal dose of CANASA, based on body surface area) and above. In a 14day rectal toxicity study of mesalamine suppositories in rabbits, intra-rectal doses up to 800 mg/kg (about 8.6 times the recommended human intra-rectal dose of CANASA, based on body surface area) was not associated with any adverse effects. In a six-month oral toxicity study in dogs, doses of 80 mg/kg (about 1.4 times the recommended human intra-rectal dose of CANASA, 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 times the recommended human intra-rectal dose of CANASA, based on body surface area) produced chronic nephritis and pyelitis. In the 12-month eye toxicity study in dogs, keratoconjunctivitis sicca (KCS) occurred at oral doses of 40 mg/kg (about 0.72 times the recommended human intra-rectal dose of CANASA, based on body surface area) and above.

Clinical Studies

Two double-blind, placebo-controlled, multicenter trials of mesalamine suppositories were conducted in North America in adult patients with mildly to moderately active ulcerative proctitis. The regimen in Study 1 was a 500 mg mesalamine suppository administered rectally three times daily and in Study 2 was a 500 mg mesalamine suppository administered rectally twice daily. In both trials, patients had an average extent of proctitis (upper disease boundary) of approximately 10 cm and approximately 80% of patients had multiple prior episodes of proctitis. A total of 173 patients were evaluated (Study 1, N=79; Study 2, N=94), of which 89 patients received mesalamine, and 84 patients received placebo. The mean age of patients was 39 years (range 17 to 73 years), 60% were female, and 97% were white.

The primary measures of efficacy were clinical disease activity index (DAI) and histologic evaluations in both trials. The DAI is a composite index reflecting rectal bleeding, stool frequency, mucosal appearance at endoscopy, and a physician’s global assessment of disease. Patients were evaluated clinically and sigmoidoscopically after 3 and 6 weeks of treatment.

Compared to placebo, mesalamine suppositories were statistically (p<0.01) superior to placebo in both trials with respect to improvement in stool frequency, rectal bleeding, mucosal appearance, disease severity, and overall disease activity after 3 and 6 weeks of treatment. The effectiveness of mesalamine suppositories was statistically significant irrespective of sex, extent of proctitis, duration of current episode, or duration of disease.

An additional multicenter, open-label, randomized, parallel group study in 99 patients diagnosed with mildly to moderately ulcerative proctitis compared 1000 mg CANASA administered rectally once daily at bedtime (N=35) to 500 mg mesalamine suppository administered rectally twice daily, in the morning and at bedtime (N=46), for 6 weeks.

The primary measures of efficacy included the clinical disease activity index (DAI) and histologic evaluations. Patients were evaluated clinically and sigmoidoscopically at 3 and 6 weeks of treatment.

The efficacy at 6 weeks was not different between the treatment groups. Both were effective in the treatment of ulcerative proctitis and resulted in a significant decrease at 6 weeks in DAI: in the mesalamine 500 mg twice daily group, the mean DAI value decreased from 6.6 to 1.6, and in the 1000 mg at bedtime group, the mean DAI value decreased from 6.2 to 1.3, which represents a decrease of greater than 75% in both groups. After 6 weeks of treatment, a DAI score of less than 3 was achieved in 78% of patients in the mesalamine 500 mg twice daily group and 86% of patients in the CANASA 1000 mg once daily group. The recommended dosage of CANASA is 1000 mg administered rectally once daily at bedtime [see DOSAGE AND ADMINISTRATION].

Canasa is a prescription medication used to treat ulcerative proctitis (swelling in the rectum). 

This medication may be prescribed for other uses. Ask your doctor or pharmacist for more information.

Serious side effects have been reported with Canasa including:

• Kidney problems. Tell your doctor if you take non-steroidal anti-inflammatory drugs or have kidney disease. Your doctor will check your kidney function with a simple blood test before you start using Canasa.
• Mesalamine may worsen ulcerative colitis. Tell your doctor if you experience the following symptoms:
  • cramping
  • acute abdominal pain
  • bloody diarrhea
  • fever
  • headache
  • rash
• Hypersensitivity reaction. An allergic reaction is possible with Canasa. Tell your doctor if you are allergic to sulfasalazine (Azulfidine) or Canasa. Serious reactions can lead to heart problems, like myocarditis or pericarditis.
• Liver failure is possible with Canasa. Tell your doctor if you have liver disease.
• Upper GI tract obstruction. Pyloric stenosis or an obstruction in the digestive tract could prevent Canasa from reaching the colon and treating ulcerative colitis.
• Pericarditis (inflammation of the lining around the heart). Tell your doctor if you experience symptoms of pericarditis including chest pain, rapid heartbeat, difficulty breathing, and fever. Your doctor may want to temporarily stop use of Canasa.

Do not use Canasa if you:

• have kidney disease
• are allergic to mesalamine or any ingredients in Canasa
• are allergic to salicylates (including aspirin)

If you take too much this medication, call your healthcare provider or local Poison Control Center, or seek emergency medical attention right away.

WARNING/CAUTION: Even though it may be rare, some people may have very bad and sometimes deadly side effects when taking a drug. Tell your doctor or get medical help right away if you have any of the following signs or symptoms that may be related to a very bad side effect:

• Signs of an allergic reaction, like rash; hives; itching; red, swollen, blistered, or peeling skin with or without fever; wheezing; tightness in the chest or throat; trouble breathing or talking; unusual hoarseness; or swelling of the mouth, face, lips, tongue, or throat.
• Signs of liver problems like dark urine, feeling tired, not hungry, upset stomach or stomach pain, light-colored stools, throwing up, or yellow skin or eyes.
• Signs of kidney problems like unable to pass urine, change in how much urine is passed, blood in the urine, or a big weight gain.
• Chest pain or pressure.
• Throwing up blood or throw up that looks like coffee grounds.
• A burning, numbness, or tingling feeling that is not normal.
• Feeling confused.
• A fast heartbeat.
• A heartbeat that does not feel normal.
• Fever or chills.
• Very bad headache.
• Very bad dizziness.
• Very bad back pain.
• Shortness of breath, a big weight gain, or swelling in the arms or legs.
• Any unexplained bruising or bleeding.
• Feeling very tired or weak.
• Some people may have a reaction to this medicine that looks like the signs of ulcerative colitis. Call your doctor right away if you have very bad belly pain or cramps, bloody stools, fever, headache, or rash.

Canasa is contraindicated in patients with known or suspected hypersensitivity to salicylates or aminosalicylates or to any ingredients in the suppository vehicle [see Warnings and Precautions (5.3), Adverse Reactions (6.2), and Description (11)].

The active ingredient in Canasa 1000 mg suppositories for rectal use is mesalamine, also known as mesalazine or 5-aminosalicylic acid (5-ASA). Chemically, mesalamine is 5-amino-2-hydroxybenzoic acid, and is classified as an anti-inflammatory drug. Each Canasa rectal suppository contains 1000 mg of mesalamine (USP) in a base of Hard Fat, NF.

The empirical formula is C7H7NO3, representing a molecular weight of 153.14. The structural formula is: