Highlights of prescribing information

HIGHLIGHTS OF PRESCRIBING INFORMATION
Hepatic failure has been reported in patients with pre-existing liver These highlights do not include all the information needed to use
disease. Use caution when treating patients with liver disease. (5.4) CANASA safely and effectively. See full prescribing information for
------------------------------ADVERSE REACTIONS-------------------------------
The most common adverse reactions occurring in more than 1% of CANASA® (mesalamine) rectal suppository
mesalamine suppository treated patients are: dizziness, rectal pain, fever, Initial U.S. Approval: 1987
----------------------------INDICATIONS AND USAGE---------------------------
To report SUSPECTED ADVERSE REACTIONS, contact Aptalis
CANASA is an aminosalicylate indicated for the treatment of mild to Pharma US, Inc. at 1-800-472-2634 or FDA at 1-800-FDA-1088 or
moderately active ulcerative proctitis. Safety and effectiveness of Canasa beyond 6 weeks have not been established. (1) ------------------------------DRUG INTERACTIONS-------------------------------
----------------------DOSAGE AND ADMINISTRATION-----------------------
Nephrotoxic agents including NSAIDs: renal reactions have been The dosage is one 1000 mg rectal suppository once daily at bedtime. (2) Azathioprine or 6-mercaptopurine: blood disorders have been ---------------------DOSAGE FORMS AND STRENGTHS----------------------
-----------------------USE IN SPECIFIC POPULATIONS------------------------
-------------------------------CONTRAINDICATIONS------------------------------
Renal impairment: Use CANASA with caution in patients with a Hypersensitivity to mesalamine or to any components of the formulation (4) history of renal disease. (5.1, 7.1, 8.5, 13.2) Nursing Women: Caution should be exercised when administered -----------------------WARNINGS AND PRECAUTIONS------------------------
Renal impairment may occur. Assess renal function at the Geriatric Patients: Monitor blood cell counts in geriatric patients. beginning of treatment and periodically during treatment. (5.1) Mesalamine-induced acute intolerance syndrome has been reported. Observe patients closely for worsening of these See 17 for PATIENT COUNSELING INFORMATION and FDA-
approved patient labeling.
Use caution when treating patients who are hypersensitive to Revised: 12/2013
Mesalamine-induced cardiac hypersensitivity reactions (myocarditis and pericarditis) have been reported. (5.3) _______________________________________________________________________________________________________________________________________

FULL PRESCRIBING INFORMATION: CONTENTS*
INDICATIONS AND USAGE
DOSAGE AND ADMINISTRATION
10 OVERDOSAGE
DOSAGE FORMS AND STRENGTHS
11 DESCRIPTION
CONTRAINDICATIONS
12 CLINICAL PHARMACOLOGY
WARNINGS AND PRECAUTIONS
5.2 Mesalamine-Induced Acute Intolerance Syndrome 13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 13.2 Animal Toxicology and/or Pharmacology 5.5 Drug-Laboratories Test Interactions 14 CLINICAL STUDIES
ADVERSE REACTIONS
16 HOW SUPPLIED/STORAGE AND HANDLING
17 PATIENT COUNSELING INFORMATION
DRUG INTERACTIONS
USE IN SPECIFIC POPULATIONS
*Sections or subsections omitted from the full prescribing information are not _______________________________________________________________________________________________________________________________________
ADVERSE REACTIONS
FULL PRESCRIBING INFORMATION
The most serious adverse reactions seen in CANASA clinical trials or with other products that contain or are metabolized to mesalamine are: INDICATIONS AND USAGE
Renal impairment, including renal failure [See Warnings and CANASA 1000 mg suppositories are indicated for the treatment of mild to moderately active ulcerative proctitis. Safety and effectiveness of Canasa Mesalamine-induced acute intolerance syndrome [See Warnings and beyond 6 weeks have not been established. Hypersensitivity reactions [See Warnings and Precautions (5.3)] DOSAGE AND ADMINISTRATION
 Hepatic impairment, including hepatic failure [See Warnings and The dosage of CANASA 1000 mg suppositories is one rectal suppository The suppository should be retained for one to three hours or longer, if possible. The usual course of therapy is from three to six weeks depending on 6.1 Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, If a patient misses a dose of CANASA, it should be administered as adverse reaction rates observed in the clinical trials of a drug cannot be soon as possible, unless it is almost time for next dose. Patients should not use directly compared to rates in the clinical trials of another drug and may not two CANASA suppositories at the same time to make up for a missed dose. The most frequent adverse reactions observed in the double-blind, DOSAGE FORMS AND STRENGTHS
placebo-controlled trials are summarized in the Table 1 below. CANASA 1000 mg suppositories for rectal administration are available as bullet shaped, light tan to grey suppositories containing 1000 mg Table 1: ADVERSE REACTIONS OCCURRING IN MORE THAN 1%
OF MESALAMINE SUPPOSITORY TREATED PATIENTS
(COMPARISON TO PLACEBO)
CONTRAINDICATIONS
Mesalamine
CANASA suppositories are contraindicated in patients who have demonstrated hypersensitivity to mesalamine (5-aminosalicylic acid) or to the suppository vehicle [saturated vegetable fatty acid esters (Hard Fat, NF)], or to salicylates (including aspirin) [See Warnings and Precautions (5.3), Adverse Reactions (6.2), and Description (11)]. WARNINGS AND PRECAUTIONS
5.1 Renal Impairment
Renal impairment, including minimal change nephropathy, acute and chronic interstitial nephritis, and, rarely, renal failure, has been reported in In a multicenter, open-label, randomized, parallel group study patients given products such as CANASA that contain mesalamine or are comparing the CANASA 1000 mg suppository administered nightly to that of converted to mesalamine. It is recommended that patients have an evaluation the CANASA 500 mg suppository twice daily, the two treatment groups had of renal function prior to initiation of CANASA therapy and periodically similar adverse event profiles. The most frequent AEs were headache while on therapy. Exercise caution when using CANASA in patients with (14.4%), flatulence (5.2%), abdominal pain (5.2%), diarrhea (3.1%), and known renal dysfunction or a history of renal disease. In animal studies, the nausea (3.1%). Three (3) patients had to discontinue medication because of an kidney was the principal organ for toxicity [See Drug Interactions (7.1) and adverse reaction; one of these adverse reactions (headache) was deemed 5.2 Mesalamine-Induced Acute Intolerance Syndrome
6.2 Postmarketing Experience
Mesalamine has been associated with an acute intolerance syndrome that In addition to the adverse reactions reported above in clinical trials may be difficult to distinguish from an exacerbation of ulcerative colitis. involving CANASA, the adverse reactions listed below have been identified Although the exact frequency of occurrence has not been determined, it has during post-approval use of CANASA and other mesalamine-containing occurred in 3% of patients in controlled clinical trials of mesalamine or products. Because these reactions are reported voluntarily from a population sulfasalazine. Symptoms include cramping, acute abdominal pain and bloody of uncertain size, it is not always possible to reliably estimate their frequency diarrhea, and sometimes fever, headache, and rash. Observe patients closely or establish a causal relationship to drug exposure. for worsening of these symptoms while on treatment. If acute intolerance Body as a Whole: drug fever, fatigue, lupus-like syndrome, syndrome is suspected, promptly discontinue treatment with CANASA. Cardiac Disorders: myocarditis, pericarditis, pericardial effusion 5.3 Hypersensitivity Reactions
Some patients who have experienced a hypersensitivity reaction to Disorders: abdominal cramps, abdominal sulfasalazine may have a similar reaction to CANASA tablets or to other distension, anal pruritus, anorectal discomfort, constipation, feces compounds that contain or are converted to mesalamine. discolored, flatulence, frequent bowel movements, gastrointestinal Mesalamine-induced cardiac hypersensitivity reactions (myocarditis and bleeding, mucus stools, nausea, painful defecation, pancreatitis, pericarditis) have been reported with CANASA and other mesalamine proctalgia, rectal discharge, rectal tenesmus, stomach discomfort, medications. Caution should be taken in prescribing CANASA to patients with hypersensitivity to 5-ASA products. Hepatic Disorders: cholestatic jaundice, hepatitis, jaundice, Kawasaki-like syndrome including changes in liver enzymes, liver 5.4 Hepatic Impairment
There have been reports of hepatic failure in patients with pre-existing liver disease who have been administered other products containing mesalamine. Caution should be exercised when administering CANASA to patients with Neurological/Psychiatric Disorders: Guillain-Barre syndrome, peripheral neuropathy, transverse myelitis Renal Disorders: interstitial nephritis 5.5 Drug-Laboratories Test Interactions
Respiratory, Thoracic and Mediastinal Disorders: hypersensitivity There have been several reports of possible interference with measurements, by liquid chromatography, of urinary normetanephrine in patients exposed to pneumonitis, interstitial pneumonitis) sulfasalazine or its metabolite, mesalamine/mesalazine. Skin and subcutaneous tissue Disorder: alopecia, erythema, erythema nodosum, pruritus, psoriasis, pyoderma gangrenosum, urticaria Urogenital: reversible oligospermia 12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
The mechanism of action of mesalamine is not fully understood, but DRUG INTERACTIONS
appears to be topical rather than systemic. Although the pathology of No investigations of interaction between CANASA and other drugs have inflammatory bowel disease is uncertain, both prostaglandins and leukotrienes been performed. However, the following interactions between mesalamine have been implicated as mediators of mucosal injury and inflammation. medications and other drugs have been reported. 12.3 Pharmacokinetics
7.1 Nephrotoxic Agents, Including Non-Steroidal Anti-Inflammatory
Absorption: Mesalamine (5-ASA) administered as a rectal suppository
is variably absorbed. In patients with ulcerative colitis treated with The concurrent use of mesalamine with known nephrotoxic agents, mesalamine 500 mg rectal suppositories, administered once every eight hours including nonsteroidal anti-inflammatory drugs (NSAIDs) may increase the 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 7.2 Azathioprine or 6-mercaptopurine
89 ng/mL (CV=89%). Absorbed mesalamine does not accumulate in the The concurrent use of mesalamine with azathioprine or 6- mercaptopurine may increase the risk for blood disorders. Distribution: Mesalamine administered as rectal suppositories
distributes in rectal tissue to some extent. In patients with ulcerative proctitis USE IN SPECIFIC POPULATIONS
treated with CANASA 1000 mg rectal suppositories, rectal tissue 8.1 Pregnancy
concentrations for 5-ASA and N-acetyl-5-ASA have not been rigorously Pregnancy Category B: Reproduction studies have been performed in rats at oral doses up to 320 mg/kg/day (about 1.7 times the recommended Metabolism: Mesalamine is extensively metabolized, mainly to N-
human intra-rectal dose, based on body surface area) and in rabbits at oral acetyl-5-ASA. The site of metabolism has not been elucidated. In patients doses up to 495 mg/kg/day (about 5.4 times the recommended human intra- with ulcerative colitis treated with one 500 mg mesalamine rectal suppository rectal dose, based on body surface area) and have revealed no evidence of every eight hours for six days, peak concentration (Cmax) of N-acetyl-5-ASA impaired fertility or harm to the fetus due to mesalamine. There are, however, ranged from 467 ng/mL to 1399 ng/mL following the initial dose and from no adequate and well controlled studies in pregnant women. Because animal 193 ng/mL to 1304 ng/mL at steady state. reproduction studies are not always predictive of human response, this drug Elimination: Mesalamine is eliminated from plasma mainly by urinary
should be used in pregnancy only if clearly needed. excretion, predominantly as N-acetyl-5-ASA. In patients with ulcerative proctitis treated with one mesalamine 500 mg rectal suppository every eight 8.3 Nursing Mothers
hours for six days, ≤ 12% of the dose was eliminated in urine as unchanged 5- Mesalamine and its N-acetyl metabolite have been detected in human ASA and 8-77% as N-acetyl-5-ASA following the initial dose. At steady state, breast milk. The clinical significance of this has not been determined. ≤ 11% of the dose was eliminated as unchanged 5-ASA and 3-35% as N- Caution should be exercised when Canasa is administered to a nursing acetyl-5-ASA. The mean elimination half-life was five hours (CV=73%) for 5-ASA and six hours (CV=63%) for N-acetyl-5-ASA following the initial dose. At steady state, the mean elimination half-life was seven hours for both 8.4 Pediatric Use
5-ASA and N-acetyl-5-ASA (CV=102% for 5-ASA and 82% for N-acetyl-5- Safety and effectiveness in pediatric patients have not been established. 8.5 Geriatric Use
13 NONCLINICAL TOXICOLOGY
Reports from uncontrolled clinical studies and postmarketing reporting 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
systems suggested a higher incidence of blood dyscrasias (i.e., neutropenia Mesalamine caused no increase in the incidence of neoplastic lesions and pancytopenia) in patients who were 65 years or older who were taking over controls in a two-year study of Wistar rats fed up to 320 mg/kg/day of mesalamine-containing products such as CANASA. Caution should be taken mesalamine admixed with diet (about 1.7 times the recommended human to closely monitor blood cell counts during mesalamine therapy. intra-rectal dose, based on body surface area). Clinical trials of CANASA did not include sufficient numbers of patients Mesalamine was not mutagenic in the Ames test, the mouse lymphoma aged 65 and over to determine whether they respond differently from younger cell (TK+/-) forward mutation test, or the mouse micronucleus test. patients. Other reported clinical experience has not identified differences in No effects on fertility or reproductive performance of the male and responses between the elderly and younger patients. Systemic exposures are female rats were observed at oral mesalamine doses up to 320 mg/kg/day increased in elderly subjects [See Clinical Pharmacology (12.3)]. In general, (about 1.7 times the recommended human intra-rectal dose, based on body dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concurrent disease or other drug 13.2 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, OVERDOSAGE
adverse renal effects were observed at a single oral dose of 600 mg/kg (about There have been no documented reports of serious toxicity in man 3.2 times the recommended human intra-rectal dose, based on body surface resulting from massive overdosing with mesalamine suppository. Under area) and at IV doses of >214 mg/kg (about 1.2 times the recommended ordinary circumstances, mesalamine absorption from the colon is limited. human intra-rectal dose, based on body surface area). In a 13-week oral gavage toxicity study in rats, papillary necrosis and/or multifocal tubular DESCRIPTION
injury were observed in males receiving 160 mg/kg (about 0.86 times the The active ingredient in CANASA 1000 mg rectal suppositories is recommended human intra-rectal dose, based on body surface area) and in mesalamine, also known as mesalazine or 5-aminosalicylic acid (5-ASA). both males and females at 640 mg/kg (about 3.5 times the recommended Chemically, mesalamine is 5-amino-2-hydroxybenzoic acid, and is classified human intra-rectal dose, based on body surface area). In a combined 52-week as an anti-inflammatory drug. Each CANASA rectal suppository contains toxicity and 127-week carcinogenicity study in rats, degeneration of the kidneys and hyalinization of basement membranes and Bowman’s capsule 1000 mg of mesalamine (USP) in a base of Hard Fat, NF. were observed at oral doses of 100 mg/kg/day (about 0.54 times the 7H7NO3, representing a molecular weight of recommended human intra-rectal dose, based on body surface area) and above. In a 14-day 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, 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, 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. 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 experience cramping, abdominal pain, bloody diarrhea, fever, intra-rectal dose, based on body surface area) and above. have a history of myocarditis or pericarditis; 14 CLINICAL STUDIES
Two double-blind, placebo-controlled, multicenter studies were conducted in North America in patients with mild to moderate active are pregnant, intend to become pregnant or are breast-feeding. ulcerative proctitis. The primary measures of efficacy were the same in both trials (clinical disease activity index (DAI) and histologic evaluations). The FDA-Approved Patient Labeling
DAI is a composite index reflecting rectal bleeding, stool frequency, mucosal appearance at endoscopy, and a physician’s global assessment of disease. The Patient Information
main difference between the studies was dosage regimen: 500 mg three times Read the Patient Information leaflet that comes with CANASA before you daily (1.5 g/d) in Study 1; and 500 mg twice daily (1.0 g/d) in Study 2. A total start taking it and each time you get a refill. There may be new information. of 173 patients were studied (Study 1, N=79; Study 2, N=94). Eighty-nine This leaflet does not take the place of talking with your doctor about your (89) patients received mesalamine suppositories, and eighty-four (84) patients medical condition or treatment. If you have any questions about CANASA, received placebo suppositories. Patients were evaluated clinically and sigmoidoscopically after three and six weeks of suppository treatment. In Study 1, patients were 17 to 73 years of age (mean = 39 years), 57% were What is CANASA?
female, and 97% were white. Patients had an average extent of proctitis (upper CANASA is a prescription medicine used to treat active ulcerative proctitis disease boundary) of 10.8 cm. Eighty-four percent (84%) of the study patients had multiple prior episodes of proctitis. In Study 2, patients were 21 to 72 years of age (mean = 39 years), 62% were female, and 96% were white. It is not known if CANASA is safe and effective for use for longer than 6
Patients had an average extent of proctitis (upper disease boundary) of 10.3 cm. Seventy-eight percent (78%) of the study patients had multiple prior It is not known if CANASA is safe and effective in children.
Compared to placebo, mesalamine suppository treatment was statistically (p<0.01) superior to placebo in both trials with respect to Who should not use CANASA?
improvement in stool frequency, rectal bleeding, mucosal appearance, disease severity, and overall disease activity at three and six weeks of treatment. The Do not use CANASA if you are:
effectiveness of mesalamine suppositories was statistically significant allergic to medicines that contain salicylates, including aspirin. irrespective of sex, extent of proctitis, duration of current episode, or duration allergic to mesalamine or any of the ingredients in CANASA. See the end of this leaflet for a complete list of ingredients in An additional multicenter, open-label, randomized, parallel group study in ninety-nine (99) patients diagnosed with mild to moderate ulcerative Ask your doctor if you are not sure if your medicine is listed above. proctitis compared the clinical efficacy of the CANASA 1000 mg suppository to that of the CANASA 500 mg suppository. The primary measures of What should I tell my doctor before using CANASA?
efficacy included the clinical disease activity index (DAI) and histologic evaluations. Patients were randomized to one of two treatment groups, with a Before using CANASA, tell your doctor if you:
dosage regimen of one 500 mg mesalamine suppository twice daily, morning have a history of allergic reaction to the medicine sulfasalazine and at bedtime, or one 1000 mg mesalamine suppository at bedtime for 6 weeks. Patients were evaluated clinically and sigmoidoscopically at three and six weeks of suppository treatment. Of the eighty-one (81) patients in the Per Protocol population, forty-six (46) patients received mesalamine 500 mg have ever had inflammation of the sac around your heart suppositories twice daily, and thirty-five (35) patients received mesalamine The efficacy of the 1000 mg at bedtime treatment was not different at 6 are pregnant or plan to become pregnant. It is not known if weeks from the 500 mg twice daily treatment, and both were effective in the CANASA can harm your unborn baby. treatment of ulcerative proctitis. Both treatments resulted in a significant are breastfeeding or plan to breastfeed. CANASA can pass into decrease at 6 weeks in DAI. In the 500 mg twice daily group, the mean DAI your milk. Talk to your doctor about the best way to feed your 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 over 6 weeks of treatment, representing a decrease of greater than 75% in both groups. Seventy-eight Tell your doctor about all the medicines you take, including prescription
percent (78%; 36/46) of patients in the 500 mg twice daily group and 86% and non-prescription medicines, vitamins and herbal supplements. (30/35) of the patients in the 1000 mg at bedtime group achieved a DAI score of less than 3 after 6 weeks of treatment. Know the medicines you take. Keep a list of them to show your doctor and 16 HOW SUPPLIED/STORAGE AND HANDLING
CANASA 1000 mg suppositories for rectal administration are available How should I use CANASA?
as bullet shaped, light tan to grey suppositories containing 1000 mg Use CANASA exactly as prescribed by your doctor. Your doctor mesalamine supplied in boxes of 30 and 42 individually plastic wrapped will tell you how long to continue using CANASA. suppositories (NDC 58914-501-56 and 58914-501-42). CANASA comes as a suppository that you insert into your rectum. Store below 25ºC (77ºF), may be refrigerated. Keep away from direct CANASA is used 1 time each day, at bedtime. After CANASA is inserted in your rectum, you should try to keep CANASA suppositories will cause staining of direct contact surfaces, (retain) the suppository in your rectum for 1 to 3 hours, or longer if including but not limited to fabrics, flooring, painted surfaces, marble, granite, CANASA can cause staining of surfaces including, clothing and other fabrics, flooring, painted surfaces, marble, granite, vinyl and PATIENT COUNSELING INFORMATION
enamel. Keep CANASA away from these surfaces to prevent See FDA-approved patient labeling (Patient Information) Instruct patients not to take CANASA if they have hypersensitivity to What are the possible side effects of CANASA?
salicylates (e.g., aspirin) or other mesalamines. CANASA may cause serious side effects, including:
Inform patients to let their physicians know all medications they are taking Allergic type reactions. This can include sudden symptoms called
“Acute intolerance syndrome.” When this happens, it is usually in are allergic to sulfasalazine, salicylates or mesalamine; people who have had an allergic reaction to medicines containing are taking non-steroidal anti-inflammatory drugs (NSAIDs) or sulfasalazine. Stop using CANASA and tell your doctor right away if are taking azathioprine or 6-mercaptopurine; Inflammation of the sac around the heart (pericarditis). Tell your
doctor right away if you get chest pain or shortness of breath. Your
doctor may tell you to stop using CANASA if you get pericarditis.
The most common side effects of CANASA include:
rectal pain (pain in the final portion of the large intestine) Tell your doctor if you have any side effect that bothers you or that does not
go away.
These are not all of the possible side effects of CANASA. For more
information ask your doctor or pharmacist.

Call your doctor for medical advice about side effects. You may report side
effects to FDA at 1-800-FDA-1088.

How should I store CANASA?
Keep CANASA away from direct heat, light, or humidity.
Keep CANASA and all medicines out of the reach of children.
General information about CANASA
Medicines are sometimes prescribed for purposes other than those listed in a
patient information leaflet. Do not use CANASA for a condition for which it
was not prescribed. Do not give CANASA to other people, even if they have
the same symptoms you have. It may harm them.

This leaflet summarizes the most important information about CANASA. If
you would like more information, talk with your doctor. You can ask your
doctor or pharmacist for information about CANASA that is written for health
professionals.

For more information, go to www.canasa.com, or call 1-800-472-2634.
What are the ingredients in CANASA?
Active ingredients: Mesalamine
Inactive ingredients: Hard fat base
Distributed by:
Aptalis Pharma US, Inc.
100 Somerset Corporate Boulevard
Bridgewater, NJ 08807 USA
www.aptalispharma.com
This Patient Information has been approved by the U.S. Food and Drug
Administration.
CANASA® is a registered trademark of Aptalis Pharma Canada Inc., an
affiliate of Aptalis Pharma US, Inc.
2013 Aptalis Pharma US, Inc.

Source: http://www.canasa.com/pdf/prescribing-info.pdf