CANASA® (mesalamine) suppositories

CANASA® (mesalamine) suppositories

CANASA® (mesalamine) suppositories

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 aminosalicylate. 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.

INDICATIONS AND USAGE

CANASA is indicated in adults for the treatment of mildly to moderately active ulcerative proctitis.

Mechanism of Action

The mechanism of action of mesalamine is not fully understood, but appears to be a topical anti-inflammatory effect on colonic epithelial cells. Mucosal production of arachidonic acid metabolites, both through the cyclooxygenase pathways, i.e., prostanoids, and through the lipoxygenase pathways, i.e., leukotrienes and hydroxyeicosatetraenoic acids, is increased in patients with ulcerative colitis, and it is possible that mesalamine diminishes inflammation by blocking cyclooxygenase and inhibiting prostaglandin production in the colon.

DOSAGE AND ADMINISTRATION

The recommended dosage of CANASAin adults is 1000 mg administered rectally once daily at bedtime for 3 to 6 weeks depending on symptoms and sigmoidoscopic findings. Safety and effectiveness of CANASA beyond 6 weeks have not been established.

Administration Instructions:

  • Evaluate renal function prior to initiation of CANASA therapy.
  • Do not cut or break the suppository.
  • Retain the suppository for one to three hours or longer, if possible.
  • Drink an adequate amount of fluids.
  • If a dose of CANASA is missed, administer as soon as possible, unless it is almost time for next dose. Do not use two CANASA suppositories at the same time to make up for a missed dose.
  • CANASAsuppositories will cause staining of direct contact surfaces, including but not limited to fabrics, flooring, painted surfaces, marble, granite, vinyl, and enamel. Keep CANASA away from these surfaces to prevent staining.

CONTRAINDICATIONS

CANASA is contraindicated in patients with known or suspected hypersensitivity to salicylates or aminosalicylates or to any ingredients in the suppository vehicle

WARNINGS AND PRECAUTIONS

Renal Impairment: Renal impairment, including minimal change disease, acute and chronic interstitial nephritis, and renal failure, has been reported in patients given products such as CANASA that contain mesalamine or are converted to mesalamine. In animal studies, the kidney was the principal organ of mesalamine toxicity.

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Evaluate renal function prior to initiation of CANASA and periodically while on therapy.

Evaluate the risks and benefits of using CANASA in patients with known renal impairment or a history of renal disease or taking concomitant nephrotoxic drugs.

Mesalamine-Induced Acute Intolerance Syndrome: Mesalamine has been associated with an acute intolerance syndrome that may be difficult to distinguish from an exacerbation ofulcerative colitis. Although the exact frequency of occurrence has not been determined, it has occurred in 3% of patients in controlledclinical trials of mesalamine or sulfasalazine. Symptoms include cramping, acute abdominal pain and bloody diarrhea, and sometimesfever, headache, malaise, pruritis, conjunctivitis, and rash. Monitor patients for worsening of these symptoms while on treatment. If acute intolerance syndrome is suspected, promptly discontinue treatment with CANASA.

Hypersensitivity Reactions: Hypersensitivity reactions have been reported in patients taking sulfasalazine. Some patients may have a similar reaction to CANASAor to other compounds that contain or are converted to mesalamine.

As with sulfasalazine, mesalamine-induced hypersensitivity reactions may present as internal organ involvement, including myocarditis, pericarditis, nephritis, hepatitis, pneumonitis and hematologic abnormalities.

Evaluate patients immediately if signs or symptoms of a hypersensitivity reaction are present. Discontinue CANASA if an alternative etiology for the signs and symptoms cannot be established.

Hepatic Failure: There have been reports of hepatic failure in patients with pre-existing liver disease who have been administered other productscontaining mesalamine. Evaluate the risks and benefits of using CANASA in patients with known liver impairment.

Severe Cutaneous Adverse Reactions: Severe cutaneous adverse reactions, including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), drug reactionwith eosinophilia and systemic symptoms (DRESS), and acute generalized exanthematous pustulosis (AGEP) have been reported inassociation with the use of mesalamine.

Discontinue CANASA at the first signs or symptoms of severecutaneous adverse reactions or other signs of hypersensitivity and consider further evaluation.

Photosensitivity: In patients treated with mesalamine or sulfasalazine who have pre-existing skin conditions such as atopic dermatitis and atopiceczema have reported more severe photosensitivity reactions. Advise patients to avoid sun exposure, wear protective clothing, and usea broad-spectrum sunscreen when outdoors.

Nephrolithiasis: Cases of nephrolithiasis have been reported with the use of mesalamine, including stones of 100% mesalamine content. Mesalamine containingstones are radiotransparent and undetectable by standard radiography or computed tomography (CT). Ensure adequatehydration during treatment with CANASA.

Interaction with Laboratory Test for Urinary Normetanephrine: Use of mesalamine may lead to spuriously elevated test results when measuring urinary normetanephrine by liquid chromatographywith electrochemical detection, because of the similarity in the chromatograms of normetanephrine and mesalamine’s main metabolite,N-acetylaminosalicylic acid. Consider an alternative, selective assay for normetanephrine.

ADVERSE REACTIONS

The following adverse reactions have been identified during post-approval use of CANASA or 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 • Endocrine: Nephrogenic diabetes insipidus
  • 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, intracranial hypertension
  • Renal Disorders: interstitial nephritis, renal failure, minimal change disease, nephrolithiasis
  • Respiratory, Thoracic and Mediastinal Disorders: hypersensitivity pneumonitis (including allergic alveolitis, eosinophilic pneumonitis, interstitial pneumonitis), pleuritis/pleurisy
  • Skin and Subcutaneous Tissue Disorder: alopecia, erythema, erythema nodosum, pruritus, psoriasis, pyoderma gangrenosum, urticaria, SJS/TEN, DRESS and AGEP
  • Urogenital: reversible oligospermia

DRUG INTERACTIONS

Nephrotoxic Agents, Including Non-Steroidal Anti-Inflammatory Drugs: The concurrent use of mesalamine with known nephrotoxic agents, including nonsteroidal anti-inflammatory drugs (NSAIDs) mayincrease the risk of nephrotoxicity. Monitor patients taking nephrotoxic drugs for changes in renal function and mesalamine-relatedadverse reactions.

Azathioprine or 6-Mercaptopurine: The concurrent use of mesalamine with azathioprine or 6-mercaptopurine and/or other drugs known to cause myelotoxicity mayincrease the risk for blood disorders, bone marrow failure, and associated complications. If concomitant use of CANASA andazathioprine or 6-mercaptopurine cannot be avoided, monitor blood tests, including complete blood cell counts and platelet counts.

Interference With Urinary Normetanephrine Measurements: Use of mesalamine may lead to spuriously elevated test results when measuring urinary normetanephrine by liquid chromatography with electrochemical detection, because of the similarity in the chromatograms of normetanephrine and mesalamine’s main metabolite, N-acetylaminosalicylic acid. Consider an alternative, selective assay for normetanephrine.

USE IN SPECIFIC POPULATIONS

Pregnancy: Limited published data on mesalamine use in pregnant women are insufficient to inform a drug-associated risk. No evidence ofteratogenicity was observed in rats or rabbits when treated during gestation with orally administered mesalamine at doses greater thanthe recommended human intra-rectal dose.

Lactation: Mesalamine and its N-acetyl metabolite are present in human milk in undetectable to small amounts. There are limited reports of diarrhea in breastfed infants. There is no information on the effects of the drug on milk production. The lack of clinical data during lactation precludes a clear determination of the risk of CANASA to an infant during lactation; therefore, the developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for CANASA and any potential adverse effects on the breastfed child from CANASA or from the underlying maternal conditions.

Pediatric Use: The safety and effectiveness of CANASA in pediatric patients for the treatment of mildly to moderately active ulcerative proctitishave not been established. CANASA was evaluated for the treatment of ulcerative proctitis in a 6-week, open-label, single-arm study

in 49 patients 5 to 17 years of age, which only included 14 patients with histologically-confirmed cases of ulcerative proctitis. However, efficacy was not demonstrated. Adverse reactions seen in pediatric patients in this trial (abdominal pain, headache, pyrexia, pharyngolaryngeal pain, diarrhea and vomiting) were similar to those seen in adult patients.

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Geriatric Use: Clinical trials of CANASA did not include sufficient numbers of patients aged 65 years and over to determine whether they responddifferently from younger patients. Reports from uncontrolled clinical studies and postmarketing reporting systems suggested a higher

incidence of blood dyscrasias (i.e., agranulocytosis, neutropenia and pancytopenia) in patients receiving mesalamine-containing products such as CANASA who were 65 years or older compared to younger patients. Monitor complete blood cell counts and platelet counts in elderly patients during treatment with CANASA. In general, consider the greater frequency of decreased hepatic, renal, or cardiac function, and of concurrent disease or other drug therapy in elderly patients when prescribing CANASA.

Renal Impairment: Mesalamine is known to be substantially excreted by the kidney, and the risk of adverse reactions may be greater in patients withimpaired renal function. Evaluate renal function in all patients prior to initiation and periodically while on CANASA therapy. Monitor

patients with known renal impairment or history of renal disease or taking nephrotoxic drugs for decreased renal function and mesalamine-related adverse reactions.

OVERDOSAGE

Mesalamine absorption from the colon is limited; however, CANASA is an aminosalicylate, and symptoms of salicylate toxicity include nausea, vomiting and abdominal pain, tachypnea, hyperpnea, tinnitus, and neurologic symptoms (headache, dizziness, confusion, seizures). Severe salicylate intoxication may lead to electrolyte and blood pH imbalance and potentially to other organ (e.g., renal and liver) involvement. There is no specific antidote for mesalamine overdose. Correct fluid and electrolyte imbalance by the administration of appropriate intravenous therapy and maintain adequate renal function.

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