Mesalamine: Package Insert and Label Information

MESALAMINE- mesalamine suppository
Greenstone LLC

1 INDICATIONS AND USAGE

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

2 DOSAGE AND ADMINISTRATION

Dosage

The recommended dosage of mesalamine in 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 mesalamine beyond 6 weeks have not been established.

Administration Instructions:

• Evaluate renal function prior to initiation of mesalamine therapy [see Warnings and Precautions ( 5.1)].

• 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 [see Warnings and Precautions ( 5.6)].

• If a dose of mesalamine is missed, administer as soon as possible, unless it is almost time for next dose. Do not use two mesalamine suppositories at the same time to make up for a missed dose.

• Mesalamine suppositories will cause staining of direct contact surfaces, including but not limited to fabrics, flooring, painted surfaces, marble, granite, vinyl, and enamel. Keep mesalamine away from these surfaces to prevent staining.

3 DOSAGE FORMS AND STRENGTHS

Mesalamine Suppository: 1000 mg in a bullet shaped, light tan to grey suppository.

4 CONTRAINDICATIONS

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

5 WARNINGS AND PRECAUTIONS

5.1 Renal Impairment

Renal impairment, including minimal change disease, acute and chronic interstitial nephritis, and renal failure, has been reported in patients given products that contain mesalamine or are converted to mesalamine. In animal studies, the kidney was the principal organ of mesalamine toxicity [see Adverse Reactions ( 6.2) , Nonclinical Toxicology ( 13.2) ].

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

Evaluate the risks and benefits of using mesalamine in patients with known renal impairment or a history of renal disease or taking concomitant nephrotoxic drugs [ s ee Drug Interactions ( 7.1) , Use in Specific Populations ( 8.6) ] .

5.2 Mesalamine-Induced Acute Intolerance Syndrome

Mesalamine has been associated with an acute intolerance syndrome that may be difficult to distinguish from an exacerbation of ulcerative colitis. Although the exact frequency of occurrence has not been determined, it has occurred in 3% of patients in controlled clinical trials of mesalamine or sulfasalazine. Symptoms include cramping, acute abdominal pain and bloody diarrhea, and sometimes fever, 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 mesalamine.

5.3 Hypersensitivity Reactions

Hypersensitivity reactions have been reported in patients taking sulfasalazine. Some patients may have a similar reaction to mesalamine or 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 mesalamine if an alternative etiology for the signs and symptoms cannot be established.

5.4 Hepatic Failure

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

5.5 Photosensitivity

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

5.6 Nephrolithiasis

Cases of nephrolithiasis have been reported with the use of mesalamine, including stones of 100% mesalamine content. Mesalamine-containing stones are radiotransparent and undetectable by standard radiography or computed tomography (CT). Ensure adequate hydration during treatment with mesalamine.

5. 7 Interaction with Laboratory Test for Urinary Normetanephrine

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.

6 ADVERSE REACTIONS

The following serious or clinically significant adverse reactions are described elsewhere in labeling:

  • Renal Impairment [ s ee Warnings and Precautions ( 5.1)]
  • Mesalamine-Induced Acute Intolerance Syndrome [ s ee Warnings and Precautions ( 5.2)]
  • Hypersensitivity Reactions [ s ee Warnings and Precautions ( 5.3)]
  • Hepatic Failure [ s ee Warnings and Precautions ( 5.4)]
  • Photosensitivity [see Warnings and Precautions ( 5.5)]
  • Nephrolithiasis [see Warnings and Precautions ( 5.6)]

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.

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)
Symptom Mesalamine (n = 177) Placebo (n = 84)
N % N %
Dizziness 5 3 2 2.4
Rectal Pain 3 1.8 0 0
Fever 2 1.2 0 0
Rash 2 1.2 0 0
Acne 2 1.2 0 0
Colitis 2 1.2 0 0

In a multicenter, open-label, randomized, parallel group study in 99 patients comparing the mesalamine 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 mesalamine is 1000 mg administered rectally once daily at bedtime [see Dosage and Administration ( 2)].

6.2 Postmarketing Experience

The following adverse reactions have been identified during post-approval use of mesalamine 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 [see Warnings and Precautions ( 5.3)]
  • Endocrine: Nephrogenic diabetes insipidus
  • Eye disorders: eye swelling
  • Gastrointestinal D isorders: 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 D isorders : cholestatic jaundice, hepatitis, jaundice, Kawasaki-like syndrome including changes in liver enzymes, liver necrosis, liver failure
  • Hematologic D isorders : agranulocytosis, aplastic anemia, thrombocytopenia
  • Neurologi ca l/Psychiatric D isorders : Guillain-Barre syndrome, peripheral neuropathy, transverse myelitis, intracranial hypertension
  • Renal Disorders: interstitial nephritis, renal failure, minimal change disease, nephrolithiasis [see Warnings and Precautions ( 5.1, 5.6)]
  • Respiratory, Thoracic and Mediastinal Disorders: hypersensitivity pneumonitis (including allergic alveolitis, eosinophilic pneumonitis, interstitial pneumonitis)
  • Skin and S ubcutaneous T issue D isorder: alopecia, erythema, erythema nodosum, pruritus, psoriasis, pyoderma gangrenosum, urticaria
  • Urogenital: reversible oligospermia

7 DRUG INTERACTIONS

7.1 Nephrotoxic Agents, Including Non-Steroidal Anti-Inflammatory Drugs

The concurrent use of mesalamine with known nephrotoxic agents, including nonsteroidal anti-inflammatory drugs (NSAIDs) may increase the risk of nephrotoxicity. Monitor patients taking nephrotoxic drugs for changes in renal function and mesalamine-related adverse reactions [see Warnings and Precautions ( 5.1)].

7.2 Azathioprine or 6- M ercaptopurine

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

7.3 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 [see Warnings and Precautions ( 5.7)].

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Risk Summary

Limited published data on mesalamine use in pregnant women are insufficient to inform a drug-associated risk. No evidence of teratogenicity was observed in rats or rabbits when treated during gestation with orally administered mesalamine at doses greater than the recommended human intra-rectal dose ( see Data ).

The estimated background risk of major birth defects and miscarriage for the indicated populations is unknown. Adverse outcomes in pregnancy occur regardless of the health of the mother or the use of medications. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.

Data

Animal Data

Reproduction studies have been performed in rats at oral doses up to 320 mg/kg/day (about 1.7 times the recommended human intra-rectal dose of mesalamine, based on body surface area) and in rabbits at oral doses up to 495 mg/kg/day (about 5.4 times the recommended human intra-rectal dose of mesalamine, based on body surface area) following administration during the period of organogenesis, and have revealed no evidence of impaired fertility or harm to the fetus due to mesalamine.

8.2 Lactation

Risk Summary

Mesalamine and its N-acetyl metabolite are present in human milk in undetectable to small amounts ( see Data ). 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 mesalamine to an infant during lactation; therefore, the developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for mesalamine and any potential adverse effects on the breastfed child from mesalamine or from the underlying maternal conditions.

Clinical Considerations

Monitor breastfed infants for diarrhea.

Data

In published lactation studies, maternal mesalamine doses from various oral and rectal formulations and products ranged from 500 mg to 3 g daily. The concentration of mesalamine in milk ranged from non-detectable to 0.11 mg/L. The concentration of the N-acetyl-5-aminosalicylic acid metabolite ranged from 5 to 18.1 mg/L. Based on these concentrations, estimated infant daily dosages for an exclusively breastfed infant are 0 to 0.017 mg/kg/day of mesalamine and 0.75 to 2.72 mg/kg/day of N-acetyl-5-aminosalicylic acid.

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