Mesalamine: Package Insert and Label Information (Page 2 of 3)

8.4 Pediatric Use

The safety and effectiveness of mesalamine in pediatric patients for the treatment of mildly to moderately active ulcerative proctitis have not been established. Mesalamine 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.

8.5 Geriatric Use

Clinical trials of mesalamine did not include sufficient numbers of patients aged 65 years and over to determine whether they respond differently 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 mesalamine who were 65 years or older compared to younger patients. Monitor complete blood cell counts and platelet counts in elderly patients during treatment with mesalamine. 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 mesalamine [see Use in Specific Populations ( 8.6)].

8.6 Renal Impairment

Mesalamine is known to be substantially excreted by the kidney, and the risk of adverse reactions may be greater in patients with impaired renal function. Evaluate renal function in all patients prior to initiation and periodically while on mesalamine 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 [see Warnings and Precautions ( 5.1), Drug Interactions ( 7.1) and Adverse Reactions ( 6.2)].

10 OVERDOSAGE

Mesalamine absorption from the colon is limited; however, mesalamine 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.

11 DESCRIPTION

The active ingredient in mesalamine 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 mesalamine 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:

The structural formula for mesalamine 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 mesalamine rectal suppository contains 1000 mg of mesalamine (USP) in a base of Hard Fat, NF.
The structural formula for mesalamine 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 mesalamine rectal suppository contains 1000 mg of mesalamine (USP) in a base of Hard Fat, NF.

12 CLINICAL PHARMACOLOGY

12.1 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.

12.3 Pharmacokinetics

Absorption

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.

Distribution

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

Elimination

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 5-ASA 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.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Mesalamine caused no increase in the incidence of neoplastic lesions over controls in a two-year study of Wistar rats fed up to 320 mg/kg/day of mesalamine admixed with diet (about 1.7 times the recommended human intra-rectal dose of mesalamine, based on body surface area).

Mesalamine was not mutagenic in the Ames test, the mouse lymphoma cell (TK+/-) forward mutation test, or the mouse micronucleus test.

No effects on fertility or reproductive performance of the male and female rats were observed at oral mesalamine doses up to 320 mg/kg/day (about 1.7 times the recommended human intra-rectal dose of mesalamine, based on body surface area).

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, 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 mesalamine, based on body surface area) and at intravenous doses of >214 mg/kg (about 1.2 times the recommended human intra-rectal dose of mesalamine, 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 mesalamine, 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 mesalamine, 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 mesalamine, 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 of mesalamine, 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 mesalamine, 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 mesalamine, 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 mesalamine, based on body surface area) and above.

14 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 mesalamine 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 mesalamine 1000 mg once daily group. The recommended dosage of mesalamine is 1000 mg administered rectally once daily at bedtime [see Dosage and Administration ( 2)].

16 HOW SUPPLIED/STORAGE AND HANDLING

Mesalamine 1000 mg suppositories for rectal administration are available as bullet shaped, light tan to grey suppositories containing 1000 mg mesalamine supplied in boxes of 30 individually plastic wrapped suppositories (NDC 59762-0118-3).

Store below 25ºC (77ºF), may be refrigerated. Keep away from direct heat, light or humidity.

17 PATIENT COUNSELING INFORMATION

Advise patients to read the FDA-approved patient labeling (Patient Information)

Administration [see Dosage and Administration (2)]

Advise patients:

  • 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 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.

Renal Impairment

  • Inform patients that mesalamine may decrease their renal function, especially if they have known renal impairment or are taking nephrotoxic drugs, including NSAIDs, and periodic monitoring of renal function will be performed while they are on therapy. Advise patients to complete all blood tests ordered by their healthcare provider [see Warnings and Precautions ( 5.1), Drug Interactions ( 7.1)].

Mesalamine-Induced Acute Intolerance Syndrome and Other Hypersensitivity Reactions

  • Inform patients of the signs and symptoms of hypersensitivity reactions. Instruct patients to stop taking mesalamine and report to their healthcare provider if they experience new or worsening symptoms Acute Intolerance Syndrome (cramping, abdominal pain, bloody diarrhea, fever, headache, malaise, conjunctivitis and rash) or other symptoms suggestive of mesalamine-induced hypersensitivity [see Warnings and Precautions ( 5.2, 5.3)].

Hepatic Failure

  • Inform patients with known liver disease of the signs and symptoms of worsening liver function and advise them to report to their healthcare provider if they experience such signs or symptoms [see Warnings and Precautions ( 5.4)].

Photosensitivity

  • Advise patients with pre-existing skin conditions to avoid sun exposure, wear protective clothing, and use a broad-spectrum sunscreen when outdoors [see Warnings and Precautions ( 5.5)].

Nephrolithiasis

  • Instruct patients to drink an adequate amount of fluids during treatment in order to minimize the risk of kidney stone formation and to contact their healthcare provider if they experience signs or symptoms of a kidney stone (e.g., severe side or back pain, blood in the urine) [ see Warnings and Precautions ( 5.6) ].

Blood Disorders

  • Inform elderly patients and those taking azathioprine or 6-mercaptopurine of the risk for blood disorders and the need for periodic monitoring of complete blood cell counts and platelet counts while on therapy. Advise patients to complete all blood tests ordered by their healthcare provider [see Drug Interactions ( 7.2), Use in Specific Populations ( 8.5)].

© 2020 Allergan. All rights reserved.

Patented. See www.allergan.com/patents

For more information, go to www.greenstonellc.com or call 1-800-438-1985

v1.0USPI0118

PATIENT INFORMATION M esalamine suppositories, for rectal use
What is mesalamine ? Mesalamine is a prescription medicine used to treat adults with active ulcerative proctitis (ulcerative rectal colitis).It is not known if mesalamine is safe and effective in children.
Do not use mesalamine if you are:
  • allergic to medicines that contain salicylates, including aspirin.
  • allergic to mesalamine or any of the ingredients in mesalamine suppositories. See the end of this Patient Information leaflet for a complete list of ingredients in mesalamine suppositories.
Ask your doctor if you are not sure if your medicine is listed above.
Before using mesalamine , tell your doctor if you have any medical conditions, including if you :
  • have a history of allergic reaction to the medicine sulfasalazine (Azulfidine).
  • have kidney problems.
  • have ever had inflammation of the sac around your heart (pericarditis).
  • have liver problems.
  • are pregnant or plan to become pregnant. It is not known if mesalamine can harm your unborn baby.
  • are breastfeeding or plan to breastfeed. Mesalamine can pass into your breast milk. Talk to your doctor about the best way to feed your baby if you use mesalamine.
Tell your doctor about all the medicines you take, including prescription and over-the-counter medicines, vitamins and herbal supplements. Using mesalamine with certain other medicines may affect each other. Using mesalamine with other medicines can cause serious side effects.Especially tell your doctor if you take nonsteroidal anti-inflammatory drugs (NSAIDS), or medicines that contain azathioprine or 6-mercaptopurine. Taking mesalamine with NSAIDS may cause kidney problems. Taking mesalamine with azathioprine or 6-mercaptopurine may cause blood problems. Ask your doctor if you are not sure if you are taking one of these medicines.Your doctor may do certain tests during treatment with mesalamine.Know the medicines you take. Keep a list of them to show your doctor and pharmacist when you get a new medicine.
How should I take mesalamine ?
  • Use mesalamine exactly as prescribed by your doctor. Your doctor will tell you how long to continue using mesalamine.
  • Mesalamine comes as a suppository that you insert into your rectum.
  • Do not cut or break the suppository.
  • Use mesalamine 1 time each day at bedtime, for 3 to 6 weeks. It is not known if mesalamine is safe and effective for use for longer than 6 weeks.
  • After you insert mesalamine in your rectum, try to keep (retain) the suppository in your rectum for 1 to 3 hours or longer if possible.
  • It is important for you to stay well hydrated during treatment with mesalamine. Be sure to drink plenty of fluids while taking mesalamine.
  • If you miss a dose of mesalamine, insert it as soon as you remember. If it is almost time for your next dose, skip the missed dose. Insert the next dose at your regular time. Do not insert 2 doses at the same time.
  • Mesalamine can stain surfaces including clothing and other fabrics, flooring, painted surfaces, marble, granite, vinyl and enamel. Keep mesalamine away from these surfaces to prevent staining.
What are the possible side effects of mesalamine ? M esalamine may cause serious side effects, including:
  • k idney problems. Your doctor will do certain tests before you start using mesalamine and during your treatment with mesalamine.
  • a cute i ntolerance s yndrome and o ther a llergic r eactions . Some people who use mesalamine can have allergic type reactions, including Acute Intolerance Syndrome. Other allergic reactions can cause heart problems including an inflammation of the sac around the heart (pericarditis), blood problems, and problems with other organs in the body including the kidneys, liver and lungs. These problems usually happen in people who have had an allergic reaction to medicines containing sulfasalazine. Stop using mesalamine and tell your doctor right away if you get any of these symptoms:
o cramps o fever
o stomach (abdominal) pain o headache
o bloody diarrhea o rash
o chest pain o shortness of breath
o decrease in the amount of urineo eye inflammation o fatigue
  • l iver problems. This can happen in people who have a history of liver problems and have taken other medicines that contain mesalamine. Tell your doctor right away if you get any of these symptoms while using mesalamine:
o yellowing of your eyes o flu-like symptoms
o itchy skin o nausea or vomiting
o feeling very tired
  • sun sensitivity. Mesalamine can make your skin sensitive to the sun if you have skin conditions such as atopic dermatitis and atopic eczema. Try to limit your time in the sun. You should use sunscreen and wear a hat and clothes that cover your skin if you have to be in the sunlight.
  • kidney stones. Drink plenty of fluids when using mesalamine to decrease your chance of getting kidney stones. Call your doctor right away if you get any of these symptoms:
The most common side effects of mesalamine include:
o dizziness o rectal pain
o acne o fever
o inflammation of the large intestine (colitis) o rash
These are not all of the possible side effects of mesalamine. 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 mesalamine ?
  • Store mesalamine at room temperature between 68°F to 77°F (20°C to 25°C).
  • mesalamine may be refrigerated.
  • Keep mesalamine away from direct heat, light, or humidity.
Keep mesalamine and all medicines out of the reach of children.
General information about the safe and effective use of mesalamine . Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use mesalamine for a condition for which it was not prescribed. Do not give mesalamine to other people, even if they have the same symptoms that you have. It may harm them.You can ask your pharmacist or healthcare provider for information about mesalamine that is written for health professionals.
What are the ingredients in mesalamine ? Active ingredients: mesalamineInactive ingredients: hard fat baseDistributed by: Greenstone LLC, Peapack, NJ 07977© 2020 Allergan. All rights reserved. Patented. See www.allergan.com/patents.For more information, go to www.greenstonellc.com or call 1-800-438-1985.

This Patient Information has been approved by the U.S. Food and Drug Administration Revised: October 2020

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