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Name:Mesalamine
Manufacturer:Perrigo New York Inc
Category:Prescription Marketed Drugs


Mesalamine Rectal Suspension USP, Enema

MESALAMINE -     
Perrigo New York Inc

----------

Mesalamine Rectal Suspension USP, Enema

 

Rectal Suspension

4 grams/unit (60 mL)

Rx Only

DESCRIPTION

The active ingredient in Mesalamine Rectal Suspension USP, Enema, a disposable (60 mL) unit, is mesalamine, also known as 5-aminosalicylic acid (5-ASA). Chemically, mesalamine is 5-amino-2-hydroxybenzoic acid.

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

Structural Formula Image

Structural Formula

Each rectal suspension enema unit contains 4 grams of mesalamine. In addition to mesalamine the preparation contains the inactive ingredients carbomer 934P, edetate disodium, potassium acetate, potassium metabisulfite, purified water and xanthan gum. Sodium benzoate is added as a preservative. The disposable unit consists of an applicator tip protected by a polyethylene cover and lubricated with USP white petrolatum. The unit has a one-way valve to prevent back flow of the dispensed product.

CLINICAL PHARMACOLOGY

Sulfasalazine is split by bacterial action in the colon into sulfapyridine (SP) and mesalamine (5-ASA).

It is thought that the mesalamine component is therapeutically active in ulcerative colitis [A.K. Azad Khan et al, Lancet 2:892-895 (1977)]. The usual oral dose of sulfasalazine for active ulcerative colitis in adults is two to four grams per day in divided doses. Four grams of sulfasalazine provide 1.6 g of free mesalamine to the colon. Each Mesalamine Rectal Suspension, USP delivers up to 4 g of mesalamine to the left side of the colon.

The mechanism of action of mesalamine (and sulfasalazine) is unknown, but appears to be topical rather than systemic. Mucosal production of arachidonic acid (AA) metabolites, both through the cyclooxygenase pathways, i.e., prostanoids, and through the lipoxygenase pathways, i.e., leukotrienes (LTs) and hydroxyeicosatetraenoic acids (HETEs) is increased in patients with chronic inflammatory bowel disease, and it is possible that mesalamine diminishes inflammation by blocking cyclooxygenase and inhibiting prostaglandin (PG) production in the colon.

Preclinical Toxicology

Preclinical studies have shown the kidney to be the major target organ for mesalamine toxicity. Adverse renal function changes were observed in rats after a single 600 mg/kg oral dose, but not after a 200 mg/kg dose. Gross kidney lesions, including papillary necrosis, were observed after a single oral >900 mg/kg dose, and after i.v. doses of > 214 mg/kg. Mice responded similarly. In a 13-week oral (gavage) dose study in rats, the high dose of 640 mg/kg/day mesalamine caused deaths, probably due to renal failure, and dose-related renal lesions (papillary necrosis and/or multifocal tubular injury) were seen in most rats given the high dose (males and females) as well as in males receiving lower doses 160 mg/kg/day. Renal lesions were not observed in the 160 mg/kg/day female rats. Minimal tubular epithelial damage was seen in the 40 mg/kg/day males and was reversible. In a six-month oral study in dogs, the no-observable dose level of mesalamine was 40 mg/kg/day and doses of 80 mg/kg/day and higher caused renal pathology similar to that described for the rat. In a combined 52-week toxicity and 127-week carcinogenicity study in rats, degeneration in kidneys was observed at doses of 100 mg/kg/day and above admixed with diet for 52 weeks, and at 127 weeks increased incidence of kidney degeneration and hyalinization of basement membranes and Bowman's capsule were seen at 100 mg/kg/day and above. In the 12 month eye toxicity study in dogs, Keratoconjunctivitis Sicca (KCS) occurred at oral doses of 40 mg/kg/day and above. The oral preclinical studies were done with a highly bioavailable suspension where absorption throughout the gastrointestinal tract occurred. The human dose of 4 grams represents approximately 80 mg/kg but when mesalamine is given rectally as a suspension, absorption is poor and limited to the distal colon (see Pharmacokinetics). Overt renal toxicity has not been observed (see ADVERSE REACTIONS and PRECAUTIONS), but the potential must be considered.

Pharmacokinetics

Mesalamine administered rectally as Mesalamine Rectal Suspension, USP is poorly absorbed from the colon and is excreted principally in the feces during subsequent bowel movements. The extent of absorption is dependent upon the retention time of the drug product, and there is considerable individual variation. At steady state, approximately 10 to 30% of the daily 4-gram dose can be recovered in cumulative 24-hour urine collections. Other than the kidney, the organ distribution and other bioavailability characteristics of absorbed mesalamine in man are not known. It is known that the compound undergoes acetylation but whether this process takes place at colonic or systemic sites has not been elucidated.

Whatever the metabolic site, most of the absorbed mesalamine is excreted in the urine as the N-acetyl-5-ASA metabolite. The poor colonic absorption of rectally administered mesalamine is substantiated by the low serum concentration of 5-ASA and N-acetyl-5-ASA seen in ulcerative colitis patients after dosage with mesalamine. Under clinical conditions patients demonstrated plasma levels 10 to 12 hours post mesalamine administration of 2 mcg/mL, about two-thirds of which was the N-acetyl metabolite. While the elimination half-life of mesalamine is short (0.5 to 1.5 h), the acetylated metabolite exhibits a half-life of 5 to 10 hours [U. Klotz, Clin. Pharmacokin 10:285-302 (1985)]. In addition, steady state plasma levels demonstrated a lack of accumulation of either free or metabolized drug during repeated daily administrations.

Efficacy

In a placebo-controlled, international, multicenter trial of 153 patients with active distal ulcerative colitis, proctosigmoiditis or proctitis, Mesalamine Rectal Suspension, USP reduced the overall disease activity index (DAI) and individual components as follows:

EFFECT OF TREATMENT ON SEVERITY OF DISEASE DATA FROM U.S.-CANADA TRIAL COMBINED RESULTS OF EIGHT CENTERS Activity Indices, mean
N Baseline Day 22 End-Point Change Baseline to End-Point *
Overall DAI Mesalamine Rectal Suspension 76 7.42 4.05 3.37 -55.07%
Placebo 77 7.40 6.03 5.83 -21.58%
Stool Frequency Mesalamine Rectal Suspension 1.58 1.11§ 1.01 -0.57§
Placebo 1.92 1.47 1.50 -0.41
Rectal Bleeding Mesalamine Rectal Suspension 1.82 0.59 0.51 -1.30
Placebo 1.73 1.21 1.11 -0.61
Mucosal Inflammation Mesalamine Rectal Suspension 2.17 1.22 0.96 -1.21
Placebo 2.18 1.74 1.61 -0.56
Physician's Assessment of Disease Severity Mesalamine Rectal Suspension 1.86 1.13 0.88 -0.97
Placebo 1.87 1.62 1.55 -0.30
Each parameter has a 4-point scale with a numerical rating:
0 = normal, 1 = mild, 2 = moderate, 3 = severe. The four parameters are added together to produce a maximum overall DAI of 12.

*

Percent change for overall DAI only (calculated by taking the average of the change for each individual patient).

Significant Mesalamine Rectal Suspension, USP /placebo difference. p<0.01

Significant Mesalamine Rectal Suspension, USP /placebo difference. p<0.001

§

Significant Mesalamine Rectal Suspension, USP /placebo difference. p<0.05

Differences between Mesalamine Rectal Suspension, USP and placebo were also statistically different in subgroups of patients on concurrent sulfasalazine and in those having an upper disease boundary between 5 and 20 or 20 and 40 cm. Significant differences between Mesalamine Rectal Suspension, USP and placebo were not achieved in those subgroups of patients on concurrent prednisone or with an upper disease boundary between 40 and 50 cm.

INDICATIONS AND USAGE

Mesalamine Rectal Suspension, USP is indicated for the treatment of active mild to moderate distal ulcerative colitis, proctosigmoiditis or proctitis.

CONTRAINDICATIONS

Mesalamine Rectal Suspension, USP is contraindicated for patients known to have hypersensitivity to the drug or any component of this medication.

WARNINGS

Mesalamine Rectal Suspension, USP contains potassium metabisulfite, a sulfite that may cause allergic-type reactions including anaphylactic symptoms and life-threatening or less severe asthmatic episodes in certain susceptible people. The overall prevalence of sulfite sensitivity in the general population is unknown but probably low. Sulfite sensitivity is seen more frequently in asthmatic or in atopic nonasthmatic persons. Epinephrine is the preferred treatment for serious allergic or emergency situations even though epinephrine injection contains sodium or potassium metabisulfite with the above-mentioned potential liabilities. The alternatives to using epinephrine in a life-threatening situation may not be satisfactory. The presence of a sulfite(s) in epinephrine injection should not deter the administration of the drug for treatment of serious allergic or other emergency situations.

PRECAUTIONS

Mesalamine has been implicated in the production of an acute intolerance syndrome characterized by cramping, acute abdominal pain and bloody diarrhea, sometimes fever , headache and a rash; in such cases prompt withdrawal is required. The patient's history of sulfasalazine intolerance, if any, should be re-evaluated. If a rechallenge is performed later in order to validate the hypersensitivity it should be carried out under close supervision and only if clearly needed, giving consideration to reduced dosage. In the literature one patient previously sensitive to sulfasalazine was rechallenged with 400 mg oral mesalamine; within eight hours she experienced headache, fever, intensive abdominal colic, profuse diarrhea and was readmitted as an emergency. She responded poorly to steroid therapy and two weeks later a pancolectomy was required.

Although renal abnormalities were not noted in the clinical trials with Mesalamine Rectal Suspension, USP, the possibility of increased absorption of mesalamine and concomitant renal tubular damage as noted in the preclinical studies must be kept in mind. Patients on Mesalamine Rectal Suspension, USP, especially those on concurrent oral products which liberate mesalamine and those with preexisting renal disease, should be carefully monitored with urinalysis, BUN (blood urea nitrogen) and creatinine studies.

In a clinical trial most patients who were hypersensitive to sulfasalazine were able to take mesalamine enemas without evidence of any allergic reaction. Nevertheless, caution should be exercised when mesalamine is initially used in patients known to be allergic to sulfasalazine. These patients should be instructed to discontinue therapy if signs of rash or fever become apparent.

While using Mesalamine Rectal Suspension, USP some patients have developed pancolitis. However, extension of upper disease boundary and/or flare-ups occurred less often in the Mesalamine Rectal Suspension, USP treated group than in the placebo-treated group.

Worsening of colitis or symptoms of inflammatory bowel disease, including melena and hematochezia, may occur after commencing mesalamine.

Rare instances of pericarditis have been reported with mesalamine containing products including sulfasalazine. Cases of pericarditis have also been reported as manifestations of inflammatory bowel disease. In the cases reported with Mesalamine Rectal Suspension, USP there have been positive rechallenges with mesalamine or mesalamine containing products. In one of these cases, however, a second rechallenge with sulfasalazine was negative throughout a 2 month follow-up. Chest pain or dyspnea in patients treated with Mesalamine Rectal Suspension, USP should be investigated with this information in mind. Discontinuation of Mesalamine Rectal Suspension, USP may be warranted in some cases, but rechallenge with mesalamine can be performed under careful clinical observation should the continued therapeutic need for mesalamine be present.

Information for Patients

See patient information enclosed.

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. Mesalamine is not mutagenic to Salmonella typhimurium tester strains TA98, TA100, TA1535, TA1537, TA1538. There were no reverse mutations in an assay using E. coli strain WP2UVRA. There were no effects in an in vivo mouse micronucleus assay at 600 mg/kg and in an in vivo sister chromatid exchange at doses up to 610 mg/kg. No effects on fertility were observed in rats receiving up to 320 mg/kg/day. The oligospermia and infertility in men associated with sulfasalazine have not been reported among patients treated with mesalamine.

Pregnancy (Category B)

Teratologic studies have been performed in rats and rabbits at oral doses up to five and eight times respectively, the maximum recommended human dose, and have revealed no evidence of harm to the embryo or the fetus. There are, however, no adequate and well controlled studies in pregnant women for either sulfasalazine or 5-ASA. Because animal reproduction studies are not always predictive of human response, 5-ASA should be used during pregnancy only if clearly needed.

Nursing Mothers

It is not known whether mesalamine or its metabolite(s) are excreted in human milk. As a general rule, nursing should not be undertaken while a patient is on a drug since many drugs are excreted in human milk.

Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

ADVERSE REACTIONS

Clinical Adverse Experience

Mesalamine Rectal Suspension, USP is usually well tolerated. Most adverse effects have been mild and transient.

ADVERSE REACTIONS OCCURRING IN MORE THAN 0.1 % OF MESALAMINE RECTAL SUSPENSION TREATED PATIENTS (COMPARISON TO PLACEBO)
MESALAMINE RECTAL SUSPENSION USP PLACEBO
SYMPTOM N=815
N
% N=128
N
%
Abdominal Pain/Cramps/Discomfort 66 8.10 10 7.81
Headache 53 6.50 16 12.50
Gas/Flatulence 50 6.13 5 3.91
Nausea 47 5.77 12 9.38
Flu 43 5.28 1 0.78
Tired/Weak/Malaise/Fatigue 28 3.44 8 6.25
Fever 26 3.19 0 0.00
Rash/Spots 23 2.82 4 3.12
Cold/Sore Throat 19 2.33 9 7.03
Diarrhea 17 2.09 5 3.91
Leg/joint Pain 17 2.09 1 0.78
Dizziness 15 1.84 3 2.34
Bloating 12 1.47 2 1.56
Back Pain 11 1.35 1 0.78
Pain on Insertion of Enema Tip 11 1.35 1 0.78
Hemorrhoids 11 1.35 0 0.00
Itching 10 1.23 1 0.78
Rectal Pain 10 1.23 0 0.00
Constipation 8 0.98 4 3.12
Hair Loss 7 0.86 0 0.00
Peripheral Edema 5 0.61 11 8.59
UTI/Urinary Burning 5 0.61 4 3.12
Rectal Pain/Soreness/Burning 5 0.61 3 2.34
Asthenia 1 0.12 4 3.12
Insomnia 1 0.12 3 2.34

In addition, the following adverse events have been identified during post-approval use of products which contain (or are metabolized to) mesalamine in clinical practice: nephrotoxicity, pancreatitis, fibrosing alveolitis and elevated liver enzymes. Cases of pancreatitis and fibrosing alveolitis have been reported as manifestations of inflammatory bowel disease as well. Published case reports and/or spontaneous post marketing surveillance have described rare instances of aplastic anemia, agranulocytosis, thrombocytopenia, eosinophilia, pancytopenia, neutropenia, oligospermia, and infertility in men. Anemia, leukocytosis and thrombocytosis can be part of the clinical presentation of inflammatory bowel disease.

Hair Loss

Mild hair loss characterized by "more hair in the comb" but no withdrawal from clinical trials has been observed in seven of 815 mesalamine patients but none of the placebo-treated patients. In the literature there are at least six additional patients with mild hair loss who received either mesalamine or sulfasalazine. Retreatment is not always associated with repeated hair loss.

OVERDOSAGE

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

DOSAGE AND ADMINISTRATION

The usual dosage of Mesalamine Rectal Suspension, USP in 60 mL units is one rectal instillation (4 grams) once a day, preferably at bedtime, and retained for approximately eight hours. While the effect of Mesalamine Rectal Suspension, USP may be seen within three to twenty-one days, the usual course of therapy would be from three to six weeks depending on symptoms and sigmoidoscopic findings. Studies available to date have not assessed if Mesalamine Rectal Suspension, USP will modify relapse rates after the 6-week short-term treatment. Mesalamine Rectal Suspension, USP is for rectal use only.

Patients should be instructed to shake the bottle well to make sure the suspension is homogeneous. The patient should remove the protective sheath from the applicator tip. Holding the bottle at the neck will not cause any of the medication to be discharged. The position most often used is obtained by lying on the left side (to facilitate migration into the sigmoid colon); with the lower leg extended and the upper right leg flexed forward for balance. An alternative is the knee-chest position. The applicator tip should be gently inserted in the rectum pointing toward the umbilicus. A steady squeezing of the bottle will discharge most of the preparation. The preparation should be taken at bedtime with the objective of retaining it all night. Patient instructions are included with every seven units.

HOW SUPPLIED

Mesalamine Rectal Suspension, USP, for rectal administration is an off-white to tan colored suspension. Each disposable enema bottle contains 4.0 grams of mesalamine in 60 mL aqueous suspension. Enema bottles are supplied in boxed, foil-wrapped trays as follows:

Carton of 7 Bottles - NDC 45802-098-51

Carton of 28 Bottles - NDC 45802-098-28

Combo Kit with 7 Bottles and Wipes - NDC 45802-923-41

Combo Kit with 28 Bottles and Wipes - NDC 45802-923-49

Mesalamine Rectal Suspension USP, Enemas are for rectal use only.

KEEP OUT OF REACH OF CHILDREN

Patient instructions are included.

Store at 20-25°C (68-77°F). [See USP Controlled Room Temperature]. Once the foil-wrapped unit of seven bottles is opened, all enemas should be used promptly as directed by your physician.

Contents of enemas removed from the foil pouch may darken with time. Slight darkening will not affect potency, however, enemas with dark brown contents should be discarded.

NOTE: Mesalamine Rectal Suspension, USP will cause staining of direct contact surfaces, including but not limited to fabrics, flooring, painted surfaces, marble, granite, vinyl, and enamel. Take care in choosing a suitable location for administration of this product.  

Rx Only

MADE IN ISRAEL

MANUFACTURED BY PERRIGO, YERUHAM 80500, ISRAEL

DISTRIBUTED BY

PERRIGO®

ALLEGAN, MI 49010

Rev. 11/09

2N900 RC J5

PATIENT INSTRUCTIONS

How to Use this Medication.

Best results are achieved if the bowel is emptied immediately before the medication is given.

NOTE: Mesalamine Rectal Suspension, USP will cause staining of direct contact surfaces, including but not limited to fabrics, flooring, painted surfaces, marble, granite, vinyl, and enamel. Take care in choosing a suitable location for administration of this product.  

1. Remove the Bottles

a. Remove the bottles from the protective foil pouch by tearing or by using scissors as shown, being careful not to squeeze or puncture bottles. Mesalamine Rectal Suspension, USP enema is an off-white to tan colored suspension. Once the foil-wrapped unit of seven bottles is opened, all enemas should be used promptly as directed by your physician. Contents of enemas removed from the foil pouch may darken with time. Slight darkening will not affect potency, however, enemas with dark brown contents should be discarded.

Remove the Bottles Image

Remove the Bottles Image

2. Prepare the Medication for Administration

a. Shake the bottle well to make sure that the medication is thoroughly mixed.

b. Remove the protective sheath from the applicator tip. Hold the bottle at the neck so as not to cause any of the medication to be discharged.

Prepare the Medication for Administration Image

Prepare the Medication for Administration Image

3. Assume the Correct Body Position

a. Best results are obtained by lying on the left side with the left leg extended and the right leg flexed forward for balance.

Assume the Correct Body Position Image #1

Assume the Correct Body Position Image #1

b. An alternative to lying on the left side is the "knee-chest" position as shown here.

Assume the Correct Body Position Image #2

Assume the Correct Body Position Image #2

4. Administer the Medication

a. Gently insert the lubricated applicator tip into the rectum to prevent damage to the rectal wall, pointed slightly toward the navel.

Administer the Medication Image

Administer the Medication Image

b. Grasp the bottle firmly, then tilt slightly so that the nozzle is aimed toward the back, squeeze slowly to instill the medication. Steady hand pressure will discharge most of the medication. After administering, withdraw and discard the bottle.

c. Remain in position for at least 30 minutes to allow thorough distribution of the medication internally. Retain the medication all night, if possible.

Rx Only

MADE IN ISRAEL

MANUFACTURED BY PERRIGO, YERUHAM 80500, ISRAEL

DISTRIBUTED BY PERRIGO, ALLEGAN, MI 49010

Rev. 11/09

Principal Display Panel

Mesalamine Rectal Suspension, USP Enema

4.0 grams/60 mL

For Rectal Use Only

Kit

Kit includes 7 complimentary cleansing wipes.

Dispense in existing packaging as one unit, do not repackage

Shake well before use

Rx Only

Mesalamine Rectal Suspension, USP Enema Image #1

Mesalamine Rectal Suspension, USP Enema Image #1

Mesalamine Rectal Suspension, USP Enema Carton Image 2

Mesalamine Rectal Suspension, USP Enema Image #2


MESALAMINE 
mesalamine kit
Product Information
Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:45802-923
Packaging
# Item Code Package Description Multilevel Packaging
1 NDC:45802-923-41 1 KIT ( KIT) in 1 CARTON None
QUANTITY OF PARTS
Part # Package Quantity Total Product Quantity
Part 1 7 BOTTLE   420 mL
Part 2 7 PACKET  
Part 1 of 2
MESALAMINE 
mesalamine enema
Product Information
Item Code (Source) NDC:45802-098
Route of Administration RECTAL DEA Schedule     
Active Ingredient/Active Moiety
Ingredient Name Basis of Strength Strength
MESALAMINE (MESALAMINE) MESALAMINE 4 g  in 60 mL
Inactive Ingredients
Ingredient Name Strength
CARBOMER HOMOPOLYMER TYPE B  
EDETATE DISODIUM  
POTASSIUM ACETATE  
POTASSIUM METABISULFITE  
WATER  
XANTHAN GUM  
SODIUM BENZOATE  
Product Characteristics
Color WHITE (off white to tan) Score     
Shape Size
Flavor Imprint Code
Contains     
Packaging
# Item Code Package Description Multilevel Packaging
1 45802-098-51 60 mL in 1 BOTTLE None
Marketing Information
Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date
ANDA ANDA076751 09/16/2009

Part 2 of 2
CLEANSING WIPES 
wipes swab
Product Information
Route of Administration TOPICAL DEA Schedule     
Inactive Ingredients
Ingredient Name Strength
BENZOIC ACID  
LEVOMENOL  
BUTYLENE GLYCOL  
BUTYLPARABEN  
CARAMEL  
DEHYDROACETIC ACID  
DEXPANTHENOL  
DIETHYLENE GLYCOL MONOETHYL ETHER  
ETHYLPARABEN  
DEXTROSE  
ISOBUTYLPARABEN  
LACTIC ACID  
METHYLPARABEN  
PHENOXYETHANOL  
POTASSIUM SORBATE  
PROPYLENE GLYCOL  
PROPYLPARABEN  
SODIUM BENZOATE  
WATER  
Product Characteristics
Color      Score     
Shape Size
Flavor Imprint Code
Contains     
Packaging
# Item Code Package Description Multilevel Packaging
1 1 SWAB ( SWAB) in 1 PACKET None
Marketing Information
Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date
Unapproved drug other 09/16/2009


Marketing Information
Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date
ANDA ANDA076751 09/01/2009

Labeler - Perrigo New York Inc (078846912)

Revised: 12/2010 Perrigo New York Inc



Source: http://dailymed.nlm.nih.gov
Reproduced with permission of U.S. National Library of Medicine


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