PENTASA (mesalamine) for oral administration is an extended-release formulation of mesalamine, an aminosalicylate anti-inflammatory agent for gastrointestinal use.
Chemically, mesalamine is 5-amino-2-hydroxybenzoic acid. It has a molecular weight of 153.14.
Each 250-mg capsule contains 250 mg of mesalamine. It also contains the following inactive ingredients: acetylated monoglyceride, castor oil, colloidal silicon dioxide, ethylcellulose, hydroxypropyl methylcellulose, starch, stearic acid, sugar, talc, and white wax. The capsule shell contains D&C Yellow #10, FD&C Blue #1, FD&C Green #3, gelatin, titanium dioxide, and other ingredients.
Each 500-mg capsule contains 500 mg of mesalamine. It also contains the following inactive ingredients: acetylated monoglyceride, castor oil, colloidal silicon dioxide, ethylcellulose, hydroxypropyl methylcellulose, starch, stearic acid, sugar, talc, and white wax. The capsule shell contains FD&C Blue #1, gelatin, titanium dioxide, and other ingredients.
The mechanism of action
The mechanism of action of mesalamine (and sulfasalazine) is not fully understood, but it appears to be a topical anti-inflammatory effect on colonic epithelial cells. 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 ulcerative colitis, and it is possible that mesalamine diminishes inflammation by blocking cyclooxygenase and inhibiting prostaglandin (PG) production in the colon.
INDICATIONS AND USAGE
PENTASA is indicated for the induction of remission and for the treatment of adult patients with mildly to moderately active ulcerative colitis.
PENTASA is contraindicated in patients with known or suspected hypersensitivity to salicylates, aminosalicylates, or any components of this medication.
Renal Impairment: Renal impairment, including minimal change disease, acute and chronic interstitial nephritis, and renal failure have been reported in patients given PENTASA or other products that contain mesalamine or are converted to mesalamine.
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 therapy with PENTASA. Evaluate the risks and benefits of using PENTASA 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 a flare of inflammatory bowel disease. Symptoms include cramping, acute abdominal pain, bloody diarrhea, and sometimes fever, headache, and rash. Monitor patients for worsening of these symptoms while on treatment. If acute intolerance syndrome is suspected, promptly discontinue treatment with PENTASA.
Hypersensitivity Reactions: Hypersensitivity reactions have been reported in patients taking sulfasalazine. Some patients may have a similar reaction to PENTASA or to other compounds that contain or are converted to mesalamine.
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 PENTASA in patients with known liver impairment.
Severe Cutaneous Adverse Reactions: Severe cutaneous adverse reactions, such as Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), drug reaction with eosinophilia and systemic symptoms (DRESS), and acute generalized exanthematous pustulosis (AGEP) have been reported in with the use of mesalamine. Discontinue PENTASA at the first signs or symptoms of severe cutaneous adverse reactions or other signs of hypersensitivity and consider further evaluation.
Photosensitivity: Patients with 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.
Nephrolithiasis: Cases of nephrolithiasis have been reported with the use of mesalamine, including stones with 100% mesalamine content. Mesalamine-containing stones are radiotransparent and undetectable by standard radiography or computed tomography (CT). Ensure adequate hydration during treatment.
Interference with Laboratory Tests: 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-acetyl-5-aminosalicylic acid (N-Ac-5-ASA). Consider an alternative, selective assay for normetanephrine.
No investigations of interactions between PENTASA and other drugs have been performed; however, the following drug-drug interactions have been reported for products containing mesalamine:
Nephrotoxic Agents, Including Non-Steroidal Anti-Inflammatory Drugs: The concurrent use of mesalamine with known nephrotoxic agents, including non-steroidal 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.
Azathioprine or 6-Mercaptopurine: The concurrent use of mesalamine with azathioprine or 6-mercaptopurine and/or any other drugs known to cause myelotoxicity may increase the risk for blood disorders, bone marrow failure, and associated complications. If concomitant use of PENTASA and azathioprine or 6-mercaptopurine cannot be avoided, monitor blood tests, including complete blood cell counts and platelet counts.
Use in specific populations
Pregnancy: Published data from meta-analyses, cohort studies, and case series on the use of mesalamine during pregnancy have not reliably informed an association with mesalamine and major birth defects, miscarriage, or adverse maternal or fetal outcomes. There is no clear evidence that mesalamine exposure in early pregnancy is associated with an increased risk of major congenital malformations, including cardiac malformations. Published epidemiologic studies have important methodological limitations which hinder interpretation of the data, including inability to control for confounders, such as underlying maternal disease, maternal use of concomitant medications, and missing information on the dose and duration of use for mesalamine products. PENTASA should only be used during pregnancy if the benefits outweigh the risks.
Published data suggest that increased disease activity is associated with the risk of developing adverse pregnancy outcomes in women with ulcerative colitis. Adverse pregnancy outcomes include preterm delivery (before 37 weeks of gestation), low birth weight (less than 2500 g) infants, and small for gestational age at birth.
Nursing Mothers: Data from published literature report the presence of mesalamine and its metabolite, N-acetyl-5-aminosalicylic acid in human milk in small amounts with relative infant doses (RID) of 0.1% or less for mesalamine. The clinical significance of this has not been determined and there is limited experience of nursing women using mesalamine.
There are reports of diarrhea observed in breastfed infants exposed to mesalamine. The effect of PENTASA on milk production is unknown. Exercise caution if PENTASA is administered to a nursing woman and monitor breastfed infants for diarrhea.
Pediatric Use: Safety and efficacy of PENTASA in pediatric patients have not been established.
The following events have been identified during post-approval use of the PENTASA brand of mesalamine in clinical practice. Because they are reported voluntarily from a population of unknown size, estimates of frequency cannot be made. These events have been chosen for inclusion due to a combination of seriousness, frequency of reporting, or potential causal connection to mesalamine:
Gastrointestinal: Reports of hepatotoxicity, including elevated liver enzymes (SGOT/AST, SGPT/ALT, GGT, LDH, alkaline phosphatase, bilirubin), hepatitis, jaundice, cholestatic jaundice, cirrhosis, and possible hepatocellular damage including liver necrosis and liver failure. Some of these cases were fatal. One case of Kawasaki-like syndrome which included hepatic function changes was also reported.
Other: anaphylactic reaction, SJS/TEN, DRESS, AGEP, pleurisy/pleuritis, pneumonitis, granulocytopenia, systemic lupus erythematosus, lupus-like syndrome, acute renal failure, interstitial lung disease, hypersensitivity pneumonitis (including interstitial pneumonitis, allergic alveolitis, eosinophilic pneumonitis), chronic renal failure, nephrogenic diabetes insipidus, nephrolithiasis, intracranial hypertension, angioedema, and oligospermia (reversible).
PENTASA is an aminosalicylate, and symptoms of salicylate toxicity may be possible, such as: nausea, vomiting, abdominal pain, tachypnea, hyperpnea, tinnitus, and neurologic symptoms (headache, dizziness, confusion, seizures). Severe intoxication with salicylates may lead to electrolyte and blood pH imbalance and potentially to other organ (e.g., renal and liver) damage.
Treatment of Overdosage: There is no specific antidote for mesalamine overdose; however, conventional therapy for salicylate toxicity may be beneficial in the event of acute overdosage and may include gastrointestinal tract decontamination to prevent further absorption. Correct fluid and electrolyte imbalance by the administration of appropriate intravenous therapy and maintain adequate renal function.
DOSAGE AND ADMINISTRATION
The recommended dosage for the induction of remission and the symptomatic treatment of mildly to moderately active ulcerative colitis in adults is 1 g (4 PENTASA 250-mg capsules or 2 PENTASA 500-mg capsules) 4 times a day for a total daily dosage of 4 g. Treatment duration in controlled trials was up to 8 weeks.
PENTASA capsules may be swallowed whole, or alternatively, the capsule may be opened and the entire contents sprinkled onto applesauce or yogurt. The entire contents should be consumed immediately. The capsules and capsule contents must not be crushed or chewed.
Drink an adequate amount of fluids.
Safety and efficacy of PENTASA in pediatric patients have not been established.