Mesalamine

Mesalamine is a 5-Aminosalicylic acid derivative belonging to anti-inflammatory agent.

Mesalamine is an amino salicylate drug used to treat mild to moderate active ulcerative colitis and to maintain remission once achieved.

Depending on the formulation administered, prescribing information for orally administered delayed-released tablets of 2.4g or 4.8g of mesalamine given once daily for 14 days to healthy volunteers was to be found to be about 21% to 22% of the administered dose while prescribing information for an orally administered controlled-release capsule formulation suggests 20% to 30% of the mesalamine in the formulation is absorbed. Mesalamine crosses placenta and enters breast milk (small amounts). Plasma protein-binding is about 40-50%. The apparent volume of distribution (Vd) of the drug in adults is approximately 0.2 L/kg. The absorbed mesalamine is rapidly acetylated in the gut mucosal wall and by the liver to N-acetyl-5 aminosalicylic acid. Absorbed mesalamine is excreted mainly by the kidney as N-acetyl-5-aminosalicylic acid. Unabsorbed mesalamine is excreted in feces.

Mesalamine shows common side effects like Muscle or joint pain, aching, tightness or stiffness, back pain, Nausea, vomiting, Heartburn, burping, constipation, Gas, dry mouth, Itching, dizziness, Sweating, acne, hair loss, decreased appetite.

Mesalamine is available in the form of Oral Tablet, Oral capsule, Rectal enema, Rectal suppository, and Rectal foam.

Mesalamine is available in India, US, Canada, Malaysia, Russia, China, Japan, and Australia.

Mesalamine belongs to the anti-inflammatory agent acts as a 5-Aminosalicylic acid.

Mesalamine (5-aminosalicylic acid) is the active component of sulfasalazine; the specific mechanism of action is unknown; however, it is thought that mesalamine modulates local chemical mediators of the inflammatory response, especially leukotrienes, and is also postulated to be a free radical scavenger or an inhibitor of tumor necrosis factor (TNF); action appears topical rather than systemic.

The onset and duration of action of Mesalamine is not clinically established.

The Tmax of Mesalamine is approximately 3-12 hours (via oral route) and 1-6 hour (via rectal route).

Mesalamine is available in the form of Oral Tablet, Oral capsule, Rectal enema, Rectal suppository, and Rectal foam.

Mesalamine Tablet and Capsule are taken orally, usually in divided dose.

Rectal enema: Shake bottle well. Instruct patient to lie on left side with left leg extended and right leg flexed forward for balance, or in “knee-chest” position. Insert lubricated applicator tip into the rectum and point slightly toward the navel. Grasp bottle firmly and tilt so nozzle is aimed toward the back; squeeze slowly to instill medication. After administration, withdraw and discard bottle. Retain enemas for 8 hours or as long as practical.

Rectal foam: Warm canister to room temperature (15°C to 30°C [59°F to 86°F]). Attach applicator to canister; shake for ~20 seconds. Insert applicator as far into the rectum as comfortable for patient. Press pump dome once and slowly release it to administer dose; hold applicator in rectum for 10 to 15 seconds after dose administered. For the second spray, press dome again and release slowly; wait a further 10 to 15 seconds, then remove the applicator and dispose.

Suppository: Remove foil wrapper; avoid excessive handling. Insert into rectum. Retain suppository for 1 to 3 hours or longer. Do not cut or break suppository.

Mesalamine is an anti-inflammatory drug used in the treatment of ulcerative colitis, a condition characterized by swelling and scarring of the colon and rectum. It is also used to control the symptoms of ulcerative colitis such as stomach pain, diarrhea, and rectal bleeding.

Mesalamine is a 5-Aminosalicylic acid derivative belonging to anti-inflammatory agent.

Mesalamine is the active moiety of sulfasalazine. The mechanism of action is uncertain but may be due to its ability to inhibit prostaglandin and leukotriene synthesis in the GI mucosa.

Mesalamine is approved for use in the following clinical indications

• Crohn disease
• Ulcerative colitis

• Crohn disease

Adult Oral: 1 g 3 to 4 times daily.

Children and Adolescents: Oral: 50 to 100 mg/kg/day divided every 6 to 12 hours; maximum dose: 1,000 mg/dose.

• Ulcerative colitis
• Adult Dose

Initial dosing regimens include

Topical treatments

Suppositories

Rectal Suppositories: 1 g once daily at bedtime or 500 mg 2 or 3 times daily or 1 g once daily at bedtime.

Rectal foam: 2 g (2 actuations) once daily at bedtime.

Rectal suspension: 1 g or 4 g enema once daily at bedtime; choose dose based on disease severity.

Oral treatments

Oral: 1.5 to 4.5 g once each morning or 1.6 g 3 times daily or 800 mg 3 times daily or 2.4 to 4.8 g once daily or 400 mg tablet (2.4 to 4.8 g/day) in 3 divided doses or 1 g 4 times daily or 1 g 3 or 4 times daily.

Duration of induction therapy: Usual course is 4 to 8 weeks before transitioning to maintenance treatment.

Maintenance of remission

Topical treatments

Rectal Suppositories: 1 g once daily at bedtime or 500 mg 2 times daily or 1 g once daily at bedtime.

Rectal suspension: 1 g or 4 g enema once daily at bedtime; choose dose based on disease severity or 2 g enema once daily at bedtime every day or 4 g enema once daily at bedtime every second or third day.

Oral treatments

Oral: 1.5 to 3 g once daily or 1.6 to 2.4 g/day in 1 to 4 divided doses or 2.4 to 3.6 g once daily or 400mg (1.6 to 2.4 g/day) in 1 to 3 divided doses or 2.4 to 3.6 g once daily or 1.5 to 4 g/day in 3 to 4 divided doses.

• Pediatric Dose

Oral treatment

(Twice-daily dosing)

Children ≥5 years and Adolescents: 17 to <33 kg: Oral: 800 mg in the morning and 400 mg in the evening for 6 weeks; maximum daily dose: 1,200 mg/day.

33 to <54 kg: Oral: 1,200 mg in the morning and 800 mg in the evening for 6 weeks; maximum daily dose: 2,000 mg/day.

54 to 90 kg: Oral: 1,200 mg in the morning and 1,200 mg in the evening for 6 weeks; maximum daily dose: 2,400 mg/day.

(Once-daily dosing)

Children and Adolescents weighing ≥24 kg

24 to 35 kg: Oral: 2,400 mg once daily for the first 8 weeks of therapy, then decrease dose to 1,200 mg once daily.

>35 to 50 kg: Oral: 3,600 mg once daily for the first 8 weeks of therapy, then decrease to 2,400 mg once daily.

>50 kg: Oral: 4,800 mg once daily for the first 8 weeks of therapy, then decrease to 2,400 mg once daily.

Topical treatment

Children and Adolescents: Rectal enema, foam: 25 mg/kg/dose once daily; maximum dose: 1,000 mg/dose.

Mesalamine is available in various strengths as 250 mg; 400 mg; 800 mg; 4 g/60 mL; 500 mg; 0.375 g; 1.2 g; 1000 mg.

Mesalamine is available in the form of Oral Tablet, Oral capsule, Rectal enema, Rectal suppository, and Rectal foam.

Mesalamine is contraindicated in patients with

• Mesalamine is contraindicated in patients with known or suspected hypersensitivity to salicylates, amino salicylates, 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 Mesalamine 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 Mesalamine. 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.

• 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 Mesalamine.

• 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.

• 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.

• 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 Mesalamine 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.

Mesalamine is not recommended for use in breastfeeding women unless necessary. If the medicine is used, close monitoring of the infant for any undesired side effects is necessary. All the risks and benefits should be considered before taking Mesalamine.

Animal reproduction studies have shown an adverse effect on the fetus and there are no adequate and well-controlled studies in humans, but potential benefits may warrant use of the drug in pregnant women despite potential risks.

Common

● Abdominal pain, constipation, eructation, Headache, nasopharyngitis, Hypertension, Acne vulgaris, alopecia, pruritus, skin rash, Increased serum triglycerides (<3%), weight loss, Abdominal distention, anorectal pain, bloody diarrhea, dyspepsia, flatulence, gastroenteritis, gastrointestinal hemorrhage, hemorrhoids, lower abdominal pain, nausea, pancreatitis, rectal pain, sclerosing cholangitis, tenesmus, upper abdominal pain, vomiting, Hematuria, urinary frequency, Decreased hematocrit, decreased hemoglobin, rectal hemorrhage, Cholestatic hepatitis, Infection, influenza, viral infection, Dizziness, fatigue, nervousness, paresthesia, vertigo, Arthralgia, arthropathy, back pain, lower extremity pain, Visual disturbance, Tinnitus, Decreased creatinine clearance.

Rare

● Edema, facial edema, hypotension, palpitations, pericarditis, tachycardia, vasodilation, Diaphoresis, ecchymoses, eczema, erythema nodosum, lichen planus, nail disease, prurigo, skin photosensitivity, urticaria, xeroderma, Albuminuria, amenorrhea, heavy menstrual bleeding, increased amylase, increased gamma-glutamyl transferase, increased lactate dehydrogenase, increased thirst, Kawasaki-like syndrome, Abnormal stools, anorexia, duodenal ulcer, dysphagia, esophageal ulcer, fecal incontinence, increased serum lipase, oral candidiasis, oral mucosa ulcer, rectal polyp, rectal tenesmus, Hypomenorrhea, mastalgia, uterine hemorrhage, Thrombocythemia, thrombocytopenia, Increased serum alanine aminotransferase, increased serum alkaline phosphatase, increased serum aspartate aminotransferase, Depression, drowsiness, insomnia, malaise, Asthenia, lower limb cramp, myalgia, tremor, Conjunctivitis, Otalgia, Pharyngolaryngeal pain, pulmonary infiltrates.

• 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 MESALAMINE and azathioprine or 6-mercaptopurine cannot be avoided, monitor blood tests, including complete blood cell counts and platelet counts.

The common side effects of Mesalamine include the following

Common side effects

● Muscle or joint pain, aching, tightness or stiffness, back pain, Nausea, vomiting, Heartburn, burping, constipation, Gas, dry mouth, Itching, dizziness, Sweating, acne, hair loss, decreased appetite.

Rare side effects

● Hypersensitivity

• Pregnancy

Pregnancy Category B

There are no adequate and well controlled studies of Mesalamine use in pregnant women. Limited published human data on mesalamine show no increase in the overall rate of congenital malformations. Some data show an increased rate of preterm birth, stillbirth, and low birth weight; however, these adverse pregnancy outcomes are also associated with active inflammatory bowel disease. Furthermore, all pregnancies, regardless of drug exposure, have a background rate of 2 to 4% for major malformations, and 15 to 20% for pregnancy loss. No evidence of fetal harm was observed in animal reproduction studies of mesalamine in rats and rabbits at oral doses approximately 1.9 times (rat) and 3.9 times (rabbit) the recommended human dose. Mesalamine should be used during pregnancy only if clearly needed.

• Nursing Mothers

Mesalamine and its N-acetyl metabolite are present in human milk. 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 doses 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. 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 the drug or from the underlying maternal condition. Caution should be exercised when Mesalamine is administered to a nursing woman.

• Pediatric Use

The safety and effectiveness of Mesalamine for the treatment of mildly to moderately active ulcerative colitis in pediatric patients 5 to 17 years of age has been established based on adequate and well controlled studies using mesalamine delayed release 400 mg tablets. Use of Mesalamine in these pediatric age groups is supported by evidence from adequate and well controlled studies of mesalamine delayed-release 400 mg tablets in adults and a single 6-week study in 82 pediatric patients 5 to 17 years of age. The safety and effectiveness of Mesalamine for the treatment of mildly to moderately active ulcerative colitis in pediatric patients below the age of 5 years have not been established. The safety and effectiveness of Mesalamine in the maintenance of remission of ulcerative colitis in pediatric patients have not been established.

• Geriatric Use

Clinical studies of mesalamine delayed-release tablets did not include enough patients aged 65 and over to determine whether they respond differently than younger patients. Reports from uncontrolled clinical studies and post marketing experience suggest a higher incidence of blood dyscrasias (agranulocytosis, neutropenia, pancytopenia) in subjects receiving mesalamine delayed-release tablets who are 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, the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy in elderly patients should be considered when prescribing Mesalamine.

There is no specific antidote for mesalamine overdose and treatment for suspected acute severe toxicity with Mesalamine should be symptomatic and supportive. This may include prevention of further gastrointestinal tract absorption, correction of fluid electrolyte imbalance, and maintenance of adequate renal function. Mesalamine is a pH dependent delayed-release product, and this factor should be considered when treating a suspected overdose.

Pharmacodynamic

Mesalamine is one of the two components of sulphasalazine, the other being sulphapyridine. It is the latter which is responsible for most of the side effects associated with sulphasalazine therapy whilst mesalamine is known to be the active moiety in the treatment of ulcerative colitis. The pharmacodynamic actions of mesalamine occur in the colonic/rectal mucosae local to the delivery of drug from mesalamine tablets into the lumen. There is information suggesting that the severity of colonic inflammation in ulcerative colitis patients treated with mesalamine is inversely correlated with mucosal concentrations of mesalamine. Plasma concentrations representing systemically absorbed mesalamine are not believed to contribute extensively to efficacy.

Pharmacokinetics

• Absorption

Depending on the formulation administered, prescribing information for orally administered delayed-released tablets of 2.4g or 4.8g of mesalamine given once daily for 14 days to healthy volunteers was to be found to be about 21% to 22% of the administered dose while prescribing information for an orally administered controlled-release capsule formulation suggests 20% to 30% of the mesalamine in the formulation is absorbed. In contrast, when mesalamine is administered orally as an unformulated 1-g aqueous suspension, Mesalamine is approximately 80% absorbed.

• Distribution

Mesalamine crosses placenta and enters breast milk (small amounts). Plasma protein-binding is about 40-50%. The apparent volume of distribution (Vd) of the drug in adults is approximately 0.2 L/kg

• Metabolism

The absorbed mesalamine is rapidly acetylated in the gut mucosal wall and by the liver to N-acetyl-5 aminosalicylic acid.

• Excretion

Absorbed mesalamine is excreted mainly by the kidney as N-acetyl-5-aminosalicylic acid. Unabsorbed mesalamine is excreted in feces. After intravenous administration, the elimination half-life of mesalamine is reported to be approximately 40 minutes. After oral dosing, the median terminal t1/2 values for mesalamine are usually about 25 hours, but are variable, ranging from 1.5 to 296 hours. There is a large inter-subject and intra-subject variability in the plasma concentrations of mesalamine and N-acetyl-5-aminosalicylic acid and in their terminal halflives following administration of Mesalamine.

• https://www.accessdata.fda.gov/drugsatfda_docs/label/2015/204412s006lbl.pdf
• https://www.rxlist.com/pentasa-drug.htm#overdosage
• https://reference.medscape.com/drug/pentasa-lialda-mesalamine-342074
• https://medlineplus.gov/druginfo/meds/a688021.html#side-effects
• https://www.mims.com/india/drug/info/mesalazine?type=full&mtype=generic
• https://go.drugbank.com/drugs/DB00244
• https://www.drugs.com/dosage/mesalamine.html
• https://www.uptodate.com/contents/mesalamine-mesalazine-drug-information#F193394
• https://www.practo.com/medicine-info/mesalazine-780-api