ASACOL® HD (mesalamine) delayed-release tablets

ASACOL® HD (mesalamine) delayed-release tablets

ASACOL® HD (mesalamine)

Each Asacol HD delayed-release tablet for oral administration contains 800 mg of mesalamine, an aminosalicylate. Asacol HD delayed-release tablets have an outer protective coat consisting of a combination of acrylic based resins, Eudragit S (methacrylic acid and methyl methacrylate copolymer (1:2), NF) and Eudragit L (methacrylic acid and methyl methacrylate copolymer (1:1), NF). The inner coat consists of an acrylic based resin, Eudragit S, which dissolves at pH 7 or greater, releasing mesalamine in the terminal ileum and beyond for topical anti-inflammatory action in the colon. Mesalamine (also referred to as 5-aminosalicylic acid or 5-ASA) has the chemical name 5-amino-2-hydroxybenzoic acid

Inactive Ingredients: Each tablet contains colloidal silicon dioxide, dibutyl sebacate, edible black ink, ferric oxide red (6.15 mg), ferric oxide yellow (1.10 mg), lactose monohydrate, magnesium stearate, methacrylic acid and methyl methacrylate copolymer (1:2) (Eudragit S), methacrylic acid and methyl methacrylate copolymer (1:1) (Eudragit L), polyethylene glycol, povidone, sodium starch glycolate, and talc.

INDICATIONS AND USAGE

Asacol® HD is indicated for the treatment of moderately active ulcerative colitis in adults.

Limitations of Use: Safety and effectiveness of Asacol HD beyond 6 weeks have not been established.

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, that is, prostanoids, and through the lipoxygenase pathways, that is, 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.

DOSAGE AND ADMINISTRATION

  • Do not substitute one Asacol HD 800 tablet for two mesalamine delayed-release 400 mg oral products.
  • Evaluate renal function prior to initiation of Asacol HD.
  • Take Asacol HD tablets on an empty stomach, at least 1 hour before and 2 hours after a meal.
  • Swallow Asacol HD tablets whole. Do not cut, break or chew the tablets.
  • Drink an adequate amount of fluids
  • Intact, partially intact, and/or tablet shells have been reported in the stool; Instruct patients to contact their healthcare provider if this occurs repeatedly.
  • Protect Asacol HD tablets from moisture.

For the treatment of moderately active ulcerative colitis, the recommended dosage of Asacol HD in adults is 1600 mg (two 800 mg tablets) three times daily (total daily dosage of 4.8 grams) for a duration of 6 weeks.

CONTRAINDICATIONS

Asacol HD is contraindicated in patients with known or suspected hypersensitivity to salicylates or aminosalicylates or to any of the ingredients of Asacol HD.

WARNINGS AND PRECAUTIONS

Renal Impairment

Renal impairment, including minimal change disease, acute and chronic interstitial nephritis, and, rarely, renal failure, has been reported in patients taking products such as Asacol HD that contain or are converted to mesalamine. In animal studies, the kidney was the principal organ of mesalamine toxicity.

Evaluate renal function prior to initiation of Asacol HD and periodically while on therapy. Evaluate the risks and benefits of using Asacol HD in patients with known renal impairment or 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 an exacerbation of ulcerative colitis. Exacerbation of the symptoms of colitis has been reported in 2.3% of Asacol HD-treated patients in controlled clinical trials. This acute reaction, characterized by cramping, abdominal pain, bloody diarrhea, and occasionally by fever, headache, malaise, pruritus, rash, and conjunctivitis, has been reported after the initiation of Asacol HD tablets as well as other mesalamine products. Symptoms usually abate when Asacol HD tablets are discontinued. Monitor patients for worsening of these symptoms while on treatment. If acute intolerance syndrome is suspected, promptly discontinue treatment with Asacol HD.

Hypersensitivity Reactions

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

Hepatic Failure

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

Severe Cutaneous Adverse Reactions

Severe cutaneous adverse reactions including 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 with use of mesalamine. Discontinue Asacol HD at the first appearance of signs or symptoms of severe cutaneous adverse reactions, or other signs of hypersensitivity and consider further evaluation.

Photosensitivity

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.

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 fluid intake during treatment with Asacol HD.

Iron Content of Asacol HD

Asacol HD contains iron oxide as a colorant in the coating of the delayed-release tablets. Each 800 mg delayed-release tablet contains 4.9 mg of iron. The total content of iron is

29.2 mg at the recommended daily dosage. Before prescribing Asacol HD to patients receiving iron supplementation or those at risk for developing iron overload, consider the combined daily amount of iron from all sources, including Asacol HD.

Interference with Laboratory Tests

Use of Asacol HD 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 the main metabolite of mesalamine, N-acetyl-5-aminosalicylic acid (N-Ac-5-ASA). Consider an alternative, selective assay for normetanephrine.

ADVERSE REACTIONS

The following adverse reactions have been identified during post-approval use of Asacol HD or other mesalamine-containing products or products that are metabolized to mesalamine. 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: Facial edema, edema, peripheral edema, asthenia, chills, infection, malaise, pain, neck pain, chest pain, back pain, abdominal enlargement, lupus-like syndrome, drug fever (rare).

Cardiovascular: Pericarditis (rare) and myocarditis (rare), pericardial effusion, vasodilation, migraine.

Endocrine: Nephrogenic diabetes insipidus.

Gastrointestinal: Dry mouth, stomatitis, oral ulcers, anorexia, increased appetite, eructation, pancreatitis, cholecystitis, gastritis, gastroenteritis, gastrointestinal bleeding, perforated peptic ulcer (rare), constipation, hemorrhoids, rectal hemorrhage, bloody diarrhea, tenesmus, stool abnormality.

Hepatic: There have been rare reports of hepatotoxicity, including jaundice, cholestatic jaundice, hepatitis, and possible hepatocellular damage including liver necrosis and liver failure. Some of these cases were fatal. Asymptomatic elevations of liver enzymes which usually resolve during continued use or with discontinuation of the drug have also been reported. One case of Kawasaki-like syndrome, that included changes in liver enzymes, was also reported.

Hematologic: Agranulocytosis (rare), aplastic anemia (rare), anemia, thrombocytopenia, leukopenia, eosinophilia, lymphadenopathy.

Musculoskeletal: Gout, rheumatoid arthritis, arthritis, arthralgia, joint disorder, myalgia, hypertonia.

Neurological/Psychiatric: Anxiety, depression, somnolence, insomnia, nervousness, confusion, emotional lability, dizziness, vertigo, tremor, paresthesia, hyperesthesia, peripheral neuropathy (rare), Guillain-Barré syndrome (rare), transverse myelitis (rare), and intracranial hypertension.

Respiratory/Pulmonary: Sinusitis, rhinitis, pharyngitis, asthma exacerbation, pleuritis/pleurisy, bronchitis, eosinophilic pneumonia, interstitial pneumonitis.

Skin: Alopecia, psoriasis (rare), pyoderma gangrenosum (rare), erythema nodosum, acne, dry skin, sweating, pruritus, urticaria, rash, SJS/TEN, DRESS, and AGEP.

Special Senses: Ear pain, tinnitus, ear congestion, ear disorder, conjunctivitis, eye pain, blurred vision, vision abnormality, taste perversion.

Renal/Urogenital: Renal failure (rare), interstitial nephritis, minimal change disease, nephrolithiasis, dysuria, urinary frequency and urgency, hematuria, epididymitis, decreased libido, dysmenorrhea, menorrhagia.

Laboratory Abnormalities: Elevated AST (SGOT) or ALT (SGPT), elevated alkaline phosphatase, elevated GGT, elevated LDH, elevated bilirubin, elevated serum creatinine and BUN.

DRUG INTERACTIONS

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.

Azathioprine or 6-Mercaptopurine

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

Interference With Urinary Normetanephrine Measurements

Use of Asacol HD may lead to spuriously elevated test results when measuring urinary normetanephrine by liquid chromatography with electrochemical detection. Consider an alternative, selective assay for normetanephrine.

USE IN SPECIFIC POPULATIONS

Pregnancy: Limited published data on mesalamine use in pregnant women are insufficient to inform a drug-associated risk.

Lactation: Mesalamine and its N-acetyl metabolite are present in human milk in undetectable to small amounts. There are limited reports of diarrhea in breastfed infants. There is no information on the effects of the drug on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for Asacol HD and any potential adverse effects on the breastfed infant from the drug or from the underlying maternal condition.

Pediatric Use: Safety and effectiveness of Asacol HD in pediatric patients have not been established. See the prescribing information for other approved mesalamine products for the safety and effectiveness of these products in pediatric patients.

OVERDOSAGE

Asacol HD 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; however, conventional therapy for salicylate toxicity may be beneficial in the event of acute overdosage and may include gastrointestinal tract decontamination to prevent of further absorption. Correct fluid and electrolyte imbalance by the administration of appropriate intravenous therapy and maintain adequate renal function.

Asacol HD is a pH dependent delayed-release product and this factor should be considered when treating a suspected overdose.

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