6.1Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Mesalamine delayed-release has been evaluated in 896 patients with ulcerative colitis in controlled studies. Three six-week, active-controlled studies were conducted comparing mesalamine delayed-release 4.8 grams per day with mesalamine-delayed release tablets 2.4 grams per day in patients with mildly to moderately active ulcerative colitis.
In these studies, 727 patients were dosed with mesalamine delayed-release (800 mg) tablets and 732 patients were dosed with mesalamine delayed-release (400 mg) tablets. The most common reactions reported in the mesalamine delayed-release group were headache (4.7%), nausea (2.8%), nasopharyngitis (2.5%), abdominal pain (2.3%), diarrhea (1.7%), and dyspepsia (1.7%); Table 1 enumerates adverse reactions that occurred in the three studies.
The most common reactions in patients with moderately active ulcerative colitis (602 patients dosed with mesalamine delayed-release and 618 patients dosed with mesalamine delayed-release 400 mg) were the same as all treated patients. Discontinuations due to adverse reactions occurred in 3.9% of patients in the mesalamine delayed-release group and in 4.2% of patients in the mesalamine delayed-release tablet comparator group.
The most common cause for discontinuation was gastrointestinal symptoms associated with ulcerative colitis. Serious adverse reactions occurred in 0.8% of patients in the mesalamine delayed-release group and in 1.8% of patients in the mesalamine delayed-release tablet comparator group. The majority involved the gastrointestinal system. Table 1. Adverse Reactions Occurring in ≥1% of All Treated Patients (Three studies combined) Adverse Reaction Mesalamine delayed-release 2.4 grams per day (400 mg Tablet) (N = 732) Mesalamine delayed-release 4.8 grams per day (800 mg Tablet) (N = 727) Headache 4.9 % 4.7 % Nausea 2.9 % 2.8 % Nasopharyngitis 1.4 % 2.5 % Abdominal pain 2.3 % 2.3 % Diarrhea 1.9 % 1.7 % Dyspepsia 0.8 % 1.7 % Vomiting 1.6 % 1.4 % Flatulence 0.7 % 1.2 % Influenza 1.2 % 1.0 % Pyrexia 1.2 % 0.7 % Cough 1.4 % 0.3 % N = number of patients within specified treatment group Percent = percentage of patients in category and treatment group
6.2Postmarketing Experience
The following adverse reactions have been identified during post-approval use of mesalamine delayed-release 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) [see Warnings and Precautions ( 5.3 )] , 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 [see Warnings and Precautions ( 5.4 )] .
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 [see Warnings and Precautions ( 5.5 )] . 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 [see Warnings and Precautions ( 5.1 , 5.7 )] , dysuria, urinary frequency and urgency, hematuria, epididymitis, decreased libido, dysmenorrhea, menorrhagia. Urine discoloration occurring ex-vivo caused by contact of mesalamine, including inactive metabolite, with surfaces or water treated with hypochlorite containing bleach.
