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部分中文ASACOL HD处方资料（仅供参考）
ASACOL HD(MESALAMINE)TABLET, DELAYED RELEASE ORAL已通用FDA批准
In addition to the adverse reactions reported above in clinical trials involving the Asacol HD tablet, the adverse events listed below have been reported in controlled clinical trials, open label studies, literature reports, or foreign and domestic marketing experience with Asacol 400 mg tablets or other products that contain mesalamine or 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. 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), and transverse myelitis (rare). Respiratory/Pulmonary: Sinusitis, rhinitis, pharyngitis, asthma exacerbation, pleuritis, bronchitis, eosinophilic pneumonia, interstitial pneumonitis. Skin: Alopecia, psoriasis (rare), pyoderma gangrenosum (rare), erythema nodosum, acne, dry skin, sweating, pruritus, urticaria, rash. 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 nephropathy [see Warnings and Precautions (5.1)], 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. 7 DRUG INTERACTIONS No formal drug interaction studies have been performed using Asacol HD with other drugs. However, the following interactions between mesalamine-containing products and other drugs have been reported. 7.1 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 renal reactions [see Warnings and Precautions (5.1)]. 7.2 Azathioprine or 6-mercaptopurine The concurrent use of mesalamine with azathioprine or 6-mercaptopurine may increase the risk for blood disorders. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category C Risk summary There are no adequate well controlled studies of Asacol HD 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 percent for major malformations, and 15 to 20 percent for pregnancy loss. No evidence of fetal harm was observed in animal reproduction studies of mesalamine in rats and rabbits at oral doses approximately 1.6 times (rat) and 3.2 times (rabbit) the recommended human dose. However, dibutyl phthalate (DBP) is an inactive ingredient in Asacol HD’s enteric coating, and in animal studies in rats at doses higher than 80 times the human dose, maternal DBP was associated with external and skeletal malformations and adverse effects on the male reproductive system. Asacol HD should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Human data Mesalamine crosses the placenta. In prospective and retrospective studies of over 600 women exposed to mesalamine during pregnancy, the observed rate of congenital malformations was not increased above the background rate in the general population. Some data show an increased rate of preterm birth, stillbirth, and low birth weight, but it is unclear whether this was due to underlying maternal disease, drug exposure, or both, as active inflammatory bowel disease is also associated with adverse pregnancy outcomes. Animal data Reproduction studies with mesalamine were performed during organogenesis in rats and rabbits at oral doses up to 480 mg/kg/day. There was no evidence of impaired fertility or harm to the fetus. These mesalamine doses were about 1.6 times (rat) and 3.2 times (rabbit) the recommended human dose, based on body surface area. Dibutyl phthalate (DBP) is an inactive ingredient in Asacol HD’s enteric coating. The human daily intake of DBP from the maximum recommended dose of Asacol HD tablets is about 48 mg. Published reports in rats show that male rat offspring exposed in utero to DBP (greater than or equal to 100 mg/kg/day, approximately 17 times the human dose based on body surface area), display reproductive system aberrations compatible with disruption of androgenic dependent development. The clinical significance of this finding in rats is unknown. At higher dosages (greater than or equal to 500 mg/kg/day, approximately 84 times the human dose based on body surface area), additional effects, including cryptorchidism, hypospadias, atrophy or agenesis of sex accessory organs, testicular injury, reduced daily sperm production, permanent retention of nipples, and decreased anogenital distance are noted. Female offspring are unaffected. High doses of DBP, administered to pregnant rats was associated with increased incidences of developmental abnormalities, such as cleft palate (greater than or equal to 630 mg/kg/day, about 106 times the human dose, based on body surface area) and skeletal abnormalities (greater than or equal to 750 mg/kg/day, about 127 times the human dose based on body surface area) in the offspring. 8.3 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. Dibutyl phthalate (DBP), an inactive ingredient in the enteric coating of Asacol HD tablets, and its primary metabolite mono-butyl phthalate (MBP) are excreted into human milk. The clinical significance of this has not been determined. 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 child from the drug or from the underlying maternal condition. Exercise caution when Asacol HD is administered to a nursing mother. 8.4 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. 8.5 Geriatric Use Clinical studies of Asacol HD did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently than younger subjects. Other reported clinical experience has not identified differences in response between the elderly and younger patients. 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 Asacol HD. Reports from uncontrolled clinical studies and postmarketing reporting systems for Asacol (mesalamine) suggested a higher incidence of blood dyscrasias, that is, agranulocytosis, neutropenia, pancytopenia, in patients who were 65 years or older. Caution should be taken to closely monitor blood cell counts during mesalamine therapy. 8.6 Renal Impairment Mesalamine is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken when prescribing this drug therapy. It is recommended that all patients have an evaluation of renal function prior to initiation of Asacol HD therapy and periodically while on Asacol HD therapy [see Dosage and Administration (2.3), Warnings and Precautions (5.1)]. 10 OVERDOSAGE There is no specific antidote for mesalamine overdose and treatment for suspected acute severe toxicity with Asacol HD 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. Asacol HD is a pH dependent delayed-release product and this factor should be considered when treating a suspected overdose. Single oral doses of 5000 mg/kg mesalamine suspension in mice (approximately 4.2 times the recommended human dose of Asacol HD based on body surface area), 4595 mg/kg in rats (approximately 7.8 times the recommended human dose of Asacol HD based on body surface area) and 3000 mg/kg in cynomolgus monkeys (approximately 10 times the recommended human dose of Asacol HD based on body surface area) were lethal. 11 DESCRIPTION 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 copolymer B, NF) and Eudragit L (methacrylic acid copolymer A, 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; its structural formula is:
One Asacol HD 800 mg tablet has not been shown to be bioequivalent to two Asacol 400 mg tablets. In a single dose, cross-over pharmacokinetic study in 20 healthy volunteers, the mean mesalamine Cmax was 36 percent lower and the mean mesalamine AUC was 25 percent lower with administration of one Asacol HD 800 mg tablet relative to two Asacol 400 mg tablets. Because the mechanism of action of mesalamine appears to be topical, the impact of these differences in measures of systemic exposure on clinical efficacy is not known. 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Dietary mesalamine was not carcinogenic in rats at doses as high as 480 mg/kg/day, or in mice at 2000 mg/kg/day. These doses are approximately 0.8 and 1.7 times the 4.8 g/day Asacol HD dose (based on body surface area). Mesalamine was not genotoxic in the Ames test, the Chinese hamster ovary cell chromosomal aberration assay, and the mouse micronucleus test. Mesalamine, at oral doses up to 480 mg/kg/day (about 0.8 times the recommended human treatment dose based on body surface area), was found to have no effect on fertility or reproductive performance of male and female rats. 13.2 Animal Toxicology and/or Pharmacology In animal studies (rats, mice, dogs), the kidney was the principal organ for toxicity. (In the following, comparisons of animal dosing to recommended human dosing are based on body surface area and a 4.8 g/day dose for a 50 kg person.) Mesalamine causes renal papillary necrosis in rats at single doses of approximately 750 mg/kg to 1000 mg/kg (1.3 to 1.7 times the recommended human dose). Doses of 170 and 360 mg/kg/day (about 0.3 and 0.6 times the recommended human dose) given to rats for six months produced papillary necrosis, papillary edema, tubular degeneration, tubular mineralization, and urothelial hyperplasia. In mice, oral doses of 4000 mg/kg/day (approximately 3.4 times the recommended human dose) for three months produced tubular nephrosis, multifocal/diffuse tubulo-interstitial inflammation, and multifocal/diffuse papillary necrosis. In dogs, single doses of 6000 mg (approximately 6.25 times the recommended human dose) of delayed- release mesalamine tablets resulted in renal papillary necrosis but were not fatal. Renal changes have occurred in dogs given chronic administration of mesalamine at doses of 80 mg/kg/day (0.5 times the recommended human dose). 14 CLINICAL STUDIES 14.1 Moderately Active Ulcerative Colitis The efficacy of Asacol HD at 4.8 g/day was studied in a six-week, randomized, double-blind, active- controlled study in 772 patients with moderately active ulcerative colitis (UC). Moderately active UC was defined as a Physician’s Global Assessment (PGA) score of 2; the PGA is a four-point scale (0 to 3) that encompasses the clinical assessments of rectal bleeding, stool frequency, and sigmoidoscopy findings. Patients were randomized 1:1 to the Asacol HD 4.8 g/day group (two Asacol HD tablets three times a day) or the Asacol (mesalamine) 2.4 g/day group (two Asacol 400 mg tablets three times a day). (One Asacol HD 800 mg tablet has not been shown to be bioequivalent to two Asacol 400 mg tablets [see Clinical Pharmacology (12.3)].) Patients characteristically had a history of previous use of oral 5-ASAs (86 percent), steroids (41 percent), and rectal therapies (49 percent), and demonstrated clinical symptoms of three or more stools over normal per day (87 percent) and obvious blood in the stool most or all of the time (70 percent). The study population was primarily Caucasian (97 percent), had a mean age of 43 years (8 percent aged 65 years or older), and included slightly more males (56 percent) than females (44 percent). The primary endpoint was treatment success defined as improvement from baseline to Week 6 based on the PGA. Treatment success rates were similar in the two groups: 70 percent in the Asacol HD group and 66 percent in the Asacol group (difference: 5 percent; 95 percent CI: [-1.9 percent, 11.2 percent]). A second controlled study supported the efficacy of Asacol HD at 4.8 g/day. Treatment success was 72 percent in patients with moderately active UC treated with Asacol HD. 16 HOW SUPPLIED/STORAGE AND HANDLING Asacol® HD (mesalamine) delayed-release tablets are available as red-brown, capsule-shaped tablets containing 800 mg mesalamine and imprinted with “WC 800” in black. N 0430-0783-27 Bottle of 180 tablets Store at controlled room temperature 20° to 25° C (68° to 77° F); excursions are permitted 15° to 30° C (59° to 86° F). [See USP Controlled Room Temperature] 17 PATIENT COUNSELING INFORMATION Instruct patients to swallow the Asacol HD tablets whole, taking care not to break, cut, or chew the tablets, because the coating is an important part of the delayed-release formulation. Inform patients that if they are switching from a previous oral mesalamine therapy to Asacol HD they should discontinue their previous oral mesalamine therapy and follow the dosing instructions for Asacol HD. Inform patients that they should not substitute one Asacol HD tablet with two Asacol 400 mg tablets [see Dosage and Administration (2.2) and Clinical Pharmacology (12.3)]. Inform patients that intact, partially intact, and/or tablet shells have been reported in the stool. Instruct patients to contact their physician if this occurs repeatedly. Instruct patients to protect Asacol HD tablets from moisture. Instruct patients to close the container tightly and to leave any desiccant pouches present in the bottle along with the tablets. Advise women who are pregnant, breastfeeding, or of childbearing potential that Asacol HD contains dibutyl phthalate, which caused malformations and adverse effects on the male reproductive system in animal studies. Dibutyl phthalate is excreted in human milk. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=03a3bff5-e652-4771-9bf7-3b6850423cc5 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
