May 2, 2016
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Asacol HD

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Asacol HD




Warnings
Precautions

WARNINGS

Included as part of the PRECAUTIONS section.

PRECAUTIONS

Renal Impairment

Renal impairment, including minimal change nephropathy, 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.

It is recommended that all patients have an evaluation of renal function prior to initiation of Asacol HD and periodically while on therapy. Prescribers should carefully evaluate the risks and benefits when using Asacol HD in patients with known renal impairment or history of renal disease [see DRUG INTERACTIONS and Nonclinical Toxicology].

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 percent 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.

Hypersensitivity Reactions

Some patients who have experienced a hypersensitivity reaction to sulfasalazine may have a similar reaction to Asacol HD tablets or to other compounds that contain or are converted to mesalamine.

Mesalamine-induced cardiac hypersensitivity reactions (myocarditis and pericarditis) have been reported with Asacol HD and other mesalamine medications. Caution should be taken in prescribing this medicine to patients with conditions predisposing them to the development of myocarditis or pericarditis.

Hepatic Failure

There have been reports of hepatic failure in patients with pre-existing liver disease who have been administered mesalamine. Caution should be exercised when administering Asacol HD to patients with liver disease.

Prolonged Gastric Retention In Patients With Upper Gastrointestinal Obstruction

Organic or functional obstruction in the upper gastrointestinal tract may cause prolonged gastric retention of Asacol HD which would delay release of mesalamine in the colon.

Nonclinical Toxicology

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.

Use In Specific Populations

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.

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.

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.

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.

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, WARNINGS AND PRECAUTIONS].

This monograph has been modified to include the generic and brand name in many instances.

Last reviewed on RxList: 4/25/2016

Warnings
Precautions

Report Problems to the Food and Drug Administration

 

You are encouraged to report negative side effects of prescription drugs to the FDA. Visit the FDA MedWatch website or call 1-800-FDA-1088.


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