Apriso

Apriso information, interactions and side effects, Each APRISO capsule contains granules composed of mesalamine in a polymer matrix with an enteric coating that dissolves at pH 6 and above.

The inactive ingredients of APRISO (mesalamine extended-release capsules) capsules are colloidal silicon dioxide, magnesium stearate, microcrystalline cellulose, simethicone emulsion ethylacrylate/methylmethacrylate copolymer nonoxynol 100 dispersion, hypromellose, methacrylic acid copolymer, talc, titanium dioxide, triethyl citrate, aspartame, anhydrous citric acid, povidone, vanilla flavor, and edible black ink.

Each APRISO (mesalamine extended-release capsules) capsule is a delayed- and extended-release dosage form for oral administration. Each capsule contains 0.375 g of mesalamine USP (5-aminosalicylic acid, 5-ASA), an anti-inflammatory drug. The structural formula of mesalamine is:

apriso1

Molecular Weight: 153.14

Molecular Formula: C7H7NO3

INDICATIONS

APRISO (mesalamine extended-release capsules) capsules are indicated for the maintenance of remission of ulcerative colitis in patients 18 years of age and older.

DOSAGE AND ADMINISTRATION

The recommended dose for maintenance of remission of ulcerative colitis in adult patients is 1.5 g (four APRISO (mesalamine extended-release capsules) capsules) orally once daily in the morning. APRISO (mesalamine extended-release capsules) may be taken without regard to meals. APRISO (mesalamine extended-release capsules) should not be co-administered with antacids. An evaluation of renal function is recommended before initiating therapy with APRISO (mesalamine extended-release capsules).

HOW SUPPLIED

Dosage Forms And Strengths

Extended-release capsules containing 0.375 g mesalamine.

Storage And Handling

APRISO (mesalamine extended-release capsules) is available as light blue opaque hard gelatin capsules containing 0.375 g mesalamine and with the letters “G” and “M” on either side of a black band imprinted on the capsule.

NDC 65649-103-02 Bottles of 120 capsules

NDC 65649-103-01 Bottles of 4 capsules

Storage

Store at 20° to 25°C (68° to 77°F); excursions permitted between 15° and 30°C (59° and 86°F). See USP Controlled Room Temperature.

SIDE EFFECTS

Clinical Studies Experience

The data described below reflect exposure to APRISO (mesalamine extended-release capsules) in 557 patients, including 354 exposed for at least 6 months and 250 exposed for greater than one year. APRISO (mesalamine extended-release capsules) was studied in two placebo-controlled trials (n = 367 treated with APRISO (mesalamine extended-release capsules) ) and in one open-label, long-term study (n = 190 additional patients). The population consisted of patients with ulcerative colitis; the mean age was 47 years, 54% were female, and 93% were white. Patients received doses of APRISO (mesalamine extended-release capsules) 1.5 g administered orally once per day for six months in the placebo-controlled trials and for up to 24 months in the open-label study.

Because clinical studies 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.

In the two placebo-controlled trials, 59% of APRISO (mesalamine extended-release capsules) -treated patients experienced an adverse reaction compared with 64% of placebo patients. Most adverse reactions with APRISO (mesalamine extended-release capsules) were mild or moderate in severity. Severe adverse reactions occurred in 6% of APRISO (mesalamine extended-release capsules) -treated patients and 5% of placebo-treated patients. Discontinuations due to adverse reactions occurred in 11% of APRISO (mesalamine extended-release capsules) -treated patients and 17% of placebo treated patients; the most common adverse reaction resulting in study discontinuation was recurrence of ulcerative colitis (APRISO (mesalamine extended-release capsules) 6%, placebo 14%). The most common reactions reported with APRISO (mesalamine extended-release capsules) ( ≥ 3%) are shown in Table 1 below.

Table 1: Treatment-Emergent Adverse Reactions during Clinical Trials Occurring in at Least 3% of APRISO (mesalamine extended-release capsules) -Treated Patients and at a Greater Rate than with Placebo

 

MedDRA Preferred Term APRISO 1.5 g/day
N=367
Placebo
N=185
Headache 11% 8%
Diarrhea 8% 7%
Abdominal Pain Upper 5% 3%
Nausea 4% 3%
Nasopharyngitis 4% 3%
Influenza & Influenza-like Illness 4% 4%
Sinusitis 3% 3%

The following adverse reactions, presented by body system, were reported at a frequency less than 3% in patients treated with APRISO (mesalamine extended-release capsules) for up to 24 months in controlled and open-label trials.

Ear and Labyrinth Disorders: tinnitus, vertigo

Dermatological Disorder: alopecia

Gastrointestinal: abdominal pain lower, rectal hemorrhage

Laboratory Abnormalities: increased triglycerides, decreased hematocrit and hemoglobin

General Disorders and Administration Site Disorders: fatigue

Hepatic: hepatitis cholestatic, transaminases increased

Renal Disorders: creatinine clearance decreased, hematuria

Musculoskeletal: pain, arthralgia

Respiratory: dyspnea

Adverse Reaction Information from Other Sources

The following adverse reactions have been identified during clinical trials of a product similar to APRISO and post approval use of other mesalamine-containing products such as APRISO (mesalamine extended-release capsules) . Because many of these reactions are reported voluntarily from a population of unknown size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Body as a Whole: lupus-like syndrome, drug fever

Cardiovascular: pericarditis, pericardial effusion, myocarditis

Gastrointestinal: pancreatitis, cholecystitis, gastritis, gastroenteritis, gastrointestinal bleeding, perforated peptic ulcer

Hepatic: jaundice, cholestatic jaundice, hepatitis, liver necrosis, liver failure, Kawasakilike syndrome including changes in liver enzymes

Hematologic: agranulocytosis, aplastic anemia

Neurological/Psychiatric: peripheral neuropathy, Guillain-Barré syndrome, transverse myelitis

Respiratory/Pulmonary: eosinophilic pneumonia, interstitial pneumonitis

Skin: psoriasis, pyoderma gangrenosum, erythema nodosum

Renal/Urogenital: reversible oligospermia

DRUG INTERACTIONS

Based on in vitro studies, APRISO (mesalamine extended-release capsules) is not expected to inhibit the metabolism of drugs that are substrates of CYP1A2, CYP2C9, CYP2C19, CYP2D6, or CYP3A4.

Antacids

Because the dissolution of the coating of the granules in APRISO (mesalamine extended-release capsules) capsules depends on pH, APRISO (mesalamine extended-release capsules) capsules should not be co-administered with antacids.

PRECAUTIONS

Renal Impairment

Renal impairment, including minimal change nephropathy, acute and chronic interstitial nephritis, and, rarely, renal failure, has been reported in patients given products such as APRISO that contain mesalamine or are converted to mesalamine.

It is recommended that patients have an evaluation of renal function prior to initiation of APRISO (mesalamine extended-release capsules) therapy and periodically while on therapy. Exercise caution when using APRISO (mesalamine extended-release capsules) in patients with known renal dysfunction or a history of renal disease.

In animal studies, the kidney was the principal organ for toxicity [See Nonclinical Toxicology]

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. Although the exact frequency of occurrence has not been determined, it has occurred in 3% of patients in controlled clinical trials of mesalamine or sulfasalazine. Symptoms include cramping, acute abdominal pain and bloody diarrhea, sometimes fever, headache, and rash. If acute intolerance syndrome is suspected, promptly discontinue treatment with APRISO (mesalamine extended-release capsules) .

Hypersensitivity

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

Hepatic Impairment

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 APRISO (mesalamine extended-release capsules) to patients with liver disease.

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 about 2.6 and 5.4 times the recommended human dose of granulated mesalamine capsules of 1.5 g/day (30 mg/kg if 50 kg body weight assumed or 1110 mg/m²), respectively, based on body surface area. Mesalamine was negative in the Ames test, the mouse lymphoma cell (L5178Y/TK+/-) forward mutation test, the sister chromatid exchange assay in the Chinese hamster bone marrow test, and the mouse bone marrow micronucleus test. Mesalamine at oral doses up to 320 mg/kg (about 1.7 times the recommended human dose based on body surface area) was found to have no effect on fertility or reproductive performance in rats.

Use In Specific Populations

Pregnancy

Pregnancy Category B. Reproduction studies with mesalamine have been performed in rats at oral doses up to 320 mg/kg/day (about 1.7 times the recommended human dose based on a body surface area comparison) and rabbits at doses up to 495 mg/kg/day (about 5.4 times the recommended human dose based on a body surface area comparison) and have revealed no evidence of impaired fertility or harm to the fetus due to mesalamine. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.

Mesalamine is known to cross the placental barrier.

Nursing Mothers

Low concentrations of mesalamine and higher concentrations of its N-acetyl metabolite have been detected in human breast milk. The clinical significance of this has not been determined and there is limited experience of nursing women using mesalamine. Caution should be exercised when APRISO (mesalamine extended-release capsules) is administered to a nursing woman.

Pediatric Use

Safety and effectiveness of APRISO (mesalamine extended-release capsules) capsules in pediatric patients have not been established.

Geriatric Use

Clinical studies of APRISO (mesalamine extended-release capsules) 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 responses between 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 APRISO (mesalamine extended-release capsules) .

Reports from uncontrolled clinical studies and postmarketing reporting systems suggested a higher incidence of blood dyscrasias, i.e., neutropenia, pancytopenia, in patients who were 65 years or older who were taking mesalamine-containing products such as APRISO. Caution should be taken to closely monitor blood cell counts during mesalamine therapy.

Mesalamine is known to be substantially excreted by the kidney, and the risk of adverse 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. [see WARNING AND PRECAUTIONS].

OVERDOSE

APRISO (mesalamine extended-release capsules) is an aminosalicylate, and symptoms of salicylate toxicity include hematemesis, tachypnea, hyperpnea, tinnitus, deafness, lethargy, seizures, confusion, or dyspnea. Severe 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. This includes prevention of further gastrointestinal tract absorption by emesis and, if necessary, by gastric lavage. Fluid and electrolyte imbalance should be corrected by the administration of appropriate intravenous therapy. Adequate renal function should be maintained. APRISO (mesalamine extended-release capsules) is a pHdependent delayed-release product and this factor should be considered when treating a suspected overdose.

CONTRAINDICATIONS

APRISO (mesalamine extended-release capsules) is contraindicated in patients with hypersensitivity to salicylates or aminosalicylates or to any of the components of APRISO (mesalamine extended-release capsules) capsules.

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