Apriso

Description

Each APRISO® capsule is a delayed- and extended-release dosage form intended for oral administration. Each capsule contains 0.375 g of mesalamine USP (5-aminosalicylic acid, 5-ASA), an aminosalicylate, with a molecular weight of 153.14 and a molecular formula of C7H7NO3. The mesalamine is formulated in granules within a polymer matrix that features an enteric coating, which dissolves at a pH of 6 and above.

The inactive ingredients in APRISO capsules include anhydrous citric acid, aspartame, colloidal silicon dioxide, edible black ink, hypromellose, magnesium stearate, methacrylic acid copolymer, microcrystalline cellulose, povidone, simethicone emulsion, ethyl acrylate/methyl methacrylate copolymer, talc, titanium dioxide, triethyl citrate, and vanilla flavor. Each APRISO 0.375 g capsule also contains 0.56 mg of phenylalanine.

Uses and Indications

APRISO is indicated for the maintenance of remission of ulcerative colitis in adults. There are no teratogenic or nonteratogenic effects associated with this medication as per the available data.

Dosage and Administration

The recommended dosage of APRISO is 1.5 g, which corresponds to four 0.375 g capsules, administered once daily in the morning.

Prior to initiating therapy, healthcare professionals should evaluate the patient's renal function to ensure safe administration. The capsules must be swallowed whole; they should not be cut, broken, crushed, or chewed to maintain the integrity of the formulation.

Co-administration with antacids is not advised, as it may affect the efficacy of the medication. Patients should be encouraged to drink an adequate amount of fluids while taking APRISO. This medication can be taken without regard to meals, allowing for flexibility in administration.

Contraindications

Use of APRISO capsules is contraindicated in patients with known or suspected hypersensitivity to salicylates, aminosalicylates, or any component of the formulation. This contraindication is based on the potential for severe allergic reactions in susceptible individuals.

Warnings and Precautions

Renal function should be assessed at the initiation of treatment and monitored periodically throughout the course of therapy. In patients with known renal impairment or those taking nephrotoxic medications, careful evaluation of the risks and benefits is essential. If there is any deterioration in renal function, treatment must be discontinued.

Healthcare professionals should be vigilant for symptoms of Mesalamine-Induced Acute Intolerance Syndrome, which may mimic an exacerbation of ulcerative colitis. Monitoring for worsening symptoms is crucial, and if acute intolerance syndrome is suspected, treatment should be discontinued immediately.

Hypersensitivity reactions, including myocarditis and pericarditis, require prompt evaluation. If a hypersensitivity reaction is suspected, the healthcare provider must discontinue the medication without delay.

In patients with known liver impairment, a thorough assessment of the risks and benefits of treatment is necessary due to the potential for hepatic failure.

Severe cutaneous adverse reactions can occur; therefore, treatment should be stopped at the first signs or symptoms of such reactions or any other indications of hypersensitivity. Further evaluation may be warranted in these cases.

Patients should be advised about the risk of photosensitivity. Those with pre-existing skin conditions should take precautions to avoid sun exposure, including wearing protective clothing and applying a broad-spectrum sunscreen when outdoors.

Nephrolithiasis is a potential risk, as mesalamine-containing stones are not detectable by standard radiography or computed tomography (CT). It is important to ensure adequate fluid intake during treatment to mitigate this risk.

For patients with phenylketonuria (PKU), it is critical to note that this medication contains phenylalanine. Prior to prescribing APRISO, healthcare providers should consider the total daily intake of phenylalanine from all sources, including APRISO.

The use of mesalamine may interfere with laboratory tests, particularly leading to spuriously elevated results when measuring urinary normetanephrine via liquid chromatography with electrochemical detection.

Regular assessment of renal function is recommended at the start of treatment and periodically thereafter, especially in patients with pre-existing renal impairment or those on nephrotoxic drugs.

In the event of a suspected hypersensitivity reaction, immediate evaluation is necessary, and the medication should be discontinued. Treatment should also be halted if acute intolerance syndrome is suspected or if any signs of severe cutaneous adverse reactions or hypersensitivity arise, with consideration for further evaluation.

Side Effects

Patients may experience a range of adverse reactions during treatment. The most common adverse reactions, occurring in 3% or more of participants, include headache, diarrhea, upper abdominal pain, nausea, and nasopharyngitis.

Serious adverse reactions warrant immediate attention. Patients should be monitored for renal impairment, with renal function assessed at the beginning of treatment and periodically thereafter. Treatment should be discontinued if renal function deteriorates. Additionally, mesalamine-induced acute intolerance syndrome may present symptoms that are difficult to distinguish from an exacerbation of ulcerative colitis; therefore, monitoring for worsening symptoms is essential, and treatment should be stopped if acute intolerance syndrome is suspected.

Hypersensitivity reactions, which may include myocarditis and pericarditis, require immediate evaluation and discontinuation of treatment if suspected. Severe cutaneous adverse reactions should also prompt discontinuation at the first signs or symptoms, along with consideration for further evaluation. Patients with known liver impairment should be carefully evaluated for the risks and benefits of treatment due to the potential for hepatic failure.

Patients are advised to take precautions against photosensitivity, particularly those with pre-existing skin conditions, by avoiding sun exposure, wearing protective clothing, and using broad-spectrum sunscreen when outdoors. Nephrolithiasis is another concern, as mesalamine-containing stones are undetectable by standard radiography or computed tomography (CT); therefore, ensuring adequate fluid intake during treatment is crucial.

For patients with phenylketonuria (PKU), it is important to consider the combined daily amount of phenylalanine from all sources, including APRISO, before prescribing. Furthermore, the use of mesalamine may interfere with laboratory tests, leading to spuriously elevated results when measuring urinary normetanephrine by liquid chromatography with electrochemical detection.

Additional adverse reactions may include symptoms of salicylate toxicity, which can manifest as nausea, vomiting, abdominal pain, tachypnea, hyperpnea, tinnitus, and neurologic symptoms such as headache, dizziness, confusion, and seizures. Severe salicylate intoxication may result in electrolyte and blood pH imbalances, potentially leading to damage to other organs, including renal and hepatic systems.

Drug Interactions

The concomitant use of nephrotoxic agents, including nonsteroidal anti-inflammatory drugs (NSAIDs), may lead to an increased risk of nephrotoxicity. It is recommended to monitor renal function closely and observe for any mesalamine-related adverse reactions in patients receiving these agents.

When azathioprine or 6-mercaptopurine is administered alongside this medication, there is an elevated risk of blood disorders. Regular monitoring of complete blood cell counts and platelet counts is advised to detect any potential hematological complications early.

Packaging & NDC

The table below lists all NDC Code configurations of Apriso (mesalamine), the U.S. brand-name prescription product. Columns show Packaging, Formulation Type, and Active Ingredient Strength.

Pediatric Use

The safety and effectiveness of APRISO in pediatric patients have not been established. There are currently no available data to support its use in this population. Healthcare professionals should exercise caution when considering APRISO for pediatric patients, as the lack of established safety and efficacy may impact treatment decisions.

Geriatric Use

Clinical studies of APRISO did not include a sufficient number of subjects aged 65 years and older to determine whether these elderly patients respond differently than younger subjects. However, reports from uncontrolled clinical studies and postmarketing surveillance have indicated a higher incidence of blood dyscrasias, including agranulocytosis, neutropenia, and pancytopenia, in patients aged 65 years and older compared to their younger counterparts who are taking mesalamine-containing products such as APRISO.

Given these findings, it is essential to monitor complete blood cell counts and platelet counts in geriatric patients during treatment with APRISO. Additionally, when prescribing APRISO to elderly patients, healthcare providers should consider the increased likelihood of decreased hepatic, renal, or cardiac function, as well as the presence of concomitant diseases or other drug therapies that may affect treatment outcomes. Careful assessment and monitoring are recommended to ensure the safety and efficacy of APRISO in this population.

Pregnancy

Published data from meta-analyses, cohort studies, and case series regarding the use of mesalamine during pregnancy have not consistently demonstrated an association with major birth defects, miscarriage, or adverse maternal or fetal outcomes. In animal reproduction studies, administration of oral mesalamine during organogenesis to pregnant rats and rabbits at doses 1.7 and 5.4 times, respectively, the maximum recommended human dose did not result in adverse developmental outcomes.

The estimated background risk of major birth defects and miscarriage for the indicated populations remains unknown. It is important to note that adverse outcomes in pregnancy can occur regardless of maternal health or medication use. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is approximately 2 to 4% and 15 to 20%, respectively.

In women with ulcerative colitis, published data suggest that increased disease activity is associated with a higher risk of adverse pregnancy outcomes, which may include preterm delivery (before 37 weeks of gestation), low birth weight (less than 2500 g), and small for gestational age infants at birth.

Furthermore, while there is no clear evidence that mesalamine exposure during early pregnancy (first trimester) is linked to an increased risk of major congenital malformations, including cardiac malformations, the interpretation of existing epidemiologic studies is complicated by methodological limitations. These limitations include the inability to control for confounding factors such as underlying maternal disease and concomitant medication use, as well as gaps in information regarding the dose and duration of mesalamine use.

Given these considerations, healthcare professionals should weigh the potential benefits of mesalamine treatment against the risks, particularly in pregnant patients or those planning to become pregnant.

Lactation

Data from published literature indicate that mesalamine and its metabolite, N-acetyl 5-aminosalicylic acid, are present in human milk in small amounts, with relative infant doses (RID) of 2% or less. The average concentration of mesalamine in milk ranges from non-detectable to 0.5 mg/L, while the average concentration of N-acetyl-5-aminosalicylic acid in milk ranges from 0.2 to 9.3 mg/L. Based on these concentrations, estimated infant daily dosages for an exclusively breastfed infant are 0 to 0.075 mg/kg/day (RID 0 to 0.1%) for mesalamine and 0.03 to 1.4 mg/kg/day for N-acetyl-5-aminosalicylic acid.

There have been case reports of diarrhea in breastfed infants exposed to mesalamine. However, there is no information available regarding the effects of the drug on milk production. The lack of clinical data during lactation prevents a clear determination of the risk of APRISO to an infant during breastfeeding. Therefore, the developmental and health benefits of breastfeeding should be weighed against the mother's clinical need for APRISO and any potential adverse effects on the breastfed child from APRISO or from the underlying maternal condition.

Healthcare providers should advise caregivers to monitor breastfed infants for signs of diarrhea.

Renal Impairment

Renal function should be assessed at the beginning of treatment and periodically throughout the course of therapy in patients with renal impairment. It is essential to evaluate the risks and benefits in these patients, particularly those who are also taking nephrotoxic drugs, and to monitor renal function closely. If there is any deterioration in renal function, discontinuation of the treatment is recommended.

Hepatic Impairment

Patients with hepatic impairment should be carefully evaluated for the risks and benefits of treatment. It is essential to assess liver function prior to initiating therapy and to monitor liver function regularly throughout the treatment course. Adjustments to the dosage may be necessary based on the severity of liver impairment. Close monitoring of liver-related laboratory values is recommended to ensure patient safety and to mitigate potential adverse effects associated with compromised liver function.

Overdosage

In the event of an overdosage of APRISO, which is classified as an aminosalicylate, healthcare professionals should be vigilant for symptoms indicative of salicylate toxicity. Common manifestations include nausea, vomiting, and abdominal pain, as well as respiratory symptoms such as tachypnea and hyperpnea. Neurologic symptoms may also present, including headache, dizziness, confusion, and seizures.

Severe cases of salicylate intoxication can result in significant electrolyte and blood pH imbalances, which may lead to damage of vital organs, including the kidneys and liver. It is crucial for healthcare providers to recognize these potential complications early in the management of an overdose.

Currently, there is no specific antidote available for mesalamine overdose. However, conventional treatment strategies for salicylate toxicity may be beneficial in cases of acute overdosage. These strategies typically involve gastrointestinal tract decontamination to minimize further absorption of the drug.

Management should also focus on correcting any fluid and electrolyte imbalances through the administration of appropriate intravenous therapy. Maintaining adequate renal function is essential during the treatment process.

It is important to note that APRISO is a pH-dependent delayed-release formulation, and this characteristic should be taken into account when addressing a suspected overdose. Prompt and effective management is critical to mitigate the risks associated with overdosage.

Nonclinical Toxicology

Dietary mesalamine was evaluated for carcinogenic potential in both rats and mice. The results indicated that mesalamine was not carcinogenic at doses of up to 480 mg/kg/day in rats and 2,000 mg/kg/day in mice. These doses correspond to approximately 2.6 and 5.4 times the recommended human dose of granulated mesalamine capsules, which is 1.5 g/day (equivalent to 30 mg/kg for a 50 kg individual or 1,110 mg/m²), based on body surface area.

In terms of mutagenicity, mesalamine demonstrated negative results in several assays, including 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.

Regarding reproductive toxicity, no adverse effects on fertility or reproductive performance were observed in male and female rats administered oral doses of mesalamine up to 320 mg/kg, which is approximately 1.7 times the recommended human dose based on body surface area.

Animal studies, including 13-week and 26-week oral toxicity studies in rats, as well as 26-week and 52-week oral toxicity studies in dogs, identified the kidney as the primary target organ for mesalamine toxicity. Lethal doses of mesalamine were determined to be 800 mg/kg (about 2.2 times the recommended human dose based on body surface area) for mice and 1,800 mg/kg (about 9.7 times the recommended human dose based on body surface area) for rats, both of which resulted in gastrointestinal and renal toxicity.

At lower oral doses of 40 mg/kg/day (approximately 0.20 times the human dose based on body surface area), minimal to slight tubular injury was noted. Doses of 160 mg/kg/day (about 0.90 times the human dose based on body surface area) or higher in rats led to renal lesions, including tubular degeneration, tubular mineralization, and papillary necrosis. Similarly, oral doses of 60 mg/kg/day (about 1.1 times the human dose based on body surface area) or higher in dogs resulted in renal lesions such as tubular atrophy, interstitial cell infiltration, chronic nephritis, and papillary necrosis.

Postmarketing Experience

Postmarketing experience has identified several adverse reactions associated with the use of APRISO. These include headache, abdominal pain, nausea, diarrhea, and rash. Additionally, hypersensitivity reactions such as angioedema and anaphylaxis have been reported. Cases of liver injury have also been documented in the postmarketing setting.

Reports of renal impairment and interstitial nephritis have been associated with APRISO use. Furthermore, some patients have experienced serious infections, including sepsis and opportunistic infections, during postmarketing surveillance.

Patient Counseling

Healthcare providers should advise patients to swallow APRISO capsules whole and to avoid cutting, breaking, crushing, or chewing them. It is important to inform patients that they should not co-administer APRISO with antacids, as this may affect the medication's efficacy.

Patients should be encouraged to drink an adequate amount of fluids while taking APRISO to ensure proper hydration. They can take APRISO capsules without regard to meals, providing flexibility in their dosing schedule.

Additionally, healthcare providers should inform patients that their urine may become discolored reddish-brown while taking APRISO, particularly when it comes into contact with surfaces or water treated with hypochlorite-containing bleach. Patients should be instructed to observe their urine flow and to report to their healthcare provider if they notice discolored urine upon leaving the body, before it contacts any surface or water, such as in the toilet.

Storage and Handling

The product is supplied in various package configurations, with specific NDC numbers available for identification. It should be stored at a temperature range of 20° to 25°C (68° to 77°F). Temporary excursions are permitted between 15° and 30°C (59° and 86°F), in accordance with USP Controlled Room Temperature guidelines. Proper storage conditions are essential to maintain the integrity and efficacy of the product.

Additional Clinical Information

No further data are available.

FDA Insert (PDF)

This document is the official FDA-approved prescribing information for Apriso as submitted by Salix Pharmaceuticals, Inc.. It includes detailed information about indications, dosage, contraindications, warnings, and clinical pharmacology.

View full prescribing information (PDF)