Apriso
(Mesalamine)Apriso Prescribing Information
APRISO
®is indicated for the maintenance of remission of ulcerative colitis in adults.
The recommended dosage in adults is 1.5 g (four 0.375 g capsules) orally once daily in the morning.
- Evaluate renal function before initiating therapy with APRISO[see Warnings and Precautions ()].
5.1 Renal ImpairmentRenal impairment, including minimal change disease, acute and chronic interstitial nephritis, and renal failure, has been reported in patients given products such as APRISO that contain mesalamine or are converted to mesalamine. In animal studies, the kidney was the principal organ of mesalamine toxicity
[seeAdverse Reactions,Nonclinical Toxicology].Evaluate renal function prior to initiation of APRISO therapy and periodically while on therapy. Evaluate the risks and benefits of using APRISO in patients with known renal impairment or a history of renal disease or taking concomitant nephrotoxic drugs. Discontinue APRISO if renal function deteriorates while on therapy
[seeDrug Interactions,Use in Specific Populations]. - Swallow APRISO capsules whole. Do not cut, break, crush or chew the capsules.
- Avoid co-administration of APRISO with antacids[see Drug Interactions ()].
7.1 AntacidsBecause the dissolution of the coating of the granules in APRISO capsules depends on pH, avoid co-administration of APRISO capsules with antacids
[see Dosage and Administration(2)]. - Drink an adequate amount of fluids[see Warnings and Precautions ()].
5.7 NephrolithiasisCases of nephrolithiasis have been reported with the use of mesalamine, including stones with 100% mesalamine content. Mesalamine-containing stones are radiotransparent and undetectable by standard radiography or computed tomography (CT). Ensure adequate fluid intake during treatment with APRISO.
- Take APRISO without regard to meals[see Clinical Pharmacology ()].
12.3 PharmacokineticsAbsorptionThe pharmacokinetics of 5-ASA and its metabolite, N-acetyl-5-aminosalicylic acid (N-Ac-5-ASA), were studied after a single and multiple oral doses of 1.5 g APRISO in a crossover study in healthy subjects under fasting conditions. In the multiple-dose period, each subject received APRISO 1.5 g (four 0.375 g capsules) once daily for 7 consecutive days. Steady state was reached on Day 6 of once daily dosing based on trough concentrations.
After single and multiple doses of APRISO, peak plasma concentrations were observed at about 4 hours post-dose. At steady state, moderate increases (1.5-fold and 1.7-fold) in systemic exposure (AUC0-24) to 5-ASA and N-Ac-5-ASA were observed when compared with a single-dose of APRISO.
Pharmacokinetic parameters after a single dose of 1.5 g APRISO and at steady state in healthy subjects under fasting condition are shown in Table 2.
Table 2: Single Dose and Multiple Dose Mean (±SD) Plasma Pharmacokinetic Parameters of Mesalamine (5-ASA) and N-Ac-5-ASA After 1.5 g APRISO Administration in Healthy Subjects Mesalamine (5-ASA)Single Dose(n=24)Multiple Dosec(n=24)aMedian (range);bHarmonic mean (pseudo SD);cafter 7 days of treatment AUC0-24(mcg*h/mL)
11±5
17±6
AUC0-inf(mcg*h/mL)
14±5
-
Cmax(mcg/mL)
2.1±1.1
2.7±1.1
Tmax(h)a
4 (2, 16)
4 (2, 8)
t½(h)b
9±7
10±8
N-Ac-5-ASAAUC0-24(mcg*h/mL)
26±6
37±9
AUC0-inf(mcg*h/mL)
51±23
-
Cmax(mcg/mL)
2.8±0.8
3.4±0.9
Tmax(h)a
4 (4, 12)
5 (2, 8)
t½(h)b
12±11
14±10
In a separate study (n=30), it was observed that under fasting conditions about 32%±11% (mean±SD) of the administered dose was systemically absorbed based on the combined cumulative urinary excretion of 5-ASA and N-Ac-5-ASA over 96 hours post-dose.
Food EffectsThe effect of a high fat meal intake on absorption of mesalamine granules (the same granules contained in APRISO capsules) was evaluated in 30 healthy subjects. Subjects received 1.6 g of mesalamine granules in sachet (2 x 0.8 g) following an overnight fast or a high fat meal in a crossover study. Under fed conditions, Tmaxfor both 5-ASA and N‑Ac‑5-ASA was prolonged by 4 and 2 hours, respectively. A high fat meal did not affect Cmaxfor 5-ASA, but a 27% increase in the cumulative urinary excretion of 5-ASA was observed with a high fat meal. The overall extent of absorption of N‑Ac-5-ASA was not affected by a high fat meal
[see Dosage and Administration (2)].DistributionIn an in vitro study, at 2.5 mcg/mL, mesalamine and N-Ac-5-ASA are 43±6% and 78±1% bound, respectively, to plasma proteins. Protein binding of N-Ac-5-ASA does not appear to be concentration dependent at concentrations ranging from 1 to 10 mcg/mL.
EliminationMetabolismThe major metabolite of mesalamine is N-acetyl-5-aminosalicylic acid (N-Ac-5-ASA). It is formed by N-acetyltransferase activity in the liver and intestinal mucosa.
ExcretionFollowing single and multiple doses of APRISO, the mean half-lives were 9 to 10 hours for 5-ASA, and 12 to 14 hours for N-Ac-5-ASA. Of the approximately 32% of the dose absorbed, about 2% of the dose was excreted unchanged in the urine, compared with about 30% of the dose excreted as N-Ac-5-ASA.
Drug Interaction StudiesIn an in vitro study using human liver microsomes, 5-ASA and its metabolite, N-Ac-5-ASA, were shown not to inhibit the major CYP enzymes evaluated (CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4). Therefore, mesalamine and its metabolite are not expected to inhibit the metabolism of other drugs that are substrates of CYP1A2, CYP2C9, CYP2C19, CYP2D6, or CYP3A4.
Extended-release capsules: 0.375 g mesalamine in a light blue opaque gelatin capsule with the letters “G” and “M” imprinted on either side of a black band.
Clinical studies of APRISO did not include sufficient numbers of subjects aged 65 years and older to determine whether they respond differently than younger subjects. Reports from uncontrolled clinical studies and postmarketing reporting systems suggested a higher incidence of blood dyscrasias (i.e., agranulocytosis, neutropenia and pancytopenia) in patients
who were 65 years or older compared to younger patients taking mesalamine-containing products such as APRISO. Monitor complete blood cell counts and platelet counts in elderly patients during treatment with APRISO. In general, consider the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy in elderly patients when prescribing APRISO
APRISO is contraindicated in patients with hypersensitivity to salicylates or aminosalicylates or to any of the components of APRISO capsules
Some patients have experienced a hypersensitivity reaction to sulfasalazine. Some patients may have a similar reaction to APRISO or to other compounds that contain or are converted to mesalamine.
As with sulfasalazine, mesalamine-induced hypersensitivity reactions may present as internal organ involvement, including myocarditis, pericarditis, nephritis, hepatitis, pneumonitis and hematologic abnormalities. Evaluate patients immediately if signs or symptoms of a hypersensitivity reaction are present. Discontinue APRISO if an alternative etiology for the signs and symptoms cannot be established.
Some patients have experienced a hypersensitivity reaction to sulfasalazine. Some patients may have a similar reaction to APRISO or to other compounds that contain or are converted to mesalamine.
As with sulfasalazine, mesalamine-induced hypersensitivity reactions may present as internal organ involvement, including myocarditis, pericarditis, nephritis, hepatitis, pneumonitis and hematologic abnormalities. Evaluate patients immediately if signs or symptoms of a hypersensitivity reaction are present. Discontinue APRISO if an alternative etiology for the signs and symptoms cannot be established.
The following adverse reactions have been identified during post approval use of APRISO or other mesalamine-containing products. 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.
- Urine discoloration occurring ex-vivo caused by contact of mesalamine, including inactive metabolite, with surfaces or water treated with hypochlorite-containing bleach.
The following adverse reactions have been identified during post approval use of APRISO or other mesalamine-containing products. 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.
- Urine discoloration occurring ex-vivo caused by contact of mesalamine, including inactive metabolite, with surfaces or water treated with hypochlorite-containing bleach.
Each APRISO®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 aminosalicylate. The structural formula of mesalamine is:
Molecular Weight: 153.14
Molecular Formula: C7H7NO3
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 capsules are: 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, vanilla flavor.
Each APRISO 0.375 g capsule contains 0.56 mg of phenylalanine.
Each APRISO®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 aminosalicylate. The structural formula of mesalamine is:
Molecular Weight: 153.14
Molecular Formula: C7H7NO3
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 capsules are: 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, vanilla flavor.
Each APRISO 0.375 g capsule contains 0.56 mg of phenylalanine.
- Renal Impairment:Assess renal function at the beginning of treatment and periodically during treatment. Evaluate the risks and benefits in patients with known renal impairment or taking nephrotoxic drugs; monitor renal function. Discontinue if renal function deteriorates. (,
5.1 Renal ImpairmentRenal impairment, including minimal change disease, acute and chronic interstitial nephritis, and renal failure, has been reported in patients given products such as APRISO that contain mesalamine or are converted to mesalamine. In animal studies, the kidney was the principal organ of mesalamine toxicity
[seeAdverse Reactions,Nonclinical Toxicology].Evaluate renal function prior to initiation of APRISO therapy and periodically while on therapy. Evaluate the risks and benefits of using APRISO in patients with known renal impairment or a history of renal disease or taking concomitant nephrotoxic drugs. Discontinue APRISO if renal function deteriorates while on therapy
[seeDrug Interactions,Use in Specific Populations].,7.2 Nephrotoxic Agents, Including Non-Steroidal Anti-Inflammatory DrugsThe concurrent use of mesalamine with known nephrotoxic agents, including non-steroidal anti-inflammatory drugs (NSAIDs) may increase the risk of nephrotoxicity. Monitor patients taking nephrotoxic drugs for changes in renal function and mesalamine-related adverse reactions
[seeWarnings and Precautions].)8.6 Renal ImpairmentMesalamine 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. Evaluate renal function in all patients prior to initiation and periodically while on APRISO therapy. Monitor patients with known renal impairment or history of renal disease or taking nephrotoxic drugs for decreased renal function and mesalamine-related adverse reactions. Discontinue APRISO if renal function deteriorates while on therapy
[seeWarnings and Precautions(5.1), Adverse Reactions (6.2),Drug Interactions (7.2)]. - Mesalamine-Induced Acute Intolerance Syndrome:Symptoms may be difficult to distinguish from an exacerbation of ulcerative colitis; monitor for worsening symptoms; discontinue treatment if acute intolerance syndrome is suspected. ()
5.2 Mesalamine-Induced Acute Intolerance SyndromeMesalamine has been associated with an acute intolerance syndrome that may be difficult to distinguish from an exacerbation of ulcerative colitis. 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. Monitor patients for worsening of these symptoms while on treatment. If acute intolerance syndrome is suspected, promptly discontinue treatment with APRISO.
- Hypersensitivity Reactions, including Myocarditis and Pericarditis:Evaluate patients immediately and discontinue if a hypersensitivity reaction is suspected. ()
5.3 Hypersensitivity ReactionsSome patients have experienced a hypersensitivity reaction to sulfasalazine. Some patients may have a similar reaction to APRISO or to other compounds that contain or are converted to mesalamine.
As with sulfasalazine, mesalamine-induced hypersensitivity reactions may present as internal organ involvement, including myocarditis, pericarditis, nephritis, hepatitis, pneumonitis and hematologic abnormalities. Evaluate patients immediately if signs or symptoms of a hypersensitivity reaction are present. Discontinue APRISO if an alternative etiology for the signs and symptoms cannot be established.
- Hepatic Failure:Evaluate the risks and benefits in patients with known liver impairment. ()
5.4 Hepatic FailureThere have been reports of hepatic failure in patients with pre-existing liver disease who have been administered mesalamine. Evaluate the risks and benefits of using APRISO in patients with known liver impairment.
- Severe Cutaneous Adverse Reactions:Discontinue at the first signs or symptoms of severe cutaneous adverse reactions or other signs of hypersensitivity and consider further evaluation. ()
5.5 Severe Cutaneous Adverse ReactionsSevere cutaneous adverse reactions, including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), drug reaction with eosinophilia and systemic symptoms (DRESS), and acute generalized exanthematous pustulosis (AGEP) have been reported with the use of mesalamine
[seeAdverse Reactions (6.2)]. Discontinue APRISO at the first signs or symptoms of severe cutaneous adverse reactions or other signs of hypersensitivity and consider further evaluation. - Photosensitivity: Advise patients with pre-existing skin conditions to avoid sun exposure, wear protective clothing, and use a broad-spectrum sunscreen when outdoors. ()
5.5 Severe Cutaneous Adverse ReactionsSevere cutaneous adverse reactions, including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), drug reaction with eosinophilia and systemic symptoms (DRESS), and acute generalized exanthematous pustulosis (AGEP) have been reported with the use of mesalamine
[seeAdverse Reactions (6.2)]. Discontinue APRISO at the first signs or symptoms of severe cutaneous adverse reactions or other signs of hypersensitivity and consider further evaluation. - Nephrolithiasis:Mesalamine-containing stones are undetectable by standard radiography or computed tomography (CT). Ensure adequate fluid intake during treatment. ()
5.6 PhotosensitivityPatients with pre-existing skin conditions such as atopic dermatitis and atopic eczema have reported more severe photosensitivity reactions. Advise patients to avoid sun exposure, wear protective clothing, and use a broad-spectrum sunscreen when outdoors.
- Risks in Patients with Phenylketonuria: Contains phenylalanine. Before prescribing APRISO to a patient with PKU, consider the combined daily amount of phenylalanine from all sources, including APRISO. ()
5.7 NephrolithiasisCases of nephrolithiasis have been reported with the use of mesalamine, including stones with 100% mesalamine content. Mesalamine-containing stones are radiotransparent and undetectable by standard radiography or computed tomography (CT). Ensure adequate fluid intake during treatment with APRISO.
- Interference with Laboratory Tests: Use of mesalamine may lead to spuriously elevated test results when measuring urinary normetanephrine by liquid chromatography with electrochemical detection. ()
5.8 Risks in Patients with PhenylketonuriaPhenylalanine can be harmful to patients with phenylketonuria (PKU). APRISO contains phenylalanine, a component of aspartame. Each APRISO 0.375 g capsule contains 0.56 mg of phenylalanine. Before prescribing APRISO to a patient with PKU, consider the combined daily amount of phenylalanine from all sources, including APRISO.