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Guide
Drug Safety-related Labeling Changes (SrLC) Database
| ANDA | Abbreviated New Drug Application |
| BLA | Biologics License Application |
| CDER | Center for Drug Evaluation and Research |
| MG | Medication Guide |
| NDA | New Drug Application |
| PCI | Patient Counseling Information |
| PI | Patient Information |
| PLR | Physician Labeling Rule |
| PLLR | Pregnancy and Lactation Labeling Rule |
| Italics | For the most part, italics indicate an FDA comment such as:
Additions and/or revisions underlined These italics usually appear at the beginning of the section. In some cases, italics may be an inherent part of the label, and will most often appear in the body of the section. |
| Underlines | Any text that is underlined indicates text that has been added or revised. There are exceptions where underlining occurs in a section subtitle or heading. This is the case when there is just one word underlined in the body of the text. |
Sections
| BW | Box Warning |
| WP | Warnings and Precautions all in one section (PLR-format) Warnings as one section (pre-PLR format) Precautions as one section (pre-PLR format) |
| AR | Adverse Reactions (in pre-PLR format, this may be a subheading under precautions). |
| DI | Drug Interactions (in pre-PLR format, this may be a subheading under precautions). |
| USP | Use in Specific Populations (Inclusive on one or more of the following: Pregnancy; Lactation (PLLR- format); Nursing Mothers (pre-PLLR format); Females and Males of Reproductive Potential (PLLR format only); Pediatric Use, Geriatric Use, Renal Impairment, Hepatic Impairment, Sex, Race (these last six may be a subheading of precautions if label in pre-PLLR format. |
| PCI/PI/MG | Patient Counseling Information (PLR format only) - summarizes the information that a health care provider should convey to a patient (or caregiver when applicable) when a counseling discussion is taking place (e.g., a physician prescribing a drug during an office visit, a nurse providing discharge instructions at a hospital, or a pharmacist conveying information at a pharmacy). Patient Information - FDA approved patient labeling. Medication Guide - paper handouts that come with many prescription medicines. The guides address issues that are specific to particular drugs and drug classes, and they contain FDA-approved information that can help patients avoid serious adverse events. |
Only NDAs and CDER regulated BLAs are included in this database. ANDAs are not included.
Applications that remain active, even if the product has been discontinued, undergo safety-related labeling changes.
APRISO (NDA-022301)
(MESALAMINE)
Safety-related Labeling Changes Approved by FDA Center for Drug Evaluation and Research (CDER)
10/24/2023 (SUPPL-22)
6 Adverse Reactions
6.2 Postmarketing ExperienceAdditions and/or
revisions underlined:
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.
…
Renal and Urinary: nephrogenic diabetes insipidus, interstitial nephritis, renal failure, minimal change disease, nephrolithiasis [see Warnings and Precautions (5.1, 5.7)]
Urine discoloration occurring ex-vivo caused by contact of mesalamine, including inactive metabolite, with surfaces or water treated with hypochlorite-containing bleach.
…
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
PATIENT COUNSELING INFORMATIONAdditions and/or
revisions underlined:
Administration Instruct patients:
Swallow the capsules whole. Do not cut, break, crush or chew the capsules.
Avoid co-administration of APRISO with antacids.
Drink an adequate amount of fluids.
APRISO capsules can be taken without regard to meals [see Dosage and Administration (2)].
Urine may become discolored reddish-brown while taking APRISO when it comes in contact with surfaces or water treated with hypochlorite-containing bleach. If discolored urine is observed, advise patients to observe their urine flow. Report to the healthcare provider only if urine is discolored on leaving the body, before contact with any surface or water (e.g., in the toilet).
…
11/16/2022 (SUPPL-21)
5 Warnings and Precautions
5.1 Renal ImpairmentNewly added information:
Discontinue APRISO if renal function deteriorates while on therapy [see Drug Interactions (7.2), Use in Specific Populations (8.6)].
8 Use in Specific Populations
8.6 Renal ImpairmentNewly added information:
Discontinue APRISO if renal function deteriorates while on therapy [see Warnings and Precautions (5.1), Adverse Reactions (6.2), Drug Interactions (7.2)].
11/01/2021 (SUPPL-18)
5 Warnings and Precautions
Newly added subsection:
5.5 Severe Cutaneous Adverse Reactions
Severe 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 [see Adverse 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.
6 Adverse Reactions
Newly added to the bulleted line listing:
Severe Cutaneous Adverse Reactions [see Warnings and Precautions (5.5)]
6.2 Postmarketing Experience
Additions and/or revisions underlined:
Respiratory/Pulmonary: Eosinophilic pneumonia, interstitial pneumonitis, asthma exacerbation, pleurisy/pleuritis.
Skin: Alopecia, psoriasis, pyoderma gangrenosum, dry skin, erythema nodosum, urticaria, SJS/TEN, DRESS, and AGEP [see Warnings and Precautions (5.5)].
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
PATIENT COUNSELING INFORMATIONNewly added information:
Severe Cutaneous Adverse Reactions
Inform patients of the signs and symptoms of severe cutaneous adverse reactions. Instruct patients to stop taking APRISO and report to their healthcare provider at first appearance of a severe cutaneous adverse reaction or other sign of hypersensitivity [see Warnings and Precautions (5.5)].
10/01/2020 (SUPPL-15)
4 Contraindications
(Additions and/or revisions underlined)
APRISO is contraindicated in patients with hypersensitivity to salicylates or aminosalicylates or to any of the components of APRISO capsules [see Warnings and Precautions (5.3), Adverse Reactions (6.2), Description (11)].
5 Warnings and Precautions
5.1 Renal Impairment(Additions and/or revisions underlined)
Renal 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 [see Adverse Reactions (6.2), Nonclinical Toxicology (13.2)].
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 [see Drug Interactions (7.2), Use in Specific Populations (8.6)].
(Additions and/or revisions underlined)
Mesalamine 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.
(Additions and/or revisions underlined)
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.
(Additions and/or revisions underlined)
There 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.
(Newly added subsection)
Patients 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.
(Newly added subsection)
Cases 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.
Phenylalanine 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.
(Newly added subsection)
Use of APRISO may lead to spuriously elevated test results when measuring urinary normetanephrine by liquid chromatography with electrochemical detection because of the similarity in the chromatograms of normetanephrine and the main metabolite of mesalamine, N-acetyl-5-aminosalicylic acid (N-Ac-5-ASA). Consider an alternative, selective assay for normetanephrine.
6 Adverse Reactions
(Newly added information)
The following clinically significant adverse reactions are described elsewhere in labeling:
Renal Impairment [see Warnings and Precautions (5.1)]
Mesalamine-Induced Acute Intolerance Syndrome [see Warnings and Precautions (5.2)]
Hypersensitivity Reactions [see Warnings and Precautions (5.3)]
Hepatic Failure [see Warnings and Precautions (5.4)]
Photosensitivity [see Warnings and Precautions (5.5)]
Nephrolithiasis [see Warnings and Precautions (5.6)]
Risks in Patients with Phenylketonuria [see Warnings and Precautions (5.7)]
(Additions and/or revisions underlined)
In the two placebo-controlled trials, the most common reactions reported in at least 3% of APRISO-treated patients and at a greater rate than placebo are shown in Table 1 below.
(Changes to Table 1; please refer to label)
(Additions and/or revisions underlined)
Cardiovascular: pericarditis, pericardial effusion, myocarditis [see Warnings and Precautions (5.3)]
Renal and Urinary: nephrogenic diabetes insipidus, interstitial nephritis, renal failure, minimal change disease, nephrolithiasis [see Warnings and Precautions (5.1, 5.6)]
7 Drug Interactions
7.2 Nephrotoxic Agents, Including Non-Steroidal Anti-Inflammatory Drugs(Newly added subsection)
The 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 [see Warnings and Precautions (5.1)].
(Newly added subsection)
The concurrent use of mesalamine with azathioprine or 6-mercaptopurine and/or other drugs known to cause myelotoxicity may increase the risk for blood disorders, bone marrow failure, and associated complications. If concomitant use of APRISO and azathioprine or 6-mercaptopurine cannot be avoided, monitor blood tests, including complete blood cell counts and platelet counts.
(Newly added subsection)
Use of APRISO may lead to spuriously elevated test results when measuring urinary normetanephrine by liquid chromatography with electrochemical detection [see Warnings and Precautions (5.8)]. Consider an alternative, selective assay for normetanephrine.
8 Use in Specific Populations
8.1 Pregnancy(Newly added information)
Risk Summary
Published data from meta-analyses, cohort studies and case series on the use of mesalamine during pregnancy have not reliably informed an association with mesalamine and major birth defects, miscarriage, or adverse maternal or fetal outcomes (see Data).
In animal reproduction studies, there were no adverse developmental outcomes with 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 (see Data).
The estimated background risk of major birth defects and miscarriage for the indicated populations is unknown. Adverse outcomes in pregnancy occur regardless of the health of the mother or the use of medications. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.
Clinical Considerations
Disease-associated maternal and embryo/fetal risk
Published data suggest that increased disease activity is associated with the risk of developing adverse pregnancy outcomes in women with ulcerative colitis. Adverse pregnancy outcomes include preterm delivery (before 37 weeks of gestation), low birth weight (less than 2500 g) infants, and small for gestational age at birth.
Data
Human Data
Published data from meta-analyses, cohort studies and case series on the use of mesalamine during early pregnancy (first trimester) and throughout pregnancy have not reliably informed an association of mesalamine and major birth defects, miscarriage, or adverse maternal or fetal outcomes. There is no clear evidence that mesalamine exposure in early pregnancy is associated with an increased risk in major congenital malformations, including cardiac malformations.
Published epidemiologic studies have important methodological limitations which hinder interpretation of the data, including inability to control for confounders, such as underlying maternal disease, and maternal use of concomitant medications, and missing information on the dose and duration of use for mesalamine products.
Animal Data
Reproduction studies with mesalamine during organogenesis 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 harm to the fetus due to mesalamine.
(Additions and/or revisions underlined)
Clinical studies of APRISO did not include sufficient numbers of subjects aged 65 years and over 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 [see Use in Specific Populations (8.6)].
(Newly added subsection)
(Additions and/or revisions underlined)
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. 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 [see Warnings and Precautions (5.1), Adverse Reactions (6.2), Drug Interactions (7.2)].
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
Patient Counseling Information(Newly added information)
Administration
Instruct patients:
Swallow the capsules whole. Do not cut, break, crush or chew the capsules.
Avoid co-administration of APRISO with antacids.
Drink an adequate amount of fluids.
APRISO capsules can be taken without regard to meals [see Dosage and Administration (2)].
Renal Impairment
Inform patients that APRISO may decrease their renal function, especially if they have known renal impairment or are taking nephrotoxic drugs, including NSAIDs, and periodic monitoring of renal function will be performed while they are on therapy. Advise patients to complete all blood tests ordered by their healthcare provider [see Warnings and Precautions (5.1), Drug Interactions (7.2)].
Mesalamine-Induced Acute Intolerance Syndrome and Other Hypersensitivity Reactions
Inform patients of the signs and symptoms of hypersensitivity reactions. Instruct patients to stop taking APRISO and report to their healthcare provider if they experience new or worsening symptoms of Acute Intolerance Syndrome (cramping, abdominal pain, bloody diarrhea, fever, headache, and rash) or other symptoms suggestive of mesalamine- induced hypersensitivity [see Warnings and Precautions (5.2, 5.3)].
Hepatic Failure
Inform patients with known liver disease of the signs and symptoms of worsening liver function and advise them to report to their healthcare provider if they experience such signs or symptoms [see Warnings and Precautions (5.4)].
Photosensitivity
Advise patients with pre-existing skin conditions to avoid sun exposure, wear protective clothing, and use a broad-spectrum sunscreen when outdoors [see Warnings and Precautions (5.5)].
Nephrolithiasis
Instruct patients to drink an adequate amount of fluids during treatment in order to minimize the risk of kidney stone formation and to contact their healthcare provider if they experience signs or symptoms of a kidney stone (e.g., severe side or back pain, blood in the urine) [see Warnings and Precautions (5.6)].
Blood Disorders
Inform elderly patients and those taking azathioprine or 6-mercaptopurine of the risk for blood disorders and the need for periodic monitoring of complete blood cell counts and platelet counts while on therapy. Advise patients to complete all blood tests ordered by their healthcare provider [see Drug Interactions (7.3), Use in Specific Populations (8.5)].
03/12/2019 (SUPPL-14)
5 Warnings and Precautions
5.5 Risks in Patients with Phenylketonuria(Newly Added Subsection)
Phenylalanine 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.
07/27/2017 (SUPPL-9)
6 Adverse Reactions
6.2 Adverse Reaction Information from Other Sources(additions underlined)
…
Nervous System: intracranial hypertension
…
Renal and Urinary: nephrogenic diabetes insipidus
...