Get Email Alerts |
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.
ROWASA (NDA-019618)
(MESALAMINE)
Safety-related Labeling Changes Approved by FDA Center for Drug Evaluation and Research (CDER)
07/30/2024 (SUPPL-33)
5 Warnings and Precautions
The following subsections created to comply with Physician Labeling Rule (PLR), please refer to label for complete information:
5.1 Hypersensitivity Reactions
5.2 Renal Impairment
5.3 Mesalamine-Induced Acute Intolerance Syndrome
5.4 Hepatic Failure
5.5 Severe Cutaneous Adverse Reactions
5.6 Photosensitivity
5.7 Nephrolithiasis
5.8 Interference with Laboratory Tests
6 Adverse Reactions
Additions and/or revisions underlined:
The following clinically significant adverse reactions are described elsewhere in the labeling:
Hypersensitivity reactions [see Warnings and Precautions (5.1)]
Renal impairment [see Warnings and Precautions (5.2)]
Mesalamine-induced acute intolerance syndrome [see Warnings and Precautions (5.3)]
Hepatic failure [see Warnings and Precautions (5.4)]
Severe cutaneous adverse reactions [see Warnings and Precautions (5.5)]
Photosensitivity [see Warnings and Precautions (5.6)]
Nephrolithiasis [see Warnings and Precautions (5.7)]
6.2 Postmarketing Experience
Additions and/or revisions underlined:
…
Cardiac Disorders: myocarditis, pericarditis [see Warnings and Precautions (5.1)] Gastrointestinal Disorders: pancreatitis
Hematologic Disorders: agranulocytosis, aplastic anemia, eosinophilia, leukopenia, neutropenia, pancytopenia, thrombocytopenia
Hepatic Disorders: elevated liver enzymes, hepatic failure [see Warnings and Precautions (5.4)]
Nervous System: intracranial hypertension
Renal and Urinary Disorders: acute renal failure, chronic renal failure, interstitial nephritis, nephrogenic diabetes insipidus, nephrolithiasis, nephrotoxicity [see Warnings and Precautions (5.2), (5.7))]
Urine discoloration occurring ex-vivo caused by contact of mesalamine including inactive metabolite, with surfaces or water treated with hypochlorite-containing bleach
Reproductive System and Breast Disorders: reversible oligospermia
Respiratory, Thoracic, and Mediastinal Disorders: fibrosing alveolitis, pleurisy/pleuritis
Skin and Subcutaneous Tissue Disorders: AGEP, DRESS, SJS/TEN [see Warnings and Precautions (5.5)]
7 Drug Interactions
7.3 Interference with Urinary Normetanephrine MeasurementsNew subsection added:
Use of ROWASA 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
PLLR conversion:
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). There are adverse effects on maternal and fetal outcomes associated with ulcerative colitis in pregnancy (see Clinical Considerations). In animal reproduction studies, rats and rabbits administered mesalamine during organogenesis at oral doses up to 5 and 8 times the maximum recommended human dose, respectively, did not reveal any evidence of harm to the embryo or the fetus (see Data).
The background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. 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, the active moiety of ROWASA, 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 increase 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 have been performed with mesalamine in rats and rabbits during organogenesis at oral doses up to 5 and 8 times respectively, the maximum recommended human dose, and have revealed no evidence of harm to the embryo or the fetus.
8.2 Lactation
PLLR conversion:
Risk Summary
Data from published literature report the presence of mesalamine and its metabolite,
N-acetyl-5-aminosalicylic acid in human milk in small amounts with relative infant doses (RID) of 0.1% or less for mesalamine (see Data). There are case reports of diarrhea observed in breastfed infants exposed to mesalamine (see Clinical Considerations). There is no information on the effects of mesalamine on milk production. The lack of clinical data during lactation precludes a clear determination of the risk of ROWASA to an infant during lactation; therefore, the developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for ROWASA and any potential adverse effects on the breastfed child from ROWASA or from the underlying maternal condition.
Clinical Considerations
Advise the caregiver to monitor the breastfed infant for diarrhea.
Data
In published lactation studies, maternal mesalamine doses from various oral and rectal formulations and products ranged from 500 mg to 4.8 g daily. The average concentration of mesalamine in milk ranged from non-detectable to 0.5 mg/L. The average concentration of N-acetyl-5-aminosalicylic acid in milk ranged 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 of mesalamine (RID 0% to 0.1%) and 0.03 to 1.4 mg/kg/day of N-acetyl-5-aminosalicylic acid.
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
PATIENT COUNSELING INFORMATIONNew section created to comply with Physician Labeling Rule (PLR); please refer to label for complete information.
Other
Physician Labeling Rule (PLR) conversion.
10/24/2023 (SUPPL-32)
5 Warnings and Precautions
PRECAUTIONSAdditions and/or revisions underlined:
…
Information for Patients
Urine Discoloration
Advise patients that urine may become discolored reddish-brown while taking ROWASA 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).
…
6 Adverse Reactions
Additions and/or revisions underlined:
…
Postmarketing Experience
The following adverse reactions have been identified during post-approval use of mesalamine. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Renal Disorders
Urine discoloration occurring ex-vivo caused by contact of mesalamine including inactive metabolite, with surfaces or water treated with hypochlorite-containing bleach (see PRECAUTIONS: Information for Patients).
…
11/16/2022 (SUPPL-30)
5 Warnings and Precautions
Renal ImpairmentNewly added information:
Discontinue ROWASA if renal function deteriorates while on therapy.
11/01/2021 (SUPPL-29)
5 Warnings and Precautions
PRECAUTIONSNewly added information:
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). Discontinue ROWASA at the first signs or symptoms of severe cutaneous adverse reactions or other signs of hypersensitivity and consider further evaluation.
6 Adverse Reactions
Clinical Adverse Experience
Additions and/or revisions underlined:
Published case reports and/or spontaneous post marketing surveillance have described rare instances of aplastic anemia, agranulocytosis, thrombocytopenia, eosinophilia, pancytopenia, neutropenia, oligospermia, and infertility in men. Anemia, leukocytosis, and thrombocytosis can be part of the clinical presentation of inflammatory bowel disease.
Postmarketing cases of severe cutaneous adverse reactions (SJS/TEN, DRESS, and AGEP) and pleurisy/pleuritis have been reported.
06/25/2021 (SUPPL-27)
8 Use in Specific Populations
Geriatric UseAdditions underlined
Clinical trials of ROWASA did not include sufficient numbers of patients aged 65 years and over to determine whether they respond differently from younger patients. Reports from uncontrolled clinical studies and postmarketing reporting systems suggested a higher incidence of blood dyscrasias (i.e., agranulocytosis, neutropenia and pancytopenia) in patients receiving
mesalamine-containing products such as ROWASA who were 65 years or older compared to younger patients, which may also be associated with ulcerative colitis, use of interacting drugs, or reduced renal function.
Consider monitoring complete blood cell counts and platelet counts in elderly patients during treatment with ROWASA, especially if used concomitantly with anticoagulants. In general, consider the greater frequency of decreased hepatic, renal, or cardiac function, and of concurrent disease or other drug therapy in elderly patients when prescribing ROWASA.
10/01/2020 (SUPPL-26)
5 Warnings and Precautions
PRECAUTIONSHepatic Failure
There have been reports of hepatic failure in patients with pre-existing liver disease who have been administered other products containing mesalamine. Evaluate the risks and benefits of using ROWASA in patients with known liver impairment.
Photosensitivity
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.
Nephrolithiasis
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 hydration during treatment.
Interference with Laboratory Tests
Use of mesalamine 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 mesalamine’s main metabolite, N-acetyl-5-aminosalicylic acid (N-Ac-5-ASA). Consider an alternative, selective assay for normetanephrine.
Hypersensitivity Reactions
Sulfite-Related Reactions
(New subsection title)
ROWASA® (mesalamine) Rectal Suspension Enema contains potassium metabisulfite, a sulfite that may cause allergic-type reactions including anaphylactic symptoms and life-threatening or less severe asthmatic episodes in certain susceptible people. The overall prevalence of sulfite sensitivity in the general population is unknown but probably low. Sulfite sensitivity is seen more frequently in asthmatic or in atopic nonasthmatic persons.
Epinephrine is the preferred treatment for serious allergic or emergency situations even though epinephrine injection contains sodium or potassium metabisulfite with the above- mentioned potential liabilities. The alternatives to using epinephrine in a life-threatening situation may not be satisfactory. The presence of a sulfite(s) in epinephrine injection should not deter the administration of the drug for treatment of serious allergic or other emergency situations.
Sulfasalazine-Associated Reactions
Hypersensitivity reactions have been reported in patients taking sulfasalazine. Some patients may have a similar reaction to ROWASA 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 ROWASA if an alternative etiology for the signs and symptoms cannot be established.
Renal Impairment
Renal impairment, including minimal change disease, acute and chronic interstitial nephritis, and renal failure have been reported in patients given products that contain mesalamine or are converted to mesalamine. In animal studies, the kidney was the principal organ of mesalamine toxicity.
Evaluate the risks and benefits of using ROWASA in patients with known renal impairment or a history of renal disease or taking concomitant nephrotoxic drugs. Mesalamine is known to be substantially excreted by the kidney, and the risk of adverse reactions may be greater in patients with impaired renal function. Evaluate renal function in all patients prior to initiation and periodically while on ROWASA therapy.
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 cannot be ascertained, 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 ROWASA.
6 Adverse Reactions
(Additions and/or revisions underlined)
In addition, the following adverse events have been identified during post-approval use of products which contain (or are metabolized to) mesalamine in clinical practice: nephrotoxicity, pancreatitis, fibrosing alveolitis, elevated liver enzymes, nephrogenic diabetes insipidus, intracranial hypertension and nephrolithiasis.
7 Drug Interactions
(Newly added information)
Nephrotoxic Agents, Including Non-Steroidal Anti-Inflammatory Drugs
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.
Azathioprine or 6-Mercaptopurine
The concurrent use of mesalamine with azathioprine or 6-mercaptopurine and/or any other drugs known to cause myelotoxicity may increase the risk for blood disorders, bone marrow failure, and associated complications. If concomitant use of ROWASA and azathioprine or 6- mercaptopurine cannot be avoided, monitor blood tests, including complete blood cell counts and platelet counts.
8 Use in Specific Populations
Geriatric Use(Newly added section)
Clinical trials of ROWASA did not include sufficient numbers of patients aged 65 years and over to determine whether they respond differently from younger patients. Reports from uncontrolled clinical studies and postmarketing reporting systems suggested a higher incidence of blood dyscrasias (i.e., agranulocytosis, neutropenia and pancytopenia) in patients receiving mesalamine-containing products such as ROWASA who were 65 years or older compared to younger patients.
Consider monitor complete blood cell counts and platelet counts in elderly patients during treatment with ROWASA. In general, consider the greater frequency of decreased hepatic, renal, or cardiac function, and of concurrent disease or other drug therapy in elderly patients when prescribing ROWASA.
07/27/2017 (SUPPL-23)
6 Adverse Reactions
Clinical Adverse Experience(additions underlined)
…
In addition, the following adverse events have been identified during post-approval use of products which contain (or are metabolized to) mesalamine in clinical practice: nephrotoxicity, pancreatitis, fibrosing alveolitis, elevated liver enzymes, nephrogenic diabetes insipidus and intracranial hypertension. Cases of pancreatitis and fibrosing alveolitis have been reported as manifestations of inflammatory bowel disease as well. Published case reports and/or spontaneous post marketing surveillance have described rare instances of aplastic anemia, agranulocytosis, thrombocytopenia, eosinophilia, pancytopenia, neutropenia, oligospermia, and infertility in men. Anemia, leukocytosis, and thrombocytosis can be part of the clinical presentation of inflammatory bowel disease.