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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.
PENTASA (NDA-020049)
(MESALAMINE)
Safety-related Labeling Changes Approved by FDA Center for Drug Evaluation and Research (CDER)
07/30/2024 (SUPPL-41)
5 Warnings and Precautions
The following subsections created to comply with Physician Labeling Rule (PLR); please refer to label for complete information:
5.1 Renal Impairment
5.2 Mesalamine-Induced Acute Intolerance Syndrome
5.3 Hypersensitivity Reactions
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:
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)]
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: chest pain, fatal myocarditis, pericarditis, T-wave abnormalities
Hematologic Disorders: agranulocytosis, anemia, aplastic anemia, leukopenia, pancytopenia
Hepatic Disorders: cirrhosis, jaundice, including cholestatic jaundice; hepatotoxicity, hepatitis, and possible hepatocellular damage including liver necrosis and liver failure. Some of these cases were fatal. One case of Kawasaki-like syndrome which included hepatic function changes was also reported.
Immune System Disorders: anaphylactic reaction, angioedema, lupus-like syndrome, systemic lupus erythematosus
Nervous System Disorders: intracranial hypertension
Renal and Urinary Disorders: acute renal failure, chronic renal failure, interstitial nephritis, nephrogenic diabetes insipidus, nephrolithiasis, nephrotic syndrome [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
Reproductive System and Breast Disorders: reversible oligospermia
Respiratory, Thoracic and Mediastinal Disorders: hypersensitivity pneumonitis (including interstitial pneumonitis, allergic alveolitis, eosinophilic pneumonitis), interstitial lung disease, pleurisy/pleuritis, pneumonitis
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 PENTASA 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, oral administration of mesalamine during organogenesis to pregnant rats at doses up to 1000 mg/kg/day (approximately 2.4 times the maximum recommended human dose of 4 g/day, based on a body surface area comparison) and rabbits at doses of 800 mg/kg/day (approximately 3.9 times the maximum recommended human dose of 4 g/day, based on a body surface area comparison) revealed no evidence of adverse developmental effects (see Data).
The background risk of major birth defects and miscarriage for the indicated populations 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 miscarriages in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.
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.
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 of 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, 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 pregnant rats at doses up to 1000 mg/kg/day (approximately 2.4 times the maximum recommended human dose of 4 g/day, based on a body surface area comparison) and rabbits at doses up to 800 mg/kg/day (approximately 3.9 times the maximum recommended human dose of 4 g/day based on a body surface area comparison) and have revealed no evidence of harm to the fetus due to mesalamine.
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 PENTASA to an infant during lactation; therefore, the developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for PENTASA and any potential adverse effects on the breastfed child from PENTASA 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; please refer to label for complete information.
Other
Physician Labeling Rule (PLR) conversion.
10/24/2023 (SUPPL-40)
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 PENTASA 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 Reports
…
Other: anaphylactic reaction, SJS/TEN, DRESS, AGEP, pleurisy/pleuritis, pneumonitis, granulocytopenia, systemic lupus erythematosus, lupus-like syndrome, acute renal failure, interstitial lung disease, hypersensitivity pneumonitis (including interstitial pneumonitis, allergic alveolitis, eosinophilic pneumonitis), chronic renal failure, nephrogenic diabetes insipidus, nephrolithiasis, intracranial hypertension, angioedema, and oligospermia (reversible).
- 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-38)
5 Warnings and Precautions
Renal ImpairmentNewly added information:
Discontinue PENTASA if renal function deteriorates while on therapy.
11/01/2021 (SUPPL-36)
5 Warnings and Precautions
PRECAUTIONSNewly added information:
Severe Cutaneous Adverse Reactions
Severe cutaneous adverse reactions, such as 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 in with the use of mesalamine (see ADVERSE REACTIONS). Discontinue PENTASA at the first signs or symptoms of severe cutaneous adverse reactions or other signs of hypersensitivity and consider further evaluation.
6 Adverse Reactions
Postmarketing Reports
Additions and/or revisions underlined:
Other: anaphylactic reaction, SJS/TEN, DRESS, AGEP, pleurisy/pleuritis, pneumonitis, granulocytopenia, systemic lupus erythematosus, lupus-like syndrome …
05/25/2021 (SUPPL-35)
4 Contraindications
(Additions and/or revisions underlined)
PENTASA is contraindicated in patients with known or suspected hypersensitivity to salicylates, aminosalicylates, or any components of this medication.
5 Warnings and Precautions
PRECAUTIONS
(Extensive changes; please refer to labeling)
6 Adverse Reactions
(Additions and/or revisions underlined)
Other: anaphylactic reaction, Stevens-Johnson syndrome (SJS), drug reaction with eosinophilia and systemic symptoms (DRESS), toxic epidermal necrolysis (TEN), pleurisy/pleuritis, pneumonitis, granulocytopenia, systemic lupus erythematosus, lupus-like syndrome, acute renal failure, interstitial lung disease, hypersensitivity pneumonitis (including interstitial pneumonitis, allergic alveolitis, eosinophilic pneumonitis), chronic renal failure, nephrogenic diabetes insipidus, nephrolithiasis, intracranial hypertension, angioedema, and oligospermia (reversible).
10/01/2020 (SUPPL-33)
4 Contraindications
(Additions and/or revisions underlined)
PENTASA is contraindicated in patients with known or suspected hypersensitivity to salicylates, aminosalicylates, or any components of this medication.
5 Warnings and Precautions
PrecautionsRenal Impairment
Renal impairment, including minimal change disease, acute and chronic interstitial nephritis, and renal failure have been reported in patients given PENTASA or other products that contain mesalamine or are converted to mesalamine.
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 therapy with PENTASA. Evaluate the risks and benefits of using PENTASA in patients with known renal impairment or a history of renal disease or taking concomitant nephrotoxic drugs.
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. Symptoms include cramping, acute abdominal pain, bloody diarrhea, and 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 PENTASA.
Hypersensitivity Reactions
Hypersensitivity reactions have been reported in patients taking sulfasalazine. Some patients may have a similar reaction to PENTASA 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 PENTASA if an alternative etiology for the signs and symptoms cannot be established.
Hepatic 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 PENTASA 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.
7 Drug Interactions
(Additions and/or revisions underlined)
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 PENTASA 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 PENTASA 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 PENTASA who were 65 years or older compared to younger patients. Monitor complete blood cell counts and platelet counts in elderly patients during treatment with PENTASA.
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 PENTASA.
07/16/2019 (SUPPL-32)
5 Warnings and Precautions
PRECAUTIONS(additions underlined)
…
Drug Interactions
No investigations of interactions between PENTASA and other drugs have been performed; however, the following drug-drug interactions have been reported for products containing mesalamine:
The concurrent use of mesalamine with known nephrotoxic agents, including non-steroidal anti-inflammatory drugs (NSAIDs), may increase the risk of renal reactions.
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.
…
8 Use in Specific Populations
Nursing Mothers(additions underlined)
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. The clinical significance of this has not been determined and there is limited experience of nursing women using mesalamine.
There are reports of diarrhea observed in breastfed infants exposed to mesalamine. The effect of PENTASA on milk production is unknown. Exercise caution if PENTASA is administered to a nursing woman and monitor breastfed infants for diarrhea.
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.
(additions underlined)
Teratogenic Effects
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. There is no clear evidence that mesalamine exposure in early pregnancy is associated with an increased risk of 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, maternal use of concomitant medications, and missing information on the dose and duration of use for mesalamine products. PENTASA should only be used during pregnancy if the benefits outweigh the risks.
In animal reproduction studies, oral administration of mesalamine during organogenesis to pregnant rats at doses up to 1000 mg/kg/day (5900 mg/m²) and rabbits at doses of
800 mg/kg/day (6856 mg/m²) revealed no evidence of teratogenic effects or harm to the fetus due to mesalamine.
The estimated background risk of major birth defects and miscarriage for the indicated populations 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 miscarriages in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.
Nonteratogenic Effects
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.
05/30/2018 (SUPPL-31)
5 Warnings and Precautions
PrecautionsAdditions and/or revisions underlined:
Mesalamine has been associated with an acute intolerance … carried out under close medical supervision at reduced dose and only if clearly needed.
Patients with pre-existing skin conditions such as atopic dermatitis and atopic eczema have reported more severe photosensitivity reactions.
6 Adverse Reactions
Additions and/or revisions underlined:
Postmarketing Reports
Other: Postmarketing reports of anaphylactic reaction … intracranial hypertension, angioedema and oligospermia (reversible) have been received in patients taking PENTASA.
08/22/2017 (SUPPL-28)
6 Adverse Reactions
Postmarketing Reports(additions underlined)
The following events have been identified during post-approval use of the PENTASA brand of mesalamine in clinical practice. Because they are reported voluntarily from a population of unknown size, estimates of frequency cannot be made. These events have been chosen for inclusion due to a combination of seriousness, frequency of reporting, or potential causal connection to mesalamine:
…
Other: Postmarketing reports of anaphylactic reaction, Stevens-Johnson syndrome (SJS), drug reaction with eosinophilia and systemic symptoms (DRESS), pneumonitis, granulocytopenia, systemic lupus erythematosus, lupus-like syndrome, acute renal failure, interstitial lung disease, Hypersensitivity pneumonitis (including interstitial pneumonitis, allergic alveolitis, eosinophilic pneumonitis), chronic renal failure, nephrogenic diabetes insipidus, intracranial hypertension and angioedema have been received in patients taking PENTASA.
07/27/2017 (SUPPL-30)
6 Adverse Reactions
6.2 Postmarketing Reports(additions underlined)
…
Other: Postmarketing reports of anaphylactic reaction, Stevens-Johnson syndrome (SJS), drug reaction with eosinophilia and systemic symptoms (DRESS), pneumonitis, granulocytopenia, systemic lupus erythematosus, acute renal failure, chronic renal failure, nephrogenic diabetes insipidus, intracranial hypertension and angioedema have been received in patients taking PENTASA.