Drug Safety-related Labeling Changes (SrLC)

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DIPENTUM (NDA-019715)

(OLSALAZINE SODIUM)

Safety-related Labeling Changes Approved by FDA Center for Drug Evaluation and Research (CDER)

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07/30/2024 (SUPPL-35)

Approved Drug Label (PDF)

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)]

  …

7 Drug Interactions

7.5 Interference With Urinary Normetanephrine Measurements

New subsection added:

Use of DIPENTUM, which is converted to mesalamine, 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, the active moiety in DIPENTUM, 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, there were adverse developmental effects observed after oral administration of olsalazine sodium in pregnant rats during organogenesis at doses of 5 to 20 times the maximum recommended human dose (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 in DIPENTUM, 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

Olsalazine has been shown to produce adverse fetal developmental effects including reduced fetal weights, retarded ossifications, and immaturity of the fetal visceral organs when given during organogenesis to pregnant rats at doses of 100 to 400 mg/kg (5 to 20 times the maximum recommended human dose.

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 in breastfed infants exposed to mesalamine (see Clinical Considerations). There is no information on the effects of the drug on milk production. The lack of clinical data during lactation precludes a clear determination of the risk of DIPENTUM to an infant during lactation; therefore, the developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for DIPENTUM and any potential adverse effects on the breastfed child from DIPENTUM 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 mesalamine 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 obtained following administration of oral or rectal mesalamine, the active moiety of olsalazine, estimated infant daily dosages for an exclusively breastfed infant are 0 to 0.075 mg/kg/day (relative infant dose 0 to 0.1% of mesalamine and 0.03 to 1.4 mg/kg/day of N- acetyl-5-aminosalicylic acid).

Oral administration of olsalazine to lactating rats in doses 5 to 20 times the maximum recommended human dose produced growth retardation in the pups.

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

PATIENT COUNSELING INFORMATION

New 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-33)

Approved Drug Label (PDF)

5 Warnings and Precautions

PRECAUTIONS

Additions and/or revisions underlined:

…

Urine Discoloration

Advise patients that urine may become discolored reddish-brown while taking DIPENTUM 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:

…

Renal and Urinary Disorders

Interstitial nephritis, nephrolithiasis

• 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-32)

Approved Drug Label (PDF)

5 Warnings and Precautions

Renal Impairment

Newly added information:

Discontinue DIPENTUM if renal function deteriorates while on therapy.

11/01/2021 (SUPPL-30)

Approved Drug Label (PDF)

5 Warnings and Precautions

PRECAUTIONS

Newly 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, the active moiety in DIPTENTUM (see ADVERSE REACTIONS). Discontinue DIPENTUM at the first signs or symptoms of severe cutaneous adverse reactions or other signs of hypersensitivity and consider further evaluation.

6 Adverse Reactions

Postmarketing

Additions and/or revisions underlined:

Respiratory, Thoracic and Mediastinal Disorders

Dyspnea, Interstitial lung disease, pleurisy/pleuritis

Skin and Subcutaneous Tissue Disorders

Angioneurotic edema, SJS/TEN, DRESS, and AGEP

06/25/2021 (SUPPL-29)

Approved Drug Label (PDF)

8 Use in Specific Populations

Geriatric Use

Additions underlined

Clinical studies of DIPENTUM did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from 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 receiving mesalamine-containing products such as DIPENTUM 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.

…

10/07/2020 (SUPPL-28)

Approved Drug Label (PDF)

4 Contraindications

(Additions and/or revisions underlined)

DIPENTUM is contraindicated in patients with known or suspected hypersensitivity to salicylates, aminosalicylates or their metabolites, or to any of the excipients in DIPENTUM.

5 Warnings and Precautions

PRECAUTIONS

(Additions and/or revisions underlined)

Hepatic Failure

There have been reports of hepatic failure in patients with pre-existing liver disease who have been administered mesalamine. Because olsalazine is converted to mesalamine, evaluate the risks and benefits of using DIPENTUM 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, the active moiety in DIPENTUM, 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 DIPENTUM, which is converted to 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.

WARNINGS

(Newly added section)

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 DIPENTUM 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 DIPENTUM therapy.

Mesalamine-Induced Acute Intolerance Syndrome

Olsalazine is converted to mesalamine, which has been associated with an acute intolerance syndrome that may be difficult to distinguish from an exacerbation of ulcerative colitis.

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 DIPENTUM.

Hypersensitivity Reactions

Some patients who have experienced a hypersensitivity reaction to sulfasalazine may have a similar reaction to DIPENTUM or to other compounds that contain or are converted to mesalamine. 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 DIPENTUM if an alternative etiology for the signs and symptoms cannot be established.

6 Adverse Reactions

(Additions and/or revisions underlined)

Olsalazine has been evaluated in ulcerative colitis patients in remission, as well as those with acute disease. Both sulfasalazine-tolerant and intolerant patients have been studied in controlled clinical trials. Overall, 10.4% of patients discontinued olsalazine because of an adverse experience compared with 6.7% of placebo patients. The most commonly reported adverse reactions leading to treatment withdrawal were diarrhea or loose stools (olsalazine 5.9%; placebo 4.8%), abdominal pain, and rash or itching (slightly more than 1% of patients receiving olsalazine).

Diarrhea

Overall, approximately 17% of subjects receiving olsalazine in clinical studies reported diarrhea sometime during therapy. This diarrhea resulted in withdrawal of treatment in 6% of patients. This diarrhea appears to be dose related, although it may be difficult to distinguish from the underlying symptoms of the disease.

…

Postmarketing

The following events have been identified during post-approval use of products that contain (or are metabolized to) 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:

Blood and Lymphatic System Disorders

Aplastic anemia, Pancytopenia

General Disorders and Administration Site Conditions

Pyrexia

Hepatobiliary Disorders

Hepatic enzyme increased, Hepatitis, Increased bilirubin

Reports of hepatotoxicity, including elevated liver function tests (SGOT/AST, SGPT/ALT, GGT, LDH, alkaline phosphatase, bilirubin), jaundice, cholestatic jaundice, cirrhosis, 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.

Musculoskeletal and Connective Tissue Disorders

Myalgia

Respiratory, Thoracic and Mediastinal Disorders

Dyspnea, Interstitial lung disease

Skin and Subcutaneous Tissue Disorders

Angioneurotic edema

Nervous System Disorders

Paresthesia, Peripheral neuropathy

Renal and Urinary Disorders

Interstitial nephritis, nephrolithiasis

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 (e.g., thioguanine) may increase the risk for blood disorders, bone marrow failure, and associated complications. If concomitant use of DIPENTUM and azathioprine or 6-mercaptopurine cannot be avoided, monitor blood tests, including complete blood cell counts and platelet counts.

Low Molecular Weight Heparins or Heparinoids

The co-administration of salicylates and low molecular weight heparins or heparinoids may result in an increased risk of bleeding (i.e., hematomas) following neuraxial anesthesia. Salicylates should be discontinued prior to the initiation of a low molecular weight heparin or heparinoid. If this is not possible, it is recommended to monitor patients closely for bleeding.

Warfarin

Increased prothrombin time in patients taking concomitant warfarin has been reported. Monitor INR and prothrombin time and adjust the dosage of warfarin, as needed with concomitant use of DIPENTUM, to maintain the target INR range.

Varicella Vaccine

It is recommended not to give salicylates for six weeks after the varicella vaccine to avoid a possible increased risk of developing Reye’s syndrome.

8 Use in Specific Populations

Geriatric Use

(Additions and/or revisions underlined)

Clinical studies of DIPENTUM did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from 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 receiving mesalamine-containing products such as DIPENTUM who were 65 years or older compared to younger patients.

Consider monitoring of complete blood cell counts and platelet counts in elderly patients during treatment with DIPENTUM, 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 DIPENTUM.

Hepatic

(Additions and/or revisions underlined)

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 DIPENTUM in patients with known liver impairment.

Renal

(Additions and/or revisions underlined)

Mesalamine is known to be substantially excreted by the kidney, and the risk of adverse reactions to DIPENTUM, which is converted to mesalamine, may be greater in patients with impaired renal function. Evaluate renal function in all patients prior to initiation and periodically while on DIPENTUM 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.