Drug Safety-related Labeling Changes (SrLC)

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CANASA (NDA-021252)

(MESALAMINE)

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

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10/24/2023 (SUPPL-30)

Approved Drug Label (PDF)

6 Adverse Reactions

6.2 Postmarketing Experience

Additions and/or revisions underlined:

The following adverse reactions have been identified during post-approval use of CANASA or other mesalamine-containing products. 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: 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 INFORMATION

Additions and/or revisions underlined:

Advise patients to read the FDA-approved patient labeling (Patient Information)

Administration [see Dosage and Administration (2)]

Advise patients:

…

• Urine may become discolored reddish-brown while taking CANASA 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).

…

PATIENT INFORMATION

Additions and/or revisions underlined:

…

General information about the safe and effective use of CANASA.

Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use CANASA for a condition for which it was not prescribed. Do not give CANASA to other people, even if they have the same symptoms that you have. It may harm them.

Urine may become discolored reddish-brown while taking CANASA when it comes in contact with surfaces or water treated with hypochlorite-containing bleach.

You can ask your pharmacist or healthcare provider for information about CANASA that is written for health professionals.

…

11/16/2022 (SUPPL-29)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.1 Renal Impairment

Newly added information:

Discontinue CANASA if renal function deteriorates while on therapy.

8 Use in Specific Populations

8.6 Renal Impairment

Newly added information:

Discontinue CANASA if renal function deteriorates while on therapy

11/01/2021 (SUPPL-28)

Approved Drug Label (PDF)

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 in association with the use of mesalamine [see Adverse Reactions (6.2)]. Discontinue CANASA at the first signs or symptoms of severe cutaneous adverse reactions or other signs of hypersensitivity and consider further evaluation.

6 Adverse Reactions

 

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, Thoracic and Mediastinal Disorders: hypersensitivity pneumonitis (including allergic alveolitis, eosinophilic pneumonitis, interstitial pneumonitis), pleuritis/pleurisy

• Skin and Subcutaneous Tissue Disorder: alopecia, erythema, erythema nodosum, pruritus, psoriasis, pyoderma gangrenosum, 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 INFORMATION

Newly added information:

Severe Cutaneous Adverse Reactions

• Inform patients of the signs and symptoms of severe cutaneous adverse reactions. Instruct patients to stop taking CANASA and report to their healthcare provider at first appearance of a severe cutaneous adverse reaction or any other sign of hypersensitivity [see Warnings and Precautions (5.5)].

PATIENT INFORMATION

Newly added information:

• serious skin reactions. Some people who use CANASA can have severe skin reactions. Stop using CANASA and tell your doctor right away if you develop any of the following signs or symptoms of a severe skin reaction, including:

  • blisters or peeling of your skin          

  • mouth sores

  • enlarged lymph nodes

  • blisters on your lips, or around your mouth or eyes

  • high fever or flu-like symptoms

  • skin rash

10/01/2020 (SUPPL-25)

Approved Drug Label (PDF)

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 CANASA 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)].

5.2 Mesalamine-Induced Acute Intolerance Syndrome

(Additions and/or revisions underlined)

Symptoms include cramping, acute abdominal pain and bloody diarrhea, and sometimes fever, headache, malaise, pruritis, conjunctivitis, and rash.

5.5 Photosensitivity

(Newly added subsection)

In patients treated with mesalamine or sulfasalazine who have 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.

5.6 Nephrolithiasis

(Newly added subsection)

Cases of nephrolithiasis have been reported with the use of mesalamine, including stones of 100% mesalamine content. Mesalamine- containing stones are radiotransparent and undetectable by standard radiography or computed tomography (CT). Ensure adequate hydration during treatment with CANASA.

6 Adverse Reactions

(Additions and/or revisions underlined)

The following serious or 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)]

6.2 Postmarketing Experience

(Additions and/or revisions underlined)

Renal Disorders: interstitial nephritis, renal failure, minimal change disease, nephrolithiasis [see Warnings and Precautions (5.1, 5.6)]

7 Drug Interactions

7.2 Azathioprine or 6-Mercaptopurine

(Additions and/or revisions underlined)

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 CANASA and azathioprine or 6-mercaptopurine cannot be avoided, monitor blood tests, including complete blood cell counts and platelet counts.

7.3 Interference With Urinary Normetanephrine Measurements

(Section title revised)

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

Patient Counseling Information

(Additions and/or revisions underlined)

Advise patients:

• Drink an adequate amount of fluids.

• Mesalamine-Induced Acute Intolerance Syndrome and Other Hypersensitivity Reactions

• Instruct patients to stop taking CANASA and report to their healthcare provider if they experience new or worsening symptoms Acute Intolerance Syndrome (cramping, abdominal pain, bloody diarrhea, fever, headache, malaise, conjunctivitis and rash) or other symptoms suggestive of mesalamine-induced hypersensitivity [see Warnings and Precautions (5.2, 5.3)].
  

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)].

Patient Information

(Additions and/or revisions underlined)

Taking CANASA with

azathioprine or 6-mercaptopurine may cause blood problems. Ask your doctor if you are not sure if you are taking one

of these medicines.

• It is important for you to stay well hydrated during treatment with CANASA. Be sure to drink plenty of fluids while

taking CANASA.

Stop using CANASA and tell your doctor right away if you get any of these

symptoms:

o eye inflammation

Tell your doctor right away if you get any of these symptoms while using CANASA:

• sun sensitivity. CANASA can make your skin sensitive to the sun if you have skin conditions such as atopic

dermatitis and atopic eczema. Try to limit your time in the sun. You should use sunscreen and wear a hat and

clothes that cover your skin if you have to be in the sunlight.

• kidney stones. Drink plenty of fluids when using CANASA to decrease your chance of getting kidney stones. Call

your doctor right away if you get any of these symptoms:

o severe pain in your side

o severe pain in your back

o blood in your urine

07/27/2017 (SUPPL-23)

Approved Drug Label (PDF)

6 Adverse Reactions

6.2 Postmarketing Experience

(additions underlined)

…

• Endocrine: Nephrogenic diabetes insipidus

  …

• Neurological/Psychiatric Disorders: Guillain-Barre syndrome, peripheral neuropathy, transverse myelitis, intracranial hypertension

  …

09/02/2016 (SUPPL-14)

Approved Drug Label (PDF)

4 Contraindications

CANASA is contraindicated in patients with known or suspected hypersensitivity to salicylates or aminosalicylates or to any ingredients in the suppository vehicle.

 

5 Warnings and Precautions

Renal Impairment (Revised)

Renal impairment, including minimal change nephropathy, acute and chronic interstitial nephritis, and renal failure, has been reported in patients given products such as CANASA that contain mesalamine or are converted to mesalamine .

Evaluate renal function prior to initiation of CANASA therapy and periodically while on therapy.

Evaluate the risks and benefits of using CANASA in patients with known renal impairment or a history of renal disease or taking concomitant nephrotoxic drugs. In animal studies, the kidney was the principal organ for toxicity.

Mesalamine-Induced Acute Intolerance Syndrome

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, 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 CANASA.

Hypersensitivity Reactions (Revised)

Hypersensitivity reactions have been reported in patients taking sulfasalazine. Some patients may have a similar reaction toCANASA 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 CANASA if an alternative etiology for the signs and symptoms cannot be established.

Hepatic Failure (Revised)

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 CANASA in patients with known liver impairment.

Interaction with Laboratory Test for Urinary Normetanephrine

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 mesalamines main metabolite, N-acetylaminosalicylic acid. Consider an alternative, selective assay for normetanephrine.

6 Adverse Reactions

The most serious adverse reactions seen in CANASA clinical trials or with other products that contain or are metabolized to mesalamine are:

• Renal Impairment

• Mesalamine-Induced Acute Intolerance Syndrome

• Hypersensitivity Reactions

• Hepatic Failure (Revised)

 

Clinical Trials Experience

The most common adverse reactions in adult patients with mildly to moderately active ulcerative proctitis in double-blind placebo-controlled trials are summarized in the Table 1 below.....

In a multicenter, open-label, randomized, parallel group study in 99 patients comparing the CANASA 1000 mg suppository administered nightly to that of the mesalamine 500 mg suppository twice daily. The most common adverse reactions in both groups were headache (14%), flatulence (5%), abdominal pain (5%), diarrhea (3%), and nausea (3%). Three (3) patients discontinued medication because of an adverse reaction; one of these adverse reactions (headache) was deemed possibly related to study medication. The recommended dosage of CANASA is 1000 mg administered rectally once daily at bedtime. (Revised)

 

Postmarketing Experience

• Renal Disorders: interstitial nephritis, renal failure, minimal change nephropathy (Revised)

 

 

7 Drug Interactions

Nephrotoxic Agents, Including Non-Steroidal Anti-Inflammatory Drugs

The concurrent use of mesalamine with known nephrotoxic agents, including nonsteroidal anti-inflammatory drugs (NSAIDs) may increase the risk of nephrotoxicity. Monitor patients taking nephrotoxic drugs for changes in (added) renal function and mesalamine- related adverse reactions.

 

Azathioprine or 6-Mercaptopurine (revised)

The concurrent use of mesalamine with azathioprine or 6-mercaptopurine may increase the risk for blood disorders. If concomitant use of CANASA and azathioprine or 6-mercaptopurine cannot be avoided, monitor blood tests, including complete blood cell counts and platelet counts.

 

Urinary Normetanephrine Measurements (added)

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-acetylaminosalicylic acid. Consider an alternative, selective assay for normetanephrine.

8 Use in Specific Populations

Pregnancy (PLLR conversations)

Risk Summary

Limited published data on mesalamine use in pregnant women are insufficient to inform a drug-associated risk. No evidence of teratogenicity was observed in rats or rabbits when treated during gestation with orally administered mesalamine at doses greater than the recommended human intra-rectal 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.

Data

Animal Data (revised)

Reproduction studies have been performed  in rats at oral doses up to 320 mg/kg/day (about 1.7 times the recommended human intra-rectal dose of CANASA, based on body surface area) and in rabbits at oral doses up to 495 mg/kg/day (about 5.4 times the recommended human intra-rectal dose of CANASA, based on body surface area) following administration during the period of organogenesis, and have revealed no evidence of impaired fertility or harm to the fetus due to mesalamine.

 

 

Lactation ( PllR conversations)

Risk Summary

Mesalamine and its N-acetyl metabolite are present in human milk in undetectable to small amounts [see Data]. There are limited reports of diarrhea in breastfed infants. 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 CANASA to an infant during lactation; therefore, the developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for CANASA and any potential adverse effects on the breastfed child from CANASA or from the underlying maternal conditions.

Clinical Considerations

Monitor breastfed infants for diarrhea.

 

Data

In published lactation studies, maternal mesalamine doses from various oral and rectal formulations and products ranged from 500 mg to 3 g daily. The concentration of mesalamine in milk ranged from non-detectable to 0.11 mg/L. The concentration of the N-acetyl-5-aminosalicylic acid metabolite ranged from 5 to 18.1 mg/L. Based on these concentrations, estimated infant daily dosages for an exclusively breastfed infant are 0 to 0.017 mg/kg/day of mesalamine and 0.75 to 2.72 mg/kg/day of N-acetyl-5aminosalicylic acid.

 

Pediatric Use (Revised)

The safety and effectiveness of CANASA in pediatric patients for the treatment of mildly to moderately active ulcerative proctitishave not been established. CANASA was evaluated for the treatment of ulcerative proctitis in a 6-week, open-label, single-arm study in 49 patients 5 to 17 years of age, which only included 14 patients with histologically-confirmed cases of ulcerative proctitis. However, efficacy was not demonstrated. Adverse reactions seen in pediatric patients .

in this trial (abdominal pain, headache, pyrexia, pharyngolaryngeal pain, diarrhea and vomiting) were similar to those seen in adult patients.

 

Geriatric Use (Revised)

Clinical trials of CANASA did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger patients. Systemic exposures are increased in elderly 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 CANASA who were 65years or older compared to younger patients. Monitor

complete blood cell counts and platelet counts in elderly patients during treatment with CANASA. In general, the greater frequency of decreased hepatic, renal, or cardiac function, and of concurrent disease or other drug therapy in elderly patients should be considered when prescribing CANASA.

 

Renal Impairment (Added)

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 CANASA 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.

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

PATIENT COUNSELING INFORMATION (Revised)

Advise patients to read the FDA-approved patient labeling (Patient Information)

 

Administration

Advise patients:

• Do not cut or break the suppository.

• Retain the suppository for one to three hours or longer, if possible.

• If a dose of CANASA is missed, administer as soon as possible, unless it is almost time for next dose. Do not use two CANASA suppositories at the same time to make up for a missed dose.

• CANASA suppositories will cause staining of direct contact surfaces, including but not limited to fabrics, flooring, painted surfaces, marble, granite, vinyl, and enamel. Keep CANASA away from these surfaces to prevent staining.

 

Renal Impairment

Inform patients that CANASA 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.

 

Mesalamine-Induced Acute Intolerance Syndrome and Other Hypersensitivity Reactions

Inform patients of the signs and symptoms of hypersensitivity reactions. Instruct patients to stop taking CANASA and report to their healthcare provider if they experience new or worsening symptoms Acute Intolerance Syndrome (cramping, abdominal pain, bloody diarrhea, fever, headache, and rash) or other symptoms suggestive of mesalamine-induced hypersensitivity.

 

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.

 

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.

 

PATIENT INFORMATION (Revised) - Please refer to label.