Drug Safety-related Labeling Changes (SrLC)

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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.

KEVEYIS (NDA-011366)

(DICHLORPHENAMIDE)

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

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11/22/2019 (SUPPL-33)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.1 Hypersensitivity and Other Life-threatening Reactions

(Additions and/or revisions underlined)

Fatalities associated with the administration of sulfonamides have occurred because of adverse reactions including Stevens-Johnson syndrome, toxic epidermal necrolysis, fulminant hepatic necrosis, agranulocytosis, aplastic anemia, and other blood dyscrasias. Pulmonary involvement can occur in isolation or as part of a systemic reaction.

KEVEYIS should be discontinued at the first appearance of skin rash or any sign of immune- mediated or other life-threatening adverse reaction.

5.2 Concomitant Use of Aspirin or Other Salicylates

(Additions and/or revisions underlined)

Carbonic anhydrase inhibitors, including KEVEYIS, can cause metabolic acidosis, which can increase the risk of salicylate toxicity. Anorexia, tachypnea, lethargy, and coma have been reported with concomitant use of dichlorphenamide and high-dose aspirin. Therefore, the concomitant use of KEVEYIS and high-dose aspirin is contraindicated.

Patients with concomitant use of KEVEYIS and low-dose aspirin should be carefully monitored.

5.3 Hypokalemia

(Additions and/or revisions underlined)

KEVEYIS increases potassium excretion and can cause hypokalemia. The risk of hypokalemia is greater when KEVEYIS is used in patients with conditions associated with hypokalemia (e.g., adrenocortical excess, renal tubular acidosis type 1 and 2), and in patients receiving other drugs that may cause hypokalemia.

Baseline and periodic measurements of serum potassium during KEVEYIS treatment is recommended.

If hypokalemia develops or persists, consideration should be given to reducing the dose or discontinuing KEVEYIS and correction of potassium levels.

5.4 Metabolic Acidosis

(Additions and/or revisions underlined

KEVEYIS can cause hyperchloremic non-anion gap metabolic acidosis. Concomitant use of KEVEYIS with other drugs that cause metabolic acidosis may increase the severity of acidosis. Concomitant use of KEVEYIS in compensated patients with respiratory acidosis, such as in advanced lung diseases, may lead to respiratory decompensation.

Baseline and periodic measurements of serum bicarbonate during KEVEYIS treatment are recommended.

If metabolic acidosis develops or persists, consideration should be given to reducing the dose or discontinuing KEVEYIS.

6 Adverse Reactions

(Additions and/or revisions underlined)

The following serious adverse reactions are described elsewhere in labeling:

Hypersensitivity and Other Life-Threatening Reactions
Hypokalemia
Metabolic Acidosis
Falls

6.2 Postmarketing Experience

(Additions and/or revisions underlined)

Adverse reactions have been identified during postapproval use of dichlorphenamide. 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.

The following are adverse reactions which have been reported during postapproval use of dichlorphenamide and were serious or are not reported in the previous section of labeling: amnesia, cardiac failure, condition aggravated, convulsion, hallucination, nephrolithiasis, pancytopenia, psychotic disorder, renal tubular necrosis, stupor, syncope, tremor.

7 Drug Interactions

7.1 Aspirin and Other Salicylates

(Additions and/or revisions underlined)

Carbonic anhydrase inhibitors, including KEVEYIS, can cause metabolic acidosis, which can increase the risk of salicylate toxicity. Anorexia, tachypnea, lethargy, and coma have been reported with concomitant use of dichlorphenamide and high-dose aspirin. Therefore, concomitant use of KEVEYIS and high-dose aspirin is contraindicated. Patients with concomitant use of KEVEYIS and low-dose aspirin should be carefully monitored.

7.2 Drugs that are Substrates of Organic Anion Transporter1 (OAT1)

(Additions and/or revisions underlined)

In vitro, dichlorphenamide is an inhibitor of OAT1 transporters. The concomitant administration of KEVEYIS may increase the plasma exposures of OAT1 substrates. Use of KEVEYIS with drugs that are sensitive to OAT1 inhibition (e.g., methotrexate, famotidine, oseltamivir) is not recommended.

7.3 Drugs that Cause Hypokalemia

(Additions and/or revisions underlined)

The risk of hypokalemia is greater with coadministration of KEYEVIS and other drugs that can cause hypokalemia (e.g., loop diuretics, thiazide diuretics, laxatives, antifungals, penicillins, and theophylline).

7.4 Drugs that Cause Metabolic Acidosis

(Additions and/or revisions underlined)

Coadministration of KEYEVIS and other drugs that can cause metabolic acidosis may increase the severity of the acidosis.

7.5 Drugs that are Inhibitors of OAT1 or OAT3

(Additions and/or revisions underlined)

An in vitro transporter study indicated that dichlorphenamide is a substrate of human transporters OAT1 and OAT3. Therefore, signs of dichlorphenamide toxicity should be monitored when administered with OAT1 or OAT3 inhibitors.

8 Use in Specific Populations

8.1 Pregnancy

(Pregnancy and Lactation Labeling Rule (PLLR) Conversion; Additions and/or revisions underlined)

Risk Summary

There are no adequate data on the developmental risk associated with the use of KEVEYIS in pregnant women. A no-effect dose has not been established. Dichlorphenamide was teratogenic when administered orally to pregnant rats.

The background risk of major birth defects and miscarriage for the indicated population is unknown. 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

Fetal/Neonatal adverse reactions

KEVEYIS treatment can cause metabolic acidosis. The effect of dichlorphenamide-induced metabolic acidosis has not been studied in pregnancy; however, metabolic acidosis in pregnancy (due to other causes) can cause decreased fetal growth, decreased fetal oxygenation, and fetal death, and may affect the fetus’ ability to tolerate labor. Pregnant patients should be monitored for metabolic acidosis and treated as in the nonpregnant state. Newborns of mothers treated with KEVEYIS should be monitored for metabolic acidosis because of possible occurrence of transient metabolic acidosis following birth.

Labor or Delivery

Although the effect of KEVEYIS on labor and delivery in humans has not been established, the development of dichlorphenamide-induced metabolic acidosis in the mother and/or in the fetus might affect the fetus’ ability to tolerate labor.

Data

Animal Data

Teratogenic effects (fetal limb reduction defects) were reported following oral administration of dichlorphenamide to pregnant rats during organogenesis at 350 mg/kg, or 17 times the maximum recommended human dose (200 mg/day) on a body surface area (mg/m2) basis. A no-effect dose for adverse effects on embryofetal development has not been established.

8.2 Lactation

(Pregnancy and Lactation Labeling Rule (PLLR) Conversion; Additions and/or revisions underlined)

Risk Summary

There are no data on the presence of dichlorphenamide in human milk, the effects on the breastfed infant, or the effects on milk production.

The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for KEVEYIS and any potential adverse effects on the breastfed infant from KEVEYIS or from the underlying maternal condition.

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

17 PATIENT COUNSELING INFORMATION

(Additions and/or revisions underlined)

Worsening of Symptoms

Advise patients to notify their physician if they experience acute worsening of symptoms of periodic paralysis.

Hypersensitivity and Other Life-threatening Reactions

Inform patients that hypersensitivity and immune mediated reactions can occur with KEVEYIS, and could be fatal. Advise patients to discontinue KEVEYIS and notify their healthcare provider immediately if they develop a rash or signs and symptoms of anaphylaxis or other life- threatening reactions.

Drug Interactions

Instruct patients to notify their healthcare provider of all of the drugs and over-the-counter medications that they take and to not take aspirin or other salicylates without first discussing with their healthcare provider.

Metabolic Acidosis

Instruct patients to contact their healthcare provider immediately if they develop possible manifestations of metabolic acidosis (e.g., fast breathing, fatigue/tiredness, loss of appetite, or irregular heart beat or palpitations).

Falls

Inform patients that KEYEVIS can increase their risk of falls.

Cognitive Impairment

Advise patients to notify their healthcare provider if they experience symptoms of cognitive impairment including confusion and memory lapse.