NDC 72065-001 Keveyis
Dichlorphenamide Tablet Oral

Product Information

What is NDC 72065-001?

The NDC code 72065-001 is assigned by the FDA to the product Keveyis which is a human prescription drug product labeled by Xeris Pharmaceuticals, Inc.. The generic name of Keveyis is dichlorphenamide. The product's dosage form is tablet and is administered via oral form. The product is distributed in a single package with assigned NDC code 72065-001-01 100 tablet in 1 bottle . This page includes all the important details about this product, including active and inactive ingredients, pharmagologic classes, product uses and characteristics, UNII information, RxNorm crosswalk and the complete product label.

NDC Product Code72065-001
Proprietary Name What is the Proprietary Name?
The proprietary name also known as the trade name is the name of the product chosen by the medication labeler for marketing purposes.
Keveyis
Non-Proprietary Name What is the Non-Proprietary Name?
The non-proprietary name is sometimes called the generic name. The generic name usually includes the active ingredient(s) of the product.
Dichlorphenamide
Product Type What kind of product is this?
Indicates the type of product, such as Human Prescription Drug or Human Over the Counter Drug. This data element matches the “Document Type” field of the Structured Product Listing.
Human Prescription Drug
Dosage FormTablet - A solid dosage form containing medicinal substances with or without suitable diluents.
Administration Route(s) What are the Administration Route(s)?
The translation of the route code submitted by the firm, indicating route of administration.
  • Oral - Administration to or by way of the mouth.
Product Labeler Information What is the Labeler Name?
Name of Company corresponding to the labeler code segment of the Product NDC.
Xeris Pharmaceuticals, Inc.
Labeler Code72065
FDA Application Number What is the FDA Application Number?
This corresponds to the NDA, ANDA, or BLA number reported by the labeler for products which have the corresponding Marketing Category designated. If the designated Marketing Category is OTC Monograph Final or OTC Monograph Not Final, then the Application number will be the CFR citation corresponding to the appropriate Monograph (e.g. “part 341”). For unapproved drugs, this field will be null.
NDA011366
Marketing Category What is the Marketing Category?
Product types are broken down into several potential Marketing Categories, such as NDA/ANDA/BLA, OTC Monograph, or Unapproved Drug. One and only one Marketing Category may be chosen for a product, not all marketing categories are available to all product types. Currently, only final marketed product categories are included. The complete list of codes and translations can be found at www.fda.gov/edrls under Structured Product Labeling Resources.
NDA - A product marketed under an approved New Drug Application.
Start Marketing Date What is the Start Marketing Date?
This is the date that the labeler indicates was the start of its marketing of the drug product.
12-13-2021
Listing Expiration Date What is the Listing Expiration Date?
This is the date when the listing record will expire if not updated or certified by the product labeler.
12-31-2023
Exclude Flag What is the NDC Exclude Flag?
This field indicates whether the product has been removed/excluded from the NDC Directory for failure to respond to FDA"s requests for correction to deficient or non-compliant submissions ("Y"), or because the listing certification is expired ("E"), or because the listing data was inactivated by FDA ("I"). Values = "Y", "N", "E", or "I".
N
NDC Code Structure

What are the uses for Keveyis?


Product Characteristics

Color(s)WHITE (C48325)
ShapeROUND (C48348)
Size(s)6 MM
Imprint(s)D;50
Score2

Product Packages

NDC Code 72065-001-01

Package Description: 100 TABLET in 1 BOTTLE

Product Details

What are Keveyis Active Ingredients?

An active ingredient is the substance responsible for the medicinal effects of a product specified by the substance's molecular structure or if the molecular structure is not known, defined by an unambiguous definition that identifies the substance. Each active ingredient name is the preferred term of the UNII code submitted.

Keveyis Active Ingredients UNII Codes

NDC to RxNorm Crosswalk

What is RxNorm? RxNorm is a normalized naming system for generic and branded drugs that assigns unique concept identifier(s) known as RxCUIs to NDC products.The NDC to RxNorm Crosswalk for this produdct indicates multiple concept unique identifiers (RXCUIs) are associated with this product:

Keveyis Inactive Ingredients UNII Codes

The inactive ingredients are all the component of a medicinal product OTHER than the active ingredient(s). The acronym "UNII" stands for “Unique Ingredient Identifier” and is used to identify each inactive ingredient present in a product.

Pharmacologic Class(es)

A pharmacologic class is a group of drugs that share the same scientifically documented properties. The following is a list of the reported pharmacologic class(es) corresponding to the active ingredients of this product.

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Keveyis Product Label

FDA filings in the form of structured product labels are documents that include all published material associated whith this product. Product label information includes data like indications and usage generic names, contraindications, active ingredients, strength dosage, routes of administration, appearance, usage, warnings, inactive ingredients, etc.

Product Label Table of Contents



1 Indications And Usage



KEVEYIS is indicated for the treatment of primary hyperkalemic periodic paralysis, primary hypokalemic periodic paralysis, and related variants.


2 Dosage And Administration




2.1 Dosage Information



Initiate dosing at 50 mg by mouth once or twice daily. The dosage may be increased or decreased based on individual response, at weekly intervals (or sooner in case of adverse reaction). The minimum recommended total daily dosage is 50 mg, and the maximum recommended total daily dosage is 200 mg.


2.2 Monitoring To Assess Effectiveness



Primary hyperkalemic periodic paralysis, primary hypokalemic periodic paralysis, and related variants are a heterogeneous group of conditions, for which the response to KEVEYIS may vary. Therefore, prescribers should evaluate the patient's response to KEVEYIS after 2 months of treatment to decide whether KEVEYIS should be continued.


2.3 Monitoring To Assess Safety



Baseline and periodic measurements of serum potassium and serum bicarbonate during KEVEYIS treatment is recommended [see Warnings and Precautions (5.3, 5.4)].


3 Dosage Forms And Strengths



Round, white tablets, scored on one side, engraved with "D" above the score and "50" below the score, the other side is plain, 50 mg each.


4 Contraindications



KEVEYIS is contraindicated in the following circumstances:

5.1 Hypersensitivity And Other Life-Threatening Reactions



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



Carbonic anhydrase inhibitors, including KEVEYIS, can cause metabolic acidosis [see Warnings and Precautions (5.4)] , 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



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 [see Drug Interactions (7.3)] .

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



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 [see Drug Interactions (7.4)] .


5.5 Falls



KEVEYIS increases the risk of falls. The risk of falls is greater in the elderly and with higher doses of KEVEYIS. Consider dose reduction or discontinuation of KEVEYIS in patients who experience falls while treated with KEVEYIS.


6 Adverse Reactions



The following serious adverse reactions are described elsewhere in labeling:

6.1 Clinical Trials Experience



Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

In a 9-week randomized controlled trial in adults with hyperkalemic or hypokalemic periodic paralysis (Study 1), the most common adverse reactions in patients treated with KEVEYIS, with rates greater than placebo, were paresthesia, cognitive disorder, dysgeusia, and confusional state. The mean dose of KEVEYIS was 94 mg/day in patients with hypokalemic periodic paralysis and 82 mg/day in patients with hyperkalemic periodic paralysis.

Table 1 lists the incidence of adverse reactions that occurred in ≥ 5% of patients treated with KEVEYIS and more commonly than in patients treated with placebo in Study 1.

Table 1: Adverse Reactions in Patients Treated with KEVEYIS with Incidence ≥ 5% and more common than in Patients Treated with Placebo in Study 1
Adverse ReactionKEVEYIS
N = 36
(%)
Placebo
N = 29
(%)
Nervous system disordersParesthesia4414
Cognitive disorder

Cognitive disorder combined cases with the preferred terms of cognitive disorder, disturbance in attention, and mental impairment.

147
Dysgeusia140
Confusional state110
Headache87
Hypoesthesia80
Lethargy80
Dizziness60
Gastrointestinal disordersDiarrhea63
Nausea60
General disorders and administration site conditionsFatigue80
Malaise60
InvestigationsWeight decreased60
Musculoskeletal and connective tissue disordersMuscle spasms80
Arthralgia63
Muscle twitching60
RespiratoryDyspnea60
Pharyngolaryngeal pain60
SkinRash80
Pruritus60


6.2 Postmarketing Experience



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 [see Clinical Trials Experience (6.1)] : amnesia, cardiac failure, condition aggravated, convulsion, hallucination, nephrolithiasis, pancytopenia, psychotic disorder, renal tubular necrosis, stupor, syncope, tremor.


7.1 Aspirin And Other Salicylates



Carbonic anhydrase inhibitors, including KEVEYIS, can cause metabolic acidosis [see Warnings and Precautions (5.2, 5.4)], 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 [see Contraindications (4) and Warnings and Precautions (5.2)].


7.2 Drugs That Are Substrates Of Organic Anion Transporter1 (Oat1)



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 [see Clinical Pharmacology (12.3)].


7.3 Drugs That Cause Hypokalemia



The risk of hypokalemia is greater with coadministration of KEVEYIS and other drugs that can cause hypokalemia (e.g., loop diuretics, thiazide diuretics, laxatives, antifungals, penicillins, and theophylline) [see Warnings and Precautions (5.3)] .


7.4 Drugs That Cause Metabolic Acidosis



Coadministration of KEVEYIS and other drugs that can cause metabolic acidosis may increase the severity of the acidosis [see Warnings and Precautions (5.4)].


7.5 Drugs That Are Inhibitors Of Oat1 Or Oat3



An in vitro transporter study indicated that dichlorphenamide is a substrate of human transporters OAT1 and OAT3 [see Clinical Pharmacology (12.3)] . Therefore, signs of dichlorphenamide toxicity should be monitored when administered with OAT1 or OAT3 inhibitors.


Other



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 [see Warnings and Precautions (5.4)]. 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/m 2) basis. A no-effect dose for adverse effects on embryofetal development has not been established.

Study 1

Study 1 was a 9-week, double blind, placebo-controlled multi-center study. Study 1 consisted of two substudies: a substudy in patients with hypokalemic periodic paralysis (n=44), and a substudy in patients with hyperkalemic periodic paralysis (n=21). The primary efficacy endpoint in both substudies was the average number of self-reported attacks of muscle weakness per week over the final 8 weeks of the trial. Withdrawal from the study for acute severe worsening (increase in attack frequency or severity) was also assessed as an endpoint.

In Study 1, the dose of KEVEYIS was 50 mg b.i.d. for treatment-naïve patients. Patients already on dichlorphenamide prior to the study continued on the same dose while on KEVEYIS during the study. In patients taking acetazolamide prior to the study, the dose of KEVEYIS was set at 20% of the acetazolamide dose. Dose reduction for tolerability was permitted.

Hypokalemic Periodic Paralysis Substudy of Study 1

In the hypokalemic periodic paralysis substudy, median age of patients was 45 years and 73% of patients were male. Patients treated with KEVEYIS (n=24) had 2.2 fewer attacks per week than patients (n=20) treated with placebo (p=0.02). None of the patients randomized to KEVEYIS reached the endpoint of withdrawal from the study for acute worsening, vs. five patients randomized to placebo. The mean dose of KEVEYIS at Week 9 was 94 mg/day.

Hyperkalemic Periodic Paralysis Substudy of Study 1

In the Hyperkalemic Periodic Paralysis substudy, median age of patients was 43 years and 43% of patients were male. During the double-blind treatment period, patients treated with KEVEYIS (n=12) had 3.9 fewer attacks per week than patients (n=9) treated with placebo (p=0.08). None of the patients randomized to KEVEYIS reached the endpoint of withdrawal from the study for acute worsening, vs. two patients randomized to placebo. The mean dose of KEVEYIS at Week 9 was 82 mg/day.

Study 2

Study 2 was a 35-week, double blind, placebo-controlled, multi-center, two-period crossover study. Study 2 also consisted of two substudies: a substudy in patients with hypokalemic periodic paralysis (n=42), and a substudy in patients with hyperkalemic periodic paralysis (n=31), including patients with Paramyotonia Congenita. The primary endpoint in the hypokalemic periodic paralysis substudy was the incidence of acute intolerable worsening (based on attack frequency or severity) necessitating withdrawal. The primary endpoint in the hyperkalemic periodic paralysis substudy was the average number of self-reported attacks of muscle weakness per week. Dosing was determined similarly to Study 1.

Hypokalemic Periodic Paralysis Substudy of Study 2

The hypokalemic periodic paralysis substudy included patients with a mean age of 38 years; 79% of patients were male. Acute intolerable worsening was observed in 2 patients on KEVEYIS vs. 11 patients on placebo (p=0.02). The mean dose of KEVEYIS at the end of the study was 96 mg/day.

Hyperkalemic Periodic Paralysis Substudy of Study 2

The hyperkalemic periodic paralysis substudy included patients with a mean age of 37 years; and 79% of patients were male. Patients treated had 2.3 fewer attacks per week on KEVEYIS than on placebo (p=0.006). The mean dose of KEVEYIS at the end of the study was 73 mg/day.

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 [see Warnings and Precautions (5.1)].

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 [see Drug Interactions (7.1, 7.2, 7.3, 7.4)].

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) [see Warnings and Precautions (5.4)].

Falls
Inform patients that KEVEYIS can increase their risk of falls [see Warnings and Precautions (5.5)].

Cognitive Impairment
Advise patients to notify their healthcare provider if they experience symptoms of cognitive impairment including confusion and memory lapse [see Adverse Reactions (6.1)].

Driving and Operating Machinery
KEVEYIS may cause drowsiness/fatigue in some patients [see Adverse Reactions (6.1)] . Caution patients on the potential for impaired ability to drive and operate machinery.

Manufactured by: Taro Pharmaceutical Industries Ltd., Haifa Bay, Israel 2624761

Distributed by: Xeris Pharmaceuticals, Inc., Chicago, IL 60601

KEVEYIS® is a registered trademark licensed exclusively in the US to Xeris Pharmaceuticals, Inc., a subsidiary of Xeris Biopharma, Inc.

XERIS PHARMACEUTICALS® and its associated logo are trademarks of Xeris Pharmaceuticals, Inc.

Copyright © 2021 Xeris Pharmaceuticals, Inc. All rights reserved.

5200904-1021-02


8.2 Lactation



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.


8.4 Pediatric Use



Safety and effectiveness of KEVEYIS in pediatric patients have not been established.


8.5 Geriatric Use



The risk of falls and of metabolic acidosis are greater in elderly patients [see Warnings and Precautions (5.4, 5.5)] ​.


10 Overdosage



Symptoms of overdosage or toxicity may include drowsiness, anorexia, nausea, vomiting, dizziness, ataxia, tremor, and tinnitus.

In the event of overdosage, induce emesis or perform gastric lavage. The electrolyte disturbances most likely to be encountered from overdosage are hypokalemia and hyperchloremic metabolic acidosis.


11 Description



KEVEYIS tablets contain dichlorphenamide, an oral carbonic anhydrase inhibitor. Dichlorphenamide, a dichlorinated benzenedisulfonamide, is known chemically as 4, 5–dichloro-1,3-benzenedisulfonamide.

Its empirical formula is C 6H 6Cl 2N 2O 4S 2 and its structural formula is:

Dichlorphenamide USP is a white or practically white, crystalline compound with a molecular weight of 305.16. It is very slightly soluble in water but soluble in dilute solutions of sodium carbonate and sodium hydroxide. Dilute alkaline solutions of dichlorphenamide are stable at room temperature.

KEVEYIS (dichlorphenamide) tablets are supplied as tablets, for oral administration, each containing 50 mg dichlorphenamide. Inactive ingredients are lactose monohydrate, magnesium stearate and pregelatinized starch.


12.1 Mechanism Of Action



Dichlorphenamide is a carbonic anhydrase inhibitor. However, the precise mechanism by which dichlorphenamide exerts its therapeutic effects in patients with primary periodic paralysis is unknown.


12.2 Pharmacodynamics



KEVEYIS can cause metabolic acidosis, which can increase the risk of salicylate toxicity with coadministration [see Warnings and Precautions (5.2)]. KEVEYIS-induced metabolic acidosis can also increase in severity with coadministration of other drugs that cause metabolic acidosis [see Warnings and Precautions (5.4)].


12.3 Pharmacokinetics



After single-dose administration in healthy subjects in fasted state, dichlorphenamide C max and AUC increased in a dose-proportional manner within the range of 25 mg to 400 mg (2 times the maximum recommended dose). The steady-state is expected to be achieved within 10 days of twice-daily dosing.

Absorption
The median time to reach maximum concentration (T max) of dichlorphenamide was about 1.5 to 3 hours postdose after both single and multiple dose administrations.

Distribution
The plasma protein binding of dichlorphenamide is approximately 88%.

Elimination
Following a single-dose administration, mean terminal half-life was in the range of 32 to 66 hours.

Metabolism
Dichlorphenamide is not a substrate for CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 and CYP3A4 isoforms when tested in vitro.

Drug Interaction Studies

In vitro Assessment of Drug Interactions

Drug-Metabolizing Enzyme Inhibition
Dichlorphenamide is not an inhibitor for CYP1A2, 2B6, 2C8, 2C9, 2C19, 2D6, or 3A4 enzymes when tested in vitro.

Drug-Metabolizing Enzyme Induction
Dichlorphenamide is not an inducer for CYP1A2, 2B6, or 3A4 enzymes when tested in vitro.

In vitro Assessment of Transporter-Drug Interactions
Dichlorphenamide is neither a substrate nor inhibitor for p-gp, BCRP, OATP1B1, OATP1B3, OAT2, OAT4, OCT1, OCT2, MATE1, or MATE2-K when tested in vitro.

Dichlorphenamide is not an inhibitor of OAT3, but is an inhibitor of OAT1 based on in vitro studies [see Drug Interactions (7.4)].

Dichlorphenamide is a substrate for transporters OAT1 and OAT3 based on in vitro studies [see Drug Interactions (7.2)] .

In Vivo Drug Interactions
The use of dichlorphenamide in combination with high-dose aspirin is contraindicated as it may lead to salicylate toxicity. The mechanism(s) of this interaction is not known.

Specific Populations
Geriatrics
The pharmacokinetics of dichlorphenamide in the elderly has not been determined.


Carcinogenesis & Mutagenesis & Impairment Of Fertility



Carcinogenesis

Studies to assess the carcinogenic potential of dichlorphenamide have not been conducted.

Mutagenesis

Studies to assess the genotoxicity of dichlorphenamide have not been conducted.

Impairment of Fertility

Studies to assess the effects of dichlorphenamide on fertility have not been conducted.


14 Clinical Studies



The efficacy of KEVEYIS was evaluated in two clinical studies, Study 1 and Study 2.


16 How Supplied/Storage And Handling



Each KEVEYIS (dichlorphenamide) tablet, 50 mg is round, white, scored on one side, engraved with "D" above the score and "50" below the score. The other side is plain.

KEVEYIS (dichlorphenamide) tablets are supplied as follows:

Bottles of 100......................................NDC 72065-001-01


Storage And Handling



Store at 20°C to 25°C (68°F to 77°F) [See USP Controlled Room Temperature].


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