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.

ZONEGRAN (NDA-020789)

(ZONISAMIDE)

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

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04/13/2020 (SUPPL-36)

Approved Drug Label (PDF)

5 Warnings and Precautions

PRECAUTIONS

(Additions and/or revisions underlined)

…

Information for Patients: Inform patients of the availability of a Medication Guide, and instruct them to read the Medication Guide prior to taking ZONEGRAN. Instruct patients to take ZONEGRAN only as prescribed.

Advise patients as follows: (See Medication Guide)

ZONEGRAN may produce drowsiness, especially at higher doses. Patients should be advised not to drive a car or operate other complex machinery until they have gained experience on ZONEGRAN sufficient to determine whether it affects their performance. Because of the potential of zonisamide to cause CNS depression, as well as other cognitive and/or neuropsychiatric adverse events, ZONEGRAN should be used with caution if used in combination with alcohol or other CNS depressants.
Patients should contact their physicians immediately if a skin rash develops.
Instruct patients to seek immediate medical attention if they experience blurred vision, visual disturbances, or periorbital pain.
Patients should contact their physician immediately if they develop signs or symptoms, such as sudden back pain, abdominal pain, and/or blood in the urine, that could indicate a kidney stone. Increasing fluid intake and urine output may reduce the risk of stone formation, particularly in those with predisposing risk factors for stones.
Patients should contact their physician immediately if a child has been taking ZONEGRAN and is not sweating as usual with or without a fever.
Because zonisamide can cause hematological complications, patients should contact their physician immediately if they develop a fever, sore throat, oral ulcers, or easy bruising
Counsel patients and caregivers that AEDs, including ZONEGRAN, may increase the risk of suicidal thoughts and behavior and advise them of the need to be alert for the emergence or worsening of symptoms of depression, any unusual changes in mood or behavior, or the emergence of suicidal thoughts, behavior, or thoughts about self-harm. Behaviors of concern should be reported immediately to healthcare providers.
Warn patients about the possible development of hyperammonemia with or without encephalopathy. Although hyperammonemia may be asymptomatic, clinical symptoms of hyperammonemic encephalopathy often include acute alterations in level of consciousness and/or cognitive function with lethargy and/or vomiting. Instruct patients to contact their physician if they develop unexplained lethargy, vomiting, or changes in mental status.
Patients should contact their physician immediately if they develop fast breathing, fatigue/tiredness, loss of appetite, or irregular heart beat or palpitations, which are possible manifestations of metabolic acidosis.
As with other AEDs, patients should contact their physician if they intend to become pregnant or are pregnant during ZONEGRAN therapy. Patients should notify their physician if they intend to breast-feed or are breast-feeding an infant.
Encourage patients to enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry if they become pregnant. This registry is collecting information about the safety of antiepileptic drugs during pregnancy. To enroll, patients can call the toll-free number 1-888-233-2334.

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Other Carbonic Anhydrase Inhibitors: Concomitant use of ZONEGRAN, a carbonic anhydrase inhibitor, with any other carbonic anhydrase inhibitor (e.g., topiramate, acetazolamide or dichlorphenamide), may increase the severity of metabolic acidosis and may also increase the risk of kidney stone formation or the risk of hyperammonemia. Therefore, if ZONEGRAN is given concomitantly with another carbonic anhydrase inhibitor, the patient should be monitored for the appearance or worsening of metabolic acidosis.

WARNINGS

(Additions and/or revisions underlined)

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Acute Myopia and Secondary Angle Closure Glaucoma:

Acute myopia and secondary angle closure glaucoma have been reported in patients receiving ZONEGRAN. Elevated intraocular pressure can lead to serious sequelae, including permanent vision loss, if left untreated.

Symptoms in reported cases have included acute onset of decreased visual acuity and/or ocular pain. Ophthalmologic findings can include myopia, anterior chamber shallowing, ocular hyperemia (redness), and increased intraocular pressure. Mydriasis may or may not be present. This syndrome may be associated with ciliochoroidal effusion resulting in

anterior displacement of the lens and iris, with secondary angle closure glaucoma. Symptoms typically occur within one month after initiating ZONEGRAN therapy.

In contrast to primary narrow angle glaucoma, which is rare under 40 years of age, secondary angle closure glaucoma associated with ZONEGRAN has been reported both in pediatric patients and in adults. The primary treatment to reverse symptoms is discontinuation of ZONEGRAN as rapidly as possible, according to the judgment of the treating physician.

Other therapeutic measures, in conjunction with discontinuation of ZONEGRAN, may be helpful. Myopia and secondary angle closure glaucoma usually resolve or improve after discontinuation of ZONEGRAN.

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Metabolic Acidosis:

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Metabolic acidosis can also increase the risk for hyperammonemia, particularly in the presence of drugs which can cause hyperammonemia.

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Hyperammonemia and Encephalopathy:

Hyperammonemia and encephalopathy have been reported with the postmarketing use of zonisamide. Zonisamide treatment inhibits carbonic anhydrase activity, which may cause metabolic acidosis that is associated with an increased risk for developing hyperammonemia. Hyperammonemia resulting from zonisamide can also be asymptomatic.

The risks of hyperammonemia and various manifestations of encephalopathy may be increased in patients treated with zonisamide and concomitantly taking other medications that can cause hyperammonemia, including valproic acid or topiramate.

Patients with inborn errors of metabolism or reduced hepatic mitochondrial activity may be at an increased risk for hyperammonemia with or without encephalopathy and this risk may be increased by zonisamide use.

Measure serum ammonia concentration if signs or symptoms (e.g., unexplained change in mental status, vomiting, or lethargy) of encephalopathy occur. Hyperammonemia resulting from zonisamide resolves when zonisamide is discontinued. Hyperammonemia from zonisamide may resolve or decrease in severity with a decrease of the daily dose.

6 Adverse Reactions

Postmarketing Experience

(Additions and/or revisions underlined)

The following serious adverse reactions have been reported since approval and use of ZONEGRAN worldwide. These reactions are reported voluntarily from a population of uncertain size; therefore, it is not possible to estimate their frequency or establish a causal relationship to drug exposure.

Acute pancreatitis, rhabdomyolysis, increased creatine phosphokinase, drug reaction with eosinophilia and systemic symptoms (DRESS), acute myopia and secondary angle closure glaucoma, and hyperammonemia and encephalopathy.

8 Use in Specific Populations

(Additions and/or revisions underlined)

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Pediatric Use: The safety and effectiveness of ZONEGRAN in children under age 16 have not been established. Acute myopia and secondary angle closure glaucoma have been reported in pediatric patients. Cases of oligohidrosis and hyperpyrexia have been reported.

Zonisamide commonly causes metabolic acidosis in pediatric patients. Hyperammonemia with encephalopathy has been reported in pediatric patients. Chronic untreated metabolic acidosis in pediatric patients may cause nephrolithiasis and/or nephrocalcinosis, osteoporosis and/or osteomalacia (potentially resulting in rickets), and may reduce growth rates. A reduction in growth rate may eventually decrease the maximal height achieved. The effect of zonisamide on growth and bone-related sequelae has not been systematically investigated.

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

MEDICATION GUIDE

(Additions and/or revisions underlined)

What is the most important information I should know about ZONEGRAN?

ZONEGRAN may cause serious side effects, including:

Serious skin rash that can cause death.
Serious allergic reactions that may affect different parts of the body.
Less sweating and increase in your body temperature (fever).
Serious eye problems
Suicidal thoughts or actions in some people.
Increased level of acid in your blood (metabolic acidosis).
Problems with your concentration, attention, memory, thinking, speech, or language.
Blood cell changes such as reduced red and white blood cell counts.

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4. ZONEGRAN may cause eye problems. Serious eye problems include:

sudden decrease in vision with or without eye pain and redness
a blockage of fluid in the eye causing increased pressure in the eye (secondary angle closure glaucoma)

These eye problems can lead to permanent loss of vision if not treated.

Call your healthcare provider right away if you have any new eye symptoms, including any eye pain or redness or any new problems with your vision.

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Before taking ZONEGRAN, tell your healthcare provider about all your medical conditions, including if you:

have or have had depression, mood problems or suicidal thoughts or behavior
have kidney problems
have liver problems
have a history of metabolic acidosis (too much acid in your blood)
have weak, brittle bones or soft bones (osteomalacia, osteopenia or osteoporosis)
have a growth problem
are on a diet high in fat called a ketogenic diet
have diarrhea
have high blood levels of ammonia

…

Other serious side effects include:

kidney stones: Back pain, stomach pain, or blood in your urine may mean you have kidney stones. Drink plenty of fluids while you take ZONEGRAN to lower your chance of getting kidney stones.

problems with mood or thinking (new or worse depression; sudden changes in mood, behavior, or loss of contact with reality, sometimes associated with hearing voices or seeing things that are not really there; feeling sleepy or tired; trouble concentrating; speech and language problems). Call your healthcare provider right away if you have any of the symptoms listed above.

high blood ammonia levels. High ammonia in the blood can affect your mental activities, slow your alertness, make you feel tired, or cause vomiting.

04/06/2016 (SUPPL-34)

Approved Drug Label (PDF)

5 Warnings and Precautions

Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)/Multi-Organ Hypersensitivity: Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), also known as multi-organ hypersensitivity, has occurred with ZONEGRAN. Some of these events have been fatal or life-threatening. DRESS typically, although not exclusively, presents with fever, rash, lymphadenopathy and/or facial swelling, in association with other organ system involvement, such as hepatitis, nephritis, hematologic abnormalities, myocarditis, or myositis, sometimes resembling an acute viral infection. Eosinophilia is often present. This disorder is variable in its expression, and other organ systems not noted here may be involved. It is important to note that early manifestations of hypersensitivity (e.g., fever, lymphadenopathy) may be present even though rash is not evident. If such signs or symptoms are present, the patient should be evaluated immediately. ZONEGRAN should be discontinued if an alternative etiology for the signs or symptoms cannot be established.