Medication Profile - Zonegran Off-Label Use for Migraine

Patient Expert

There's a wide variety of medications used for Migraine, most of which are prescribed off-label. If Zonegran (zonisamide) has been prescribed for you, or if you and your doctor have been considering it, here's some information that should be helpful.

Type of medication:

Zonisamide, brand name Zonegran, is in a class of medications called carbonic anhydrase inhibitor anticonvulsants. Zonegran also has sulfa properties in it and can be prescribed off-label for Migraine and headache prevention. Other medications in this class include Topamax and Diamox.


Zonisamide can be used for the adjunctive treatment for partial epilepsy in adults and other disorders as determined by your doctor. The Food and Drug Administration (FDA) has determined that treatment with zonisamide can cause metabolic acidosis in some patients. Zonisamide is indicated as adjunctive therapy in the treatment of partial seizures in adults with epilepsy.

Metabolic acidosis is a disturbance in the body's acid-base balance that results in excessive acidity of the blood. Metabolic acidosis is diagnosed by laboratory tests measuring the serum bicarbonate level in the blood to determine the presence and severity of metabolic acidosis.

Metabolic acidosis can result in hyperventilation, and non-specific symptoms such as fatigue and anorexia, or more severe symptoms including cardiac arrhythmias or stupor. Chronic metabolic acidosis can have adverse effects on the kidneys and on bones, and can retard growth in children. Patients with predisposing conditions or therapies, including renal disease, severe respiratory disorders, diarrhea, surgery, ketogenic diet, or certain other drugs may be at greater risk for developing metabolic acidosis following treatment with zonisamide. The risk of zonisamide-induced metabolic acidosis appears to be more frequent and severe in younger patients.

The FDA recommends that healthcare professionals measure serum bicarbonate before starting treatment and periodically during treatment with zonisamide, even in the absence of symptoms. If metabolic acidosis develops and persists, consideration should be given to reducing the dose or discontinuing zonisamide (using dose tapering), and modifying the patient's antiepileptic treatment as appropriate. If the decision is made to continue patients with metabolic acidosis on zonisamide, then alkali treatment should be considered.

The FDA is working with the makers of zonisamide to revise the product labeling to reflect this new safety information. ¹


  • If you are allergic to zonisamide or sulfa medications, do not use this drug.

  • Some anticonvulsant medications may cause people to be irritable, agitated or show other abnormal behaviors. It may also cause you to become more depressed or have suicidal thought and tendencies. If you have any of these side effects, please tell your doctor right away.

  • If you are depressed or have a history of depression, caution should be used when taking zonisamide.

  • If you develop a skin rash while taking zonisamide, get in touch with your doctor right away.

  • Metabolic acidosis may occur when taking zonisamide. This risk may be higher is children and people who have serious breathing issues, status epilepticus, people with kidney issues and those taking certain medications, having surgery and being on a ketogenic diet. It is important to contact your doctor right away if you have any breathing that is too fast, abnormal weakness or tiredness, fainting, loss of appetite or irregular heartbeat.

  • Caution is advised when taking zonisamide if you have kidney problems or failure, or liver problems.

  • The elderly population may be more sensitive to it effects and caution must be used when taking it.

  • Effective birth control is a must for those women taking zonisamide.

  • Tremendous caution must be utilized when using zonisamide in children under 16-years-old as the efficacy and safety is not totally understood. Children may be at an increased risk of low growth, kidney stones, increased risk of heat stroke and metabolic acidosis.

  • Do not stop this medication abruptly, even if you are feeling good, as you may have very unpleasant withdrawal symptoms that may include seizures. You may need to slowly taper off zonisamide.

  • Please keep all regularly scheduled doctors visits while taking zonisamide, your doctor will need to check you to make sure you are tolerating it.

  • Zonisamide may weaken your thinking and reaction time; care must be used when operating machinery, a car or anything that needs attentiveness.

  • Do not take any other medication, prescription, over-the-counter medications and/or herbal supplements unless you have discussed them with your doctor.

  • If you are having surgery including dental work, let the doctor who is performing the surgery know you are taking zonisamide.

  • Zonisamide can cause and increase in drowsiness, dizziness and/or vision issues and alcohol and/or certain other medications may make them worse.

  • Decreased sweating may occur when taking zonisamide, which can raise the risk of heat stroke, namely in children. Take care to drink plenty of water, especially during exercise and hot weather, and look for signs of decreased sweating. Treat any signs of decreased sweating by getting to a cooler spot. If signs of unexplained fever, headache, mood changes and dizziness occur get medical help right away.

** Pregnancy and Breastfeeding:**

  • FDA Pregnancy Category C: This generally means there are no sufficient studies done on pregnant women OR no animal studies have been conducted. However, for zonisamide, it may cause metabolic acidosis which can harm a fetus. In animal studies zonisamide has been shown to cause birth defects and infant death.
  • Inform your doctor if you are or are planning to become pregnant. He may want you to join a pregnancy registry for pregnant patients taking anticonvulsant medications.
  • Breastfeeding is not suggesting while taking zonisamide. It can pass into breast milk and harm a baby who is nursing.

Other medical conditions:

Be sure to let your doctor know of other medical problems you may have, especially:

  • a bone disorder causing low bone mineral density or soft or weak bones;
  • a history of a growth disorder;
  • any history of being on a higher protein and/or lower carbohydrate diet;
  • any history of stomach flu or illness that causes diarrhea;
  • any history of suicidal ideation;
  • asthma or other breathing issues;
  • kidney disease;
  • liver disease;
  • thrombocytopenia - low platelet count - use zonisamide with caution it may make these conditions worse.

Other medications:

Be sure to let your doctor know of ALL medications you are taking, especially;

  • anticholinergics
  • any supplements
  • aspirin
  • carbonic anhydrase inhibitors
  • cold and allergy medication
  • sleeping pills

The following medications should be avoided when taking zonisamide:

  • conivaptan
  • ginkgo
  • ophthalmologic carbonic anhydrase inhibitors

Medications that need to be monitored closely while taking zonisamide:

  • bosentan
  • sevelamer
  • systemic carbonic anhydrase inhibitors
  • topiramate

Please use caution when taking zonisamide and the following medications:

  • acetaminophen and acetaminophen combinations

  • aldesleukin

  • all benzodiazepines

  • amiodarone

  • anticholinergics

  • antidepressants

  • antihistamine and decongestant combinations

  • aprepitant

  • aripiprazole

  • artemether/lumefantrien

  • asenapine

  • aspirin and aspirin combinations

  • azole antifungals

  • baclofen and baclofen intrathecal

  • barbiturates

  • bexarotene

  • boceprevir

  • brompheniramine and brompheniramine combinations

  • butalbital and butalbital combinations

  • calendula

  • cannabinoids

  • capsicum

  • carbamazepine

  • carisoprodol

  • carisoprodol/aspirin

  • cetirizine

  • chlorpheniramine and chlorpheniramine combinations

  • chlorzoxazone

  • ciprofloxacin

  • clarithromycin

  • German chamomile

  • nasal azelastine

  • sedating antihistamines

  • all MAOI's

  • clozapine

  • cobicistat

  • crizotinib

  • cyclobenzaprine

  • danazol

  • darifenacin

  • delavirdine

  • dexmedetomidine

  • dihydrocodeine/aspirin/caffeine

  • diltiazem

  • disopyramide

  • doxylamine/dextromethorphan

  • droperidol

  • efavirenz

  • efavirenz/emtricitabine/tenofovir disoproxil

  • enzalutamide

  • ephedra

  • ephedrine

  • erthromycin

  • ethanol

  • ethosuximide

  • ezogabine

  • fluvoxamine

  • gabapentin

  • goldenseal

  • gotu kola

  • griseofulvin

  • hawthorn

  • HIV protease inhibitors

  • hydrocodone and hydrocodone combinations

  • iloperidone

  • imatinib

  • kava

  • lemon balm

  • levocetirizine

  • linagliptin/metformin

  • loxapine

  • lurasidone

  • meprobamate

  • metaxalone

  • Siberian ginseng

  • metformin/sulfonylurea and metformin combinations

  • methacarbamol

  • methadone

  • metoclopramide

  • mitotane

  • modafinil

  • nasal olopatadine

  • nefazodone

  • nevirapine

  • NSAID/chlorpheniramine/pseudoephedrine combination

  • NSAID/diphenhydramine combinations

  • olanzapine

  • opiate agonist-antagonists

  • opiate/acetaminophen combinations

  • opiate/aspirin combinations

  • opiates

  • orphenadrine

  • oxcarbazepine

  • oxycodone/ibuprofen

  • paliperidone

  • passionflower

  • pheniramine/dextromethorphan/phenylephrine

  • phenobarbital/hyoscyamine/atropine/scopolamine

  • phenothiazines

  • phenytoin

  • pimozide

  • pramipexole

  • pregabalin

  • promethazine/codeine

  • propofol

  • propoxyphene

  • propoxyphene/acetaminophen

  • quetiapine

  • quinqpristin/dalfopristin

  • rifabutin

  • rifampins

  • rifapentine

  • risperidone

  • ropinirole

  • rufinamide

  • saxagliptin/metformin

  • transdermal rotigotine

  • sedatives and hypnotics

  • sitagliptin/metformin

  • sodium oxybate

  • solifenacin

  • somatropin

  • St. John's wort

  • tapentadol

  • telaprevir

  • telithromycin

  • tesamorelin

  • tetrabenazine

  • thalidomide

  • thiothixene

  • tizanidine

  • tramadol

  • tramadol/acetaminophen

  • tricyclic antidepressants

  • valerian

  • valproic acid

  • verapamils

  • vigabatrin

  • ziconotide

  • ziprasidone

Potential side effects:Please take immediate action and get emergency medical attention if you have any of the following indications you may be having an allergic reaction to this medication:

  • any swelling of your face, lips, tongue and/or throat;
  • hard time breathing;
  • hive;
  • skin rash.

Call the doctor right away and stop taking zonisamide if you experience any of these potential serious side effects:

  • blistering, peeling, or shedding of skin, the chills, a cough, diarrhea, itching, joint or muscle pain, reddish skin wounds that many times have a purple center, sores, ulcers and/or white spots in your mouth or on your lips. This may be Stevens-Johnson syndrome - a rare painful disorder starting with flu type symptoms and moving onto a painful purple or red rash which spreads and blisters making the skin to die and fall off.
  • Toxic epidermal necrolysis - some researchers believe this is a more serious form of Stevens-Johnson syndrome.

Contact your doctor if you experience any new or worsening symptoms including:

  • anxiety and/or panic attacks;

  • changes in mood or behavior;

  • feeling more depressed, thoughts of hurting yourself or others or suicide;

  • hostility;

  • nervousness, restlessness, and mentally or physically hyperactive.

Additional potential serious side effects that may occur while taking zonisamide and need to be discussed with your doctor include:

  • aplastic anemia;
  • blood in urine or severe low back pain or not being able to urinate;
  • decreased appetite;
  • fatigue;
  • feeling faint or having shortness of breath, a rapid heart rate, pale skin or trouble concentrating, especially in a hot tub or hot shower;
  • feelings of sadness, emptiness or being discouraged;
  • heat stroke;
  • stopping zonisamide suddenly may increase withdrawal seizures;
  • increasing or worsening of seizures;
  • kidney stones;
  • lack of sweating;
  • metabolic acidosis;
  • moodiness or changes in mental status;
  • not being able to find pleasure in or the loss of interest in things;
  • notable increase in body temperature;
  • pancreatitis;
  • problems with bone marrow not making enough white blood cells;
  • problems with depression;
  • psychosis;
  • rhabdomyolysis - breakdown of muscle fibers which starts the discharge of muscle fibers in the bloodstream. This may lead to kidney problems;
  • short-tempered;
  • status epilepticus;
  • suicidal ideation;
  • trouble sleeping and concentrating.

Less serious potential side effects while taking zonisamide may include:

  • achy muscle or joints;
  • blue or purple patches on skin;
  • burping;
  • constipation and/or diarrhea;
  • foul taste in the mouth and/or changes in taste;
  • hallucinations and delusions;
  • hard time speaking and/or thinking, mentally slowed down;
  • malaise, fever, chills, sneezing, runny or stuffy nose;
  • mouth dryness;
  • upset stomach, heartburn, indigestion;
  • weight loss.

Brand names:

  • U.S.: Zonegran

Related Information:* ** Migraine preventive medications - too many options to give up!*** ** Preventive, Abortive, and Rescue Medications - What's the Difference?*** ** The Evolving Role of Migraine Prevention - Video**


¹Post Market Drug Safety Information for Patients and Providers."Information for Healthcare Professionals: Zonisamide (marketed as Zonegran, and generics)." FDA. Last updated July 29, 2009.

Cerner Multum, Inc. "Zonisamide." Last revised March 9, 2012.

Foster, Stephen C, MD, FACS, FACR, FAAO; Roy, Hampton, MD. "Stevens-Johnson Syndrome." Medscape. Last updated November 27, 2012.

Wolters Kluwer. "Zonisamide." Drugs.Com. Last revised February 6, 2013.

Wolters Kluwer."Rhabdomyolysis." Drugs.Com. Last revised February 6, 2013.

The material on this page is for informational purposes only, and should not be construed as medical advice. This is an abbreviated medication profile. For complete information, always consult your physician or pharmacist regarding medications.

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© The HealthCentral Network, 2013 Last Updated February 19, 2013.