Topiramate: Limit Use to Treatment of Seizures, Do Not Use for Other Conditions

Topiramate (TOPAMAX, TROKENDI XR) is a second-generation antiepileptic drug that was originally approved by the Food and Drug Administration (FDA) in 1996 as an adjunctive treatment (add-on treatment used in combination with another, first-line antiepileptic drug) for partial-onset seizures in adults.[2]

By 2011, the FDA-approved uses of the drug had expanded to include initial primary monotherapy (singledrug) treatment in patients aged 2 years or older with partial-onset seizures, primary generalized tonicclonic seizures or seizures associated with Lennox-Gastaut syndrome.[3]

Public Citizen’s Health Research Group has designated topiramate as Limited Use for these types of seizure disorders because there are other, more effective first-line antiepileptic drug treatments available.[4] For example, carbamazepine (CARBATROL, EPITOL, EQUETRO, TEGRETOL, TERIL) and lamotrigine (LAMICTAL) are first-choice treatments in patients with partial-onset seizures.[5],[6] Topiramate, therefore, should be used only in patients who have failed to respond adequately to first-line antiepileptic drugs.

The FDA approved topiramate for the prevention of migraine headaches in adults in 2004[7] and in children age 12 or older in 2014.[8]

Public Citizen’s Health Research Group has designated topiramate as Do Not Use for this purpose because it has many serious adverse effects and, in contrast to epileptic seizures, migraine headaches are not imminently life-threatening.

Thus, topiramate should not be used for migraine prevention or for any uses not approved by the FDA (off-label uses), such as for weight loss or alcoholism.

Adverse effects similar to other antiepileptic drugs, but some more frequent

Alongside it not being a firstchoice drug for any type of seizure, topiramate is, like many antiepileptic drugs, associated with many serious adverse effects, including fetal toxicity, specifically cleft palate and low birth weight; psychiatric disorders, including depression, suicidal thoughts and aggressive behavior; and cognitive impairment.[9]

But evidence from pre-approval clinical trials indicates that some of these risks may be greater with topiramate. For example, among adult subjects with partial-onset or generalized tonic-clonic seizures, the incidence of memory problems was substantially greater in those taking topiramate in combination with older antiepileptic drugs (12 percent), including carbamazepine, than in those taking one or two other antiepileptic drugs (3 percent).[10] Likewise, in these same trials, confusion occurred in 11 percent of subjects receiving topiramate and 5 percent of subjects not receiving topiramate.

Clinical trials in children (ages 2 to 15 years) with partial-onset seizures, generalized tonic-clonic seizures or Lennox-Gastaut syndrome also documented topiramate’s greater risk of cognitive and psychiatric adverse effects, including difficulty concentrating, excessive sleepiness and aggressive behavior.[11]

Fetal toxicity caused by topiramate is also more worrisome given that this drug, like carbamazepine, can decrease the effectiveness of oral contraceptives, thereby resulting in unplanned pregnancies.[12] Lamotrigine is one of several antiepileptic drugs that do not appear to decrease the effectiveness of oral contraceptives.[13]

Serious adverse effects unique to topiramate

In 2003, the FDA required that the product labeling for topiramate be updated to include a warning about an increased risk of oligohidrosis (decreased sweating) and accompanying hyperthermia (elevated body temperature) associated with the use of the drug, especially among children.[14] This adverse effect is serious if left untreated and can lead to hospitalization or death.

Topiramate often causes metabolic acidosis (the accumulation of excess acid in the body) by impairing the ability of the kidneys to remove acid from the blood.[15] In randomized clinical trials testing topiramate as an add-on treatment to other antiepileptic drugs, 32 percent of topiramatetreated subjects had evidence of metabolic acidosis on routine blood tests, compared with only 1 percent of control subjects taking only other antiepileptic drugs.[16] Signs and symptoms of severe metabolic acidosis include rapid breathing, loss of appetite, fatigue, decreased consciousness and abnormal heart rhythms.

Prolonged metabolic acidosis from topiramate use also can lead to kidney stones, growth retardation and rickets (weakened, soft bones) in children, and osteoporosis in adults.[17] In addition, a post-approval study indicated that topiramate is associated with an increased risk of bone fractures, whereas lamotrigine and carbamazepine are not.[18]

Product labeling for topiramate warns about an increased risk of serious eye disorders in both children and adults treated with topiramate. In particular, the drug is associated with a type of glaucoma known as secondary angle closure glaucoma, which can impair vision and lead to permanent blindness if not treated.[19]

The product labeling also warns that the drug can cause hyperammonemia (high blood ammonia levels), which can lead to altered levels of consciousness, lethargy and vomiting.[20] This adverse effect is seen most commonly in patients who are also taking valproic acid.

Finally, topiramate is associated with an increased risk of low blood potassium levels and decreased kidney function.[21]

What You Can Do

You should only take topiramate for seizures if your seizure disorder has not been controlled adequately with other, first-line antiepileptic drugs. If you are taking it for migraine headaches or any other condition, talk to your doctor about switching to another treatment. Never stop taking topiramate without first talking to your doctor, as doing so suddenly could trigger seizures.

If you need to take the drug, be on alert for early signs and symptoms of adverse effects, including dizziness, fatigue, mental status changes including speech and language difficulties, loss of appetite, rapid breathing, severe pain in the back or groin possibly indicating kidney stones, blurred vision, eye pain or sudden development of nearsightedness, or — especially in children — decreased sweating and increased temperature. Notify your doctor immediately if you experience any of these adverse effects as you may need to be slowly tapered off topiramate.

Your doctor should monitor your blood acid levels before and regularly during treatment. If your child is being treated with topiramate, make sure he or she is well hydrated before and during strenuous activities, such as exercise, or exposure to warm temperatures.

References

[1] Janssen Pharmaceuticals. Drug label: topiramate tablets (TOPOMAX). May 2017. https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/020505s057_020844s048lbl.pdf. Accessed January 12, 2018.

[2] Food and Drug Administration. Approval Letter for NDA #20-505. December 24, 1996. https://www.accessdata.fda.gov/drugsatfda_docs/nda/96/020505_000_aprvl_ltr.pdf. Accessed January 12, 2018.

[3] Janssen Pharmaceuticals. Drug label: topiramate tablets (TOPOMAX). May 2017. https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/020505s057_020844s048lbl.pdf. Accessed January 12, 2018.

[4] National Clinical Guideline Centre (UK). Pharmacological Update of Clinical Guideline 20: The Epilepsies: The diagnosis and management of the epilepsies in adults and children in primary and secondary care. London: Royal College of Physicians (UK). January 2012. https://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0068980/pdf/PubMedHealth_PMH0068980.pdf. Accessed January 12, 2018.

[5] Drugs for epilepsy. Med Lett Drugs Ther. 2017;59(1526):121-130.

[6] Nevitt SJ, Sudell M, Weston J, et al. Antiepileptic drug monotherapy for epilepsy: a network meta-analysis of individual participant data. Cochrane Database Syst Rev. 2017 Dec 15;12:CD011412.

[7] Food and Drug Administration. Approval letter for NDAs 20-505/S-022 and 20-844/S-019 and NDAs 20-505/S-025 and 20-844/S-021. August 11, 2004. https://www.accessdata.fda.gov/drugsatfda_docs/appletter/2004/20505s022,025,20844s019,021ltr.pdf. Accessed January 13, 2018.

[8] Food and Drug Administration. Approval letter for NDA 20-505/S-052 and NDA 20-844/S-043. March 28, 2014. https://www.accessdata.fda.gov/drugsatfda_docs/appletter/2014/020505Orig1s052,020844Orig1s043ltr.pdf. Accessed January 13, 2018.

[9] Janssen Pharmaceuticals. Drug label: topiramate tablets (TOPOMAX). May 2017. https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/020505s057_020844s048lbl.pdf. Accessed January 12, 2018.

[10] Ibid.

[11] Ibid.

[12] Carl JS, Weaver SP, Tweed E, Edgerton L. Effect of antiepileptic drugs on oral contraceptives. Am Fam Physician. 2008;78(5):634-635. PubMed PMID: 18788241.

[13] Ibid.

[14] Food and Drug Administration. Approval letter for NDA 20-505/S-020 and NDA 20-844/S-017. June 12, 2003. https://www.accessdata.fda.gov/drugsatfda_docs/appletter/2003/20505slr020,20844slr017ltr.pdf. Accessed January 13, 2018.

[15] Janssen Pharmaceuticals. Drug label: topiramate tablets (TOPOMAX). May 2017. https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/020505s057_020844s048lbl.pdf. Accessed January 13, 2018.

[16] Metabolic acidosis due to topiramate. Prescrire Int. 2004 Oct;13(73):186.

[17] Janssen Pharmaceuticals. Drug label: topiramate tablets (TOPOMAX). May 2017. https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/020505s057_020844s048lbl.pdf. Accessed January 12, 2018.

[18] Shen C, Chen F, Zhang Y, et al. Association between use of antiepileptic drugs and fracture risk: a systematic review and meta-analysis. Bone. 2014 Jul;64:246-253.

[19] Janssen Pharmaceuticals. Drug label: topiramate tablets (TOPOMAX). May 2017. https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/020505s057_020844s048lbl.pdf. Accessed January 12, 2018.

[20] Ibid.

[21] Ibid.