Topiramate (Topamax)

Excerpt from Cafer's Mood Stabilizers and Antiepileptic Drugs

 Topiramate (TOPAMAX)

 toh PEER a mate / TOH pah max

“Top at max (speed on) Top (of) pyramid”

❖ Antiepileptic  

❖ Voltage-gated sodium and  calcium channel blocker  

❖ Glutamate ⇩
FDA approved for: 

❖ Focal seizures  

❖ Bilateral tonic-clonic seizures  

❖ Lennox-Gastaut syndrome 

❖ Migraine prophylaxis 

❖ Obesity, long-term tx 

(in combination with phentermine)
Used off label for:

❖ Alcoholism (relapse prevention) 

❖ Bipolar disorder (adjunct) 

❖ Weight loss (monotherapy) 

❖ Binge eating disorder 

❖ PTSD Nightmares

Topiramate is prescribed by psychiatrists for several off-label uses. The most compelling data is for preventing alcohol relapse. Although not FDA-approved for alcoholism, it is recommended in the 2015 US Veterans Affairs guidelines for moderate/severe alcohol use disorder. 

Nicknamed "Dopamax” or “Stupamax”, topiramate commonly causes cognitive problems including “brain fog”, psychomotor slowing, difficulty concentrating and word-finding difficulty. Cognitive impairment due to topiramate is reversible, and usually only problematic at doses over 200 mg daily. A patient taking 200 mg BID told the author that, at a stoplight, she had trouble remembering if green meant stop or go. The recommended dose for epilepsy is 200–400 mg daily. It can be dosed lower for other purposes. The starting dose for any purpose, except nightmares, is 25 mg BID (25 mg HS for nightmares).

The two AEDs prescribed by psychiatrists that are highly effective for migraine prophylaxis are topiramate and valproate (Depakote, Depakene). The recommended Topamax dose to prevent migraines is 50 mg BID, which is not expected to impair cognition. 

Paresthesia (tingling feelings) is common, and a favorable predictor of migraine prophylaxis. Dysgeusia (metallic taste) is possible.

Because topiramate is excreted unchanged in urine, there are few pharmacokinetic interactions. There are no genetic polymorphisms that affect its metabolism. In other words, no one is a poor metabolizer or ultrarapid metabolizer of topiramate.

Topiramate has undesirable carbonic anhydrase activity, hence alkalinizing urine and bringing a 15% risk of kidney stones with chronic use. 

Another consequence of the carbonic anhydrase activity is lowered blood pH (acidification) due to raised urine pH (alkalization). Evidence of lowered blood pH is seen on a metabolic panel as low bicarbonate, which is listed as CO2. Signs of metabolic acidosis (serum bicarbonate < 20 mmol/L) include tachycardia, headache, confusion, fatigue, nausea, and vomiting. Chronic acidosis can contribute to osteoporosis. 

Topiramate is commonly prescribed off-label as an appetite suppressant. Topiramate ER is available in a fixed-dose combination with phentermine (appetite-suppressing stimulant) branded as Qsymia ($190) for long-term treatment of obesity. Qsymia is available only from certified pharmacies and certified prescribers to ensure female patients are counseled on the risk of birth defects. Topiramate itself increases the risk of oral clefts 4-fold. 

Dosing: For nightmares, start 25 mg HS and go to 50 mg HS if necessary. For migraine prophylaxis or obesity, give 25 mg BID x 1 week then 50 mg BID. The maintenance dose for seizure disorders is 100–200 mg BID. Since topiramate impairs cognition when dosed 200 mg/day or higher, for other psychiatric uses try not to exceed 100 mg BID. For alcoholism titrate to 100 mg BID. Extended release formulations of topiramate (Trokendi XR, Qudexy XR) can be dosed once daily. 

Dynamic interactions:  ❖ Sedation/CNS depression ❖ Increased risk of hyperammonemia with valproic acid (Depakene, Depakote) ❖  Increased risk of hypokalemia with hydrochlorothiazide (HCTZ) ❖ Increased risk of acidosis with metformin, which also decreases bicarb (CO2). Keep this in mind when prescribing weight loss medications. Metformin or topiramate can be prescribed off-label for weight loss, but they should not be prescribed in combination.

Kinetic interactions: ❖ Topiramate is a weak 3A4 inDucer, which is insignificant at lower doses. However, if dosed > 200 mg/day, topiramate’s induction of 3A4 substrates may be clinically significant, i.e., by Decreasing blood levels of victim drugs. ❖ Topiramate can decrease lithium levels. As a carbonic anhydrase inhibitor, it raises urine pH, which increases excretion of lithium. The effect is expected to be mild and of little clinical significance. Topiramate can alter levels of other drugs whose excretion is affected by pH of urine.