Topamax Special Precautions

Withdrawal of TOPAMAX: In patients with or without a history of seizures or epilepsy, AEDs, including TOPAMAX should be gradually withdrawn to minimize the potential for seizures or increased seizure frequency. In clinical trials, daily dosages were decreased in weekly intervals by 50 to 100 mg in adults with epilepsy and by 25 to 50 mg in adults receiving TOPAMAX at doses up to 100 mg/day for migraine prophylaxis. In clinical trials of children, TOPAMAX was gradually withdrawn over a 2 to 8 week period. In situations where rapid withdrawal of TOPAMAX is medically required, appropriate monitoring is recommended.
Renal impairment: The major route of elimination of unchanged topiramate and its metabolites is via the kidney. Renal elimination is dependent on renal function and is independent of age. Patients with moderate or severe renal impairment may take 10 to 15 days to reach steady state plasma concentrations as compared to 4 to 8 days in patients with normal renal function.
As with all patients, the titration schedule should be guided by clinical outcome (i.e., seizure control, avoidance of side effects) with the knowledge that subjects with known renal impairment may require a longer time to reach steady-state at each dose (see Special Populations: Renal impairment under Dosage & Administration and Pharmacology: Pharmacokinetics: Special populations: Renal impairment under Actions).
Hydration: Oligohidrosis (decreased sweating) and anhidrosis have been reported in association with the use of topiramate. Decreased sweating and hyperthermia (rise in body temperature) may occur especially in young children exposed to high ambient temperatures (see Adverse Reactions).
Adequate hydration while using topiramate is very important. Hydration can reduce the risk of nephrolithiasis (see Nephrolithiasis under Precautions). Proper hydration prior to and during activities such as exercise or exposure to warm temperatures may reduce the risk of heat-related adverse events (see Adverse Reactions).
Mood disturbances/depression: An increased incidence of mood disturbances and depression has been observed during topiramate treatment.
Suicide/suicidal ideation: Potential for an increase in risk of suicidal thoughts or behaviors.
AEDs, including TOPAMAX, increase the risk of suicidal thoughts or behavior in patients taking these drugs for any indication. A meta-analysis of randomised placebo-controlled trials of AEDs has shown an increased risk of suicidal ideation and behaviour (0.43% on AEDs versus 0.24% on placebo). The mechanism of this risk is not known.
In double-blind clinical trials, suicide-related events (suicidal ideation, suicide attempts and suicide) occurred at a frequency of 0.5% in topiramate treated patients (46 out of 8652 patients treated) compared to 0.2% treated with placebo (8 out of 4045 patients treated). One completed suicide was reported in a bipolar disorder double-blind trial in a patient on topiramate.
Patients therefore should be monitored for signs of suicidal ideation and behaviour and appropriate treatment should be considered. Patients (and, when appropriate, caregivers of patients) should be advised to seek immediate medical advice should signs of suicidal ideation or behaviour emerge.
Serious skin reactions: Serious skin reactions [Stevens Johnson Syndrome (SJS) and Toxic Epidermal Necrolysis (TEN)] have been reported in patients receiving TOPAMAX (see Adverse Reactions). The majority of cases have occurred in patients concurrently taking other medications that are known to be associated with SJS and TEN. There have also been several cases in patients receiving monotherapy. It is recommended that patients be informed about the signs of serious skin reactions. If SJS or TEN are suspected, use of TOPAMAX should be discontinued.
Nephrolithiasis: Some patients, especially those with a predisposition to nephrolithiasis, may be at increased risk for renal stone formation and associated signs and symptoms such as renal colic, renal pain or flank pain.
Risk factors for nephrolithiasis include prior stone formation, a family history of nephrolithiasis and hypercalciuria. None of these risk factors can reliably predict stone formation during topiramate treatment. In addition, patients taking other medication associated with nephrolithiasis may be at increased risk (see Other forms of interactions: Agents predisposing to nephrolithiasis under Interactions).
Hepatic impairment: In hepatically-impaired patients, topiramate should be administered with caution as the clearance of topiramate may be decreased (see Special Populations: Hepatic impairment under Dosage & Administration and Pharmacology: Pharmacokinetics: Special populations: Hepatic impairment under Actions).
Acute myopia and secondary angle closure glaucoma syndrome: A syndrome consisting of acute myopia associated with secondary angle closure glaucoma has been reported in patients receiving TOPAMAX. Symptoms include acute onset of decreased visual acuity and/or ocular pain. Ophthalmologic findings can include some or all of the following: myopia, mydriasis, anterior chamber shallowing, ocular hyperemia (redness), choroidal detachments, retinal pigment epithelial detachments, macular striae, and increased intraocular pressure. This syndrome may be associated with supraciliary effusion resulting in anterior displacement of the lens and iris, with secondary angle closure glaucoma. Symptoms typically occur within 1 month of initiating TOPAMAX therapy. In contrast to primary narrow angle glaucoma, which is rare under 40 years of age, secondary angle closure glaucoma associated with topiramate has been reported in pediatric patients as well as adults. Treatment includes discontinuation of TOPAMAX, as rapidly as possible in the judgment of the treating physician, and appropriate measures to reduce intraocular pressure. These measures generally result in a decrease in intraocular pressure.
Elevated intraocular pressure of any etiology, if left untreated, can lead to serious sequelae including permanent vision loss.
Visual field defects: Visual field defects have been reported in patients receiving topiramate independent of elevated intraocular pressure. In clinical trials, most of these events were reversible following topiramate discontinuation, however some cases were not. In a large proportion of postmarketing case reports reversibility was unknown, but in cases where an outcome was reported, the majority was reversible. If visual problems occur at any time during topiramate treatment, consideration should be given to discontinuing the drug.
Metabolic acidosis and sequelae: Hyperchloremic, non-anion gap, metabolic acidosis (i.e. decreased serum bicarbonate below the normal reference range in the absence of respiratory alkalosis) is associated with topiramate treatment. This decrease in serum bicarbonate is due to the inhibitory effect of topiramate on renal carbonic anhydrase. Generally, the decrease in bicarbonate occurs early in treatment although it can occur at any time during treatment. These decreases are usually mild to moderate (average decrease of 4 mmol/L at doses of 100 mg/day or above in adults and at approximately 6 mg/kg/day in pediatric patients). Rarely, patients have experienced decreases to values below 10 mmol/L. Conditions or therapies that predispose to acidosis (such as renal disease, severe respiratory disorders, status epilepticus, diarrhea, surgery, ketogenic diet, or certain drugs) may be additive to the bicarbonate lowering effects of topiramate.
Chronic, untreated metabolic acidosis may increase the risk of nephrocalcinosis.
Chronic metabolic acidosis in pediatric patients can reduce growth rates. The effect of topiramate on growth and bone-related sequelae has not been systematically investigated in adult populations. A one year, open-label study in pediatric patients aged 6 to 15 years including 63 subjects with recent or new onset of epilepsy was conducted to assess the effects of topiramate (28 subjects) versus levetiracetam on growth, development, and bone mineralization. Continued growth was observed in both treatment groups but the topiramate group showed statistically significant reductions in mean annual change from baseline in body weight and bone mineral density compared to the levetiracetam group. A similar trend was also observed for height and height velocity but were not statistically significant. Growth-related changes were not clinically significant nor treatment limiting. Other confounding factors cannot be excluded.
Depending on underlying conditions, appropriate evaluation including serum bicarbonate levels is recommended with topiramate therapy. If metabolic acidosis develops and persists, consideration should be given to reducing the dose or discontinuing topiramate (using dose tapering).
Hyperammonemia and encephalopathy: Hyperammonemia with or without encephalopathy has been reported with topiramate treatment (see Adverse Reactions). The risk for hyperammonemia with topiramate appears dose-related. Hyperammonemia has been reported more frequently when topiramate is used concomitantly with valproic acid (see Interactions).
Clinical symptoms of hyperammonemic encephalopathy often include acute alterations in level of consciousness and/or cognitive function with lethargy. In most cases, hyperammonemic encephalopathy abated with discontinuation of treatment. In patients who develop unexplained lethargy, or changes in mental status associated with topiramate monotherapy or adjunctive therapy, it is recommended to consider hyperammonemic encephalopathy and measuring ammonia levels.
Nutritional supplementation: A dietary supplement or increased food intake may be considered if the patient is losing weight while on this medication.
Effects on Ability to Drive and Use Machines: TOPAMAX acts on the central nervous system and may produce drowsiness, dizziness or other related symptoms. It may also cause visual disturbances and/or blurred vision. These adverse events could potentially be dangerous in patients driving a vehicle or operating machinery, particularly until such time as the individual patient's experience with the drug is established.
Use in Pregnancy: Women of childbearing potential: TOPAMAX may cause fetal harm when administered to a pregnant woman. There is an increased risk of pre-term labor and premature delivery associated with the use of AEDs, including topiramate.
TOPAMAX should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus (see Use in Pregnancy & Lactation).