Topamax (Page 4 of 11)

5.7 Fetal Toxicity

TOPAMAX ® can cause fetal harm when administered to a pregnant woman. Data from pregnancy registries indicate that infants exposed to topiramate in utero have an increased risk for cleft lip and/or cleft palate (oral clefts) and for being small for gestational age (SGA). When multiple species of pregnant animals received topiramate at clinically relevant doses, structural malformations, including craniofacial defects, and reduced fetal weights occurred in offspring [see Use in Specific Populations (8.1)] .

Consider the benefits and the risks of TOPAMAX ® when administering this drug in women of childbearing potential, particularly when TOPAMAX ® is considered for a condition not usually associated with permanent injury or death [see Use in Specific Populations (8.1), Patient Counseling Information (17)] . TOPAMAX ® should be used during pregnancy only if the potential benefit outweighs the potential risk. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus [see Use in Specific Populations (8.1)] .

5.8 Withdrawal of Antiepileptic Drugs

In patients with or without a history of seizures or epilepsy, antiepileptic drugs, including TOPAMAX ® , should be gradually withdrawn to minimize the potential for seizures or increased seizure frequency [see Clinical Studies (14)] . In situations where rapid withdrawal of TOPAMAX ® is medically required, appropriate monitoring is recommended.

5.9 Decrease in Bone Mineral Density

Results of a one-year active-controlled study in pediatric patients (N=63) demonstrated negative effects of TOPAMAX ® monotherapy on bone mineral acquisition via statistically significant decreases in bone mineral density (BMD) measured in lumbar spine and in total body less head [see Use in Specific Populations (8.4)] . Twenty-one percent of TOPAMAX ® -treated patients experienced clinically important reductions in BMD (Z score change from baseline of –0.5 or greater) compared to 0 patients in the control group. Although decreases in BMD occurred across all pediatric age subgroups, patients 6 to 9 years of age were most commonly affected. The sample size and study duration were too small to determine if fracture risk is increased. Decreased BMD in the lumbar spine was correlated with decreased serum bicarbonate, which commonly occurs with TOPAMAX treatment and reflects metabolic acidosis, a known cause of increased bone resorption [see Warnings and Precautions (5.4)] . Although small decreases in some markers of bone metabolism (e.g., serum alkaline phosphatase, calcium, phosphorus, and 1,25-dihydroxyvitamin D) occurred in TOPAMAX ® -treated patients, more significant decreases in serum parathyroid hormone and 25-hydroxyvitamin D, hormones involved in bone metabolism, were observed, along with an increased excretion of urinary calcium .

5.10 Negative Effects on Growth (Height and Weight)

Results of a one-year active-controlled study of pediatric patients (N=63) demonstrated negative effects of TOPAMAX ® monotherapy on growth (i.e., height and weight) [see Use in Specific Populations (8.4)] . Although continued growth was observed in both treatment groups, the TOPAMAX ® group showed statistically significant reductions in mean annual change from baseline in body weight compared to the control group. A similar trend of attenuation in height velocity and height change from baseline was also observed in the TOPAMAX ® group compared to the control group. Negative effects on weight and height were seen across all TOPAMAX ® age subgroups. Growth (height and weight) of children receiving prolonged TOPAMAX ® therapy should be carefully monitored.

5.11 Serious Skin Reactions

Serious skin reactions (Stevens-Johnson Syndrome [SJS] and Toxic Epidermal Necrolysis [TEN]) have been reported in patients receiving topiramate. TOPAMAX should be discontinued at the first sign of a rash, unless the rash is clearly not drug-related. If signs or symptoms suggest SJS/TEN, use of this drug should not be resumed and alternative therapy should be considered. Inform patients about the signs of serious skin reactions.

5.12 Hyperammonemia and Encephalopathy (Without and With Concomitant Valproic Acid Use)

Topiramate treatment can cause hyperammonemia with or without encephalopathy [see Adverse Reactions (6.2)] . The risk for hyperammonemia with topiramate appears dose-related. Hyperammonemia has been reported more frequently when topiramate is used concomitantly with valproic acid. Postmarketing cases of hyperammonemia with or without encephalopathy have been reported with topiramate and valproic acid in patients who previously tolerated either drug alone [see Drug Interactions (7.1)] .

Clinical symptoms of hyperammonemic encephalopathy often include acute alterations in level of consciousness and/or cognitive function with lethargy and/or vomiting. In most cases, hyperammonemic encephalopathy abated with discontinuation of treatment.

The incidence of hyperammonemia in pediatric patients 12 to 17 years of age in the preventive treatment of migraine trials was 26% in patients taking TOPAMAX ® monotherapy at 100 mg/day, and 14% in patients taking TOPAMAX ® at 50 mg/day, compared to 9% in patients taking placebo. There was also an increased incidence of markedly increased hyperammonemia at the 100 mg dose.

Dose-related hyperammonemia was also seen in pediatric patients 1 to 24 months of age treated with TOPAMAX ® and concomitant valproic acid for partial-onset epilepsy and this was not due to a pharmacokinetic interaction.

In some patients, hyperammonemia can be asymptomatic.

Monitoring for Hyperammonemia

Patients with inborn errors of metabolism or reduced hepatic mitochondrial activity may be at an increased risk for hyperammonemia with or without encephalopathy. Although not studied, topiramate treatment or an interaction of concomitant topiramate and valproic acid treatment may exacerbate existing defects or unmask deficiencies in susceptible persons.

In patients who develop unexplained lethargy, vomiting or changes in mental status associated with any topiramate treatment, hyperammonemic encephalopathy should be considered and an ammonia level should be measured.

5.13 Kidney Stones

TOPAMAX ® increases the risk of kidney stones. During adjunctive epilepsy trials, the risk for kidney stones in TOPAMAX ® -treated adults was 1.5%, an incidence about 2 to 4 times greater than expected in a similar, untreated population. As in the general population, the incidence of stone formation among TOPAMAX ® -treated patients was higher in men. Kidney stones have also been reported in pediatric patients taking TOPAMAX ® for epilepsy or migraine. During long-term (up to 1 year) TOPAMAX ® treatment in an open-label extension study of 284 pediatric patients 1–24 months old with epilepsy, 7% developed kidney or bladder stones. TOPAMAX ® is not approved for treatment of epilepsy in pediatric patients less than 2 years old [see Use in Specific Populations (8.4)].

TOPAMAX ® is a carbonic anhydrase inhibitor. Carbonic anhydrase inhibitors can promote stone formation by reducing urinary citrate excretion and by increasing urinary pH [see Warnings and Precautions (5.4)] . The concomitant use of TOPAMAX ® with any other drug producing metabolic acidosis, or potentially in patients on a ketogenic diet, may create a physiological environment that increases the risk of kidney stone formation, and should therefore be avoided.

Increased fluid intake increases the urinary output, lowering the concentration of substances involved in stone formation. Hydration is recommended to reduce new stone formation.

An increase in urinary calcium and a marked decrease in urinary citrate was observed in TOPAMAX-treated pediatric patients in a one-year active-controlled study [see Use in Specific Populations (8.4)] . This increased ratio of urinary calcium/citrate increases the risk of kidney stones and/or nephrocalcinosis.

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