IMPORTANT SAFETY INFORMATION
CONTRAINDICATIONS
TROKENDI XR is contraindicated in patients with:
- Recent alcohol use (within 6 hours prior to and 6 hours after TROKENDI XR use).
- A history of hypersensitivity reaction to topiramate. TROKENDI XR, or any of the inactive ingredients of TROKENDI XR. Anaphylaxis and angioedema have occurred.
WARNINGS & PRECAUTIONS
• Acute Myopia and Secondary Angle Closure Glaucoma Syndrome: Has been reported in patients receiving topiramate. 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 topiramate therapy. The primary treatment to reverse symptoms is discontinuation of TROKENDI XR as rapidly as possible. Elevated intraocular pressure of any etiology, if left untreated, can lead to serious sequelae including permanent vision loss.
• Visual field defects (independent of elevated intraocular pressure): Have been reported in patients receiving topiramate. In clinical trials, most events were reversible after topiramate discontinuation. If visual problems occur at any time during treatment with TROKENDI XR, consideration should be given to discontinuing the drug.
• Oligohydrosis and Hyperthermia: Resulting in hospitalization in some cases, have been reported with topiramate use. Some cases were reported after exposure to elevated environmental temperatures. The majority of reports have been in pediatric patients. Patients, especially pediatric patients, should be monitored closely for evidence of decreased sweating and increased body temperature, especially in hot weather. Caution should be used when TROKENDI XR is given with other drugs that predispose patients to heat-related disorders (e.g., other carbonic anhydrase inhibitors and drugs with anticholinergic activity).
• Metabolic Acidosis: Hyperchloremic, non-anion gap, metabolic acidosis has been reported in adults and pediatric patients treated with topiramate. This metabolic acidosis is caused by renal bicarbonate loss due to the inhibitory effect of topiramate on carbonic anhydrase and can occur at any time during treatment. Conditions or therapies that predispose patients to acidosis may be additive to the bicarbonate-lowering effects of topiramate. Measurement of baseline and periodic serum bicarbonate during topiramate treatment is recommended. If metabolic acidosis develops and persists, consideration should be given to reducing the dose or discontinuing TROKENDI XR (using dose tapering). If the decision is made to continue patients on TROKENDI XR in the face of persistent acidosis, alkali treatment should be considered.
• Interaction with Alcohol: In vitro data show that, in the presence of alcohol, the pattern of topiramate release from TROKENDI XR capsules is significantly altered. As a result, plasma levels of topiramate with TROKENDI XR may be markedly higher soon after dosing and subtherapeutic later in the day. Alcohol use should be completely avoided within 6 hours prior to and 6 hours after TROKENDI XR administration.
• Suicidal Behavior and Ideation: Antiepileptic drugs (AEDs) increase the risk of suicidal thoughts or behavior in patients taking these drugs for any indication. Patients treated with any AED, including TROKENDI XR for any indication, should be monitored for the emergence or worsening of depression, suicidal thoughts, or behavior, and/or any unusual changes in mood or behavior. Anyone considering prescribing TROKENDI XR must balance the risk of suicidal thoughts or behavior with the risk of untreated illness. Many illnesses for which AEDs are prescribed are themselves associated with morbidity and mortality and an increased risk of suicidal thoughts and behavior. Should suicidal thoughts and behavior emerge during treatment, the prescriber needs to consider whether the emergence of these symptoms in any given patient may be related to the illness being treated.
• Cognitive/Neuropsychiatric Adverse Reactions: Immediate-release topiramate can cause, and therefore expected to be caused by TROKENDI XR, cognitive/neuropsychiatric adverse reactions. The most frequent of these can be classified into three general categories: Cognitive-related dysfunction; psychiatric/behavioral disturbances; and somnolence or fatigue.
• Fetal Toxicity: TROKENDI XR can cause fetal harm when administered to a pregnant woman. Data from pregnancy registries indicate that infants exposed to topiramate in utero can have an increased risk of major congenital malformations, including but not limited to cleft lip and/or cleft palate, and of being small for gestational age. Consider the benefits and risks of TROKENDI XR when administering the drug in women of childbearing potential, particularly for a condition not usually associated with permanent injury or death. TROKENDI XR should only be used during pregnancy 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 informed of the potential hazard to a fetus.
• Withdrawal of Antiepileptic Drugs: In patients with or without a history of seizures or epilepsy, antiepileptic drugs, including TROKENDI XR, should be gradually withdrawn to minimize the potential for seizures or increased seizure frequency. In situations where rapid withdrawal of TROKENDI XR is medically required, appropriate monitoring is recommended.
• Decrease in Bone Mineral Density: Results of a one-year active-controlled study in pediatric patients (N=63) demonstrated negative effects of immediate-release topiramate monotherapy on bone mineral acquisition via statistically significant decreases in bone mineral density (BMD) measured in lumbar spine and in total body less head. Twenty-one percent of immediate-release topiramate-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. Decreased BMD in the lumbar spine was correlated with decreased serum bicarbonate, which commonly occurs with topiramate treatment and reflects metabolic acidosis, a known cause of increased bone resorption.
• Negative Effects on Growth (Height and Weight): Immediate-release topiramate monotherapy demonstrated negative effects on growth (height and weight) among pediatric patients in a one-year active controlled study (N=63). Negative effects on growth were seen across all immediate-release topiramate age subgroups. Growth of children receiving prolonged TROKENDI XR therapy should be carefully monitored.
• Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)/Multiorgan Hypersensitivity Reactions: DRESS, also known as multiorgan hypersensitivity, has been reported in patients taking topiramate and may be fatal or life-threatening. DRESS typically presents with fever, rash, lymphadenopathy, and/or facial swelling, in association with other organ system involvement, such as hepatitis, nephritis, hematological abnormalities, myocarditis, or myositis sometimes resembling an acute viral infection. Other organ systems not noted here may be involved. Early manifestations of hypersensitivity, such as fever or lymphadenopathy, may be present even though rash is not evident. If such signs or symptoms are present, the patient should be evaluated immediately. TROKENDI XR should be discontinued if an alternative etiology for the signs or symptoms cannot be established.
• Serious Skin Reactions: Stevens-Johnson Syndrome (SJS) and Toxic Epidermal Necrolysis (TEN) have been reported in patients receiving topiramate. TROKENDI XR 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.
• Anaphylaxis and Angioedema: Hypersensitivity reactions, including anaphylaxis and angioedema, have occurred in patients treated with topiramate in the postmarketing setting. If a hypersensitivity reaction occurs, discontinue TROKENDI XR and initiate appropriate therapy.
• Hyperammonemia and Encephalopathy (Without and With Concomitant Valproic Acid Use): Can be caused by topiramate treatment and risk 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. 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. 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 or TROKENDI XR treatment or an interaction of concomitant topiramate-based product 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.
• Kidney Stones: Topiramate increases the risk of kidney stones. TROKENDI XR would be expected to have the same effect. Topiramate is a carbonic anhydrase inhibitor that can promote stone formation by reducing urinary citrate excretion and increasing urinary pH. The concomitant use of TROKENDI XR with any other drug producing metabolic acidosis, or potentially in patients on a ketogenic diet, may increase the risk of kidney stone formation and should therefore be avoided. Increased fluid intake increases fluid output, lowering the concentration of substances involved in stone formation. Hydration is recommended to reduce new stone formation.
• Hypothermia with Concomitant Valproic Acid Use: Has been reported in association with topiramate use with concomitant valproic acid both in the presence and in the absence of hyperammonemia. It can occur after starting topiramate treatment or after increasing the daily dose of topiramate. Consideration should be given to stopping TROKENDI XR or valproate in patients who develop hypothermia; clinical management and assessment should include examination of blood ammonia levels.
ADVERSE REACTIONS
• The most common (≥5% more frequent than placebo) adverse reactions in adult and pediatric patients were: paresthesia, anorexia, weight loss, difficulty with memory, taste perversion, diarrhea, hypoesthesia, nausea, abdominal pain, and upper respiratory tract infection.
INDICATION
TROKEND XR® (topiramate) extended-release capsules is indicated for preventive treatment of migraine in patients 12 years of age and older.
Please see full Prescribing Information.
