It is estimated that in the United States, there are 3.4 million people, including 3 million adults and 470,000 children, with epilepsy.1 For patients with epilepsy, the burden of the disorder is substantial and complex, comprising obvious physiological dysfunction as well as psychological and social impairments. Patient-centered care and optimization of therapy are essential to positive therapeutic outcomes.2
The availability of oral liquid anti-seizure medications provides greater dosing flexibility, precise dose titration and customization, and enhances ease of administration—especially in those for whom administering a solid dosage form is not feasible (e.g., pediatric patients, patients who have difficulty swallowing tablets and capsules [or those who prefer not to])—and may improve adherence, especially in younger patients.3,4
However, there are significant differences between compounded medications and FDA-approved drugs. Compounding oral liquid medications from commercially available solid dosage forms has challenges, including:
- Calculation errors, which pose the greatest risk of medication errors
- Lack of assurance of potency, bioequivalence, stability, and sterility as they are exempt from Good Manufacturing Practice regulations and testing
- Health safety risks from crushing hazardous drugs (HDs)
- Lack of standardized product labeling or prescribing information with instructions for safe use
- Lack of preservatives in the final preparation to prevent microbial growth problems with patient acceptability (taste, order, palatability, and appearance)
- Problems with patient acceptability (taste, order, palatability, and appearance)
- Use of solubilizers or other compounds that may be inappropriate for children such as alcohol or propylene glycol.5-11
Analyzing Compounding Product Potency
For example, in 2018 the FDA reported the findings of sampling and analysis testing of 37 products made by 12 compounding pharmacies. Ten (34%) of the 29 sampled products failed one or more standard quality tests. Nine of the 10 products with failing analytical results did not pass assay or potency testing. All of the sampled products that failed potency analyses were subpotent. The average percent of declared potency ranged from 59% to 89% of the expected potency.12
Furthermore, an online survey of pharmacists found that there was a high degree of variability among compounded oral liquids for pediatric patients. The number of differing concentrations reported for 147 oral pediatric medications varied from one concentration up to nine concentrations. Among the anti-seizure medications, zonisamide was compounded using six different formulations and topiramate with five different concentrations.13 Compounding issues that may disproportionately affect children include formulation failure and dosing miscalculations.3 More than 20% of medical errors in pediatric patients involve preparation or administration of oral liquids.23
Adhering to Safety Protocols
The National Institute of Occupational Safety and Health (NIOSH) List of Antineoplastic and Other Hazardous Drugs in Healthcare Settings, 2016 lists both topiramate and zonisamide as “non-antineoplastic drugs that primarily have adverse reproductive effects.”24
Exposure HDs can place healthcare professionals at risk. USP 800 states “Healthcare personnel should avoid manipulating HDs such as crushing tablets or opening capsules if possible. Liquid formulations are preferred if solid oral dosage forms are not appropriate for the patient. If HD dosage forms do require manipulation such as crushing tablet(s) or opening capsule(s) for a single dose, personnel must don appropriate personal protective equipment and use a plastic pouch to contain any dust or particles generated.”14
FDA Guidance on Compounded Medications
The FDA has issued guidance on compounding drug products that are essentially copies of approved drug products under Section 503A and 503B of the Federal Food, Drug, and Cosmetic (FD&C) Act when commercially available formulations of the required oral liquid drug are available. This practice is generally discouraged, except under specific conditions.15,16
Unlike with FDA-approved products, consumers and prescribers should not assume that compounded drugs were made by validated processes or that appropriate laboratory tests were performed to verify potency, purity, and quality of the compounded drugs.
The lowest risk of harm risk occurs when oral liquid formulations are prepared by the pharmaceutical industry and the products are licensed and registered in the regulatory agencies.17 Under the FD&C Act, brand-name drugs and generic drugs approved by the FDA must be safe and effective and must be manufactured in accordance with Current Good Manufacturing Practices to ensure their identity, strength, quality, and purity.6
Risks associated with extemporaneous compounding have been addressed by professional pharmacy organizations. In its technical assistance bulletin on compounding nonsterile preparations in pharmacies, the American Society of Health-System Pharmacists has recommended that “Dispensing a commercial product is preferable to extemporaneously compounding a drug product because commercial products carry the manufacturer’s guarantee of labeled potency and stability.”18
Topiramate and Zonisamide Background
While there is a plethora of anti-seizure medications available to choose from, as of 2022 two of the most commonly used are topiramate and zonisamide.19 Topiramate is indicated as initial monotherapy or as adjunctive treatment for partial-onset seizures or primary generalized tonic-clonic seizures for patients aged >2 years. It is also indicated for seizures associated with Lennox-Gastaut syndrome in this age group and for prevention of migraines in patients aged >12 years. Zonisamide, a sulfonamide antiepileptic agent, is indicated as adjunctive therapy for the treatment of partial-onset seizures in adults and pediatric patients aged 16+ years. Both of these medications were only available in a solid oral dosage form—topiramate as capsules, extended-release capsules, and tablets, and zonisamide only as capsules.20 EPRONTIA® (topiramate oral solution 25 mg/mL) received FDA approval on November 5, 2021, and Zonisade® (zonisamide oral suspension) was granted approval status on July 15, 2022.20 These are the first and only FDA-approved liquid formulations of topiramate and zonisamide meeting a distinct need for HCPs and patients.
Compounding topiramate liquid is discouraged by USP and ASHP, as stability, safety, and efficacy has not been established when film-coated topiramate tablets are altered.14,18 This may result in incomplete administration of the dose. Further, the drug has a bitter taste, which may adversely affect adherence with therapy.21
The availability of ready-to-use EPRONTIA® (topiramate oral solution 25 mg/mL) and ZONISADE®* (zonisamide oral suspension 100 mg/mL) eliminate the need for crushing and compounding these anti-seizure molecules and some of the challenges that come with this.
* ZONISADE must be shaken well before each administration.
EPRONTIA® IMPORTANT SAFETY INFORMATION
EPRONTIA® (topiramate) oral solution, 25 mg/mL
EPRONTIA is indicated for initial monotherapy for the treatment of partial-onset or primary generalized tonicclonic seizures in patients 2 years of age and older; adjunctive therapy for the treatment of partial-onset seizures, primary generalized tonic-clonic seizures, or seizures associated with Lennox-Gastaut syndrome in patients 2 years of age and older; and preventive treatment of migraine in patients 12 years of age and older.
Inform patients that a calibrated measuring device is recommended to measure and deliver the prescribed dose accurately. A household teaspoon or tablespoon is not an adequate measuring device.
ADDITIONAL IMPORTANT SAFETY INFORMATION
Warnings and Precautions: 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 EPRONTIA (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 EPRONTIA therapy. The primary treatment to reverse symptoms is discontinuation of EPRONTIA.
Visual Field Defects: Visual field defects have been reported in clinical trials and in postmarketing experience in patients receiving topiramate. In clinical trials, most of these events were reversible after topiramate discontinuation. If visual problems occur, consideration should be given to discontinuing the drug.
Oligohidrosis and Hyperthermia: Oligohidrosis (decreased sweating), infrequently resulting in hospitalization, has been reported in association with EPRONTIA use. The majority of the 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 EPRONTIA is prescribed with other drugs that predispose patients to heat-related disorders; these drugs include, but are not limited to, other carbonic anhydrase inhibitors and drugs with anticholinergic activity.
Metabolic Acidosis: Metabolic acidosis was commonly observed in adult and pediatric patients in clinical trials and is caused by renal bicarbonate loss due to carbonic anhydrase inhibition by EPRONTIA. Conditions or therapies that predispose patients to acidosis (such as renal disease, severe respiratory disorders, status epilepticus, diarrhea, ketogenic diet, or specific drugs) may be additive to the bicarbonate lowering effects of EPRONTIA. Topiramate treatment that causes metabolic acidosis during pregnancy can possibly produce adverse effects on the fetus and might also cause metabolic acidosis in the neonate from possible transfer of topiramate to the fetus. Baseline and periodic serum bicarbonate measurements are recommended during EPRONTIA treatment. If metabolic acidosis develops and persists, consideration should be given to either dose reduction or discontinuation of therapy using dose tapering.
Suicidal Behavior and Ideation: Antiepileptic drugs (AEDs), including EPRONTIA, increase the risk of suicidal thoughts or behavior in patients taking these drugs for any indication. Patients treated with any AED should be monitored for the emergence or worsening of depression, suicidal thoughts or behavior, and/or any unusual changes in mood or behavior.
Cognitive/Neuropsychiatric Adverse Reactions: EPRONTIA can cause cognitive/neuropsychiatric adverse reactions. The most frequent of these can be classified into 3 categories: 1) cognitive related dysfunction (eg, confusion, difficulty with concentration, difficulty with memory, speech or language problems); 2) psychiatric/behavioral disturbances (eg, depression or mood problems); and 3) somnolence or fatigue.
Fetal Toxicity: EPRONTIA can cause fetal harm when administered to pregnant women. The benefits and risks should be considered when administering this drug in women of childbearing potential.
Withdrawal of Antiepileptic Drugs: EPRONTIA should be gradually withdrawn to minimize the potential for seizures or increased seizure frequency. If rapid withdrawal is required, appropriate monitoring is recommended.
Decrease in Bone Mineral Density: EPRONTIA has been shown to decrease bone mineral density (BMD) and bone mineral content in pediatric patients. Decreased BMD 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): Negative effects on height and weight have been seen in pediatric patients receiving topiramate treatment. EPRONTIA may slow height increase and weight gain; carefully monitor children receiving prolonged topiramate therapy.
Serious Skin Reactions: Serious skin reactions (Stevens-Johnson Syndrome [SJS] and Toxic Epidermal Necrolysis [TEN]) have been reported in patients receiving topiramate. EPRONTIA 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.
Hyperammonemia and Encephalopathy (Without and With Concomitant Valproic Acid Use): EPRONTIA treatment can cause hyperammonemia with or without encephalopathy, the risk of which appears to be dose-related, and which has been reported more frequently with concomitant use of valproic acid. In patients who develop unexplained lethargy, vomiting, or changes in mental status associated with topiramate, hyperammonemic encephalopathy should be considered and an ammonia level should be measured.
Kidney Stones: EPRONTIA can cause an increased risk of kidney stones. The concomitant use of topiramate with any other drug producing metabolic acidosis, or potentially in patients on a ketogenic diet, may increase the risk of kidney stone formation. An increase in urinary calcium and a marked decrease in urinary citrate have been observed in topiramate-treated pediatric patients. This increased ratio of urinary calcium/citrate increases the risk of kidney stones and/or nephrocalcinosis. Instruct patients to stay well hydrated while taking EPRONTIA.
Hypothermia With Concomitant Valproic Acid Use: Hypothermia has been reported in association with topiramate use with concomitant valproic acid both in conjunction with hyperammonemia and in the absence of hyperammonemia. Consider discontinuation of topiramate or valproate in patients who develop hypothermia. Clinical management should include examination of blood ammonia levels.
Adverse Reactions: The most common adverse reactions associated with EPRONTIA include:
• Taste perversion
• Weight loss
• Upper respiratory tract infection
• Speech problems
• Psychomotor slowing
• Difficulty with memory
• Abdominal pain
• Abnormal vision
Use in Specific Populations
Topiramate can cause fetal harm when administered to a pregnant woman. Small for gestational age (SGA) has been observed at all doses and appears to be dose-dependent. Patients should be encouraged to enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry if they become pregnant. This registry collects information about the safety of antiepileptic drugs during pregnancy. To enroll, patients can call the toll-free number 1-888-233-2334. Information about the North American Drug Pregnancy Registry can be found at http://www.aedpregnancyregistry.org/.
Topiramate is excreted in human milk. The effects of topiramate on milk production are unknown. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for topiramate and any potential adverse effects on the breastfed infant from topiramate or from the underlying maternal condition.
Women of Reproductive Potential
Women of childbearing potential who are not planning a pregnancy should use effective contraception because of the risks of oral clefts and SGA.
The clearance of topiramate is reduced in patients with moderate (creatinine clearance 30 to 69 mL/min/1.73 m2) and severe (creatinine clearance <30 mL/min/1.73 m2) renal impairment. A dosage adjustment is recommended in patients with moderate or severe renal impairment.
Patients Undergoing Hemodialysis
Topiramate is cleared by hemodialysis at a rate that is 4 to 6 times greater than in a normal individual. A dosage adjustment may be required.
For full prescribing information visit EPRONTIA.com
ZONISADE® IMPORTANT SAFETY INFORMATION
ZONISADE® (zonisamide oral suspension), 100 mg/5 mL
ZONISADE is indicated as adjunctive therapy for the treatment of partial-onset seizures in adults and pediatric patients 16 years of age and older.
Inform patients that a calibrated measuring device is recommended to measure and deliver the prescribed dose accurately. A household teaspoon or tablespoon is not an adequate measuring device.
ADDITIONAL IMPORTANT SAFETY INFORMATION
Known hypersensitivity to sulfonamides, zonisamide, or any formulation ingredients.
Warnings and Precautions
Potentially fatal reaction to Sulfonamides: Fatalities have occurred as a result of severe reactions to sulfonamides (ZONISADE is a sulfonamide) including Stevens-Johnson syndrome, toxic epidermal necrolysis, fulminant hepatic necrosis, agranulocytosis, aplastic anemia, and other blood dyscrasias. If signs of hypersensitivity or other serious reactions occur, discontinue ZONISADE immediately.
Serious Skin Reaction: Serious skin reactions (Stevens-Johnson syndrome and toxic epidermal necrolysis) have been reported. Consideration should be given to discontinuing ZONISADE in patients who develop an otherwise unexplained rash. If the drug is not discontinued, patients should be observed frequently. Inform patients about the signs of serious skin reactions.
Serious Hematologic Events: Aplastic anemia and agranulocytosis have been reported in patients who received zonisamide treatment. There is inadequate information to assess the relationship, if any, between dose and duration of treatment and these events.
Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)/Multi-Organ Hypersensitivity: Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), also known as multi-organ hypersensitivity, has occurred with zonisamide. Some of these events have been fatal or life-threatening. If signs or symptoms of DRESS are present, the patient should be evaluated immediately. ZONISADE should be discontinued if an alternative etiology for the signs or symptoms cannot be established.
Oligohidrosis and Hyperthermia in Pediatric Patients: ZONISADE is not approved for use in pediatric patients below 16 years of age. Pediatric patients appear to be at an increased risk for zonisamide-associated oligohidrosis and hyperthermia. Patients, especially pediatric patients, treated with ZONISADE should be monitored closely for evidence of decreased sweating and increased body temperature, especially in warm or hot weather. Caution should be used when ZONISADE is prescribed with other drugs that predispose patients to heat-related disorders; these drugs include but are not limited to, carbonic anhydrase inhibitors and drugs with anticholinergic activity.
Acute Myopia and Secondary Angle Closure Glaucoma: Acute myopia and secondary angle closure glaucoma have been reported in patients receiving zonisamide. Elevated intraocular pressure can lead to serious sequelae, including permanent vision loss if left untreated. Symptoms typically occur within one month after initiating zonisamide therapy. The primary treatment to reverse symptoms is the discontinuation of zonisamide. Myopia and secondary angle closure glaucoma usually resolve or improve after discontinuation of zonisamide.
Suicidal Behavior and Ideation: Antiepileptic drugs (AEDs), including ZONISADE, increase the risk of suicidal thoughts or behavior in patients taking these drugs for any indication. Patients treated with any AED 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.
Metabolic Acidosis: Metabolic acidosis was commonly observed in adults and pediatric patients in clinical trials and is caused by renal bicarbonate loss due to the inhibitory effect of zonisamide on carbonic anhydrase. Pediatric patients may be more likely to develop metabolic acidosis than adults. Conditions or therapies that predispose to acidosis (such as renal disease, severe respiratory disorders, status epilepticus, diarrhea, ketogenic diet, or specific drugs) may be additive to the bicarbonate lowering effects of zonisamide. Measurement of baseline and periodic serum bicarbonate during treatment is recommended. If metabolic acidosis develops, consideration should be given to either dose reduction or discontinuation of therapy using dose tapering.
Seizures on Withdrawal: As with other AEDs, abrupt withdrawal of ZONISADE in patients with epilepsy may precipitate increased seizure frequency or status epilepticus. Dose reduction or discontinuation of ZONISADE should be done gradually.
Teratogenicity: ZONISADE may cause fetal harm when administered to pregnant women and should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Women of childbearing potential who are given ZONISADE should be advised to use effective contraception.
Cognitive/Neuropsychiatric Adverse Reactions: Use of zonisamide was frequently associated with central nervous system-related adverse reactions including psychiatric symptoms, cognitive dysfunction, and somnolence or fatigue.
Hyperammonemia and Encephalopathy: Hyperammonemia and encephalopathy have been reported with the postmarketing use of zonisamide. The risks may be increased in patients treated with zonisamide and concomitantly taking valproic acid or topiramate. Measure serum ammonia concentration if signs or symptoms of encephalopathy occur. Hyperammonemia resulting from zonisamide resolves when zonisamide is discontinued. Hyperammonemia from zonisamide may resolve or decrease in severity with a decrease of the daily dose.
Kidney Stones: ZONISADE may increase the risk for kidney stones. Instruct patients to stay well hydrated while taking ZONISADE.
Effect on Renal Function: ZONISADE can cause an increase in serum creatinine and blood urea nitrogen (BUN). ZONISADE should be discontinued in patients who develop acute renal failure or a clinically significant sustained increase in the creatinine/BUN concentration. ZONISADE should not be used in patients with renal failure (estimated [GFR] < 50 mL/min) as there has been insufficient experience concerning drug dosing and toxicity.
Status Epilepticus: Status epilepticus has been reported at a rate of 1% across all controlled and uncontrolled epilepsy studies in patients treated with zonisamide.
Laboratory Tests: ZONISADE may increase serum chloride and alkaline phosphatase, and decrease serum bicarbonate, phosphorus, calcium, and albumin. Clinical management should include a periodic assessment of laboratory values.
The most common adverse reactions with ZONISADE (an incidence at least 4% greater than placebo) in controlled clinical trials and shown in descending order of frequency were somnolence, anorexia, dizziness, ataxia, agitation/irritability, and difficulty with memory and/or concentration.
ZONISADE should be used with caution if used in combination with alcohol or other CNS depressants.
Concomitant use of ZONISADE with any other carbonic anhydrase inhibitor may increase the severity of metabolic acidosis and may also increase the risk of kidney stone formation.
USE IN SPECIFIC POPULATIONS
ZONISADE may cause serious adverse fetal effects, based on clinical and nonclinical data.
Advise pregnant patients to enroll in the NAAED Pregnancy Registry. This can be done by calling the toll-free number 1-888-233-2334 and must be done by patients themselves.
Zonisamide is excreted in human milk. Because of the potential for serious adverse reactions in nursing infants from ZONISADE, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.
Female and Males of Reproductive Potential
Based on animal data, ZONISADE can cause fetal harm when administered to a pregnant woman, and female fertility may be compromised with ZONISADE.
The safety and effectiveness of ZONISADE in pediatric patients below the age of 16 have not been established.
Please see full Prescribing Information for ZONISADE®.
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