Selecting the appropriate dosage form and route of administration is a crucial, but underappreciated, component in the successful treatment of children with epilepsy. For example, some children have difficulty swallowing solid dosage forms; there are occasions when oral therapy is not possible due to an illness or trauma, and lastly, there are circumstances when rescue therapy for seizure emergencies is indicated. In recent decades, a number of child-friendly antiepileptic drug (AED) formulations have been marketed, such as extended-release formulations, and injectables, rectal, and nasal products have either been introduced or are in late-stage development. Child-friendly formulations allow the clinician to individualize drug regimens; however, ignoring the differences among dosage forms and routes of administration can result in failure to receive the full therapeutic benefit of the medication.
THEORETICAL ASPECTS IN ANTIEPILEPTIC DRUG DOSAGE FORM SELECTION
Parenteral Formulations
Intravenous (IV) administration of an AED results in high plasma drug concentrations immediately after the end of the injection and rapid distribution of drug throughout the body, including the central nervous system (CNS) (1,2). While an important component of the clinician’s armamentarium, IV formulations have limitations. Only drugs that are water-soluble or that are soluble in a solvent that has little or no pharmacologic activity can be formulated as an IV dosage form. In some cases (e.g., phenytoin), the solvent can contribute to toxicity that occurs with excessively rapid infusion (3). Generally, intravenous administration requires the presence of trained medical personnel and specialized equipment, such as infusion pumps and monitoring equipment, which limits use of this approach when treating seizure emergencies. Therefore, IV drug administration is indicated only when rapid attainment of drug concentrations is needed, as in status epilepticus, or when the patient is unable or unwilling to take medications by mouth.
Oral Formulations
All oral medications must be in solution in order for the drug to be absorbed. The processes leading up to dissolution will vary depending on the dosage form and the physical-chemical properties of the drug. For any given drug, the rate of absorption from a dosage form is as follows: solution > suspension > liquid-filled capsule > particle-filled capsule > solid tablet. In general, tablets first must disintegrate, or break apart, into granules or particles. Similarly, capsule coatings must dissolve, liberating the drug as particles. After particles dissolve into solution, the drug must be in an un-ionized state, which can occur in either the stomach or the intestines depending on the drug’s pH, in order to be absorbed (Figure 46.1). Immediate-release solid dosage forms typically disintegrate in the stomach shortly after ingestion. However, dissolution time (the time to dissolve in gastrointestinal [GI] fluids) and rate of absorption are affected by GI surface area, water and lipid solubility, gastric pH (and the ionization state of the drug), temperature, mechanical stimulation, particle size, and fat composition of GI content.
Effect of Anatomy and Physiology on Absorption
Most drugs are weak acids or weak bases and exist in solution in equilibrium between the ionized and un-ionized forms. It is the un-ionized form that passively diffuses across the epithelial lining of the GI tract. The continuous flow of blood to the GI tract ensures a concentration gradient that facilitates diffusion of drug from an area of high concentration in the gut to low concentration in capillary blood. Once a drug is dissolved, the rate of absorption is determined by the ratio of ionized to un-ionized forms. Weak acids are absorbed more rapidly at pH 1.0 than at pH 8.0, and the converse is true for weak bases, because more of the un-ionized form is present. The formulation of poorly soluble drugs as salts may enhance solubility and result in better absorption. Generally, drug absorption is greater in the small intestine than the stomach, due to the larger surface area, higher permeability, and greater blood flow (4). Absorption diminishes in the large intestine secondary to diminished fluid volume and increasing fecal content. The average GI transit time in an adult is 16 to 96 hours, although there is substantial intra- and interpatient variability, particularly in children (5). This can affect the bioavailability of certain extended-release formulations, which are engineered to release drug over a 24-hour period.
FIGURE 46.1 Processes required for drug absorption from oral dosage forms.
Physiologically or pharmacologically induced changes in GI pH may affect the disintegration of tablets or capsules, the dissolution time, and/or the equilibrium between the ionized and un-ionized forms, which may alter the rate and/or extent of drug absorption (6). Achlorhydria, a condition in which gastric acid production is absent, may alter disintegration and dissolution. Diarrhea decreases the absorption of phenytoin and other slowly absorbed drugs because GI transit rate is increased, reducing drug contact time at intestinal absorption sites (3). Similarly, foods and drugs may affect gastric emptying time and drug absorption. For example, food decreases the rate, but not the extent, of absorption of valproic acid, resulting in a delayed time to peak concentration (Tmax) (7). In contrast, food enhances the bioavailability of carbamazepine (8). The coadministration of drugs that reduce or neutralize gastric acid may alter drug absorption. Large doses of antacids decrease the absorption of phenytoin, presumably by chelating drug to the cations in the antacids (9).
Some drugs are absorbed by active transport processes. For example, gabapentin is carried across the GI membrane via L-alpha amino acid transport (LAT1) enzyme (10). Absorption may become saturated with this type of process. When the amount of drug in the GI tract is low relative to the number of transport enzyme-binding sites, the extent of absorption is relatively high and constant. With increasing doses, the drug concentration in the GI tract approaches the capacity limits of the transport enzymes, resulting in a decreasing bioavailability.
In some cases, a drug may be metabolized as it passes across the gut wall. Further metabolism may take place in the liver before the drug reaches the systemic circulation. This phenomenon is known as first-pass metabolism. Systemic bioavailability is determined by the fraction of the dose that crossed the GI epithelial tissue, efflux of drug back into the GI tract, the degree of first-pass metabolism occurring in the GI tract, hepatic blood flow, and metabolism in the liver before the drug reaches the systemic circulation. Taking these factors into consideration, switching between oral and IV formulations in drugs exhibiting a significant first-pass effect, such as midazolam and carbamazepine, requires dose changes. If a drug has extensive first-pass metabolism, it may not be suitable for oral administration. Furthermore, efflux transporters such as P-glycoprotein increase the excretion of drugs from systemic circulation, resulting in decreased bioavailability (11). Moreover, coadministration of food with these drugs may affect hepatic blood flow, which can influence the systemic bioavailability of drugs.
Age per se may alter absorption. In the newborn, intragastric pH and the type and quantity of gut enzymes change rapidly (12,13). Because of relative achlorhydria in the newborn and infant, there should be an increased absorption of acid-labile drugs such as penicillin (14). Age effects on pharmacokinetics are discussed in Chapter 45.
Effect of Dosage Form and Absorption
Antiepileptic drugs exhibit a wide range of absorption rate profiles: fast, intermediate, and slow absorption. For example, among AEDs, the Tmax after tablet dissolution ranges from levetiracetam (T ~1 hr), to topiramate (~2 hrs), and carbamazepine (~4–6 hrs), respectively (15–17). In addition, if a drug has a fast or intermediate Tmax and a short elimination half-life, multiple daily doses are required to minimize extreme fluctuations in drug concentrations. However, such dosing strategies may result in poor compliance.
While most immediate-release drugs are designed to disintegrate in the stomach, modified-release formulations are engineered to delay or control the rate of drug release to attain better patient compliance and/or therapeutic efficacy, and/or improve tolerance. Delayed-release or enteric-coated products are designed to delay liberation until the drug reaches the small intestine. This may be desirable if the drug is better absorbed in fluids that have higher pH, or if high drug concentrations cause gastrointestinal distress. In contrast, extended-release formulations allow a drug to be liberated throughout the GI tract at a controlled rate, duration, and location. Such formulations are described as extended-release, controlled-release, prolonged-release, time-release, slow-release, sustained-release, prolonged-action, or extended-action products. Although there is some interchangeability among these terms, different products bearing these descriptions may differ in design and performance and should be examined individually to differentiate their drug-release mechanisms. By definition, an extended-release product is designed to allow at least a twofold reduction in dosing frequency compared to its immediate-release competitor (18). With the exception of certain scored extended-release products, extended-release tablets should be swallowed whole without alteration by dividing the tablet, crushing, or chewing. The advantages of extended-release dosage formulations include one or more of the following: (a) reduction in fluctuations in plasma drug levels, (b) decreased dosing frequency, (c) enhanced patient convenience and adherence (d) reduction in adverse side effects (19), and (e) reduction in health care costs (6). Potential disadvantages of extended-release formulations include (a) prolonged effects if the patient develops an adverse drug reaction or becomes accidentally intoxicated, (b) the possibility of interactions with the contents of the GI tract, and (c) changes in GI motility resulting in “dose dumping,” in which a large fraction of the dose is absorbed at once. Among AEDs, carbamazepine, valproic acid, lamotrigine, levetiracetam, oxcarbazepine, and topiramate are available as extended-release formulations.
In contrast to extended- and controlled-release formulations, there are also orally disintegrating tablets (ODTs) that allow for rapid disintegration of a solid tablet and oromucosal absorption of the drug. These tablets disintegrate instantly on the tongue and should not be swallowed. Orally disintegrating tablets may benefit children with dysphagia or nausea, and those who are reluctant to swallow a tablet or a capsule. Formulation of an ODT typically involves the use of highly water-soluble and sugar-based excipients, disintegrants, and increased tablet porosity. These factors allow water to enter the tablet quickly, promoting disintegration and making ODTs highly sensitive to humidity (6). Because oral disintegration of the drug allows oromucosal absorption, and can facilitate gastric absorption, some ODT formulations can exhibit greater bioavailability than their tablet formulations. Breaking the ODT into a powder would not affect the safety or efficacy of the product.
Liquid dosage forms, such as solutions (in which the drug is already dissolved) and suspensions (in which the drug is suspended as very small particles), generally exhibit more rapid absorption than solid dosage forms. Liquid dosage forms are available in a variety of solutions depending on their sugar and/or alcohol content. Syrups are intensely sweet (simple syrup contains 85% sucrose in water) with little to no alcohol, while elixirs also contain a high amount of sucrose and, traditionally, contain some amount of ethanol (19). In contrast to liquid solutions, suspensions are comprised of immiscible compounds, which require sufficient agitation prior to administration to ensure that drug particles are evenly dispersed throughout the suspension.
Generic Formulations
When a drug patent expires, companies other than the innovator may manufacture a generic equivalent. Because generic drugs often are less expensive, they offer an cost-saving advantage for patients. The U.S. Food and Drug Administration (FDA) requires that a generic product have the same quantity of active ingredient and a similar rate and extent of drug absorption as the innovator’s product. Bioequivalence (BE) studies are performed to prove that there is no difference in the two products (18,20). This usually is done by administering a single equal dose of the brand-name product and the generic product to a population of between 24 and 36 normal healthy, fasting adults in a randomized, two-period, two-treatment, crossover design (20). Multiple blood samples are collected to determine the extent of drug absorption, as assessed by the total area under the concentration–time curve (AUC) and the rate of drug absorption as determined by the maximum concentration (Cmax). The means of these parameters are determined, and a ratio of the log-transformed data is calculated. Bioequivalence is accepted when the 90% confidence intervals of the AUC and Cmax ratios fall between 0.8 and 1.25 of those of the branded product. In 1999, the FDA reviewed 127 in vivo BE studies performed in 273 generic drug applications approved in 1997 (21). This review reported that the mean difference between the innovator and generic product for AUC(0-inf) was +/- 3.25%; and for Cmax was +/- 4.29%. Because coadministration of food with the drug may affect systemic bioavailability, BE studies in fed subjects are recommended by the FDA in addition to fasting BE studies, except when the “Dosage and Administration” section of the reference listed drug labeling states that the product should only be taken on an empty stomach (22). FDA regulations require that a generic product need only be compared to the innovator and not to other generics. The lot-to-lot consistency within a brand product and within a generic product are regulated by in vitro dissolution rate testing (18) as opposed to BE studies.
The FDA Center for Drug Evaluation and Research annually publishes a listing of approved drug products. The official title of this publication is Approved Drug Products with Therapeutic Equivalence Evaluations, but it is commonly known as the Orange Book. An electronic version known as “the Electronic Orange Book” is available online and is updated continuously. The FDA has “A” and “B” rated products for generic drugs. An “A rated” drug is one that is considered to be “therapeutically equivalent” to the innovator’s drug product. A “B rated” drug is one that is found NOT to be bioequivalent to the innovator’s drug product. Products that are A-rated can be substituted for one another, whereas B-rated products cannot. The FDA further categorizes equivalency ratings by formulation type. For example, “AA rated” products are oral products whose BE is presumed and considered self-evident, such as is the case for solutions, or satisfied for solid oral dosage forms by meeting an acceptable in vitro dissolution standard (23). However, most solid oral dosage forms are identified with an “AB” designation, meaning that such products were subjected to studies to demonstrate BE. Bioequivalent parenteral solutions are designated with “AP” rating.
Because of physician and patient concerns about switching among brand and generic products (24), Berg et al conducted a single-dose, prospective study entitled “EQUIvalence among GENeric AEDs (EQUIGEN)” to determine the interchangeability among various generics and the branded product of the same drug (25). The study compared the pharmacokinetic parameter values between lamotrigine brand (Lamictal®) and its two distinct generic products in people with epilepsy with comorbidities. Results from this study along with those from the EQUIGEN chronic-dose study are expected to reveal the differences in variability between two generic formulations of lamotrigine and Lamictal® in the desired study population.
ALTERNATE ROUTES OF ADMINISTRATION: RECTAL, INTRANASAL, BUCCAL/SUBLINGUAL, AND INTRAMUSCULAR
General Considerations
Occasionally, drug administration by routes other than oral or parenteral is needed to treat patients. Circumstances such as out-of-hospital therapy of seizure emergencies, or bridge therapy when taking medications by mouth is not possible, require other methods of drug administration. The choice of therapy depends on the drug’s physical, chemical, and pharmacokinetic characteristics, the route of administration, and the indication. These characteristics vary substantially among AEDs. Several of the factors that affect oral bioavailability are even more important when administering a drug by an alternate route. For example, the limited surface area in the nasal and rectal cavities requires drugs that are very lipid soluble and sufficiently potent to allow administration in small volumes.
Rectal Formulations
The rectal route of administration may be indicated in situations where the child is unconscious, vomiting, or incapable of swallowing drugs without risk of aspiration. It is particularly useful in treating seizure emergencies or for bridge therapy because the route is accessible and can be safely and easily administered by nonmedical caregivers. There are anatomic, physiological, and pharmaceutical factors that influence the rate and extent of absorption by this route. Compared to a mean intestinal surface area of approximately 32 m2 (26), the rectum has an absorptive surface area of 200–400 cm2 (27), or roughly 0.015% of the former. This limited absorptive surface area favors drugs that are highly lipid soluble. Physiological factors affecting rectal drug absorption include colonic content, low pH (7.2), small fluid volume (1–3 mL), lack of buffering capacity of rectal fluids, and rectal blood flow (19). Drug absorption from the lower two-thirds of the rectum avoids hepatic first-pass metabolism because venous drainage from this area bypasses the liver. In general, drugs delivered either as a suppository or as a solution tend to distribute in the lower two-thirds of the cavity (6). The disintegration and dissolution problems associated with oral products also occur with rectal dosage formulations (28). Solutions and suppositories are the most commonly used rectal dosage forms. Suppositories usually are formulated with a substance that is solid at room temperature, and can melt, soften, or dissolve easily at body temperature. If the substance irritates rectal tissue, it may stimulate a colonic response and start a bowel movement, preventing complete drug release and reducing bioavailability. Adequate retention time in the rectum is also essential for complete absorption. The inability to retain the suppository or solution diminishes the usefulness of this route of administration. Disadvantages of rectal administration include irregular and unpredictable absorption of some drugs, social objections, and legal barriers. Rectal administration of particular AEDs is discussed in greater detail later in this chapter.
Intranasal Administration
The advantages of intranasal (IN) drug delivery include easy access, lack of need for patient cooperation, the potential for rapid and extensive absorption of selected drugs, and avoidance of first-pass metabolism. In contrast, there are several disadvantages: only small volumes (< 200 uL total) can be administered (6); the absorptive surface area of the nasal cavity is small (150 cm2) (29); delivery of drug to the deep sinus cavities is problematic; and the residence time in the cavity is only about 20 minutes as mucus drains into the throat (30). Further, the nasal mucosa is an enzymatically active tissue and has the potential to metabolize certain drugs (31). Therefore, the choice of a therapeutic agent administered intranasally must be limited to drugs that are both highly potent and lipid soluble with a low molecular weight, and capable of being administered as a solution. The limitation in volume and the short residence time make this route best suited for treatment of seizure emergencies (32). Providers should take these factors into consideration prior to administering a solution using commercially available intranasal mucosal atomization devices (MADs) (33). The results of research on this route of administration are discussed later in this chapter.
Buccal/Sublingual Administration
Buccal administration is defined as placement of a drug formulation in the buccal pouch of the oral cavity, which includes the spaces in the cheek adjacent to the mouth. The buccal mucosa is rich in blood supply and has substantial lymphatic drainage, leading to rapid, systemic drug absorption into the jugular vein, avoiding hepatic first-pass metabolism (34). The buccal cavity has a pH of approximately 6.3 (35) and a surface area of 200 cm2 (36), which is similar to the areas of the rectal and nasal cavities. Sublingual administration refers to placement of drug, usually as a solid formulation, under the tongue, with absorption occurring at the mucosal epithelium. The area under the tongue has a pH of approximately 6.5 and an absorptive surface area smaller than that of the buccal cavity. Given the small surface area, the drug product can be easily displaced unless disintegration and dissolution are rapid (i.e., within seconds).
Compared with other routes of administration, the practical advantages of buccal administration are obvious: It is much simpler and safer than intravenous or intramuscular injections; it is less embarrassing and inconvenient for patients and caregivers than rectal administration; and it may permit use of larger volumes than would be possible via intranasal administration (32).
Buccal administration, however, has several disadvantages. The maximum rate of absorption is obtained when the solution can be spread uniformly over the buccal pouch and retained in the cavity. This may be difficult to accomplish if the patient’s head is moving, as might occur during a seizure, resulting in the pooling or swallowing of the drug solution. Moreover, placement of drug in the buccal pouch during a seizure may be hazardous for both the patient and the caregiver and runs counter to first-aid guidelines for seizures. Regarding sublingual administration, similar problems exist with placement and retention of the formulation under the tongue. When given as solutions, volumes must be small, which often limits the size of the dose. These routes are best suited to treatment of seizure emergencies (32). The research results on this route of administration are discussed in a later section of this chapter.
Intramuscular Administration
In general, the extent of absorption after intramuscular (IM) administration is nearly 100%. However, the rate of absorption among different drugs can vary substantially due to solubility, ionization, tissue composition, and blood flow. Factors such as physical activity, heat, and movement that increases blood flow result in a faster rate of drug absorption. Similarly, blood flow and tissue composition vary with location (37). For example, injections given in the gluteus maximus muscle can have a slower absorption rate compared to injections in the deltoid muscle. This is likely due to the higher content of fatty tissue and lower muscle blood flow in the former (30,38). The injection location also defines the maximum volume that can be administered. For example, the deltoid muscle is limited to a volume of 2 mL in a larger child, while maximum volume for the vastus lateralis is 5 mL (or larger if necessary) (39). Regardless of the maximum volumes reported in the literatrue, standard nursing practice is to limit injection volumes to 3 to 5 mL (40). It is also standard nursing practice to rotate injection sites when repeated injections are prescribed, in order to prevent muscle injury. Typical sites of injection include the deltoid muscle in older children, the vastus lateralis (thigh) muscle, and the anterolateral quadriceps in infants and smaller children. Therefore, the clinician should provide instructions as to the preferred sites when rotating injections. Other disadvantages of IM administration include patient discomfort, irritation at the site of injection, needle phobia, and training on proper technique. Among AEDs, benzodiazepines (diazepam, lorazepam, midazolam), fosphenytoin, and phenobarbital are available in solutions for IM injection (41). Given these limitations, IM injections should be generally limited to short-term situations.
SELECTION OF PARENTERAL AND ORAL ANTIEPILEPTIC DRUG DOSAGE FORMS FOR PEDIATRIC PATIENTS
At a minimum, AEDs should be available as parenteral formulations suitable for IV and IM administration as well as oral solid and liquid products. Among the AEDs used for maintenance therapy, only levetiracetam, lacosamide, phenytoin/fosphenytoin, phenobarbital, and valproic acid are available as parenteral formulations.
For maintenance therapy, when a child is unable to swallow a tablet or capsule, consideration should be given to chewable tablets, sprinkle formulations, or liquids. As a last resort, solid tablets can be crushed and capsules can be opened and mixed with water to create a crude suspension, but the bioavailability of such extemporaneous formulations is not assured. Patients with a nasogastric tube may be given AED solutions. Obviously, liquid medicines should be palatable or capable of being mixed with beverages or enteral feedings without interactions so that the patient is able to ingest the medicine. It is possible to give loading doses of oral medications to attain therapeutic concentrations more quickly, although the efficacy of this approach will vary by drug. Examples of AEDs that are reasonably soluble and in a liquid dosage form are diazepam, lorazepam, and midazolam oral solutions.
Benzodiazepines
Diazepam (Valium®) is available as 2 mg, 5 mg, and 10 mg scored tablets. Generic diazepam is also available as a 10 mg/2 mL IV solution in a CarpujectTM glass syringe; a 5 mg/mL IV solution in a 10 mL multiple-dose vial; 1 mg/mL oral solutions (in volumes of 5 mL and 500 mL); and a 150 mg/30 mL oral concentrated solution (Diazepam IntensolTM) (42). Diazepam Intensol should be mixed with liquid or semisolid foods prior to administration. Only the calibrated dropper provided should be used to measure and administer the drug into liquid or semisolid food. This mixture should be consumed immediately and not stored for future use (43).
Lorazepam (Ativan®) is available as 0.5 mg tablets; 1 mg and 2 mg scored tablets; and 2 mg/mL and 4 mg/mL injectable solutions (in volumes of 1 mL and 10 mL). Generic lorazepam is also supplied as 0.5 mg scored tablets and a 2 mg/mL oral concentrated solution (Lorazepam IntensolTM) (44). All lorazepam solutions should be stored in a refrigerator (45).
Midazolam is available as a 2 mg/mL oral solution and as 1 mg/mL and 5 mg/mL IV solutions (in volumes of 2 mL, 5 mL, and 10 mL) (46). Although the IV solution is buffered to a pH of 3.5 (47), there is little if any local irritation when administered IV or IM.
Clobazam (Onfi®) is available as 10 mg and 20 mg scored tablets, and as a 300 mg/120 mL berry-flavored suspension (48). If the daily dose exceeds 5 mg, clobazam should be given twice daily. The oral tablet and suspension demonstrated similar bioavailability in the fasting state and can be used as therapeutic equivalents. Crushing the tablets for administration with applesauce does not alter the absorption, although the absorption of the suspension with meals has not been studied. In addition, the Onfi® tablets contain a lactose excipient. Given that a suspension formulation is available, it is not recommended to administer a crushed tablet as a slurry via NG/NJ tube.
Clonazepam (Klonopin®) is available as 0.5 mg scored tablets, and as 1 mg and 2 mg tablets (49). Generic clonazepam is also supplied in 1 mg and 2 mg scored tablets. Orally disintegrating tablets are available in 0.125, 0.25, 0.5, 1, and 2 mg strengths. Although not commercially available, an extemporaneously compounded suspension can be prepared by crushing tablets and mixing with a 1:1 Ora-Plus/Ora-Sweet mixture (50). This suspension is stable at refrigerated or room temperature for 60 days (51). Both brand and generic clonazepam immediate-release tablets contain a lactose excipient (52). The orally disintegrating tablets do not contain lactose (53).
Carbamazepine
Carbamazepine (Tegretol®) is available as a 100 mg scored chewable tablet, 200 mg partially scored tablet; 100 mg, 200 mg, and 400 mg extended-release tablets (Tegretol XR); and a 100 mg/5 mL citrus-vanilla flavored suspension (54). Extended-release capsules are also supplied in 100, 200, and 300 mg strengths (Carbatrol® and its generics). Generic carbamazepine is manufactured as 100 mg unscored tablets; and as 200, 300, and 400 mg scored tablets. A single-dose study in normal volunteers demonstrated that the bioavailability of chewable tablets is comparable to the bioavailability of swallowed tablets (55). A multidose bioavailability study in patients with epilepsy, which compared equal total daily doses of carbamazepine suspension administered three times a day to tablets administered twice a day, also demonstrated that the suspension is absorbed faster than the tablets (56). If the faster absorption rate is not considered in scheduling dosage administration times, the suspension will produce higher peaks (greater chance of side effects) and lower troughs (greater chance of loss of efficacy) than a comparable dose using carbamazepine tablets.
Tegretol-XR® employs an osmotic pressure-based technology that is provided in a wax matrix with a permeable membrane. As water enters the tablet, the excipient within the tablet forms a gel of a predetermined viscosity, resulting in a suspension that is pushed out of the tablet’s delivery orifice at a controlled rate (57). For example, 10 mg of drug is released per hour for the 100 mg tablet. The casing of the tablet is excreted in the feces. Patients should be told that although casings will appear in the stool, the drug was absorbed. Any disruption to the tablet results in a loss of the controlled-release design. Therefore, this Tegretol XR® must not be crushed, chewed, or opened (58). In contrast, Carbatrol® employs three different types of beads with different release characteristics (immediate-release, extended-release, and enteric-release) in a fixed ratio (25:40:35, respectively). The coating on the beads defines the release pattern of the drug from the capsule (57). The capsules may be opened and mixed with food. The ability to use this formulation as a “sprinkle” is an advantage in pediatric patients (59). Both dosage formulations, when given twice daily, are bioequivalent to the four-times-daily dosing with immediate-release tablets.
A novel, cyclodextrin-based IV carbamazepine formulation has been studied in adults with epilepsy (complex partial, generalized tonic–clonic, or mixed patterns of both seizure types) who were already on oral carbamazepine therapy, and a New Drug Application (NDA) is currently under FDA review (60). Because approximately 30% of the drug exhibits first-pass metabolism, the IV doses were given at 70% of the subjects’ prescribed oral total daily dose, divided into 4 doses given every 6 hours. The solution exhibited a favorable tolerability profile. With the exception of infusion-site reactions, the safety and tolerability profiles among three different infusion rates (2- or 5-min, 15-min, and 30-min) were similar, with the most common adverse effects being dizziness, somnolence, and blurred vision occurring during the infusion period.
Divalproex Sodium/Valproic Acid
Divalproex sodium (Depakote®) is available as 125 mg particle capsules (listed as sprinkle, coated pellets, or delayed-release); 125, 250, and 500 mg delayed-release tablets; and 250 and 500 mg extended-release tablets (Depakote ER®) (61). Valproic acid (Depakene) comes as a 250 mg liquid-filled capsule and a 250 mg/5 mL syrup (62). Valproate sodium injection (Depacon) is supplied as a 100 mg/mL IV solution (in 5 mL vials) (63).
The divalproex sodium particle formulation, although not specifically designed as an extended-release product, does have a slow absorption profile, which minimizes peak-to-trough fluctuations (see Figure 46.2) (64). Further, this dosage form allows the patient or parent to open the capsule and sprinkle the particles over a small amount (teaspoonful) of soft food (such as applesauce or pudding) that can be swallowed all at once.
The rate and extent of absorption from divalproex sodium delayed-release tablets are affected by both food and time of day. For most drugs, the minimum concentration (Cmin) occurs just before the next dose. In contrast, the absorption of delayed-release divalproex sodium produces Cmin 2 to 4 hours after the dose when given on an empty stomach, while coadministration with food extends the time to Cmin from 2 to 8 hours after administration (65). When taken at bedtime, the delayed-release product is absorbed more slowly and the amount of drug absorbed is reduced, resulting in decreased bioavailability (Figure 46.3) (66). These changes in absorption profiles must be considered in evaluating plasma valproate concentrations, particularly if the timing between drug administration and meals varies. The delayed-release tablet should not be crushed, as this compromises its mechanism.
FIGURE 46.2 The effect of formulation on the time course of valproate absorption. Divalproex sodium sprinkle capsules are denoted by “Depakote sprinkle,” while valproic acid syrup is denoted by “Depakene syrup.”
Source: From Ref. (64). Cloyd JC, Kriel RL, Janes-Saete CM, et al. Comparison of sprinkle vs syrup formulations of valproate for bioavailability, tolerance and preference. J Pediatr. 1992;120:634–638.
Divalproex sodium also comes in an extended-release formulation utilizing a hydrophilic-matrix controlled-release tablet system (61). Upon entering the stomach, the film coating dissolves, exposing a hydrophilic polymer matrix tablet. As hydration of the outer layer of the matrix takes places, a gel coating is formed, which initiates drug release. Continued hydration of the matrix surface permits further controlled release of the drug. Once the outer layer is fully hydrated, it erodes and is released from the tablet core. Fluid can continue to penetrate into the tablet core, resulting in the last phase of drug release. This system of polymer wetting, hydration, and erosion results in drug release in the stomach, small intestine, and large intestine over an 18- to 24-hour period (67,68). Divalproex sodium extended-release is designed for once-a-day dosing (69). The absolute bioavailability of divalproex sodium extended-release administered as a single dose after a meal is approximately 80% to 90% relative to an IV infusion. After multiple dosing, divalproex sodium extended-release tablets given once daily produce percent fluctuation (defined as 100% X (Cmax − Cmin)/average concentration) that is 10% to 20% lower than that of regular divalproex sodium given twice a day. Because of the lower bioavailability of the ER tablets, it is not bioequivalent to the delayed-release tablets. It has been recommended that, in converting a patient from Depakote® to Depakote-ER®, the total daily dose of Depakote® be increased by 14% to 20% given as Depakote-ER® (70,71).
FIGURE 46.3 Steady-state 24-hour valproate concentration-time profiles in eight patients randomly assigned to twice-daily dosing in a crossover fashion of an investigational particle-coated tablet (PCT) or divalproex sodium enteric-coated tablet (ECT). The particle-coated tablet was not marketed.
Source: From Ref. (66). Cloyd JC. Pharmacokinetic pitfalls of present antiepileptic medications. Epilepsia. 1991;32(Suppl 5):S53–S65.
Valproate sodium injection should not be given IM because the very high valproate concentrations in tissue result in toxic muscle necrosis (72). At doses up to 60 mg/kg/day, bioequivalence between valproate sodium injection and divalproex sodium can be assumed, due to the linear kinetics of unbound valproate (73).
Eslicarbazepine
Eslicarbazepine (Aptiom®) is available in 200, 400, 600, and 800 mg tablets (74). Scoring on the 200, 600, and 800 mg tablets allows for easy tablet splitting. Tablets can also be crushed, and can be given with food, without altering bioavailability.
Ethosuximide
Ethosuximide (Zarontin®) is available as 250 mg liquid-filled capsules and a 250 mg/5 mL solution (75). Bioequivalency has been established between the two dosage forms; however, the solution exhibits a faster absorption rate (76). Some patients may develop GI side effects with once-daily dosing and require twice-daily dosing (77).
Ezogabine
Ezogabine (Potiga®) is available as 50, 200, 300, and 400 mg film-coated tablets. Tablets should be swallowed whole and can taken three times daily with or without food (78). At room temperature, ezogabine is practically insoluble in aqueous solutions at pH greater than 4 (79). Therefore, it is not recommended that the tablets be crushed and administered as a slurry via a NG/NJ tube.
Felbamate
Felbamate (Felbatol®) is available as 400 and 600 mg scored tablets, and a 600 mg/5 mL suspension (80). Tablets should be swallowed whole with a full glass of water and must not be crushed or chewed (81).
Gabapentin
Gabapentin (Neurontin®) is supplied as 100, 300, and 400 mg capsules; 600 and 800 mg tablets; and a 250 mg/5 mL oral solution (82). The manufacturer indicates that gabapentin may be administered by solution, capsule, tablet, or any combination of these formulations (83). Gabapentin is also available as an extended-release formulation in 300 and 600 mg strengths as Gralise®, which may be taken once daily. Once-daily dosing has been shown to produce comparable drug exposure with an equal daily dose of the immediate-release formulation administered three times daily. Gralise® utilizes AcuFormTM technology, which is a polymer-based drug delivery system that retains the tablet in the stomach and upper GI tract for a prolonged period of time (84). For optimal absorption, Gralise® should be taken with an evening meal. With both immediate- and extended-release formulations, if an aluminum- or magnesium-containing antacid is needed, it should be taken at least 2 hours before the next gabapentin dose.
Lacosamide
Lacosamide (Vimpat®) is available as 50, 100, 150, and 200 mg tablets, a 10 mg/mL oral solution, and a 10 mg/mL IV solution (available in 20 mL vials) (85). The IV solution can be administered without further dilution or may be mixed with sodium chloride 0.9%, dextrose 5% water, or lactated Ringer’s solution. The diluted product should not be stored for more than 4 hours at room temperature. When switching from its oral formulation to the IV solution, the initial dosing of the IV solution should be equal to that used for oral administration. Intravenous and oral formulations should be administered twice daily, roughly 12 hours apart, with or without food, and should follow the same recommended dosing titration. The 30- and 60-min infusions of the IV injection and the oral solution containing 10 mg/mL are considered bioequivalent to the oral tablet.
Lamotrigine
Lamotrigine (Lamictal®) is supplied as 25, 100, 150, and 200 mg scored tablets; as 2, 5, and 25 mg chewable dispersible tablets; as 25, 50, 100, 200, 250, and 300 mg extended-release tablets (Lamictal XR®); and as 25, 50, 100, and 200 mg ODTs (Lamictal ODT®) (86). The immediate-release tablets should be swallowed whole because chewing them may leave a bitter taste (87). In contrast, the chewable dispersible tablet may be swallowed whole, chewed, or mixed in water or diluted fruit juice. If the tablets are chewed, consume a small amount of water or diluted fruit juice to aid in swallowing. To disperse the chewable/dispersible tablet, add the tablets to a small amount of liquid—1 teaspoon (5 mL), or enough to cover the medication—in a glass or spoon. Approximately 1 minute later, when the tablets are completely dispersed, mix the solution and take the entire amount immediately. The lamotrigine chewable/dispersible tablets were shown to be bioequivalent in terms of rate and extent of absorption, whether they were administered dispersed in water, chewed and swallowed, or swallowed whole, to the lamotrigine compressed tablets. The extended-release formulation utilizes the DiffCORE® matrix technology developed by GlaxoSmithKline. This approach involves creating holes of different numbers and sizes in coated tablets. When swallowed, GI fluids enter the tablet hole in the outer shell and penetrate the core, releasing the drug. Release rate can be modulated by the composition of the internal matrix (57). Patients can be directly converted from the immediate-release tablets to the extended-release tablets without a dose change; that is, the initial dose of extended-release tablets should equal the total daily dose of the immediate-release tablets from the previous day (88). The ODT product was formulated using Advatab® technology, which involves microencapsulating the drug within polymers that can quickly disintegrate in the mouth without water. When combined with Microcaps® technology (a taste-masking technology), drug products can have both palatable taste and a “smooth” mouth feel (89). Each ODT tablet should be placed on the tongue and moved around the mouth, with or without food or water, for rapid disintegration (87).
Levetiracetam
Levetiracetam (Keppra®) is manufactured as 250, 500, 750, and 1,000 mg scored immediate-release tablets; 500 and 750 mg extended-release tablets (Keppra XR®); a 100 mg/mL oral solution; and a 100-mg/mL IV solution (90). Levetiracetam is also supplied as 1 g and 1.5 g extended-release tablets under the name Elepsia XR®. The IV formulation is supplied in vials of 500 mg/5 mL. The drug should be diluted in 100 mL of sodium chloride 0.9%, lactated Ringer’s injection, or dextrose 5% injection USP (15). Diluted IV solution is also available in 100 mL bags containing 5, 10, and 15 mg/mL of levetiracetam in sodium chloride 0.9%. The recommended administration time for IV levetiracetam is 15 minutes. When switching from its oral formulation to IV solution, the initial dosing of the IV solution should be equal to that used for oral administration. The extended-release tablets are designed with a dual-release matrix mechanism that involves using both immediate- and modified-release particles in one tablet. The modified-release particles are released as part of the tablet’s diffusion-controlled formulation (57). It may be given with or without food (15).
Oxcarbazepine
Oxcarbazepine (Trileptal®) is available as 150, 300, and 600 mg scored tablets; 150, 300, and 600 mg extended-release tablets (Oxtellar XR®); and as a 300 mg/5 mL oral suspension (91). The immediate-release tablets and the suspension are bioequivalent (92). However, the suspension exhibits a larger median Tmax than the tablets (6 hours and 4.5 hours, respectively). A 10 mL dosing syringe and press-in bottle adapter are provided with oxcarbazepine suspension. The suspension should be used within 7 weeks of first opening the bottle. The extended-release tablet utilizes a matrix delivery technology involving a dissolving homogenous drug–polymer core (93). The extended-release once-daily dose is not bioequivalent to the same total dose of the immediate-release tablets given twice daily. At steady state, Oxtellar XR® administered once daily produced exposures (Cmax and AUC) roughly 19% lower than the immediate-release tablets given twice daily at the same total daily dose (94). Therefore, patients should not be switched from the immediate-release to the extended-release at the same dose. Oxtellar XR® should be taken on an empty stomach (at least 1 hour before or 2 hours after meals).
Perampanel
Perampanel (Fycompa®) is manufactured as 2, 4, 6, 8, 10, and 12 mg film-coated tablets (95). For optimal absorption, tablets should be swallowed whole and given at bedtime, with or without food. The tablets contain lactose as an excipient.
Phenobarbital and Primidone
Phenobarbital is available as 15, 16.2, 30, 32.4, 60, 64.8, 97.2, and 100 mg tablets; a 20 mg/5 mL oral elixir; and 30 mg/mL, 65 mg/mL, and 130 mg/mL parenteral solution (phenobarbital sodium) (96). The parenteral form can be given by rapid IV infusion or by IM injection (97). Primidone (Mysoline®) is available as 50 and 250 mg scored tablets (98). Both brand and generic tablets contain a lactose excipient (99).
Phenytoin/Fosphenytoin
Phenytoin sodium is available as extended-release capsules with the following strengths: 30 mg (Dilantin), 100 mg (Dilantin), 200 mg (Phenytek), and 300 mg (Phenytek). Phenytoin is supplied as a 50 mg chewable tablet (Dilantin Infatab), and a 125 mg/5 mL suspension (Dilantin-125) (100). Phenytoin sodium also comes in a 50 mg/mL injectable solution. Fosphenytoin (Cerebyx®) is supplied as a 50 mg phenytoin sodium equivalent/mL parenteral solution.
All 30, 100, 200, and 300 mg phenytoin sodium capsules have extended-release properties (100). The Tmax following a single dose (300–400 mg) of the extended-release formulations ranges from 4 to 12 hours, which in combination with the drug’s long elimination half-life permits once-daily dosing (101). At doses of 800–1,600 mg and above, the rate, but not the extent of absorption, is reduced, with Tmax from 3 to 31 hours (102). Consequently, use of oral phenytoin loading doses for seizure emergencies is not recommended.
The 200 and 300 mg Phenytek™ capsules employ an erodible-matrix delivery system that includes two and three erodible-matrix tablets, respectively (30). After ingestion, the capsule shell dissolves to expose two (200 mg) or three (300 mg) tablets. As water permeates these tablets, a gel layer is formed, which in turn allows the gradual release of phenytoin. Phenytek™ capsules should not be opened, nor should the contents be crushed or taken separately (103).
As noted in Chapter 49, the various formulations of phenytoin differ in phenytoin content (Table 46.1). The chewable tablet and suspension both contain 100% phenytoin, as opposed to phenytoin sodium capsules, which are 92% phenytoin. Because phenytoin follows Michaelis–Menten kinetics, children being switched from the chewable tablet or suspension may require a larger mg/kg dose of the capsule to maintain desired plasma drug concentrations. The Tmax for the chewable tablet and suspension is shorter than for the capsules, ranging from 1.5 to 3 hours. The chewable tablet has a sweet, mint flavor and may be confused for candy. Although true for all medications, it is especially important that the chewable Infatabs be kept out of reach of children. Phenytoin suspension is particularly prone to settling; hence, vigorous shaking of the bottle prior to measuring the dose is required. Phenytoin should be administered with food to minimize gastric irritation (103). If any antacids are needed, they should be given at least 1 hour after phenytoin administration.
TABLE 46.1
Phenytoin is poorly soluble in water, which necessitates the use of propylene glycol and ethanol (organic solvents), along with buffering to a pH of 12 in the injectable formulation. The solvents can cause cardiac arrhythmias and hypotension, particularly when administered at fast infusion rates to medically frail patients. The combination of cosolvent effects and the alkaline pH commonly cause pain and inflammation at the infusion site and, if the indwelling catheter is displaced, can result in a “blue glove” injury distal to the infusion site (104). Therefore, phenytoin infusions are limited to a rate no faster than 1 to 3 mg/kg/min in otherwise healthy children. Because of the high ionization constant (pKa) of phenytoin, it is unstable in most IV solutions. It may be diluted with normal saline in concentration ranges of 2 to 20 mg/mL, but the use of an in-line 20-micron filter is recommended to reduce and remove small particle precipitants. Admixtures should be stored for no longer than 24 hours (105).
Fosphenytoin sodium injection (Cerebyx®) is an inactive prodrug formed by the addition of a phosphate ester to the phenytoin molecule. This addition significantly increases the water solubility of fosphenytoin. The ester must be cleaved by systemic phosphatases in order to form the active drug, phenytoin. The conversion half-life of fosphenytoin to phenytoin is rapid, 8 to 15 minutes, and complete (106). The phosphatases are not affected by age, gender, race, hepatic impairment, or renal function (107).
Because fosphenytoin is more water-soluble than phenytoin, it does not require organic solvents and is compatible with all IV fluids. Further, fosphenytoin can be infused at a much faster rate (150 mg/min) than phenytoin. Another advantage of fosphenytoin is that in comparative studies, it causes less thrombophlebitis, burning, pain, and irritation at the injection site (108). This results in fewer changes in the site of administration. The decreased venous irritation is a particular advantage in premature infants, neonates, and children, in whom venous access is a serious problem. The primary infusion site reactions of fosphenytoin are pruritus and paresthesias (106), which are common to phosphate esters and disappear with a reduction in the infusion rate or when the infusion is completed.
Pregabalin
Pregabalin (Lyrica®) is supplied as 25, 50, 75, 100, 150, 200, 225, and 300 mg capsules and as a 20 mg/mL oral solution (109). Both capsules and solution can be given with or without food. Lyrica® capsules also contain a lactose excipient.
Rufinamide
Rufinamide (Banzel®) is available as 200 and 400 mg film-coated and scored tablets, and a 40 mg/mL orange-flavored oral suspension (110). With doses greater than 400 mg, Cmax and AUC increase in a less than proportional manner. The tablets may be cut in half, crushed, or swallowed whole, and should be taken with food. Banzel tablets contain a lactose excipient.
Tiagabine
Tiagabine (Gabitril®) is supplied as 2, 4, 12, and 16 mg tablets. Generic tiagabine is available in 2 and 4 mg tablets (111). For optimal absorption, tiagabine should be given with food (112). Extemporaneous compounding of a suspension can be made with an Ora-Sweet and Ora-Plus mixture. This suspension should be stored in a plastic amber vial, and remains stable for 42 days at room temperature or 91 days refrigerated (113).
Topiramate
Topiramate (Topamax®) is available as 25, 50, 100, and 200 mg tablets; 15 and 25 mg immediate-release sprinkle capsules; 25, 50, 100, 150, and 200 mg extended-release sprinkle capsules (Qudexy XR®); and 25, 50, 100, and 200 mg extended-release capsules (Trokendi XR®) (114). Extemporaneous compounding of an oral suspension using the immediate-release tablets can be made using a mixture of Ora-Sweet and Ora-Plus. This suspension is stable for 90 days refrigerated (preferred) or at room temperature (115). The sprinkle capsules contain coated beads; the capsules may be swallowed whole or opened and sprinkled onto soft foods. The immediate-release sprinkle formulation is bioequivalent to the immediate-release tablets and may be substituted as a therapeutic equivalent. If the sprinkle capsule is to be administered as a sprinkle, the patient should be instructed to hold the capsule upright and carefully twist off the top. The entire contents of the capsule should be emptied onto a spoonful of the soft food with which the drug is to be mixed. The patient should swallow the entire contents of the spoonful of food and topiramate. The patient should not chew the food–drug mixture and should follow the ingestion with fluids to ensure that the entire contents are swallowed. The mixture should never be stored for later use (16). Qudexy XR® can be opened to sprinkle the entire contents on a small amount of soft food (116); in contrast, Trokendi XR® should not be opened, as this may disrupt the triphasic release properties of this formulation (117). Bioequivalence between Qudexy XR® and Trokendi XR® has not been demonstrated.
Vigabatrin
Vigabatrin (Sabril®) is available as 500 mg scored tablets and as a 500 mg oral solution powder (118). The tablet and powder formulations are bioequivalent. Prior to administration of the oral solution powder, the entire contents of the packet should be emptied into a clean cup of 10 mL of cold or room-temperature water, and administered with the provided oral syringe immediately after reconstitution. Any solution that is not clear, colorless, or free of particles should be discarded. In addition, any unused portion of the solution should be discarded after the correct dose has been given. Vigabatrin can be given with or without food.
Zonisamide
Zonisamide (Zonegran®) is supplied as 25, 50, and 100 mg capsules (119). Zonisamide capsules should be swallowed whole and may be taken with or without food (120). Although there is no commercially available solution or suspension, an oral suspension may be extemporaneously compounded with simple syrup and is stable for 28 days (121).
USE OF ANTIEPILEPTIC DRUGS BY ALTERNATE ROUTES
Stay updated, free articles. Join our Telegram channel
Full access? Get Clinical Tree
