OXcarbazepine 150 MG Oral Tablet
Generic Name: OXCARBAZEPINE
Brand Name: OXCARBAZEPINE
- Substance Name(s):
- OXCARBAZEPINE
DRUG INTERACTIONS
7 Oxcarbazepine can inhibit CYP2C19 and induce CYP3A4/5 with potentially important effects on plasma concentrations of other drugs.
The inhibition of CYP2C19 by oxcarbazepine and MHD can cause increased plasma concentrations of drugs that are substrates of CYP2C19.
Oxcarbazepine and MHD induce a subgroup of the cytochrome P450 3A family (CYP3A4 and CYP3A5) responsible for the metabolism of dihydropyridine calcium antagonists, oral contraceptives and cyclosporine resulting in a lower plasma concentration of these drugs.
[see Clinical Pharmacology (12.3)] In addition, several AEDs that are cytochrome P450 inducers can decrease plasma concentrations of oxcarbazepine and MHD.
No autoinduction has been observed with oxcarbazepine tablets, USP.
Phenytoin: Increased phenytoin levels.
Reduced dose of phenytoin may be required.
( 7.1) Carbamazepine: Decreased plasma levels of MHD (the active metabolite).
Dose adjustments may be necessary.
( 7.1) Phenobarbital: Decreased plasma levels of MHD.
Dose adjustments may be necessary.
( 7.1) Oral Contraceptive: Patients should be advised that oxcarbazepine tablets, USP may decrease the effectiveness of hormonal contraceptives.
( 7.2) 7.1 Antiepileptic Drugs Potential interactions between oxcarbazepine tablets, USP and other AEDs were assessed in clinical studies.
The effect of these interactions on mean AUCs and C min are summarized in Table 7.
Table 7 Summary of AED Interactions with Oxcarbazepine Tablets, USP AED Coadministered Dose of AED (mg/day) Oxcarbazepine Tablets Dose (mg/day) Influence of Oxcarbazepine Tablets on AED Concentration (Mean Change, 90% Confidence Interval) Influence of AED on MHD Concentration (Mean Change, 90% Confidence Interval) Carbamazepine 400-2000 900 nc nc denotes a mean change of less than 10% 40% decrease [CI: 17% decrease, 57% decrease] Phenobarbital 100-150 600-1800 14% increase [CI: 2% increase, 24% increase] 25% decrease [CI: 12% decrease, 51% decrease] Phenytoin 250-500 600-1800 >1200-2400 nc , Pediatrics up to 40% increase Mean increase in adults at high oxcarbazepine tablets, USP doses [CI: 12% increase, 60% increase] 30% decrease [CI: 3% decrease, 48% decrease] Valproic acid 400-2800 600-1800 nc 18% decrease [CI: 13% decrease, 40% decrease] In vivo, the plasma levels of phenytoin increased by up to 40% when oxcarbazepine tablets, USP was given at doses above 1200 mg/day.
Therefore, when using doses of oxcarbazepine tablets, USP greater than 1200 mg/day during adjunctive therapy, a decrease in the dose of phenytoin may be required.
The increase of phenobarbital level, however, is small (15%) when given with oxcarbazepine tablets, USP.
Strong inducers of cytochrome P450 enzymes (i.e., carbamazepine, phenytoin and phenobarbital) have been shown to decrease the plasma levels of MHD (29%-40%).
No autoinduction has been observed with oxcarbazepine tablets, USP.
7.2 Hormonal Contraceptives Coadministration of oxcarbazepine tablets, USP with an oral contraceptive has been shown to influence the plasma concentrations of the two hormonal components, ethinylestradiol (EE) and levonorgestrel (LNG).
The mean AUC values of EE were decreased by 48% [90% CI: 22-65] in one study and 52% [90% CI: 38-52] in another study.
The mean AUC values of LNG were decreased by 32% [90% CI: 20-45] in one study and 52% [90% CI: 42-52] in another study.
Therefore, concurrent use of oxcarbazepine tablets, USP with hormonal contraceptives may render these contraceptives less effective.
Studies with other oral or implant contraceptives have not been conducted.
7.3 Calcium Antagonists After repeated coadministration of oxcarbazepine tablets, USP, the AUC of felodipine was lowered by 28% [90% CI: 20-33].
Verapamil produced a decrease of 20% [90% CI: 18-27] of the plasma levels of MHD.
7.4 Other Drug Interactions Cimetidine, erythromycin and dextropropoxyphene had no effect on the pharmacokinetics of MHD.
Results with warfarin show no evidence of interaction with either single or repeated doses of oxcarbazepine tablets, USP.
7.5 Drug/Laboratory Test Interactions There are no known interactions of oxcarbazepine tablets, USP with commonly used laboratory tests.
OVERDOSAGE
10 Human Overdose Experience Isolated cases of overdose with oxcarbazepine tablets, USP have been reported.
The maximum dose taken was approximately 24,000 mg.
All patients recovered with symptomatic treatment.
Treatment and Management There is no specific antidote.
Symptomatic and supportive treatment should be administered as appropriate.
Removal of the drug by gastric lavage and/or inactivation by administering activated charcoal should be considered.
DESCRIPTION
11 Oxcarbazepine tablet is an antiepileptic drug available as 150 mg, 300 mg and 600 mg film-coated tablets for oral administration.
Oxcarbazepine is 10,11-Dihydro-10-oxo-5 H-dibenz[b,ƒ]azepine-5-carboxamide, and its structural formula is Oxcarbazepine is a white to faintly orange crystalline powder.
It is slightly soluble in chloroform, dichloromethane, acetone, and methanol and practically insoluble in ethanol, ether and water.
Its molecular weight is 252.27.
Oxcarbazepine film-coated tablets contain the following inactive ingredients: microcrystalline cellulose, crospovidone, hypromellose, colloidal silicon dioxide, magnesium stearate, talc.
Coating: polyvinyl alcohol, talc, titanium dioxide, polyethylene glycol, Contains FD&C Yellow No.
6 as a color additive.FD&C Yellow No.
6 aluminum lake, lecithin, FD&C Blue No.
2 aluminum lake, Contains FD&C Yellow No.
5 as a color additive.
[See WARNINGS AND PRECAUTIONS (5.12)].
FD&C Yellow No.
5 aluminum lake.
Allergen Statement: This product contains soy.
Oxcarbazepine Tablets, USP complies with USP Dissolution Test 2.
Chemical Structure
CLINICAL STUDIES
14 The effectiveness of oxcarbazepine tablets, USP as adjunctive and monotherapy for partial seizures in adults, and as adjunctive therapy in children aged 2-16 years was established in seven multicenter, randomized, controlled trials.
The effectiveness of oxcarbazepine tablets, USP as monotherapy for partial seizures in children aged 4-16 years was determined from data obtained in the studies described, as well as by pharmacokinetic/pharmacodynamic considerations.
14.1 Oxcarbazepine Tablets, USP Monotherapy Trials Four randomized, controlled, double-blind, multicenter trials, conducted in a predominately adult population, demonstrated the efficacy of oxcarbazepine tablets, USP as monotherapy.
Two trials compared oxcarbazepine tablets, USP to placebo and two trials used a randomized withdrawal design to compare a high dose (2400 mg) with a low dose (300 mg) of oxcarbazepine tablets, USP, after substituting oxcarbazepine tablets, USP 2400 mg/day for one or more antiepileptic drugs (AEDs).
All doses were administered on a twice-a-day schedule.
A fifth randomized, controlled, rater-blind, multicenter study, conducted in a pediatric population, failed to demonstrate a statistically significant difference between low and high dose oxcarbazepine tablets, USP treatment groups.
One placebo-controlled trial was conducted in 102 patients (11-62 years of age) with refractory partial seizures who had completed an inpatient evaluation for epilepsy surgery.
Patients had been withdrawn from all AEDs and were required to have 2-10 partial seizures within 48 hours prior to randomization.
Patients were randomized to receive either placebo or oxcarbazepine tablets, USP given as 1500 mg/day on Day 1 and 2400 mg/day thereafter for an additional nine days, or until one of the following three exit criteria occurred: 1) the occurrence of a fourth partial seizure, excluding Day 1, 2) two new-onset secondarily generalized seizures, where such seizures were not seen in the one-year period prior to randomization, or 3) occurrence of serial seizures or status epilepticus.
The primary measure of effectiveness was a between-group comparison of the time to meet exit criteria.
There was a statistically significant difference in favor of oxcarbazepine tablets, USP (see Figure 1), p=0.0001.
Figure 1 Kaplan-Meier Estimates of Exit Rate by Treatment Group The second placebo-controlled trial was conducted in 67 untreated patients (8-69 years of age) with newly-diagnosed and recent-onset partial seizures.
Patients were randomized to placebo or oxcarbazepine tablets, USP, initiated at 300 mg twice a day and titrated to 1200 mg/day (given as 600 mg twice a day) in six days, followed by maintenance treatment for 84 days.
The primary measure of effectiveness was a between-group comparison of the time to first seizure.
The difference between the two treatments was statistically significant in favor of oxcarbazepine tablets, USP (see Figure 2), p=0.046.
Figure 2 Kaplan-Meier Estimates of First Seizure Event Rate by Treatment Group A third trial substituted oxcarbazepine tablets, USP monotherapy at 2400 mg/day for carbamazepine in 143 patients (12-65 years of age) whose partial seizures were inadequately controlled on carbamazepine (CBZ) monotherapy at a stable dose of 800 to 1600 mg/day, and maintained this oxcarbazepine tablets, USP dose for 56 days (baseline phase).
Patients who were able to tolerate titration of oxcarbazepine tablets, USP to 2400 mg/day during simultaneous carbamazepine withdrawal were randomly assigned to either 300 mg/day of oxcarbazepine tablets, USP or 2400 mg/day oxcarbazepine tablets, USP.
Patients were observed for 126 days or until one of the following four exit criteria occurred: 1) a doubling of the 28-day seizure frequency compared to baseline, 2) a two-fold increase in the highest consecutive two-day seizure frequency during baseline, 3) a single generalized seizure if none had occurred during baseline, or 4) a prolonged generalized seizure.
The primary measure of effectiveness was a between-group comparison of the time to meet exit criteria.
The difference between the curves was statistically significant in favor of the oxcarbazepine tablets, USP 2400 mg/day group (see Figure 3), p=0.0001.
Figure 3 Kaplan-Meier Estimates of Exit Rate by Treatment Group Another monotherapy substitution trial was conducted in 87 patients (11-66 years of age) whose seizures were inadequately controlled on one or two AEDs.
Patients were randomized to either oxcarbazepine tablets, USP 2400 mg/day or 300 mg/day and their standard AED regimen(s) were eliminated over the first six weeks of double-blind therapy.
Double-blind treatment continued for another 84 days (total double-blind treatment of 126 days) or until one of the four exit criteria described for the previous study occurred.
The primary measure of effectiveness was a between-group comparison of the percentage of patients meeting exit criteria.
The results were statistically significant in favor of the oxcarbazepine tablets, USP 2400 mg/day group (14/34; 41.2%) compared to the oxcarbazepine tablets, USP 300 mg/day group (42/45; 93.3%) (p<0.0001).
The time to meeting one of the exit criteria was also statistically significant in favor of the oxcarbazepine tablets, USP 2400 mg/day group (see Figure 4), p=0.0001.
Figure 4 Kaplan-Meier Estimates of Exit Rate by Treatment Group A monotherapy trial was conducted in 92 pediatric patients (1 month to 16 years of age) with inadequately-controlled or new-onset partial seizures.
Patients were hospitalized and randomized to either oxcarbazepine tablets, USP 10 mg/kg/day or were titrated up to 40-60 mg/kg/day within three days while withdrawing the previous AED on the second day of oxcarbazepine therapy.
Seizures were recorded through continuous video-EEG monitoring from Day 3 to Day 5.
Patients either completed the 5-day treatment or met one of the two exit criteria: 1) three study-specific seizures (i.e., electrographic partial seizures with a behavioral correlate), 2) a prolonged study-specific seizure.
The primary measure of effectiveness was a between-group comparison of the time to meet exit criteria in which the difference between the curves was not statistically significant (p=0.904).
The majority of patients from both dose groups completed the 5-day study without exiting.
Although this study failed to demonstrate an effect of oxcarbazepine as monotherapy in pediatric patients, several design elements, including the short treatment and assessment period, the absence of a true placebo, and the likely persistence of plasma levels of previously administered AEDs during the treatment period, make the results uninterpretable.
For this reason, the results do not undermine the conclusion, based on pharmacokinetic/pharmacodynamic considerations, that oxcarbazepine is effective as monotherapy in pediatric patients 4 years old and older.
Figure 1 Figure 2 Figure 3 Figure 4 14.2 Oxcarbazepine Tablets, USP Adjunctive Therapy Trials The effectiveness of oxcarbazepine tablets, USP as an adjunctive therapy for partial seizures was established in two multicenter, randomized, double-blind, placebo-controlled trials, one in 692 patients (15-66 years of age) and one in 264 pediatric patients (3-17 years of age), and in one multicenter, rater-blind, randomized, age-stratified, parallel-group study comparing two doses of oxcarbazepine in 128 pediatric patients (1 month to <4 years of age).
Patients in the two placebo-controlled trials were on 1-3 concomitant AEDs.
In both of the trials, patients were stabilized on optimum dosages of their concomitant AEDs during an 8-week baseline phase.
Patients who experienced at least 8 (minimum of 1-4 per month) partial seizures during the baseline phase were randomly assigned to placebo or to a specific dose of oxcarbazepine tablets, USP in addition to their other AEDs.
In these studies, the dose was increased over a two-week period until either the assigned dose was reached, or intolerance prevented increases.
Patients then entered a 14- (pediatrics) or 24-week (adults) maintenance period.
In the adult trial, patients received fixed doses of 600, 1200 or 2400 mg/day.
In the pediatric trial, patients received maintenance doses in the range of 30-46 mg/kg/day, depending on baseline weight.
The primary measure of effectiveness in both trials was a between-group comparison of the percentage change in partial seizure frequency in the double-blind treatment phase relative to baseline phase.
This comparison was statistically significant in favor of oxcarbazepine tablets, USP at all doses tested in both trials (p=0.0001 for all doses for both trials).
The number of patients randomized to each dose, the median baseline seizure rate, and the median percentage seizure rate reduction for each trial are shown in Table 8.
It is important to note that in the high-dose group in the study in adults, over 65% of patients discontinued treatment because of adverse events; only 46 (27%) of the patients in this group completed the 28-week study [see Adverse Reactions (6)] , an outcome not seen in the monotherapy studies.
Table 8 Summary of Percentage Change in Partial Seizure Frequency from Baseline for Placebo-Controlled Adjunctive Therapy Trials Trial Treatment Group N Baseline Median Seizure Rate = # per 28 days Median % Reduction 1 (pediatrics) Oxcarbazepine Tablets, USP 136 12.5 34.8 p=0.0001 Placebo 128 13.1 9.4 2 (adults) Oxcarbazepine Tablets, USP 2400 mg/day 174 10.0 49.9 Oxcarbazepine Tablets, USP 1200 mg/day 177 9.8 40.2 Oxcarbazepine Tablets, USP 600 mg/day 168 9.6 26.4 Placebo 173 8.6 7.6 Subset analyses of the antiepileptic efficacy of oxcarbazepine tablets, USP with regard to gender in these trials revealed no important differences in response between men and women.
Because there were very few patients over the age of 65 in controlled trials, the effect of the drug in the elderly has not been adequately assessed.
The third adjunctive therapy trial enrolled 128 pediatric patients (1 month to <4 years of age) with inadequately-controlled partial seizures on 1-2 concomitant AEDs.
Patients who experienced at least 2 study-specific seizures (i.e., electrographic partial seizures with a behavioral correlate) during the 72-hour baseline period were randomly assigned to either oxcarbazepine tablets, USP 10 mg/kg/day or were titrated up to 60 mg/kg/day within 26 days.
Patients were maintained on their randomized target dose for 9 days and seizures were recorded through continuous video-EEG monitoring during the last 72 hours of the maintenance period.
The primary measure of effectiveness in this trial was a between-group comparison of the change in seizure frequency per 24 hours compared to the seizure frequency at baseline.
For the entire group of patients enrolled, this comparison was statistically significant in favor of oxcarbazepine tablets, USP 60 mg/kg/day.
In this study, there was no evidence that oxcarbazepine tablets, USP were effective in patients below the age of 2 years (N=75).
HOW SUPPLIED
16 /STORAGE AND HANDLING Oxcarbazepine Tablets, USP are provided as: 150 mg Film-Coated Tablets: beige, film-coated, modified oval shaped tablet, scored on both sides, debossed “B2|92” on one side and plain on the other side.
Unit dose packages of 100 (10 x 10) NDC 68084-845-01 300 mg Film-Coated Tablets: beige, film-coated, modified oval shaped tablet, scored on both sides, debossed “B|293” on one side and plain on the other side.
Unit dose packages of 100 (10 x 10) NDC 68084-853-01 600 mg Film-Coated Tablets: beige, film-coated, modified oval shaped tablet, scored on both sides, debossed “B|294” on one side and plain on the other side.
Unit dose packages of 100 (10 x 10) NDC 68084-867-01 Store at 20°-25°C (77°F); excursions permitted to 15°-30°C (59°-86°F) [See USP Controlled Room Temperature].
FOR YOUR PROTECTION: Do not use if blister is torn or broken.
RECENT MAJOR CHANGES
Warnings and Precautions ( 5.4) 06/2014
GERIATRIC USE
8.5 Geriatric Use There were 52 patients over age 65 in controlled clinical trials and 565 patients over the age of 65 in other trials.
Following administration of single (300 mg) and multiple (600 mg/day) doses of oxcarbazepine tablets, USP in elderly volunteers (60-82 years of age), the maximum plasma concentrations and AUC values of MHD were 30%-60% higher than in younger volunteers (18-32 years of age).
Comparisons of creatinine clearance in young and elderly volunteers indicate that the difference was due to age-related reductions in creatinine clearance.
DOSAGE FORMS AND STRENGTHS
3 Film-coated Tablets: 150 mg, 300 mg and 600 mg.
Film-coated tablets: 150 mg, 300 mg and 600 mg ( 3)
MECHANISM OF ACTION
12.1 Mechanism of Action The pharmacological activity of oxcarbazepine tablets, USP is primarily exerted through the 10-monohydroxy metabolite (MHD) of oxcarbazepine [see Clinical Pharmacology (12.3)].
The precise mechanism by which oxcarbazepine and MHD exert their antiseizure effect is unknown; however, in vitro electrophysiological studies indicate that they produce blockade of voltage-sensitive sodium channels, resulting in stabilization of hyperexcited neural membranes, inhibition of repetitive neuronal firing, and diminution of propagation of synaptic impulses.
These actions are thought to be important in the prevention of seizure spread in the intact brain.
In addition, increased potassium conductance and modulation of high-voltage activated calcium channels may contribute to the anticonvulsant effects of the drug.
No significant interactions of oxcarbazepine or MHD with brain neurotransmitter or modulator receptor sites have been demonstrated.
INDICATIONS AND USAGE
1 Oxcarbazepine tablets, USP are indicated for use as monotherapy or adjunctive therapy in the treatment of partial seizures in adults and as monotherapy in the treatment of partial seizures in children aged 4 years and above with epilepsy, and as adjunctive therapy in children aged 2 years and above with partial seizures.
Oxcarbazepine tablets, USP are an antiepileptic drug indicated for: Adults: Monotherapy or adjunctive therapy in the treatment of partial seizures Children: Monotherapy in the treatment of partial seizures in children 4-16 years Adjunctive therapy in the treatment of partial seizures in children 2-16 years ( 1)
PEDIATRIC USE
8.4 Pediatric Use Oxcarbazepine tablets, USP are indicated for use as adjunctive therapy for partial seizures in patients aged 2-16 years.
Oxcarbazepine tablets, USP are also indicated as monotherapy for partial seizures in patients aged 4-16 years.
Oxcarbazepine tablets, USP have been given to 898 patients between the ages of 1 month-17 years in controlled clinical trials (332 treated as monotherapy) and about 677 patients between the ages of 1 month-17 years in other trials [ see Adverse Reactions (6.1) for a description of the adverse events associated with oxcarbazepine tablets, USP use in this population].
PREGNANCY
8.1 Pregnancy Oxcarbazepine tablets, USP levels may decrease during pregnancy [see Warnings and Precautions (5.10)] .
Pregnancy Category C There are no adequate and well-controlled clinical studies of oxcarbazepine tablets, USP in pregnant women; however, oxcarbazepine tablets, USP is closely related structurally to carbamazepine, which is considered to be teratogenic in humans.
Given this fact, and the results of the animal studies described, it is likely that oxcarbazepine tablets, USP is a human teratogen.
Oxcarbazepine tablets, USP should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Increased incidences of fetal structural abnormalities and other manifestations of developmental toxicity (embryolethality, growth retardation) were observed in the offspring of animals treated with either oxcarbazepine or its active 10-hydroxy metabolite (MHD) during pregnancy at doses similar to the maximum recommended human dose.
When pregnant rats were given oxcarbazepine (30, 300, or 1000 mg/kg) orally throughout the period of organogenesis, increased incidences of fetal malformations (craniofacial, cardiovascular, and skeletal) and variations were observed at the intermediate and high doses (approximately 1.2 and 4 times, respectively, the maximum recommended human dose [MRHD] on a mg/m 2 basis).
Increased embryofetal death and decreased fetal body weights were seen at the high dose.
Doses ≥300 mg/kg were also maternally toxic (decreased body weight gain, clinical signs), but there is no evidence to suggest that teratogenicity was secondary to the maternal effects.
In a study in which pregnant rabbits were orally administered MHD (20, 100, or 200 mg/kg) during organogenesis, embryofetal mortality was increased at the highest dose (1.5 times the MRHD on a mg/m 2 basis).
This dose produced only minimal maternal toxicity.
In a study in which female rats were dosed orally with oxcarbazepine (25, 50, or 150 mg/kg) during the latter part of gestation and throughout the lactation period, a persistent reduction in body weights and altered behavior (decreased activity) were observed in offspring exposed to the highest dose (0.6 times the MRHD on a mg/m 2 basis).
Oral administration of MHD (25, 75, or 250 mg/kg) to rats during gestation and lactation resulted in a persistent reduction in offspring weights at the highest dose (equivalent to the MRHD on a mg/m 2 basis).
To provide information regarding the effects of in utero exposure to oxcarbazepine tablets, USP, physicians are advised to recommend that pregnant patients taking oxcarbazepine tablets, USP 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.
Information on the registry can also be found at the website http://www.aedpregnancyregistry.org/.
NUSRING MOTHERS
8.3 Nursing Mothers Oxcarbazepine and its active metabolite (MHD) are excreted in human milk.
A milk-to-plasma concentration ratio of 0.5 was found for both.
Because of the potential for serious adverse reactions to oxcarbazepine tablets, USP in nursing infants, a decision should be made about whether to discontinue nursing or to discontinue the drug in nursing women, taking into account the importance of the drug to the mother.
WARNING AND CAUTIONS
5 WARNINGS AND PRECAUTIONS Hyponatremia ( 5.1) Anaphylactic Reactions and Angioedema ( 5.2) Patients with a Past History of Hypersensitivity Reaction to Carbamazepine ( 5.3) Serious Dermatological Reactions ( 5.4) Suicidal Behavior and Ideation ( 5.5) Withdrawal of AEDs ( 5.6) Cognitive/Neuropsychiatric Adverse Events ( 5.7) Drug reaction with Eosinophilia and Systemic Symptoms (DRESS)/Multi-Organ Hypersensitivity ( 5.8) Hematologic Events ( 5.9) Seizure Control During Pregnancy ( 5.10) Laboratory Tests ( 5.11) 5.1 Hyponatremia Clinically significant hyponatremia (sodium <125 mmol/L) can develop during oxcarbazepine tablets, USP use.
In the 14 controlled epilepsy studies 2.5% of oxcarbazepine tablets, USP-treated patients (38/1,524) had a sodium of less than 125 mmol/L at some point during treatment, compared to no such patients assigned placebo or active control (carbamazepine and phenobarbital for adjunctive and monotherapy substitution studies, and phenytoin and valproate for the monotherapy initiation studies).
Clinically significant hyponatremia generally occurred during the first three months of treatment with oxcarbazepine tablets, USP, although there were patients who first developed a serum sodium <125 mmol/L more than one year after initiation of therapy.
Most patients who developed hyponatremia were asymptomatic but patients in the clinical trials were frequently monitored and some had their oxcarbazepine tablets, USP dose reduced, discontinued, or had their fluid intake restricted for hyponatremia.
Whether or not these maneuvers prevented the occurrence of more severe events is unknown.
Cases of symptomatic hyponatremia have been reported during post-marketing use.
In clinical trials, patients whose treatment with oxcarbazepine tablets, USP was discontinued due to hyponatremia generally experienced normalization of serum sodium within a few days without additional treatment.
Measurement of serum sodium levels should be considered for patients during maintenance treatment with oxcarbazepine tablets, USP, particularly if the patient is receiving other medications known to decrease serum sodium levels (for example, drugs associated with inappropriate ADH secretion) or if symptoms possibly indicating hyponatremia develop (e.g., nausea, malaise, headache, lethargy, confusion, obtundation, or increase in seizure frequency or severity).
5.2 Anaphylactic Reactions and Angioedema Rare cases of anaphylaxis and angioedema involving the larynx, glottis, lips and eyelids have been reported in patients after taking the first or subsequent doses of oxcarbazepine tablets, USP.
Angioedema associated with laryngeal edema can be fatal.
If a patient develops any of these reactions after treatment with oxcarbazepine tablets, USP, the drug should be discontinued and an alternative treatment started.
These patients should not be rechallenged with the drug [see Warnings and Precautions (5.3)].
5.3 Patients with a Past History of Hypersensitivity Reaction to Carbamazepine Patients who have had hypersensitivity reactions to carbamazepine should be informed that approximately 25%-30% of them will experience hypersensitivity reactions with oxcarbazepine tablets, USP.
For this reason patients should be specifically questioned about any prior experience with carbamazepine, and patients with a history of hypersensitivity reactions to carbamazepine should ordinarily be treated with oxcarbazepine tablets, USP only if the potential benefit justifies the potential risk.
If signs or symptoms of hypersensitivity develop, oxcarbazepine tablets, USP should be discontinued immediately [see Warnings and Precautions (5.2, 5.8)].
5.4 Serious Dermatological Reactions Serious dermatological reactions, including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), have been reported in both children and adults in association with oxcarbazepine tablets, USP use.
Such serious skin reactions may be life threatening, and some patients have required hospitalization, with very rare reports of fatal outcome.
The median time of onset for reported cases was 19 days after treatment initiation.
Recurrence of the serious skin reactions following rechallenge with oxcarbazepine tablets, USP has also been reported.
The reporting rate of TEN and SJS associated with oxcarbazepine tablets, USP use, which is generally accepted to be an underestimate due to underreporting, exceeds the background incidence rate estimates by a factor of 3- to 10-fold.
Estimates of the background incidence rate for these serious skin reactions in the general population range between 0.5 to 6 cases per million-person years.
Therefore, if a patient develops a skin reaction while taking oxcarbazepine tablets, USP, consideration should be given to discontinuing oxcarbazepine tablets, USP use and prescribing another antiepileptic medication.
Association with HLA-B*1502 Patients carrying the HLA-B*1502 allele may be at increased risk for SJS/TEN with oxcarbazepine tablets, USP treatment.
Human Leukocyte Antigen (HLA) allele B*1502 increases the risk for developing SJS/TEN in patients treated with carbamazepine.
The chemical structure of oxcarbazepine is similar to that of carbamazepine.
Available clinical evidence, and data from nonclinical studies showing a direct interaction between oxcarbazepine tablets, USP and HLA-B*1502 protein, suggest that the HLA-B*1502 allele may also increase the risk for SJS/TEN with oxcarbazepine tablets, USP.
The frequency of HLA-B*1502 allele ranges from 2 to 12% in Han Chinese populations, is about 8% in Thai populations, and above 15% in the Philippines and in some Malaysian populations.
Allele frequencies up to about 2% and 6% have been reported in Korea and India, respectively.
The frequency of the HLA-B*1502 allele is negligible in people from European descent, several African populations, indigenous peoples of the Americas, Hispanic populations, and in Japanese (< 1%).
Testing for the presence of the HLA-B*1502 allele should be considered in patients with ancestry in genetically at-risk populations, prior to initiating treatment with oxcarbazepine tablets, USP.
The use of oxcarbazepine tablets, USP should be avoided in patients positive for HLA-B*1502 unless the benefits clearly outweigh the risks.
Consideration should also be given to avoid the use of other drugs associated with SJS/TEN in HLA-B*1502 positive patients, when alternative therapies are otherwise equally acceptable.
Screening is not generally recommended in patients from populations in which the prevalence of HLA-B*1502 is low, or in current oxcarbazepine tablets, USP users, as the risk of SJS/TEN is largely confined to the first few months of therapy, regardless of HLA-B*1502 status.
The use of HLA-B*1502 genotyping has important limitations and must never substitute for appropriate clinical vigilance and patient management.
The role of other possible factors in the development of, and morbidity from, SJS/TEN, such as antiepileptic drug (AED) dose, compliance, concomitant medications, comorbidities, and the level of dermatologic monitoring have not been well characterized.
5.5 Suicidal Behavior and Ideation Antiepileptic drugs (AEDs), including oxcarbazepine tablets, USP, 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.
Pooled analyses of 199 placebo-controlled clinical trials (mono- and adjunctive therapy) of 11 different AEDs showed that patients randomized to one of the AEDs had approximately twice the risk (adjusted Relative Risk 1.8, 95% CI:1.2, 2.7) of suicidal thinking or behavior compared to patients randomized to placebo.
In these trials, which had a median treatment duration of 12 weeks, the estimated incidence rate of suicidal behavior or ideation among 27,863 AED-treated patients was 0.43%, compared to 0.24% among 16,029 placebo-treated patients, representing an increase of approximately one case of suicidal thinking or behavior for every 530 patients treated.
There were four suicides in drug-treated patients in the trials and none in placebo-treated patients, but the number is too small to allow any conclusion about drug effect on suicide.
The increased risk of suicidal thoughts or behavior with AEDs was observed as early as one week after starting drug treatment with AEDs and persisted for the duration of treatment assessed.
Because most trials included in the analysis did not extend beyond 24 weeks, the risk of suicidal thoughts or behavior beyond 24 weeks could not be assessed.
The risk of suicidal thoughts or behavior was generally consistent among drugs in the data analyzed.
The finding of increased risk with AEDs of varying mechanisms of action and across a range of indications suggests that the risk applies to all AEDs used for any indication.
The risk did not vary substantially by age (5-100 years) in the clinical trials analyzed.
Table 2 shows absolute and relative risk by indication for all evaluated AEDs.
Table 2 Risk by Indication for Antiepileptic Drugs in the Pooled Analysis Indication Placebo Patients with Events Per 1,000 Patients Drug Patients with Events Per 1,000 Patients Relative Risk: Incidence of Events in Drug Patients/Incidence in Placebo Patients Risk Difference: Additional Drug Patients with Events Per 1,000 Patients Epilepsy 1.0 3.4 3.5 2.4 Psychiatric 5.7 8.5 1.5 2.9 Other 1.0 1.8 1.9 0.9 Total 2.4 4.3 1.8 1.9 The relative risk for suicidal thoughts or behavior was higher in clinical trials for epilepsy than in clinical trials for psychiatric or other conditions, but the absolute risk differences were similar for the epilepsy and psychiatric indications.
Anyone considering prescribing oxcarbazepine tablets, USP or any other AED must balance the risk of suicidal thoughts or behavior with the risk of untreated illness.
Epilepsy and many other 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.
Patients, their caregivers, and families should be informed that AEDs increase the risk of suicidal thoughts and behavior and should be advised of the need to be alert for the emergence or worsening of the signs and symptoms of depression, any unusual changes in mood or behavior, or the emergence of suicidal thoughts, behavior, or thoughts about self-harm.
Behaviors of concern should be reported immediately to healthcare providers.
5.6 Withdrawal of AEDs As with all antiepileptic drugs, oxcarbazepine tablets, USP should be withdrawn gradually to minimize the potential of increased seizure frequency.
5.7 Cognitive/Neuropsychiatric Adverse Events Use of oxcarbazepine tablets, USP has been associated with central nervous system-related adverse events.
The most significant of these can be classified into three general categories: 1) cognitive symptoms including psychomotor slowing, difficulty with concentration, and speech or language problems, 2) somnolence or fatigue, and 3) coordination abnormalities, including ataxia and gait disturbances.
Adult Patients In one large, fixed-dose study, oxcarbazepine tablets, USP were added to existing AED therapy (up to three concomitant AEDs).
By protocol, the dosage of the concomitant AEDs could not be reduced as oxcarbazepine tablets, USP were added, reduction in oxcarbazepine tablets, USP dosage was not allowed if intolerance developed, and patients were discontinued if unable to tolerate their highest target maintenance doses.
In this trial, 65% of patients were discontinued because they could not tolerate the 2400 mg/day dose of oxcarbazepine tablets, USP on top of existing AEDs.
The adverse events seen in this study were primarily CNS related and the risk for discontinuation was dose related.
In this trial, 7.1% of oxcarbazepine-treated patients and 4% of placebo-treated patients experienced a cognitive adverse event.
The risk of discontinuation for these events was about 6.5 times greater on oxcarbazepine than on placebo.
In addition, 26% of oxcarbazepine-treated patients and 12% of placebo-treated patients experienced somnolence.
The risk of discontinuation for somnolence was about 10 times greater on oxcarbazepine than on placebo.
Finally, 28.7% of oxcarbazepine-treated patients and 6.4% of placebo-treated patients experienced ataxia or gait disturbances.
The risk for discontinuation for these events was about seven times greater on oxcarbazepine than on placebo.
In a single placebo-controlled monotherapy trial evaluating 2400 mg/day of oxcarbazepine tablets, USP, no patients in either treatment group discontinued double-blind treatment because of cognitive adverse events, somnolence, ataxia, or gait disturbance.
In the two dose-controlled conversion to monotherapy trials comparing 2400 mg/day and 300 mg/day oxcarbazepine tablets, USP, 1.1% of patients in the 2400 mg/day group discontinued double-blind treatment because of somnolence or cognitive adverse events compared to 0% in the 300 mg/day group.
In these trials, no patients discontinued because of ataxia or gait disturbances in either treatment group.
Pediatric Patients A study was conducted in pediatric patients (3 to 17 years old) with inadequately controlled partial seizures in which oxcarbazepine tablets, USP were added to existing AED therapy (up to two concomitant AEDs).
By protocol, the dosage of concomitant AEDs could not be reduced as oxcarbazepine tablets, USP were added.
Oxcarbazepine tablets, USP were titrated to reach a target dose ranging from 30 mg/kg to 46 mg/kg (based on a patient’s body weight with fixed doses for predefined weight ranges).
Cognitive adverse events occurred in 5.8% of oxcarbazepine-treated patients (the single most common event being concentration impairment, 4 of 138 patients) and in 3.1% of patients treated with placebo.
In addition, 34.8% of oxcarbazepine-treated patients and 14.0% of placebo-treated patients experienced somnolence.
(No patient discontinued due to a cognitive adverse event or somnolence.).
Finally, 23.2% of oxcarbazepine-treated patients and 7.0% of placebo-treated patients experienced ataxia or gait disturbances.
Two (1.4%) oxcarbazepine-treated patients and 1 (0.8%) placebo-treated patient discontinued due to ataxia or gait disturbances.
5.8 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 oxcarbazepine tablets, USP.
Some of these events have been fatal or life-threatening.
DRESS typically, although not exclusively, presents with fever, rash, and/or lymphadenopathy, in association with other organ system involvement, such as hepatitis, nephritis, hematologic abnormalities, myocarditis, or myositis, sometimes resembling an acute viral infection.
Eosinophilia is often present.
This disorder is variable in its expression, and other organ systems not noted here may be involved.
It is important to note that early manifestations of hypersensitivity (e.g., fever, lymphadenopathy) may be present even though rash is not evident.
If such signs or symptoms are present, the patient should be evaluated immediately.
Oxcarbazepine tablets, USP should be discontinued if an alternative etiology for the signs or symptoms cannot be established.
Although there are no case reports to indicate cross sensitivity with other drugs that produce this syndrome, the experience amongst drugs associated with DRESS/multi-organ hypersensitivity would indicate this to be a possibility [see Warnings and Precautions (5.3)].
5.9 Hematologic Events Rare reports of pancytopenia, agranulocytosis, and leukopenia have been seen in patients treated with oxcarbazepine tablets, USP during post-marketing experience.
Discontinuation of the drug should be considered if any evidence of these hematologic events develop.
5.10 Seizure Control During Pregnancy Due to physiological changes during pregnancy, plasma levels of the active metabolite of oxcarbazepine, the 10-monohydroxy derivative (MHD), may gradually decrease throughout pregnancy.
It is recommended that patients be monitored carefully during pregnancy.
Close monitoring should continue through the postpartum period because MHD levels may return after delivery.
5.11 Laboratory Tests Serum sodium levels below 125 mmol/L have been observed in patients treated with oxcarbazepine tablets, USP [see Warnings and Precautions (5.1)].
Experience from clinical trials indicates that serum sodium levels return toward normal when the oxcarbazepine tablets, USP dosage is reduced or discontinued, or when the patient was treated conservatively (e.g., fluid restriction).
Laboratory data from clinical trials suggest that oxcarbazepine tablets, USP use was associated with decreases in T 4, without changes in T 3 or TSH.
5.12 FD&C Yellow No.
5 (Tartrazine) This product contains FD&C Yellow No.
5 (tartrazine) which may cause allergic type reactions (including bronchial asthma) in certain susceptible persons.
Although the overall incidence of FD&C Yellow No.
5 (tartrazine) sensitivity in the general population is low, it is frequently seen in patients who also have aspirin sensitivity.
INFORMATION FOR PATIENTS
17 PATIENT COUNSELING INFORMATION Patients and caregivers should be informed of the availability of a Medication Guide, and they should be instructed to read the Medication Guide prior to taking oxcarbazepine tablets, USP.
Patients should be advised that oxcarbazepine tablets, USP may reduce the serum sodium concentrations especially if they are taking other medications that can lower sodium.
Patients should be advised to report symptoms of low sodium like nausea, tiredness, lack of energy, confusion, and more frequent or more severe seizures [see Warnings and Precautions (5.1)].
Anaphylactic reactions and angioedema may occur during treatment with oxcarbazepine tablets, USP.
Patients should be advised to report immediately signs and symptoms suggesting angioedema (swelling of the face, eyes, lips, tongue or difficulty in swallowing or breathing) and to stop taking the drug until they have consulted with their physician [see Warnings and Precautions (5.2)].
Patients who have exhibited hypersensitivity reactions to carbamazepine should be informed that approximately 25%-30% of these patients may experience hypersensitivity reactions with oxcarbazepine tablets, USP.
Patients should be advised that if they experience a hypersensitivity reaction while taking oxcarbazepine tablets, USP they should consult with their physician immediately [see Warnings and Precautions (5.3)].
Patients should be advised that serious skin reactions have been reported in association with oxcarbazepine tablets, USP.
In the event a skin reaction should occur while taking oxcarbazepine tablets, USP, patients should consult with their physician immediately [see Warnings and Precautions (5.4)].
Patients should be instructed that a fever associated with other organ system involvement (rash, lymphadenopathy, etc.) may be drug related and should be reported to the physician immediately [see Warnings and Precautions (5.8)].
Patients should be advised that there have been rare reports of blood disorders reported in patients treated with oxcarbazepine tablets, USP.
Patients should be instructed to immediately consult with their physician if they experience symptoms suggestive of blood disorders [see Warnings and Precautions (5.9)].
Female patients of childbearing age should be warned that the concurrent use of oxcarbazepine tablets, USP with hormonal contraceptives may render this method of contraception less effective [see Drug Interactions (7.2)].
Additional non-hormonal forms of contraception are recommended when using oxcarbazepine tablets, USP.
Patients, their caregivers, and families should be counseled that AEDs, including oxcarbazepine tablets, USP, may increase the risk of suicidal thoughts and behavior and should be advised of the need to be alert for the emergence or worsening of symptoms of depression, any unusual changes in mood or behavior, or the emergence of suicidal thoughts, behavior, or thoughts about self-harm.
Behaviors of concern should be reported immediately to healthcare providers.
Caution should be exercised if alcohol is taken in combination with oxcarbazepine tablets, USP therapy, due to a possible additive sedative effect.
Patients should be advised that oxcarbazepine tablets, USP may cause dizziness and somnolence.
Accordingly, patients should be advised not to drive or operate machinery until they have gained sufficient experience on oxcarbazepine tablets, USP to gauge whether it adversely affects their ability to drive or operate machinery.
Patients should be encouraged to enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry if they become pregnant.
This registry is collecting information about the safety of antiepileptic drugs during pregnancy.
To enroll, patients can call the toll free number 1-888-233-2334 [see Use in Specific Populations (8.1)] .
DOSAGE AND ADMINISTRATION
2 All dosing should be given in a twice-a-day regimen.
Oxcarbazepine oral suspension and oxcarbazepine film-coated tablets may be interchanged at equal doses.
Oxcarbazepine tablets, USP should be kept out of the reach and sight of children.
Oxcarbazepine tablets, USP can be taken with or without food [see Clinical Pharmacology (12.3)] .
ADULTS: initiated with a dose of 600 mg/day, given in twice-a-day regimen Adjunctive Therapy: Maximum increment of 600 mg/day at approximately weekly intervals.
The recommended daily dose is 1200 mg/day ( 2.1) Conversion to Monotherapy: Concomitant AEDs should be completely withdrawn over 3-6 weeks, while maximum dose of oxcarbazepine tablets, USP should be reached in about 2-4 weeks.
Maximum increment of 600 mg/day at approximately weekly intervals to a recommended daily dose of 2400 mg/day ( 2.2) Initiation of Monotherapy: Increments of 300 mg/day every third day to a dose of 1200 mg/day ( 2.3) CHILDREN: initiation with 8-10 mg/kg/day, given in twice-a-day regimen.
For patients aged 2 – <4 years and under 20 kg, a starting dose of 16 to 20 mg/kg/day may be considered.
Recommended daily dose is dependent upon patient weight Adjunctive Patients (Aged 2-16 Years): For patients aged 4-16 years, target maintenance dose should be achieved over 2 weeks ( 2.4).
For patients aged 2 – <4 years, maximum maintenance dose should be achieved over 2-4 weeks and should not to exceed 60mg/kg/day ( 2.4) Conversion to Monotherapy for Patients (Aged 4-16 Years): Maximum increment of 10 mg/kg/day at weekly intervals, concomitant antiepileptic drugs can be completely withdrawn over 3-6 weeks ( 2.5) Initiation of Monotherapy for Patients (Aged 4-16 Years): Increments of 5 mg/kg/day every third day ( 2.6) 2.1 Adjunctive Therapy for Adults Treatment with oxcarbazepine tablets, USP should be initiated with a dose of 600 mg/day, given in a twice-a-day regimen.
If clinically indicated, the dose may be increased by a maximum of 600 mg/day at approximately weekly intervals; the recommended daily dose is 1200 mg/day.
Daily doses above 1200 mg/day show somewhat greater effectiveness in controlled trials, but most patients were not able to tolerate the 2400 mg/day dose, primarily because of CNS effects.
It is recommended that the patient be observed closely and plasma levels of the concomitant AEDs be monitored during the period of oxcarbazepine tablets, USP titration, as these plasma levels may be altered, especially at oxcarbazepine tablets, USP doses greater than 1200 mg/day [see Drug Interactions (7.1)] .
2.2 Conversion to Monotherapy for Adults Patients receiving concomitant AEDs may be converted to monotherapy by initiating treatment with oxcarbazepine tablets, USP at 600 mg/day (given in a twice-a-day regimen) while simultaneously initiating the reduction of the dose of the concomitant AEDs.
The concomitant AEDs should be completely withdrawn over 3-6 weeks, while the maximum dose of oxcarbazepine tablets, USP should be reached in about 2-4 weeks.
Oxcarbazepine tablets, USP may be increased as clinically indicated by a maximum increment of 600 mg/day at approximately weekly intervals to achieve the recommended daily dose of 2400 mg/day.
A daily dose of 1200 mg/day has been shown in one study to be effective in patients in whom monotherapy has been initiated with oxcarbazepine tablets, USP.
Patients should be observed closely during this transition phase.
2.3 Initiation of Monotherapy for Adults Patients not currently being treated with AEDs may have monotherapy initiated with oxcarbazepine tablets, USP.
In these patients, oxcarbazepine tablets, USP should be initiated at a dose of 600 mg/day (given in a twice-a-day regimen); the dose should be increased by 300 mg/day every third day to a dose of 1200 mg/day.
Controlled trials in these patients examined the effectiveness of a 1200 mg/day dose; a dose of 2400 mg/day has been shown to be effective in patients converted from other AEDs to oxcarbazepine tablets, USP monotherapy (see above).
2.4 Adjunctive Therapy for Pediatric Patients (Aged 2-16 Years) In pediatric patients aged 4-16 years, treatment should be initiated at a daily dose of 8-10 mg/kg generally not to exceed 600 mg/day, given in a twice-a-day regimen.
The target maintenance dose of oxcarbazepine tablets, USP should be achieved over two weeks, and is dependent upon patient weight, according to the following chart: 20-29 kg – 900 mg/day 29.1-39 kg – 1200 mg/day >39 kg – 1800 mg/day In the clinical trial, in which the intention was to reach these target doses, the median daily dose was 31 mg/kg with a range of 6-51 mg/kg.
In pediatric patients aged 2 to <4 years, treatment should also be initiated at a daily dose of 8-10 mg/kg generally not to exceed 600 mg/day, given in a twice-a-day regimen.
For patients under 20 kg, a starting dose of 16-20 mg/kg may be considered [see Clinical Pharmacology (12.3)] .
The maximum maintenance dose of oxcarbazepine tablets, USP should be achieved over 2-4 weeks and should not exceed 60 mg/kg/day in a twice-a-day regimen.
In the clinical trial in pediatric patients (2 to 4 years of age) in which the intention was to reach the target dose of 60 mg/kg/day, 50% of patients reached a final dose of at least 55 mg/kg/day.
Under adjunctive therapy (with and without enzyme-inducing AEDs), when normalized by body weight, apparent clearance (L/hr/kg) decreased when age increased such that children 2 to <4 years of age may require up to twice the oxcarbazepine dose per body weight compared to adults; and children 4 to ≤12 years of age may require a 50% higher oxcarbazepine dose per body weight compared to adults.
2.5 Conversion to Monotherapy for Pediatric Patients (Aged 4-16 Years) Patients receiving concomitant antiepileptic drugs may be converted to monotherapy by initiating treatment with oxcarbazepine tablets, USP at approximately 8-10 mg/kg/day given in a twice-a-day regimen, while simultaneously initiating the reduction of the dose of the concomitant antiepileptic drugs.
The concomitant antiepileptic drugs can be completely withdrawn over 3-6 weeks while oxcarbazepine tablets, USP may be increased as clinically indicated by a maximum increment of 10 mg/kg/day at approximately weekly intervals to achieve the recommended daily dose.
Patients should be observed closely during this transition phase.
The recommended total daily dose of oxcarbazepine tablets, USP is shown in the table below.
2.6 Initiation of Monotherapy for Pediatric Patients (Aged 4-16 Years) Patients not currently being treated with antiepileptic drugs may have monotherapy initiated with oxcarbazepine tablets, USP.
In these patients, oxcarbazepine tablets, USP should be initiated at a dose of 8-10 mg/kg/day given in a twice-a-day regimen.
The dose should be increased by 5 mg/kg/day every third day to the recommended daily dose shown in the table below.
Table 1 Range of Maintenance Doses of Oxcarbazepine Tablets, USP for Children by Weight During Monotherapy From To Weight in kg Dose (mg/day) Dose (mg/day) 20 600 900 25 900 1200 30 900 1200 35 900 1500 40 900 1500 45 1200 1500 50 1200 1800 55 1200 1800 60 1200 2100 65 1200 2100 70 1500 2100 2.7 Patients with Hepatic Impairment In general, dose adjustments are not required in patients with mild-to-moderate hepatic impairment [see Clinical Pharmacology (12.3)].
2.8 Patients with Renal Impairment In patients with impaired renal function (creatinine clearance <30 mL/min) oxcarbazepine therapy should be initiated at one-half the usual starting dose (300 mg/day) and increased slowly to achieve the desired clinical response [see Clinical Pharmacology (12.3)].