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Talk to your doctor if you take a calcium channel blocker, other seizure control medication or elvitegravir/cobicistat, an HIV combination drug.
This medication can make you drowsy so taking other medications that cause drowsiness could double the effect. Tell your doctor if you take medicine for sleep, anxiety, sedatives, narcotic pain relievers, muscle relaxers, psychiatric medications, or an antihistamine that causes drowsiness. Also check over-the-counter (OTC) cough and cold products since they often contain ingredients that cause you to feel sleepy.
The following medications can interact with Trileptal:
- Amiodarone (Cordarone)
- Amlodipine (Norvasc)
- Felodipine (Plendil)
- Nifedipine (Procardia)
- Nimodipine (Nimotop)
- Verapamil (Calan, Covera, Isoptin, Verelan)
- Lansoprazole (Prevacid)
- Omeprazole (Prilosec)
- Pantoprazole (Protonix)
- Citalopram (Celexa)
- Sertraline (Zoloft)
This is not a complete list of drugs that interact with Trileptal. Give your healthcare provider a complete list of all the prescription drugs, including OTC medications, vitamins, supplements, and any illegal or recreational drugs.
Trileptal and Alcohol
Trileptal can increase drowsiness so it's best to avoid alcohol.
Dosage Forms And StrengthsFilm-coated Tablets
- 150 mg: pale grey-green, ovaloid, slightly biconvex, scored on both sides. Imprinted with T/D on one side and C/G on the other side.
- 300 mg: yellow, ovaloid, slightly biconvex, scored on both sides. Imprinted with TE/TE on one side and CG/CG on the other side.
- 600 mg: light pink, ovaloid, slightly biconvex, scored on both sides. Imprinted with TF/TF on one side and CG/CG on the other side.
- 300 mg/5 mL (60 mg/mL): off-white to slightly brown or slightly red suspension.
Storage And HandlingTablets
150 mg Film-Coated Tablets: pale grey-green, ovaloid, slightly biconvex, scored on both sides. Imprinted with T/D on one side and C/G on the other side.
Bottle of 100..........NDC 0078-0456-05
Unit Dose (blister pack) Box of 100 (strips of 10..........NDC 0078-0456-35
300 mg Film-Coated Tablets: yellow, ovaloid, slightly biconvex, scored on both sides. Imprinted with TE/TE on one side and CG/CG on the other side.
Bottle of 100..........NDC 0078-0337-05
Unit Dose (blister pack) Box of 100 (strips of 10)..........NDC 0078-0337-06 600 mg
Film-Coated Tablets: light pink, ovaloid, slightly biconvex, scored on both sides. Imprinted with TF/TF on one side and CG/CG on the other side.
Bottle of 100..........NDC 0078-0457-05
Unit Dose (blister pack) Box of 100 (strips of 10)..........NDC 0078-0457-35
Store at 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature]. Dispense in tight container (USP).Suspension
300 mg/5 mL (60 mg/mL) Oral Suspension: off-white to slightly brown or slightly red suspension. Available in amber glass bottles containing 250 mL of oral suspension. Supplied with a 10 mL dosing syringe and press-in bottle adapter.
Bottle containing 250 mL of oral suspension..........NDC 0078-0357-52
Store TRILEPTAL oral suspension in the original container. Shake well before using.
Use within 7 weeks of first opening the bottle.
Store at 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature].
Distributed by: Novartis Pharmaceuticals Corporation, East Hanover, New Jersey 07936. Revised: Mar 2017
What should i avoid while taking oxcarbazepine (trileptal)?
Avoid becoming overheated or dehydrated during exercise and in hot weather. Follow your doctor's instructions about the type and amount of liquids you should drink. In some cases, drinking too much liquid can be as unsafe as not drinking enough.
Oxcarbazepine may impair your thinking or reactions. Be careful if you drive or do anything that requires you to be alert.
Drinking alcohol can increase certain side effects of oxcarbazepine. Alcohol may also increase the risk of seizures.
Side Effects of Oxcarbazepine
See “Drug Precautions”.
Oxcarbazepine may cause other serious side effects including:
- your seizures can happen more often or become worse
- trouble concentrating
- problems with your speech and language
- feeling confused
- feeling sleepy and tired
- trouble walking and with coordination
Get medical help right away if you have any of the symptoms listed above or listed in “Drug Precautions”.
The most common side effects of oxcarbazepine include:
- double vision
- problems with vision
- stomach pain
- upset stomach
- problems with walking and coordination (unsteadiness)
- infections (especially in children)
These are not all the possible side effects of oxcarbazepine. For more information, ask your healthcare provider or pharmacist.
Tell your healthcare provider about all the medicines you take, including prescription and non-prescription medicines, vitamins, and herbal supplements. Especially tell your healthcare provider if you take:
- amiodarone (Cordarone)
- amitriptyline (Elavil)
- amlodipine (Norvasc)
- diltiazem (Cardizem, Dilacor, Tiazac)
- felodipine (Plendil)
- isradipine (DynaCirc)
- nicardipine (Cardene)
- nifedipine (Procardia)
- nimodipine (Nimotop)
- nisoldipine (Sular)
- verapamil (Calan, Covera, Isoptin, Verelan)
- chlorpromazine (Thorazine)
- clomipramine (Anafranil)
- cyclophosphamide (Cytoxan, Neosar)
- desmopressin (DDAVP, Minirin, Stimate)
- diazepam (Valium)
- hormonal contraceptives (birth control pills, rings, patches, implants, injections, and intrauterine devices)
- indapamide (Natrilix)
- other medications for seizures such as carbamazepine (Carbatrol, Epitol, Equetro, Tegretol), phenobarbital, phenytoin (Dilantin), and valproic acid (Depakene, Depakote)
- proton-pump inhibitors such as lansoprazole (Prevacid), omeprazole (Prilosec), and pantoprazole (Protonix)
- theophylline (Theo-Dur)
- selective serotonin reuptake inhibitors (SSRIs) such as citalopram (Celexa), duloxetine (Cymbalta), escitalopram (Lexapro), fluoxetine (Prozac, Sarafem), fluvoxamine (Luvox), paroxetine (Paxil), and sertraline (Zoloft).
Taking oxcarbazepine with certain other medicines may cause side effects or affect how well they work. Do not start or stop other medicines without talking to your healthcare provider.
What is the most important information I should know about oxcarbazepine?
Oxcarbazepine can reduce the sodium in your body to dangerously low levels, which can cause a life-threatening electrolyte imbalance. Call your doctor right away if you have headache, confusion, tiredness, nausea, or increased or more severe seizures.
Report any new or worsening symptoms to your doctor, such as: mood or behavior changes, anxiety, panic attacks, trouble sleeping, or if you feel impulsive, irritable, agitated, hostile, aggressive, restless, hyperactive (mentally or physically), more depressed, or have thoughts about suicide or hurting yourself.
Oxcarbazepine Dosage and Administration
Withdraw gradually to minimize the potential for increased seizure frequency.1 (See Discontinuance of Therapy under Cautions.)
Closely monitor for notable changes in behavior that could indicate emergence or worsening of suicidal thoughts or behavior or depression.18 19 22 23 (See Suicidality Risk under Cautions.)
Administer orally twice daily without regard to meals.1 2
Tablets and suspension can be used interchangeably on a mg-for-mg basis.1Suspension
Shake suspension well prior to administration of each dose.1
Measure and administer appropriate dose using an oral dosing syringe; dose may be added to a small glass of water or swallowed directly from the syringe.1 After each use, rinse the oral syringe with warm water and allowed to dry thoroughly.1
Pediatric PatientsPartial Seizures Monotherapy Oral
Children 4–16 years of age: Initially, 8–10 mg/kg daily in 2 divided doses.1 Increase by 5 mg/kg every third day to recommended maintenance dosage.1 (See Table 1.)
Dosage Range (mg/day)
Children 4–16 years of age: Initially, 8–10 mg/kg daily (≤600 mg daily) in 2 divided doses.1 Increase to the target maintenance dosage over 2 weeks.1 (See Table 2.)
Target Dosage (mg/day)
Children 4–16 years of age: Initially, 8–10 mg/kg daily in 2 divided doses.1 Increase dosage, based on patient response, by ≤10 mg/kg daily at weekly intervals to the recommended maintenance dosage for monotherapy.1 (See Table 1.) Observe patients closely during this transition phase.1
As oxcarbazepine replaces the existing anticonvulsant regimen, dosage of the other anticonvulsant(s) is simultaneously reduced and discontinued over 3–6 weeks.1 4 Observe patient closely during transition phase.1
AdultsPartial Seizures Monotherapy Oral
Initially, 600 mg daily administered in 2 equally divided doses.1 Increase dosage by 300-mg daily increments every third day up to a dosage of 1200 mg daily.1 4Combination Therapy Oral
Initially, 600 mg daily in 2 equally divided doses.1 Increase dosage by 600-mg daily increments at approximately weekly intervals to recommended daily dosage of 1200 mg.1 4 Efficacy may be somewhat higher in patients receiving dosages >1200 mg daily,1 3 4 10 but most patients cannot tolerate daily dosages of 2400 mg, mainly because of adverse CNS effects.1
Observe patients closely and monitor plasma concentrations of concomitantly administered anticonvulsants during dosage titration of oxcarbazepine; plasma concentrations of these drugs may be altered when dosage of oxcarbazepine exceeds 1200 mg daily.1 4Conversion to Monotherapy Oral
Initially, 600 mg daily in 2 equally divided doses.1 Increase dosage by 600-mg daily increments at approximately weekly intervals to recommended daily dosage of 2400 mg, usually within 2–4 weeks.1 4
As oxcarbazepine replaces the existing anticonvulsant regimen, dosage of the other anticonvulsant(s) is simultaneously reduced and discontinued over 3–6 weeks.1 4 Observe patient closely during transition phase.1
No dosage adjustment required in patients with mild to moderate hepatic impairment.1
Initially, 300 mg daily in patients with CLcr <30 mL/minute; increase dosage slowly based on patient response.1
Manufacturer makes no specific dosage recommendations.1
oxcarbazepine Side Effects
Along with its needed effects, a medicine may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.
Check with your doctor immediately if any of the following side effects occur:More common
- Change in vision
- change in walking or balance
- clumsiness or unsteadiness
- cough, fever, sneezing, or sore throat
- double vision
- false sense of well-being
- feeling of constant movement of self or surroundings
- mental depression
- sensation of spinning
- uncontrolled back-and-forth and/or rolling eye movements
- bloody or cloudy urine
- blurred vision
- convulsions (seizures)
- decreased urination
- difficulty with focusing eyes
- faintness or lightheadedness when getting up suddenly from a lying or sitting position
- fast or irregular heartbeat
- frequent falls
- frequent urge to urinate
- increased thirst
- itching of the vagina
- loss of consciousness
- memory loss
- muscle cramps
- pain or burning while urinating
- pain or tenderness around the eyes or cheekbones
- problems with coordination
- shaking or trembling of the arms, legs, hands, and feet
- skin rash
- stuffy or runny nose
- tightness in the chest
- trouble with walking
- troubled breathing
- unusual feelings
- unusual tiredness or weakness
- bleeding or crusting sores on the lips
- burning feeling in the chest or stomach
- chest pain
- hives or itching
- joint pain
- large, hive-like swelling on the face, eyelids, lips, tongue, throat, hands, legs, feet, or sex organs
- muscle pain or weakness
- purple spots on the skin
- rectal bleeding
- redness, blistering, peeling, or loosening of the skin
- sores, ulcers, or white spots in the mouth or on the lips
- stomach upset
- swelling of the legs
- swollen glands
Some side effects may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:More common
- Abdominal or stomach pain
- burning feeling in the chest or stomach
- nausea and vomiting
- sleepiness or unusual drowsiness
- Acid or sour stomach
- back pain
- bloody nose
- blurred vision
- change in your sense of taste
- difficulty with speaking
- dryness of the mouth
- feeling of warmth and redness of the face, neck, arms, and occasionally chest
- increased sweating
- increased urination
- trouble sleeping
Other side effects not listed may also occur in some patients. If you notice any other effects, check with your healthcare professional.
Call your doctor for medical advice about side effects. You may report side effects to the FDA at 1-800-FDA-1088.
Oxcarbazepine Dosage and Administration
Adjunctive Therapy for Adults
Initiate Oxcarbazepine with a dose of 600 mg/day, given twice-a-day. If clinically indicated, the dose may be increased by a maximum of 600 mg/day at approximately weekly intervals; the maximum recommended daily dose is 1,200 mg/day. Daily doses above 1,200 mg/day show somewhat greater effectiveness in controlled trials, but most patients were not able to tolerate the 2,400 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 titration, as these plasma levels may be altered, especially at Oxcarbazepine doses greater than 1,200 mg/day [see Drug Interactions (7.1) ].
Conversion to Monotherapy for Adults
Patients receiving concomitant AEDs may be converted to monotherapy by initiating treatment with Oxcarbazepine 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 to 6 weeks, while the maximum dose of Oxcarbazepine should be reached in about 2 to 4 weeks. Oxcarbazepine may be increased as clinically indicated by a maximum increment of 600 mg/day at approximately weekly intervals to achieve the maximum recommended daily dose of 2,400 mg/day. A daily dose of 1,200 mg/day has been shown in one study to be effective in patients in whom monotherapy has been initiated with Oxcarbazepine. Patients should be observed closely during this transition phase.
Initiation of Monotherapy for Adults
Patients not currently being treated with AEDs may have monotherapy initiated with Oxcarbazepine. In these patients, initiate Oxcarbazepine at a dose of 600 mg/day (given a twice-a-day); the dose should be increased by 300 mg/day every third day to a dose of 1,200 mg/day. Controlled trials in these patients examined the effectiveness of a 1,200 mg/day dose; a dose of 2,400 mg/day has been shown to be effective in patients converted from other AEDs to Oxcarbazepine monotherapy (see above).
Adjunctive Therapy for Pediatric Patients (Aged 2 to 16 Years)
In pediatric patients aged 4 to 16 years, initiate Oxcarbazepine at a daily dose of 8 to 10 mg/kg generally not to exceed 600 mg/day, given twice-a-day. The target maintenance dose of Oxcarbazepine should be achieved over 2 weeks, and is dependent upon patient weight, according to the following chart:
20 to 29 kg - 900 mg/day
29.1 to 39 kg - 1,200 mg/day
>39 kg – 1,800 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 to 51 mg/kg.
In pediatric patients aged 2 to <4 years, initiate Oxcarbazepine at a daily dose of 8 to 10 mg/kg generally not to exceed 600 mg/day, given twice-a-day. For patients less than 20 kg, a starting dose of 16 to 20 mg/kg may be considered [see Clinical Pharmacology (12.3)]. The maximum maintenance dose of Oxcarbazepine should be achieved over 2 to 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.
Conversion to Monotherapy for Pediatric Patients (Aged 4 to 16 Years)
Patients receiving concomitant antiepileptic drugs may be converted to monotherapy by initiating treatment with Oxcarbazepine at approximately 8 to 10 mg/kg/day given twice-a-day, while simultaneously initiating the reduction of the dose of the concomitant antiepileptic drugs. The concomitant antiepileptic drugs can be completely withdrawn over 3 to 6 weeks while Oxcarbazepine 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 is shown in Table 1.
Initiation of Monotherapy for Pediatric Patients (Aged 4 to 16 Years)
Patients not currently being treated with antiepileptic drugs may have monotherapy initiated with Oxcarbazepine. In these patients, initiate Oxcarbazepine at a dose of 8 to 10 mg/kg/day given twice-a-day. The dose should be increased by 5 mg/kg/day every third day to the recommended daily dose shown in the table below.
Weight in kg
|20 ||600 ||900 |
|25 ||900 ||1,200 |
|30 ||900 ||1,200 |
|35 ||900 ||1,500 |
|40 ||900 ||1,500 |
|45 ||1,200 ||1,500 |
|50 ||1,200 ||1,800 |
|55 ||1,200 ||1,800 |
|60 ||1,200 ||2,100 |
|65 ||1,200 ||2,100 |
|70 ||1,500 ||2,100 |
Dosage Modification for Patients with Renal Impairment
In patients with impaired renal function (creatinine clearance <30 ml/min) initiate Oxcarbazepine at one-half the usual starting dose (300 mg/day, given twice-a-day) and increase slowly to achieve the desired clinical response [see Clinical Pharmacology (12.3)].
Oxcarbazepine can be taken with or without food [see Clinical Pharmacology (12.3)]. Oxcarbazepine oral suspension and Oxcarbazepine film-coated tablets may be interchanged at equal doses.
Warnings and Precautions
Clinically significant hyponatremia (sodium <125 mmol/L) can develop during Oxcarbazepine use. In the 14 controlled epilepsy studies 2.5% of Oxcarbazepine-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 3 months of treatment with Oxcarbazepine, although there were patients who first developed a serum sodium <125 mmol/L more than 1 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 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 and syndrome of inappropriate antidiuretic hormone secretion (SIADH) have been reported during postmarketing use. In clinical trials, patients whose treatment with Oxcarbazepine 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, particularly if the patient is receiving other medications known to decrease serum sodium levels (e.g., 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).
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. Angioedema associated with laryngeal edema can be fatal. If a patient develops any of these reactions after treatment with Oxcarbazepine, 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)].
Cross Hypersensitivity Reaction to Carbamazepine
Approximately 25% to 30% of patients who have had hypersensitivity reactions to carbamazepine will experience hypersensitivity reactions with Oxcarbazepine. 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 only if the potential benefit justifies the potential risk. If signs or symptoms of hypersensitivity develop, Oxcarbazepine should be discontinued immediately [see Warnings and Precautions (5.2, 5.8)].
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 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 has also been reported.
The reporting rate of TEN and SJS associated with Oxcarbazepine 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, consideration should be given to discontinuing Oxcarbazepine 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 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 and HLA-B*1502 protein, suggest that the HLA-B*1502 allele may also increase the risk for SJS/TEN with Oxcarbazepine.
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. The use of Oxcarbazepine 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 HLAB* 1502 is low, or in current Oxcarbazepine 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.
Suicidal Behavior and Ideation
Antiepileptic drugs (AEDs), including Oxcarbazepine, 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 4 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 to 100 years) in the clinical trials analyzed. Table 2 shows absolute and relative risk by indication for all evaluated AEDs.
|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 ||3.4 ||3.5 ||2.4 |
|Psychiatric ||5.7 ||8.5 ||1.5 ||2.9 |
|Other ||1 ||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 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.
Withdrawal of AEDs
As with most antiepileptic drugs, Oxcarbazepine should generally be withdrawn gradually because of the risk of increased seizure frequency and status epilepticus [see Dosage and Administration (2.4) and Clinical Studies (14)].But if withdrawal is needed because of a serious adverse event, rapid discontinuation can be considered.
Cognitive/Neuropsychiatric Adverse Reactions
Use of Oxcarbazepine has been associated with central nervous system-related adverse reactions. The most significant of these can be classified into 3 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.
Patients should be monitored for these signs and symptoms and advised not to drive or operate machinery until they have gained sufficient experience on Oxcarbazepine to gauge whether it adversely affects their ability to drive or operate machinery.
In one large, fixed-dose study, Oxcarbazepine was added to existing AED therapy (up to three concomitant AEDs). By protocol, the dosage of the concomitant AEDs could not be reduced as Oxcarbazepine was added, reduction in Oxcarbazepine 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 2,400 mg/day dose of Oxcarbazepine 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 reaction. 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 7 times greater on Oxcarbazepine than on placebo.
In a single placebo-controlled monotherapy trial evaluating 2,400 mg/day of Oxcarbazepine, no patients in either treatment group discontinued double-blind treatment because of cognitive adverse events, somnolence, ataxia, or gait disturbance.
In the 2 dose-controlled conversion to monotherapy trials comparing 2,400 mg/day and 300 mg/day Oxcarbazepine, 1.1% of patients in the 2,400 mg/day group discontinued double-blind treatment because of somnolence or cognitive adverse reactions 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.
A study was conducted in pediatric patients (3 to 17 years old) with inadequately controlled partial seizures in which Oxcarbazepine was added to existing AED therapy (up to 2 concomitant AEDs). By protocol, the dosage of concomitant AEDs could not be reduced as Oxcarbazepine was added. Oxcarbazepine was 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% of placebo-treated patients experienced somnolence. (No patient discontinued due to a cognitive adverse reaction or somnolence.). Finally, 23.2% of Oxcarbazepine-treated patients and 7% 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.
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. Some of these events have been fatal or life-threatening. DRESS typically, although not exclusively, presents with fever, rash, lymphadenopathy and/or facial swelling, 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 eventhough rash is not evident. If such signs or symptoms are present, the patient should be evaluated immediately. Oxcarbazepine should be discontinued if an alternative etiology for the signs or symptoms cannot be established.
Rare reports of pancytopenia, agranulocytosis, and leukopenia have been seen in patients treated with Oxcarbazepine during postmarketing experience. Discontinuation of the drug should be considered if any evidence of these hematologic events develops.
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.
Risk of Seizure Aggravation
Exacerbation of or new onset primary generalized seizures has been reported with Oxcarbazepine. The risk of aggravation of primary generalized seizures is seen especially in children but may also occur in adults. In case of seizure aggravation, Oxcarbazepine should be discontinued.
Oxcarbazepine - Clinical Pharmacology
Mechanism of Action
The pharmacological activity of Oxcarbazepine 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.
Oxcarbazepine and its active metabolite (MHD) exhibit anticonvulsant properties in animal seizure models. They protected rodents against electrically induced tonic extension seizures and, to a lesser degree, chemically induced clonic seizures, and abolished or reduced the frequency of chronically recurring focal seizures in Rhesus monkeys with aluminum implants. No development of tolerance (i.e., attenuation of anticonvulsive activity) was observed in the maximal electroshock test when mice and rats were treated daily for 5 days and 4 weeks, respectively, with Oxcarbazepine or MHD.
Following oral administration of Oxcarbazepine tablets, Oxcarbazepine is completely absorbed and extensively metabolized to its pharmacologically active 10-monohydroxy metabolite (MHD). In a mass balance study in people, only 2% of total radioactivity in plasma was due to unchanged Oxcarbazepine, with approximately 70% present as MHD, and the remainder attributable to minor metabolites.
The half-life of the parent is about 2 hours, while the half-life of MHD is about 9 hours, so that MHD is responsible for most antiepileptic activity.
Based on MHD concentrations, Oxcarbazepine tablets and suspension were shown to have similar bioavailability.
After single-dose administration of Oxcarbazepine tablets to healthy male volunteers under fasted conditions, the median tmax was 4.5 (range 3 to 13) hours.
Steady-state plasma concentrations of MHD are reached within 2 to 3 days in patients when Oxcarbazepine is given twice a day. At steady state the pharmacokinetics of MHD are linear and show dose proportionality over the dose range of 300 to 2,400 mg/day.
Food has no effect on the rate and extent of absorption of Oxcarbazepine from Oxcarbazepine tablets. Therefore, Oxcarbazepine tablets can be taken with or without food.
The apparent volume of distribution of MHD is 49 L.
Approximately 40% of MHD is bound to serum proteins, predominantly to albumin. Binding is independent of the serum concentration within the therapeutically relevant range. Oxcarbazepine and MHD do not bind to alpha-1-acid glycoprotein.
Metabolism and Excretion
Oxcarbazepine is rapidly reduced by cytosolic enzymes in the liver to its 10-monohydroxy metabolite, MHD, which is primarily responsible for the pharmacological effect of Oxcarbazepine. MHD is metabolized further by conjugation with glucuronic acid. Minor amounts (4% of the dose) are oxidized to the pharmacologically inactive 10,11-dihydroxy metabolite (DHD).
Oxcarbazepine is cleared from the body mostly in the form of metabolites which are predominantly excreted by the kidneys. More than 95% of the dose appears in the urine, with less than 1% as unchanged Oxcarbazepine. Fecal excretion accounts for less than 4% of the administered dose. Approximately 80% of the dose is excreted in the urine either as glucuronides of MHD (49%) or as unchanged MHD (27%); the inactive DHD accounts for approximately 3% and conjugates of MHD and Oxcarbazepine account for 13% of the dose.
The half-life of the parent is about 2 hours, while the half-life of MHD is about 9 hours.
Following administration of single (300 mg) and multiple (600 mg/day) doses of Oxcarbazepine to elderly volunteers (60 to 82 years of age), the maximum plasma concentrations and AUC values of MHD were 30% to 60% higher than in younger volunteers (18 to 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.
Weight-adjusted MHD clearance decreases as age and weight increases, approaching that of adults. The mean weight-adjusted clearance in children 2 years to <4 years of age is approximately 80% higher on average than that of adults.
Therefore, MHD exposure in these children is expected to be about one-half that of adults when treated with a similar weight-adjusted dose. The mean weight-adjusted clearance in children 4 to 12 years of age is approximately 40% higher on average than that of adults. Therefore, MHD exposure in these children is expected to be about three-quarters that of adults when treated with a similar weight-adjusted dose. As weight increases, for patients 13 years of age and above, the weight-adjusted MHD clearance is expected to reach that of adults.
No gender-related pharmacokinetic differences have been observed in children, adults, or the elderly.
No specific studies have been conducted to assess what effect, if any, race may have on the disposition of Oxcarbazepine.
There is a linear correlation between creatinine clearance and the renal clearance of MHD. When Oxcarbazepine is administered as a single 300 mg dose in renally-impaired patients (creatinine clearance <30 mL/min), the elimination half-life of MHD is prolonged to 19 hours, with a 2-fold increase in AUC [see Dosage and Administration (2.7) and Use in Specific Populations (8.6)].
The pharmacokinetics and metabolism of Oxcarbazepine and MHD were evaluated in healthy volunteers and hepatically-impaired subjects after a single 900-mg oral dose. Mild-to-moderate hepatic impairment did not affect the pharmacokinetics of Oxcarbazepine and MHD [see Dosage and Administration (2.8)].
Due to physiological changes during pregnancy, MHD plasma levels may gradually decrease throughout pregnancy [see Use in Specific Populations (8.1)]
• In Vitro
Oxcarbazepine can inhibit CYP2C19 and induce CYP3A4/5 with potentially important effects on plasma concentrations of other drugs. In addition, several AEDs that are cytochrome P450 inducers can decrease plasma concentrations of Oxcarbazepine and MHD. No autoinduction has been observed with Oxcarbazepine.
Oxcarbazepine was evaluated in human liver microsomes to determine its capacity to inhibit the major cytochrome P450 enzymes responsible for the metabolism of other drugs. Results demonstrate that Oxcarbazepine and its pharmacologically active 10-monohydroxy metabolite (MHD) have little or no capacity to function as inhibitors for most of the human cytochrome P450 enzymes evaluated (CYP1A2, CYP2A6, CYP2C9, CYP2D6, CYP2E1, CYP4A9 and CYP4A11) with the exception of CYP2C19 and CYP3A4/5. Although inhibition of CYP3A4/5 by Oxcarbazepine and MHD did occur at high concentrations, it is not likely to be of clinical significance. The inhibition of CYP2C19 by Oxcarbazepine and MHD can cause increased plasma concentrations of drugs that are substrates of CYP2C19, which is clinically relevant.
In vitro, the UDP-glucuronyl transferase level was increased, indicating induction of this enzyme. Increases of 22% with MHD and 47% with Oxcarbazepine were observed. As MHD, the predominant plasma substrate, is only a weak inducer of UDP-glucuronyl transferase, it is unlikely to have an effect on drugs that are mainly eliminated by conjugation through UDP-glucuronyl transferase (e.g., valproic acid, lamotrigine).
In addition, 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.
As binding of MHD to plasma proteins is low (40%), clinically significant interactions with other drugs through competition for protein binding sites are unlikely.
• In Vivo
For in vivo drug interactions [see Drug Interactions (7)]. Hormonal Contraceptives
Coadministration of Oxcarbazepine 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 to 65] in one study and 52% [90% CI: 38 to 52] in another study. The mean AUC values of LNG were decreased by 32% [90% CI: 20 to 45] in one study and 52% [90% CI: 42 to 52] in another study.
Other Drug Interactions
Calcium Antagonists: After repeated coadministration of Oxcarbazepine, the AUC of felodipine was lowered by 28% [90% CI: 20 to 33]. Verapamil produced a decrease of 20% [90% CI: 18 to 27] of the plasma levels of MHD.
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.
Package label.principal display panel-150 mg
PHARMACIST: Dispense the Medication Guide provided separately to each patient.
(ox car BAZ e peen)
- GP 47680
Special Populations Elderly
Max plasma concentration and AUC values of MHD were 30% to 60% higher.
Off Label Uses
Data from a multicenter, double-blind, placebo-controlled study supports the use of oxcarbazepine monotherapy in the treatment of neuropathic pain of diabetic origin [Dogra 2005], [Zhou 2013]. Additional trials may be necessary to further define the role of oxcarbazepine in this condition.
Based on the American Academy of Neurology evidence-based guidelines for the Treatment of Painful Diabetic Neuropathy, oxcarbazepine is probably not effective and should probably not be considered for the management of painful diabetic neuropathy. However, based on the International Association for the Study of Pain (IASP) evidence-based recommendations for the Pharmacologic Management of Neuropathic Pain, oxcarbazepine given for painful diabetic neuropathy is suggested for patients who have not responded to first- and second-line medications [Dworkin 2007].
Immediate release: Refer to adult dosing.
Extended release: Initial: 300 mg or 450 mg once daily should be considered; dosage may be increased by 300 to 450 mg daily increments at weekly intervals to desired clinical response.
Immediate-release: Data not available
Extended-release: Use is not recommended