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Oxcarbazepine

REMEDYREPACK INC.


FULL PRESCRIBING INFORMATION: CONTENTS*




FULL PRESCRIBING INFORMATION

OXCARBAZEPINE DESCRIPTION


Oxcarbazepine


PRECAUTIONS

CLINICAL PHARMACOLOGY

Mechanism of Action
Metabolism and Excretion

Pharmacodynamics
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 five days and four weeks, respectively, with oxcarbazepine or MHD.

Pharmacokinetics
Following oral administration of Oxcarbazepine tablets, oxcarbazepine is completely absorbed and extensively metabolized to its pharmacologically active 10-monohydroxy metabolite (MHD). The half-life of the parent is about two hours, while the half-life of MHD is about nine 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.
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.

Effect of Food
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.
Steady-state plasma concentrations of MHD are reached within 2-3 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 2400 mg/day.

Distribution
The apparent volume of distribution of MHD is 49L.
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.

Special Populations

Hepatic Impairment
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. No dose adjustment for Oxcarbazepine is recommended in patients with mild-to-moderate hepatic impairment. The pharmacokinetics of oxcarbazepine and MHD have not been evaluated in severe hepatic impairment and, therefore, caution should be exercised when dosing severely impaired patients.

Renal Impairment
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 two-fold increase in AUC. Dose adjustment for Oxcarbazepine is recommended in these patients (seePRECAUTIONSandDOSAGE AND ADMINISTRATIONsections).

Pediatric Use
Weight-adjusted MHD clearance decreases as age and weight increases approaching that of adults. The mean weight-adjusted clearance in children 2 years-<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 412 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.

Geriatric Use
Following administration of single (300 mg) and multiple (600 mg/day) doses of Oxcarbazepine to 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.

Gender
No gender-related pharmacokinetic differences have been observed in children, adults, or the elderly.

Race
No specific studies have been conducted to assess what effect, if any, race may have on the disposition of oxcarbazepine.

CLINICAL STUDIES




Oxcarbazepine Monotherapy Trials

Figure 1

Oxcarbazepine
Figure 2

Oxcarbazepine
Figure 3

Oxcarbazepine
Figure 4

Oxcarbazepine



Oxcarbazepine Adjunctive Therapy Trials



ADVERSE REACTIONS

TrialTreatment GroupNBaseline Median Seizure Rate*Median % Reduction*1 (pediatrics)Oxcarbazepine13612.534.8Placebo12813.19.42 (adults)Oxcarbazepine 2400 mg/day17410.049.9Oxcarbazepine 1200 mg/day1779.840.2Oxcarbazepine 600 mg/day1689.626.4Placebo1738.67.6Subset analyses of the antiepileptic efficacy of Oxcarbazepine 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 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 60 mg/kg/day. In this study, there was no evidence that Oxcarbazepine was effective in patients below the age of 2 years (N=75).

INDICATIONS & USAGE



OXCARBAZEPINE CONTRAINDICATIONS



WARNINGS

Hyponatremia



Anaphylactic Reactions and Angioedema
WARNINGS, Patients with a Past History of Hypersensitivity Reaction to Carbamazepine

Patients with a Past History of Hypersensitivity Reaction to Carbamazepine
WARNINGS, Anaphylactic Reactions and AngioedemaPRECAUTIONS, Multi-Organ Hypersensitivitysubsection).

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. The median time of onset for reported cases was 19 days. Such serious skin reactions may be life threatening, and some patients have required hospitalization with very rare reports of fatal outcome. 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.

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 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
IndicationPlacebo Patients with Events Per 1,000 PatientsDrug Patients with Events Per 1,000 PatientsRelative Risk: Incidence of Events in Drug Patients/Incidence in Placebo PatientsRisk Difference: Additional Drug Patients with Events Per 1,000 PatientsEpilepsy1.03.43.52.4Psychiatric5.78.51.52.9Other1.01.81.90.9Total2.44.31.81.9The 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 all antiepileptic drugs, Oxcarbazepine should be withdrawn gradually to minimize the potential of increased seizure frequency.

PRECAUTIONS

FD&C Yellow No. 5 (Tartrazine)


Cognitive/Neuropsychiatric Adverse Events


Adult Patients





Pediatric Patients



Multi-Organ Hypersensitivity
WARNINGS, Patients with a Past History of Hypersensitivity Reaction to Carbamazepine

INFORMATION FOR PATIENTS

WARNINGS, Anaphylactic Reactions and Angioedema
WARNINGS, Patients with a Past History of Hypersensitivity Reaction to Carbamazepine
WARNINGS, Serious Dermatological Reactions
PRECAUTIONS, Multi-Organ Hypersensitivity
Drug Interactions



PRECAUTIONS, Pregnancy Category C

LABORATORY TESTS

WARNINGS


DRUG INTERACTIONS







Antiepileptic Drugs


AED CoadministeredDose of AED (mg/day)Oxcarbazepine Dose (mg/day)Influence of Oxcarbazepine on AED Concentration (Mean Change, 90% Confidence Interval)Influence of AED on MHD Concentration (Mean Change, 90% Confidence Interval)****



Hormonal Contraceptives
Drug Interactions

Calcium Antagonists



Other Drug Interactions


DRUG & OR LABORATORY TEST INTERACTIONS



CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY





PREGNANCY








LABOR & DELIVERY



NURSING MOTHERS


Patients with Renal Impairment
CLINICAL PHARMACOLOGY, Pharmacokinetics

PEDIATRIC USE

ADVERSE REACTIONS

GERIATRIC USE



OXCARBAZEPINE ADVERSE REACTIONS

Most Common Adverse Events in All Clinical Studies

Adjunctive Therapy/Monotherapy in Adults Previously Treated with other AEDs



Monotherapy in Adults Not Previously Treated with other AEDs



Adjunctive Therapy/Monotherapy in Pediatric Patients 4 Years Old and Above Previously Treated with other AEDs



Monotherapy in Pediatric Patients 4 Years Old and Above not Previously Treated with other AEDs



Adjunctive Therapy/Monotherapy in Pediatric Patients 1 month to < 4 Years Old Previously Treated or not Previously Treated with other AEDs



Incidence in Controlled Clinical Studies


Controlled Clinical Studies of Adjunctive Therapy/Monotherapy in Adults Previously Treated with other AEDs


Oxcarbazepine Dosage (mg/day)Body System/ Adverse EventOXC 600 N=163 %OXC 1200 N=171 %OXC 2400 N=126 %Placebo N=166 %

Oxcarbazepine Dosage (mg/day)Body System/ Adverse Event2400 N=86 %300 N=86 %
Controlled Clinical Study of Monotherapy in Adults not Previously Treated with other AEDs


Body System/ Adverse EventOxcarbazepine N=55 %Placebo N=49 %
Controlled Clinical Studies of Adjunctive Therapy/Monotherapy in Pediatric Patients Previously Treated with other AEDs


Body System/ Adverse EventOxcarbazepine N=171 %Placebo N=139 %
Other Events Observed in Association with the Administration of Oxcarbazepine

Body as a Whole:
Cardiovascular System:
Digestive System:
Hemic and Lymphatic System:
Laboratory Abnormality:
Musculoskeletal System:
Nervous System:
Respiratory System:
Skin and Appendages:
Special Senses:
Surgical and Medical Procedures:
Urogenital and Reproductive System:
Other:

Post-Marketing and Other Experience

Body as a Whole:PRECAUTIONS, Multi-Organ Hypersensitivity
WARNINGS, Anaphylactic Reactions and Angioedema
Digestive System:
Skin and Appendages:WARNINGS, Serious Dermatological Reactions

DRUG ABUSE AND DEPENDENCE

Abuse


Dependence


OVERDOSAGE

Human Overdose Experience


Treatment and Management


DOSAGE & ADMINISTRATION




CLINICAL PHARMACOLOGY, Pharmacokinetics

Adults

Adjunctive Therapy
PRECAUTIONS, Drug Interactions

Conversion to Monotherapy


Initiation of Monotherapy


Pediatric Patients

Adjunctive Therapy (Aged 2-16 years)




CLINICAL PHARMACOLOGY



Conversion to Monotherapy (Aged 4-16 years)




Initiation of Monotherapy (Aged 4-16 years)


FromToWeight in kgDose (mg/day)Dose (mg/day)
Patients with Hepatic Impairment
CLINICAL PHARMACOLOGY, Pharmacokinetics, Special Populations

Patients with Renal Impairment
CLINICAL PHARMACOLOGY, Pharmacokinetics, Special Populations

HOW SUPPLIED






STORAGE AND HANDLING




SPL MEDGUIDE

Oxcarbazepine Tablets contains FD&C yellow no. 5 (tartrazine) which may cause allergic-type reactions (including bronchial asthma) in certain susceptible individuals. 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 hypersensitivity.

What is the most important information I should know about Oxcarbazepine tablets?
Do not stop taking Oxcarbazepine tablets without first talking to your healthcare provider.


Oxcarbazepine tablets can cause serious side effects, including:


  • ●               nausea
  • ●               tiredness, lack of energy
  • ●               headache
  • ●               confusion
  • ●               more frequent or more severe seizures.



     Call your healthcare provider right away if you have any of the following:
  • ●               swelling of your face, eyes, lips, or tongue
  • ●               trouble swallowing or breathing
  • ●               a skin rash
  • ●               hives
  • ●               fever, swollen glands, or sore throat that do not go away or come and go
  • ●               painful sores in the mouth or around your eyes
  • ●               yellowing of your skin or eyes
  • ●               unusual bruising or bleeding
  • ●               severe fatigue or weakness
  • ●               severe muscle pain
  • ●               frequent infections or infections that do not go away

Like other antiepileptic drugs, Oxcarbazepine tablets may cause suicidal thoughts or actions in a very small number of people, about 1 in 500.
     Call a doctor right away if you have any of these symptoms, especially if they are new, worse, or worry you:

  • ●               thoughts about suicide or dying
  • ●               attempts to commit suicide
  • ●               new or worse depression
  • ●               new or worse anxiety
  • ●               feeling agitated or restless
  • ●               panic attacks
  • ●               trouble sleeping (insomnia)
  • ●               new or worse irritability
  • ●               acting aggressive, being angry, or violent
  • ●               acting on dangerous impulses
  • ●               an extreme increase in activity and talking (mania)
  • ●               other unusual changes in behavior or mood
     How can I watch for early symptoms of suicidal thoughts and actions?
  • ●               Pay attention to any changes, especially sudden changes, in mood, behaviors, thoughts, or feelings.
  • ●               Keep all follow-up visits with your healthcare provider as scheduled.

     Do not stop taking Oxcarbazepine tablets without first talking to a healthcare provider.


What are Oxcarbazepine tablets?

  • ●     alone or with other medicines to treat partial seizures in adults.
  • ●     alone to treat partial seizures in children 4 years and older.
  • ●     with other medicines to treat partial seizures in children 2 years and older.
Who should not take Oxcarbazepine tablets?
  • ●     Do not take Oxcarbazepine tablets if you are allergic to Oxcarbazepine tablets or any of the other ingredients in Oxcarbazepine tablets. Seethe end of this leaflet for a complete list of ingredients in Oxcarbazepine tablets.
  • ●     Many people who are allergic to carbamazepine are also allergic to Oxcarbazepine tablets. Tell your healthcare provider if you are allergic to carbamazepine.
What should I tell my healthcare provider before taking Oxcarbazepine tablets?
Before taking Oxcarbazepine tablets, tell your healthcare provider about all your medical conditions, including if you:

  • ●     have or have had suicidal thoughts or actions, depression or mood problems
  • ●     have liver problems
  • ●     have kidney problems
  • ●     are allergic to carbamazepine. Many people who are allergic to carbamazepine are also allergic to Oxcarbazepine tablets.
  • ●     use birth control medicine. Oxcarbazepine tablets may cause your birth control medicine to be less effective. Talk to your healthcare provider about the best birth control method to use.
  • ●     are pregnant or plan to become pregnant.

  • ●               If you become pregnant while taking Oxcarbazepine tablets, talk to your healthcare provider about registering with the North American Antiepileptic Drug (NAAED) Pregnancy Registry. The purpose of this registry is to collect information about the safety of antiepileptic medicine during pregnancy. You can enroll in this registry by calling 1-888-233-2334.
  • ●     are breastfeeding or plan to breastfeed.

Tell your healthcare provider about all the medicines you take,


How should I take Oxcarbazepine tablets?
  • ●     Do not stop taking Oxcarbazepine tablets without talking to your healthcare provider.

  • ●     Take Oxcarbazepine tablets exactly as prescribed. Your healthcare provider may change your dose. Your healthcare provider will tell you how many Oxcarbazepine tablets to take.
  • ●     Take Oxcarbazepine tablets 2 times a day.
  • ●     Take Oxcarbazepine tablets with or without food.
  • ●     If you take too many Oxcarbazepine tablets, call your healthcare provider or local Poison Control Center right away.
What should I avoid while taking Oxcarbazepine tablets?
  • ●     Do not drive, operate heavy machinery, or do other dangerous activities until you know how Oxcarbazepine tablets affects you. Oxcarbazepine tablets may slow your thinking and motor skills.
  • ●     Do not drink alcohol or take other drugs that make you sleepy or dizzy while taking Oxcarbazepine tablets until you talk to your healthcare provider. Oxcarbazepine tablets taken with alcohol or drugs that cause sleepiness or dizziness may make your sleepiness or dizziness worse.
What are the possible side effects of Oxcarbazepine tablets?
What is the most important information I should know about Oxcarbazepine tablets?
Oxcarbazepine tablets 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 "What is the most important information I should know about Oxcarbazepine tablets?"

  • ●     dizziness
  • ●     sleepiness
  • ●     double vision
  • ●     tiredness
  • ●     nausea
  • ●     vomiting
  • ●     problems with vision
  • ●     stomach pain
  • ●     trembling
  • ●     upset stomach
  • ●     problems with walking and coordination (unsteadiness)
  • ●     rash
  • ●     infections (especially in children)

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.
How should I store Oxcarbazepine tablets?

  • ●     Store Oxcarbazepine tablets between 15to 30(59to 86
  • ●     Keep Oxcarbazepine tablets dry.
Keep Oxcarbazepine tablets and all medicines out of the reach of children.
General Information about the safe and effective use of Oxcarbazepine tablets




What are the ingredients in Oxcarbazepine tablets?
Active ingredient:

12


PACKAGE LABEL.PRINCIPAL DISPLAY PANEL SECTION














Oxcarbazepine

Oxcarbazepine

Oxcarbazepine

Oxcarbazepine TABLET

Product Information

Product Type Human prescription drug label Item Code (Source) NDC:49349-904(NDC:51991-293)
Route of Administration ORAL DEA Schedule

Active Ingredient/Active Moiety

Ingredient Name Basis of Strength Strength
OXCARBAZEPINE OXCARBAZEPINE 300 mg

Inactive Ingredients

Ingredient Name Strength
CROSPOVIDONE
SILICON DIOXIDE
HYPROMELLOSES
MAGNESIUM STEARATE
cellulose, microcrystalline
polyethylene glycol
titanium dioxide
POLYVINYL ALCOHOL
ALUMINUM OXIDE
LECITHIN, SOYBEAN
talc
FD&C BLUE NO. 2
FD&C YELLOW NO. 5
FD&C YELLOW NO. 6

Product Characteristics

Color Size Imprint Code Shape
brown 15 mm B293 OVAL

Packaging

# Item Code Package Description Marketing Start Date Marketing End Date
1 NDC:49349-904-02 30 in 1 BLISTER PACK

Marketing Information

Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date
ANDA ANDA078069 2012-03-12


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Be sure to consult your doctor before taking any medication!
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