PEDIATRIC USE SECTION.


8.4 Pediatric Use. The safety and effectiveness of EQUETRO have not been established in pediatric patients for indications other than Epilepsy [see Indications and Usage 1.3 )].

PHARMACOKINETICS SECTION.


12.3 Pharmacokinetics. Carbamazepine (CBZ)Absorption: Following single 200 mg oral extended-release dose of carbamazepine, peak plasma concentration was 1.9 +- 0.3 mcg/mL and the time to reach the peak was 19 +- hours. Following repeat dose administration (800 mg every 12 hours), the peak levels were 11.0 +- 2.5 mcgt/mL and the time to reach the peak was 5.9 +- 1.8 hours. The pharmacokinetics of extended-release carbamazepine is linear over the single dose range of 200-800 mg.Carbamazepine is 76% bound to plasma proteins. Carbamazepine is primarily metabolized in the liver. Cytochrome P450 3A4 was identified as the major isoform responsible for the formation of carbamazepine-10,11-epoxide. Since carbamazepine induces its own metabolism, the half-life is also variable. The average half-life ranged from 35 to 40 hours following single extended-release dose of carbamazepine and from 12 to 17 hours following repeated dosing. The apparent oral clearance was 25 +- mL/min following single dose and 80 +- 30 mL/min following multiple dosing.Carbamazepine-10,11-epoxide (CBZ-E): Carbamazepine-10,11-epoxide is considered to be an active metabolite of carbamazepine. Following single 200 mg oral extended-release dose of carbamazepine, the peak plasma concentration of carbamazepine-10,11-epoxide was 0.11 +- 0.012 mcg/mL and the time to reach the peak was 36 +- hours. Following chronic administration of an extended-release dose of carbamazepine (800 mg every 12 hours), the peak levels of carbamazepine-10,11-epoxide were 2.2 +- 0.9 mcg/mL and the time to reach the peak was 14 +- hours. The plasma half-life of carbamazepine-10,11-epoxide following administration of carbamazepine is 34 +- hours. Following single oral dose of extended-release carbamazepine (200-800 mg) the AUC and Cmax of carbamazepine-10,11-epoxide were less than 10% of carbamazepine. Following multiple dosing of extended-release carbamazepine (800-1600 mg daily for 14 days), the AUC and Cmax of carbamazepine-10,11-epoxide were dose-related, ranging from 15.7 mcg.hr/mL and 1.5 mcg/mL at 800 mg/day to 32.6 mcg.hr/mL and 3.2 mcg/mL at 1600 mg/day, respectively, and were less than 30% those of carbamazepine. Carbamazepine-10,11-epoxide is 50% bound to plasma proteins.Food Effect: high-fat meal diet increased the rate of absorption of single 400 mg dose (mean Tmax was reduced from 24 hours, in the fasting state, to 14 hours, and Cmax increased from 3.2 to 4.3 mcg/mL) but not the extent (AUC) of absorption. The elimination half-life remained unchanged between fed and fasting state. The multiple-dose study conducted in the fed state showed that the steady-state Cmax values were within the therapeutic concentration range. The pharmacokinetic profile of extended-release carbamazepine was similar when given by sprinkling the beads over applesauce compared to the intact capsule administered in the fasted state.Elimination: After oral administration of 14C-carbamazepine, 72% of the administered radioactivity was found in the urine and 28% was found in the feces. This urinary radioactivity was composed largely of hydroxylated and conjugated metabolites, with only 3% of unchanged carbamazepine. Metabolism: In vitro data indicate carbamazepine is metabolized mainly by cytochrome P450 (CYP) 3A4 to the active carbamazepine-10,11-epoxide, which is further metabolized to the trans-diol by epoxide hydrolase. Human microsomal epoxide hydrolase has been identified as the enzyme responsible for the formation of the 10,11-transdiol derivative from carbamazepine-10,11-epoxide.Renal Impairment: The effect of renal impairment on the pharmacokinetics of carbamazepine is not known.Hepatic Impairment: The effect of hepatic impairment on the pharmacokinetics of carbamazepine is not known. Consider reducing the dosage in patients with hepatic impairment. Effect of Age: Carbamazepine is more rapidly metabolized to carbamazepine-10,11-epoxide in young children than in adults. In children below the age of 15, there is an inverse relationship between CBZ-E/CBZ ratio and increasing age. The safety and effectiveness of EQUETRO have not been established in pediatric patients for indications other than Epilepsy [see Indications and Usage 1.3 )]. Effect of Gender: No difference in the mean AUC and Cmax of carbamazepine and carbamazepine-10,11-epoxide was found between males and females.

LABOR & DELIVERY SECTION.


8.2 Labor and Delivery The effect of carbamazepine on human labor and delivery is unknown.Carbamazepine and its epoxide metabolite are transferred to breast milk during lactation. There is potential for serious adverse reactions in nursing infants exposed to carbamazepine. Nursing mothers should consider the potential benefits and risks of treatment when deciding on whether to discontinue nursing or to discontinue treatment with EQUETRO, taking into account the importance of the drug to the mother.

MECHANISM OF ACTION SECTION.


12.1 Mechanism of Action. Although numerous pharmacological effects of carbamazepine have been described in the published literature (e.g., modulation of ion channels [sodium and calcium], receptor-mediated neurotransmission [GABAergic, glutamatergic, and monoaminergic], and intracellular signaling pathways in experimental preparations), the contribution of these effects to the efficacy of carbamazepine in acute manic or mixed episodes associated with bipolar disorder is unknown.

POSTMARKETING EXPERIENCE SECTION.


6.2 Postmarketing Experience. The following adverse reactions have been identified during post approval use of EQUETRO. Because these reactions are reported voluntarily from population of uncertain size, it is not always possible to reliably estimate their frequency or establish causal relationship to drug exposure.Nervous System: confusion, diplopia, oculomotor disturbances, nystagmus, speech disturbances, abnormal involuntary movements, tinnitus.Digestive System: gastric distress, abdominal pain, diarrhea, anorexia.Laboratory Tests: thyroid function tests (T3, T4)- decreased valuesOther: lupus erythematosus-like syndrome One case of aseptic meningitis, accompanied by myoclonus and peripheral eosinophilia, has been reported in patient taking carbamazepine in combination with other medications. The patient was successfully dechallenged, and the meningitis reappeared upon rechallenge with carbamazepine.

NONCLINICAL TOXICOLOGY SECTION.


13 NONCLINICAL TOXICOLOGY. 13.1 Carcinogenesis, Mutagenesis, and Impairment of Fertility. Carcinogenicity: Administration of carbamazepine to Sprague-Dawley rats for years in the diet at doses of 25, 75, and 250 mg/kg/day (low dose approximately 0.2 times the human daily dose of 1200 mg on mg/m2 basis) resulted in dose-related increase in the incidence of hepatocellular tumors in females and of benign interstitial cell adenomas in the testes of males.Mutagenicity: Bacterial and mammalian mutagenicity studies using carbamazepine produced negative results. Impairment of Fertility: The effects of carbamazepine on male and female fertility have not been studied. Testicular atrophy occurred in rats receiving carbamazepine orally from 4-52 weeks at dosage levels of 50-400 mg/kg/day. Additionally, rats receiving carbamazepine in the diet for years at dosage levels of 25, 75, and 250 mg/kg/day had dose-related incidence of testicular atrophy and aspermatogenesis.

NURSING MOTHERS SECTION.


8.3 Nursing Mothers. Carbamazepine and its epoxide metabolite are excreted in human milk. Because of the potential for serious adverse reactions in nursing infants exposed to EQUETRO, decision should be made whether to discontinue nursing or to discontinue treatment with EQUETRO, taking into account the importance of the drug to the mother.

OVERDOSAGE SECTION.


10 OVERDOSAGE. 10.1 Human Experience. Lowest known lethal dose of carbamazepine: adults, greater than 60 grams (39-year-old man). Highest known doses survived: adults, 30 grams (31-year-old woman); children, 10 grams (6-year-old boy); small children, grams (3-year-old girl). Signs and Symptoms: The first signs and symptoms of carbamazepine overdose appear after to hours. Neuromuscular disturbances are the most prominent. Cardiovascular disorders are generally milder, and severe cardiac complications occur only when very high doses (greater than60 grams) have been ingested.Respiration: Irregular breathing, respiratory depression.Cardiovascular System: Tachycardia, hypotension or hypertension, shock, conduction disorders.Nervous System and Muscles: Impairment of consciousness ranging in severity to deep coma. Convulsions, especially in small children. Motor restlessness, muscular twitching, tremor, athetoid movements, opisthotonos, ataxia, drowsiness, dizziness, mydriasis, nystagmus, adiadochokinesia, ballism, psychomotor disturbances, dysmetria. Initial hyperreflexia, followed by hyporeflexia.Gastrointestinal Tract: Nausea, vomiting.Kidneys and Bladder: Anuria or oliguria, urinary retention.Laboratory Findings: Isolated instances of overdosage have included leukocytosis, reduced leukocyte count, glycosuria, and acetonuria. ECG may show dysrhythmias.Combined Poisoning: When alcohol, tricyclic antidepressants, barbiturates, or hydantoins are taken at the same time, the signs and symptoms of acute poisoning with carbamazepine may be aggravated or modified.. 10.2 Management of Overdosage. For the most up to date information on management of EQUETRO overdose, contact the certified poison center for your area by calling 1-800-222-1222 (or at www.poison.org). In case of an overdose, provide supportive care, including close medical supervision and monitoring. Treatment should consist of those general measures employed in the management of overdosage with any drug. Consider the possibility of multiple drug overdose. Ensure an adequate airway, oxygenation, and ventilation. Monitor cardiac rhythm and vital signs. Use supportive and symptomatic measures.

ADVERSE REACTIONS SECTION.


6 ADVERSE REACTIONS. The following serious adverse reactions are discussed in more detail in other sections of the labeling:Serious Dermatologic Reactions: Toxic Epidermal Necrolysis and Stevens-Johnson Syndrome [see Warnings and Precautions 5.1 Aplastic anemia/agranulocytosis [see Warnings and Precautions 5.2 )] Drug Reaction with Eosinophilia and Systemic Symptoms/Multiorgan Hypersensitivity [see Warnings and Precautions 5.3 )] Suicidal Behavior and Ideation [see Warnings and Precautions 5.4 )] Embryofetal Toxicity [see Warnings and Precautions 5.5 )] Abrupt Discontinuation and Seizure Risk [see Warnings and Precautions 5.6 )] Hyponatremia [see Warnings and Precautions 5.7 )] Cognitive and Motor Impairment [see Warnings and Precautions 5.8 )] Drug Interaction with Non-Nucleoside Reverse Transcriptase Inhibitors [see Warnings and Precautions 5.9 )] Liver Damage [see Warnings and Precautions 5.10 )] AV Heart Block [see Warnings and Precautions 5.11 )] Hepatic Porphyria [see Warnings and Precautions 5.12 )] Increased Intraocular Pressure [see Warnings and Precautions 5.13 )] Serious Dermatologic Reactions: Toxic Epidermal Necrolysis and Stevens-Johnson Syndrome [see Warnings and Precautions 5.1 . Aplastic anemia/agranulocytosis [see Warnings and Precautions 5.2 )] Drug Reaction with Eosinophilia and Systemic Symptoms/Multiorgan Hypersensitivity [see Warnings and Precautions 5.3 )] Suicidal Behavior and Ideation [see Warnings and Precautions 5.4 )] Embryofetal Toxicity [see Warnings and Precautions 5.5 )] Abrupt Discontinuation and Seizure Risk [see Warnings and Precautions 5.6 )] Hyponatremia [see Warnings and Precautions 5.7 )] Cognitive and Motor Impairment [see Warnings and Precautions 5.8 )] Drug Interaction with Non-Nucleoside Reverse Transcriptase Inhibitors [see Warnings and Precautions 5.9 )] Liver Damage [see Warnings and Precautions 5.10 )] AV Heart Block [see Warnings and Precautions 5.11 )] Hepatic Porphyria [see Warnings and Precautions 5.12 )] Increased Intraocular Pressure [see Warnings and Precautions 5.13 )] Most common (>5% and times placebo) adverse reactions were dizziness, somnolence, nausea, vomiting, ataxia, constipation, pruritus, dry mouth, asthenia, blurred vision, and speech disorder (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Validus Pharmaceuticals LLC at 1-866-9VALIDUS (1-866-982-5438) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.The most commonly reported adverse reactions (>5% in the EQUETRO group and at least twice placebo) in the pooled 3-week placebo-controlled trials in patients with acute mania associated with Bipolar Disorder (Studies and 2) were dizziness, somnolence, nausea, vomiting, ataxia, constipation, pruritus, dry mouth, asthenia, blurred vision, and speech disorder see Clinical Studies 14.1 ]. The EQUETRO doses used were 400 to 1600 mg per day.Table 2. Common Adverse Reactions Reported in Bipolar Disorder Studies and (Incidence 2% and greater than placebo)Adverse ReactionsEQUETRO(R) (N 251) Placebo (N 248)Dizziness44%12%Somnolence32%13%Nausea29%10%Vomiting18%3%Ataxia15%0.4%Constipation10%5%Pruritus8%2%Dry Mouth8%3%Asthenia8%4%Rash7%4%Blurred vision6%2%Speech Disorder6%0.4%Hypertension 3%0.4%Paresthesia2%1%Thinking abnormal2%0.4%Tremor3%1%Twitching2%1%Vertigo2%1%. 6.2 Postmarketing Experience. The following adverse reactions have been identified during post approval use of EQUETRO. Because these reactions are reported voluntarily from population of uncertain size, it is not always possible to reliably estimate their frequency or establish causal relationship to drug exposure.Nervous System: confusion, diplopia, oculomotor disturbances, nystagmus, speech disturbances, abnormal involuntary movements, tinnitus.Digestive System: gastric distress, abdominal pain, diarrhea, anorexia.Laboratory Tests: thyroid function tests (T3, T4)- decreased valuesOther: lupus erythematosus-like syndrome One case of aseptic meningitis, accompanied by myoclonus and peripheral eosinophilia, has been reported in patient taking carbamazepine in combination with other medications. The patient was successfully dechallenged, and the meningitis reappeared upon rechallenge with carbamazepine.. 6.3 Additional Adverse Reactions Associated with Carbamazepine. The following is list of additional adverse reactions identified in clinical trials or postmarketing reports of other forms of carbamazepine and not reported above for EQUETRO. Because these reactions were reported voluntarily from population of uncertain size, it is not always possible to estimate their frequency reliably or to establish causal relationship to drug exposure.Nervous System: Isolated cases of neuroleptic malignant syndrome have been reported in carbamazepine use both with and without concomitant use of other psychotropic drugs.Skin: onychomadesis, acute generalized exanthematous pustulosis (AGEP).To report SUSPECTED ADVERSE REACTIONS, contact Validus Pharmaceuticals LLC at 1-866-9VALIDUS(1-866-982-5438) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

BOXED WARNING SECTION.


WARNING: SERIOUS DERMATOLOGIC REACTIONS AND APLASTIC ANEMIA AND AGRANULOCYTOSIS. Serious Dermatologic Reactions and HLA-B1502 AlleleSerious and sometimes fatal dermatologic reactions, including toxic epidermal necrolysis (TEN) and Stevens-Johnson Syndrome (SJS), have occurred in patients treated with carbamazepine. These syndromes may be accompanied by mucous membrane ulcers, fever, or painful rash. These reactions are estimated to occur in to per 10,000 new users in countries with mainly Caucasian populations, but the risk in patients of Asian descent is estimated to be about 10 times higher. There is strong association between the risk of developing SJS/TEN and the presence of HLA-B1502, an inherited allelic variant of the HLA-B gene. Test for HLA-B1502, prior to initiating EQUETRO in patients with an increased likelihood of carrying this allele. Avoid use of EQUETRO in patients testing positive for the allele unless the benefit clearly outweighs the risk. Discontinue EQUETRO if you suspect that the patient has serious dermatologic reaction [see Warnings and Precautions (5.1)].Aplastic Anemia and AgranulocytosisAplastic anemia and agranulocytosis can occur during treatment with EQUETRO. The risk of developing these reactions with EQUETRO is 5-8 times greater than in the general population. However, the overall risk in the general population is low (6 cases in population of one million per year for agranulocytosis and two cases in population of one million per year for aplastic anemia). Obtain complete blood count before beginning treatment with EQUETRO, and monitor CBC periodically.Consider discontinuing EQUETRO if significant bone marrow depression develops [see Warnings and Precautions (5.2)].. WARNING: SERIOUS DERMATOLOGIC REACTIONS AND APLASTIC ANEMIA AND AGRANULOCYTOSISSee full prescribing information for complete boxed warning. Serious Dermatologic Reactionso Serious and sometimes fatal dermatologic reactions, including toxic epidermal necrolysis (TEN) and Stevens-Johnson Syndrome (SJS), have occurred with EQUETRO (5.1) Patients of Asian ancestry have 10-fold greater risk of TEN/SJS, compared to other populations. In genetically at-risk patients, test for the HLA-B1502 allele prior to initiating EQUETRO (2.1, 5.1)o Discontinue EQUETRO if these reactions occur (5.1) Aplastic Anemia and Agranulocytosis Aplastic anemia and agranulocytosis occurred with EQUETRO (5.2)o Obtain complete pretreatment hematological testing. Consider discontinuing EQUETRO if significant bone marrow depression develops (2.1, 5.2).

CLINICAL PHARMACOLOGY SECTION.


12 CLINICAL PHARMACOLOGY. 12.1 Mechanism of Action. Although numerous pharmacological effects of carbamazepine have been described in the published literature (e.g., modulation of ion channels [sodium and calcium], receptor-mediated neurotransmission [GABAergic, glutamatergic, and monoaminergic], and intracellular signaling pathways in experimental preparations), the contribution of these effects to the efficacy of carbamazepine in acute manic or mixed episodes associated with bipolar disorder is unknown.. 12.3 Pharmacokinetics. Carbamazepine (CBZ)Absorption: Following single 200 mg oral extended-release dose of carbamazepine, peak plasma concentration was 1.9 +- 0.3 mcg/mL and the time to reach the peak was 19 +- hours. Following repeat dose administration (800 mg every 12 hours), the peak levels were 11.0 +- 2.5 mcgt/mL and the time to reach the peak was 5.9 +- 1.8 hours. The pharmacokinetics of extended-release carbamazepine is linear over the single dose range of 200-800 mg.Carbamazepine is 76% bound to plasma proteins. Carbamazepine is primarily metabolized in the liver. Cytochrome P450 3A4 was identified as the major isoform responsible for the formation of carbamazepine-10,11-epoxide. Since carbamazepine induces its own metabolism, the half-life is also variable. The average half-life ranged from 35 to 40 hours following single extended-release dose of carbamazepine and from 12 to 17 hours following repeated dosing. The apparent oral clearance was 25 +- mL/min following single dose and 80 +- 30 mL/min following multiple dosing.Carbamazepine-10,11-epoxide (CBZ-E): Carbamazepine-10,11-epoxide is considered to be an active metabolite of carbamazepine. Following single 200 mg oral extended-release dose of carbamazepine, the peak plasma concentration of carbamazepine-10,11-epoxide was 0.11 +- 0.012 mcg/mL and the time to reach the peak was 36 +- hours. Following chronic administration of an extended-release dose of carbamazepine (800 mg every 12 hours), the peak levels of carbamazepine-10,11-epoxide were 2.2 +- 0.9 mcg/mL and the time to reach the peak was 14 +- hours. The plasma half-life of carbamazepine-10,11-epoxide following administration of carbamazepine is 34 +- hours. Following single oral dose of extended-release carbamazepine (200-800 mg) the AUC and Cmax of carbamazepine-10,11-epoxide were less than 10% of carbamazepine. Following multiple dosing of extended-release carbamazepine (800-1600 mg daily for 14 days), the AUC and Cmax of carbamazepine-10,11-epoxide were dose-related, ranging from 15.7 mcg.hr/mL and 1.5 mcg/mL at 800 mg/day to 32.6 mcg.hr/mL and 3.2 mcg/mL at 1600 mg/day, respectively, and were less than 30% those of carbamazepine. Carbamazepine-10,11-epoxide is 50% bound to plasma proteins.Food Effect: high-fat meal diet increased the rate of absorption of single 400 mg dose (mean Tmax was reduced from 24 hours, in the fasting state, to 14 hours, and Cmax increased from 3.2 to 4.3 mcg/mL) but not the extent (AUC) of absorption. The elimination half-life remained unchanged between fed and fasting state. The multiple-dose study conducted in the fed state showed that the steady-state Cmax values were within the therapeutic concentration range. The pharmacokinetic profile of extended-release carbamazepine was similar when given by sprinkling the beads over applesauce compared to the intact capsule administered in the fasted state.Elimination: After oral administration of 14C-carbamazepine, 72% of the administered radioactivity was found in the urine and 28% was found in the feces. This urinary radioactivity was composed largely of hydroxylated and conjugated metabolites, with only 3% of unchanged carbamazepine. Metabolism: In vitro data indicate carbamazepine is metabolized mainly by cytochrome P450 (CYP) 3A4 to the active carbamazepine-10,11-epoxide, which is further metabolized to the trans-diol by epoxide hydrolase. Human microsomal epoxide hydrolase has been identified as the enzyme responsible for the formation of the 10,11-transdiol derivative from carbamazepine-10,11-epoxide.Renal Impairment: The effect of renal impairment on the pharmacokinetics of carbamazepine is not known.Hepatic Impairment: The effect of hepatic impairment on the pharmacokinetics of carbamazepine is not known. Consider reducing the dosage in patients with hepatic impairment. Effect of Age: Carbamazepine is more rapidly metabolized to carbamazepine-10,11-epoxide in young children than in adults. In children below the age of 15, there is an inverse relationship between CBZ-E/CBZ ratio and increasing age. The safety and effectiveness of EQUETRO have not been established in pediatric patients for indications other than Epilepsy [see Indications and Usage 1.3 )]. Effect of Gender: No difference in the mean AUC and Cmax of carbamazepine and carbamazepine-10,11-epoxide was found between males and females.

CLINICAL STUDIES SECTION.


6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.The most commonly reported adverse reactions (>5% in the EQUETRO group and at least twice placebo) in the pooled 3-week placebo-controlled trials in patients with acute mania associated with Bipolar Disorder (Studies and 2) were dizziness, somnolence, nausea, vomiting, ataxia, constipation, pruritus, dry mouth, asthenia, blurred vision, and speech disorder see Clinical Studies 14.1 ]. The EQUETRO doses used were 400 to 1600 mg per day.Table 2. Common Adverse Reactions Reported in Bipolar Disorder Studies and (Incidence 2% and greater than placebo)Adverse ReactionsEQUETRO(R) (N 251) Placebo (N 248)Dizziness44%12%Somnolence32%13%Nausea29%10%Vomiting18%3%Ataxia15%0.4%Constipation10%5%Pruritus8%2%Dry Mouth8%3%Asthenia8%4%Rash7%4%Blurred vision6%2%Speech Disorder6%0.4%Hypertension 3%0.4%Paresthesia2%1%Thinking abnormal2%0.4%Tremor3%1%Twitching2%1%Vertigo2%1%.

CONTRAINDICATIONS SECTION.


4 CONTRAINDICATIONS. Bone marrow depression [see Warnings and Precautions 5.2 ] Known hypersensitivity to carbamazepine, such as anaphylaxis or serious hypersensitivity reaction [see Warnings and Precautions 5.3 ] Known hypersensitivity to any of the tricyclic compounds (e.g., amitriptyline, desipramine, imipramine, protriptyline, and nortriptyline. Hypersensitivity reactions include anaphylaxis and serious rash. Concomitant use of delavirdine or other non-nucleoside reverse transcriptase inhibitors that are substrates for CYP3A4. EQUETRO can substantially reduce the concentrations of these drugs through induction of CYP3A4. This can lead to loss of virologic response and possible resistance to these medications [see Warnings and Precautions 5.9 and Drug Interactions 7.2 ] Concomitant use of monoamine oxidase inhibitors (MAOIs). Before beginning treatment with EQUETRO, MAOIs should be discontinued for minimum of 14 days. Concomitant use can cause serotonin syndrome. Concomitant use of nefazodone. This may result in insufficient plasma concentrations of nefazodone and its active metabolite to achieve therapeutic effect. Bone marrow depression [see Warnings and Precautions 5.2 ] . Known hypersensitivity to carbamazepine, such as anaphylaxis or serious hypersensitivity reaction [see Warnings and Precautions 5.3 ] . Known hypersensitivity to any of the tricyclic compounds (e.g., amitriptyline, desipramine, imipramine, protriptyline, and nortriptyline. Hypersensitivity reactions include anaphylaxis and serious rash. Concomitant use of delavirdine or other non-nucleoside reverse transcriptase inhibitors that are substrates for CYP3A4. EQUETRO can substantially reduce the concentrations of these drugs through induction of CYP3A4. This can lead to loss of virologic response and possible resistance to these medications [see Warnings and Precautions 5.9 and Drug Interactions 7.2 ] . Concomitant use of monoamine oxidase inhibitors (MAOIs). Before beginning treatment with EQUETRO, MAOIs should be discontinued for minimum of 14 days. Concomitant use can cause serotonin syndrome. Concomitant use of nefazodone. This may result in insufficient plasma concentrations of nefazodone and its active metabolite to achieve therapeutic effect. Bone marrow depression (4) Known hypersensitivity to carbamazepine (4) Known hypersensitivity to tricyclic antidepressants (4) Concomitant use with monoamine oxidase inhibitors (MAOIs) or use within 14 days of discontinuing an MAOI (4) Concomitant use with delavirdine or other non-nucleoside reverse transcriptase inhibitors that are substrates for CYP3A4. EQUETRO decreases efficacy of these drugs (4, 5.9) Concomitant use of nefazodone (4). Bone marrow depression (4) Known hypersensitivity to carbamazepine (4) Known hypersensitivity to tricyclic antidepressants (4) Concomitant use with monoamine oxidase inhibitors (MAOIs) or use within 14 days of discontinuing an MAOI (4) Concomitant use with delavirdine or other non-nucleoside reverse transcriptase inhibitors that are substrates for CYP3A4. EQUETRO decreases efficacy of these drugs (4, 5.9) Concomitant use of nefazodone (4).

DESCRIPTION SECTION.


11 DESCRIPTION. EQUETRO (carbamazepine) is mood stabilizer available for oral administration as 100 mg, 200 mg, and 300 mg extended-release capsules of carbamazepine, USP. Carbamazepine is white to off-white powder, practically insoluble in water and soluble in alcohol and in acetone. Its molecular weight is 236.27. The chemical name of carbamazepine is 5H-dibenz[b,f]azepine-5-carboxamide, and the structural formula is:EQUETRO(R) is multi-component capsule formulation consisting of three different types of beads: immediate-release beads, extended-release beads, and enteric-release beads. The three bead types are combined in specific ratio to provide twice-daily dosing of EQUETRO(R).Inactive ingredients: citric acid, colloidal silicon dioxide, lactose monohydrate, microcrystalline cellulose, polyethylene glycol, povidone, sodium lauryl sulfate, talc, triethyl citrate, and other ingredients.The 100 mg capsule shells contain gelatin-NF, FD&C Blue 2, Yellow Iron Oxide, and Titanium Dioxide, and are imprinted with white ink; the 200 mg capsule shells contain gelatin-NF, Yellow Iron Oxide, FD&C Blue 2, and Titanium Dioxide, and are imprinted with white ink; and the 300 mg capsule shells contain gelatin-NF, FD&C Blue 2, Yellow Iron Oxide, and Titanium Dioxide, and are imprinted with white ink.. The structural formula for EQUETRO (carbamazepine) is mood stabilizer available for oral administration as 100 mg, 200 mg, and 300 mg extended-release capsules of carbamazepine, USP. Carbamazepine is white to off-white powder, practically insoluble in water and soluble in alcohol and in acetone. Its molecular weight is 236.27.

DOSAGE & ADMINISTRATION SECTION.


2 DOSAGE AND ADMINISTRATION. SEE DOSAGE FOR BIPOLAR DISORDER, TRIGEMINULLL NEURALGIA, AND EPILEPSY (2.2, 2.3, 2.4) When discontinuing treatment, reduce dose gradually (2.6, 5.6) Monitoring serum carbamazepine concentrations may be useful in dose selection and minimizing risk of toxicity (2.7) Swallow capsules whole or open capsules and sprinkle beads over food (2.8) Do not crush or chew the capsule or beads (2.8). SEE DOSAGE FOR BIPOLAR DISORDER, TRIGEMINULLL NEURALGIA, AND EPILEPSY (2.2, 2.3, 2.4) When discontinuing treatment, reduce dose gradually (2.6, 5.6) Monitoring serum carbamazepine concentrations may be useful in dose selection and minimizing risk of toxicity (2.7) Swallow capsules whole or open capsules and sprinkle beads over food (2.8) Do not crush or chew the capsule or beads (2.8). 2.1 Pretreatment Screening. Prior to initiating treatment with EQUETRO, test patients with ancestry in genetically at-risk populations for the presence of the HLA-B1502 allele. The high resolution genotype test is positive if one or two HLA-B1502 alleles are present. Avoid use of EQUETRO in patients testing positive for the allele, unless the benefit clearly outweighs the risk see Boxed Warning Warnings and Precautions 5.1 )]. Complete pretreatment blood counts, including platelets and possibly reticulocytes and serum iron, should be obtained as baseline. If patient in the course of treatment exhibits low or decreased white blood cell or platelet counts, the patient should be monitored closely. Discontinuation of EQUETRO should be considered if any evidence of significant bone marrow depression develops [see Warnings and Precautions 5.2 )] Baseline and periodic evaluations of liver function, particularly in patients with history of liver disease, must be performed during treatment with EQUETRO because liver damage may occur. Discontinue EQUETRO in cases of aggravated liver dysfunction or active liver disease [see Warnings and Precautions 5.10 )]. Baseline and periodic eye examinations, including slit-lamp, funduscopy, and tonometry, are recommended since many phenothiazines and related drugs have been shown to cause eye changes [see Warnings and Precautions 5.13 )].Baseline and periodic complete urinalysis and BUN determinations are recommended for patients treated with this agent because of observed renal dysfunction.. 2.2 Dosage for Acute Manic or Mixed Episodes Associated with Bipolar Disorder. The recommended initial dose of EQUETRO is 200 mg administered twice daily. The dose may be increased by 200 mg per day to achieve optimal clinical response. Doses higher than 1600 mg per day have not been studied in mania associated with bipolar disorder.. 2.3 Dosage for Pain of Trigeminal Neuralgia. Initial: On the first day, start with one 200 mg capsule once daily. This dose may be increased by up to 200 mg/day using increments of 100 mg every 12 hours only as needed to reach an effective and tolerated dose. Do not exceed total daily dose of 1200 mg.Maintenance: Control of pain can be maintained in most patients with 400 mg to 800 mg daily. However, some patients may be maintained on as little as 200 mg daily, while others may require as much as 1200 mg daily. At least once every months throughout the treatment period, attempts should be made to reduce the dose to the minimum effective level or even to discontinue the drug.. 2.4 Dosage for Epilepsy. Adults and Children over 12 Years of Age The recommended initial dose is 200 mg administered twice daily. Increase in weekly increments of 200 mg day, administered as an equally divided, twice daily dose, until an optimal response is obtained. Dosage generally should not exceed 500 mg twice daily in children 12 to 15 years old; 600 mg twice daily in children 15 to 18 years old; and 800 mg twice daily in adults. Children Under 12 Years of Age Ordinarily, optimal clinical response is achieved at daily doses below 35 mg/kg [see Dosage and Administration 2.5 )]. No recommendation regarding the safety of EQUETRO for use at doses above 35 mg/kg/24 hours can be made.Co-Administration with Other AEDs EQUETRO may be used alone or with other AEDs. When added to existing AEDs, add EQUETRO gradually while the dosage(s) of other AEDs are maintained or gradually decreased. Potential drug interactions should be considered when using carbamazepine with other AEDs see Drug Interactions 7.1 7.2 ].. 2.5 Switching from Immediate-Release Carbamazepine to EQUETRO. EQUETRO is an extended-release formulation for twice day administration. When converting patients from immediate release carbamazepine to EQUETRO extended-release capsules, the same total daily mg dose of carbamazepine should be administered. Following conversion to EQUETRO, patients should be closely monitored for seizure control. Depending on the therapeutic response after conversion, the total daily dose may need to be adjusted within the recommended dosing instructions.. 2.6 Discontinuation of EQUETRO. When discontinuing EQUETRO used for any indication, reduce the dose gradually and avoid abrupt discontinuation in order to decrease the risk of seizure [see Warnings and Precautions 5.6 )] . 2.7 Monitoring Serum Carbamazepine Concentration. Monitoring serum carbamazepine concentrations may be useful for dose selection, minimizing toxicity, and verifying drug compliance, especially in clinical conditions in which alterations in EQUETRO metabolism can occur (e.g., drug interactions) [see Drug Interactions 7 ]. In pediatric patients treated with EQUETRO for epilepsy, if satisfactory clinical response has not been achieved, measure plasma levels to determine whether or not they are in the therapeutic range.. 2.8 Administration Instructions. Swallow EQUETRO capsules whole or open and sprinkle the beads over food, such as teaspoon of applesauce. Do not crush or chew EQUETRO capsules or the beads inside the capsule. EQUETRO can be taken with or without meals.

DOSAGE FORMS & STRENGTHS SECTION.


3 DOSAGE FORMS AND STRENGTHS. EQUETRO (carbamazepine) extended-release capsules for oral administration is supplied in three dosage strengths:100 mg -- Two-piece hard gelatin capsule yellow opaque cap with bluish green opaque body printed with SPD417 on one end and SPD417 and 100 mg on the other in white ink. 200 mg -- Two-piece hard gelatin capsule yellow opaque cap with blue opaque body printed with SPD417 on one end and SPD417 and 200 mg on the other in white ink. 300 mg -- Two-piece hard gelatin capsule yellow opaque cap with blue body printed with SPD417 on one end and SPD417 and 300 mg on the other in white ink. 100 mg -- Two-piece hard gelatin capsule yellow opaque cap with bluish green opaque body printed with SPD417 on one end and SPD417 and 100 mg on the other in white ink. 200 mg -- Two-piece hard gelatin capsule yellow opaque cap with blue opaque body printed with SPD417 on one end and SPD417 and 200 mg on the other in white ink. 300 mg -- Two-piece hard gelatin capsule yellow opaque cap with blue body printed with SPD417 on one end and SPD417 and 300 mg on the other in white ink. Extended-Release Capsules: 100 mg, 200 mg, and 300 mg (3).

DRUG INTERACTIONS SECTION.


7 DRUG INTERACTIONS. Cytochrome (CYP) 3A4 inhibitors, epoxide hydrolase inhibitors, CYP3A4 inducers, drugs metabolized by CYP1A2 or CYP3A4 (oral contraceptives, delavirdine, nefazodone), phenytoin, CNS depressants, lithium, chloroquine, mefloquine (7.1, 7.2, 7.3) Equetro may decrease the effectiveness of hormonal contraceptives. Use alternative form of birth control (7.2). Cytochrome (CYP) 3A4 inhibitors, epoxide hydrolase inhibitors, CYP3A4 inducers, drugs metabolized by CYP1A2 or CYP3A4 (oral contraceptives, delavirdine, nefazodone), phenytoin, CNS depressants, lithium, chloroquine, mefloquine (7.1, 7.2, 7.3) Equetro may decrease the effectiveness of hormonal contraceptives. Use alternative form of birth control (7.2). 7.1 Pharmacokinetic Effects of other Drugs on EQUETRO. Drugs that Inhibit Cytochrome P450 3A4 (CYP3A4) EQUETRO is metabolized primarily by CYP3A4 to the active carbamazepine-10,11-epoxide, which is further metabolized to the trans-diol by epoxide hydrolase. Inhibitors of CYP 3A4 and/or epoxide hydrolase can increase plasma levels of EQUETRO and its active metabolites, increasing plasma concentrations of EQUETRO and the risk of adverse reactions. It may be necessary to reduce the EQUETRO dose if used concomitantly with inhibitors of CYP3A4 and/or epoxide hydrolase. The following drugs are CYP3A4 inhibitors:Acetazolamide, aprepitant, azole antifungals (e.g., ketoconazole, itraconazole, fluconazole, voriconazole,, cimetidine, ciprofloxacin, clarithromycin, dalfopristin, danazol, dantrolene, delavirdine, diltiazem, erythromycin, fluoxetine, fluvoxamine, grapefruit juice, ibuprofen, isoniazid, loratadine, nefazodone, niacinamide, nicotinamide, olanzapine, omeprazole, oxybutynin, quinine, quinupristin, ticlopidine, troleandomycin, valproate, verapamil, zileuton.Drugs that Inhibit Epoxide Hydrolase and CYP3A4Clarithromycin, erythromycin, loxapine, quetiapine, and valproate also inhibit epoxide hydrolase, resulting in increased levels of the active metabolite carbamazepine-10,11-epoxide [see Clinical Pharmacology 12.3 ].Drugs that Induce CYP3A4CYP3A4 inducers can decrease serum concentrations of EQUETRO and decrease its effectiveness. It may be necessary to increase the dose of EQUETRO if used concomitantly with CYP3A4 inducer. Such drugs include the following:Aminophylline, cisplatin, doxorubicin, felbamate, phosphenytoin, methsuximide, phenobarbital, phenytoin, primidone, rifampin and theophylline. 7.2 Pharmacokinetic Effects of EQUETRO on other Drugs. EQUETRO is potent inducer of hepatic 3A4 and is also known to be an inducer of CYP1A2, 2B6, 2C9/19 and may therefore reduce plasma concentrations of co-medications mainly metabolized by CYP 1A2, 2B6, 2C9/19 and 3A4, through induction of their metabolism. When used concomitantly with EQUETRO, monitoring of concentrations or dosage adjustment of these agents may be necessary. EQUETRO decreases the concentrations of the following drugs through induction of their metabolism:Oral Contraceptives (CYP3A4 Substrates)EQUETRO is strong inducer of CYP3A4. EQUETRO can increase the metabolism of certain oral contraceptives (through CYP3A4 induction), leading to significantly lower concentrations. This can cause contraceptive failure or breakthrough bleeding. Consider alternatives to oral contraceptives that are significantly affected by induction of CYP3A4; or consider alternatives to EQUETRO.Delavirdine and other Non-Nucleoside Reverse Transcriptase Inhibitors (CYP3A4 Substrates)Through induction of CYP3A4, EQUETRO increases the metabolism of delavirdine and certain non-nucleoside reverse transcriptase inhibitors and significantly reduces the plasma concentrations of these drugs. This can cause inadequate antiviral activity, loss of virologic response, and possible resistance to delavirdine or other non-nucleoside reverse transcriptase inhibitors. Therefore, the use of EQUETRO with these non-nucleoside reverse transcriptase inhibitors is contraindicated [see Contraindications 4 and Warnings and Precautions 5.9 )] Nefazodone (CYP3A4 Substrate)The use of EQUETRO is contraindicated with the use of nefazodone because the concomitant use may result in insufficient plasma concentrations of nefazodone and its active metabolite to achieve therapeutic effect of nefazodone.Warfarin (CYP1A2 and CYP3A4 Substrate)Through induction of CYP1A2 and CYP3A4, EQUETRO decreases the concentration of warfarin and decreases its anticoagulant effectiveness. AripiprazoleWhen carbamazepine is added to aripiprazole, the aripiprazole dose should be doubled. Additional dose increases should be based on clinical evaluation. If carbamazepine is later withdrawn, the aripiprazole dose should be reduced.TacrolimusWhen carbamazepine is used with tacrolimus, monitoring of tacrolimus blood concentrations and appropriate dosage adjustments are recommended. TemsirolimusThe use of concomitant strong CYP3A4 inducers such as carbamazepine should be avoided with temsirolimus. If patients must be coadministered carbamazepine with temsirolimus, an adjustment of temsirolimus dosage should be considered.LapatinibThe use of carbamazepine with lapatinib should generally be avoided. If carbamazepine is started in patient already taking lapatinib, the dose of lapatinib should be gradually titrated up. If carbamazepine is discontinued, the lapatinib dose should be reduced. HIV Protease Inhibitors Due to strong induction of CYP3A4 caused by carbamazepine, use of EQUETRO with HIV protease inhibitors is not recommended.Other CYP1A2 and CYP3A4 SubstratesEQUETRO induces CYP1A2 and CYP3A4, leading to decreased concentrations of drugs metabolized by CYP3A4 or CYP1A2. It may be necessary to increase the doses of such drugs when used concomitantly with EQUETRO. Drugs metabolized by CYP3A4 or CYP1A2 include the following:Acetaminophen, albendazole, alprazolam, aprepitant, buprenorphone, bupropion, buspirone, citalopram, clobazam, clonazepam, clozapine, cyclosporin, delavirdine, desipramine, diazepam, dicumarol, dihydropyridine calcium channel blockers (e.g., felodipine), doxycycline, ethosuximide, everolimus, felbamate, glucocorticoids, haloperidol, imatinib, itraconazole, lamotrigine, levothyroxine, lorazepam, methadone, methsuxamide, mianserin, midazolam, mirtazapine, nefazodone, olanzapine, oral and other hormonal contraceptives, oxcarbazepine, paliperidone, phenytoin, praziquantel, quetiapine, risperidone, sertraline, sirolimus, tadalafil, theophylline, topiramate, tiagabine, tramadol, triazolam, tricyclic antidepressants (e.g., imipramine, amitriptyline, nortriptyline), trazodone, valproate, warfarin ziprasidone, and zonisamide. EQUETRO increases the plasma levels of the following drugs by inhibition of their metabolism:Clomipramine, Phenytoin, and PrimidoneEQUETRO can increase the concentrations of clomipramine, phenytoin, and primidone. If patient has been titrated to stable dosage on one of these agents in this category, and then begins treatment with EQUETRO, it may be necessary to decrease the dose of these drugs.Phenytoin Phenytoin levels have been reported to increase or decrease in the presence of carbamazepine. There are multiple pharmacokinetic mechanisms for changes in phenytoin levels when used concomitantly with EQUETRO. Monitor phenytoin serum levels carefully when used concomitantly with EQUETRO.CyclophosphamideCyclophosphamide is an inactive prodrug and is converted to its active metabolite in part by CYP3A. The rate of metabolism and the leukopenic activity of cyclophosphamide are reportedly increased by chronic co-administration of CYP3A4 inducers. There is potential for increased cyclophosphamide toxicity when coadministered with carbamazepine. 7.3 Pharmacodynamic Drug Interactions. Monoamine Oxidase InhibitorsConcomitant treatment with EQUETRO is contraindicated during use of an MAOI or within 14 days after discontinuing an MAOI. Concomitant use can cause serotonin syndrome.Lithium Concomitant administration of EQUETRO and lithium can increase the risk of neurotoxic adverse reactions. Consider reducing the dose of lithium or EQUETRO when using these drugs concomitantly. IsoniazidConcomitant use of carbamazepine and isoniazid has been reported to increase isoniazid-induced hepatotoxicity. CNS Depressants The concomitant use of EQUETRO and other CNS depressants can increase the risk of respiratory depression, profound sedation, hypotension, and syncope. CNS depressants include: alcohol, opioid analgesics, benzodiazepines, tricyclic antidepressants, sedative/hypnotics, anticonvulsants, antipsychotics, antihistamines, anticholinergics, alpha and beta blockers, general anesthetics, muscle relaxants, and illicit CNS depressants. Consider reducing the dose of CNS depressants or EQUETRO when using these drugs concomitantly. Chloroquine and MefloquineThe anti-malarial drugs chloroquine and mefloquine can antagonize the activity of EQUETRO.Neuromuscular Blocking AgentsResistance to the neuromuscular blocking action of the nondepolarizing neuromuscular blocking agents pancuronium, vecuronium, rocuronium and cisatracurium has occurred in patients chronically administered carbamazepine. Whether or not carbamazepine has the same effect on other nondepolarizing agents is unknown. Patients should be monitored closely for more rapid recovery from neuromuscular blockade than expected, and infusion rate requirements may be higher.

GERIATRIC USE SECTION.


8.5 Geriatric Use. Clinical studies of EQUETRO did not include sufficient numbers of subjects age 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

HOW SUPPLIED SECTION.


16 HOW SUPPLIED/STORAGE AND HANDLING. 16.1 How Supplied. EQUETRO (carbamazepine) extended-release capsules are supplied in three dosage strengths.100 mg -- Two-piece hard gelatin capsule yellow opaque cap with bluish green opaque body printed with SPD417 on one end and SPD417 and 100 mg on the other in white ink: Supplied in bottles of 120NDC 30698-419-12200 mg -- Two-piece hard gelatin capsule yellow opaque cap with blue opaque body printed with SPD417 on one end and SPD417 and 200 mg on the other in white ink: Supplied in bottles of 120NDC 30698-421-12300 mg -- Two-piece hard gelatin capsule yellow opaque cap with blue body printed with SPD417 on one end and SPD417 and 300 mg on the other in white ink: Supplied in bottles of 120NDC 30698-423-12 100 mg -- Two-piece hard gelatin capsule yellow opaque cap with bluish green opaque body printed with SPD417 on one end and SPD417 and 100 mg on the other in white ink: Supplied in bottles of 120NDC 30698-419-12. 200 mg -- Two-piece hard gelatin capsule yellow opaque cap with blue opaque body printed with SPD417 on one end and SPD417 and 200 mg on the other in white ink: Supplied in bottles of 120NDC 30698-421-12. 300 mg -- Two-piece hard gelatin capsule yellow opaque cap with blue body printed with SPD417 on one end and SPD417 and 300 mg on the other in white ink: Supplied in bottles of 120NDC 30698-423-12 16.2 Storage. Store at 25 (77 F); excursions permitted to 15 -30 (59 -86 F) [see USP controlled room temperature].Protect from light and moisture.

INDICATIONS & USAGE SECTION.


1 INDICATIONS AND USAGE. EQUETRO is:A mood stabilizer indicated for the treatment of acute manic or mixed episodes associated with bipolar disorder (1.1) Indicated for the treatment of the pain associated with trigeminal neuralgia (1.2) An anti-epileptic drug (AED) indicated for the treatment of partial seizures with complex symptomatology, generalized tonic-clonic seizures, and mixed seizures (1.3). mood stabilizer indicated for the treatment of acute manic or mixed episodes associated with bipolar disorder (1.1) Indicated for the treatment of the pain associated with trigeminal neuralgia (1.2) An anti-epileptic drug (AED) indicated for the treatment of partial seizures with complex symptomatology, generalized tonic-clonic seizures, and mixed seizures (1.3). 1.1 Acute Manic or Mixed Episodes associated with Bipolar Disorder. EQUETRO is indicated for treatment of patients with acute manic or mixed episodes associated with bipolar disorder [see Clinical Studies 14.1 ].. 1.2 Pain of Trigeminal Neuralgia. EQUETRO is indicated in the treatment of the pain associated with trigeminal neuralgia. Beneficial results have also been reported in glossopharyngeal neuralgia. This drug is not simple analgesic and should not be used for the relief of trivial aches or pains.. 1.3 Epilepsy. EQUETRO is indicated for the treatment of partial seizures with complex symptomatology (e.g., psychomotor, temporal lobe), generalized tonic-clonic seizures (grand mal), and mixed seizure patterns, which include the seizure types listed here or other partial or generalized seizures.Limitations of UsageEQUETRO is not indicated for the treatment of absence seizures (petit mal).Carbamazepine has been associated with increased frequency of generalized convulsions in these patients.

INFORMATION FOR PATIENTS SECTION.


17 PATIENT COUNSELING INFORMATION. See FDA-approved patient labeling (Medication Guide).Inform patients and caregivers that Medication Guide is available. Instruct them to read the Medication Guide before taking EQUETRO. Serious Dermatologic Reactions Inform patients and caregivers about the risk of potentially fatal, serious skin reactions and the signs and symptoms that may signal serious skin reaction. Instruct patients to consult with their healthcare provider immediately if skin reaction occurs during treatment with EQUETRO [see Warnings and Precautions 5.1 )]. Agranulocytosis and Aplastic AnemiaInform patients and caregivers about the risk of potentially fatal agranulocytosis and aplastic anemia and the signs and symptoms that may signal these reactions. Instruct them to contact their healthcare provider immediately if symptoms occur [see Warnings and Precautions (5.2)].Drug Reaction with Eosinophilia and Systemic SymptomsInform patients of the early toxic signs and symptoms of potential hematologic, dermatologic, hypersensitivity, or hepatic reactions. Advise patients that these signs and symptoms may signal serious reaction and to report any occurrence immediately to their healthcare provider [s ee Warnings and Precautions 5.3 )]. Suicidal Ideation and BehaviorCounsel patients, their caregivers, and families that AEDs, including EQUETRO, may increase the risk of suicidal thinking and behavior and advise them 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. Instruct patients, caregivers and families to report behaviors of concern immediately to healthcare providers [see Warnings and Precautions (5.4)].Embryofetal ToxicityAdvise women of childbearing potential that EQUETRO may cause fetal harm. Use in pregnancy only if the potential benefits of treatment outweigh the risks [see Warning and Precautions 5.5 and Use in Specific Populations 8.1 ].Encourage patients to enroll in the North American Antiepileptic Drug (NULLAED) Pregnancy Registry if they become pregnant. This registry is collecting information about the safety of antiepileptic drugs during pregnancy [see Warning and Precautions 5.5 and Use in Specific Populations 8.1 ]. Abrupt Discontinuation and Risk of SeizureInform patients that abrupt discontinuation of EQUETRO can cause seizures or an increase in seizure frequency. Advise patients that the drug should be tapered when discontinued [see Warning and Precautions 5.6 )]. Hyponatremia Advise patients that EQUETRO may reduce serum sodium concentrations especially if they are taking other medications that can lower sodium. Advise patients to report symptoms of low sodium like nausea, tiredness, lack of energy, confusion, seizures, or more frequent or more severe seizures [see Warnings and Precautions (5.7)].Potential for Cognitive and Motor ImpairmentAdvise patients not to drive or operate machinery until they have gained sufficient experience on EQUETRO to gauge whether it adversely affects their ability to drive or operate machinery.Advise patients to exercise caution if alcohol is taken in combination with EQUETRO therapy, due to possible additive sedative effect s ee Warnings and Precautions 5.8 )]. Concomitant Use with other Carbamazepine ProductsInform patients that EQUETRO contains carbamazepine and should not be used in combination with any other medications containing carbamazepine.Decreased Effectiveness of Oral ContraceptivesInform patients that EQUETRO can significantly decrease the effectiveness of oral contraception. This can cause contraceptive failure or breakthrough bleeding. Manufactured for Validus Pharmaceuticals LLC, 119 Cherry Hill Road, Suite 310, Parsippany, NJ 070541-866-9VALIDUS (1-866-982-5438)infovaliduspharma.comhttp://www.equetro.comMade in U.S.A. (C) 2016 Validus Pharmaceuticals LLC60079-01 October 2016. Serious Dermatologic Reactions Inform patients and caregivers about the risk of potentially fatal, serious skin reactions and the signs and symptoms that may signal serious skin reaction. Instruct patients to consult with their healthcare provider immediately if skin reaction occurs during treatment with EQUETRO [see Warnings and Precautions 5.1 )]. Agranulocytosis and Aplastic AnemiaInform patients and caregivers about the risk of potentially fatal agranulocytosis and aplastic anemia and the signs and symptoms that may signal these reactions. Instruct them to contact their healthcare provider immediately if symptoms occur [see Warnings and Precautions (5.2)].. Drug Reaction with Eosinophilia and Systemic SymptomsInform patients of the early toxic signs and symptoms of potential hematologic, dermatologic, hypersensitivity, or hepatic reactions. Advise patients that these signs and symptoms may signal serious reaction and to report any occurrence immediately to their healthcare provider [s ee Warnings and Precautions 5.3 )]. Suicidal Ideation and BehaviorCounsel patients, their caregivers, and families that AEDs, including EQUETRO, may increase the risk of suicidal thinking and behavior and advise them 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. Instruct patients, caregivers and families to report behaviors of concern immediately to healthcare providers [see Warnings and Precautions (5.4)].. Embryofetal ToxicityAdvise women of childbearing potential that EQUETRO may cause fetal harm. Use in pregnancy only if the potential benefits of treatment outweigh the risks [see Warning and Precautions 5.5 and Use in Specific Populations 8.1 ].Encourage patients to enroll in the North American Antiepileptic Drug (NULLAED) Pregnancy Registry if they become pregnant. This registry is collecting information about the safety of antiepileptic drugs during pregnancy [see Warning and Precautions 5.5 and Use in Specific Populations 8.1 ]. Abrupt Discontinuation and Risk of SeizureInform patients that abrupt discontinuation of EQUETRO can cause seizures or an increase in seizure frequency. Advise patients that the drug should be tapered when discontinued [see Warning and Precautions 5.6 )]. Hyponatremia Advise patients that EQUETRO may reduce serum sodium concentrations especially if they are taking other medications that can lower sodium. Advise patients to report symptoms of low sodium like nausea, tiredness, lack of energy, confusion, seizures, or more frequent or more severe seizures [see Warnings and Precautions (5.7)].. Potential for Cognitive and Motor ImpairmentAdvise patients not to drive or operate machinery until they have gained sufficient experience on EQUETRO to gauge whether it adversely affects their ability to drive or operate machinery.Advise patients to exercise caution if alcohol is taken in combination with EQUETRO therapy, due to possible additive sedative effect s ee Warnings and Precautions 5.8 )]. Concomitant Use with other Carbamazepine ProductsInform patients that EQUETRO contains carbamazepine and should not be used in combination with any other medications containing carbamazepine.. Decreased Effectiveness of Oral ContraceptivesInform patients that EQUETRO can significantly decrease the effectiveness of oral contraception. This can cause contraceptive failure or breakthrough bleeding.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.


PRINCIPAL DISPLAY PANELNDC 30698-419-12EquetroCarbamazepineExtended ReleaseCapsules100 mg120 CapsulesRx Only. PRINCIPAL DISPLAY PANELNDC 30698-419-12EquetroCarbamazepineExtended ReleaseCapsules100 mg120 CapsulesRx Only.

PREGNULLNCY SECTION.


8.1 Pregnancy Pregnancy Category Risk SummaryEQUETRO can cause fetal harm when administered to pregnant woman. Epidemiological data suggest that there may be an association between the use of carbamazepine during pregnancy and congenital malformations, including spina bifida. Adverse developmental effects were seen in animal reproduction studies with carbamazepine. If this drug is used during pregnancy, or if the patient becomes pregnant while taking the drug, the patient should be apprised of the potential hazard to the fetus [see Warning and Precautions 5.4 )]. Pregnancy Registry Patients should be encouraged to enroll in the North American Antiepileptic Drug (NULLAED) 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 1888-233-2334. Information about the North American Drug Pregnancy Registry can be found at http://www.aedpregnancyregistry.org/ [see Warning and Precautions 5.4 )].Clinical ConsiderationsWhen treating pregnant woman with EQUETRO, carefully consider both the potential risks and benefits of treatment and provide appropriate counseling. Tests to detect major congenital malformations using current accepted procedures should be considered part of routine prenatal care in pregnant women receiving carbamazepine [see Warning and Precautions 5.4 )].Human DataEpidemiological data suggest that there may be an association between the use of carbamazepine during pregnancy and congenital malformations, including spina bifida. Retrospective case reviews suggest that, compared with monotherapy, there may be higher prevalence of teratogenic effects associated with the use of anticonvulsants in combination therapy.Transplacental passage of carbamazepine is rapid (30-60 minutes), and the drug is accumulated in the fetal tissues, with higher levels found in liver and kidney than in brain and lung.There have been few cases of neonatal seizures and/or respiratory depression associated with maternal carbamazepine and other concomitant anticonvulsant drug use. few cases of neonatal vomiting, diarrhea, and/or decreased feeding have also been reported in association with maternal carbamazepine use. These symptoms may represent neonatal withdrawal syndrome.Animal DataCarbamazepine has been shown to have adverse effects in reproduction studies in rats when given orally in dosages 10 to 25 times human daily dosage of 1200 mg on mg/kg basis or 1.5 to times the human daily dosage of 1200 mg on mg/m2 basis. In rat teratology studies, of 135 offspring showed kinked ribs at 250 mg/kg, and of 119 offspring showed other anomalies at 650 mg/kg (cleft palate, 1; talipes, 1; anophthalmos, 2).

RECENT MAJOR CHANGES SECTION.


Indications and Usage (1)9/2016Dosage and Administration (2)9/2016Warnings and Precautions (5)9/2016Contraindications, delavirdine or other non-nucleoside reverse transcriptase inhibitors that are substrates for CYP3A4 (4, 5.9)9/2016.

SPL MEDGUIDE SECTION.


Medication GuideEQUETRO (e-kwe-tro)(carbamazepine)Extended-Release CapsulesRead this Medication Guide before you start taking EQUETRO and each time you get refill. There may be new information. This information does not take the place of talking to your healthcare provider about your medical condition or treatment. What is the most important information should know about EQUETRODo not stop taking EQUETRO without first talking to your healthcare provider. Stopping EQUETRO suddenly can cause serious problems. If you have any of the problems listed below call your healthcare provider right away. EQUETRO can cause serious side effects, including: 1. EQUETRO may cause rare but serious rashes that may lead to death. These serious skin reactions are more likely to happen within the first four months after you start taking EQUETRO, but may occur at later times. These reactions can happen to anyone, but are more likely in people of Asian descent. If you are of Asian descent, you may need genetic blood test before you take EQUETRO to see if you are at higher risk for serious skin reactions with this medicine. Symptoms may include: skin rash hives sores in your mouth blistering or peeling of the skin 2. EQUETRO may cause rare but serious blood problems. Symptoms may include:fever shortness of breath fatigue easy bruising red or purple spots on your body unusual bleeding such as bleeding gums, nose bleeds, or heavy menstrual bleeding swollen glands and sore throat3. EQUETRO may cause serious or life-threatening allergic reaction that may affect your skin or other parts of your body such as your liver or blood cells. You may or may not have rash with these types of reactions. Call healthcare provider right away if you have any of the following symptoms:skin rash hives fever swollen glands that do not go away swelling of your lips or tongue yellowing of your skin or eyes unusual bruising or bleeding severe fatigue or weakness unexpected, severe muscle pain frequent infections These symptoms may be the first signs of serious reaction. healthcare provider should examine you to decide if you should continue taking EQUETRO.4. EQUETRO may cause suicidal thoughts or actions in very small number of people, about in 500. Call your healthcare provider 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 or talking (mania) other unusual changes in behavior or moodHow can watch for early symptoms of suicidal thoughts and actionsPay attention to any changes, especially sudden changes, in mood, behaviors, thoughts, or feelings. Keep all follow-up visits with your healthcare provider as scheduled.Call your healthcare provider between visits as needed, especially if you are worried about symptoms.Do not stop EQUETRO without first talking to healthcare provider.Stopping EQUETRO suddenly can cause serious problems. You should talk to your healthcare provider before stopping.Suicidal thoughts or actions can be caused by things other than medicines. If you have suicidal thoughts or actions, your healthcare provider may check for other causes. What is EQUETROEQUETRO is prescription medicine used to treat people with:acute manic or mixed episodes that happen with Bipolar Disorder certain types of nerve pain (trigeminal neuralgia and glossopharyngeal neuralgia) certain types of seizures (partial, tonic-clonic, mixed)EQUETRO is not regular pain medicine and should not be used for aches or pains.EQUETRO should not be used to treat people with absence seizures (petit mal).It is not known if EQUETRO is safe and effective in children and adolescents for the treatment of Bipolar Disorder and nerve pain. Who should not take EQUETRODo not take EQUETRO if you:have history of bone marrow depression. are allergic to carbamazepine or any of the ingredients in EQUETRO. See the end of this Medication Guide for complete list of ingredients in EQUETRO. are allergic to medicines called tricyclic antidepressants (TCAs). Ask your healthcare provider or pharmacist for list of these medicines if you are not sure. are taking delaviridine or other medicines called reverse transcriptase inhibitors. Ask your healthcare provider or pharmacist for list of these medicines if you are not sure. have taken medicine called Monoamine Oxidase Inhibitor (MAOI) in the last 14 days. Ask your healthcare provider or pharmacist for list of these medicines if you are not sure. are taking nefazodone. What should tell my healthcare provider before taking EQUETROBefore you take EQUETRO, tell your healthcare provider if you:have or have had suicidal thoughts or actions, depression or mood problems have or ever had heart problems have or ever had blood problems have or ever had liver problems have or ever had kidney problems have or ever had allergic reactions to medicines have or ever had increased pressure in your eye have any other medical conditions drink grapefruit juice or eat grapefruit use birth control. EQUETRO may make your birth control less effective. Tell your healthcare provider if your menstrual bleeding changes while you take birth control and EQUETRO. are pregnant or plan to become pregnant. EQUETRO may harm your unborn baby. Tell your healthcare provider right away if you become pregnant while taking EQUETRO. You and your healthcare provider will decide if you should take EQUETRO while you are pregnant. If you become pregnant while taking EQUETRO, talk to your healthcare provider about registering with the North American Antiepileptic Drug (NULLAED) Pregnancy Registry. The purpose of this registry is to collect information about the safety of antiepileptic medicines during pregnancy. EQUETRO is also an antiepileptic drug. You can enroll in this registry by calling 1-888-233-2334. are breastfeeding or plan to breastfeed. EQUETRO can pass into breast milk. You and your healthcare provider should decide if you will take EQUETRO or breastfeed. You should not do both. Tell your healthcare provider about all the medicines you take, including prescription and non-prescription medicines, vitamins, and herbal supplements. Taking EQUETRO with certain other medicines may cause side effects or affect how well they work. Do not stop or start other medicines without talking to your healthcare provider.Know the medicines you take. Keep list of them and show it to your healthcare provider and pharmacist when you get new medicine. How should take EQUETRODo not stop taking EQUETRO without first talking to your healthcare provider. Stopping EQUETRO suddenly can cause serious problems. Take EQUETRO exactly as prescribed. Your healthcare provider will tell you how much EQUETRO to take. Your healthcare provider may change your dose. Do not change your dose of EQUETRO without talking to your healthcare provider. Swallow EQUETRO capsules whole. Do not crush or chew. If you cannot swallow EQUETRO capsules whole, you may open the EQUETRO capsules and sprinkle the beads over food such as teaspoon of applesauce and swallow the mixture. Do not crush or chew the beads. Take EQUETRO with or without food. If you take too much EQUETRO, call your healthcare provider or local Poison Control Center right away. What should avoid while taking EQUETRODo not drink alcohol or take other drugs that make you sleepy or dizzy while taking EQUETRO until you talk to your healthcare provider. EQUETRO taken with alcohol or drugs that cause sleepiness or dizziness may make your sleepiness or dizziness worse. Do not drive, operate heavy machinery, or do other dangerous activities until you know how EQUETRO affects you. EQUETRO can slow your thinking and motor skills.What are the possible side effects of EQUETROSee What is the most important information should know about EQUETRO EQUETRO may cause other serious side effects, including: Seizure risk. Stopping EQUTERO suddenly may cause you to have seizure. The risk of seizures may be higher in people who already have seizures. Do not stop taking EQUETRO without first talking with your healthcare provider. Low level of sodium in your blood (hyponatremia). Symptoms of hyponatremia may include: headache new seizures or an increased number of seizures difficulty concentrating memory problems confusion weakness balance problems Problems with judgment, thinking, and movement.Liver problems. Symptoms of liver problems may include: yellowing of your skin or the whites of your eyes dark urine pain on the right side of your stomach area (abdominal pain) easy bruising loss of appetite nausea or vomitingGet medical help right away if you have any of the symptoms listed above or listed in What is the most important information should know about EQUETROThe most common side effects of EQUETRO include: dizziness drowsiness nausea vomiting problems with walking and coordination (unsteadiness) constipation itching dry mouth weakness blurred vision problems speakingThese are not all the possible side effects of EQUETRO. For more information, ask your healthcare provider or pharmacist. Tell your healthcare provider if you have any side effect that bothers you or that does not go away.To report SUSPECTED ADVERSE REACTIONS, contact Validus Pharmaceuticals LLC at 1-866-9VALIDUS(1-866-982-5438) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatchHow should store EQUETROStore EQUETRO between 680F to 770F (200C to 250C). Keep EQUETRO capsules out of the light. Keep EQUETRO capsules dry.Keep EQUETRO and all medicines out of the reach of children.General Information about the safe and effective use of EQUETRO.Medicines are sometimes prescribed for purposes other than those listed in Medication Guide. Do not use EQUETRO for condition for which it was not prescribed. Do not give EQUETRO to other people, even if they have the same symptoms that you have. It may harm them.This Medication Guide summarizes the most important information about EQUETRO. If you would like more information, talk with your healthcare provider. You can ask your pharmacist or healthcare provider for information about EQUETRO that is written for health professionals.For more information, go to www.EQUETRO.com or call 1-866-982-5438.What are the ingredients in EQUETROActive ingredient: carbamazepine Inactive ingredients: citric acid, colloidal silicon dioxide, lactose monohydrate, microcrystalline cellulose, polyethylene glycol, povidone, sodium lauryl sulfate, talc, triethyl citrate, and other ingredients.100mg capsule shell contains: gelatin-NF, FD&C Blue 2, Yellow Iron Oxide, and Titanium Dioxide, and are imprinted with white ink.200mg capsule shell contains: gelatin-NF, Yellow Iron Oxide, FD&C Blue 2, and Titanium Dioxide, and are imprinted with white ink. 300mg capsule shell contains: gelatin-NF, FD&C Blue 2, Yellow Iron Oxide, and Titanium Dioxide, and are imprinted with white ink.This Medication Guide has been approved by the U. S. Food and Drug Administration.Validus Pharmaceuticals LLC, 119 Cherry Hill Road, Suite 310, Parsippany, NJ 07054 1-866-9VALIDUS (1-866-982-5438)60080-01 Revised: October 2016. skin rash hives sores in your mouth blistering or peeling of the skin fever shortness of breath fatigue easy bruising red or purple spots on your body unusual bleeding such as bleeding gums, nose bleeds, or heavy menstrual bleeding swollen glands and sore throat. skin rash hives fever swollen glands that do not go away swelling of your lips or tongue yellowing of your skin or eyes unusual bruising or bleeding severe fatigue or weakness unexpected, severe muscle pain frequent infections 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 or talking (mania) other unusual changes in behavior or mood. 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.. acute manic or mixed episodes that happen with Bipolar Disorder certain types of nerve pain (trigeminal neuralgia and glossopharyngeal neuralgia) certain types of seizures (partial, tonic-clonic, mixed). have history of bone marrow depression. are allergic to carbamazepine or any of the ingredients in EQUETRO. See the end of this Medication Guide for complete list of ingredients in EQUETRO. are allergic to medicines called tricyclic antidepressants (TCAs). Ask your healthcare provider or pharmacist for list of these medicines if you are not sure. are taking delaviridine or other medicines called reverse transcriptase inhibitors. Ask your healthcare provider or pharmacist for list of these medicines if you are not sure. have taken medicine called Monoamine Oxidase Inhibitor (MAOI) in the last 14 days. Ask your healthcare provider or pharmacist for list of these medicines if you are not sure. are taking nefazodone. have or have had suicidal thoughts or actions, depression or mood problems have or ever had heart problems have or ever had blood problems have or ever had liver problems have or ever had kidney problems have or ever had allergic reactions to medicines have or ever had increased pressure in your eye have any other medical conditions drink grapefruit juice or eat grapefruit use birth control. EQUETRO may make your birth control less effective. Tell your healthcare provider if your menstrual bleeding changes while you take birth control and EQUETRO. are pregnant or plan to become pregnant. EQUETRO may harm your unborn baby. Tell your healthcare provider right away if you become pregnant while taking EQUETRO. You and your healthcare provider will decide if you should take EQUETRO while you are pregnant. If you become pregnant while taking EQUETRO, talk to your healthcare provider about registering with the North American Antiepileptic Drug (NULLAED) Pregnancy Registry. The purpose of this registry is to collect information about the safety of antiepileptic medicines during pregnancy. EQUETRO is also an antiepileptic drug. You can enroll in this registry by calling 1-888-233-2334. are breastfeeding or plan to breastfeed. EQUETRO can pass into breast milk. You and your healthcare provider should decide if you will take EQUETRO or breastfeed. You should not do both. Do not stop taking EQUETRO without first talking to your healthcare provider. Stopping EQUETRO suddenly can cause serious problems. Take EQUETRO exactly as prescribed. Your healthcare provider will tell you how much EQUETRO to take. Your healthcare provider may change your dose. Do not change your dose of EQUETRO without talking to your healthcare provider. Swallow EQUETRO capsules whole. Do not crush or chew. If you cannot swallow EQUETRO capsules whole, you may open the EQUETRO capsules and sprinkle the beads over food such as teaspoon of applesauce and swallow the mixture. Do not crush or chew the beads. Take EQUETRO with or without food. If you take too much EQUETRO, call your healthcare provider or local Poison Control Center right away. Do not drink alcohol or take other drugs that make you sleepy or dizzy while taking EQUETRO until you talk to your healthcare provider. EQUETRO taken with alcohol or drugs that cause sleepiness or dizziness may make your sleepiness or dizziness worse. Do not drive, operate heavy machinery, or do other dangerous activities until you know how EQUETRO affects you. EQUETRO can slow your thinking and motor skills.. Seizure risk. Stopping EQUTERO suddenly may cause you to have seizure. The risk of seizures may be higher in people who already have seizures. Do not stop taking EQUETRO without first talking with your healthcare provider. Low level of sodium in your blood (hyponatremia). Symptoms of hyponatremia may include: headache new seizures or an increased number of seizures difficulty concentrating memory problems confusion weakness balance problems Problems with judgment, thinking, and movement.. Liver problems. Symptoms of liver problems may include: yellowing of your skin or the whites of your eyes dark urine pain on the right side of your stomach area (abdominal pain) easy bruising loss of appetite nausea or vomiting. dizziness drowsiness nausea vomiting problems with walking and coordination (unsteadiness) constipation itching dry mouth weakness blurred vision problems speaking. Store EQUETRO between 680F to 770F (200C to 250C). Keep EQUETRO capsules out of the light. Keep EQUETRO capsules dry.. 100mg capsule shell contains: gelatin-NF, FD&C Blue 2, Yellow Iron Oxide, and Titanium Dioxide, and are imprinted with white ink.. 200mg capsule shell contains: gelatin-NF, Yellow Iron Oxide, FD&C Blue 2, and Titanium Dioxide, and are imprinted with white ink. 300mg capsule shell contains: gelatin-NF, FD&C Blue 2, Yellow Iron Oxide, and Titanium Dioxide, and are imprinted with white ink.

SPL UNCLASSIFIED SECTION.


1.1 Acute Manic or Mixed Episodes associated with Bipolar Disorder. EQUETRO is indicated for treatment of patients with acute manic or mixed episodes associated with bipolar disorder [see Clinical Studies 14.1 ].

STORAGE AND HANDLING SECTION.


16.2 Storage. Store at 25 (77 F); excursions permitted to 15 -30 (59 -86 F) [see USP controlled room temperature].Protect from light and moisture.

USE IN SPECIFIC POPULATIONS SECTION.


8 USE IN SPECIFIC POPULATIONS. Pregnancy: Can cause fetal harm. (5.5, 8.1)Nursing Mothers: Discontinue drug or discontinue nursing, taking into consideration importance of drug to mother (8.3). 8.1 Pregnancy Pregnancy Category Risk SummaryEQUETRO can cause fetal harm when administered to pregnant woman. Epidemiological data suggest that there may be an association between the use of carbamazepine during pregnancy and congenital malformations, including spina bifida. Adverse developmental effects were seen in animal reproduction studies with carbamazepine. If this drug is used during pregnancy, or if the patient becomes pregnant while taking the drug, the patient should be apprised of the potential hazard to the fetus [see Warning and Precautions 5.4 )]. Pregnancy Registry Patients should be encouraged to enroll in the North American Antiepileptic Drug (NULLAED) 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 1888-233-2334. Information about the North American Drug Pregnancy Registry can be found at http://www.aedpregnancyregistry.org/ [see Warning and Precautions 5.4 )].Clinical ConsiderationsWhen treating pregnant woman with EQUETRO, carefully consider both the potential risks and benefits of treatment and provide appropriate counseling. Tests to detect major congenital malformations using current accepted procedures should be considered part of routine prenatal care in pregnant women receiving carbamazepine [see Warning and Precautions 5.4 )].Human DataEpidemiological data suggest that there may be an association between the use of carbamazepine during pregnancy and congenital malformations, including spina bifida. Retrospective case reviews suggest that, compared with monotherapy, there may be higher prevalence of teratogenic effects associated with the use of anticonvulsants in combination therapy.Transplacental passage of carbamazepine is rapid (30-60 minutes), and the drug is accumulated in the fetal tissues, with higher levels found in liver and kidney than in brain and lung.There have been few cases of neonatal seizures and/or respiratory depression associated with maternal carbamazepine and other concomitant anticonvulsant drug use. few cases of neonatal vomiting, diarrhea, and/or decreased feeding have also been reported in association with maternal carbamazepine use. These symptoms may represent neonatal withdrawal syndrome.Animal DataCarbamazepine has been shown to have adverse effects in reproduction studies in rats when given orally in dosages 10 to 25 times human daily dosage of 1200 mg on mg/kg basis or 1.5 to times the human daily dosage of 1200 mg on mg/m2 basis. In rat teratology studies, of 135 offspring showed kinked ribs at 250 mg/kg, and of 119 offspring showed other anomalies at 650 mg/kg (cleft palate, 1; talipes, 1; anophthalmos, 2). 8.2 Labor and Delivery The effect of carbamazepine on human labor and delivery is unknown.Carbamazepine and its epoxide metabolite are transferred to breast milk during lactation. There is potential for serious adverse reactions in nursing infants exposed to carbamazepine. Nursing mothers should consider the potential benefits and risks of treatment when deciding on whether to discontinue nursing or to discontinue treatment with EQUETRO, taking into account the importance of the drug to the mother.. 8.3 Nursing Mothers. Carbamazepine and its epoxide metabolite are excreted in human milk. Because of the potential for serious adverse reactions in nursing infants exposed to EQUETRO, decision should be made whether to discontinue nursing or to discontinue treatment with EQUETRO, taking into account the importance of the drug to the mother.. 8.4 Pediatric Use. The safety and effectiveness of EQUETRO have not been established in pediatric patients for indications other than Epilepsy [see Indications and Usage 1.3 )]. 8.5 Geriatric Use. Clinical studies of EQUETRO did not include sufficient numbers of subjects age 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

WARNINGS AND PRECAUTIONS SECTION.


5 WARNINGS AND PRECAUTIONS. Drug Reaction with Eosinophilia and Systemic Symptoms: Monitor for hypersensitivity. Discontinue if another cause can not be established (5.3) Suicidal Behavior and Ideation: Monitor for depression, suicidal thoughts or behavior, and/or any unusual changes in mood or behavior (5.4) Embryofetal Toxicity: Advise women of child-bearing potential of possible risks to the fetus (5.5, 8.1) Abrupt Discontinuation and Risk of Seizure: Taper the dose when discontinuing treatment (5.6).Hyponatremia: Consider discontinuing EQUETRO in patients with significant symptomatic hyponatremia (5.7). Cognitive and Motor Impairment: Advise patients not to drive or operate machinery until they have gained sufficient experience on EQUETRO to gauge whether it adversely affects these activities (5.8). Liver Damage: Monitor liver function. Discontinue EQUETRO with aggravated liver dysfunction or active liver disease (5.10). Hepatic Porphyria: Avoid EQUETRO use in patients with hepatic porphyria: can cause acute episodes of porphyria (5.12). Drug Reaction with Eosinophilia and Systemic Symptoms: Monitor for hypersensitivity. Discontinue if another cause can not be established (5.3) Suicidal Behavior and Ideation: Monitor for depression, suicidal thoughts or behavior, and/or any unusual changes in mood or behavior (5.4) Embryofetal Toxicity: Advise women of child-bearing potential of possible risks to the fetus (5.5, 8.1) Abrupt Discontinuation and Risk of Seizure: Taper the dose when discontinuing treatment (5.6).. Hyponatremia: Consider discontinuing EQUETRO in patients with significant symptomatic hyponatremia (5.7). Cognitive and Motor Impairment: Advise patients not to drive or operate machinery until they have gained sufficient experience on EQUETRO to gauge whether it adversely affects these activities (5.8). Liver Damage: Monitor liver function. Discontinue EQUETRO with aggravated liver dysfunction or active liver disease (5.10). Hepatic Porphyria: Avoid EQUETRO use in patients with hepatic porphyria: can cause acute episodes of porphyria (5.12). 5.1 Serious Dermatologic Reactions Serious and sometimes fatal dermatologic reactions, including toxic epidermal necrolysis (TEN) and Stevens-Johnson syndrome (SJS), have been reported with carbamazepine treatment. These syndromes may be accompanied by mucous membrane ulcers, fever, or painful rash. Over 90% of carbamazepine-treated patients who experienced SJS/TEN developed these reactions within the first few months of treatment. The risk of these reactions is estimated to be about to per 10,000 new users in countries with mainly Caucasian populations. However, the risk in some Asian countries is estimated to be about 10 times higher. Discontinue EQUETRO if you suspect that the patient has serious dermatologic reaction. If signs or symptoms suggest SJS/TEN, do not resume treatment with EQUETRO. SJS, TEN, and HLA-B1502 AlleleRetrospective case-control studies have found that in patients of Chinese ancestry there is strong association between the risk of developing SJS/TEN with EQUETRO treatment and the presence of the HLA-B1502 allele (an inherited variant of the HLA-B gene). Prior to initiating EQUETRO therapy in patients at higher likelihood for this allele, perform testing for HLA-B1502. The high resolution genotype test is positive if one or two HLA-B1502 alleles are present. Avoid use of EQUETRO in patients positive for the HLA-B1502 allele unless the benefits clearly outweighs the risks of serious dermatologic reactions. Tested patients who are found to be negative for the allele are thought to have low risk of SJS/TEN associated with carbamazepine treatment. The prevalence of the HLA-B1502 allele may be higher in Asian populations: Hong Kong, Thailand, Malaysia, and parts of the Philippines (greater than 15%); Taiwan (10%), North China (4%); south Asians, including Indians (2 to 4%); and Japan and Korea (less than 1%). HLA-B1502 is largely absent in individuals not of Asian origin (e.g., Caucasians, African-Americans, Hispanics, and Native Americans). The accuracy of estimated rates of the HLA-B1502 allele in these populations may be limited by wide variability in rates within ethnic groups, the difficulty in ascertaining ethnic ancestry, and the likelihood of mixed ancestry. The HLA-B1502 allele has not been found to predict risk of less severe adverse cutaneous reactions from carbamazepine, such as maculopapular eruption (MPE) or to predict Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) s ee Warnings and Precautions 5.3 )] Limited evidence suggests that HLA-B1502 may be risk factor for the development of SJS/TEN in patients of Chinese ancestry taking other anti-epileptic drugs associated with SJS/TEN, including phenytoin. Consideration should be given to avoiding use of other drugs associated with SJS/TEN in HLA-B1502 positive patients, when alternative therapies are otherwise equally acceptable [se Dosage and Administration 2.1 )].Hypersensitivity Reactions and HLA-A3101 AlleleRetrospective case-control studies in patients of European, Korean, and Japanese ancestry have found moderate association between the risk of developing hypersensitivity reactions and the presence of HLA-A3101, an inherited allelic variant of the HLA-A gene, in patients using carbamazepine. These hypersensitivity reactions include SJS/TEN, maculopapular eruptions, and Drug Reaction with Eosinophilia and Systemic Symptoms s ee Warnings and Precautions 5.3 ]. HLA-A3101 is expected to be present in the following frequencies: greater than 15% in patients of Japanese, Native American, Southern Indian (for example, Tamil Nadu) and some Arabic ancestry; up to about 10% in patients of Han Chinese, Korean, European, Latin American, and other Indian ancestry; and up to about 5% in African-Americans and patients of Thai, Taiwanese, and Chinese (Hong Kong) ancestry. The risks and benefits of EQUETRO therapy should be weighed before considering EQUETRO in patients known to be positive for HLA-A3101. Hypersensitivity and Limitations of HLA Genotyping Application of HLA genotyping as screening tool has important limitations and must never substitute for appropriate clinical vigilance and patient management. Many HLA-B1502-positive and HLA-A3101- positive patients treated with EQUETRO will not develop SJS/TEN or other hypersensitivity reactions, and these reactions can still occur infrequently in HLA-B1502-negative and HLA-A3101-negative patients of any ethnicity. The role of other possible factors in the development of, and morbidity from, SJS/TEN and other hypersensitivity reactions, such as AED dose, compliance, concomitant medications, co-morbidities, and the level of dermatologic monitoring have not been studied. 5.2 Aplastic Anemia and Agranulocytosis. Aplastic anemia and agranulocytosis have occurred in patients treated with carbamazepine. Data from population-based case-control study suggest that the risk of developing these reactions is 5-8 times greater than in the general population. However, the overall risk of these reactions in the untreated general population is low, approximately six patients per one million population per year for agranulocytosis and two patients per one million population per year for aplastic anemia.Although reports of transient or persistent decreased platelet or white blood cell counts are not uncommon in association with the use of carbamazepine, data are not available to estimate accurately their incidence or outcome. However, the vast majority of the cases of leukopenia have not progressed to the more serious conditions of aplastic anemia or agranulocytosis.Because of the very low incidence of agranulocytosis and aplastic anemia, the vast majority of minor hematologic changes observed in monitoring of patients on EQUETRO are unlikely to signal the occurrence of either abnormality. Nonetheless, complete pretreatment hematological testing should be obtained as baseline. If patient in the course of treatment exhibits low or decreased white blood cell or platelet counts, the patient should be monitored closely. Consider discontinuing EQUETRO if any evidence of significant bone marrow depression develops. Clinical features can include fever, dyspnea on exertion, fatigue, easy bruising, petechiae, epistaxis, gingival bleeding, and heavy menses. 5.3 Drug Reaction with Eosinophilia and Systemic Symptoms/Multiorgan Hypersensitivity. Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), also known as Multiorgan Hypersensitivity, have occurred with carbamazepine. 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 even though rash is not evident. If such signs or symptoms are present, the patient should be evaluated immediately. EQUETRO should be discontinued if an alternative etiology for the signs or symptoms cannot be established. HypersensitivityHypersensitivity reactions to carbamazepine have been reported in patients who previously experienced this reaction to anticonvulsants including phenytoin, primidone, and phenobarbital. If such history is present, benefits and risks should be carefully considered, and, if EQUETRO is initiated, the signs and symptoms of hypersensitivity should be carefully monitored.In patients who have exhibited hypersensitivity reactions to carbamazepine, approximately 25 to 30% may experience hypersensitivity reactions with oxcarbazepine. 5.4 Suicidal Behavior and Ideation. Antiepileptic drugs (AEDs), including EQUETRO, 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 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 range of indications suggests that the risk applies to all AEDs used for any indication. The risk did not vary substantially by age (5 to100 years) in the clinical trials analyzed. Table presents the absolute and relative risk by indication for all evaluated AEDs.Table Risk of suicidal thoughts or behavior (reactions) for antiepileptic drugs by indication in the pooled analysis PlaceboAntiepileptic DrugsIndicationReactions Per1000 PatientsReactions Per 1000PatientsRelative Risk:Incidence of Reactions in AEDGroup/ Incidence of Reactions inPlacebo GroupRisk Difference: Additional DrugPatients with Events Per 1000 PatientsEpilepsyPsychiatricOtherTotal1.05.71.02.43.48.51.84.33.51.51.91.82.42.90.91.9The 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 differences were similar for the epilepsy and psychiatric indications.Anyone considering prescribing EQUETRO or any other AED must balance the risk of suicidal thought 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 behaviors 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.. 5.5 Embryofetal Toxicity. EQUETRO is Category drug [see Use in Specific Populations 8.1 )]. EQUETRO can cause fetal harm when administered to pregnant woman. Apprise women of childbearing potential of this risk. Use in pregnancy only if the potential benefits of treatment outweigh the risks. Epidemiological data suggest that there may be an association between the use of carbamazepine during pregnancy and congenital malformations, including spina bifida. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus.Retrospective case reviews suggest that, compared with monotherapy, there may be higher prevalence of teratogenic effects associated with the use of anticonvulsants in combination therapy.In humans, transplacental passage of carbamazepine is rapid (30-60 minutes), and the drug is accumulated in the fetal tissues, with higher levels found in liver and kidney than in brain and lung.Carbamazepine has been shown to have adverse effects in reproduction studies in rats when given orally in dosages 10 to 25 times human daily dosage of 1200 mg on mg/kg basis or 1.5 to times the human daily dosage of 1200 mg on mg/m2 basis. In rat teratology studies, of 135 offspring showed kinked ribs at 250 mg/kg, and of 119 offspring showed other anomalies at 650 mg/kg (cleft palate, 1; talipes, 1; anophthalmos, 2). Tests to detect defects using current accepted procedures should be considered part of routine prenatal care in childbearing women receiving EQUETRO.To provide additional information regarding the effects of in utero exposure to EQUETRO, physicians are advised to recommend that pregnant patients taking EQUETRO enroll in the North American Antiepileptic Drug (NULLAED) 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/. 5.6 Abrupt Discontinuation and Risk of Seizure. Do not discontinue EQUETRO abruptly, because of the risk of seizure and other withdrawal signs/symptoms. Patients with seizure disorder are at increased risk of developing seizure and status epilepticus with attendant hypoxia and threat to life. However, in the event of an allergic or hypersensitivity reaction, more rapid substitution of alternative therapy may be necessary.. 5.7 Hyponatremia. Hyponatremia can occur as result of treatment with EQUETRO. In many cases, the hyponatremia appears to be caused by the syndrome of inappropriate antidiuretic hormone secretion (SIADH). The risk of developing SIADH with EQUETRO treatment appears to be dose-related. Elderly patients and patients treated with diuretics are at greater risk of developing hyponatremia. Signs and symptoms of hyponatremia include headache, new or increased seizure frequency, difficulty concentrating, memory impairment, confusion, weakness, and unsteadiness, which can lead to falls. Consider discontinuing EQUETRO in patients with symptomatic hyponatremia.. 5.8 Potential for Cognitive and Motor Impairment. EQUETRO has the potential to cause impairment in judgment, cognition, and motor function. Caution patients about operating hazardous machinery, including automobiles, until they are reasonably certain the EQUETRO does not affect them adversely. Adverse reactions in the clinical trials in bipolar disorder included (EQUETRO, N= 251 and Placebo, N= 248): somnolence (32% vs. 13%), ataxia (15% vs. 0.4%), dizziness (44% vs. 12%), vertigo (2% vs. 1%), thinking abnormal (2% vs. 0.4%), tremor 3% vs. 1%), and blurred vision (6% vs. 2%) [see Adverse Reactions 6.1 )]. 5.9 Potential for Loss of Virologic Response to Non-nucleoside Reverse Transcriptase Inhibitors that are substrates for CYP3A4 with Concomitant Use of EQUETRO. Coadministration of EQUETRO with non-nucleoside reverse transcriptase inhibitors, including delavirdine, is contraindicated because it may lead to loss of virologic response and possible resistance. Through induction of CYP3A4, EQUETRO can markedly decrease the concentrations of these drugs. Coadministration of delavirdine, an NNRTI and substrate of CYP3A4, and EQUETRO can decrease delavirdine concentrations by 90% see Contraindications 4 ), Drug Interactions 7.2 )] . 5.10 Liver Damage. Hepatic effects, ranging from slight elevations in liver enzymes to rare cases of hepatic failure have been reported. In some cases, hepatic effects may progress despite discontinuation of the drug. In addition rare instances of vanishing bile duct syndrome have been reported. This syndrome consists of cholestatic process with variable clinical course ranging from fulminant to indolent, involving the destruction and disappearance of the intrahepatic bile ducts. Some, but not all, cases are associated with features that overlap with other immunoallergenic syndromes such as serious dermatologic reactions and Drug Reaction with Eosinophilia and Systemic Symptoms/Multiorgan Hypersensitivity [see Warnings and Precautions 5.1 5.2 )] Baseline and periodic evaluations of liver function, particularly in patients with history of liver disease, must be performed during treatment with this drug since liver damage may occur. The drug should be discontinued immediately in cases of aggravated liver dysfunction or active liver disease.. 5.11 AV Heart Block. AV heart block, including second and third degree block, have been reported following carbamazepine treatment. This occurred generally, but not solely, in patients with underlying EKG abnormalities or risk factors for conduction disturbances.. 5.12 Hepatic Porphyria. The use of EQUETRO should be avoided in patients with history of hepatic porphyria (e.g., acute intermittent porphyria, variegate porphyria, porphyria cutanea tarda). Acute attacks have been reported in such patients receiving carbamazepine therapy. EQUETRO administration has also been demonstrated to increase porphyrin precursors in rodents, presumed mechanism for the induction of acute attacks of porphyria.. 5.13 Increased Intraocular Pressure Carbamazepine has mild anticholinergic activity. In patients with history of increased intraocular pressure, consider assessing intraocular pressure before initiating treatment and periodically during therapy.