EQUETRO™ is available for oral administration as 100 mg, 200 mg and 300 mg extended- release capsules of carbamazepine, USP. Carbamazepine is a white to off-white powder, practically insoluble in water and soluble in alcohol and in acetone. Its molecular weight is 236.27. Its chemical name is 5H-dibenz[b,f]azepine-5-carboxamide, and its structural formula is:

EQUETRO™ is a 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 a specific ratio to provide twice daily dosing of EQUETRO™ .

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, 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.

EQUETRO™ is indicated for the treatment of acute manic and mixed episodes associated with Bipolar I Disorder.

A manic episode is a distinct period of abnormally and persistently elevated, expansive, or irritable mood. A mixed episode is characterized by the criteria for a manic episode in conjunction with those for a major depressive episode (depressed mood, loss of interest or pleasure in nearly all activities).

The efficacy of EQUETRO™ in acute mania was established in 2 placebo-controlled, double-blind, 3-week studies in patients meeting DSM-IV criteria for Bipolar I Disorder who currently displayed an acute manic or mixed episode (see CLINICAL PHARMACOLOGY).

The effectiveness of EQUETRO™ for longer-term use and for prophylactic use in mania has not been systematically evaluated in controlled clinical trials. Therefore, physicians who elect to use EQUETRO™ for extended periods should periodically re-evaluate the long-term risks and benefits of the drug for the individual patient (See DOSAGE AND ADMINISTRATION).

The recommended initial dose of EQUETRO™ is 400 mg/day given in divided doses, twice daily. The dose should be adjusted in 200 mg daily increments to achieve optimal clinical response. Doses higher than 1600 mg/day have not been studied.

Monitoring of blood levels (see PRECAUTIONS, Laboratory Tests) may be useful for verification of drug compliance, assessing safety and determining the cause of toxicity including when more than one medication is being used.

The EQUETRO™ capsules may be opened and the beads sprinkled over food, such as a teaspoon of applesauce or other similar food products if this method of administration is preferred. EQUETRO™ capsules or their contents should not be crushed or chewed.

EQUETRO™ can be taken with or without meals.

EQUETRO™ (carbamazepine) extended-release capsules is supplied in three dosage strengths.

100 mg-Two-piece hard gelatin capsule yellow opaque cap with bluish green opaque body printed with the SPD417 on one end, SPD417 and 100 mg on the other in white ink:
Supplied in bottles of 120           NDC 54092-419-12

200 mg-Two-piece hard gelatin capsule yellow opaque cap with blue opaque body printed with the SPD417 on one end and SPD417 and 200 mg on the other in white ink:
Supplied in bottles of 120           NDC 54092-421-12

300 mg-Two-piece hard gelatin capsule yellow opaque cap with blue body printed with the SPD417 on one end and SPD417 and 300 mg on the other in white ink:
Supplied in bottles of 120           NDC 54092-423-12

Store at 25° C (77° F); excursions permitted to 15-30° C (59-86° F) [see USP controlled room temperature]. PROTECT FROM LIGHT AND MOISTURE.

Manufactured for: Validus Pharmaceuticals, Inc. 2001 Route 46 East, Suite 310., Parsippany, NJ 07054. (Rev. 1/2007). FDA rev date: 12/19/2007

General: The most severe adverse reactions previously observed with carbamazepine were reported in the hemopoietic system (see BOX WARNING), the skin, and the cardiovascular system.

The most frequently observed adverse reactions, particularly during the initial phases of therapy, are dizziness, drowsiness, unsteadiness, nausea, and vomiting. To minimize the possibility of such reactions, therapy should be initiated at the lowest dosage recommended.

The most commonly observed adverse experiences (5% and at least twice placebo) seen in association with the use of EQUETRO™ (400 to 1600 mg/day, dose adjusted in 200mg daily increments in week 1 in Bipolar I Disorder in the double-blind, placebo-controlled trials of 3 weeks' duration are included in Table 1 below:

Table 1. Most Common Adverse Events Reported in Double-Blind, Placebo Controlled Trials
(Incidence ≥ 5% and at least twice Placebo)

EQUETRO™ and placebo-treated patients from the two double-blind, placebo-controlled studies were enrolled in a 6-month open- label study. The table below summarizes the most common adverse events with an incidence of 5% or more.

Table 2. Most Common Adverse Events Reported in Open Label
(Incidence ≥ 5%)

Other significant adverse events seen in less than 5% of patients include: Suicide Attempt, Manic Reaction, Insomnia, Nervousness, Depersonalization and Extrapyramidal Symptoms, Infections (Fungal, Viral, Bacterial), Pharyngitis, Rhinitis, Sinusitis, Bronchitis, Urinary Tract Infection, Leukopenia and Lymphadenopathy, Liver Function Tests Abnormal, Edema, Peripheral Edema, Allergic Reaction, Photosensitivity Reaction, Alopecia, Diplopia and Ear Pain.

The following additional adverse reactions were previously reported with carbamazepine:

Hemopoietic System: Aplastic anemia, agranulocytosis, pancytopenia, bone marrow depression, thrombocytopenia, leukopenia, leukocytosis, eosinophilia, acute intermittent porphyria

Skin: Pruritic and erythematous rashes, urticaria, toxic epidermal necrolysis (Lyell's syndrome) (see WARNINGS), Stevens-Johnson syndrome (see WARNINGS), photosensitivity reactions, alterations in skin pigmentation, exfoliative dermatitis, erythema multiforme and nodosum, purpura, aggravation of disseminated lupus erythematosus, alopecia, and diaphoresis. In certain cases, discontinuation of therapy may be necessary. Isolated cases of hirsutism have been reported, but a causal relationship is not clear.

Cardiovascular System: Congestive heart failure, edema, aggravation of hypertension, hypotension, syncope and collapse, aggravation of coronary artery disease, arrhythmias and AV block, thrombophlebitis, thromboembolism, and adenopathy or lymphadenopathy. Some of these cardiovascular complications have resulted in fatalities. Myocardial infarction has been associated with other tricyclic compounds.

Liver: Abnormalities in liver function tests, cholestatic and hepatocellular jaundice, hepatitis.

Respiratory System: Pulmonary hypersensitivity characterized by fever, dyspnea, pneumonitis, or pneumonia.

Genitourinary System: Urinary frequency, acute urinary retention, oliguria with elevated blood pressure, azotemia, renal failure, and impotence. Albuminuria, glycosuria, elevated BUN, and microscopic deposits in the urine have also been reported.

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 2 years at dosage levels of 25, 75, and 250 mg/kg/day had a dose-related incidence of testicular atrophy and aspermatogenesis. In dogs, it produced a brownish discoloration, presumably a metabolite, in the urinary bladder at dosage levels of 50 mg/kg/day and higher. Relevance of these findings to humans is unknown.

Nervous System: Dizziness, drowsiness, disturbances of coordination, confusion, headache, fatigue, blurred vision, visual hallucinations, transient diplopia, oculomotor disturbances, nystagmus, speech disturbances, abnormal involuntary movements, peripheral neuritis and paresthesias, depression with agitation, talkativeness, tinnitus, and hyperacusis. There have been reports of associated paralysis and other symptoms of cerebral arterial insufficiency, but the exact relationship of these reactions to the drug has not been established. Isolated cases of neuroleptic malignant syndrome have been reported with concomitant use of psychotropic drugs.

Digestive System: Nausea, vomiting, gastric distress and abdominal pain, diarrhea, constipation, anorexia, and dryness of the mouth and pharynx, including glossitis and stomatitis.

Eyes: Scattered punctate cortical lens opacities, as well as conjunctivitis, have been reported. Although a direct causal relationship has not been established, many phenothiazines and related drugs have been shown to cause eye changes.

Musculoskeletal System: Aching joints and muscles, and leg cramps.

Metabolism: Fever and chills, inappropriate antidiuretic hormone (ADH) secretion syndrome has been reported. Cases of frank water intoxication, with decreased serum sodium (hyponatremia) and confusion have been reported in association with carbamazepine use (see PRECAUTIONS, Laboratory Tests). Decreased levels of plasma calcium have been reported.

Other: Isolated cases of a lupus erythematosus-like syndrome have been reported. There have been occasional reports of elevated levels of cholesterol, HDL cholesterol, and triglycerides in patients taking anticonvulsants.

A case of aseptic meningitis, accompanied by myoclonus and peripheral eosinophilia, has been reported in a patient taking carbamazepine in combination with other medications.The patient was successfully dechallenged, and the meningitis reappeared upon rechallenge with carbamazepine.

DRUG ABUSE AND DEPENDENCE

No evidence of abuse potential has been associated with carbamazepine, nor is there evidence of psychological or physical dependence in humans.

Clinically meaningful drug interactions have occurred with concomitant medications and include, but are not limited to the following:

Agents Highly Bound to Plasma Protein:

Carbamazepine is not highly bound to plasma proteins; therefore, administration of EQUETRO™ to a patient taking another drug that is highly protein bound should not cause increased free concentrations of the other drug.

Agents that Inhibit Cytochrome P450 Isoenzymes and/or Epoxide Hydrolase:

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. Therefore, the potential exists for interaction between carbamazepine and any agent that inhibits CYP3A4 and/or epoxide hydrolase. Agents that are CYP3A4 inhibitors that have been found, or are expected, to increase plasma levels of EQUETRO™ are the following:

Acetazolamide, azole antifungals, cimetidine, clarithromycin⁽¹⁾, dalfopristin, danazol, delavirdine, diltiazem, erythromycin⁽¹⁾, fluoxetine, fluvoxamine, grapefruit juice, isoniazid, itraconazole, ketoconazole, loratadine, nefazodone, niacinamide, nicotinamide, protease inhibitors, propoxyphene, quinine, quinupristin, troleandomycin, valproate⁽¹⁾, verapamil, zileuton. ⁽¹⁾also inhibits epoxide hydrolase resulting in increased levels of the active metabolite carbamazepine 10, 11- epoxide

Thus, if a patient has been titrated to a stable dosage of EQUETRO™ , and then begins a course of treatment with one of these CYP3A4 or epoxide hydrolase inhibitors, it is reasonable to expect that a dose reduction for EQUETRO™ may be necessary.

Agents that Induce Cytochrome P450 Isoenzymes:

Carbamazepine is metabolized by CYP3A4. Therefore, the potential exists for interaction between carbamazepine and any agent that induces CYP3A4. Agents that are CYP inducers that have been found, or are expected, to decrease plasma levels of EQUETRO™ are the following:

Cisplatin, doxorubicin HCl, felbamate, rifampin, phenobarbital, Phenytoin⁽²⁾, primidone, methsuximide, and theophylline ⁽²⁾ Phenytoin plasma levels have also been reported to increase and decrease in the presence of carbamazepine, see below.

Thus, if a patient has been titrated to a stable dosage on EQUETRO™ , and then begins a course of treatment with one of these CYP3A4 inducers, it is reasonable to expect that a dose increase for EQUETRO™ may be necessary.

Agents with Decreased Levels in the Presence of Carbamazepine due to Induction of Cytochrome P450 Enzymes:

Carbamazepine is known to induce CYP1A2 and CYP3A4. Therefore, the potential exists for interaction between carbamazepine and any agent metabolized by one (or more) of these enzymes. Agents that have been found, or are expected to have decreased plasma levels in the presence of EQUETRO™ due to induction of CYP enzymes are the following:

Acetaminophen, alprazolam, amitriptyline, bupropion, buspirone, citalopram, clobazam, clonazepam, clozapine, cyclosporin, delavirdine, desipramine, diazepam, dicumarol, doxycycline, ethosuximide, felbamate, felodipine, glucocorticoids, haloperidol, itraconazole, lamotrigine, levothyroxine, lorazepam, methadone, midazolam, mirtazapine, nortriptyline, olanzapine, oral contraceptives⁽³⁾, oxcarbazepine, phenytoin⁽⁴⁾, praziquantel, protease inhibitors, quetiapine, risperidone, theophylline, topiramate, tiagabine, tramadol, triazolam, trazodone⁽⁵⁾, valproate, warfarin⁽⁶⁾, ziprasidone, and zonisamide.

⁽³⁾ Break through bleeding has been reported among patients receiving concomitant oral contraceptives and their reliability may be adversely affected.

⁽⁴⁾ Phenytoin has also been reported to increase in the presence of carbamazepine. Careful monitoring of phenytoin plasma levels following co-medication with carbamazepine is advised.

⁽⁵⁾ Following co-administration of carbamazepine 400 mg/day with trazodone 100 mg to 300 mg daily, carbamazepine reduced the plasma concentration of trazodone (as well as meta-chlorophenylpiperazine [mCPP]) by 76 and 60% respectively, compared to pre- carbamazepine values.

⁽⁶⁾ Warfarin's anticoagulant effect can be reduced in the presence of carbamazepine.

Thus, if a patient has been titrated to a stable dosage on one of the agents in this category, and then begins a course of treatment with EQUETRO™ , it is reasonable to expect that a dose increase for the concomitant agent may be necessary.

Agents with Increased Levels in the Presence of Carbamazepine:

EQUETRO™ increases the plasma levels of the following agents:

Clomipramine HCl, phenytoin⁽⁷⁾, and primidone

⁽⁷⁾ Phenytoin has also been reported to decrease in the presence of carbamazepine. Careful monitoring of phenytoin plasma levels following co-medication with carbamazepine is advised. Thus, if a patient has been titrated to a stable dosage on one of the agents in this category, and then begins a course of the treatment with EQUETRO™ , it is reasonable to expect that a dose decrease for the concomitant agent may be necessary.

Pharmacological/Pharmacodynamic Interactions with Carbamazepine:

Concomitant administration of carbamazepine and lithium may increase the risk of neurotoxic side effects.

Given the anticonvulsant properties of carbamazepine, EQUETRO™ may reduce the thyroid function as has been reported with other anticonvulsants. Additionally, anti-malarial drugs, such as chloroquine and mefloquine, may antagonize the activity of carbamazepine.

Thus if a patient has been titrated to a stable dosage on one of the agents in this category, and then begins a course of treatment with EQUETRO™ , it is reasonable to expect that a dose adjustment may be necessary.

Because of its primary CNS effect, caution should be used when EQUETRO™ is taken with other centrally acting drugs and alcohol.

Patients should be made aware that EQUETRO™ contains carbamazepine and should not be used in combination with any other medications containing carbamazepine.

Usage in Pregnancy

Carbamazepine can cause fetal harm when administered to a pregnant woman.

Epidemiological data suggest that there may be an association between the use of carbamazepine during pregnancy and congenital malformations, including spina bifida. The prescribing physician will wish to weigh the benefits of therapy against the risks in treating or counseling women of childbearing potential. 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 a 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 10-25 times a human daily dosage of 1200 mg on a mg/kg basis or 1.5-4 times the human daily dosage on a mg/m2 basis. In rat teratology studies, 2 of 135 offspring showed kinked ribs at 250 mg/kg and 4 of 119 offspring at 650 mg/kg showed other anomalies (cleft palate, 1; talipes, 1; anophthalmos, 2). In reproduction studies in rats, nursing offspring demonstrated a lack of weight gain and an unkempt appearance at a maternal dosage level of 200 mg/kg.

Tests to detect defects using current accepted procedures should be considered a part of routine prenatal care in childbearing women receiving carbamazepine.

General

Patients with a history of adverse hematologic reaction to any drug may be particularly at risk.

Severe dermatologic reactions, including toxic epidermal necrolysis (Lyell's syndrome) and Stevens-Johnson syndrome have been reported with carbamazepine. These reactions have been extremely rare. However, a few fatalities have been reported.

In patients with seizure disorder, carbamazepine should not be discontinued abruptly because of the strong possibility of precipitating status epilepticus with attendant hypoxia and threat to life.

Carbamazepine has shown mild anticholinergic activity; therefore, patients with increased intraocular pressure should be closely observed during therapy.

Because of the relationship of the drug to other tricyclic compounds, the possibility of activation of a latent psychosis and, in elderly patients, of confusion or agitation should be considered.

Co-administration of carbamazepine and delavirdine may lead to loss of virologic response and possible resistance to RESCRIPTOR or to the class of non-nucleoside reverse transcriptase inhibitors.

General

Before initiating therapy, a detailed history and physical examination should be made.

Therapy should be prescribed only after critical benefit-to-risk appraisal in patients with a history of cardiac, hepatic, or renal damage; adverse hematologic reaction to other drugs; or interrupted courses of therapy with carbamazepine.

Suicide: The possibility of suicide attempt is inherent in Bipolar Disorder and close supervision of high risk patients should accompany drug therapy. Prescriptions for EQUETRO™ should be written for the smallest quantity consistent with good patient management in order to reduce the risk of overdose.

Laboratory Tests

Complete pretreatment blood counts, including platelets and possibly reticulocytes and serum iron, should be obtained as a baseline. If a patient in the course of treatment exhibits low or decreased white blood cell or platelet counts, the patient should be monitored closely. Discontinuation of the drug should be considered if any evidence of significant bone marrow depression develops.

Baseline and periodic evaluations of liver function, particularly in patients with a 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.

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.

Baseline and periodic complete urinalysis and BUN determinations are recommended for patients treated with this agent because of observed renal dysfunction.

Increases in total cholesterol, LDL and HDL have been observed in some patients taking anticonvulsants. Therefore, periodic evaluation of these parameters is also recommended.

Monitoring of blood levels (see CLINICAL PHARMACOLOGY) may be useful for verification of drug compliance, assessing safety and determining the cause of toxicity including when more than one medication is being used.

Thyroid function tests have been reported to show decreased values with carbamazepine administered alone.

Hyponatremia has been reported in association with carbamazepine use, either alone or in combination with other drugs.

Interference with some pregnancy tests has been reported.

Carcinogenesis, Mutagenesis, Impairment of Fertility:

Administration of carbamazepine to Sprague-Dawley rats for two 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 a mg/m2 basis), resulted in a dose-related increase in the incidence of hepatocellular tumors in females and of benign interstitial cell adenomas in the testes of males.

Carbamazepine must, therefore, be considered to be carcinogenic in Sprague-Dawley rats. Bacterial and mammalian mutagenicity studies using carbamazepine produced negative results. The significance of these findings relative to the use of carbamazepine in humans is, at present, unknown.

Usage in Pregnancy: Pregnancy Category D (See WARNINGS)

Labor and Delivery: The effect of carbamazepine on human labor and delivery is unknown.

Nursing Mothers: Carbamazepine and its epoxide metabolite are transferred to breast milk and during lactation. Because of the potential for serious adverse reactions in nursing infants from carbamazepine, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric Use: The safety and effectiveness of EQUETRO™ in pediatric and adolescent patients have not been established.

Geriatric Use: No systematic studies in geriatric patients have been conducted.

Acute Toxicity

Lowest known lethal dose: adults, > 60 g (39-year-old man). Highest known doses survived: adults, 30 g (31-year-old woman); children, 10 g (6-year-old boy); small children, 5 g (3-year-old girl). Oral LD 50 in animals (mg/kg): mice, 1100-3750; rats, 3850-4025; rabbits, 1500-2680; guinea pigs, 920.

Signs and Symptoms

The first signs and symptoms appear after 1-3 hours. Neuromuscular disturbances are the most prominent. Cardiovascular disorders are generally milder, and severe cardiac complications occur only when very high doses ( > 60 g) 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.

Treatment

For the most up to date information on management of carbamazepine overdose, pleasecontact the poison center for your area by calling 1-800-222-1222. The prognosis in cases ofcarbamazepine poisoning is generally favorable. Of 5,645 cases of carbamazepineexposures reported to US poison centers in 2002, a total of 8 deaths (0.14% mortality rate)occurred. Over 39% of the cases reported to these poison centers were managed safely athome with conservative care. Successful management of large or intentional carbamazepineexposures requires implementation of supportive care, frequent monitoring of serum drugconcentrations, as well as aggressive but appropriate gastric decontamination.

Elimination of the Drug: The primary method for gastric decontamination of carbamazepineoverdose is use of activated charcoal. For substantial recent ingestions, gastric lavage mayalso be considered. Administration of activated charcoal prior to hospital assessment has thepotential to significantly reduce drug absorption. There is no specific antidote. In overdose,absorption of carbamazepine may be prolonged and delayed. More than one dose ofactivated charcoal may be beneficial in patients that have evidence of continued absorption(e.g., rising serum carbamazepine levels).

Measures to Accelerate Elimination: The data on use of dialysis to enhance elimination incarbamazepine is scarce. Dialysis, particularly high flux or high efficiency hemodialysis, may beconsidered in patients with severe carbamazepine poisoning associated with renal failure or in cases of status epilepticus, or where thereare rising serum drug levels and worsening clinical status despite appropriate supportive care and gastric decontamination. For severecases of carbamazepine overdose unresponsive to other measures, charcoal hemoperfusion may be used to enhance drug clearance.

Respiratory Depression: Keep the airways free; resort, if necessary, to endotracheal intubation, artificial respiration, and administration of oxygen.

Hypotension, Shock: Keep the patient's legs raised and administer a plasma expander. If blood pressure fails to rise despite measures taken to increase plasma volume, use of vasoactive substances should be considered.

Convulsions: Diazepam or barbiturates.

Warning: Diazepam or barbiturates may aggravate respiratory depression (especially in children), hypotension, and coma. Howeverbarbiturates should not be used if drugs that inhibit monoamine oxidase have also been taken by the patient either in overdosage orin recent therapy (within 1 week).

Surveillance: Respiration, cardiac function (ECG monitoring), blood pressure, body temperature, pupillary reflexes, and kidney and bladder function should be monitored for several days.

Treatment of Blood Count Abnormalities: If evidence of significant bone marrow depression develops, the following recommendations are suggested: (1) stop the drug, (2) perform daily CBC, platelet, and reticulocyte counts, (3) do a bone marrow aspiration and trephine biopsy immediately and repeat with sufficient frequency to monitor recovery. Special periodic studies might be helpful as follows: (1) white cell and platelet antibodies, (2) 59Fe-ferrokinetic studies, (3) peripheral blood cell typing, (4) cytogenetic studies on marrow and peripheral blood, (5) bone marrow culture studies for colony-forming units, (6) hemoglobin electrophoresis for A₂ and F hemoglobin, and (7) serum folic acid and B₁₂ levels.

A fully developed aplastic anemia will require appropriate, intensive monitoring and therapy, for which specialized consultation should be sought.

Carbamazepine should not be used in patients with a history of previous bone marrow depression, hypersensitivity to the drug, or known sensitivity to any of the tricyclic compounds, such as amitriptyline, desipramine, imipramine, protriptyline and nortriptyline. Likewise, on theoretical grounds its use with monoamine oxidase inhibitors is not recommended. Before administration of carbamazepine, MAO inhibitors should be discontinued for a minimum of 14 days, or longer if the clinical situation permits.

In controlled clinical trials, carbamazepine has been shown to be effective in the treatment of Bipolar I Disorder.

Mechanism of Action

The mechanism(s) of action of carbamazepine in the treatment of bipolar disorder has not been elucidated. 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 bipolar disorder is unknown.

Pharmacokinetics

Carbamazepine (CBZ): Following a single 200 mg oral extended-release dose of carbamazepine, peak plasma concentration was 1.9 ± 0.3 µg/mL and the time to reach the peak was 19 ± 7 hours. Following repeat dose administration (800 mg every 12 hours), the peak levels were 11.0 ± 2.5 µg/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. Following a single extended-release dose of carbamazepine, the average half-life ranged from 35-40 hours and 12-17 hours following repeated dosing. The apparent oral clearance following a single dose was 25 ± 5 mL/min and following multiple dosing was 80 ± 30 mL/min.

After oral administration of ¹⁴C-carbamazepine, 72% of the administered radioactivity was found in the urine and 28% in the feces. This urinary radioactivity was composed largely of hydroxylated and conjugated metabolites, with only 3% of unchanged carbamazepine. Carbamazepine-10,11-epoxide (CBZ-E): Carbamazepine-10,11-epoxide is considered to be an active metabolite of carbamazepine. Following a single 200 mg oral extended-release dose of carbamazepine, the peak plasma concentration of carbamazepine-10,11- epoxide was 0.11 ± 0.012 µg/mL and the time to reach the peak was 36 ± 6 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 µg/mL and the time to reach the peak was 14 ± 8 hours. The plasma half-life of carbamazepine-10,11-epoxide following administration of carbamazepine is 34 ± 9 hours. Following a 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 µg.hr/mL and 1.5 µg/mL at 800 mg/day to 32.6 µg.hr/mL and 3.2 µg/mL at 1600 mg/day, respectively, and were less than 30% of carbamazepine. Carbamazepine-10,11-epoxide is 50% bound to plasma proteins.

Food Effect: A high fat meal diet increased the rate of absorption of a 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 µg/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.

Special Populations

Hepatic Dysfunction: The effect of hepatic impairment on the pharmacokinetics of carbamazepine is not known. However, given that carbamazepine is primarily metabolized in the liver, it is prudent to proceed with caution in patients with hepatic dysfunction.

Renal Dysfunction: The effect of renal impairment on the pharmacokinetics of carbamazepine is not known.

Gender: No difference in the mean AUC and Cmax of carbamazepine and carbamazepine-10,11-epoxide was found between males and females.

Age: Carbamazepine is more rapidly metabolized to carbamazepine-10,11-epoxide in young children than 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™ in pediatric and adolescent patients have not been established.

Race: No information is available on the effect of race on the pharmacokinetics of carbamazepine.

CLINICAL STUDIES

The effectiveness of EQUETRO™ in the acute treatment of manic and mixed symptoms in patients with Bipolar I Disorder was established in 2 (3 week) multicenter, randomized, double-blind, flexible dose, placebo controlled studies in adult patients who met the DSM-IV criteria for Bipolar I Disorder with manic or mixed episode. In both studies, patients were titrated to a dose range from 400 mg/day to 1600 mg/day, given in divided doses, twice daily. The mean carbamazepine ER dose during the last week was 952 mg/day in the first study, and 726 mg/day in the second.

The primary rating instrument used for assessing manic symptoms in these trials was the Young Mania Rating Scale (YMRS), an 11-item clinician-rated scale traditionally used to assess the degree of manic symptomatology in a range from 0 (no manic features) to 60 (maximum score). The primary outcome in these trials was change from baseline in the YMRS total score.

EQUETRO™ was significantly more effective than placebo in reduction of the YMRS total score for both studies.

Patients should be made aware of the early toxic signs and symptoms of a potential hematologic problem, such as fever, sore throat, rash, ulcers in the mouth, easy bruising, petechial or purpuric hemorrhage, and should be advised to report to the physician immediately if any such signs or symptoms appear.

Since dizziness and drowsiness may occur, patients should be cautioned about the hazards of operating machinery or automobiles or engaging in other potentially dangerous tasks.

If necessary, the EQUETRO™ capsules can be opened and the contents sprinkled over food, such as a teaspoon of applesauce or other similar food products. EQUETRO™ capsules or their contents should not be crushed or chewed.

EQUETRO™ may interact with some drugs. Therefore, patients should be advised to report to their doctors the use of any other prescription or non-prescription medication or herbal products.

IMPORTANT NOTE: This is a summary and does not contain all possible information about this product. For complete information about this product or your specific health needs, ask your health care professional. Always seek the advice of your health care professional if you have any questions about this product or your medical condition. This information is not intended as individual medical advice and does not substitute for the knowledge and judgment of your health care professional. This information does not contain any assurances that this product is safe, effective, or appropriate for you.

CARBAMAZEPINE SUSTAINED-ACTION CAPSULE - ORAL

(kar-bam-AZZ-eh-peen)

COMMON BRAND NAME(S): Carbatrol

WARNING: Carbamazepine may rarely cause very serious (possibly fatal) skin reactions. Certain ethnic groups (including people of Asian/South Asian descent) are at greater risk. Your doctor may order a blood test (HLA-B 1502) to measure your risk before prescribing this medication. If the blood test shows you are at greater risk, discuss the risks and benefits of carbamazepine and other treatment choices with your doctor. Such skin reactions have developed mostly within the first few months of treatment. Seek immediate medical attention if you develop any of the following symptoms: skin rash/blisters/peeling, itching, or swelling. Ask your doctor or pharmacist for more details.

This drug has rarely caused a severe decrease in bone marrow function (aplastic anemia, agranulocytosis). Your doctor will monitor your blood counts to minimize the chance of this side effect. Keep all medical and laboratory appointments. Tell your doctor immediately if any of these rare but very serious side effects occur: signs of infection (e.g., fever, persistent sore throat), unusual weakness or fatigue, or easy bleeding/bruising.

USES: Carbamazepine is used to prevent and control seizures. It is known as an anticonvulsant or anti-epileptic drug. It is also used to relieve a certain type of nerve pain (trigeminal neuralgia). In addition, carbamazepine is used to treat acute manic episodes and mixed episodes (acute mania with depression) in people with bipolar disorder. This medication works by reducing excessive nerve signals in the brain and restoring the normal balance of nerve activity. It also works to stabilize the mood and reduce extremes in behavior.

OTHER USES: This section contains uses of this drug that are not listed in the approved professional labeling for the drug but that may be prescribed by your health care professional. Use this drug for a condition that is listed in this section only if it has been so prescribed by your health care professional.

This drug may also be used to treat certain other mental/mood conditions (e.g., schizophrenia) and other types of nerve pain.

HOW TO USE: Take this medication by mouth with or without meals, usually twice a day, or as directed by your doctor. Swallow the medication whole. Do not crush or chew the capsules.

If you have trouble swallowing capsules, you may open them and sprinkle the contents onto a teaspoonful of applesauce or other soft food. Swallow the food/medication mixture immediately. Do not chew the mixture or prepare a supply in advance because this may increase side effects or destroy the drug.

Dosage is based on your medical condition and response to therapy. Your doctor may gradually increase your dose. Follow these directions carefully.

For the treatment of trigeminal nerve pain, do not take more than 1,200 milligrams per day.

Avoid eating grapefruit or drinking grapefruit juice while being treated with this medication unless your doctor instructs you otherwise. Grapefruit juice can increase the amount of certain medications in your bloodstream. Consult your doctor or pharmacist for more details.

Take this medication regularly at evenly spaced intervals in order to get the most benefit from it. Remember to use it at the same times each day to keep the amount of medicine in your body at a constant level.

Do not take more of this medicine than prescribed or stop taking it without consulting your doctor. Some conditions (e.g., seizures) may become worse when the drug is suddenly stopped. Your dose may need to be gradually decreased.

Inform your doctor if your condition does not improve or worsens.

SIDE EFFECTS: See also the Warning section.

Nausea, vomiting, dizziness, drowsiness, or unsteadiness may occur as your body adjusts to this medication. If any of these effects persist or worsen, notify your doctor or pharmacist promptly.

Remember that your doctor has prescribed this medication because he or she has judged that the benefit to you is greater than the risk of side effects. Many people using this medication do not have serious side effects.

Tell your doctor immediately if any of these unlikely but serious side effects occur: swelling of the ankles/feet, fatigue, fast/slow/irregular heartbeat, persistent or severe headache, fainting, trouble urinating, change in the amount of urine, decreased sexual ability, unusual eye movements (nystagmus), vision changes, hearing problems, mental/mood changes, pain/redness/swelling of the arms or legs, numbness/tingling of the hands/feet, sun sensitivity, joint pain, hair loss.

This medication rarely may cause mood or behavior changes, such as anxiety, agitation, hostility, pressured/rapid speech, or thoughts of suicide. Tell your doctor immediately if you develop unusual (possibly sudden) mood changes.

Tell your doctor immediately if any of these rare but very serious side effects occur: persistent nausea or vomiting, severe stomach/abdominal pain, yellowing eyes and skin, dark urine, swollen glands, persistent mouth sores.

Seek immediate medical attention if any of these rare but very serious side effects occur: chest pain, trouble breathing.

A very serious allergic reaction to this drug is unlikely, but seek immediate medical attention if it occurs. Symptoms of a serious allergic reaction may include: rash, itching, swelling, severe dizziness, trouble breathing.

This is not a complete list of possible side effects. If you notice other effects not listed above, contact your doctor or pharmacist.

Contact your doctor for medical advice about side effects. The following numbers do not provide medical advice, but in the US you may report side effects to the Food and Drug Administration (FDA) at 1-800-FDA-1088. In Canada, you may call Health Canada at 1-866-234-2345.

PRECAUTIONS: Before taking carbamazepine, tell your doctor or pharmacist if you are allergic to it; or to other anti-seizure medications (e.g., phenobarbital, phenytoin) or tricyclic antidepressants (e.g., amitriptyline, desipramine); or if you have any other allergies.

This medication should not be used if you have certain medical conditions. Before using this medicine, consult your doctor or pharmacist if you have: decreased bone marrow function (bone marrow depression), a certain blood disorder (acute intermittent porphyria).

Before using this medication, tell your doctor or pharmacist your medical history, especially of: high blood pressure, blood clots, blood vessel disease, heart disease (e.g., coronary artery disease, congestive heart failure, heart rhythm or conduction disorders), kidney disease, liver disease, glaucoma, certain types of seizures (atypical absence seizures), history of decreased bone marrow function due to other drugs.

This drug may make you dizzy or drowsy; use caution engaging in activities requiring alertness such as driving or using machinery. Limit alcoholic beverages.

This medication may make you more sensitive to the sun. Avoid prolonged sun exposure, tanning booths or sunlamps. Use a sunscreen and wear protective clothing when outdoors.

This medication is not recommended for use during pregnancy due to the risk of possible birth defects and complications in the infant at birth. Discuss the risks and benefits with your doctor. If you become pregnant while taking this drug, contact your doctor immediately. If you are pregnant, prenatal care including tests for spinal cord defects is recommended.

This medication passes into breast milk and may have undesirable effects on a nursing infant. Therefore, breast-feeding while using this drug is not recommended. Consult your doctor before breast-feeding.

DRUG INTERACTIONS: See also the How to Use section.

Your healthcare professionals (e.g., doctor or pharmacist) may already be aware of any possible drug interactions and may be monitoring you for it. Do not start, stop or change the dosage of any medicine before checking with them first.

Avoid taking MAO inhibitors (e.g., furazolidone, isocarboxazid, linezolid, moclobemide, phenelzine, procarbazine, rasagiline, selegiline, tranylcypromine) within 2 weeks before or after treatment with this medication. In some cases a serious, possibly fatal, drug interaction may occur.

This drug should not be used with the following medications because very serious interactions may occur: darunavir, delavirdine, etravirine, nefazodone, telithromycin, voriconazole.

Before using this medication, tell your doctor or pharmacist of all prescription and nonprescription/herbal products you may use, especially of: other anti-seizure medications (e.g., felbamate, valproic acid), lithium, SSRI antidepressants (e.g., fluoxetine), tramadol, drugs affecting liver enzymes that remove carbamazepine from your body (such as azole antifungals-including itraconazole, macrolide antibiotics-including erythromycin, cimetidine, rifamycins-including rifabutin, St John's wort, propoxyphene, danazol, calcium channel blockers-including verapamil).

Carbamazepine can cause certain liver enzymes to speed up the removal of other drugs from your body, possibly decreasing their effectiveness. These affected drugs include (this is not a complete list): certain cancer drugs (dasatinib, lapatinib, sunitinib, irinotecan), caspofungin, cyclosporine, doxycycline, HIV protease inhibitors (e.g., amprenavir, saquinavir), levothyroxine, psychiatric medications (e.g., clozapine, haloperidol, risperidone, trazodone), theophylline, warfarin.

This medication may decrease the effectiveness of birth control products that contain hormones including combination-type birth control pills, patches, injections, and implants. This can result in pregnancy. You may need to use an additional form of reliable birth control while using this medication. Consult your doctor or pharmacist for details.

Tell your doctor or pharmacist if you also take drugs that cause drowsiness such as: certain antihistamines (e.g., diphenhydramine), anti-anxiety drugs (e.g., diazepam), medicine for sleep (e.g., sedatives), muscle relaxants, narcotic pain relievers (e.g., codeine), psychiatric medicines (e.g., phenothiazines such as chlorpromazine, tricyclic antidepressants such as amitriptyline), tranquilizers.

Check the labels on all your medicines (e.g., cough-and-cold products) because they may contain ingredients that cause drowsiness. Ask your pharmacist about the safe use of those products.

This product can affect the results of certain lab tests (e.g., thyroid function, some pregnancy tests). Make sure laboratory personnel and your doctors know you are using this drug.

This document does not contain all possible interactions. Therefore, before using this product, tell your doctor or pharmacist of all the products you use. Keep a list of all your medications with you, and share the list with your doctor and pharmacist.

OVERDOSE: If overdose is suspected, contact your local poison control center or emergency room immediately. US residents can call the US national poison hotline at 1-800-222-1222. Canadian residents should call their local poison control center directly. Symptoms of overdose may include: slowed breathing, loss of consciousness, muscle twitching, uncontrolled movements, very fast heartbeat.

NOTES: Do not share this medication with others.

Laboratory and/or medical tests (e.g., complete blood count, blood chemistry, kidney and liver function tests, eye exams, carbamazepine blood levels) should be performed periodically to monitor your progress or check for side effects. Keep all laboratory and medical appointments. Consult your doctor for more details.

Wear or carry identification indicating you are using this drug.

MISSED DOSE: If you miss a dose, use it as soon as you remember. If it is near the time of the next dose, skip the missed dose and resume your usual dosing schedule. Do not double the dose to catch up. Call your doctor if you miss more than one dose in a day.

STORAGE: Store at room temperature (77 degrees F or 25 degrees C) away from light and moisture. Brief storage between 59-86 degrees F (15-30 degrees C) is permitted. Do not store in the bathroom. Keep all medicines away from children and pets.

Do not flush medications down the toilet or pour them into a drain unless instructed to do so. Properly discard this product when it is expired or no longer needed. Consult your pharmacist or local waste disposal company for more details about how to safely discard your product.

MEDICAL ALERT: Your condition can cause complications in a medical emergency. For enrollment information call MedicAlert at 1-800-854-1166 (USA), or 1-800-668-1507 (Canada).

Information last revised July 2008 Copyright(c) 2008 First DataBank, Inc.