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Name:Equetro
Manufacturer:Validus Pharmaceuticals Llc
Category:Prescription Marketed Drugs


EQUETRO®(carbamazepine) Extended-Release Capsules

EQUETRO - carbamazepine capsule, extended release 
Validus Pharmaceuticals LLC

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EQUETRO®
(carbamazepine) Extended-Release Capsules

Prescribing Information

WARNING

SERIOUS DERMATOLOGIC REACTIONS AND HLA-B*1502 ALLELE

SERIOUS AND SOMETIMES FATAL DERMATOLOGIC REACTIONS, INCLUDING TOXIC EPIDERMAL NECROLYSIS (TEN) AND STEVENS-JOHNSON SYNDROME (SJS), HAVE BEEN REPORTED DURING TREATMENT WITH CARBAMAZEPINE. THESE REACTIONS ARE ESTIMATED TO OCCUR IN 1 TO 6 PER 10,000 NEW USERS IN COUNTRIES WITH MAINLY CAUCASIAN POPULATIONS, BUT THE RISK IN SOME ASIAN COUNTRIES IS ESTIMATED TO BE ABOUT 10 TIMES HIGHER. STUDIES IN PATIENTS OF CHINESE ANCESTRY HAVE FOUND A STRONG ASSOCIATION BETWEEN THE RISK OF DEVELOPING SJS/TEN AND THE PRESENCE OF HLA-B*1502, AN INHERITED ALLELIC VARIANT OF THE HLA-B GENE. HLA-B*1502 IS FOUND ALMOST EXCLUSIVELY IN PATIENTS WITH ANCESTRY ACROSS BROAD AREAS OF ASIA. PATIENTS WITH ANCESTRY IN GENETICALLY AT-RISK POPULATIONS SHOULD BE SCREENED FOR THE PRESENCE OF HLA-B*1502 PRIOR TO INITIATING TREATMENT WITH EQUETRO®. PATIENTS TESTING POSITIVE FOR THE ALLELE SHOULD NOT BE TREATED WITH EQUETRO® UNLESS THE BENEFIT CLEARLY OUTWEIGHS THE RISK (see WARNINGS and PRECAUTIONS, Laboratory Tests).


APLASTIC ANEMIA AND AGRANULOCYTOSIS

APLASTIC ANEMIA AND AGRANULOCYTOSIS HAVE BEEN REPORTED IN ASSOCIATION WITH THE USE OF CARBAMAZEPINE. DATA FROM A POPULATION-BASED CASE-CONTROL STUDY DEMONSTRATE 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 CARBAMAZEPINE ARE UNLIKELY TO SIGNAL THE OCCURRENCE OF EITHER ABNORMALITY. NONETHELESS, COMPLETE PRETREATMENT HEMATOLOGICAL TESTING 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.

Before prescribing EQUETRO®, the physician should be thoroughly familiar with the details of this prescribing information, particularly regarding use with other drugs, especially those which accentuate toxicity potential.

DESCRIPTION

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-01

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, 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.

CLINICAL PHARMACOLOGY

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. The average half-life ranged from 35 to 40 hours following a single extended-release dose of carbamazepine and from 12 to 17 hours following repeated dosing. The apparent oral clearance was 25 ± 5 mL/min following a single dose and 80 ± 30 mL/min following multiple dosing.

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.

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% those 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 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® 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.

INDICATIONS AND USAGE

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).

CONTRAINDICATIONS

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.

Coadministration of carbamazepine and nefazodone may result in insufficient plasma concentrations of nefazodone and its active metabolite to achieve a therapeutic effect. Coadministration of carbamazepine with nefazodone is contraindicated.

WARNINGS

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. The risk of these events is estimated to be about 1 to 6 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. EQUETRO® should be discontinued at the first sign of a rash, unless the rash is clearly not drug-related. If signs or symptoms suggest SJS/TEN, use of this drug should not be resumed and alternative therapy should be considered.

SJS/TEN and HLA-B*1502 Allele

Retrospective case-control studies have found that in patients of Chinese ancestry there is a strong association between the risk of developing SJS/TEN with carbamazepine treatment and the presence of an inherited variant of the HLA-B gene, HLA-B*1502. The occurrence of higher rates of these reactions in countries with higher frequencies of this allele suggests that the risk may be increased in allele-positive individuals of any ethnicity.

Across Asian populations, notable variation exists in the prevalence of HLA-B*1502. Greater than 15% of the population is reported positive in Hong Kong, Thailand, Malaysia, and parts of the Philippines, compared to about 10% in Taiwan and 4% in North China. South Asians, including Indians, appear to have intermediate prevalence of HLA-B*1502, averaging 2 to 4%, but higher in some groups. HLA-B*1502 is present in <1% of the population in Japan and Korea.

HLA-B*1502 is largely absent in individuals not of Asian origin (e.g., Caucasians, African-Americans, Hispanics, and Native Americans).

Prior to initiating EQUETRO® therapy, testing for HLA-B*1502 should be performed in patients with ancestry in populations in which HLA-B*1502 may be present. In deciding which patients to screen, the rates provided above for the prevalence of HLA-B*1502 may offer a rough guide, keeping in mind the limitations of these figures due to wide variability in rates even within ethnic groups, the difficulty in ascertaining ethnic ancestry, and the likelihood of mixed ancestry. EQUETRO® should not be used in patients positive for HLA-B*1502 unless the benefits clearly outweigh the risks. Tested patients who are found to be negative for the allele are thought to have a low risk of SJS/TEN (see WARNINGS and PRECAUTIONS, Laboratory Tests).

Over 90% of carbamazepine-treated patients who will experience SJS/TEN have this reaction within the first few months of treatment. This information may be taken into consideration in determining the need for screening of genetically at-risk patients currently on EQUETRO®.

The HLA-B*1502 allele has not been found to predict risk of less severe adverse cutaneous reactions from carbamazepine, such as anticonvulsant hypersensitivity syndrome or non-serious rash (maculopapular eruption [MPE]).

Limited evidence suggests that HLA-B*1502 may be a risk factor for the development of SJS/TEN in patients of Chinese ancestry taking other anti-epileptic drugs associated with SJS/TEN. Consideration should be given to avoiding use of other drugs associated with SJS/TEN in HLA-B*1502-positive patients when alternative therapies are otherwise equally acceptable.

Application of HLA-B*1502 genotyping as a screening tool has important limitations and must never substitute for appropriate clinical vigilance and patient management. Many HLA-B*1502-positive Asian patients treated with carbamazepine will not develop SJS/TEN, and these reactions can still occur infrequently in HLA-B*1502-negative patients of any ethnicity. The role of other possible factors in the development of, and morbidity from, SJS/TEN, such as AED dose, compliance, concomitant medications, co-morbidities, and the level of dermatologic monitoring, has not been studied.

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

Aplastic Anemia and Agranulocytosis

Aplastic anemia and agranulocytosis have been reported in association with the use of carbamazepine. Data from a population-based case-control study demonstrate 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 carbamazepine are unlikely to signal the occurrence of either abnormality. Nonetheless, complete pretreatment hematological testing 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

Suicidal Behavior and Ideation

Antiepileptics 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 a median treatment duration of 12 weeks, the estimated incidence rate of suicidal behavior or ideation among 27,863 AED-treated patients was 0.43%, compared to 0.24% among 16,029 placebo-treated patients, representing an increase of approximately one case of suicidal thinking or behavior for every 530 patients treated. There were four suicides in drug-treated patients in the trials and none in placebo-treated patients, but the number is too small to allow any conclusion about drug effect on suicide.

The increased risk of suicidal thoughts or behavior with AEDs was observed as early as one week after starting drug treatment with AEDs and persisted for the duration of treatment assessed. Because most trials included in the analysis did not extend beyond 24 weeks, the risk of suicidal thoughts or behavior beyond 24 weeks could not be assessed.

The risk of suicidal thoughts or behavior was generally consistent among drugs in the data analyzed. The finding of increased risk with AEDs of varying mechanisms of action and across a range of indications suggests that the risk applies to all AEDs used for any indication. The risk did not vary substantially by age (5-100 years) in the clinical trials analyzed. Table 1 shows absolute and relative risk by indication for all evaluated AEDs.

Table 1 Risk by indication for antiepileptic drugs in the pooled analysis
Indication Placebo Patients with Events Per 1000 Patients Drug Patients with Events Per 1000 Patients Relative Risk: Incidence of Events in Drug Patients/Incidence in Placebo Patients Risk Difference: Additional Drug Patients with Events Per 1000 Patients
Epilepsy 1.0 3.4 3.5 2.4
Psychiatric 5.7 8.5 1.5 2.9
Other 1.0 1.8 1.9 0.9
Total 2.4 4.3 1.8 1.9

The relative risk for suicidal thoughts or behavior was higher in clinical trials for epilepsy than in clinical trials for psychiatric or other conditions, but the absolute 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.

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 showed other anomalies at 650 mg/kg (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.

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 (NAAED) Pregnancy Registry. This can be done by calling the toll-free number 1-888-233-2334, and must be done by patients themselves. Information on the registry can also be found at the website http://www.aedpregnancyregistry.org/.

General

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

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.

PRECAUTIONS

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.

Bipolar Disorder and 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 (See WARNINGS).

Information for Patients

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, and petechial or purpuric hemorrhage, and should be advised to report to the physician immediately if any such signs or symptoms appear.

Patients, their caregivers, and families should be counseled that AEDs, including Equetro, may increase the risk of suicidal thoughts and behaviors and should be advised of the need to be alert for the emergence or worsening of symptoms of depression, any unusual changes in mood or behavior, or the emergence of suicidal thoughts, behaviors, or thoughts about self-harm. Behaviors of concern should be reported immediately to healthcare providers.

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.

Please see Medication Guide.

Laboratory Tests

For genetically at-risk patients [see WARNINGS], high-resolution 'HLA-B*1502 typing' is recommended. The test is positive if either one or two HLA-B*1502 alleles are detected and negative if no HLA-B*1502 alleles are detected.

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 examination, 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.

Drug Interactions

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) Breakthrough 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.


Carcinogenesis, Mutagenesis, Impairment of Fertility: Administration of carbamazepine to Sprague-Dawley rats for 2 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). Patients should be encouraged to enroll in the NAAED Pregnancy Registry if they become pregnant. This registry is collecting information about the safety of antiepileptic drugs during pregnancy. To enroll, patients can call the toll-free number 1-888-233-2334 (see WARNINGS section).


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 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.

ADVERSE REACTIONS

General

The most severe adverse reactions previously observed with carbamazepine were reported in the hemopoietic system and skin (see BOXED WARNING) and in 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 200 mg 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)
Adverse Events EQUETRO® (N = 251) Placebo (N = 248)
* Reported as blurred vision
DIZZINESS 44% 12%
SOMNOLENCE 32% 13%
NAUSEA 29% 10%
VOMITING 18% 3%
ATAXIA 15% 0%
PRURITUS 8% 2%
DRY MOUTH 8% 3%
AMBLYOPIA* 6% 2%
SPEECH DISORDER 6% 0%

EQUETRO® and placebo-treated patients from two of the double-blind, placebo-controlled studies were enrolled in a 6-month open-label study. Table 2 below summarizes the most common adverse events with an incidence of 5% or more.

Table 2. Most Common Adverse Events Reported in Open-Label Trials (Incidence ≥5%)
^ Amnesia includes poor memory, forgetful, and memory disturbance.
* Depression includes suicidal ideation.
Body as a Whole % events reported Nervous System % events reported
Headache 22% Dizziness 16%
Infection 12% Somnolence 12%
Pain 12% Amnesia^ 8%
Asthenia 8% Anxiety 7%
Accidental Injury 7% Depression* 7%
Chest Pain 5% Manic Depressive Reaction 7%
Back Pain 5% Ataxia 5%
Digestive Skin Appendages
Diarrhea 10% Rash 13%
Dyspepsia 10% Pruritus 5%
Nausea 10%
Constipation 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: Toxic epidermal necrolysis (TEN) and Stevens-Johnson syndrome (SJS) (see BOXED WARNING), pruritic and erythematous rashes, urticaria, 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 and inappropriate antidiuretic hormone (ADH) secretion syndrome have 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.

OVERDOSAGE

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 LD50 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, please contact the poison center for your area by calling 1-800-222-1222. The prognosis in cases of carbamazepine poisoning is generally favorable. Of 5,645 cases of carbamazepine exposures 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 at home with conservative care. Successful management of large or intentional carbamazepine exposures requires implementation of supportive care, frequent monitoring of serum drug concentrations, and aggressive but appropriate gastric decontamination.

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

Measures to Accelerate Elimination: The data on use of dialysis to enhance elimination in carbamazepine is scarce. Dialysis, particularly high-flux or high-efficiency hemodialysis, may be considered in patients with severe carbamazepine poisoning associated with renal failure or in cases of status epilepticus, or where there are rising serum drug levels and worsening clinical status despite appropriate supportive care and gastric decontamination. For severe cases 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. However, barbiturates should not be used if drugs that inhibit monoamine oxidase have also been taken by the patient either in overdosage or in 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.

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.

HOW SUPPLIED

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 SPD417 on one end and SPD417 and 100 mg on the other in white ink: Supplied in bottles of 120   NDC 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 120   NDC 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 120   NDC 30698-423-12

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 LLC, 119 Cherry Hill Road, Suite 310, Parsippany, NJ 07054, 1-866-9VALIDUS (1-866-982-5438)

info@validuspharma.com
http://www.equetro.com

Made in U.S.A.
© 2008 Validus Pharmaceuticals LLC

005595
110704
(Rev 10/2010)

Medication Guide


EQUETRO (ē-kwĕ-trō)
(carbamazepine)
Extended-Release Capsules


Read this Medication Guide before you start taking EQUETRO and each time you get a 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 I should know about EQUETRO?

Do not stop taking EQUETRO without first talking to your healthcare provider.

Stopping EQUETRO suddenly can cause serious problems.

EQUETRO can cause serious side effects, including:

  1. EQUETRO may cause rare but serious rash that may lead to death. These serious skin reactions are more likely to happen within the first four months of EQUETRO treatment, 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 a genetic blood test before you take EQUETRO to see if you are at higher risk for serious skin reactions with this medicine. If you have any of the problems listed below call your healthcare provider right away:
    • skin rash
    • hives
    • sores in your mouth
    • your skin blisters and peels
  2. EQUETRO may cause rare but serious blood problems. Symptoms may include:
    • fever, swollen glands, or sore throat that come and go or do not go away
    • easy bruising
    • red or purple spots on your body
    • bleeding gums or nose bleeds
  3. Like other antiepileptic drugs, EQUETRO may cause suicidal thoughts or actions in a very small number of people, about 1 in 500.
    Call your healthcare provide 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 mood

How can I watch for early symptoms of suicidal thoughts and actions?

  • Pay attention to any changes, especially sudden changes, in mood, behaviors, thoughts, or feelings.
  • Keep all follow-up visits with your healthcare provider as scheduled.

Call your healthcare provider between visits as needed, especially if you are worried about symptoms.

Do not stop EQUETRO without first talking to a healthcare provider.

Stopping EQUETRO suddenly can cause serious problems. You should talk to your health care 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 EQUETRO?

EQUETRO is a prescription medicine used in adults to treat acute manic and mixed episodes associated with Bipolar Disorder.

It is not known if EQUETRO is safe or effective in children and adolescents.


Who should not take EQUETRO?

Do not take EQUETRO if you:

  • have a history of bone marrow depression.
  • are allergic to carbamazepine or any of the ingredients in EQUETRO. See the end of this Medication Guide for a complete list of ingredients in EQUETRO.
  • are allergic to medicines called tricyclic antidepressants (TCAs) .
  • have taken a Monoamine Oxidase Inhibitor (MAOI) in the last 14 days. Ask your healthcare provider or pharmacist for a list of these medicines if you are not sure.
  • are taking nefazodone.


What should I tell my healthcare provider before taking EQUETRO?

Before you take EQUETRO, tell your healthcare provider if you:

  • have or ever had heart problems
  • have or ever had blood problems
  • have or ever had liver or kidney problems
  • have or ever had allergic reactions to medicines
  • have or ever had increased pressure in your eye
  • have or have had depression, mood problems, or suicidal thoughts or behavior
  • 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 (NAAED) Pregnancy Registry. The purpose of this registry is to collect information about the safety of antiepileptic medicine 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 can 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 a list of them and show it to your healthcare provider and pharmacist when you get a new medicine.


How should I take EQUETRO?

  • 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.
  • Do not stop taking EQUETRO without first talking to your healthcare provider. Stopping EQUETRO suddenly can cause serious problems.
  • Take EQUETRO with or without food.
  • Do not crush, chew, or break EQUETRO capsules or the beads inside the capsules. But, the EQUETRO capsules can be opened and sprinkled over food such as a teaspoon of applesauce.
  • Tell your healthcare provider if you can not swallow EQUETRO whole.
  • If you take too much EQUETRO, call your healthcare provider or local Poison Control Center right away.


WHAT should I avoid while taking EQUETRO?

  • 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.


What are the possible side effects of EQUETRO?

See "What is the most important information I should know about EQUETRO?".

EQUETRO may cause other rare, but serious side effects. These include:

  • Irregular heart rate - symptoms include:
    • Fast, slow, or pounding heartbeat
    • Shortness of breath
    • Feeling lightheaded
    • Fainting
  • Liver problems - symptoms 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

Get medical help right away if you have any of the symptoms listed above.

The most common side effects of EQUETRO include:

  • dizziness
  • drowsiness
  • problems with walking and coordination (unsteadiness)
  • nausea
  • vomiting

These 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.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.


How should I store EQUETRO?

  • Store EQUETRO between 59°F to 86°F (15°C to 30°C).
  • Keep EQUETRO out of the light.
  • Keep EQUETRO capsules dry.

Keep EQUETRO and all medicines out of the reach of children.


General Information about EQUETRO

Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use EQUETRO for a 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 doctor. You can ask your pharmacist or doctor 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 EQUETRO?

Active 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.
In addition:

  • the 100 mg capsules contain gelatin-NF, FD&C Blue #2, Yellow Iron Oxide, and Titanium Dioxide, and are imprinted with white ink
  • the 200 mg capsules contain gelatin-NF, Yellow Iron Oxide, FD&C Blue #2, and Titanium Dioxide, and are imprinted with white ink
  • the 300 mg capsules contain 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.

110705
Issued October 2010

Validus Pharmaceuticals LLC, 119 Cherry Hill Road, Suite 310, Parsippany, NJ 07054
1-866-9VALIDUS (1-866-982-5438)

PRINCIPAL DISPLAY PANEL - 100 mg

NDC 30698-419-12

Equetro®
carbamazepine
extended-release
capsules

100mg
120 Capsules

Rx Only


equetro-02

PRINCIPAL DISPLAY PANEL - 200 mg

NDC 30698-421-12

Equetro®
carbamazepine
extended-release
capsules

200mg
120 Capsules

Rx Only


equetro-03

PRINCIPAL DISPLAY PANEL - 300 mg

NDC 30698-423-12

Equetro®
carbamazepine
extended-release
capsules

300mg
120 Capsules

Rx Only


equetro-04

 


EQUETRO 
carbamazepine capsule, extended release
Product Information
Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:30698-419
Route of Administration ORAL DEA Schedule     
Active Ingredient/Active Moiety
Ingredient Name Basis of Strength Strength
CARBAMAZEPINE (CARBAMAZEPINE) CARBAMAZEPINE 100 mg
Inactive Ingredients
Ingredient Name Strength
CITRIC ACID MONOHYDRATE  
SILICON DIOXIDE  
LACTOSE MONOHYDRATE  
CELLULOSE, MICROCRYSTALLINE  
POLYETHYLENE GLYCOL  
POVIDONE  
SODIUM LAURYL SULFATE  
TALC  
TRIETHYL CITRATE  
GELATIN  
FD&C BLUE NO. 2  
FERRIC OXIDE YELLOW  
TITANIUM DIOXIDE  
Product Characteristics
Color YELLOW (YELLOW) , BLUE (BLUE) Score no score
Shape CAPSULE (CAPSULE) Size 15mm
Flavor Imprint Code SPD417;100;mg
Contains     
Packaging
# Item Code Package Description Multilevel Packaging
1 NDC:30698-419-12 120 CAPSULE, EXTENDED RELEASE ( CAPSULE) in 1 BOTTLE None

Marketing Information
Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date
NDA NDA021710 12/10/2004

EQUETRO 
carbamazepine capsule, extended release
Product Information
Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:30698-421
Route of Administration ORAL DEA Schedule     
Active Ingredient/Active Moiety
Ingredient Name Basis of Strength Strength
CARBAMAZEPINE (CARBAMAZEPINE) CARBAMAZEPINE 200 mg
Inactive Ingredients
Ingredient Name Strength
CITRIC ACID MONOHYDRATE  
SILICON DIOXIDE  
LACTOSE MONOHYDRATE  
CELLULOSE, MICROCRYSTALLINE  
POLYETHYLENE GLYCOL  
POVIDONE  
SODIUM LAURYL SULFATE  
TALC  
TRIETHYL CITRATE  
GELATIN  
FD&C BLUE NO. 2  
FERRIC OXIDE YELLOW  
TITANIUM DIOXIDE  
Product Characteristics
Color YELLOW (YELLOW) , BLUE (BLUE) Score no score
Shape CAPSULE (CAPSULE) Size 21mm
Flavor Imprint Code SPD417;200;mg
Contains     
Packaging
# Item Code Package Description Multilevel Packaging
1 NDC:30698-421-12 120 CAPSULE, EXTENDED RELEASE ( CAPSULE) in 1 BOTTLE None

Marketing Information
Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date
NDA NDA021710 12/10/2004

EQUETRO 
carbamazepine capsule, extended release
Product Information
Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:30698-423
Route of Administration ORAL DEA Schedule     
Active Ingredient/Active Moiety
Ingredient Name Basis of Strength Strength
CARBAMAZEPINE (CARBAMAZEPINE) CARBAMAZEPINE 300 mg
Inactive Ingredients
Ingredient Name Strength
CITRIC ACID MONOHYDRATE  
SILICON DIOXIDE  
LACTOSE MONOHYDRATE  
CELLULOSE, MICROCRYSTALLINE  
POLYETHYLENE GLYCOL  
POVIDONE  
SODIUM LAURYL SULFATE  
TALC  
TRIETHYL CITRATE  
GELATIN  
FD&C BLUE NO. 2  
FERRIC OXIDE YELLOW  
TITANIUM DIOXIDE  
Product Characteristics
Color YELLOW (YELLOW) , BLUE (BLUE) Score no score
Shape CAPSULE (CAPSULE) Size 23mm
Flavor Imprint Code SPD417;300;mg
Contains     
Packaging
# Item Code Package Description Multilevel Packaging
1 NDC:30698-423-12 120 CAPSULE, EXTENDED RELEASE ( CAPSULE) in 1 BOTTLE None

Marketing Information
Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date
NDA NDA021710 12/10/2004

Labeler - Validus Pharmaceuticals LLC (801194619)
Establishment
Name Address ID/FEI Operations
Shire US Manufacturing Inc. 964907406 MANUFACTURE
Establishment
Name Address ID/FEI Operations
DSM Pharmaceuticals, Inc. 076301910 MANUFACTURE

Revised: 10/2010 Validus Pharmaceuticals LLC



Source: http://dailymed.nlm.nih.gov
Reproduced with permission of U.S. National Library of Medicine


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Prescription Marketed Drugs Alphabetically
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Categories:
Prescription(RX) Drugs
Over-the-counter (OTC) Drugs
Homeopathic Drugs
Animal Drugs
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