Carbamazepine XR

EQUETRO (carbamazepine) is a mood stabilizer 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. The chemical name of carbamazepine is 5H-dibenz[b,f]azepine-5-carboxamide, and the 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, 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.

Mechanism Of Action

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

Pharmacokinetics

Absorption

Following a single 200 mg oral extended-release dose of carbamazepine, peak plasma concentration was 1.9 ± 0.3 mcg/mL and the time to reach the peak was 19 ± 7 hours. Following repeat dose administration (800 mg every 12 hours), the peak levels were 11.0 ± 2.5 mcg/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.

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 mcg/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 mcg/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 mcg.hr/mL and 1.5 mcg/mL at 800 mg/day to 32.6 mcg.hr/mL and 3.2 mcg/mL at 1600 mg/day, respectively, and were less than 30% those of carbamazepine. Carbamazepine-10,11-epoxide is 50% bound to plasma proteins.

Food Effect

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 mcg/mL) but not the extent (AUC) of absorption. The elimination half-life remained unchanged between fed and fasting state. The multiple-dose study conducted in the fed state showed that the steady-state Cmax values were within the therapeutic concentration range. The pharmacokinetic profile of extended-release carbamazepine was similar when given by sprinkling the beads over applesauce compared to the intact capsule administered in the fasted state.

Elimination

After oral administration of 14C-carbamazepine, 72% of the administered radioactivity was found in the urine and 28% was found in the feces. This urinary radioactivity was composed largely of hydroxylated and conjugated metabolites, with only 3% of unchanged carbamazepine

In vitro data indicate carbamazepine is metabolized mainly by cytochrome P450 (CYP) 3A4 to the active carbamazepine-10,11-epoxide, which is further metabolized to the trans-diol by epoxide hydrolase. Human microsomal epoxide hydrolase has been identified as the enzyme responsible for the formation of the 10,11-transdiol derivative from carbamazepine-10,11-epoxide.

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

The effect of hepatic impairment on the pharmacokinetics of carbamazepine is not known. Consider reducing the dosage in patients with hepatic impairment.

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.

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

Clinical Studies

The efficacy of EQUETRO in the acute treatment of manic or mixed symptoms associated with bipolar I disorder was established in two 3-week, multicenter, randomized, double-blind, placebo-controlled, flexible-dose studies (Studies 1 and 2) in adult patients who met the DSM-IV criteria for bipolar I disorder, manic or mixed episode. In both studies, patients must have had a history of at least one previous manic or mixed episode. They must have had a Young Mania Rating Scale (YMRS) baseline score of at least 20. The YMRS is an 11-item instrument, ranging from 0 to 60 (greater score indicates a more severe manic disorder) that measures symptoms associated with a manic state: elevated mood, increased motor activity/energy, sexual interest, sleep, irritability, speech, language-thought disorder, content, disruptive/aggressive behavior, appearance, and insight.

In Studies 1 and 2, patients were hospitalized for at least one week. They received placebo during a 5-day lead-in period and subsequently were randomized to receive placebo or EQUETRO, initially at a dose of 200 mg twice daily (400 mg per day). If tolerated, the total daily dose could be increased by 200 mg once daily to a maximum dose of 800 mg twice daily (1600 mg/day). The mean EQUETRO dose during the last week was 952 mg/day in Study 1 and 726 mg/day in Study 2.

Patients were permitted to receive lorazepam for agitation or insomnia (up to 6 mg/day during the placebo-lead in period, up to 4 mg/day during the first week of controlled treatment, and up to 2 mg/day during the second week of treatment; no lorazepam was permitted during the third week of treatment. They were permitted to continue their routine psychotherapy. Patients were not allowed to use antipsychotics, lithium, antidepressants, or sedatives/hypnotics (other than lorazepam) during the studies. There were no significant differences in lorazepam use between the EQUETRO and placebo groups in both studies.

In Studies 1 and 2, the primary endpoint was the mean change from baseline in the YMRS total score at Day 21. In both studies, treatment with EQUETRO was statistically significantly superior to placebo, as measured by the mean decrease in YMRS score at Day 21 (Table 3)

The key secondary efficacy endpoint in both trials was the change in Clinical Global Impression-Severity (CGI-S) Scale score. The CGI-S an investigator-rated global assessment of symptom severity that is scored on a 7-point scale (1 = normal, not ill); 7 = severely ill). In both studies, there was a statistically significant decrease from baseline in the mean CGI-S score at Day 21, compared to placebo (Table 3).

Table 3.Efficacy Results in the 2 Trials in Patients with Bipolar I Disorder – Change in mean YMRS score from baseline to Week 3 and change in mean CGI-S from baseline to Week 3

Evidence supporting efficacy of carbamazepine as an anticonvulsant was derived from active drug-controlled studies that enrolled patients with the following seizure types:

1. Partial seizures with complex symptomatology (psychomotor, temporal lobe). Patients with these seizures appear to show greater improvements than those with other types.
2. Generalized tonic-clonic seizures (grand mal).
3. Mixed seizure patterns which include the above, or other partial or generalized seizures.

Absence seizures (petit mal) do not appear to be controlled by carbamazepine.

EQUETRO
(e-kwe-tro)
(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.

If you have any of the problems listed below call your healthcare provider right away.

EQUETRO can cause serious side effects, including:

1. EQUETRO may cause rare but serious rashes that may lead to death. These serious skin reactions are more likely to happen within the first four months after you start taking EQUETRO, but may occur at later times. These reactions can happen to anyone, but are more likely in people of Asian descent. If you are of Asian descent, you may need a genetic blood test before you take EQUETRO to see if you are at higher risk for serious skin reactions with this medicine. Symptoms may include:
   • skin rash
   • hives
   • sores in your mouth
   • blistering or peeling of the skin
2. EQUETRO may cause rare but serious blood problems. Symptoms may include:
   • fever
   • shortness of breath
   • fatigue
   • easy bruising
   • red or purple spots on your body
   • unusual bleeding such as bleeding gums, nose bleeds, or heavy menstrual bleeding
   • swollen glands and sore throat
3. EQUETRO may cause a serious or life-threatening allergic reaction that may affect your skin or other parts of your body such as your liver or blood cells. You may or may not have rash with these types of reactions. Call a healthcare provider right away if you have any of the following symptoms:
   • skin rash
   • hives
   • fever
   • swollen glands that do not go away
   • swelling of your lips or tongue
   • yellowing of your skin or eyes
   • unusual bruising or bleeding
   • severe fatigue or weakness
   • unexpected, severe muscle pain
   • frequent infections

These symptoms may be the first signs of a serious reaction. A healthcare provider should examine you to decide if you should continue taking EQUETRO.

4. EQUETRO may cause suicidal thoughts or actions in a very small number of people, about 1 in 500.
   Call your healthcare provider right away if you have any of these symptoms, especially if they are new, worse, or worry you:
   • thoughts about suicide or dying
   • attempts to commit suicide
   • new or worse depression
   • new or worse anxiety
   • feeling agitated or restless
   • panic attacks
   • trouble sleeping (insomnia)
   • new or worse irritability
   • acting aggressive, being angry, or violent
   • acting on dangerous impulses
   • an extreme increase in activity or talking (mania)
   • other unusual changes in behavior or 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 healthcare provider before stopping.

Suicidal thoughts or actions can be caused by things other than medicines. If you have suicidal thoughts or actions, your healthcare provider may check for other causes.

What is EQUETRO?

EQUETRO is a prescription medicine used to treat people with:

• acute manic or mixed episodes that happen with Bipolar I Disorder
• certain types of nerve pain (trigeminal neuralgia and glossopharyngeal neuralgia)
• certain types of seizures (partial, tonic-clonic, mixed)

EQUETRO is not a regular pain medicine and should not be used for aches or pains.

EQUETRO should not be used to treat people with absence seizures (petit mal).

It is not known if EQUETRO is safe and effective in children and adolescents for the treatment of Bipolar I Disorder and nerve pain.

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). Ask your healthcare provider or pharmacist for a list of these medicines if you are not sure.
• are taking delaviridine or other medicines called reverse transcriptase inhibitors. Ask your healthcare provider or pharmacist for a list of these medicines if you are not sure.
• have taken a medicine called 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 have had suicidal thoughts or actions, depression or mood problems
• have or ever had heart problems
• have or ever had blood problems
• have or ever had liver problems
• have or ever had kidney problems
• have or ever had allergic reactions to medicines
• have or ever had increased pressure in your eye
• have any other medical conditions
• drink grapefruit juice or eat grapefruit
• use birth control. EQUETRO may make your birth control less effective. Tell your healthcare provider if your menstrual bleeding changes while you take birth control and EQUETRO.
• are pregnant or plan to become pregnant. EQUETRO may harm your unborn baby. Tell your healthcare provider right away if you become pregnant while taking EQUETRO. You and your healthcare provider will decide if you should take EQUETRO while you are pregnant.
  • If you become pregnant while taking EQUETRO, talk to your healthcare provider about registering with the North American Antiepileptic Drug (NAAED) Pregnancy Registry. The purpose of this registry is to collect information about the safety of antiepileptic medicines during pregnancy. EQUETRO is also an antiepileptic drug. You can enroll in this registry by calling 1-888-233-2334.
• are breastfeeding or plan to breastfeed. EQUETRO can pass into breast milk. You and your healthcare provider should decide if you will take EQUETRO or breastfeed. You should not do both.

Tell your healthcare provider about all the medicines you take, including prescription and non-prescription medicines, vitamins, and herbal supplements.

Taking EQUETRO with certain other medicines may cause side effects or affect how well they work. Do not stop or start other medicines without talking to your healthcare provider.

Know the medicines you take. Keep a list of them and show it to your healthcare provider and pharmacist when you get a new medicine.

How should I take EQUETRO?

• Do not stop taking EQUETRO without first talking to your healthcare provider. Stopping EQUETRO suddenly can cause serious problems.
• Take EQUETRO exactly as prescribed. Your healthcare provider will tell you how much EQUETRO to take.
• Your healthcare provider may change your dose. Do not change your dose of EQUETRO without talking to your healthcare provider.
• Swallow EQUETRO capsules whole. Do not crush or chew.
  • If you cannot swallow EQUETRO capsules whole, you may open the EQUETRO capsules and sprinkle the beads over food such as a teaspoon of applesauce and swallow the mixture. Do not crush or chew the beads.
• Take EQUETRO with or without food.
• If you take too much EQUETRO, call your healthcare provider or local Poison Control Center right away.

What should 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 serious side effects, including:

• Seizure risk. Stopping EQUTERO suddenly may cause you to have a seizure. The risk of seizures may be higher in people who already have seizures. Do not stop taking EQUETRO without first talking with your healthcare provider.
• Low level of sodium in your blood (hyponatremia). Symptoms of hyponatremia may include:
  • headache
  • new seizures or an increased number of seizures
  • difficulty concentrating
  • memory problems
  • confusion
  • weakness
  • balance problems
• Problems with judgment, thinking, and movement.
• Liver problems. Symptoms of liver problems may include:
  • yellowing of your skin or the whites of your eyes
  • dark urine
  • pain on the right side of your stomach area (abdominal pain)
  • easy bruising
  • loss of appetite
  • nausea or vomiting

Get medical help right away if you have any of the symptoms listed above or listed in “What is the most important information I should know about EQUETRO?”

The most common side effects of EQUETRO include:

• dizziness
• drowsiness
• nausea
• vomiting
• problems with walking and coordination (unsteadiness)
• constipation
• itching
• dry mouth
• weakness
• blurred vision
• problems speaking

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 68°F to 77°F (20°C to 25°C).
• Keep EQUETRO capsules out of the light.
• Keep EQUETRO capsules dry.

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

General Information about the safe and effective use of EQUETRO.

Medicines are sometimes prescribed for purposes other than those listed in 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 healthcare provider. You can ask your pharmacist or healthcare provider for information about EQUETRO that is written for health professionals.

For more information, go to www.EQUETRO.com or call 1-866-982-5438.

What are the ingredients in 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.

• 100mg capsule shell contains: gelatin-NF, FD&C Blue #2, Yellow Iron Oxide, and Titanium Dioxide, and are imprinted with white ink.
• 200mg capsule shell contains: gelatin-NF, Yellow Iron Oxide, FD&C Blue #2, and Titanium Dioxide, and are imprinted with white ink.
• 300mg capsule shell contains: gelatin-NF, FD&C Blue #2, Yellow Iron Oxide, and Titanium Dioxide, and are imprinted with white ink.

This Medication Guide has been approved by the U. S. Food and Drug Administration.

You should not take carbamazepine if you have a history of bone marrow suppression, or if you are allergic to carbamazepine or to an antidepressant such as amitriptyline, desipramine, doxepin, imipramine, or nortriptyline.

Do not use carbamazepine if you have taken an MAO inhibitor in the past 14 days. A dangerous drug interaction could occur. MAO inhibitors include furazolidone, isocarboxazid, linezolid, phenelzine, rasagiline, selegiline, and tranylcypromine.

Carbamazepine may cause severe or life-threatening skin rash, and especially in people of Asian ancestry. Your doctor may recommend a blood test before you start the medication to determine your risk.

To make sure carbamazepine is safe for you, tell your doctor if you have any of these conditions:

• heart disease, high blood pressure, high cholesterol or triglycerides;
• liver or kidney disease;
• glaucoma;
• a thyroid disorder;
• lupus;
• porphyria; or
• a history of mental illness, psychosis, or suicidal thoughts or actions.

You may have thoughts about suicide while taking carbamazepine. Tell your doctor if you have symptoms of depression or suicidal thoughts. Your family or other caregivers should also be alert to changes in your mood or symptoms.

FDA pregnancy category D. Do not start or stop taking carbamazepine during pregnancy without your doctor's advice. Carbamazepine may cause harm to an unborn baby, but having a seizure during pregnancy could harm both mother and baby. Tell your doctor right away if you become pregnant while taking carbamazepine for seizures.

Carbamazepine can make birth control pills or implants less effective. Use a barrier form of birth control (such as a condom or diaphragm with spermicide) to prevent pregnancy while taking carbamazepine.

Carbamazepine can pass into breast milk and may harm a nursing baby. You should not breast-feed while you are using carbamazepine.

This medication may impair your thinking or reactions. Be careful if you drive or do anything that requires you to be alert.

Drinking alcohol can increase some of the side effects of carbamazepine, and can also increase your risk of seizures.

Avoid exposure to sunlight or tanning beds. Carbamazepine can make you sunburn more easily. Wear protective clothing and use sunscreen (SPF 30 or higher) when you are outdoors.

Grapefruit and grapefruit juice may interact with carbamazepine and lead to unwanted side effects. Discuss the use of grapefruit products with your doctor.

• Bipolar Disorder
• Chronic Pain
• Depression
• Restless Leg Syndrome
• Seizure (Epilepsy)
• Trigeminal Neuralgia