Carbamazepine - Indication, Dosage, Precautions, and Pharmacological Aspects

Overview:

Carbamazepine is a medication used to control seizures, nerve pain, and bipolar disorder. It works by reducing abnormal nerve activity in the brain. It was approved by the FDA (Food and Drug Administration) in 1965. However, it can cause severe allergic reactions like Stevens-Johnson syndrome (skin and mucous membrane disorder) or toxic epidermal necrolysis (skin disorder - blisters and skin peel). A genetic test may be done before prescribing to assess the risk. Contact the doctor immediately if a person notices a painful rash, blistering, or other serious skin issues. Additionally, Carbamazepine may lower blood cell production, leading to potential health problems, so inform the doctor if the person has had blood disorders in the past. Watch for signs of infection or unusual bleeding while taking this medication.

Drug Group:

Carbamazepine is a medication for seizures and nerve pain. It is an anticonvulsant drug. It comes in chewable and regular tablets, as well as extended-release (XR) tablets and a liquid form.

• Physical Appearance - The active ingredient is a white powder.

• Solubility - Does not dissolve well in water but does in alcohol and acetone.

• Components - The drug's inactive components vary by formulation and may include flavorings, colorings, and binders. The suspension has citric acid, flavorings, and other substances. Carbamazepine tablets contain compounds like cellulose, iron oxides, and more.

• Molecular Weight - 236.27. and has various inactive ingredients depending on the form.

Available Doses and Dosage Forms:

Carbamazepine dosage should be tailored to individual patient needs, with monitoring of blood levels for optimal efficacy and safety. Carbamazepine suspension should not be administered simultaneously with other liquid medications due to potential precipitation formation. Starting with low doses and gradually increasing helps minimize unwanted side effects.

• Epilepsy: For epilepsy in adults, an initial dose is 200 mg b.i.d. (twice a day) for tablets or XR tablets or one teaspoon q.i.d. (four times a day) for suspension. The maintenance dose is usually 800 to 1200 mg (milligrams) daily. In children (six to 12 years) with epilepsy, initial doses are 100 mg b.i.d. for tablets or XR tablets or half teaspoon q.i.d. for suspension, with maintenance dose typically at 400 to 800 mg daily.

Carbamazepine-XR is an extended-release formulation for twice-a-day administration. Conversion from tablets to suspension involves administering the same total daily mg dose in smaller, more frequent doses. Tablets must be swallowed whole, and Carbamazepine-XR tablets should not be crushed or chewed. Regular attempts should be made to reduce the dose to the minimum effective level or discontinue the drug. Dosage adjustments may be necessary when combining Carbamazepine with other anticonvulsants.

For Patients:

What Is Epilepsy?

Epilepsy is a long-term brain condition that causes recurrent seizures, which are short episodes of involuntary movements involving either part or the whole body. These episodes can include loss of consciousness and control over bowel or bladder function. Seizures happen when groups of brain cells release too much electrical activity. Different areas of the brain can be involved, leading to varying types and severity of seizures. They can range from momentary lapses of attention or muscle twitches to more severe and prolonged convulsions. The frequency of seizures varies from less than one per year to several per day. Experiencing one seizure does not necessarily mean a person has epilepsy, as up to 10 percent of people worldwide may have one seizure in their lifetime. Epilepsy is diagnosed when a person has two or more unprovoked seizures.

What Is the Dosage of Carbamazepine?

Carbamazepine comes in different forms, such as tablets, chewable, extended-release capsules, oral suspension, and IV (intravenous) solutions. It is used for epilepsy to treat various types of seizures. The typical daily dose is 800 to 1200 mg, but it can go up to 1600 mg in rare cases. For trigeminal neuralgia, it is used to relieve pain with a maintenance dose of 400 to 800 mg per day. In bipolar disorder, it is used with an initial dose of 200 mg twice a day, increasing as needed but not exceeding 1600 mg per day.

How Effective Is Carbamazepine?

Carbamazepine is a medication used by itself or with other drugs to manage specific types of seizures in individuals with epilepsy. It is also employed in treating trigeminal neuralgia, a condition causing facial nerve pain. In some cases, Carbamazepine extended-release capsules are utilized to address episodes of mania or mixed episodes in patients with bipolar I disorder. This disorder involves episodes of depression, mania, and other unusual moods. Carbamazepine falls under the category of drugs known as anticonvulsants, and its function involves reducing abnormal electrical activity in the brain.

What Are the Things to Inform the Doctor Before Taking the Carbamazepine?

• Avoid Carbamazepine if a person has bone marrow problems or is allergic to it or specific antidepressants.

• Do not use it if a person has taken MAO (monoamine oxidase) inhibitors in the last 14 days.

• Consider a blood test before starting due to the risk of a severe skin rash.

• Inform the doctor about any history of heart issues, liver or kidney disease, glaucoma (nerve damage leading to vision loss), porphyria (buildup of porphyrins, essential for red blood cells to produce hemoglobin), low sodium, depression, or suicidal thoughts.

• Regular check-ups are essential to monitor mood changes or suicidal thoughts.

• Consult the doctor before adjusting seizure medication during pregnancy to assess potential risks to the baby.

• If pregnant, notify the doctor immediately.

• Carbamazepine can reduce the effectiveness of birth control; use additional barrier methods.

• Avoid breastfeeding while using Carbamazepine.

How Is Carbamazepine Administered?

Carbamazepine comes in different forms, such as regular tablets, extended-release tablets, suspensions, and solutions. The extended-release tablets should not be crushed or chewed. Carbamazepine and Carbamazepine XR should be taken with food, while Carbatrol capsules can be opened and sprinkled on food. Adults typically start with 200 mg twice a day, gradually increasing to find the right dose. For epilepsy, the effective dose for adults and children over 12 is usually between 800 mg and 1200 mg daily. In children aged six to 12, the effective dose for epilepsy treatment is usually between 400 mg and 800 mg daily.

What Are the Side Effects of Carbamazepine?

• Carbamazepine can cause severe adverse reactions, particularly in the bone marrow, skin, liver, and cardiovascular system.

• Common side effects during initial therapy include dizziness, drowsiness, nausea, vomiting, and unsteadiness.

• Serious reactions may include issues with blood cells, skin conditions like Stevens-Johnson syndrome, and liver problems.

• Cardiovascular complications, including heart failure and arrhythmias, have been reported, sometimes resulting in fatalities.

• Liver abnormalities, pancreatitis, and respiratory issues like pneumonitis have been observed.

• Genitourinary complications include urinary problems, kidney issues, and testicular atrophy.

• Neurological side effects involve disturbances in coordination, confusion, headache, and visual disturbances.

• Digestive system issues include nausea, vomiting, abdominal pain, and dryness of the mouth.

• Eye problems like lens opacities and conjunctivitis, as well as musculoskeletal discomfort, may occur.

• Metabolic reactions include fever, chills, and inappropriate antidiuretic hormone secretion.

• Multiorgan hypersensitivity reactions have been reported, affecting various organs and manifesting in different ways.

• Lupus erythematosus (immune system attacks the body, causes inflammation and damage), like syndrome, and aseptic meningitis (swelling of brain and spinal cord coverings) are rare but reported complications associated with Carbamazepine use.

Dietary Considerations:

• Drinking alcohol while taking this medication can result in side effects and may also raise the risk of seizures.

• Consuming grapefruit or grapefruit products may interact with Carbamazepine, causing undesirable effects. It is advisable to avoid grapefruit when using this medication.

• Until a person understands how this medication affects them, they should refrain from activities like driving or other tasks that demand alertness, as it may impair their reactions.

• Carbamazepine might increase sensitivity to sunlight, making the individual more prone to sunburn. To protect oneself, avoid prolonged sun exposure, tanning beds, and wear protective clothing along with sunscreen (SPF 30 or higher) when outdoors.

Missed Dose:

If it is almost time for the next dose, skip the missed one, and one should take the medication as soon as one remember. Never take two doses at once.

Overdose:

Severe sleepiness, shallow or weak breathing, and loss of consciousness are some of the symptoms of an overdose.

Storage:

• Store this medication in its original container, tightly sealed, and away from children.

• Keep it at room temperature, avoiding exposure to light, excessive heat, and moisture (not in the bathroom).

• To safeguard children from accidental ingestion, always store medications out of their sight and reach.

• Make use of child-resistant containers and lock safety caps. Place medications in a secure location, and do not leave them where children can easily access them.

• For proper disposal, do not flush the medication down the toilet. Instead, inquire about medicine take-back programs from the pharmacist or local waste management.

For Doctors:

Indication:

• Carbamazepine is prescribed as an anticonvulsant for epilepsy based on evidence from controlled studies.

• Effective for partial seizures with complex symptomatology (psychomotor, temporal lobe), showing greater improvement.

• Indicated for generalized tonic-clonic seizures (grand mal) and mixed seizure patterns, excluding absence seizures (petit mal).

• Carbamazepine is recommended for treating pain associated with true trigeminal neuralgia.

• Positive outcomes are reported in glossopharyngeal neuralgia.

• Carbamazepine is not a simple analgesic and should not be used for minor pain relief.

Dosing Considerations:

• Immediate-Release (IR) and Extended-Release (ER) Dosage:

• IR Initial Dose: 200 mg orally twice daily for tablets, 100 mg orally four times daily for oral suspension.

• ER Initial Dose: 200 mg orally twice daily.

Dose adjustments are made in weekly increments of up to 200 mg daily (IR) or 400 mg daily (ER) until optimal response. The maintenance dose is 800 to 1200 mg daily for both IR and ER. The maximum dose is 1600 mg daily for both IR and ER. Switching from IR to ER is the same total daily dose, divided twice daily. Switching to oral suspension is the same total daily dose, with increased frequency to three or four times a day. Coadministration with other antiepileptic drugs by gradual addition to existing therapy; monitor closely.

Pediatric Epilepsy:

• Less Than Six Years: Initial dose 10 to 20 mg/kg/day (milligram per kilogram per day), increase weekly to a maximum of 35 mg/kg/day.

• Six to 12 Years: Initial dose 100 mg twice daily for tablets, 100 mg four times daily for oral suspension; increase weekly to a maximum of 1000 mg daily.

• Over 12 Years: Initial dose 200 mg twice daily for tablets, 100 mg four times daily for oral suspension; increase weekly to a maximum of 1000 mg daily (12 to 15 years) or 1200 mg daily (over 15 years).

Renal and Liver Considerations:

Adjusting the renal dose should be done with caution. Starting with lower dosages are advised for oral suspension; liver dose modifications should be done cautiously.

What Are the Pharmacological Aspects of Carbamazepine?

• Pharmacodynamics: Carbamazepine exerts its therapeutic effects by inhibiting sodium channels, effectively treating seizures, and alleviating symptoms of trigeminal neuralgia. In cases of bipolar 1 disorder, it has demonstrated a clinically significant reduction in mania symptoms based on the Young Mania Rating Scale (YMRS). It is important to note that Carbamazepine operates within a narrow therapeutic index. Regarding genetic factors, studies involving patients of Han Chinese ancestry revealed a notable correlation between the HLA (human leukocyte antigen)-B*1502 genotype and the occurrence of Steven Johnson syndrome or toxic epidermal necrolysis (SJS/TEN) as adverse reactions to Carbamazepine use.

• Mechanism of Action: Carbamazepine exerts its effects by modulating voltage-gated sodium channels (VGSC), resulting in the inhibition of action potentials and reduced synaptic transmission. Similar to other anticonvulsant medications, Carbamazepine is believed to interact with the alpha subunit of VGSC, specifically within a binding pocket formed by the external pore loop and the pore-lining region of domain IV. This interaction is thought to maintain sodium channels in inactivated states, reducing their availability for opening and thereby suppressing the generation of action potentials. Additionally, Carbamazepine binds to various voltage-gated ion channels, including voltage-gated calcium channels.Carbamazepine exhibits anticonvulsant effects in rodents with electrically and chemically induced seizures, likely through the reduction of polysynaptic responses and inhibition of post-tetanic potentiation. It effectively mitigates or eliminates pain resulting from infraorbital nerve stimulation in cats and rats, affecting thalamic potential and various reflexes. Carbamazepine’s mechanism of action, although unclear, distinguishes it chemically from other anticonvulsants and pain-controlling drugs for trigeminal neuralgia. The primary metabolite, Carbamazepine-10,11-epoxide, demonstrates anticonvulsant activity in animal models, yet its clinical relevance to Carbamazepine’s safety and efficacy remains undetermined.

• Pharmacokinetics: Carbamazepine suspension, conventional tablets, and XR tablets demonstrated comparable systemic drug delivery. The suspension exhibited slightly faster absorption, while the XR tablet had a slightly slower absorption rate compared to the conventional tablet. The bioavailability of the XR tablet was 89 percent about the suspension. When administered twice daily, the suspension resulted in higher peak levels and lower trough levels than the conventional tablet. However, when given thrice daily, Carbamazepine suspension maintained steady-state plasma levels comparable to the conventional tablet at the same daily dosage. Carbamazepine XR tablets, with a twice-daily regimen, achieved plasma levels similar to conventional Carbamazepine tablets given four times a day at the same total daily dose. Carbamazepine is approximately 76 percent bound to plasma proteins. Plasma levels vary widely from 0.5 to 25 µg/mL (microgram per milliliter ), with no clear correlation to daily intake. Common therapeutic levels in adults range from four to 12 µg/mL. Carbamazepine induces its metabolism, resulting in variable half-life values, ranging from 25 to 65 hours initially and decreasing to 12 to 17 hours with repeated doses. Metabolism primarily occurs in the liver, with cytochrome P450 3A4 identified as the major isoform responsible for Carbamazepine-10,11-epoxide formation. After oral administration, 72 percent of the administered radioactivity is found in urine, with only three percent unchanged Carbamazepine. Pharmacokinetic parameters are similar in children and adults, but there is a poor correlation between Carbamazepine plasma concentrations and Carbamazepine dose in children. In children under 15, Carbamazepine is more rapidly metabolized to Carbamazepine-10,11-epoxide. The impact of race and gender on Carbamazepine pharmacokinetics is yet to be systematically assessed.

Toxicity:

In adults, Carbamazepine doses exceeding 24 grams have been associated with fatal outcomes. Acute toxicity manifests one to three hours after ingestion, displaying neuromuscular disturbances. Symptoms include impaired consciousness leading to coma, tremors, restlessness, athetoid movements, psychomotor disturbances, dizziness, drowsiness, mydriasis, and nystagmus. Initially, hyperreflexia is observed, but it progresses to hyporeflexia during intoxication. Cardiac and vascular signs are generally mild at low toxicity levels, but doses exceeding 60 grams can result in severe cardiac dysfunction. Acute toxicity may lead to respiratory depression, ECG (electrocardiogram) abnormalities, tachycardia, shock, and urinary retention, necessitating monitoring and management to prevent organ damage. Overdose treatment focuses on eliminating the drug through measures like inducing vomiting, gastric lavage, activated charcoal, and forced diuresis. Gastric lavage is recommended even after four hours of ingestion. Seizures resulting from Carbamazepine poisoning should be managed with benzodiazepines such as diazepam.

What Are the Contraindications of Carbamazepine?

• Carbamazepine is contraindicated in patients with a history of prior bone marrow depression, hypersensitivity to the drug, or known sensitivity to tricyclic compounds such as amitriptyline, desipramine, imipramine, protriptyline, nortriptyline, etc.

• Theoretical considerations discourage its use with monoamine oxidase inhibitors (MAOIs). Before Carbamazepine administration, discontinuation of MAOIs is recommended for a minimum of 14 days, or longer if the clinical situation allows.

• Coadministration of Carbamazepine and Nefazodone may lead to insufficient plasma concentrations of Nefazodone and its active metabolite, preventing therapeutic effectiveness. Therefore, concurrent use of Carbamazepine and Nefazodone is contraindicated.

Warnings and Precautions:

• Skin Reactions: Rarely, Carbamazepine may cause severe skin reactions, more common in certain ethnic groups. A pre-treatment blood test assesses the risk, with immediate medical attention required for skin issues.

• Blood Disorders: Severe blood disorders are rare but monitored through regular blood counts. Prompt medical attention is crucial for signs like infection, weakness, or bleeding/bruising.

• Allergies and Medical History: Disclose allergies, and discuss medical history, especially related to various health conditions.

• Dizziness and Drowsiness: Carbamazepine can induce dizziness or drowsiness. Caution is advised for activities requiring alertness, and alcohol should be avoided.

• Sun Sensitivity: Increased sun sensitivity may occur, necessitating sun protection measures.

• Sugar Content: Chewable tablets or suspensions may contain sugar, requiring caution for those with dietary restrictions.

• Surgery: Inform healthcare providers of all used products before surgery.

• Seniors: Older adults may be more susceptible to certain side effects.

• Pregnancy and Breastfeeding: Pregnancy considerations involve careful weighing of benefits and risks. Reliable birth control methods should be discussed if needed. The medication passes into breast milk, requiring consultation before breastfeeding.

What Are the Drug Interactions of Carbamazepine?

• Interactions with other drugs can alter the effectiveness or increase the risk of severe side effects. It is crucial to maintain a comprehensive list of all medications, including prescription or nonprescription drugs and herbal products, and share it with healthcare professionals. Any adjustments to the dosage or initiation or cessation of medications should be done under the guidance of a doctor.

• Certain products may interact with this drug, including specific azole antifungals (Isavuconazonium, Voriconazole) and Orlistat. Combining this medication with MAO inhibitors (Isocarboxazid, Linezolid, Metaxalone, Methylene blue, Moclobemide, Phenelzine, Procarbazine, Rasagiline, Safinamide, Selegiline, Tranylcypromine) can result in a serious, potentially fatal drug interaction. The use of most MAO inhibitors should be avoided two weeks before or during treatment with this medication.

• Other medications can impact the elimination of Carbamazepine from the body, affecting its efficacy. Examples include macrolide antibiotics (such as Erythromycin), and Rifamycins. Carbamazepine may expedite the removal of various drugs, influencing their effectiveness. Examples of affected drugs include Artemether or Lumefantrine, certain anticoagulants, specific calcium channel blockers, Nefazodone, HIV NNRTIs (human immunodeficiency virus non-nucleoside and nucleoside reverse transcriptase inhibitors), Praziquantel, and Ranolazine, among others. This medication may diminish the efficacy of hormonal birth control methods, increasing the risk of pregnancy. Patients should discuss the use of reliable backup birth control methods with their doctor or pharmacist while taking this medication. Any new spotting or breakthrough bleeding should be reported, as they may indicate reduced efficacy of birth control.

• Inform the doctor or pharmacist if an individual is taking other products causing drowsiness, including alcohol, marijuana (cannabis), antihistamines, drugs for sleep or anxiety, muscle relaxants, and opioid pain relievers.

• Checking labels for drowsiness-inducing ingredients in all medicines, including allergy or cough-and-cold products, is advisable.

• It is important to note that this medication may interfere with specific lab tests (such as thyroid function and some pregnancy tests), potentially yielding false results. Healthcare professionals should be informed about the use of this drug during lab tests.

Specific Considerations:

• Pregnant: A pregnancy registry monitors outcomes for women using antiepileptic drugs during pregnancy. Women of childbearing age should use effective non hormonal contraception or barrier methods during treatment. The medication may cause fetal harm, leading to birth defects and developmental delays. Consideration should be given to discontinuing therapy in pregnant or attempting-to-conceive women if the benefits outweigh the risks. Abruptly stopping the medication in pregnant women with epilepsy can lead to life-threatening seizures. Neonatal symptoms such as seizures, respiratory issues, vomiting, diarrhea, and feeding problems have been reported. Routine tests for birth defects are advisable during pregnancy.

• Breastfeeding: Breastfeeding individuals should consider the benefits of breastfeeding along with potential effects on the infant and consult with their healthcare provider.

• Geriatric: Elderly individuals may require caution and a dose adjustment for Carbamazepine due to the increased risk of confusion, agitation, hyponatremia (low sodium in the blood), and age-related liver, renal, or cardiac problems.

• Children: When treating adults and children with partial and convulsive generalized epilepsy, Carbamazepine is a useful antiepileptic medication. Children's pharmacokinetic profiles are comparable to those of adults. However, long-term pediatric medication has a half-life of six to 12 hours as opposed to 15 hours for adults.