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Home , Porphyria

CARBAMAZEPINE

Dana Bartlett, RN, BSN, MSN, MA, CSPI

Dana Bartlett is a professional nurse and author. His clinical experience includes 16 years of ICU and ER experience and over 20 years of as a poison control center information specialist. Dana has published numerous CE and journal articles, written NCLEX material, written textbook chapters, and done editing and reviewing for publishers such as Elsevier, Lippincott, and Thieme. He has written widely on the subject of toxicology and was a contributing editor, toxicology section, for Critical Care Nurse journal. He is currently employed at the Rocky Mountain Poison Control Center.

ABSTRACT

Carbamazepine is an anti- medication that has other uses than for the treatment of epilepsy. Patients who are treated with carbamazepine are often prescribed other medications in combination depending on the primary symptoms being treated. For this reason, monitoring medications closely through laboratory testing and by patient observation is a necessary aspect of ongoing clinical care. Carbamazepine is considered effective as monotherapy and adjunctive therapy for symptom control by both and psychiatry medical sections.

1 nursece4less.com nursece4less.com nursece4less.com nursece4less.com Policy Statement

This activity has been planned and implemented in accordance with the policies of NurseCe4Less.com and the continuing nursing education requirements of the American Nurses Credentialing Center's Commission on Accreditation for registered nurses. It is the policy of NurseCe4Less.com to ensure objectivity, transparency, and best practice in clinical education for all continuing nursing education (CNE) activities.

Continuing Education Credit Designation

This educational activity is credited for 2.5 hours. Nurses may only claim credit commensurate with the credit awarded for completion of this course activity. Pharmacology content is 2.5 hours.

Statement of Learning Need

Carbamazepine is considered an effective medication for seizure control and to manage symptoms of a mood disorder, specifically for individuals diagnosed with . Its use as monotherapy or adjunctive therapy depends on a patient’s symptoms and tolerance of the medication. There are significant side effects that clinicians need to monitor for and educate patients about prior to starting treatment.

Course Purpose

To inform health clinicians of the indications, uses, contraindications and potential side effects of carbamazepine.

2 nursece4less.com nursece4less.com nursece4less.com nursece4less.com Target Audience

Advanced Practice Registered Nurses and Registered Nurses (Interdisciplinary Health Team Members, including Vocational Nurses and Medical Assistants may obtain a Certificate of Completion)

Course Author & Planning Team Conflict of Interest Disclosures

Dana Bartlett, RN, BSN, MSN, MA, CSPI, William S. Cook, PhD, Douglas Lawrence, MA, Susan DePasquale, MSN, FPMHNP-BC – All have no disclosures

Acknowledgement of Commercial Support

There is no commercial support for this course.

Please take time to complete a self-assessment of knowledge, on page 4, sample questions before reading the article. Opportunity to complete a self-assessment of knowledge learned will be provided at the end of the course.

3 nursece4less.com nursece4less.com nursece4less.com nursece4less.com 1. Carbamazepine is an anticonvulsant that has a labeled use for treatment of

a. critically ill patients who have neuropathic pain. b. bipolar 1 disorder. c. the neuropsychiatric symptoms of . d. restless legs syndrome.

2. The mechanism of action by which carbamazepine is effective for treating acute manic or mixed episodes in patients who have bipolar 1 disorder is

a. not known. b. by inhibition of sodium through sodium ion channels. c. through stabilization of neuronal membranes. d. by inhibiting HMG CoA reductase.

3. The usual 24-hour total dose for carbamazepine when treating an adult with epilepsy is

a. 400 mg. b. 600 mg – 800 mg. c. 200 mg. d. 800 mg – 1200 mg.

4. In geriatric patients, adult dosing of carbamazepine is appropriate but a clinician should be aware of the potential for , typically as part of

a. trigeminal or glossopharyngeal neuralgia. b. aplastic anemia. c. agranulocytosis. d. syndrome of inappropriate antidiuretic hormone (SIADH).

5. Carbamazepine use has been associated with folate and vitamin B2, B6, B12 deficiencies and these deficiencies may contribute to the development of ______, a risk factor for the development of cardiovascular disease.

a. trigeminal neuralgia b. hyperhomocysteinemia c. depression d. hyponatremia

4 nursece4less.com nursece4less.com nursece4less.com nursece4less.com Introduction

Carbamazepine is a first-generation anticonvulsant that has labeled uses for the treatment of specific types of epilepsy (partial and generalized ), bipolar disorder, and trigeminal or glossopharyngeal neuralgia. It has also been used as a mood stabilizer and for treatment of neuropathic pain syndromes. Carbamazepine inhibits neuron depolarization and decreases glutamate release. It is also anticholinergic. Carbamazepine in toxic or overdosing is known to antagonize adenosine receptors, resulting in a proconvulsant effect and seizure activity is commonly seen in carbamazepine toxicity.

Pharmacological Profile

This section includes an overview of the drug qualities of carbamazepine. Basic information on the pharmacology and the clinical uses of carbamazepine, drug-drug interactions, dosing recommendations and monitoring in special populations or in patients with comorbid conditions, and a detailed discussion of issues that are of practical interest to clinicians, is presented.

Category

Anticonvulsant, miscellaneous

Mechanism of Action

Carbamazepine stabilizes neuronal membranes by inhibition of the movement of sodium through sodium ion channels, and this prevents repetitive discharges from seizure foci and transmission of these impulses. Carbamazepine also has anticholinergic, antineuralgic, antidiuretic, muscle relaxant, antimanic, antidepressive, and antiarrhythmic properties.1 The mechanism of action by which carbamazepine is effective for treating

5 nursece4less.com nursece4less.com nursece4less.com nursece4less.com acute manic or mixed episodes in patients who have bipolar disorder is not known.2

Drug Uses

Bipolar Disorder:

Equetro is a brand name for a form of extended release carbamazepine. Equetro is the only form of carbamazepine that has a labeled use for treating acute manic or mixed episodes in patients who have bipolar disorder.

Epilepsy:

Carbamazepine has a labeled use for treating partial seizures with complex symptomatology (psychomotor, temporal lobe), generalized tonic-clonic seizures (grand mal), or mixed seizure patterns.1-3

Trigeminal or Glossopharyngeal Neuralgia:

Oral carbamazepine is used for the treatment of pain associated with trigeminal or glossopharyngeal neuralgia.1-3 This is a labeled use.

Carbamazepine has been used off-label to treat critically ill patients who have neuropathic pain, the neuropsychiatric symptoms of dementia, and restless legs syndrome.1

Dosing: Adult1

Bipolar Disorder:

6 nursece4less.com nursece4less.com nursece4less.com nursece4less.com A dose of 400 mg a day of Equetro in divided doses is given for bipolar disorder. Clinicians may increase the dose by 200 mg a day to a maximum daily dose of 1600 mg.

Epilepsy:

Begin with 400 mg a day in divided doses (two or four doses, tablets and suspension, respectively). Increase the dose once a week by 200 mg (again, twice a day with oral tablets, three-four times a day for the suspension). Increase the dose until the desired effect and therapeutic level have been achieved. The usual 24-hour total dose is 800 mg – 1200 mg; the maximum 24-hour total dose is 1600 mg.

The suspension will produce a higher peak serum level than an equal dose in oral tablet form, so smaller, more frequent doses are recommended for this form of the drug.3 Intravenous (IV) carbamazepine is used as a short-term replacement for oral carbamazepine. The IV formulation should not be used for > 7 days and the conversion to oral form should be done as soon as possible. The 24-hour daily dose of IV carbamazepine should be 70% of the oral dose, divided into 4 doses, one every 6 hours, and infused in over 30 minutes.

Trigeminal or Glossopharyngeal Neuralgia:

For trigeminal or glossopharyngeal neuralgia, begin with 200 mg a day in a single dose (extended-release capsule), two divided doses (tablet forms) or four doses (suspension). Increase the dose in increments of 200 mg a day, as needed. The extended-release capsule should be given in two divided doses if the 24-hour total dose exceeds 200 mg. The maintenance dose is usually 400 mg – 800 mg a day, two doses if using tablets and four doses if using the suspension. The 24-hour maximum dose is 1200 mg.

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Dosing: Geriatric

For geriatric patients, use the adult dosing but be aware of the potential for syndrome of inappropriate antidiuretic hormone (SIADH) or hyponatremia.1,2 of SIADH can include , , seizures, and weakness. Carbamazepine may activate latent , confusion, or agitation in elderly patients.1

Dosing Adjustment: Hepatic Impairment

There are no specific dosing recommendations for patients who have hepatic impairment but carbamazepine is primarily metabolized by the , and it would be prudent to use carbamazepine at a lower dose and monitor serum levels if the patient has hepatic impairment.1 There are other issues regarding carbamazepine and hepatic impairment, discussed below.

Dosing Adjustment: Renal Impairment

The prescribing information does not provide dosing recommendations for patients who have decreased renal function.

Available Forms

● Oral tablets: Generic, 200 mg; Brand name, Epitol 200 mg and Tegretol 200 mg.

● Oral chewable tablet: Generic, 100 mg.

● Oral tablet, extended release: Generic, 100 mg, 200 mg, 400 mg; Brand name, Tegretol XR, 100 mg, 200 mg, 400 mg.

● Oral capsules, extended release: Generic, 100 mg, 200 mg, 300 mg; brand name, Equetro 100 mg, 200 mg, 300 mg; brand name Carbatrol, 100 mg. 200 mg, 300 mg

8 nursece4less.com nursece4less.com nursece4less.com nursece4less.com ● Oral suspension: Generic, 5 mL/100 mg; brand name Tegretol, 5 mL/100 mg

Contraindications1

Contraindications include a hypersensitivity to carbamazepine or any of the components of the preparation, hypersensitivity to tricyclic , and bone marrow depression.

The concomitant use of a monoamine oxidase (MAO) inhibitor or within 14 days prior to administering carbamazepine should be avoided. The same is true of the concomitant use of carbamazepine with nefazodone, boceprevir, or delavirdine or other non-nucleoside reverse transcriptase inhibitors that are substrates of CYP3A4.

US Boxed Warning

Carbamazepine can cause serious and potentially fatal dermal adverse effects, Stevens-Johnson syndrome and toxic epidermal necrolysis (TEN). The risk of these adverse effects for patients of Asian ethnicity has been estimated to be 10 times higher than that of Caucasian patients.2 This increased risk has been associated with a specific variant of the HLA-B*1502 that is found almost exclusively in Asian populations. Patients from this at-risk population should be screened for the presence of HLA-B*1502 before starting therapy with carbamazepine. If the patient is positive, carbamazepine should not be given unless the benefits clearly outweigh the risks.

Aplastic anemia and agranulocytosis have also been reported to be associated with or caused by carbamazepine, the risk being five to eight times greater than in the general population. The risk for the general

9 nursece4less.com nursece4less.com nursece4less.com nursece4less.com population, however, is very low; six patients per 1 million population per year for agranulocytosis and two patients per 1 million population per year for aplastic anemia. Nonetheless, patients should have a complete count (CBC) done before therapy with carbamazepine is started, and periodic CBC measurements should be done. If there is evidence of bone marrow depression the patient may need to stop taking the drug.

Warnings

Carbamazepine should be used cautiously for patients who have combined generalized and focal seizure disorder (often called a mixed seizure disorder) that includes atypical absence seizures as the drug may increase the frequency of generalized seizures.

Anticholinergic Effects:

Carbamazepine has anticholinergic activity,2,4 and it should be used cautiously if the patient is taking other drugs that have anticholinergic properties or if the patients has glaucoma, urinary retention, or .1,2

Cardiovascular Disease:

Second and third-degree atrioventricular (AV) block has been associated with carbamazepine. This effect can occur in patients who have electrocardiogram (ECG) abnormalities and/or risk factors for a cardiac conduction abnormality but in may occur in patients who do not.1,2 In 2016, the American Heart Association (AHA) identified carbamazepine as a drug that may precipitate or exacerbate heart failure.5

Central :

10 nursece4less.com nursece4less.com nursece4less.com nursece4less.com Carbamazepine may cause central nervous system (CNS) depression.

Hepatic Effects:

The effects of carbamazepine on the liver are complex. Slight elevations of liver transaminases that resolve and do not reflect liver damage are common. Hepatic failure has been reported, as well, and this can occur in patients with or without underlying ; and as part of a hypersensitivity reaction called Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) syndrome, in association with Stevens- Johnson syndrome or TEN. In addition, there have been rare reports of carbamazepine causing a condition called vanishing bile duct syndrome and hepatic failure.2,6

Hepatic Porphyria:

Carbamazepine should be avoided if the patient has as it may cause acute porphyria attacks.1,2,7

Hyponatremia:

Carbamazepine can cause hyponatremia, typically as part of SIADH. The risk of developing hyponatremia and/or SIADH may be dose-related, due to age, and associated with concomitant use of a diuretic.1,2 Because of this potential adverse effect, the BEERS criteria has identified carbamazepine as a drug that is potentially inappropriate for elderly patients and one that should be used with caution in this patient population.8 Elderly Patients:

Ataxia and drowsiness are common adverse effects of carbamazepine. These increase the risk for falling, and consequently the BEERS criteria have

11 nursece4less.com nursece4less.com nursece4less.com nursece4less.com identified carbamazepine as a drug that is potentially inappropriate for elderly patients and to be used with caution in this patient population.8

Hypersensitivity Reactions:

The DRESS syndrome, Stevens-Johnson syndrome, and TEN may be caused by carbamazepine.1,2 People who have the HLA gene variants HLA-A*3101 or HLA-B*1502 and other HLA variants and take carbamazepine may be at an increased risk for developing these pathologies.1,2 The prevalence of these HLA variants is particularly high in certain ethnic populations, however not all patients who have these variants will develop DRESS, Stevens-Johnson or TEN;2 and Stevens-Johnson syndrome and TEN have developed in their absence, as well.

Psychiatric:

Carbamazepine may activate a latent psychosis.1 The antiepileptics have been associated with an increased risk for suicidal behavior and ideation, with an incidence rate of 0.43% versus 0.24% for placebo.1 Patients taking carbamazepine should be evaluated for their risk for suicide and monitored closely for depression and suicidal behavior and ideation.

Renal:

Renal toxicity caused by carbamazepine has been reported.1

Adverse Effects

The most common adverse effects of carbamazepine are ataxia, constipation, dizziness, drowsiness, , somnolence, and .1-3

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Drug Interactions

Before administering the first doses of carbamazepine or before administering the first dose of a drug to a patient who is taking carbamazepine, it is imperative to determine if a harmful drug-drug interaction is possible. There are many potential pitfalls to using carbamazepine with other medications. The levetiracetam, lamotrigine, , , and valproic acid can increase or decrease the serum concentration of carbamazepine.9

The Lexicomp Drug Interactions database lists 175 carbamazepine-drug interactions that are considered potentially serious and for which the benefits of concomitant use do not outweigh the risks, or for which concomitant use requires dosing adjustment and close patient monitoring. Included in those 175 interactions are commonly used drugs like doxycycline, oral contraceptives, rivaroxaban, tramadol, and zolpidem.9

Medications that are CYP3A4 inducers or inhibitors may affect the of drugs like carbamazepine that are substrates of CYP3A4; there are many commonly used medications that may cause these effects. Central nervous system depression is a common adverse effect of carbamazepine and of many other drugs.

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Cytochrome P450 System The CYP450 enzyme system is one of the primary ways that drugs are metabolized, and the activity of CYP450 can be decreased or increased; this is known as inhibition and induction. there are wide variations in the expression and function of these enzymes, aka the characteristic of polymorphism. These variations can take the form of increasing or inhibiting enzymatic activity – typically called inducing or inhibiting – thus significantly influencing the clinical response to a drug, and medications themselves can induce or inhibit a CYP450 enzyme.

Pregnancy and Breastfeeding

Carbamazepine is a pregnancy risk category D drug; studies have shown that when used during pregnancy it can cause fetal harm like cardiovascular malformations, craniofacial defects, hypospadias, and spina bifida. Carbamazepine may be used during pregnancy but only if the benefits outweigh the risks. The potential of a drug to cause fetal harm has been categorized by a system developed by the Food and Drug Administration (FDA). The system uses five categories, A, B, C, D, and X; A is the most benign and X is the most dangerous. This system has been replaced by the FDA’s Pregnancy and Lactation Labeling Rule (PLLR), and available online at: https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInfor mation/Guidances/UCM450636.pdf. It should be noted, however that the A- X system is still widely used.

Pregnancy can decrease carbamazepine levels during the second and third trimesters. In utero exposure to carbamazepine may cause developmental delays, but environmental factors may influence these effects.

14 nursece4less.com nursece4less.com nursece4less.com nursece4less.com Breastfeeding

The parent drug and the pharmacologically active metabolite of carbamazepine, carbamazepine-10,11-epoxide, are both excreted in breast milk. Carbamazepine has been detected in the serum of nursing infants whose mothers were taking the drug, and case studies have reported transient hepatic dysfunction and other adverse effects in nursing infants attributed to transfer of carbamazepine via breast milk.

The benefits and risks of using carbamazepine during breastfeeding should be determined on a case-by case basis and if the drug is used by a nursing mother, the infant should be closely observed for signs of toxicity.

Dietary Concerns

Carbamazepine use has been associated with folate and vitamin B2, B6, B12 deficiencies and these deficiencies may contribute to the development of hyperhomocysteinemia, a risk factor for the development of cardiovascular disease. Some clinicians recommend that patients who are taking carbamazepine should take folate and B vitamin supplements.1

Clinical Pearls: Carbamazepine

This section provides detailed information on issues that are of practical interest to clinicians. Many of the topics from the basic pharmacology section will be covered here.

Drug Uses

Bipolar Disorder:

Bipolar disorder may be characterized by hypomanic or manic episodes and may involve a depressive episode. Manic and hypomanic episodes are

15 nursece4less.com nursece4less.com nursece4less.com nursece4less.com distinguished by the duration and intensity of the symptoms, with manic episodes being more intense and with varied primary symptoms of psychosis. Patients who have bipolar disorder often have what are called mixed episodes, or cycling manic and depressive symptoms. In the current Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5), patients manifesting with mixed (manic-depressive) symptoms would be diagnosed as Bipolar disorder with mixed features.10

The efficacy of extended release carbamazepine as a treatment for acute in patients who have bipolar disorder was established in a randomized, double-blind, placebo-controlled study, and subsequent research and literature reviews has confirmed the acceptance and effectiveness of carbamazepine for this purpose.11-15 The evidence for the effectiveness of carbamazepine for treating mixed features has been positive, but there has only been a small number of randomized controlled trials that have investigated this issue.13,66

Epilepsy:

Carbamazepine has a labeled use for the treatment of partial seizures with complex symptomatology (psychomotor, temporal lobe), generalized tonic- clonic seizures (grand mal seizures), or mixed seizure patterns.1-3

A focal seizure (partial seizure or a localization seizure) is unlike a generalized seizure in that only part of the cerebral cortex is involved. Focal seizures can be divided into two types, focal seizures with retained awareness and focal seizures with impaired awareness (focal seizures with complex symptomatology).17 Focal seizures with complex symptomatology are characterized by a temporary impairment of consciousness that may include a pre-seizure aura, abnormal, repetitive, and stereotyped behavior,

16 nursece4less.com nursece4less.com nursece4less.com nursece4less.com amnesia, dystonic postures, no awareness of or response to environmental cues, staring, and occasionally loss of consciousness; tonic-clonic movements (convulsions) do not occur during a focal seizure.17,18 Some patients who have focal seizures (approximately one-third) will have a focal seizure that progresses to a bilateral convulsive seizure. These seizures can only be distinguished from a generalized tonic-clonic seizure by an electroencephalogram (EEG).19

Seizure terminology can be confusing as there are often several different terms that continue to be used to describe the same type of seizure. The prescribing information for carbamazepine uses the term partial seizures with complex symptomatology. However, focal seizure, not partial seizure is the current preferred term. Other terms are used to describe the type of focal seizure that is treated with carbamazepine, such as partial seizure with complex symptomatology, complex partial seizure, focal seizures with impaired awareness, and focal seizure with dyscognitive feature.

Carbamazepine is an established first-line drug for treating partial seizures with complex symptomatology, and its effectiveness compared to other antiepileptics has been established.19-24 For example, in patients with partial onset seizure, the time to first seizure and the six and 12-month remission rates were not significantly different for carbamazepine compared to phenytoin.22 Comparing carbamazepine to zonisamide, the percentage of patients who were seizure-free for ≥ 24 months was 35.2% and 32.3%, respectively, and in a comparative study of patients with partial onset seizures 71.1% treated with eslicarbazepine and 75.6% of patients treated with carbamazepine were seizure-free for

≥6 months.23,25

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A generalized tonic-clonic seizure is a type of general onset seizure, and these are seizures that involve the entire brain. Generalized tonic-clonic seizures can be caused by a wide variety of pathologies that may include drug intoxication or drug withdrawal, infection, metabolic disorders, and trauma, but generalized tonic-clonic seizures that require long-term anticonvulsant therapy are often caused by epilepsy. Epilepsy (the word epilepsy is derived from a Greek word epilepsia, which means seizing or taking hold of) is one of the most common neurologic diseases, and is characterized by transient and unpredictable disturbances in brain function

The pathogenesis of a tonic-clonic seizure is complex but its basis involves paroxysmal and abnormal electrical discharge from a seizure focus that overwhelms the resting state of the surrounding neurons in the cortex. A generalized tonic-clonic seizure, which is often called a grand mal seizure, is the most common type of generalized seizure. A generalized tonic-clonic seizure is characterized by the following characteristics:17

● Sudden loss of consciousness

● Tonic contractures of the muscles, most often in the arms, chest, and legs. Tonic contractures of the chest muscles prevent normal breathing during a grand mal seizure.

● Clonic movements, most often in the arms, chest, and the legs

● A period called the postictal period in which tonic and clonic movements stop and the patient is in a deep, unarousable sleep. The postictal period may last for minutes or hours. (The term ictal is defined as of or relating to a seizure).

● Agitation and/or confusion after the patient regains consciousness from the postictal period.

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Generalized tonic-clonic seizures often occurs unexpectedly, but identifiable stimuli can trigger a seizure and some people experience a warning called an aura, a sensory change in smell, taste or vision that they experience prior to a seizure.

Most generalized tonic-clonic seizures end in two to three minutes and the patient does not suffer harm. However, there are obvious risks associated with loss of consciousness, violent, uncontrolled muscle contractions, and interruption of normal breathing. A generalized tonic-clonic seizure may indicate the presence of a serious underlying pathology, and some generalized tonic-clonic seizures do not resolve spontaneously.

Carbamazepine has been successfully used to treat generalized tonic-clonic seizures.19,21 The research however is somewhat limited and there is no evidence that any of the antiepileptics offer a distinct advantage compared to the others for the treatment of tonic-clonic seizures .19

A concern exists that when carbamazepine is used to treat generalized tonic- clonic seizures it can increase the incidence of absence seizures and myoclonic seizures.19,26-28 This appears to be a rare occurrence and is not mentioned in the prescribing information. There is also insufficient evidence to determine if this adverse effect is an idiosyncratic reaction or a true risk.29-32

Oral carbamazepine is used for the treatment of pain associated with trigeminal or glossopharyngeal neuralgia.1-3 Trigeminal neuralgia is a rare, chronic neurologic condition that is characterized by brief, recurring episodes of pain in the cheek, eye, forehead gums, jaw, lips, or teeth. The painful

19 nursece4less.com nursece4less.com nursece4less.com nursece4less.com episodes are sudden in onset, typically last from a few seconds to one or two minutes, and they are often precipitated by tactile stimuli such as chewing, smiling, or talking. These attacks are almost always on one side, and rarely are they bilateral.33,34

Trigeminal neuralgia is caused by compression of the trigeminal nerve root, most often by a section of an artery or a vein that is pressing on the nerve.33 It is more common in women, it usually begins after age 50, and the duration, intensity, and frequency will often increase with time. For some patients the pain becomes constant.33,34

Carbamazepine is considered the first-choice drug for treating trigeminal neuralgia, and its effectiveness, defined by complete or almost complete relief of pain, has been reported as 58%-100%.33-35-37 Glossopharyngeal neuralgia is caused by irritation of the glossopharyngeal nerve, and it is very similar to trigeminal neuralgia in its signs, symptoms, and the pattern of the attacks.38 Treatment of glossopharyngeal neuralgia is the same as for trigeminal neuralgia, and carbamazepine is often used for pain relief.38,39

US Boxed Warning

Carbamazepine can cause serious and potentially fatal dermal adverse effects; Stevens-Johnson syndrome and toxic epidermal necrolysis (TEN). Drug-induced Stevens-Johnson syndrome and TEN are idiosyncratic, immune-mediated dermatologic pathologies that are characterized by necrosis and subsequent detachment of the epidermis. Stevens-Johnson syndrome and TEN are essentially the same, and they are distinguished only by the extent of dermal involvement; Stevens-Johnson syndrome is less severe than TEN.40,41 If the dermal involvement is <10% this indicates

20 nursece4less.com nursece4less.com nursece4less.com nursece4less.com Stevens-Johnson syndrome, >30% indicates TEN, and 10%-30% involvement is Stevens-Johnson Syndrome-Ten overlap.42,43 The onset of Stevens-Johnson syndrome and TEN almost always occurs in the first few weeks or months after the patient begins taking phenytoin 44 (rarely, the onset may be several months after initiation of therapy), and the duration of drug therapy and the dose do not seem to influence their occurrence. Non-specific signs and symptoms like conjunctival irritation, cough, , and malaise precede dermal involvement by several days or a week, and then the mucocutaneous lesions begin to develop.40,44-46 These lesions are typically on the mucosa of the eyes, genitals, and mouth and on the face, palms, soles, and the trunk.42 As the disease progresses the lesions worsen, epidermal necrosis and sloughing start to happen and in some cases the lungs, other areas of the respiratory tract, the liver, and the kidneys may be affected.46

The mortality rate for Stevens-Johnson syndrome has been estimated to be between 3%-10% and for TEN, 20%-40%.34 Genetic and immunologic factors may be the cause of Stevens-Johnson syndrome and TEN, but the pathogenesis is not completely understood.47

The risk of these adverse effects for patients of Asian ethnicity has been estimated to be 10 times higher than Caucasian patients. This increased risk for Asian patients has been associated with a specific variant of the HLA- B*1502 gene, found almost exclusively in Asian populations. It is recommended that patients from this at-risk population be screened for the presence of HLA-B*1502 before starting therapy with carbamazepine. If the patient is positive, carbamazepine should not be given unless the benefits clearly outweigh the risks.

21 nursece4less.com nursece4less.com nursece4less.com nursece4less.com A strong association has been consistently noted between the presence of specific HLA (human leukocyte antigen) gene variations and the development of carbamazepine-induced Stevens-Johnson syndrome and TEN, and these HLA variations are relatively common in certain ethnic groups; for example, the prevalence of the HLA-B*15:02 allele is 7%-10% in patients of Chinese and South Asian descent.40,48-51 A recent (2018) systematic review and meta-analysis noted that the HLA-B*15:02 polymorphism was significantly associated with serious cutaneous reactions to carbamazepine (OR, 27.325, 95% CI: 9.933-51.166), and “... the results reveal strong evidence that the HLA-B*15:02 polymorphism can induce SCRs (serious cutaneous reactions) among Asian CBZ users.”48

The HLA-B*1502 polymorphism is very uncommon in people of African- American, Caucasian, Hispanics and Native Americans descent.3 Not all patients who have these variants will develop Stevens-Johnson or TEN and Stevens-Johnson-syndrome and TEN have developed in their absence, as well.2

Aplastic Anemia and Agranulocytosis:

Aplastic anemia and agranulocytosis have been reported in association with the use of carbamazepine, but these are rare events, and there are few documented cases.52-54 The risk for these blood dyscrasias in patients taking carbamazepine has been estimated to be five to eight times greater than in the general population but that level of risk is very low; six patients per 1 million population per year for agranulocytosis and two patients per 1 million population per year for aplastic anemia.2 There is not enough data to be able to identify factors that increase the susceptibility for these adverse effects.

22 nursece4less.com nursece4less.com nursece4less.com nursece4less.com Mild and temporary decreases in WBC are common in patients taking carbamazepine (approximately 7% of adults and 12% of children), but the vast majority of patients will not develop agranulocytosis.1,2,52 Given the possibility and potential seriousness of carbamazepine-induced aplastic anemia and agranulocytosis, a baseline CBC should be measured before starting therapy with carbamazepine, and the patient should be closely monitored for clinical signs and symptoms and laboratory evidence of bone marrow suppression.1,2,52 Aplastic anemia or agranulocytosis usually occur in the first few months after the patient has begun taking the drug.52

Dosing Adjustment: Geriatric Patients

Carbamazepine can cause hyponatremia, typically as part of SIADH. Because of this potential adverse effect, the BEERS criteria have identified carbamazepine as a drug that is potentially inappropriate for elderly patients and one that should be used with caution in this patient population.8

The incidence of hyponatremia caused by carbamazepine has been reported to be 4.8% to almost 50%.55-58 Many of these patients develop symptomatic hyponatremia, and in the study by Berghuis, et al. (2017), 7% of the patients had severe hyponatremia, and coma and seizures have been reported.57,58 Factors that may increase the risk for carbamazepine-induced hyponatremia include advanced age, concomitant use of diuretics or other antiepileptics, female gender, a high carbamazepine level, and the presence of congestive heart failure, but this adverse effect has occurred in the absence of these risk factors.56,57

The pathogenesis of carbamazepine-induced hyponatremia is not completely understood, but carbamazepine may affect the activity of antidiuretic hormone (ADH) or cause an inappropriate secretion of ADH, or it may have a

23 nursece4less.com nursece4less.com nursece4less.com nursece4less.com direct effect on the kidney tubules.55,56,60 SIADH is a common cause of hyponatremia and is an adverse effect of carbamazepine.60,61

The Beers Criteria (named after its founder, Dr. Mark Beers), mentioned previously, is a list produced by the American Geriatrics Society and identifies medications that should be avoided in older adults or used with caution and close monitoring because of the risk of harmful adverse effects.8 The prescribing information states that there are no specific dosing adjustments of carbamazepine for elderly patients, but there are pharmacokinetic, physiological, and practical issues specific to this patient population, and because of these issues, it may be prudent to give elderly patients lower doses and to monitor closely.2,62,63

Drug-Drug Interactions:

Elderly patients are more likely to take multiple medications, and there are many commonly used drugs that can affect serum levels of carbamazepine, for example, and calcium channel blockers.64

Hepatic Impairment:

Carbamazepine is metabolized by the liver, and liver mass, hepatic blood flow, and hepatic metabolism decrease with age.66,66

Renal Impairment:

Carbamazepine is primarily excreted by the kidneys. Renal function has been estimated to decrease by 10% for each decade over age 40, and many older adults have some degree of renal impairment.62,67 Aging is associated with a decreased serum albumin concentration, body composition changes, and

24 nursece4less.com nursece4less.com nursece4less.com nursece4less.com altered gastric absorption, all of which can affect the pharmacokinetics of a drug.62

Adverse Effects:

Common adverse effects of carbamazepine like ataxia, constipation, dizziness, and drowsiness and somnolence may be especially troubling for older adults.67 Carbamazepine has anticholinergic effects, and it is advisable to use anticholinergic medications cautiously in elderly patients.

Dosing Adjustment: Hepatic Impairment

There are no specific dosing recommendations for patients who have hepatic impairment, but carbamazepine is primarily metabolized by the liver, and it would be prudent to use carbamazepine at a lower dose and monitor serum levels if the patient has hepatic impairment.1

Approximately 1%-22% of patients taking carbamazepine will develop mild and temporary elevations of the serum transaminases.68 Significant liver damage caused by carbamazepine almost always occurs in the context of a specific hypersensitivity reaction called the drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome or from Stevens-Johnson syndrome or TEN.68 DRESS is a rare, immune-system mediated hypersensitivity reaction that can be caused by many medications, and it involves multiple, complicated patterns of tissue and organ damage.

The clinical presentation of the DRESS syndrome varies, but the characteristic signs of DRESS are fever, rashes, eosinophilia,

25 nursece4less.com nursece4less.com nursece4less.com nursece4less.com lymphadenopathy, and hepatic damage, and the kidneys, the lungs, and other organs can be affected.68-71

The DRESS syndrome usually begins after several weeks or one-two months of therapy with the drug with non-specific signs and symptoms and a maculopapular rash, followed by the more serious systemic effects.70,71 This time of onset is considerably longer than that of other drug-induced rashes and hypersensitivity reactions, and this is a useful diagnostic sign. The rash does not involve the mucous membranes which helps distinguish DRESS from Stevens-Johnson syndrome and TEN.69 Hematologic abnormalities are very common and can include agranulocytosis, leukopenia, thrombocytopenia, and other blood dyscrasias.69-71 Generalized and local lymphadenopathy will be seen, liver damage is common as well, and liver damage caused by DRESS is particularly dangerous and severe. Hepatitis with jaundice is the most common cause of death from DRESS, with a fatality rate >10%.68,70

Carbamazepine-induced DRESS syndrome is a well-known and well- described phenomenon, but DRESS itself is rare.72-76 The incidence of this adverse effect is not known, but the data from several small case series and literature reviews of DRESS reported that carbamazepine was the drug most commonly implicated as the causative agent of DRESS (27%-60% of the cases).72,74,77 The DRESS syndrome happens regardless of the dose that is given, there are no clearly identified risk factors, and there is cross-reactivity between anticonvulsants like phenytoin and carbamazepine and other structurally similar drugs, so using one drug in place of another that has caused DRESS would present a risk.70

Dosing Adjustment: Renal Impairment

26 nursece4less.com nursece4less.com nursece4less.com nursece4less.com The prescribing information does not provide dosing recommendations for patients who have decreased renal function, but there are authoritative sources that mention using carbamazepine cautiously in patients who have renal impairment and note that renal toxicity caused by carbamazepine has been reported.1 Several cases of renal failure caused by carbamazepine have been reported, but carbamazepine has been in use for almost 50 years and the lack of published data suggests that this is a rare event.78,79

Contradictions

Hypersensitivity to Tricyclic Antidepressants:

Carbamazepine is structurally like tricyclic antidepressants (TCAs).5 A cross- reactivity between carbamazepine and TCAs that caused a significant hypersensitivity reaction in five patients who were given a TCA has been reported.80

It should be noted that carbamazepine induces a CYP450 enzyme that metabolizes tricyclic antidepressants (TCAs), and concomitant use of carbamazepine and a TCA can decrease the serum concentration of , desipramine, doxepin, and .81 It is not known if this can affect the therapeutic efficacy of TCAs.81

Bone Marrow Depression:

Bone marrow depression was previously discussed in the US Boxed Warning section. Concomitant use of carbamazepine and a MAO inhibitor or use of a MAO inhibitor within the prior 14 days should be avoided. There is a theoretical risk that concomitant use of carbamazepine and a MAO inhibitor would increase the effects of the MAO inhibitor.82 This interaction is rated as major, and the reliability of the data supporting this recommendation is

27 nursece4less.com nursece4less.com nursece4less.com nursece4less.com rated as fair. The concomitant use of these drugs may also cause serotonin syndrome.

Concomitant Use of Nefazodone:

Carbamazepine is primarily metabolized to its active metabolite carbamazepine-10,11-epoxide by CYPA34. Nefazodone can inhibit the CYPA34 enzyme activity, and concomitant use of carbamazepine and nefazodone can increase the serum level of carbamazepine and cause signs and symptoms of carbamazepine toxicity.83 This interaction is rated as major, and the reliability of the data supporting this recommendation is rated as good. The use of these two drugs together can also decrease the serum concentration of nefazodone.2

Concomitant Use of Boceprevir:

Concomitant use of carbamazepine and boceprevir may lower the serum concentration of boceprevir and diminish its antiviral efficacy. This interaction is rated as major, and the reliability of the data supporting this recommendation is rated as fair.

Other:

Concomitant use of carbamazepine and delavirdine or other non-nucleoside reverse transcriptase inhibitors (NNRTIs) may lower the serum concentrations of these drugs and diminish their antiviral efficacy.85 This interaction is rated as major, and the reliability of the data supporting this recommendation is rated as fair.

28 nursece4less.com nursece4less.com nursece4less.com nursece4less.com Warnings

Anticholinergic Effects:

Carbamazepine has anticholinergic activity.2,4 It should be used cautiously if the patient is taking other drugs that have anticholinergic properties or if the patient has glaucoma, urinary retention, or constipation.1,2,86 Cardiovascular Effects:

Second- and third-degree AV block and bradycardia are unusual, albeit well described adverse effects of carbamazepine.87-89 These arrhythmias almost always happen to elderly women and occur after years of use. The serum carbamazepine level in these patients is normal and often subtherapeutic, and the patients are often quite symptomatic and require aggressive intervention. The arrhythmias resolve after the patients stops taking the drug.87-89 It is not known why these adverse effects occur and why elderly women are so often affected.

In 2016 the American Heart Association (AHA) identified carbamazepine as a drug that may precipitate or exacerbate heart failure. This is a rare adverse effect.90-93 The AHA statement noted that the magnitude of this effect is major with onset occurring weeks to months of starting drug therapy, and the evidence supporting this adverse effect was categorized as level C. Very limited populations were evaluated, and the data was from the consensus opinion of experts, case studies, and standards of care. Moreover, the AHA stated that carbamazepine-induced signs of heart failure have occurred in patients who did not have cardiovascular disease, and that severe left ventricular dysfunction caused by carbamazepine has only occurred after overdose.5

29 nursece4less.com nursece4less.com nursece4less.com nursece4less.com Carbamazepine has been defined as a negative chronotrope and inotrope that suppresses SA node automaticity and AV node conduction, and depresses phase 2 repolarization.5

Hepatic Porphyria:

Carbamazepine should be avoided if the patient has hepatic porphyria as it may cause acute attacks of porphyria.1,2,7 Porphyria is a rare genetic, metabolic disease, a group of eight acute and chronic disorders that share the characteristic of an accumulation of or precursors.

The porphyrins are chemical compounds that are used to synthesize , , and other respiratory pigments, and porphyria is caused by abnormal activity of enzymes that control the biosynthetic pathway of hemoglobin formation.94 Porphyrias are classified as erythropoietic or hepatic, depending on whether the porphyrin precursors accumulate in the bone marrow or the liver,94 and there are four different types of hepatic porphyrias.

The clinical course of porphyria is variable. Patients can have asymptomatic periods, chronic signs and symptoms, and acute attacks of porphyria. The acute attacks of hepatic porphyria are characterized by gastrointestinal and neurological signs and symptoms like and , and hepatic porphyria can be exacerbated by carbamazepine.94- 96 The American Porphyria Association drug database considers carbamazepine “... very likely to be unsafe for prolonged use by individuals with an acute porphyria, based on consistent evidence.”96

Psychiatric:

30 nursece4less.com nursece4less.com nursece4less.com nursece4less.com The prescribing information and an authoritative review of carbamazepine both state that carbamazepine may activate a latent psychosis,1,3 particularly in elderly patients. A literature search did not find any published reports of this adverse effect.

The antiepileptics have been associated with an increased risk for suicidal behavior and ideation, with an incidence rate of 0.43% versus 0.24% for placebo.1 Patients taking carbamazepine should be evaluated for their risk for suicide and monitored closely for depression and suicidal behavior and ideation. Studies of the antiepileptics have shown that there is an increased risk of suicidal thoughts/behavior in patients who are taking these drugs. The increase can begin one week after starting therapy with the drug.

All patients taking an antiepileptic should be closely monitored for signs and symptoms of depression and suicidal behavior and thoughts. In 2008 the Food and Drug Administration (FDA) released an alert to health clinicians after a meta-analysis of controlled trials of the use of antiepileptics (multiple uses), suggesting that people taking an antiepileptic had an increased risk for suicidal behavior and thoughts.97 Later that year the FDA published the details of their investigation;98 data was collected from 11 controlled trials involving 27,863 patients. The drugs involved were carbamazepine, felbamate, , lamotrigine, levetiracetam, oxcarbazepine, pregabalin, tiagabine, , , and zonisamide. These antiepileptics were being used to treat epilepsy (25% of the patients), psychiatric conditions (27% of the patients), and other conditions (48% of the patients). There were 4 completed suicides in the treated patients, none in the placebo group.

31 nursece4less.com nursece4less.com nursece4less.com nursece4less.com The conclusion of the FDA investigation of controlled trials was that patients taking an antiepileptic were significantly more likely to have suicidal behavior and thoughts (odds ratio 1.8, confidence interval 1.24-2.66). The incidence rate for suicidal behavior and thoughts was 0.43% for the treated patients and 0.24% for patients receiving placebo. The relative risk was highest for patients who had epilepsy, and the relative risk for patients with other conditions was not considered to be significant. The risk for suicidal behavior and thoughts was observed to begin as soon as 1 week after treatment with a drug had started. There were 252 patients who were taking carbamazepine and all of them were taking it for treatment of a psychiatric condition. There were two incidents of suicidal behavior/ideation in this patient group and three in the placebo group. Based on this information the FDA required manufacturers to include a warning in their prescribing information (not a Boxed Warning) that states that studies of the antiepileptics have shown that there is an increased risk of suicidal thoughts/behavior in patients who are taking these drugs.

In 2013 the International League Against Epilepsy published an expert consensus statement on antiepileptic drugs and suicide, and a summary of the main points of the consensus statement is provided below.99 The consensus statement can be viewed online at: https://www.ilae.org/guidelines, which is where the Guidelines & Reports may be viewed with a section on the Antiepileptic Drugs.

Some antiepileptic drugs can be associated with treatment-emergent psychiatric problems that can lead to suicidal ideation and behavior. The true risk of suicide associated with these drugs is not known but it appears to be very low. Stopping antiepileptic drugs or not giving them to people who need them can cause serious harm and death.

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Suicidality in epilepsy is multifactorial. Clinicians should carefully evaluate a patient for the presence of suicide risk factors before prescribing an antiepileptic drug and make an appropriate referral if risk factors are present, but they should not withhold antiepileptic drugs from patients who need them, even if the patient has risk factors for suicide.

When starting an antiepileptic drug or switching from one to another the patient should be carefully monitored for suicidal behavior and thoughts or for mood changes. Patients should be instructed to inform the treating clinician if they have suicidal behavior or suicidal thoughts or changes in mood.

Carbamazepine should be used cautiously for patients who have combined generalized and focal seizure disorder (often called a mixed seizure disorder) that includes atypical absence seizures as the drug may increase the frequency of generalized seizures.19

Vanishing Bile Duct:

There have been rare reports of a condition called vanishing bile duct syndrome occurring as an adverse effect of carbamazepine.2,6,68,100,101 Vanishing bile duct syndrome is a disorder that is characterized by progressive destruction of the intrahepatic bile ducts, and is reversible and irreversible.

Drug-induced vanishing bile duct syndrome is well described in the medical literature. Four cases of vanishing bile duct syndrome caused by carbamazepine were found during a literature search, and insufficient data

33 nursece4less.com nursece4less.com nursece4less.com nursece4less.com exists to identify characteristic patterns or risk factors of this disorder specific to carbamazepine use.

Pregnancy and Breastfeeding

Carbamazepine is a pregnancy risk category D drug; human studies have shown that when used during pregnancy it can cause fetal harm like cardiovascular malformations, craniofacial defects, hypospadias, and spina bifida. Carbamazepine may be used during pregnancy, but only if the benefits outweigh the risks. A recent (2017) study of antiepileptic drugs and pregnancy found that carbamazepine was associated with an increased risk for major and minor congenital malformations.103

Pregnancy can decrease carbamazepine levels during the second and third trimesters, but this effect has been described as small, and it is not mentioned in the prescribing information or in a recent (2016) authoritative review of epilepsy and pregnancy.1,104 Thangartinam, et al. (2018) evaluated the utility of monitoring antiepileptic drug levels during pregnancy (including carbamazepine), and they concluded that measuring and monitoring drug levels did not make a significant difference in the measured outcomes of time to first seizure and incidence of seizures, and a reduction in serum level did not cause an increased number of seizures.105

Folic Acid and Vitamin K Supplementation:

All women who are or may become pregnant are advised to take 0.4 mg to 0.8 mg of folic acid once a day as a prophylactic measure to prevent neural tube defects (NTD) in the fetus. Women who take carbamazepine during pregnancy have a higher than average risk of having a child who has a NTD, and it is recommended that these women take 4 mg a day.104,106 The efficacy of this has not been clinically proven, and the recommendation is derived

34 nursece4less.com nursece4less.com nursece4less.com nursece4less.com from the use of high-dose folic acid supplementation in women who, for other reasons, have a higher than average risk of delivering a child who has an NTD. For these patients, extra folic acid during pregnancy has been shown to prevent this birth defect.106 In addition, short-term use of 4 mg a day of folic acid – four times the amount that is usually considered the upper limit – is considered safe.106

There are no established guidelines for folic acid supplementation for women who take carbamazepine but Goetzl (2018) recommended 4 mg once a day one to three months before conception, to continue this dose for the first 12 weeks of the pregnancy, and then decrease the dose to 0.4 mg a day.106

Pregnant women taking antiepileptic drugs have often been advised to take vitamin K supplementation of 10 mg-20 mg orally every day during the last trimester.104 Carbamazepine (and other antiepileptics) is a CYP450 enzyme- inducing drug that crosses the placenta, and its use during pregnancy has been thought to decrease the fetal level of clotting factors that require vitamin K for their synthesis and thus increase the risk of bleeding.104 However, the evidence for this effect is limited and weak,and the decision to use prophylactic vitamin K should be made on a case-by-case basis.104, 107- 109

The parent drug and the pharmacologically active metabolite of carbamazepine, carbamazepine-10,11-epoxide, are both excreted in breast milk, and carbamazepine has been detected in the serum of nursing infants whose mothers were taking the drug. Case studies have reported poor sucking, sedation, transient hepatic dysfunction, and withdrawal reactions in nursing infants exposed to carbamazepine, but confounding factors like concomitant use of other drugs make it difficult to interpret the importance

35 nursece4less.com nursece4less.com nursece4less.com nursece4less.com of these incidents.102 Exposure to carbamazepine during nursing does not appear to negatively affect growth and development. There is no information on the effects of carbamazepine on lactation.102

Dietary Concerns

Carbamazepine use has been associated with folate and vitamin B2, B6, B12 deficiencies, which can cause hyperhomocysteinemia, a known risk factor for cardiovascular disease.110-113 Elevated homocysteine levels are a well- described and consistently reported consequence of carbamazepine therapy.110-112 Long-term antiepileptic therapy has been associated with an increased risk for cardiovascular disease, and there is good evidence that patients who take carbamazepine have high levels of markers of cardiovascular disease like increased carotid artery intima-media thickness, elevated cholesterol level, and a harmful ratio of low-density lipoproteins to high-density lipoproteins.114-119 Some clinicians recommend that patients who are taking carbamazepine should take folate and B vitamin supplements, but there are no guidelines for this, and there is no evidence for a beneficial effect of vitamin B supplementation for lowering homocysteine levels.1,113

Measuring Carbamazepine Levels

Measuring and monitoring serum carbamazepine levels is strongly advised and is considered a standard of care.120 Schachter (2018) recommends measuring a patient’s carbamazepine level at three weeks, six weeks and nine weeks after beginning therapy with the drug; the desired level is 4-12 mcg/mL. After week nine, the level should be checked at least every two months until several consecutive measurements clearly show that a constant level has been attained.52

36 nursece4less.com nursece4less.com nursece4less.com nursece4less.com Carbamazepine Overdose

A toxic dose of carbamazepine is unknown. The lowest fatal dose has been reported to be 3.2 grams, but patients who have ingested 40-60 grams have survived.121 The correlation between serum levels and the intensity of signs and symptoms is not precise, but a serum level >40 appears to increase the risk for coma and hypotension.122

The primary effects of carbamazepine overdose are anticholinergic, cardiovascular, and neurologic.4,121,122 Mild poisoning will typically cause ataxia, decreased bowel sounds, drowsiness, nystagmus, and . Patients who have ingested large amounts may develop arrhythmias, bradycardia, coma, dystonias, hypotension, QRS and QTc prolongation, respiratory depression, and seizures. The signs and symptoms, particularly the level of CNS depression, can wax and wane in intensity.

Treatment of Overdose

There is no antidote for a carbamazepine overdose. Treatment should be symptomatic and supportive. Multiple doses of activated charcoal (MDAC) is no longer considered a standard treatment for carbamazepine overdose, and gastric lavage and whole bowel irrigation should not be used.4,121,122

Intravenous lipid solution or lipid rescue therapy, has been successfully used to treat carbamazepine overdose, but it should not be routinely given. A toxicologist should be consulted about its use. The use of extracorporeal elimination techniques like hemodialysis and hemoperfusion should be reserved for seriously symptomatic patients in worsening condition and who have not responded to supportive care.122

37 nursece4less.com nursece4less.com nursece4less.com nursece4less.com A baseline carbamazepine level should be obtained, and serial measurements done, every four to six hours until the level is clearly decreasing. The peak serum level may be delayed for up to 96 hours post- ingestion. It should be noted that carbamazepine can cause a false positive for tricyclic in a drug screen.122

Case Study

The following case study was obtained through a PubMed search to highlight the use of carbamazepine to treat other conditions besides epilepsy and mood disorder that may not be as well known amongst clinicians.124 The authors of this case study reported on a male infant who was born at full term and required forceps-assisted vaginal birth due to fetal distress following spontaneous onset of labor. His birth mother was a Caucasian female who had been treated with labetalol for pregnancy-induced . At birth, the infant weighed 2680 g (0.4th centile), and appeared hypotonic and was having respiratory distress and bradycardia. Apgar scores showed 5 at 1 minute and 7 at 5 minutes. The cord arterial pH was 7.25 and venous pH 7.3.

The Apgar score is a scoring system for a rapid assessment of a newborn’s clinical status at 1 minute of age to evaluate the need for rapid intervention to establish breathing. The Apgar score comprises five components:125 1) color, 2) heart rate, 3) reflexes, 4) muscle tone, and 5) respiration, and each are given a score of 0, 1, or 2. Clinical signs are rated of neonatal depression (cyanosis or pallor), bradycardia, muscle tone (hypotonia or depressed reflex response to stimulation), and apnea or gasping respirations.

The score is reported at 1 minute and 5 minutes after birth for all infants, and at 5-minute intervals until a score less than 7 (until 20 minutes). The Apgar score is used to report the status of the newborn infant immediately after birth and the response to resuscitation, if needed. A 5-minute Apgar score of 7–10 as reassuring, a score of 4–6 as moderately abnormal, and a score of 0–3 as low in the term infant and late-preterm infant.

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The infant was ventilated with a bag and mask and the slow heart rate improved but his hypotonic condition with poor respiratory effort continued, and he required transfer to a neonatal care unit where he received continuous positive airway pressure (CPAP). were started while sepsis, meningitis, and metabolic causes of apnea were ruled out.

The infant failed multiple attempts to wean from CPAP. During these efforts to wean, the infant resumed being apneic and oxygen desaturation occurred, notably while sleeping. Apneic episodes also occurred while the infant was crying or being handled, and were accompanied by abnormal body posturing (stiff arms and legs and non-rhythmic jerks of upper and lower limbs, similar to breath-holding episodes). The infant also showed pallor and central cyanosis lasting for about 30 to 60 seconds associated with apnea episodes. The authors reported that the infant continued to be hypotonic with head lag, but showed reasonable antigravity movements.

Monitoring of the infant’s progress included overnight oxygen saturation and transcutaneous CO2 monitoring, which showed multiple desaturations and mild elevation of CO2. By age 2 months, the infant required respiratory support by noninvasive ventilation (NIV) and high-flow oxygen therapy. A trial of caffeine citrate failed and respiratory support was required during sleep. The authors noted that apneic episodes tended to be brief and self- correcting but stimulation and occasionally bag and mask ventilation were required during some apneic episodes.

The possibility of congenital myotonia (an inherited myopathy of the skeletal muscles characterized by rigidity and slow muscle relaxation) was

39 nursece4less.com nursece4less.com nursece4less.com nursece4less.com considered. At 3 months of age further investigations included electromyography with findings consistent with myotonia. Carbamazepine was administered (5 mg/kg in 2 divided doses) because of the diagnosis of congenital myotonia, which reduced the daytime apneic episodes and resolved the episodes of limb stiffness and jerky movements in the infant. An episode of nonrhythmic jerky movement and limb stiffness was documented that corresponded with a drop in serum level of carbamazepine level as the infant’s weight increased, and improvement was noticed upon increasing the carbamazepine dosage.

Ongoing investigations such as routine blood tests, metabolic screening, creatinine kinase, 24-hour electrocardiography, heart scan, and magnetic resonance imaging of the brain were unremarkable. Adrenal insufficiency testing (short synacthen test) to measure the serum cortisol level at baseline was normal. Multichannel electroencephalogram, including during sleep periods, was unremarkable. Additionally, bronchoscopy showed the infant had normal airway anatomy. Of note, testing of the associated with non-dystrophic myotonia turned out to be normal (including SCN4A, CLCN1, CACNA15, and KCN12).

At 4 months of age, a polysomnography was done and the report was consistent with the diagnosis of congenital central hypoventilation syndrome (CCHS). The study, which was performed in room air, showed central hypoventilation mainly observed during sleep. On the basis of the study, overnight NIV was started.

Further genetic screening was performed of the 3 exons of PHOX2B gene by direct sequence analysis, which revealed a heterozygous novel missense variant. The authors explained that bioinformatics analysis predicts that this

40 nursece4less.com nursece4less.com nursece4less.com nursece4less.com variant is likely to be pathogenic by affecting normal protein function. The parents were tested and were found free of this gene. Both parents were also reported in good health. A family history of sudden infant death in 2 infants on the paternal side nearly 2 decades ago (the father’s cousins) was reported.

The infant also had developed feeding difficulties, and nasogastric tube feeding was needed. A fundoplication and formation of a gastrostomy was eventually needed due to severe gastroesophageal reflux.

Eventually, the patient was able to discharge to home on overnight NIV (with face mask) at 6 months of age. Polysomnography at one year of age showed effective ventilation. Measurements when off the ventilator demonstrated central hypoventilation, with 3 desaturations, which were effectively managed with mask ventilation.

The authors reported follow-up of the patient at 3 years of age with normal developmental progress. NIV by facemask continued at night with 3 to 4 brief desaturations which mainly self-corrected, however occasionally minimal stimulation was needed. Daytime sleepiness was accompanied by occasional desaturations that required ventilator support. The patient depended on the gastrostomy tube feeding but had progressed to pureed food by mouth. Constipation was an issue that required medical management; abdominal ultrasound scan and gastrointestinal contrast studies ruled out any abnormality.

Discussion

Carbamazepine has been used to successfully treat certain types of seizure, neuralgia, mood disorders, and congenital myotonia. The authors of this

41 nursece4less.com nursece4less.com nursece4less.com nursece4less.com case study noted that “Carbamazepine produces a wide variety of biochemical effects on channels, receptors, and signaling pathways. It mainly acts by reducing the ability of neurons to fire at high frequency by blocking voltage-gated sodium channels. It also acts on synaptic transmission and neurotransmitter receptors including noradrenaline, adenosine, dopamine and gamma-aminobutyric acid receptors.”124 The authors also reported an unusual effect of carbamazepine related to a genetic of Paired-Like Homeobox 2B (PHOX2B) gene in this male infant.

Pathogenic variants in PHOX2B gene cause congenital central hypoventilation syndrome (CCHS), which is “a rare disorder of the nervous system characterized by absent or reduced ventilatory response to hypoxia and hypercapnia”.124 CCHS is treated by optimizing ventilation and no medication has been proven effective in improving ventilation. Of note, the authors explain that most CCHS cases are caused by polyalanine repeat expansion (the cause in 8% of cases with a more severe clinical presentation). The infant in this case had a novel gene variant other than the 9 CCHS-causing mutations reported thus far.

Improvement in the infant’s apneic episodes was observed following initiation of treatment with carbamazepine. Carbamazepine was noted to improve daytime apneic episodes but not the sleep-related hypoventilation.

Carbamazepine had not previously been used for the management of CCHS or central sleep apnea. The authors noted, however, that a single case in the medical literature had discussed that the use of carbamazepine for seizures coincided with improved central sleep apnea; however not enough clinical information on that case report was available.

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When given for mood regulation, the authors noted that carbamazepine inhibited both synaptic uptake and release of noradrenaline in the brain. They hypothesized that carbamazepine may also affect ventilation through blocking noradrenaline receptors. Caffeine had been initially used as an efficient respiratory stimulant and reportedly was used to treat neonatal apnea. However, in this case, the authors suggested that the effect of carbamazepine on adenosinergic receptors “... could, in theory, explain the clinical improvement observed in our patient. However, despite the similarities in actions of carbamazepine and caffeine on adenosine receptors, they appear to produce paradoxical pharmacological effects, with anticonvulsant and sedative effects of carbamazepine compared to the stimulant effect of caffeine.”124 The authors in this case study concluded that the clinical relevance of their observations in a male infant with CCHS remained to be determined but posed that carbamazepine “could be an exciting therapeutic agent for CCHS”.124

Summary

Carbamazepine is a first-generation anticonvulsant that has labeled uses for the treatment of specific types of epilepsy, bipolar disorder, and trigeminal or glossopharyngeal neuralgia. The drug stabilizes neuronal membranes by inhibition of the movement of sodium through sodium ion channels, and this prevents repetitive discharges from seizure foci and transmission of these impulses. Carbamazepine also has anticholinergic, antineuralgic, antidiuretic, muscle relaxant, antimanic, antidepressive, and antiarrhythmic properties.

The side effects and contraindications of carbamazepine use have been discussed, including serious and potentially fatal dermal adverse effects, Stevens-Johnson syndrome and toxic epidermal necrolysis (TEN), aplastic

43 nursece4less.com nursece4less.com nursece4less.com nursece4less.com anemia, and agranulocytosis. The risk for developing Stevens-Johnson syndrome and TEN is higher for patients of Asian ethnicity, and screening guidelines should be followed before starting therapy with carbamazepine. Additionally, laboratory testing that includes a complete blood count should be done before therapy with carbamazepine is started, and periodic CBC measurements should be done to evaluate for any evidence of bone marrow depression. Carbamazepine should be stopped if this is found to occur.

Carbamazepine should be used cautiously in special groups, such as the elderly, pregnant or breastfeeding women, and those with hepatic impairment and other comorbid conditions. The drug should be avoided in individuals with such pre-existing conditions or monitored carefully if the benefit of using carbamazepine outweighs the risk. Measuring and monitoring serum carbamazepine levels is strongly advised and is considered a standard of care.

Much of the information available to clinicians highlights the many potential pitfalls to using carbamazepine with other medications. Some of the ones raised included other anticonvulsants, such as levetiracetam, lamotrigine, phenobarbital, phenytoin, and valproic acid, which can increase or decrease the serum concentration of carbamazepine. Alternatively, there is ongoing research on newer beneficial uses of carbamazepine that are outside the scope of this paper but that clinicians may find interesting in the case reports. The benefit of carbamazepine in the case of infant/child central sleep apnea raises a fascinating option for the combined use of the drug with other treatments.

44 nursece4less.com nursece4less.com nursece4less.com nursece4less.com Please take time to help NurseCe4Less.com course planners evaluate the nursing knowledge needs met by completing the self-assessment of Knowledge Questions after reading the article, and providing feedback in the online course evaluation.

Completing the study questions is optional and is NOT a course requirement. 1. Carbamazepine is an anticonvulsant that has a labeled use for treatment of

a. critically ill patients who have neuropathic pain. b. bipolar 1 disorder. c. the neuropsychiatric symptoms of dementia. d. restless legs syndrome.

2. The mechanism of action by which carbamazepine is effective for treating acute manic or mixed episodes in patients who have bipolar 1 disorder is

a. not known. b. by inhibition of sodium through sodium ion channels. c. through stabilization of neuronal membranes. d. by inhibiting HMG CoA reductase.

3. The usual 24-hour total dose for carbamazepine when treating an adult with epilepsy is

a. 400 mg. b. 600 mg – 800 mg. c. 200 mg. d. 800 mg – 1200 mg.

4. In geriatric patients, adult dosing of carbamazepine is appropriate but a clinician should be aware of the potential for hyponatremia, typically as part of

a. trigeminal or glossopharyngeal neuralgia. b. aplastic anemia. c. agranulocytosis. d. syndrome of inappropriate antidiuretic hormone (SIADH).

45 nursece4less.com nursece4less.com nursece4less.com nursece4less.com 5. Carbamazepine use has been associated with folate and vitamin B2, B6, B12 deficiencies and these deficiencies may contribute to the development of ______, a risk factor for the development of cardiovascular disease.

a. trigeminal neuralgia b. hyperhomocysteinemia c. bone marrow depression d. hyponatremia

6. Hepatic failure has been reported in patients taking carbamazepine in cases where the patient

a. does not have an underlying liver disease. b. has an underlying liver disease. c. has Stevens-Johnson syndrome. d. All of the above

7. Which of the following describes the guidelines for taking folate and B vitamin supplements during the time a patient takes carbamazepine?

a. These supplements are required to lower homocysteine levels. b. The required dose is 400 micrograms (mcg) folate and 100 mcg vitamin B complex. c. There are no guidelines. d. These supplements are required to treat hepatic porphyria.

8. Carbamazepine is a pregnancy risk category D drug, which means that

a. there is no evidence of risk to a fetus. b. it may be used during pregnancy only if the benefits outweigh the risks. c. the potential fetal harm outweighs any potential benefit to the mother. d. there are no adequate or well-controlled studies of carbamazepine on pregnant women.

46 nursece4less.com nursece4less.com nursece4less.com nursece4less.com 9. Pregnancy can decrease carbamazepine levels during the second and third trimesters,

a. which requires monitoring the drug’s levels in the second and third trimesters. b. which causes an increased in the number of seizures for the mother. c. but the effect of this is minor. d. requiring cessation of the drug n the second and third trimesters.

10. Exposure of an infant to carbamazepine during nursing

a. does not appear to negatively affect the infant’s growth and development. b. results in permanent hepatic dysfunction. c. the potential harm to the infant outweighs any potential benefit to the mother. d. has been tied to severe withdrawal syndrome for the nursing infant.

11. True or False: All women who take carbamazepine and who are or may become pregnant are advised to take 0.4 mg to 0.8 mg of folic acid once a day as a prophylactic measure to prevent neural tube defects (NTD) in the fetus.

a. True b. False

12. When a patient begins treating with carbamazepine, the patient’s serum carbamazepine levels should be measured and monitored

a. only if signs of hepatic porphyria are present. b. once a month after beginning therapy with the drug. c. three weeks, six weeks and nine weeks after beginning therapy with the drug, then every two months. d. weekly for the first two months, then once a month thereafter.

47 nursece4less.com nursece4less.com nursece4less.com nursece4less.com 13. Carbamazepine can cause serious and potentially fatal immune- mediated dermatologic pathologies that are characterized by necrosis and subsequent detachment of the epidermis known as

a. Stevens-Johnson syndrome and toxic epidermal necrolysis (TEN). b. agranulocytosis and syndrome of inappropriate antidiuretic hormone (SIADH). c. DRESS syndrome - drug reaction with eosinophilia and systemic symptoms. d. glossopharyngeal neuralgia and trigeminal neuralgia.

14. Mild overdose or poisoning from carbamazepine will typically cause

a. dystonias. b. tachycardia. c. coma. d. seizures.

15. Standard treatment of carbamazepine overdose is

a. multiple doses of activated charcoal (MDAC). b. gastric lavage and whole bowel irrigation. c. to treat the symptoms and provide supportive care. d. by balancing porphyrins.

48 nursece4less.com nursece4less.com nursece4less.com nursece4less.com CORRECT ANSWERS:

1. Carbamazepine is an anticonvulsant that has a labeled use for treatment of

b. bipolar 1 disorder.

“Bipolar 1 disorder: Equetro is a brand name for a form of extended release carbamazepine. Equetro is the only form of carbamazepine that has a labeled use for treating acute manic or mixed episodes in patients who have bipolar 1 disorder…. Carbamazepine has been used off-label to treat critically ill patients who have neuropathic pain, the neuropsychiatric symptoms of dementia, and restless legs syndrome.”

2. The mechanism of action by which carbamazepine is effective for treating acute manic or mixed episodes in patients who have bipolar 1 disorder is

a. not known.

“Carbamazepine stabilizes neuronal membranes by inhibition of the movement of sodium through sodium ion channels, and this prevents repetitive discharges from seizure foci and transmission of these impulses. Carbamazepine also has anticholinergic, antineuralgic, antidiuretic, muscle relaxant, antimanic, antidepressive, and antiarrhythmic properties. The mechanism of action by which carbamazepine is effective for treating acute manic or mixed episodes in patients who have bipolar 1 disorder is not known.”

3. The usual 24-hour total dose for carbamazepine when treating an adult with epilepsy is

d. 800 mg – 1200 mg.

“Dosing: Adult Epilepsy: Begin with 400 mg a day in divided doses (two or four doses, tablets and suspension, respectively). Increase the dose once a week by 200 mg (again, twice a day with oral tablets, three-four times a day for the suspension). Increase the dose until the desired effect and therapeutic level have been achieved. The usual 24-hour total dose is 800 mg – 1200 mg; the maximum 24-hour total dose is 1600 mg.”

49 nursece4less.com nursece4less.com nursece4less.com nursece4less.com 4. In geriatric patients, adult dosing of carbamazepine is appropriate but a clinician should be aware of the potential for hyponatremia, typically as part of

d. syndrome of inappropriate antidiuretic hormone (SIADH).

“Use the adult dosing but be aware of the potential for syndrome of inappropriate antidiuretic hormone (SIADH) or hyponatremia…. Carbamazepine can cause hyponatremia, typically as part of SIADH (syndrome of inappropriate anti-diuretic hormone secretion). The risk of developing hyponatremia and/or SIADH is apparently age and dose-related and associated with concomitant use of a diuretic.”

5. Carbamazepine use has been associated with folate and vitamin B2, B6, B12 deficiencies and these deficiencies may contribute to the development of ______, a risk factor for the development of cardiovascular disease.

b. hyperhomocysteinemia

“Carbamazepine use has been associated with folate and vitamin B2, B6, B12 deficiencies and these deficiencies may contribute to the development of hyperhomocysteinemia, a risk factor for the development of cardiovascular disease. Some clinicians recommend that patients who are taking carbamazepine should take folate and B vitamin supplements.”

6. Hepatic failure has been reported in patients taking carbamazepine in cases where the patient

a. does not have an underlying liver disease. b. has an underlying liver disease. c. has Stevens-Johnson syndrome. d. All of the above [correct answers]

“The effects of carbamazepine on the liver are complex…. Hepatic failure has been reported, as well, and this can occur: a) in patients who do not have underlying liver disease: b) in those who have liver disease: c) as part of a hypersensitivity reaction called drug reaction with eosinophilia and systemic symptoms, aka the DRESS syndrome; or, d) in association with Stevens- Johnson syndrome or TEN.”

50 nursece4less.com nursece4less.com nursece4less.com nursece4less.com 7. Which of the following describes the guidelines for taking folate and B vitamin supplements during the time a patient takes carbamazepine?

c. There are no guidelines.

“Some clinicians recommend that patients who are taking carbamazepine should take folate and B vitamin supplements, but there are no guidelines for this, and there is no evidence for a beneficial effect of vitamin B supplementation for lowering homocysteine levels.”

8. Carbamazepine is a pregnancy risk category D drug, which means that

b. it may be used during pregnancy only if the benefits outweigh the risks.

“Carbamazepine is a pregnancy risk category D drug: human studies have shown that when used during pregnancy it can cause fetal harm like cardiovascular malformations, craniofacial defects, hypospadias, and spina bifida. Carbamazepine may be used during pregnancy, but only if the benefits outweigh the risks.”

9. Pregnancy can decrease carbamazepine levels during the second and third trimesters,

c. but the effect of this is minor.

“Pregnancy can decrease carbamazepine levels during the second and third trimesters, but this effect has been described as small, … Thangartinam et al., (2018) evaluated the utility of monitoring antiepileptic drug levels during pregnancy (including carbamazepine), and the authors’ concluded that measuring and monitoring drug levels did not make a significant difference in the measured outcomes of time to first seizure and incidence of seizures, and a reduction in serum level did not cause an increased number of seizures.”

51 nursece4less.com nursece4less.com nursece4less.com nursece4less.com

10. Exposure of an infant to carbamazepine during nursing a. does not appear to negatively affect the infant’s growth and development.

“The parent drug and the pharmacologically active metabolite of carbamazepine, carbamazepine-10,11-epoxide, are both excreted in breast milk, and carbamazepine has been detected in the serum of nursing infants whose mothers were taking the drug. Case studies have reported poor sucking, sedation, transient hepatic dysfunction, and withdrawal reactions in nursing infants exposed to carbamazepine, but confounding factors like concomitant use of other drugs make it difficult to interpret the importance of these incidents. Exposure to carbamazepine during nursing does not appear to negatively affect growth and development. There is no information on the effects of carbamazepine on lactation.”

11. True or False: All women who take carbamazepine and who are or may become pregnant are advised to take 0.4 mg to 0.8 mg of folic acid once a day as a prophylactic measure to prevent neural tube defects (NTD) in the fetus. a. True

“Folic acid and vitamin K supplementation: All women who are or may become pregnant are advised to take 0.4 mg to 0.8 mg of folic acid once a day as a prophylactic measure to prevent neural tube defects (NTD) in the fetus.”

12. When a patient begins treating with carbamazepine, the patient’s serum carbamazepine levels should be measured and monitored c. three weeks, six weeks and nine weeks after beginning therapy with the drug, then every two months.

“Measuring and monitoring serum carbamazepine levels is strongly advised and is considered a standard of care. Schachter (2018) recommends measuring a patient’s carbamazepine level at three weeks, six weeks and nine weeks after beginning therapy with the drug: the desired level is 4-12 mcg/mL. After week nine, the level should be checked at least every two months until several consecutive measurements clearly show that a constant level has been attained.”

52 nursece4less.com nursece4less.com nursece4less.com nursece4less.com

13. Carbamazepine can cause serious and potentially fatal immune- mediated dermatologic pathologies that are characterized by necrosis and subsequent detachment of the epidermis known as a. Stevens-Johnson syndrome and toxic epidermal necrolysis (TEN).

“Carbamazepine can cause serious and potentially fatal dermal adverse effects: Stevens-Johnson syndrome and toxic epidermal necrolysis (TEN). Drug-induced Stevens-Johnson syndrome and TEN are idiosyncratic, immune-mediated dermatologic pathologies that are characterized by necrosis and subsequent detachment of the epidermis. Stevens-Johnson syndrome and TEN are essentially the same, and they are distinguished only by the extent of dermal involvement, with Stevens-Johnson syndrome being less severe than TEN. If the dermal involvement is <10% this indicates Stevens-Johnson syndrome, > 30% indicates TEN, and a 10%-30% involvement is Stevens-Johnson Syndrome-Ten overlap.”

14. Mild overdose or poisoning from carbamazepine will typically cause b. tachycardia.

“Mild poisoning will typically cause ataxia, decreased bowel sounds. drowsiness, nystagmus, and tachycardia. Patients who have ingested large amounts may develop arrhythmias, bradycardia, coma, dystonias, hypotension, QRS and QTc prolongation, respiratory depression, and seizures. The signs and symptoms, particularly the level of CNS depression, can wax and wane in intensity.”

15. Standard treatment of carbamazepine overdose is c. to treat the symptoms and provide supportive care.

“There is no antidote for a carbamazepine overdose. Treatment should be symptomatic and supportive. Multiple doses of activated charcoal (MDAC) is no longer considered a standard treatment for carbamazepine overdose, and gastric lavage and whole bowel irrigation should not be used.”

53 nursece4less.com nursece4less.com nursece4less.com nursece4less.com References

The References below include published works and in-text citations of published works that are intended as helpful material for your further reading.

1. Lexicomp (2018). Carbamazepine. UpToDate. Retrieved from https://www.uptodate.com/contents/carbamazepine-drug- information?search=carbamazepine&source=search_result&selectedTit le=1~148&usage_type=default&display_rank=1#F50987676. 2. Equetro (2016). Package Insert. Parsippany, NJ: Validus Pharmaceuticals. Retrieved from http://equetro.com/static/pdf/equetro-prescribing-info.pdf. 3. Tegretol (2018). Package Insert. East Hanover, NJ: Novartis Pharmaceuticals; Retrieved from https://www.pharma.us.novartis.com/sites/www.pharma.us.novartis.c om/files/tegretol.pdf. 4. Kearney TE. (2012). Carbamazepine. In: Olsen KR, Anderson IB, Benowitz NL, Blanc PD, Clark RF, Kearney TE, Kim-Katz SY, Wu AHB, eds. Poisoning & Drug Overdose. 7th ed. McGraw-Hill Education: New York, NY;178-181. 5. O'Bryant CL, Cheng D, et al (2016). American Heart Association Clinical Pharmacology and Heart Failure and Transplantation Committees of the Council on Clinical Cardiology; Council on Cardiovascular Surgery and Anesthesia; Council on Cardiovascular and Stroke Nursing; and Council on Quality of Care and Outcomes Research. Drugs That May Cause or Exacerbate Heart Failure: A Scientific Statement from the American Heart Association. Circulation. 2016;134(6): e32-e69. 6. Reau N. (2016). Hepatic ductopenia and vanishing bile duct syndrome. UpToDate. Retrieved from https://www.uptodate.com/contents/hepatic-ductopenia-and- vanishing-bile-duct- syndrome?search=vanishing%20bile%20duct%20syndrome.&source= search_result&selectedTitle=1~8&usage_type=default&display_rank= 1. 7. Singal AK, Anderson KE. (2017). and hepatoerythropoietic porphyria: Management and prognosis. UpToDate. Retrieved from https://www.uptodate.com/contents/porphyria-cutanea-tarda-and- hepatoerythropoietic-porphyria-management-and- prognosis?search=porphyria%20cutanea%20tarda&source=search_res ult&selectedTitle=2~57&usage_type=default&display_rank=2#H5157 82.

54 nursece4less.com nursece4less.com nursece4less.com nursece4less.com 8. American Geriatrics Society (2015). Beers Criteria Update Expert Panel. American Geriatrics Society 2015 updated Beers Criteria for potentially inappropriate medication use in older adults. J Am Geriatr Soc. 2015;63(11):2227-2246. 9. Lexicomp (2018). Drug Interactions: Carbamazepine. UpToDate. Retrieved from https://www.uptodate.com/drug- interactions/?source=responsive_home#di-analyze. 10. Muneer A. (2017). Mixed states in bipolar disorder: Etiology, pathogenesis and treatment. Chonnam Med J. 2017;53(1):1-13. 11. Weisler RH, Hirschfeld R, Cutler, et al. (2006). Extended-release carbamazepine capsules as monotherapy in bipolar disorder: pooled results from two randomised, double-blind, placebo-controlled trials. CNS Drugs. 2006;20(3):219–231. 12. Pichler EM, Hattwich G, Grunze H, Muehlbacher M. (2015). Safety and tolerability of anticonvulsant medication in bipolar disorder. Expert Opin Drug Saf. 2015;14(11):1703-1724. 13. Fountoulakis KN, Yatham L, Grunze H, et al. (2017). The International College of Neuro-Psychopharmacology (CINP) Treatment Guidelines for Bipolar Disorder in Adults (CINP-BD-2017), Part 2: Review, Grading of the Evidence, and a Precise Algorithm. Int J Neuropsychopharmacol. 2017;20(2):121-179. 14. Takeshima M. (2017). Treating mixed mania/hypomania: review and synthesis of the evidence. CNS Spectr. 2017;22:177–185. 15. Stoval J. (2018). Bipolar disorder in adults: Choosing pharmacotherapy for acute mania and hypomania. UpToDate. Retrieved from https://www.uptodate.com/contents/bipolar-disorder- in-adults-choosing-pharmacotherapy-for-acute-mania-and- hypomania?search=Biploar%20disorder%20carbamazepine&source=s earch_result&selectedTitle=1~150&usage_type=default&display_rank =1. 16. Betzler F, Stöver LA, Sterzer P, Köhler S. (2017). Mixed states in bipolar disorder - changes in DSM-5 and current treatment recommendations. Int J Psychiatry Clin Pract. 2017;21(4):244-258. 17. Schachter SC. (2018). Evaluation and management of the first seizure in adults. UpToDate. Retrieved from https://www.uptodate.com/contents/evaluation-and-management-of- the-first-seizure-in- adults?search=tonic%20clonic%20seizure&source=search_result&sele ctedTitle=2~150&usage_type=default&display_rank=2. 18. Benbadis SR. (2018). Localization-related (focal) epilepsy: Causes and clinical features. UpToDate. Retrieved from https://www.uptodate.com/contents/localization-related-focal- epilepsy-causes-and-clinical-

55 nursece4less.com nursece4less.com nursece4less.com nursece4less.com features?search=temporal%20lobe%20seizures&source=search_result &selectedTitle=1~65&usage_type=default&display_rank=1#H7 19. Karceski S. (2017). Initial treatment of epilepsy in adults. UpToDate. Retrieved from https://www.uptodate.com/contents/initial-treatment- of-epilepsy-in-adults?topicRef=2231&source=see_link#H33. 20. Barton L, Gore L, Hornecker J, Haire M. (2017). Eslicarbazepine and other treatment advances for focal seizures. US Pharm. 2017;42(1): HS21-HS24. 21. Glauser T, Ben-Menachem E, Bourgeois B, et al. (2013). Updated ILAE evidence review of antiepileptic drug efficacy and effectiveness as initial monotherapy for epileptic seizures and syndromes. Epilepsia. 2013;54(3):551-563. 22. Nevitt SJ, Marson AG, Weston J, Tudur Smith C. (2017). Carbamazepine versus phenytoin monotherapy for epilepsy: an individual participant data review. Cochrane Database Syst Rev. 2017 Feb 27;2:CD001911. 23. Baulac M, Patten A, Giorgi L. (2014). Long-term safety and efficacy of zonisamide versus carbamazepine monotherapy for treatment of partial seizures in adults with newly diagnosed epilepsy: results of a phase III, randomized, double-blind study. Epilepsia. 2014; 55(10):1534-1543. 24. Baulac M, Brodie MJ, Patten A, Segieth J, Giorgi L. (2012). Efficacy and tolerability of zonisamide and controlled release carbamazepine in newly diagnosed partial epilepsy: a phase 3, randomized, double-blind, non-inferiority trial. Lancet Neurol. 2012; 11(7):579–588. 25. Trinka E, Ben-Menachem E, Kowacs PA, et al. (2018). Efficacy and safety of eslicarbazepine acetate versus controlled-release carbamazepine monotherapy in newly diagnosed epilepsy: A phase III double-blind, randomized, parallel-group, multicenter study. Epilepsia. 2018;59(2):479-491. 26. Striano P, Belcastro V. (2017). Update on pharmacotherapy of myoclonic seizures. Expert Opin Pharmacother. 2017;18(2):187-193. 27. Ferlazzo E, Trenite DK, Haan GJ, et al. (2017). Update on pharmacological treatment of progressive myoclonus epilepsies. Curr Pharm Des. 2017;23(37):5662-5666. 28. Guerrini R, Belmonte A, Genton P. (1998) Antiepileptic drug-induced worsening of seizures in children. Epilepsia. 1998;39:S2–S10. 29. Kenyon K, Mintzer S, Nei M. (2014). Carbamazepine treatment of generalized tonic-clonic seizures in idiopathic generalized epilepsy. Seizure. 2014;23(3):234-236. 30. Somerville ER. (2009) Some treatments cause seizure aggravation in idiopathic epilepsies (especially absence epilepsy). Epilepsia 2009; 50(Suppl. 8):31–36.

56 nursece4less.com nursece4less.com nursece4less.com nursece4less.com 31. Gayatri NA, Livingston JH. (2006). Aggravation of epilepsy by anti- epileptic drugs. Dev Med Child Neurol. 2006;48(5):394-398. 32. Chaves J, Sander JW. (2005). Seizure aggravation in idiopathic generalized epilepsies. Epilepsia. 2005;46 Suppl 9:133-139. 33. Baiwa ZH, Ho CC, Khan SA. (2018). Trigeminal neuralgia. UpToDate. Retrieved from https://www.uptodate.com/contents/trigeminal- neuralgia?topicRef=3355&source=see_link. 34. Feller L, Khammissa RAG, Fourie J, Bouckaert M, Lemmer J. (2017). Postherpetic neuralgia and trigeminal neuralgia. Pain Res Treat. 2017:1681765. 35. Yang F, Lin Q, Dong L, Gao X, Zhang S. (2018). Efficacy of 8 different drug treatments for patients with trigeminal neuralgia: A network meta-analysis. Clin J Pain. 2018;34(7):685-690. 36. Oomens MA, Forouzanfar T. (2015). Pharmaceutical management of trigeminal neuralgia in the elderly. Drugs & Aging. 2015;32(9):717– 726. 37. Di Stefano G, La Cesa S, Truini A, Cruccu G. (2014). Natural history and outcome of 200 outpatients with classical trigeminal neuralgia treated with carbamazepine or oxcarbazepine in a tertiary centre for neuropathic pain. J Headache Pain. 2014 Jun 9;15:34. 38. Bajwa ZH, Cho CC, Khan SA, Garza I. (2018). Overview of craniofacial pain. UpToDate. Retrieved from https://www.uptodate.com/contents/overview-of-craniofacial- pain?search=glossopharyngeal%20neuralgia&source=search_result&s electedTitle=1~6&usage_type=default&display_rank=1. 39. Gaitour E, Nick ST, Roberts C, et al. (2012). Glossopharyngeal neuralgia secondary to vascular compression in a patient with multiple sclerosis: a case report. J Med Case Rep. 2012 Jul 19;6:213. 40. High WA, Roujeau J-C. (2017). Stevens-Johnson syndrome and toxic epidermal necrolysis: Pathogenesis, clinical manifestations, and diagnosis. UpToDate. Retrieved from https://www.uptodate.com/contents/stevens-johnson-syndrome-and- toxic-epidermal-necrolysis-pathogenesis-clinical-manifestations-and- diagnosis?topicRef=2092&source=see_link. 41. Kodliwadmath A. (2017). Phenytoin-induced Stevens-Johnson syndrome with myocarditis: a rare case report. Int Med Case Rep J. 2017;10:229-231 42. Al-Quteimat OM. (2016). Phenytoin-induced toxic epidermal necrolysis: Review and recommendations. J Pharmacol Pharmacother. 2016;7(3):127-132. 43. Ordoñez L, Salgueiro E, Jimeno FJ, Manso G. (2015). Spontaneous reporting of Stevens-Johnson syndrome and toxic epidermal necrolysis associated with antiepileptic drugs. Eur Rev Med Pharmacol Sci. 2015;19(14):2732-2737.

57 nursece4less.com nursece4less.com nursece4less.com nursece4less.com 44. Trivedi BS, Darji NH, Malhotra SD, Patel PR. (2016). Antiepileptic drug- induced Stevens-Johnson syndrome: A case series. J Basic Clin Pharm. 2016;8(1):42-44. 45. High WA, Roujeaua J-C. (2017). Stevens-Johnson syndrome and toxic epidermal necrolysis: Management, prognosis, and long-term sequelae. UpToDate. Retrieved from https://www.uptodate.com/contents/stevens-johnson-syndrome-and- toxic-epidermal-necrolysis-management-prognosis-and-long-term- sequelae?search=stevens%20johnson%20syndrome%20treatment&so urce=search_result&selectedTitle=1~150&usage_type=default&displa y_rank=1. 46. Pannu BS, Egan AM, Iyer VN. (2016). Phenytoin induced Stevens- Johnson syndrome and bronchiolitis obliterans - case report and review of literature. Respir Med Case Rep. 2016;17:54-56 47. Egunsola O, Star K, Juhlin K, Kardaun SH, Choonara I, Sammons HM. (2017). Retrospective review of paediatric case reports of Stevens- Johnson syndrome and toxic epidermal necrolysis with lamotrigine from an international pharmacovigilance database. BMJ Paediatr Open. 2017 Aug 4;1(1):e000039. 48. Chouchi M, Kaabachi W, Tizaoui K, Daghfous R, Aidli SE, Hila L. (2018). The HLA-B*15:02 polymorphism and Tegretol®-induced serious cutaneous reactions in epilepsy: An updated systematic review and meta-analysis. Rev Neurol (Paris). 2018;174(5):278-291. 49. Sukasem C, Chaichan C, Nakkrut T, et al. (2018). Association between HLA-B Alleles and carbamazepine-induced maculopapular exanthema and severe cutaneous reactions in Thai patients. J Immunol Res. 2018 Jan 10;2018:2780272. 50. Wang Q, Sun S, Xie M, Zhao K, Li X, Zhao Z. (2017). Association between the HLA-B alleles and carbamazepine-induced SJS/TEN: A meta-analysis. Epilepsy Res. 2017 Sep;135:19-28. 51. Trivedi BS, Darji NH, Malhotra SD, Patel PR. (2016). Antiepileptic drugs-induced Stevens-Johnson syndrome: A case series. J Basic Clin Pharm. 2016;8(1):42-44. 52. Schachter SC. (2018). Antiseizure drugs: Mechanism of action, pharmacology, and adverse effects. UpToDate. Retrieved from https://www.uptodate.com/contents/antiseizure-drugs-mechanism-of- action-pharmacology-and-adverse- effects?sectionName=Carbamazepine&topicRef=8374&anchor=H3&sou rce=see_link#H3. 53. Handoko KB, Souverein PC, van Staa TP, et al. (2006). Risk of aplastic anemia in patients using antiepileptic drugs. Epilepsia. 2006;47(7):1232-1236.

58 nursece4less.com nursece4less.com nursece4less.com nursece4less.com 54. Blackburn SC, Oliart AD, Garcia Rodriguez LA, et al. (1998). Antiepileptics and blood dyscrasias: a cohort study. Pharmacotherapy. 1998; 18(6):1277–1783. 55. Intravooth T, Staack AM, Juerges K, Stockinger J, Steinhoff BJ. (2018). Antiepileptic drugs-induced hyponatremia: Review and analysis of 560 hospitalized patients. Epilepsy Res. 2018 Jul;143:7-10. 56. Sekiya N, Awazu M. (2018). A case of nephrogenic syndrome of inappropriate antidiuresis caused by carbamazepine. CEN Case Rep. 2018;7(1):66-68. 57. Berghuis B, van der Palen J, de Haan GJ, et al. (2017). Carbamazepine- and oxcarbazepine-induced hyponatremia in people with epilepsy. Epilepsia. 2017;58(7):1227-1233. 58. Berghuis B, de Haan GJ, van den Broek MP, Sander JW, Lindhout D, Koeleman BP. (2016). Epidemiology, pathophysiology and putative genetic basis of carbamazepine- and oxcarbazepine-induced hyponatremia. Eur J Neurol. 2016;23(9):1393-1399. 59. Gandhi S, McArthur E, Mamdani MM, et al. (2016). Antiepileptic drugs and hyponatremia in older adults: Two population-based cohort studies. Epilepsia. 2016;57(12):2067-2079. 60. Sterns RH. (2017). Pathophysiology and etiology of the syndrome of inappropriate antidiuretic hormone secretion (SIADH). UpToDate. Retrieved from https://www.uptodate.com/contents/pathophysiology- and-etiology-of-the-syndrome-of-inappropriate-antidiuretic-hormone- secretion- siadh?sectionName=ETIOLOGY&topicRef=2374&anchor=H8&source=s ee_link#H11 61. van der Lubbe N, Thompson CJ, Zietse R, Hoorn EJ. (2009). The clinical challenge of SIADH-three cases. NDT Plus; 2(Suppl_3):iii20- iii24. 62. Choi H, Mendiratta A. (2017). Treatment of seizures and epilepsy in older adults. UpToDate. Retrieved from https://www.uptodate.com/contents/treatment-of-seizures-and- epilepsy-in-older- adults?search=hepatic%20impairment%20epilepsy&source=search_re sult&selectedTitle=6~150&usage_type=default&display_rank=6. 63. Bruun E, Virta LJ, Kälviäinen R, Keränen T. (2105). Choice of the first anti-epileptic drug in elderly patients with newly diagnosed epilepsy: A Finnish retrospective study. Seizure. 2015;31:27-32. 64. Lexicomp (2018). Drug Interactions: Carbamazepine. UpToDate. Retrieved from https://www.uptodate.com/drug- interactions/?source=responsive_home#di-analyze. 65. Ruscin JM. (2014). Pharmacokinetics in the elderly. Merck Manual: Professional Version. Retrieved from

59 nursece4less.com nursece4less.com nursece4less.com nursece4less.com https://www.merckmanuals.com/professional/geriatrics/drug-therapy- in-the-elderly/pharmacokinetics-in-the-elderly. 66. Schmucker DL, Sanchez H. (2011). Liver regeneration and aging: a current perspective. Curr Gerontol Geriatr Res. 2011; 2011:526379. 67. Rule AD, Glassock RJ. (2016). The aging kidney. UpToDate. Retrieved from https://www.uptodate.com/contents/the-aging- kidney?search=Renal%20function%20and%20the%20elderly&source= search_result&selectedTitle=1~150&usage_type=default&display_rank =1 68. Arif H, Buchsbaum R, Pierro J, et al. (2010). Comparative effectiveness of 10 antiepileptic drugs in older adults with epilepsy. Arch Neurol. 2010;67(4):408-415. 69. National Institutes of Health (2018). LiverTox: Carbamazepine. NIH. Retrieved from https://livertox.nlm.nih.gov/Carbamazepine.htm. 70. Roujeau J-C. (2018). Drug reaction with eosinophilia and systemic symptoms (DRESS). UpToDate. Retrieved from https://www.uptodate.com/contents/drug-reaction-with-eosinophilia- and-systemic-symptoms-dress?source=history_widget. 71. Watanabe H. (2018). Recent advances in drug-induced hypersensitivity syndrome/drug reaction with eosinophilia and systemic symptoms. J Immunol Res. 2018 Mar 18;2018:5163129. 72. De A, Rajagopalan M, Sarda A, Das S, Biswas P. (2018). Drug reaction with eosinophilia and systemic symptoms: An update and review of recent literature. Indian J Dermatol. 2018;63(1):30-40. 73. Mehrholz D, Urban AE, Herstowska M, Nowicki R, Cubała W, Barańska- Rybak W. (2017). [Article in English, Polish]. A retrospective study of DRESS - drug reaction with eosinophilia and systemic symptoms. Psychiatr Pol. 2017;51(6):1079-1093. 74. Ksouda K, Affes H, Mahfoudh N, et al. (2017). HLA-A*31:01 and carbamazepine-induced DRESS syndrome in a sample of North African population. Seizure. 2017 Dec;53:42-46. 75. Lee JY, Lee SY, Hahm JE, Ha JW, Kim CW, Kim SS. (2017). Clinical features of drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome: a study of 25 patients in Korea. Int J Dermatol. 2017 Sep;56(9):944-951. 76. Brown SC, Dauterive RL. (2017). Anticonvulsant hypersensitivity syndrome secondary to carbamazepine. Proc (Bayl Univ Med Cent). 2017;30(1):94-96. 77. E L omairi N, Abourazzak S, Chaouki S, Atmani S, Hida M. (2014). Drug reaction with eosinophilia and systemic symptom (DRESS) induced by carbamazepine: a case report and literature review. Pan Afr Med J. 2014 May 2;18:9.

60 nursece4less.com nursece4less.com nursece4less.com nursece4less.com 78. Patrice Cacoub, Philippe Musette, Vincent Descamps. (2011). The DRESS syndrome: A literature review. Am J Med. 2011;124(7):588- 597. 79. Mayan H, Golubev N, Dinour D, Farfel Z. (2001). Lithium intoxication due to carbamazepine-induced renal failure. Ann Pharmacother. 2001;35(5):560-562. 80. Jubert P, Almirall J, Casanovas A, Garcia M. (1994). Carbamazepine- induced acute renal failure. Nephron. 1994;66(1):121. 81. Seitz CS, Pfeuffer P, Raith P, Bröcker EB, Trautmann A. (2006). Anticonvulsant hypersensitivity syndrome: cross-reactivity with tricyclic antidepressant agents. Ann Allergy Asthma Immunol. 2006;97(5):698-702. 82. Lexicomp (2018). Drug Interactions: UpToDate. Tricyclic Antidepressants/Carbamazepine. Retrieved from https://www.uptodate.com/drug- interactions/?source=responsive_home#di-document. 83. Lexicomp (2018). Drug Interactions: Monoamine Oxidase Inhibitors/Carbamazepine. UpToDate. Retrieved from https://www.uptodate.com/drug- interactions/?source=responsive_home#di-document. 84. Lexicomp (2018). Drug Interactions: Nefazodone/Carbamazepine. UpToDate. Retrieved from https://www.uptodate.com/drug- interactions/?source=responsive_home#di-document. 85. Lexicomp (2018). Drug Interactions: Boceprevir / Carbamazepine. UpToDate. Retrieved from https://www.uptodate.com/drug- interactions/?source=responsive_home#di-document. 86. Lexicomp (2018). Drug Interactions: Delavirdine / Carbamazepine. UpToDate. Retrieved from https://www.uptodate.com/drug- interactions/?source=responsive_home#di-document. 87. Hmouda H, Ben Salem C, Grira M, Slim R, Bouraoui K. (2007). Carbamazepine-induced urinary retention. Br J Clin Pharmacol. 2007;64(6):833-834. 88. Can İ Tholakanahalli V. (2016). Carbamazepine-induced atrioventricular block in an elderly woman. Turk Kardiyol Dern Ars. 2016;44(1):68-70. 89. Celik IE, Akyel A, Colgecen M, Ozeke O. (2015). A rare cause of 2:1 atrioventricular block: carbamazepine. Am J Emerg Med. 2015;33(10):1541.e3-e4. 90. Koutsampasopoulos K, Zotos A, Papamichalis M, Papaioannou K. (2014). Carbamazepine induced atrial tachycardia with complete AV block. Hippokratia. 2014;18(2):185-186. 91. Faisy C, Guerot E, Diehl JL, Rezgui N, Labrousse J. (2000). Carbamazepine-associated severe left ventricular dysfunction. J Toxicol Clin Toxicol. 2000;38(3):339–342.

61 nursece4less.com nursece4less.com nursece4less.com nursece4less.com 92. Apfelbaum JD, Caravati EM, Kerns WP 2nd, Bossart PJ, Larsen G. (1995). Cardiovascular effects of carbamazepine toxicity. Ann Emerg Med. 1995;25(5):631–635. 93. Tibballs J. (1992). Acute toxic reaction to carbamazepine: clinical effects and serum concentrations. J Pediatr. 1992;121(2):295–299. 94. Terrence CF, Fromm G. (1980). Congestive heart failure during carbamazepine therapy. Ann Neurol. 1980;8(2):200–201. 95. Anderson KE. (2018). Porphyrias: An overview. UpToDate. Retrieved from https://www.uptodate.com/contents/porphyrias-an- overview?search=hepatic%20porphyria&source=search_result&selecte dTitle=1~150&usage_type=default&display_rank=1. 96. Sood GK, Anderson KE. (2018). Acute intermittent porphyria: Pathogenesis, clinical features, and diagnosis. UpToDate. Retrieved from https://www.uptodate.com/contents/acute-intermittent- porphyria-pathogenesis-clinical-features-and- diagnosis?topicRef=7101&source=see_link#H10089558 97. American Porphyria Foundation. Drug Database. Retrieved from http://www.porphyriafoundation.com/drug-database/. 98. U.S. Food and Drug Administration. (2008). Information for Healthcare Professionals: Suicidality and Antiepileptic Drugs. 99. U.S. Food and Drug Administration. (2008). Statistical Review and Evaluation. Antiepileptic Drugs. May 23, 2008. Retrieved online from http://www.fda.gov/ohrms/dockets/ac/08/briefing/2008-4372b1-01- FDA.pdf. 100. Mula M, Kanner AM, Schmitz B, Schachter S. (2013). Antiepileptic drugs and suicidality: an expert consensus statement from the Task Force on Therapeutic Strategies of the ILAE Commission on Neuropsychobiology. Epilepsia. 2013 Jan;54(1):199-203. 101. Ramos AM, Gayotto LC, Clemente CM, Mello ES, Luz KG, Freitas ML. (2002). Reversible vanishing bile duct syndrome induced by carbamazepine. Eur J Gastroenterol Hepatol. 2002;14(9):1019-1922. 102. Forbes GM, Jeffrey GP, Shilkin KB, Reed WD. (1992). Carbamazepine hepatotoxicity: another cause of the vanishing bile duct syndrome. Gastroenterology. 1992;102(4 Pt 1):1385-1388. 103. U.S. National Library of Medicine (nd). TOXNET. LactMed: Carbamazepine. Retrieved from https://www.toxnet.nlm.nih.gov/cgi- bin/sis/search2/f?./temp/~ROO7VJ:1. 104. Veroniki AA, Cogo E, Rios P, e al. (2017). Comparative safety of anti- epileptic drugs during pregnancy: a systematic review and network meta-analysis of congenital malformations and prenatal outcomes. BMC Med. 2017 May 5;15(1):95. 105. Schachter SC. (2016). Management of epilepsy and pregnancy. UpToDate. Retrieved from https://www.uptodate.com/contents/management-of-epilepsy-and-

62 nursece4less.com nursece4less.com nursece4less.com nursece4less.com pregnancy?search=epilepsy%20pregnancy&source=search_result&sele ctedTitle=1~150&usage_type=default&display_rank=1#H8. 106. Thangaratinam S, Marlin N, Newton S, et al. (2018). AntiEpileptic drug Monitoring in PREgnancy (EMPiRE): a double-blind randomised trial on effectiveness and acceptability of monitoring strategies. Health Technol Assess. 2018 May;22(23):1-152 107. Goetzl LM. (2018). Folic acid supplementation in pregnancy. UpToDate. Retrieved from https://www.uptodate.com/contents/folic- acid-supplementation-in-pregnancy?topicRef=2224&source=see_link. 108. Sveberg L, Vik K, Henriksen T, Taubøll E. (2015). Women with epilepsy and post-partum bleeding--Is there a role for vitamin K supplementation? Seizure. 2015 May;28:85-7. 109. Kazmin A, Wong RC, Sermer M, Koren G. (2010). Antiepileptic drugs in pregnancy and hemorrhagic disease of the newborn: an update. [Article in English, French]. Can Fam Physician. 2010;56(12):1291- 1292. 110. Rezvani M, Koren G. (2006). Does vitamin K prophylaxis prevent bleeding in neonates exposed to enzyme-inducing antiepileptic drugs in utero? Can Fam Physician. 2006;52:721-722 111. Dinç D, Schulte PFJ. (2018). [The use of anticonvulsants and the levels of folate, vitamin B12 and homocysteine]. [Article in Dutch]. Tijdschr Psychiatr. 2018;60(1):20-28 112. Shakir S, Ali N, Nazish H, et al. (2018). Carbamazepine versus valproic Acid as monotherapy in epileptic patients. J Coll Physicians Surg Pak. 2018;28(5):357-360. 113. Sharma TK, Vardey SK, Sitaraman S. (2016). Serum homocysteine, folate, and vitamin B12 levels in carbamazepine treated epileptic children. Clin Lab. 2016;62(7):1217-1224. 114. Rosenson RS, Kang DS. (2018). Overview of homocysteine. UpToDate. Retrieved from https://www.uptodate.com/contents/overview-of- homocysteine?search=hyperhomocysteinemia&source=search_result& selectedTitle=1~150&usage_type=default&display_rank=1#H2. 115. Kim DW, Kim HK, Bae EK. (2017). The effects of lifestyle modification and statin therapy on the circulatory markers for vascular risk in patients with epilepsy. Epilepsy Behav. 2017;76:133-135. 116. Schachter SC. (2018). Overview of the management of epilepsy in adults. UpToDate. Retrieved from https://www.uptodate.com/contents/overview-of-the-management-of- epilepsy-in-adults?topicRef=2221&source=see_link. 117. Lai Q, Shen C, Zheng Y, Zhang Y, Guo Y, Ding M. (2017). Effects of antiepileptic drugs on the carotid artery intima-media thickness in epileptic patients. J Clin Neurol. 2017;13(4):371-379. 118. Bano S, Zuberi NA, Alam SM. (2017). Correlation between hyperhomocysteinemia and common carotid artery intima media

63 nursece4less.com nursece4less.com nursece4less.com nursece4less.com thickness in carbamazepine treated epileptic patients using ultrasonography. Pak J Med Sci. 2017;33(5):1205-1209. 119. Zuberi NA, Baig M, Bano S, Batool Z, Haider S, Perveen T. (2017). Assessment of atherosclerotic risk among patients with epilepsy on valproic acid, lamotrigine, and carbamazepine treatment. Neurosciences (Riyadh). 2017;22(2):114-118. 120. El-Farahaty RM, El-Mitwalli A, Azzam H, Wasel Y, Elrakhawy MM, Hasaneen BM. (2015). Atherosclerotic effects of long-term old and new antiepileptic drugs monotherapy: a cross-sectional comparative study. J Child Neurol. 2015;30(4):451-457. 121. Hiemke C, Bergemann N, Clement HW, et al. (2018). Consensus guidelines for therapeutic drug monitoring in neuropsychopharmacology: Update 2017. Pharmacopsychiatry. 2018;51(1-02):9-62. 122. Micromedex (2018). Poisindex: Carbamazepine. Retrieved from www.dhha.org. 123. Greene S, O’Connor A. (2018). Carbamazepine poisoning. UpToDate. Retrieved from https://www.uptodate.com/contents/carbamazepine- poisoning?search=carbamazepine%20toxicity&source=search_result&s electedTitle=2~148&usage_type=default&display_rank=5#H4. 124. Schirwani, S., et al (2017). Carbamazepine Improves Apneic Episodes in Congenital Central Hypoventilation Syndrome (CCHS) With a Novel PHOX2B Exon 1 Missense Mutation. J Clin Sleep Med. 13(11): 1359– 1362. Retrieved from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5656487/. 125. American College of Obstetricians and Gynecologists (2015). The Apgar score. Committee Opinion No. 644. American College of Obstetricians and Gynecologists. Obstet Gynecol;126:e52–5. Retrieved from https://www.acog.org/Clinical-Guidance-and- Publications/Committee-Opinions/Committee-on-Obstetric- Practice/The-Apgar-Score.

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