Carbamazepine Injection

Name: Carbamazepine Injection

Indications

CARNEXIV is indicated as replacement therapy for oral carbamazepine formulations, when oral administration is temporarily not feasible, in adults with the following seizure types:

  • Partial seizures with complex symptomatology
  • Generalized tonic-clonic seizures
  • Mixed seizure patterns which include the above, or other partial or generalized seizures

Limitations Of Usage

CARNEXIV is not indicated for the treatment of absence seizures (including atypical absence). Carbamazepine has been associated with increased frequency of generalized convulsions in these patients.

Overdose

Signs, Symptoms And Laboratory Findings Of Acute Oral Carbamazepine Overdosage

Acute Toxicity

Lowest known lethal oral dose: adults, 3.2 g (a 24-year-old woman died of cardiac arrest and a 24-year-old man died of pneumonia and hypoxic encephalopathy); children, 4 g (a 14-year-old girl died of a cardiac arrest), 1.6 g (a 3year-old girl died of aspiration pneumonia).

The first signs and symptoms appear 1 to 3 hours after oral carbamazepine administration. Neurologic disturbances are the most prominent. Cardiovascular disorders are generally milder, and severe cardiac complications occur only when very high doses (greater than 60 g) have been ingested.

In a study of carbamazepine intoxications, peak serum levels of carbamazepine below 19.9 mcg/mL were associated with few incidences of severe toxicity (e.g., 1 out of 26 patients were in a coma). Peak serum levels of carbamazepine 19.9 to 39.9 mcg/mL were associated with increased incidences of severe toxicity (e.g., 9 out of 33 patients were in a coma), while peak levels above 40 mcg/mL were always (3 out of 3 patients) associated with a severe toxicity-like coma. Likewise, the incidences of seizures and requirement for mechanical ventilation were correlated with plasma concentrations.

Signs And Symptoms

Respiration

Irregular breathing, respiratory depression

Cardiovascular System

Tachycardia, hypotension or hypertension, shock, conduction disorders

Neurological Disturbances

Impairment of consciousness ranging in severity to deep coma. Convulsions, especially in small children. Motor restlessness, muscular twitching, tremor, athetoid movements, opisthotonos, ataxia, drowsiness, dizziness, mydriasis, nystagmus, adiadochokinesia, ballism, psychomotor disturbances, dysmetria. Initial hyperreflexia, followed by hyporeflexia.

Gastrointestinal Tract

Nausea, vomiting

Kidneys and Bladder

Anuria or oliguria, urinary retention

Laboratory Findings

Isolated instances of overdosage have included leukocytosis, reduced leukocyte count, glycosuria, and acetonuria. Electrocardiogram may show dysrhythmias.

Combined Poisoning

When alcohol, tricyclic antidepressants, barbiturates, or hydantoins are taken at the same time, the signs and symptoms of acute poisoning with carbamazepine may be aggravated or modified.

Management Of Overdosage

Contact a certified Poison Control Center for up-to-date information on the management of overdose with carbamazepine. There is no specific antidote for overdose with CARNEXIV. Consider the possibility of multiple drug overdose. Monitor cardiac rhythm and vital signs. Ensure an adequate airway, oxygenation, and ventilation.

Clinical pharmacology

Mechanism Of Action

The mechanism by which carbamazepine exerts its anticonvulsant activity is unknown. The principal metabolite of carbamazepine, carbamazepine-10,11-epoxide, has demonstrated anticonvulsant activity in in vivo animal models of seizures. However, its contribution to the therapeutic effect of carbamazepine is unknown.

Pharmacokinetics

Carbamazepine

Plasma levels of carbamazepine are variable and may range from 0.5 to 25 mcg/mL, with no apparent relationship to the daily intake of the drug. Usual adult therapeutic levels are between 4 and 12 mcg/mL. In patients on concomitant medications, the concentration of carbamazepine and concomitant drugs may be increased or decreased, and drug effects may be altered [see DRUG INTERACTIONS].

Bioavailability

The conversion factor for switching patients from oral dose to intravenous dose is 70%. Following adjustment of the intravenous dose by the 70% conversion factor, daily plasma exposures of carbamazepine following 15-minute or 30-minute infusions every 6 hours were comparable to those observed following oral dosing. The pharmacokinetics of carbamazepine-10,11-epoxide were similar following both intravenous and oral dosing.

Distribution

Carbamazepine is 76% bound to plasma proteins and carbamazepine-10,11-epoxide is 50% bound to plasma proteins.

Metabolism

Carbamazepine is primarily metabolized in the liver. CYP3A4 was identified as the major isoform responsible for the formation of carbamazepine-10,11-epoxide. Human microsomal epoxide hydrolase has been identified as the enzyme responsible for the formation of the 10,11-transdiol derivative from carbamazepine-10,11-epoxide. Since carbamazepine induces its own metabolism, the half-life is also variable. Autoinduction is completed after 3 to 5 weeks of a fixed dosing regimen. Initial half-life values range from 25 to 65 hours, decreasing to 12 to 17 hours on repeated doses. The apparent oral clearance was 25±5 mL/min following a single dose and 80±30 mL/min following multiple dosing.

Elimination

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

Specific Populations

Age

Geriatric Population

The pharmacokinetics of carbamazepine in geriatric patients have not been evaluated.

Age

Pediatric Population

The pharmacokinetics of CARNEXIV in pediatric and adolescent patients have not been evaluated.

Sex

No difference in the mean area under the concentration-time curve (AUC) and peak plasma concentrations (Cmax) of carbamazepine and carbamazepine-10,11-epoxide was found between males and females.

Race

The effect of race on the pharmacokinetics of carbamazepine has not been established.

Renal Impairment

Carbamazepine clearance was comparable between patients with normal renal function and patients with mild renal impairment (creatinine clearance 60 to 89 mL/min) for both oral carbamazepine and intravenous CARNEXIV. The effects of moderate and severe renal impairment (creatinine clearance 30 to 59 mL/min and 15 to 29 mL/min, respectively) on carbamazepine pharmacokinetics are not known [see DOSAGE AND ADMINISTRATION, WARNINGS AND PRECAUTIONS].

The accumulation of sulfobutylether beta-cyclodextrin sodium salt, a potentially nephrotoxic ingredient of CARNEXIV was comparable between patients with normal renal function and mild renal impairment after 7 days of CARNEXIV treatment. Sulfobutylether beta-cyclodextrin sodium salt is known to accumulate in patients with moderate to severe renal impairment.

Hepatic Impairment

The effect of hepatic impairment on the pharmacokinetics of carbamazepine is not known. Patients with hepatic impairment may experience elevated concentrations when switching from oral to intravenous carbamazepine administration (in comparison to patients with normal hepatic function) due to reduction of the first-pass effect [see Use In Specific Populations].

Clinical Studies

The efficacy of CARNEXIV is based upon bioavailability studies comparing oral carbamazepine to CARNEXIV [see CLINICAL PHARMACOLOGY].

Side effects

The following serious adverse reactions are discussed in more detail in other sections of the labeling:

  • Serious Dermatologic Reactions: Toxic epidermal necrolysis and Stevens-Johnson syndrome [see BOX WARNING, WARNINGS AND PRECAUTIONS]
  • Aplastic Anemia/Agranulocytosis [see BOX WARNING, WARNINGS AND PRECAUTIONS]
  • Impairment of Renal Function [see WARNINGS AND PRECAUTIONS]
  • Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)/Multiorgan Hypersensitivity [see WARNINGS AND PRECAUTIONS]
  • Suicidal Behavior and Ideation [see WARNINGS AND PRECAUTIONS]
  • Embryofetal Toxicity [see WARNINGS AND PRECAUTIONS]
  • Abrupt Discontinuation and Seizure Risk [see WARNINGS AND PRECAUTIONS]
  • Hyponatremia [see WARNINGS AND PRECAUTIONS]
  • Potential Impairment of Neurologic Function [see WARNINGS AND PRECAUTIONS]
  • Hepatic Toxicity [see WARNINGS AND PRECAUTIONS]
  • Increased Intraocular Pressure [see WARNINGS AND PRECAUTIONS]
  • Hepatic Porphyria [see WARNINGS AND PRECAUTIONS]

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Clinical Trial Experience With CARNEXIV

The data described below are based on an open-label 7-day study with CARNEXIV in 98 patients, and an open-label 5-day study with CARNEXIV in 105 patients. All infusions were administered in equally divided doses given separately every 6 hours. Of the 203 patients in the studies, 160 received multiple 15-minute infusions and 43 received multiple 30-minute infusions. Most patients received a total daily intravenous dose ranging from 280 mg to 1,120 mg (equivalent to total daily oral dose of 400 mg to 1,600 mg) in divided doses given every 6 hours. Eight patients received up to 1,400 mg total daily intravenous dose (equivalent to total daily oral dose of 2,000 mg).

The most common adverse reactions in all patients during treatment with CARNEXIV (incidence greater than or equal to 2%) were dizziness, somnolence, blurred vision, diplopia, headache, infusion-related reaction, infusion site pain, and anemia (Table 4).

Table 4. Most Common Adverse Reactions* During Treatment with CARNEXIV

Adverse Reactions** 15 min Infusion† (n=160) % 30 min Infusion
(n=43)
%
Total Incidence
(N=203)
%
Dizzinesss 21 9 18
Somnolence 7 5 6
Blurred vision 6 5 5
Diplopia 4 5 4
Headache 4 0 3
Infusion-related reaction 3 0 2
Infusion site pain 3 0 2
Anemia 1 7 2
*Incidence greater than or equal to 2%
**3.6% of 4088 infusions of CARNEXIV were delivered over 2 to 5 minutes during the study. This was faster than the recommended 30-minute infusion rate. The most common adverse reaction was dizziness (11%).
†Infusion rate two times more rapid than recommended

Other notable adverse reactions occurring in less than 2% of patients included hyponatremia, atrial tachycardia, and electrocardiogram T wave inversion.

Clinical Trial Experience With Oral Carbamazepine (Tegretol® And Tegretol®-XR)

The most common adverse reactions seen with oral carbamazepine treatment, particularly during the initial phases of therapy, were dizziness, drowsiness, unsteadiness, nausea, and vomiting.

Postmarketing Experience

The following adverse reactions have been identified during post-approval use of oral carbamazepine formulations. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

The most serious adverse reactions previously observed with oral carbamazepine were reported in the hematopoietic system and skin, the liver, and in the cardiovascular system.

Hematopoietic System

Pancytopenia, bone marrow depression, thrombocytopenia, leukopenia, leukocytosis, eosinophilia

Skin

Acute Generalized Exanthematous Pustulosis (AGEP), pruritic and erythematous rashes, urticaria, photosensitivity reactions, alterations in skin pigmentation, erythema multiforme and nodosum, purpura, aggravation of disseminated lupus erythematosus, alopecia, diaphoresis, onychomadesis, and hirsutism. In certain cases, discontinuation of therapy may be necessary.

Cardiovascular System

Congestive heart failure, edema, aggravation of hypertension, hypotension, syncope and collapse, aggravation of coronary artery disease, arrhythmias and AV block, thrombophlebitis, thromboembolism (e.g., pulmonary embolism), and adenopathy or lymphadenopathy

Some of these cardiovascular complications have resulted in fatalities. Myocardial infarction has been associated with other tricyclic compounds.

Pancreatic

Pancreatitis

Respiratory System

Pulmonary hypersensitivity characterized by fever, dyspnea, pneumonitis, or pneumonia

Genitourinary System

Urinary frequency, acute urinary retention, oliguria with elevated blood pressure, azotemia, renal failure, and impotence. Albuminuria, glycosuria, elevated blood urea nitrogen (BUN), and microscopic deposits in the urine have also been reported. There have been rare reports of impaired male fertility and/or abnormal spermatogenesis.

Nervous System Confusion, fatigue, visual hallucinations, oculomotor disturbances, nystagmus, speech disturbances, abnormal involuntary movements, peripheral neuritis and paresthesias, depression with agitation, talkativeness, tinnitus, hyperacusis

There have been reports of associated paralysis and other symptoms of cerebral arterial insufficiency, but the exact relationship of these reactions to the drug has not been established.

Isolated cases of neuroleptic malignant syndrome have been reported both with and without concomitant use of psychotropic drugs.

Digestive System

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

Eyes

Scattered punctate cortical lens opacities, increased intraocular pressure [see WARNINGS AND PRECAUTIONS] as well as conjunctivitis, have been reported.

Musculoskeletal System

Aching joints and muscles, and leg cramps

Metabolism

Hyponatremia [see WARNINGS AND PRECAUTIONS]. Decreased levels of plasma calcium, and osteoporosis

Laboratory Tests

Thyroid function tests (T3, T4) – decreased values

Other

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

A case of aseptic meningitis, accompanied by myoclonus and peripheral eosinophilia, has been reported in a patient taking carbamazepine in combination with other medications.

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