CARNEXIV

1 INDICATIONS AND USAGE 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. CARNEXIV is indicated as replacement therapy for oral carbamazepine formulations, when oral administration is temporarily not feasible, in adults with the following seizure types ( 1 ): Partial seizures with complex symptomatology Generalized tonic-clonic seizures Mixed seizure patterns which include the above, or other partial or generalized seizures

6 ADVERSE REACTIONS 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 Boxed Warning , Warnings and Precautions ( 5.1 )] Aplastic Anemia/Agranulocytosis [see Boxed Warning , Warnings and Precautions ( 5.2 )] Impairment of Renal Function [see Warnings and Precautions ( 5.3 )] Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)/Multiorgan Hypersensitivity [see Warnings and Precautions ( 5.4 )] Hypersensitivity [see Warnings and Precautions ( 5.5 )] Suicidal Behavior and Ideation [see Warnings and Precautions ( 5.6 )] Embryofetal Toxicity [see Warnings and Precautions ( 5.7 )] Abrupt Discontinuation and Seizure Risk [see Warnings and Precautions ( 5.8 )] Hyponatremia [see Warnings and Precautions ( 5.9 )] Potential Impairment of Neurologic Function [see Warnings and Precautions ( 5.10 )] Hepatic Toxicity [see Warnings and Precautions ( 5.11 )] Increased Intraocular Pressure [see Warnings and Precautions ( 5.12 )] Hepatic Porphyria [see Warnings and Precautions ( 5.13 )] Most common adverse reactions with CARNEXIV (incidence greater than or equal to 2%) were dizziness, somnolence, blurred vision, diplopia, headache, infusion-related reaction, infusion site pain, and anemia ( 6.1 ) The most common adverse reactions with oral carbamazepine were dizziness, drowsiness, unsteadiness, nausea, and vomiting ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Lundbeck at 1-800-455-1141 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 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) % Dizziness 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. 6.2 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 ( 5.12 )] as well as conjunctivitis, have been reported. Musculoskeletal System Aching joints and muscles, and leg cramps Metabolism Hyponatremia [see Warnings and Precautions ( 5.9 )] . 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.

4 CONTRAINDICATIONS CARNEXIV is contraindicated in patients with: Bone marrow depression [see Warnings and Precautions ( 5.2 )] Known hypersensitivity to carbamazepine [see Warnings and Precautions ( 5.5 )] Known hypersensitivity to any of the tricyclic antidepressants (e.g., amitriptyline, imipramine, and nortriptyline ) [see Drug Interactions ( 7.1 )] Concomitant use of boceprevir; CARNEXIV can reduce boceprevir concentrations through induction of CYP3A4; this can diminish boceprevir’s virologic activity [see Drug Interactions ( 7.1 )] Use of monoamine oxidase inhibitors (MAOIs) within the past 14 days; concomitant use can cause serotonin syndrome [see Drug Interactions ( 7.3 )] Concomitant use of nefazodone; this may result in insufficient plasma concentrations of nefazodone and its active metabolite to achieve a therapeutic effect [see Drug Interactions ( 7.1 )] Concomitant use of delavirdine or other non-nucleoside reverse transcriptase inhibitors. CARNEXIV can substantially reduce the concentrations of these drugs through induction of CYP3A4. This can lead to loss of virologic response and possible resistance to these medications [see Drug Interactions ( 7.1 )] Bone marrow depression ( 4 , 5.2 ) Hypersensitivity to carbamazepine ( 4 , 5.5 ) Hypersensitivity to tricyclic antidepressants ( 4 , 7.1 ) Concomitant use of boceprevir ( 4 , 7.1 ). Use of MAOIs within the past 14 days ( 4 , 7.3 ) Concomitant use of nefazodone ( 4 , 7.1 ) Concomitant use with delavirdine or other non-nucleoside reverse transcriptase inhibitors ( 4 , 7.1 )

11 DESCRIPTION CARNEXIV (carbamazepine) injection is available as a clear, colorless, sterile solution for intravenous infusion. The chemical name of carbamazepine, an anticonvulsant, is 5 H -dibenz[ b,f ]azepine-5-carboxamide, and its molecular weight is 236.27. It has the following structural formula: Carbamazepine is a white to off-white powder, practically insoluble in water and soluble in alcohol and in acetone. CARNEXIV injection is supplied in single-dose 20 mL vials containing 200 mg carbamazepine. Each mL contains 10 mg of carbamazepine, 250 mg of betadex sulfobutyl ether sodium, and 0.78 mg of sodium phosphate monobasic dihydrate in water for injection. The product may contain sodium hydroxide and/or hydrochloric acid for pH adjustment to pH 6.2. Structural Formula

2 DOSAGE AND ADMINISTRATION CARNEXIV total daily dose is 70% of the total daily dose of oral carbamazepine from which patients are being switched; divide the total daily dose of CARNEXIV equally in four infusions separated by 6 hours; dilute each dose of CARNEXIV in 100 mL of diluent and infuse intravenously over 30 minutes ( 2.1 , 2.2 ) Use of CARNEXIV is not recommended for periods longer than 7 days ( 2.1 ) Closely monitor patients with renal impairment; CARNEXIV should generally not be used in patients with moderate or severe renal impairment ( 2.3 , 5.3 ) 2.1 Dosage Information CARNEXIV is a replacement therapy for oral carbamazepine. Carbamazepine treatment should generally be initiated with an oral carbamazepine formulation. The total daily dose of CARNEXIV is 70% of the total daily oral carbamazepine dose from which patients are being switched (see Table 1). The total daily dose of CARNEXIV should be equally divided in four 30-minute infusions, separated by 6 hours. Patients should be switched back to oral carbamazepine administration at their previous total daily oral dose and frequency of administration as soon as clinically appropriate. The use of CARNEXIV for periods of more than 7 days has not been studied. Table 1. Determination of Total Daily Dose for CARNEXIV Infusion Total Daily Oral Carbamazepine Dose (mg/day) Corresponding Total Daily Dose of CARNEXIV (mg/day) Dose of CARNEXIV to be administered every 6 hours (mg) 400 280 70 600 420 105 800 560 140 1,000 700 175 1,200 840 210 1,400 980 245 1,600 1,120 280 2.2 Administration Information CARNEXIV is for intravenous use only and must be diluted in a compatible diluent prior to infusion. Using Table 2 as a guide, prepare the solution for each infusion by transferring the single dose volume of CARNEXIV to 100 mL of diluent solution (0.9% sodium chloride, lactated Ringer's solution, or 5% dextrose) and mixing gently. Before administration, the prepared solution for infusion may be stored for a maximum of 4 hours at 20°C to 25°C (68°F to 77°F) or a maximum of 24 hours if refrigerated at 2°C to 8°C (36°F to 46°F). Parenteral drug products should be inspected visually for particulate matter, cloudiness, or discoloration prior to administration, whenever solution and container permit. If any of these are present, discard the solution. Administer each infusion intravenously over 30 minutes. CARNEXIV injection vials are for single-dose only. Discard any unused portion. Table 2. CARNEXIV Dose to Volume and Infusion Table CARNEXIV Single Dose (mg/every 6 hours) CARNEXIV Single Dose Volume (Vials Required) Diluent Volume Infusion Duration Dose Frequency 70 7 mL (1) 100 mL 30 min Every 6 hours 105 10.5 mL (1) 140 14 mL (1) 175 17.5 mL (1) 210 21 mL (2) 245 24.5 mL (2) 280 28 mL (2) 2.3 Renal Function Monitoring Patients with renal impairment may be at greater risk for an adverse effect of CARNEXIV on renal function, and should have close monitoring of renal function during treatment with CARNEXIV. CARNEXIV should generally not be used in patients with moderate or severe renal impairment [see Warnings and Precautions ( 5.3 ) and Use in Specific Populations ( 8.6 )] . 2.4 Serum Level Monitoring Monitor serum carbamazepine concentrations in conditions in which alterations in carbamazepine metabolism can occur. This includes patients who have hepatic impairment and patients on drugs that either induce or inhibit carbamazepine metabolism [see Warnings and Precautions ( 5.11 , 5.13 ), Drug Interactions ( 7.2 ) and Use in Specific Populations ( 8.7 )] . 2.5 Laboratory Testing Prior to Carbamazepine Initiation Prior to initial treatment with carbamazepine, test patients with ancestry in genetically at-risk populations for the presence of the HLA-B*1502 allele. The high resolution genotype test is positive if one or two HLA-B*1502 alleles are present. Avoid use of CARNEXIV in patients testing positive for the allele, unless the benefit clearly outweighs the risk [see Boxed Warning and Warnings and Precautions ( 5.1 )] . Complete pretreatment blood counts, including platelets and possibly reticulocytes and serum iron, should be obtained as a baseline. If a patient in the course of treatment exhibits low or decreased white blood cell or platelet counts, the patient should be monitored closely. Discontinuation of CARNEXIV should be considered if any evidence of significant bone marrow depression develops [see Warnings and Precautions ( 5.2 )]. Baseline and periodic evaluations of liver function, particularly in patients with a history of liver disease, must be performed during treatment with carbamazepine because liver damage may occur. Discontinue CARNEXIV in cases of aggravated liver dysfunction or active liver disease [see Warnings and Precautions ( 5.11 )] .

10 OVERDOSAGE 10.1 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 a 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 3-year-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. 10.2 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.

7 DRUG INTERACTIONS Carbamazepine may reduce plasma concentrations of concomitant medications metabolized by CYP1A2, 2B6, 2C9/19, and 3A4 ( 7.1 ) CYP3A4 inhibitors can increase plasma carbamazepine levels ( 7.2 ) CYP3A4 inducers can decrease carbamazepine levels ( 7.2 ) 7.1 Effects of CARNEXIV on Other Drugs Carbamazepine is a potent inducer of hepatic CYP1A2, 2B6, 2C9/19 and 3A4 and may reduce plasma concentrations of concomitant medications mainly metabolized by CYP1A2, 2B6, 2C9/19, and 3A4 through induction of their metabolism (see Tables 5 and 6). Table 5. Effects of Carbamazepine on Other Drugs Concomitant Drug Name Effect of Carbamazepine on Other Drugs Clinical Recommendation Boceprevir Decrease in boceprevir levels Coadministration of carbamazepine with boceprevir is contraindicated Acetaminophen, albendazole, alprazolam, aprepitant, buprenorphone, bupropion, citalopram, clonazepam, clozapine, corticosteroids (e.g., prednisolone, dexamethasone), cyclosporine, dicumarol, dihydropyridine calcium channel blockers (e.g., felodipine), doxycycline, eslicarbazepine, ethosuximide, everolimus, haloperidol, imatinib, itraconazole, lamotrigine, levothyroxine, methadone, methsuximide, mianserin, midazolam, olanzapine, oral and other hormonal contraceptives, oxcarbazepine, paliperidone, phensuximide, phenytoin, praziquantel, protease inhibitors, risperidone, sertraline, sirolimus, tadalafil, theophylline, tiagabine, topiramate, tramadol, trazodone, tricyclic antidepressants (e.g., imipramine, amitriptyline, nortriptyline), valproate, warfarin, ziprasidone, zonisamide Decrease in concomitant drug levels Monitor the concentration and consider a dosage adjustment of the concomitant drug(s) Cyclophosphamide Increase in cyclo-phosphamide levels (potential for increased toxicity) Monitor for signs of increased cyclophosphamide toxicity Aripiprazole Decrease in aripiprazole levels When carbamazepine is added to aripiprazole, the aripiprazole dose should be doubled; additional dose increases should be based on clinical evaluation; when carbamazepine is withdrawn from the combination therapy, the aripiprazole dose should be reduced Tacrolimus Decrease in tacrolimus levels Monitor tacrolimus blood concentrations and make appropriate dosage adjustments Temsirolimus Decrease in temsirolimus levels The use of concomitant strong CYP3A4 inducers such as carbamazepine should be avoided with temsirolimus; if carbamazepine must be coadministered with temsirolimus, consider adjusting the dosage of temsirolimus Lapatinib Decrease in lapatinib levels The use of carbamazepine with lapatinib should generally be avoided; dosage adjustment should be considered if lapatinib is coadministered with carbamazepine; if carbamazepine is started in a patient already taking lapatinib, the dose of lapatinib should be gradually titrated up; if carbamazepine is discontinued, the lapatinib dose should be reduced Nefazodone Decrease in nefazodone levels Coadministration of carbamazepine with nefazodone is contraindicated Valproate Decrease in valproate levels Monitor valproate concentrations when carbamazepine is introduced or withdrawn in patients using valproic acid Table 6. Effects of Carbamazepine on Other Drugs (Continued) Concomitant Drug Name Effect of Carbamazepine on Other Drugs Clinical Recommendation Lithium May increase the risk of neurotoxic side effects Use with intensive monitoring Isoniazid May increase isoniazid-induced hepatotoxicity Diuretics (e.g., hydrochlorothiazide, furosemide) May lead to symptomatic hyponatremia Hormonal contraceptives (e.g., oral and levonorgestrel subdermal implant contraceptives) May render the contraceptives less effective because the plasma concentrations of the hormones may be decreased; breakthrough bleeding and unintended pregnancies have been reported Consider alternative or back-up methods of contraception Neuromuscular blocking agents (e.g., pancuronium, vecuronium, rocuronium, and cisatracurium) Resistance to the neuromuscular blocking action of the non-depolarizing neuromuscular blocking agents Closely monitor patients for more rapid recovery from neuromuscular blockade than expected; infusion rate may need to be higher Direct acting oral anticoagulants (e.g., rivaroxaban, apixaban, dabigatran, and edoxaban) Decreased plasma concentrations of these anticoagulants that may be insufficient to achieve the intended therapeutic effect Coadministration with carbamazepine should generally be avoided Delavirdine or other non-nucleoside reverse transcriptase inhibitors (NNRTIs) Decrease in delavirdine or NNRTI levels Contraindicated with carbamazepine 7.2 Effects of Other Drugs on CARNEXIV CYP3A4 inhibitors inhibit CARNEXIV metabolism and can thus increase plasma carbamazepine levels. CYP3A4 inducers can increase the rate of CARNEXIV metabolism and thus decrease carbamazepine levels (see Table 7). Table 7. Effects of Other Drugs on Carbamazepine Concomitant Drug Name Effect of Concomitant Drug on Carbamazepine Clinical Recommendation Aprepitant, cimetidine, ciprofloxacin, danazol, diltiazem, delavirdine, macrolides, erythromycin, troleandomycin, clarithromycin, fluoxetine, fluvoxamine, trazodone, olanzapine, loratadine, terfenadine, omeprazole, oxybutynin, dantrolene, isoniazid, niacinamide, nicotinamide, ibuprofen, propoxyphene, azoles (e.g., ketaconazole, itraconazole, fluconazole, voriconazole), acetazolamide, verapamil, ticlopidine, grapefruit juice, protease inhibitors Increase in carbamazepine level (by CYP3A4 inhibition) Closely monitor carbamazepine levels; dosage adjustment may be required Cisplatin, doxorubicin HCl, felbamate, fosphenytoin, rifampin, phenobarbital, phenytoin, primidone, methsuximide, theophylline, aminophylline Decrease in carbamazepine level (by CYP3A4 induction) Loxapine, quetiapine and valproic acid Decrease in carbamazepine level and increase in metabolite (carbamazepine-10,11-epoxide) levels (both by inhibition of human microsomal epoxide hydrolase) Closely monitor carbamazepine levels; dosage adjustment may be required 7.3 Pharmacodynamic Drug Interactions Monoamine Oxidase Inhibitors Concomitant treatment with CARNEXIV is contraindicated during use of an MAOI or within 14 days after discontinuing an MAOI. Concomitant use can cause serotonin syndrome.

12 CLINICAL PHARMACOLOGY 12.1 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. 12.3 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 ( 7 )] . 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 14 C-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 (C max ) 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 ( 2.3 ), Warnings and Precautions ( 5.3 )] . 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 ( 8.7 )] .

12.1 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.

12.3 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 ( 7 )] . 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 14 C-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 (C max ) 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 ( 2.3 ), Warnings and Precautions ( 5.3 )] . 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 ( 8.7 )] .

20211201

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3 DOSAGE FORMS AND STRENGTHS CARNEXIV injection contains 200 mg/20 mL (10 mg/mL) carbamazepine as a clear, colorless, sterile solution in a single dose-vial. Injection: 200 mg/20 mL (10 mg/mL) single-dose vial ( 3 )

CARNEXIV Carbamazepine CARBAMAZEPINE CARBAMAZEPINE SODIUM PHOSPHATE, MONOBASIC, DIHYDRATE SODIUM HYDROXIDE HYDROCHLORIC ACID SULFOBUTYLETHER .BETA.-CYCLODEXTRIN WATER

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenicity Oral administration of carbamazepine to rats for 2 years at doses of 25, 75, and 250 mg/kg/day resulted in a dose-related increase in the incidence of hepatocellular tumors (females) and of benign interstitial cell adenomas in the testes. Mutagenicity Carbamazepine was negative in in vitro bacterial and mammalian genotoxicity studies. Impairment of Fertility The effects of carbamazepine on male and female fertility have not been adequately studied.

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenicity Oral administration of carbamazepine to rats for 2 years at doses of 25, 75, and 250 mg/kg/day resulted in a dose-related increase in the incidence of hepatocellular tumors (females) and of benign interstitial cell adenomas in the testes. Mutagenicity Carbamazepine was negative in in vitro bacterial and mammalian genotoxicity studies. Impairment of Fertility The effects of carbamazepine on male and female fertility have not been adequately studied.

NDA206030

CARNEXIV

Carbamazepine

67386-621

HUMAN PRESCRIPTION DRUG

INTRAVENOUS

PRINCIPAL DISPLAY PANEL NDC 67386-621-52 Single Use Vial Carnexiv ™ (carbamazepine) Injection 200 mg/20mL 10 mg/mL For Intravenous use only. MUST BE DILUTED PRIOR TO INFUSION. NDC 67386-621-52 Single Use Vial Carnexiv™ (carbamazepine) Injection 200 mg/20mL 10 mg/mL For Intravenous use only. MUST BE DILUTED PRIOR TO INFUSION.

17 PATIENT COUNSELING INFORMATION Serious Dermatological Reactions Advise patients that serious skin reactions have been reported in association with carbamazepine especially if they are of Asian ancestry and/or have screened positive for the presence of the HLA-B*1502 gene [see Boxed Warning , Warnings and Precautions (5.1)]. Aplastic Anemia and Agranulocytosis Inform patients and caregivers about the risk of potentially fatal agranulocytosis and aplastic anemia and the signs and symptoms that may signal these reactions. Advise them to report these signs and symptoms immediately [see Boxed Warning , Warnings and Precautions ( 5.2 )] . Drug Reaction with Eosinophilia and Systemic Symptoms Inform patients of the early signs and symptoms of DRESS and the potential later hematologic, dermatologic, hepatic, and other organ system reactions. Advise them that these signs and symptoms may signal a serious reaction and to report any occurrence immediately to their healthcare provider [see Warnings and Precautions ( 5.4 ) ] . Anaphylaxis and Angioedema Advise patients that anaphylactic reactions and angioedema may occur during treatment with CARNEXIV and that they should immediately report signs and symptoms suggesting angioedema (swelling of the face, eyes, lips, or tongue, or difficulty in swallowing or breathing) to their healthcare provider. Advise patients who experience signs or symptoms suggesting anaphylaxis or angioedema to stop taking the drug until they have consulted with their healthcare provider [see Warnings and Precautions ( 5.5 )] . Suicidal Behavior and Ideation Counsel patients, their caregiver(s), and families that AEDs, including CARNEXIV, may increase the risk of suicidal thoughts and behavior and advise them of the need to be alert for the emergence or worsening of symptoms of depression, any unusual changes in mood or behavior, or the emergence of suicidal thoughts, behavior, or thoughts of self-harm. Tell them to report behaviors of concern immediately to healthcare providers [see Warnings and Precautions ( 5.6 )]. Drug Interactions Carbamazepine may interact with some drugs. Therefore, advise patients to report to their doctors the use of any other prescription or nonprescription medications or herbal products [see Drug Interactions ( 7.1 , 7.2 )] . Effects on Driving or Operating Machinery Advise patients to use caution if alcohol is taken in combination with CARNEXIV therapy, due to a possible additive sedative effect. Since dizziness and drowsiness may occur, caution patients about the hazards of operating machinery or automobiles or engaging in other potentially dangerous tasks. Pregnancy Advise women of childbearing potential that CARNEXIV may cause fetal harm. Instruct patients to notify their physician if they become pregnant or intend to become pregnant during therapy. Advise patients that there is a pregnancy exposure registry that collects information about the safety of antiepileptic drugs during pregnancy [see Warnings and Precautions ( 5.7 ) , Use in Specific Populations ( 8.1 ) ] . Manufactured by: Baxter Pharmaceuticals Solutions, LLC, Bloomington, IN 47403, U.S.A. For: Lundbeck, Deerfield, IL 60015, U.S.A. CARNEXIV is a trademark of Lundbeck All other trademarks or registered trademarks are the property of their respective owners Company logo

14 CLINICAL STUDIES The efficacy of CARNEXIV is based upon bioavailability studies comparing oral carbamazepine to CARNEXIV [see Clinical Pharmacology ( 12.3 ) ] .

8.5 Geriatric Use No studies in geriatric patients have been conducted with CARNEXIV.

8.2 Lactation Risk Summary Carbamazepine and its epoxide metabolite are excreted in human milk. There are no data to assess the effects of carbamazepine or its metabolites on milk production, or on the breastfed infant, of mothers taking CARNEXIV. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for CARNEXIV and any potential adverse effects on the breastfed infant from CARNEXIV or from the underlying maternal condition.

8.4 Pediatric Use Safety and effectiveness in pediatric patients have not been established.

8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to antiepileptic drugs (AEDs), including CARNEXIV, during pregnancy. Encourage women who are taking CARNEXIV during pregnancy to enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry. This can be done by calling the toll-free number 1-888-233-2334 or visiting http://www.aedpregnancyregistry.org , and must be done by the patient herself. Risk Summary Carbamazepine can cause fetal harm when administered to a pregnant woman. An association between the use of carbamazepine during pregnancy and congenital malformations, including spina bifida and malformations involving other body systems (e.g., craniofacial defects and cardiovascular malformations) has been demonstrated. Developmental delays have been reported. In animal studies, administration of carbamazepine during pregnancy resulted in developmental toxicity, including increased incidences of fetal malformations. Women of childbearing potential should be informed of the potential risk to the fetus. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. The background risk of major birth defects and miscarriage for the indicated population is unknown. Clinical Considerations Disease-associated Maternal and/or Embryofetal Risk Consideration should be given to discontinuing carbamazepine in women who are pregnant or attempting to become pregnant if the benefits of discontinuation outweigh the risks of recurrent seizures. Women with epilepsy should not discontinue carbamazepine abruptly due to the risk of status epilepticus and less severe seizures which may be life-threatening. Fetal/Neonatal Adverse Reactions There have been a few cases of neonatal seizures and/or respiratory depression associated with maternal carbamazepine in combination with other antiepileptic drugs. A few cases of neonatal vomiting, diarrhea, and/or decreased feeding have also been reported in association with maternal carbamazepine use. These symptoms may represent a neonatal withdrawal syndrome. Tests to detect birth defects using currently accepted procedures should be considered a part of routine prenatal care in childbearing women receiving carbamazepine. Evidence suggests that folic acid supplementation prior to conception and during the first trimester of pregnancy decreases the risk for congenital neural tube defects in the general population. It is not known whether the risk of neural tube defects in the offspring of women receiving carbamazepine is reduced by folic acid supplementation, but dietary folic acid supplementation both prior to conception and during pregnancy should be recommended for patients using carbamazepine. Data Human Data Pregnancy registry and epidemiological data suggest that there may be an association between the use of carbamazepine during pregnancy and congenital malformations, including spina bifida and malformations involving other body systems (e.g., craniofacial defects and cardiovascular malformations). The North American Antiepileptic Drug (NAAED) Pregnancy Registry has reported a rate of major congenital malformations of 3.0% (95% CI: 2.1, 4.2) among mothers exposed to carbamazepine monotherapy (n=1,033) during the first trimester with a relative risk of 2.7 (95% CI: 1.0, 7.0) compared to pregnant women not taking an antiepileptic drug. There have also been postmarketing reports of developmental delays based on neurobehavioral assessments. Animal Data In studies in which pregnant rodents were administered carbamazepine orally during organogenesis, dose-related increases in the rates of fetal structural abnormalities (craniofacial, skeletal, cardiac, and urogenital defects), intrauterine growth retardation, and embryofetal death occurred at clinically relevant doses.

8 USE IN SPECIFIC POPULATIONS Hepatic Impairment: monitor carbamazepine concentrations ( 8.7 ) 8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to antiepileptic drugs (AEDs), including CARNEXIV, during pregnancy. Encourage women who are taking CARNEXIV during pregnancy to enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry. This can be done by calling the toll-free number 1-888-233-2334 or visiting http://www.aedpregnancyregistry.org , and must be done by the patient herself. Risk Summary Carbamazepine can cause fetal harm when administered to a pregnant woman. An association between the use of carbamazepine during pregnancy and congenital malformations, including spina bifida and malformations involving other body systems (e.g., craniofacial defects and cardiovascular malformations) has been demonstrated. Developmental delays have been reported. In animal studies, administration of carbamazepine during pregnancy resulted in developmental toxicity, including increased incidences of fetal malformations. Women of childbearing potential should be informed of the potential risk to the fetus. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. The background risk of major birth defects and miscarriage for the indicated population is unknown. Clinical Considerations Disease-associated Maternal and/or Embryofetal Risk Consideration should be given to discontinuing carbamazepine in women who are pregnant or attempting to become pregnant if the benefits of discontinuation outweigh the risks of recurrent seizures. Women with epilepsy should not discontinue carbamazepine abruptly due to the risk of status epilepticus and less severe seizures which may be life-threatening. Fetal/Neonatal Adverse Reactions There have been a few cases of neonatal seizures and/or respiratory depression associated with maternal carbamazepine in combination with other antiepileptic drugs. A few cases of neonatal vomiting, diarrhea, and/or decreased feeding have also been reported in association with maternal carbamazepine use. These symptoms may represent a neonatal withdrawal syndrome. Tests to detect birth defects using currently accepted procedures should be considered a part of routine prenatal care in childbearing women receiving carbamazepine. Evidence suggests that folic acid supplementation prior to conception and during the first trimester of pregnancy decreases the risk for congenital neural tube defects in the general population. It is not known whether the risk of neural tube defects in the offspring of women receiving carbamazepine is reduced by folic acid supplementation, but dietary folic acid supplementation both prior to conception and during pregnancy should be recommended for patients using carbamazepine. Data Human Data Pregnancy registry and epidemiological data suggest that there may be an association between the use of carbamazepine during pregnancy and congenital malformations, including spina bifida and malformations involving other body systems (e.g., craniofacial defects and cardiovascular malformations). The North American Antiepileptic Drug (NAAED) Pregnancy Registry has reported a rate of major congenital malformations of 3.0% (95% CI: 2.1, 4.2) among mothers exposed to carbamazepine monotherapy (n=1,033) during the first trimester with a relative risk of 2.7 (95% CI: 1.0, 7.0) compared to pregnant women not taking an antiepileptic drug. There have also been postmarketing reports of developmental delays based on neurobehavioral assessments. Animal Data In studies in which pregnant rodents were administered carbamazepine orally during organogenesis, dose-related increases in the rates of fetal structural abnormalities (craniofacial, skeletal, cardiac, and urogenital defects), intrauterine growth retardation, and embryofetal death occurred at clinically relevant doses. 8.2 Lactation Risk Summary Carbamazepine and its epoxide metabolite are excreted in human milk. There are no data to assess the effects of carbamazepine or its metabolites on milk production, or on the breastfed infant, of mothers taking CARNEXIV. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for CARNEXIV and any potential adverse effects on the breastfed infant from CARNEXIV or from the underlying maternal condition. 8.4 Pediatric Use Safety and effectiveness in pediatric patients have not been established. 8.5 Geriatric Use No studies in geriatric patients have been conducted with CARNEXIV. 8.6 Renal Impairment Though no dose adjustment is necessary for patients with mild renal impairment, close monitoring during CARNEXIV treatment should be conducted due to potential accumulation of sulfobutylether beta-cyclodextrin sodium salt. Accumulation of sulfobutylether beta-cyclodextrin sodium salt is associated with a greater risk for an adverse effect on renal function in patients with moderate or severe renal impairment. Therefore, CARNEXIV should generally not be used in patients with moderate or severe renal impairment [see Warnings and Precautions ( 5.3 ) and Clinical Pharmacology ( 12.3 )] . 8.7 Hepatic Impairment Monitor serum carbamazepine concentrations in patients with hepatic impairment treated with CARNEXIV, as the first-pass effect may be reduced in these patients [see Clinical Pharmacology ( 12.3 )] .

16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied CARNEXIV (carbamazepine) 200 mg/20 mL (10 mg/mL) injection is a clear, colorless, sterile solution. It is supplied in single-dose 20 mL glass vials, available in cartons of one vial (NDC 67386-621-52). Not made with natural rubber latex. 16.2 Storage and Handling Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature].

WARNING: SERIOUS DERMATOLOGIC REACTIONS and APLASTIC ANEMIA AND AGRANULOCYTOSIS Serious Dermatologic Reactions and HLA-B*1502 Allele Serious and sometimes fatal dermatologic reactions, including toxic epidermal necrolysis (TEN) and Stevens-Johnson syndrome (SJS), have occurred in patients treated with carbamazepine. There is a strong association between the risk of developing SJS/TEN and the presence of HLA-B*1502, an inherited allelic variant of the HLA-B gene that is found almost exclusively in patients with Asian ancestry. Avoid use of CARNEXIV in patients testing positive for the allele unless the benefit clearly outweighs the risk. Discontinue CARNEXIV if you suspect that the patient is having a serious dermatologic reaction [see Warnings and Precautions ( 5.1 )] . Aplastic Anemia and Agranulocytosis Aplastic anemia and agranulocytosis can occur during treatment with CARNEXIV. Obtain a complete blood count (CBC) before beginning treatment with CARNEXIV, and monitor CBC periodically. Consider discontinuing CARNEXIV if significant bone marrow depression develops [see Warnings and Precautions ( 5.2 )]. WARNING: SERIOUS DERMATOLOGIC REACTIONS and APLASTIC ANEMIA AND AGRANULOCYTOSIS See full prescribing information for complete boxed warning. Serious Dermatologic Reactions Serious and sometimes fatal dermatologic reactions, including toxic epidermal necrolysis (TEN) and Stevens-Johnson syndrome (SJS), have occurred with carbamazepine. Discontinue CARNEXIV if these reactions occur ( 5.1 ) Patients of Asian ancestry have a 10-fold greater risk of TEN/SJS, compared to other populations. Avoid use of CARNEXIV in genetically at-risk patients, including those positive for the HLA-B*1502 allele ( 5.1 ) Aplastic Anemia and Agranulocytosis Aplastic anemia and agranulocytosis can occur with CARNEXIV ( 5.2 ) Obtain complete CBC prior to initiation of CARNEXIV. Consider discontinuing CARNEXIV if significant bone marrow depression develops ( 5.2 )