Carnexiv Side Effects Center

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 BOXED WARNING, WARNINGS AND PRECAUTIONS]
• Aplastic Anemia/Agranulocytosis [see BOXED 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]
• 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) %
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.

Post Marketing 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 hiirsutism. 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.

DRUG INTERACTIONS

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 cyclophosphamide 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 nondepolarizing 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

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

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.

Read the entire FDA prescribing information for Carnexiv (Carbamazepine Injection)