Data from FDA (Food and Drug Administration, USA) - Curated by EPG Health - Last updated 12 April 2018

Indication(s)

1 INDICATIONS AND USAGE TRILEPTAL is indicated for use as monotherapy or adjunctive therapy in the treatment of partial seizures in adults and as monotherapy in the treatment of partial seizures in pediatric patients aged 4 years and above with epilepsy, and as adjunctive therapy in pediatric patients aged 2 years and above with partial seizures. TRILEPTAL is indicated for: Adults: Monotherapy or adjunctive therapy in the treatment of partial seizures Pediatrics: - Monotherapy in the treatment of partial seizures in children 4–16 years - Adjunctive therapy in the treatment of partial seizures in children 2–16 years (1)

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contraindications
4 CONTRAINDICATIONS TRILEPTAL is contraindicated in patients with a known hypersensitivity to oxcarbazepine or to any of its components, or to eslicarbazepine acetate [see Warnings and Precautions (5.2, 5.3)]. Known hypersensitivity to oxcarbazepine or to any of its components, or to eslicarbazepine acetate (4, 5.2)
Adverse reactions
6 ADVERSE REACTIONS The following serious adverse reactions are described below and elsewhere in the labeling: Hyponatremia [see Warnings and Precautions (5.1)] Anaphylactic Reactions and Angioedema [see Warnings and Precautions (5.2)] Cross Hypersensitivity Reaction to Carbamazepine [see Warnings and Precautions (5.3)] Serious Dermatological Reactions [see Warnings and Precautions (5.4)] Suicidal Behavior and Ideation [see Warnings and Precautions (5. 5 )] Cognitive/Neuropsychiatric Adverse Reactions [see Warnings and Precautions (5. 7 )] Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)/Multi-Organ Hypersensitivity [see Warnings and Precautions (5. 8 )] Hematologic Events [see Warnings and Precautions (5. 9 )] The most common (≥10% more than placebo for adjunctive or low dose for monotherapy) adverse reactions in adults and pediatrics were: dizziness, somnolence, diplopia, fatigue, nausea, vomiting, ataxia, abnormal vision, headache, nystagmus, tremor, and abnormal gait. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Novartis Pharmaceuticals Corporation at 1-888-669-6682 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. Most Common Adverse Reactions in All Clinical Studies Adjunctive Therapy/Monotherapy in Adults Previously Treated with O ther AEDs The most common (≥10% more than placebo for adjunctive or low dose for monotherapy) adverse reactions with TRILEPTAL: dizziness, somnolence, diplopia, fatigue, nausea, vomiting, ataxia, abnormal vision, headache, nystagmus tremor, and abnormal gait. Approximately 23% of these 1,537 adult patients discontinued treatment because of an adverse reaction. The adverse reactions most commonly associated with discontinuation were: dizziness (6.4%), diplopia (5.9%), ataxia (5.2%), vomiting (5.1%), nausea (4.9%), somnolence (3.8%), headache (2.9%), fatigue (2.1%), abnormal vision (2.1%), tremor (1.8%), abnormal gait (1.7%), rash (1.4%), hyponatremia (1.0%). Monotherapy in Adults Not Previously Treated with O ther AEDs The most common (≥5%) adverse reactions with TRILEPTAL in these patients were similar to those in previously treated patients. Approximately 9% of these 295 adult patients discontinued treatment because of an adverse reaction. The adverse reactions most commonly associated with discontinuation were: dizziness (1.7%), nausea (1.7%), rash (1.7%), headache (1.4%). Adjunctive Therapy/Monotherapy in Pediatric Patients 4 Years Old and Above Previously Treated with O ther AEDs The most common (≥5%) adverse reactions with TRILEPTAL in these patients were similar to those seen in adults. Approximately 11% of these 456 pediatric patients discontinued treatment because of an adverse reaction. The adverse reactions most commonly associated with discontinuation were: somnolence (2.4%), vomiting (2.0%), ataxia (1.8%), diplopia (1.3%), dizziness (1.3%), fatigue (1.1%), nystagmus (1.1%). Monotherapy in Pediatric Patients 4 Years Old and Above Not Previously Treated with O ther AEDs The most common (≥5%) adverse reactions with TRILEPTAL in these patients were similar to those in adults. Approximately 9.2% of 152 pediatric patients discontinued treatment because of an adverse reaction. The adverse reactions most commonly associated (≥1%) with discontinuation were rash (5.3%) and maculopapular rash (1.3%). Adjunctive Therapy/Monotherapy in Pediatric Patients 1 Month to <4 Years Old Previously Treated or Not Previously Treated with O ther AEDs: The most common (≥5%) adverse reactions with TRILEPTAL in these patients were similar to those seen in older children and adults except for infections and infestations which were more frequently seen in these younger children. Approximately 11% of these 241 pediatric patients discontinued treatment because of an adverse reaction. The adverse reactions most commonly associated with discontinuation were: convulsions (3.7%), status epilepticus (1.2%), and ataxia (1.2%). Controlled Clinical Studies of Adjunctive Therapy/Monotherapy in Adults Previously Treated with O ther AEDs Table 3 lists adverse reactions that occurred in at least 2% of adult patients with epilepsy, treated with TRILEPTAL or placebo as adjunctive treatment and were numerically more common in the patients treated with any dose of TRILEPTAL. Table 4 lists adverse reactions in patients converted from other AEDs to either high-dose TRILEPTAL (2400 mg/day) or low-dose (300 mg/day) TRILEPTAL. Note that in some of these monotherapy studies patients who dropped out during a preliminary tolerability phase are not included in the tables. Table 3: Adverse Reactions in a Controlled Clinical Study of Adjunctive Therapy with TRILEPTAL in Adults TRILEPTAL Dosage (mg/day) Body System/ Adverse Reaction TRILEPTAL 600 N=163 % TRILEPTAL 1200 N=171 % TRILEPTAL 2400 N=126 % Placebo N=166 % Body as a Whole Fatigue 15 12 15 7 Asthenia 6 3 6 5 Leg Edema 2 1 2 1 Increased Weight 1 2 2 1 Feeling Abnormal 0 1 2 0 Cardiovascular System Hypotension 0 1 2 0 Digestive System Nausea 15 25 29 10 Vomiting 13 25 36 5 Abdominal Pain 10 13 11 5 Diarrhea 5 6 7 6 Dyspepsia 5 5 6 2 Constipation 2 2 6 4 Gastritis 2 1 2 1 Metabolic and Nutritional Disorders Hyponatremia 3 1 2 1 Musculoskeletal System Muscle Weakness 1 2 2 0 Sprains and Strains 0 2 2 1 Nervous System Headache 32 28 26 23 Dizziness 26 32 49 13 Somnolence 20 28 36 12 Ataxia 9 17 31 5 Nystagmus 7 20 26 5 Abnormal Gait 5 10 17 1 Insomnia 4 2 3 1 Tremor 3 8 16 5 Nervousness 2 4 2 1 Agitation 1 1 2 1 Abnormal Coordination 1 3 2 1 Abnormal EEG 0 0 2 0 Speech Disorder 1 1 3 0 Confusion 1 1 2 1 Cranial Injury NOS 1 0 2 1 Dysmetria 1 2 3 0 Abnormal Thinking 0 2 4 0 Respiratory System Rhinitis 2 4 5 4 Skin and Appendages Acne 1 2 2 0 Special Senses Diplopia 14 30 40 5 Vertigo 6 12 15 2 Abnormal Vision 6 14 13 4 Abnormal Accommodation 0 0 2 0 Table 4: Adverse Reactions in Controlled Clinical Studies of Monotherapy with TRILEPTAL in Adults Previously Treated with Other AEDs Body System/ Adverse Reaction TRILEPTAL 2400 mg/day N=86 % TRILEPTAL 300 mg/day N=86 % Body as a Whole Fatigue 21 5 Fever 3 0 Allergy 2 0 Generalized Edema 2 1 Chest Pain 2 0 Digestive System Nausea 22 7 Vomiting 15 5 Diarrhea 7 5 Dyspepsia 6 1 Anorexia 5 3 Abdominal Pain 5 3 Dry Mouth 3 0 Hemorrhage Rectum 2 0 Toothache 2 1 Hemic and Lymphatic System Lymphadenopathy 2 0 Infections and Infestations Viral Infection 7 5 Infection 2 0 Metabolic and Nutritional Disorders Hyponatremia 5 0 Thirst 2 0 Nervous System Headache 31 15 Dizziness 28 8 Somnolence 19 5 Anxiety 7 5 Ataxia 7 1 Confusion 7 0 Nervousness 7 0 Insomnia 6 3 Tremor 6 3 Amnesia 5 1 Aggravated Convulsions 5 2 Emotional Lability 3 2 Hypoesthesia 3 1 Abnormal Coordination 2 1 Nystagmus 2 0 Speech Disorder 2 0 Respiratory System Upper Respiratory Tract Infection 10 5 Coughing 5 0 Bronchitis 3 0 Pharyngitis 3 0 Skin and Appendages Hot Flushes 2 1 Purpura 2 0 Special Senses Abnormal Vision 14 2 Diplopia 12 1 Taste Perversion 5 0 Vertigo 3 0 Earache 2 1 Ear Infection NOS 2 0 Urogenital and Reproductive System Urinary Tract Infection 5 1 Micturition Frequency 2 1 Vaginitis 2 0 Controlled Clinical Study of Monotherapy in Adults Not Previously Treated with O ther AEDs Table 5 lists adverse reactions in a controlled clinical study of monotherapy in adults not previously treated with other AEDs that occurred in at least 2% of adult patients with epilepsy treated with TRILEPTAL or placebo and were numerically more common in the patients treated with TRILEPTAL. Table 5: Adverse Reactions in a Controlled Clinical Study of Monotherapy with TRILEPTAL in Adults Not Previously Treated with Other AEDs Body System/ Adverse Reaction TRILEPTAL N=55 % Placebo N=49 % Body as a Whole Falling Down NOS 4 0 Digestive System Nausea 16 12 Diarrhea 7 2 Vomiting 7 6 Constipation 5 0 Dyspepsia 5 4 Musculoskeletal System Back Pain 4 2 Nervous System Dizziness 22 6 Headache 13 10 Ataxia 5 0 Nervousness 5 2 Amnesia 4 2 Abnormal Coordination 4 2 Tremor 4 0 Respiratory System Upper Respiratory Tract Infection 7 0 Epistaxis 4 0 Infection Chest 4 0 Sinusitis 4 2 Skin and Appendages Rash 4 2 Special Senses Vision Abnormal 4 0 Controlled Clinical Studies of Adjunctive Therapy/Monotherapy in Pediatric Patients Previously Treated with O ther AEDs Table 6 lists adverse reactions that occurred in at least 2% of pediatric patients with epilepsy treated with TRILEPTAL or placebo as adjunctive treatment and were numerically more common in the patients treated with TRILEPTAL. Table 6: Adverse Reactions in Controlled Clinical Studies of Adjunctive Therapy/Monotherapy with TRILEPTAL in Pediatric Patients Previously Treated with Other AEDs Body System/ Adverse Reaction TRILEPTAL N=171 % Placebo N=139 % Body as a Whole Fatigue 13 9 Allergy 2 0 Asthenia 2 1 Digestive System Vomiting 33 14 Nausea 19 5 Constipation 4 1 Dyspepsia 2 0 Nervous System Headache 31 19 Somnolence 31 13 Dizziness 28 8 Ataxia 13 4 Nystagmus 9 1 Emotional Lability 8 4 Abnormal Gait 8 3 Tremor 6 4 Speech Disorder 3 1 Impaired Concentration 2 1 Convulsions 2 1 Involuntary Muscle Contractions 2 1 Respiratory System Rhinitis 10 9 Pneumonia 2 1 Skin and Appendages Bruising 4 2 Increased Sweating 3 0 Special Senses Diplopia 17 1 Abnormal Vision 13 1 Vertigo 2 0 Other Events Observed in Association with the Administration of TRILEPTAL In the paragraphs that follow, the adverse reactions, other than those in the preceding tables or text, that occurred in a total of 565 children and 1,574 adults exposed to TRILEPTAL and that are reasonably likely to be related to drug use are presented. Events common in the population, events reflecting chronic illness and events likely to reflect concomitant illness are omitted particularly if minor. They are listed in order of decreasing frequency. Because the reports cite events observed in open label and uncontrolled trials, the role of TRILEPTAL in their causation cannot be reliably determined. Body as a Whole: fever, malaise, pain chest precordial, rigors, weight decrease. Cardiovascular System: bradycardia, cardiac failure, cerebral hemorrhage, hypertension, hypotension postural, palpitation, syncope, tachycardia. Digestive System: appetite increased, blood in stool, cholelithiasis, colitis, duodenal ulcer, dysphagia, enteritis, eructation, esophagitis, flatulence, gastric ulcer, gingival bleeding, gum hyperplasia, hematemesis, hemorrhage rectum, hemorrhoids, hiccup, mouth dry, pain biliary, pain right hypochondrium, retching, sialoadenitis, stomatitis, stomatitis ulcerative. Hematologic and Lymphatic System: thrombocytopenia. Laboratory Abnormality: gamma-GT increased, hyperglycemia, hypocalcemia, hypoglycemia, hypokalemia, liver enzymes elevated, serum transaminase increased. Musculoskeletal System: hypertonia muscle. Nervous System: aggressive reaction, amnesia, anguish, anxiety, apathy, aphasia, aura, convulsions aggravated, delirium, delusion, depressed level of consciousness, dysphonia, dystonia, emotional lability, euphoria, extrapyramidal disorder, feeling drunk, hemiplegia, hyperkinesia, hyperreflexia, hypoesthesia, hypokinesia, hyporeflexia, hypotonia, hysteria, libido decreased, libido increased, manic reaction, migraine, muscle contractions involuntary, nervousness, neuralgia, oculogyric crisis, panic disorder, paralysis, paroniria, personality disorder, psychosis, ptosis, stupor, tetany. Respiratory System: asthma, dyspnea, epistaxis, laryngismus, pleurisy. Skin and Appendages: acne, alopecia, angioedema, bruising, dermatitis contact, eczema, facial rash, flushing, folliculitis, heat rash, hot flushes, photosensitivity reaction, pruritus genital, psoriasis, purpura, rash erythematous, rash maculopapular, vitiligo, urticaria. Special Senses: accommodation abnormal, cataract, conjunctival hemorrhage, edema eye, hemianopia, mydriasis, otitis externa, photophobia, scotoma, taste perversion, tinnitus, xerophthalmia. Surgical and Medical Procedures: procedure dental oral, procedure female reproductive, procedure musculoskeletal, procedure skin. Urogenital and Reproductive System: dysuria, hematuria, intermenstrual bleeding, leukorrhea, menorrhagia, micturition frequency, pain renal, pain urinary tract, polyuria, priapism, renal calculus. Other: Systemic lupus erythematosus. Laboratory Tests Serum sodium levels below 125 mmol/L have been observed in patients treated with TRILEPTAL [see Warnings and Precautions (5.1)]. Experience from clinical trials indicates that serum sodium levels return toward normal when the TRILEPTAL dosage is reduced or discontinued, or when the patient was treated conservatively (e.g., fluid restriction). Laboratory data from clinical trials suggest that TRILEPTAL use was associated with decreases in T4, without changes in T3 or TSH. 6.2 Postmarketing Experience The following adverse reactions have been identified during postapproval use of TRILEPTAL. 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. Body as a Whole: multi-organ hypersensitivity disorders characterized by features such as rash, fever, lymphadenopathy, abnormal liver function tests, eosinophilia and arthralgia [see Warnings and Precautions (5.8)] Cardiovascular System: atrioventricular block Immune System Disorders: anaphylaxis [see Warnings and Precautions (5.2)] Digestive System: pancreatitis and/or lipase and/or amylase increase Hem atolog ic and Lymphatic System s : aplastic anemia [see Warnings and Precautions (5.9)] Metabolism and Nutrition Disorders : hypothyroidism and syndrome of inappropriate antidiuretic hormone secretion (SIADH) Skin and Subcutaneous Tissue Disorders : erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis [see Warnings and Precautions (5.4)], Acute Generalized Exanthematous Pustulosis (AGEP) Musculoskeletal, connective tissue and bone disorders: There have been reports of decreased bone mineral density, osteoporosis and fractures in patients on long-term therapy with TRILEPTAL. Injury, Poisoning, and Procedural Complications: fall Nervous System Disorders: dysarthria

Usage information

Dosing and administration
2 DOSAGE AND ADMINISTRATION Adults: initiate with a dose of 600 mg/day, given twice-a-day Adjunctive Therapy: Maximum increment of 600 mg/day at approximately weekly intervals. The recommended daily dose is 1200 mg/day (2.1) Conversion to Monotherapy: withdrawal concomitant over 3 to 6 weeks; reach maximum dose of TRILEPTAL in 2 to 4 weeks with increments of 600 mg/day at weekly intervals to a recommended daily dose of 2400 mg/day (2.2) Initiation of Monotherapy: Increments of 300 mg/day every third day to a dose of 1200 mg/day (2.3) Initiate at one-half the usual starting dose and increase slowly in patients with a creatinine clearance <30 mL/min, (2.7) Pediatrics : initiation with 8 to 10 mg/kg/day, given twice-a-day. For patients aged 2 to <4 years and under 20 kg, a starting dose of 16 to 20 mg/kg/day may be considered. Recommended daily dose is dependent upon patient weight. Adjunctive Patients (Aged 2–16 Years): For patients aged 4 to 16 years, target maintenance dose should be achieved over 2 weeks (2.4). For patients aged 2 to <4 years, maximum maintenance dose should be achieved over 2 to 4 weeks and should not to exceed 60 mg/kg/day (2.4) Conversion to Monotherapy for Patients (Aged 4–16 Years) Maximum increment of 10 mg/kg/day at weekly intervals, concomitant antiepileptic drugs can be completely withdrawn over 3 to 6 weeks (2.5) Initiation of Monotherapy for Patients (Aged 4–16 Years) Increments of 5 mg/kg/day every third day (2.6) 2.1 Adjunctive Therapy for Adults Initiate TRILEPTAL with a dose of 600 mg/day, given twice-a-day. If clinically indicated, the dose may be increased by a maximum of 600 mg/day at approximately weekly intervals; the maximum recommended daily dose is 1200 mg/day. Daily doses above 1200 mg/day show somewhat greater effectiveness in controlled trials, but most patients were not able to tolerate the 2400 mg/day dose, primarily because of CNS effects. Dosage adjustment is recommended with concomitant use of strong CYP3A4 enzyme inducers or UGT inducers, which include certain antiepileptic drugs (AEDs) [see Drug Interactions (7.1, 7.2)]. 2.2 Conversion to Monotherapy for Adults Patients receiving concomitant AEDs may be converted to monotherapy by initiating treatment with TRILEPTAL at 600 mg/day (given in a twice-a-day regimen) while simultaneously initiating the reduction of the dose of the concomitant AEDs. The concomitant AEDs should be completely withdrawn over 3 to 6 weeks, while the maximum dose of TRILEPTAL should be reached in about 2 to 4 weeks. TRILEPTAL may be increased as clinically indicated by a maximum increment of 600 mg/day at approximately weekly intervals to achieve the maximum recommended daily dose of 2400 mg/day. A daily dose of 1200 mg/day has been shown in one study to be effective in patients in whom monotherapy has been initiated with TRILEPTAL. Patients should be observed closely during this transition phase. 2.3 Initiation of Monotherapy for Adults Patients not currently being treated with AEDs may have monotherapy initiated with TRILEPTAL. In these patients, initiate TRILEPTAL at a dose of 600 mg/day (given a twice-a-day); the dose should be increased by 300 mg/day every third day to a dose of 1200 mg/day. Controlled trials in these patients examined the effectiveness of a 1200 mg/day dose; a dose of 2400 mg/day has been shown to be effective in patients converted from other AEDs to TRILEPTAL monotherapy (see above). 2.4 Adjunctive Therapy for Pediatric Patients (Aged 2–16 Years) In pediatric patients aged 4–16 years, initiate TRILETPAL at a daily dose of 8 to 10 mg/kg generally not to exceed 600 mg/day, given twice-a-day. The target maintenance dose of TRILEPTAL should be achieved over 2 weeks, and is dependent upon patient weight, according to the following chart: 20 to 29 kg – 900 mg/day 29.1 to 39 kg – 1200 mg/day >39 kg – 1800 mg/day In the clinical trial, in which the intention was to reach these target doses, the median daily dose was 31 mg/kg with a range of 6 to 51 mg/kg. In pediatric patients aged 2 to <4 years, initiate TRILEPTAL at a daily dose of 8 to 10 mg/kg generally not to exceed 600 mg/day, given twice-a-day. For patients less than 20 kg, a starting dose of 16 to 20 mg/kg may be considered [see Clinical Pharmacology (12. 3 )]. The maximum maintenance dose of TRILEPTAL should be achieved over 2 to 4 weeks and should not exceed 60 mg/kg/day in a twice-a-day regimen. In the clinical trial in pediatric patients (2 to 4 years of age) in which the intention was to reach the target dose of 60 mg/kg/day, 50% of patients reached a final dose of at least 55 mg/kg/day. Under adjunctive therapy (with and without enzyme-inducing AEDs), when normalized by body weight, apparent clearance (L/hr/kg) decreased when age increased such that children 2 to <4 years of age may require up to twice the oxcarbazepine dose per body weight compared to adults; and children 4 to ≤12 years of age may require a 50% higher oxcarbazepine dose per body weight compared to adults. Dosage adjustment is recommended with concomitant use of strong CYP3A4 enzyme inducers or UGT inducers, which include certain antiepileptic drugs (AEDs) [see Drug Interactions (7.1, 7.2)]. 2.5 Conversion to Monotherapy for Pediatric Patients (Aged 4–16 Years) Patients receiving concomitant antiepileptic drugs may be converted to monotherapy by initiating treatment with TRILEPTAL at approximately 8 to 10 mg/kg/day given twice-a-day, while simultaneously initiating the reduction of the dose of the concomitant antiepileptic drugs. The concomitant antiepileptic drugs can be completely withdrawn over 3 to 6 weeks while TRILEPTAL may be increased as clinically indicated by a maximum increment of 10 mg/kg/day at approximately weekly intervals to achieve the recommended daily dose. Patients should be observed closely during this transition phase. The recommended total daily dose of TRILEPTAL is shown in Table 1. 2.6 Initiation of Monotherapy for Pediatric Patients (Aged 4–16 Years) Patients not currently being treated with antiepileptic drugs may have monotherapy initiated with TRILEPTAL. In these patients, initiate TRILEPTAL at a dose of 8 to 10 mg/kg/day given twice-a-day. The dose should be increased by 5 mg/kg/day every third day to the recommended daily dose shown in the table below. Table 1: Range of Maintenance Doses of TRILEPTAL for Pediatrics by Weight During Monotherapy From To Weight in kg Dose (mg/day) Dose (mg/day) 20 600 900 25 900 1200 30 900 1200 35 900 1500 40 900 1500 45 1200 1500 50 1200 1800 55 1200 1800 60 1200 2100 65 1200 2100 70 1500 2100 2.7 Dosage Modification for Patients with Renal Impairment In patients with impaired renal function (creatinine clearance <30 mL/min) initiate TRILEPTAL at one-half the usual starting dose (300 mg/day, given twice-a-day) and increase slowly to achieve the desired clinical response [see Clinical Pharmacology (12. 3 )]. 2.8 Administration Information TRILEPTAL can be taken with or without food [see Clinical Pharmacology (12.3)]. Before using TRILEPTAL oral suspension, shake the bottle well and prepare the dose immediately afterwards. The prescribed amount of oral suspension should be withdrawn from the bottle using the oral dosing syringe supplied. TRILEPTAL oral suspension can be mixed in a small glass of water just prior to administration or, alternatively, may be swallowed directly from the syringe. After each use, close the bottle and rinse the syringe with warm water and allow it to dry thoroughly. TRILEPTAL oral suspension and TRILEPTAL film-coated tablets may be interchanged at equal doses.
Use in special populations
8 USE IN SPECIFIC POPULATIONS Pregnancy: May cause fetal harm (8.1 ) 8.1 Pregnancy Clinical Considerations TRILEPTAL levels may decrease during pregnancy [see Warnings and Precautions (5. 10 )]. Pregnancy Category C Fetal Risk Summary There are no adequate and well-controlled clinical studies of TRILEPTAL in pregnant women; however, TRILEPTAL is closely related structurally to carbamazepine, which is considered to be teratogenic in humans. Data on a limited number of pregnancies from pregnancy registries suggest congenital malformations associated with TRILEPTAL monotherapy use (e.g., craniofacial defects such as oral clefts and cardiac malformations such as ventricular septal defects). TRILEPTAL should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Data Animal Increased incidences of fetal structural abnormalities and other manifestations of developmental toxicity (embryolethality, growth retardation) were observed in the offspring of animals treated with either oxcarbazepine or its active 10-hydroxy metabolite (MHD) during pregnancy at doses similar to the maximum recommended human dose (MRHD). When pregnant rats were given oxcarbazepine (30, 300, or 1000 mg/kg) orally throughout the period of organogenesis, increased incidences of fetal malformations (craniofacial, cardiovascular, and skeletal) and variations were observed at the intermediate and high doses (approximately 1.2 and 4 times, respectively, the MRHD on a mg/m2 basis). Increased embryofetal death and decreased fetal body weights were seen at the high dose. Doses ≥300 mg/kg were also maternally toxic (decreased body weight gain, clinical signs), but there is no evidence to suggest that teratogenicity was secondary to the maternal effects. In a study in which pregnant rabbits were orally administered MHD (20, 100, or 200 mg/kg) during organogenesis, embryofetal mortality was increased at the highest dose (1.5 times the MRHD on a mg/m2 basis). This dose produced only minimal maternal toxicity. In a study in which female rats were dosed orally with oxcarbazepine (25, 50, or 150 mg/kg) during the latter part of gestation and throughout the lactation period, a persistent reduction in body weights and altered behavior (decreased activity) were observed in offspring exposed to the highest dose (0.6 times the MRHD on a mg/m2 basis). Oral administration of MHD (25, 75, or 250 mg/kg) to rats during gestation and lactation resulted in a persistent reduction in offspring weights at the highest dose (equivalent to the MRHD on a mg/m2 basis). Pregnancy Registry To provide information regarding the effects of in utero exposure to TRILEPTAL, physicians are advised to recommend that pregnant patients taking TRILEPTAL enroll in the NAAED Pregnancy Registry. This can be done by calling the toll-free number 1-888-233-2334, and must be done by patients themselves. Information on the registry can also be found at the website: http://www.aedpregnancyregistry.org/. 8.3 Nursing Mothers Oxcarbazepine and its active metabolite (MHD) are excreted in human milk. A milk-to-plasma concentration ratio of 0.5 was found for both. Because of the potential for serious adverse reactions to TRILEPTAL in nursing infants, a decision should be made about whether to discontinue nursing or to discontinue the drug in nursing women, taking into account the importance of the drug to the mother. 8.4 Pediatric Use TRILEPTAL is indicated for use as adjunctive therapy for partial seizures in patients aged 2 to 16 years. The safety and effectiveness for use as adjunctive therapy for partial seizures in pediatric patients below the age of 2 have not been established. TRILEPTAL is also indicated as monotherapy for partial seizures in patients aged 4 to 16 years. The safety and effectiveness for use as monotherapy for partial seizures in pediatric patients below the age of 4 have not been established. TRILEPTAL has been given to 898 patients between the ages of 1 month to 17 years in controlled clinical trials (332 treated as monotherapy) and about 677 patients between the ages of 1 month to 17 years in other trials [s ee Warnings and Precautions (5.11), Adverse Reactions (6.1) , Clinical Pharmacology (12.3), and Clinical Studies (14 )]. 8.5 Geriatric Use There were 52 patients over age 65 in controlled clinical trials and 565 patients over the age of 65 in other trials. Following administration of single (300 mg) and multiple (600 mg/day) doses of TRILEPTAL in elderly volunteers (60 to 82 years of age), the maximum plasma concentrations and AUC values of MHD were 30% to 60% higher than in younger volunteers (18 to 32 years of age). Comparisons of creatinine clearance in young and elderly volunteers indicate that the difference was due to age-related reductions in creatinine clearance. Close monitoring of sodium levels is required in elderly patients at risk for hyponatremia [see Warnings and Precautions (5.1)]. 8.6 Renal Impairment Dose adjustment is recommended for renally impaired patients (CLcr <30 mL/min) [see Dosage and Administration (2. 7 ) and Clinical Pharmacology (12.3)].
Pregnancy and lactation
8.3 Nursing Mothers Oxcarbazepine and its active metabolite (MHD) are excreted in human milk. A milk-to-plasma concentration ratio of 0.5 was found for both. Because of the potential for serious adverse reactions to TRILEPTAL in nursing infants, a decision should be made about whether to discontinue nursing or to discontinue the drug in nursing women, taking into account the importance of the drug to the mother.

Interactions

7 DRUG INTERACTIONS Phenytoin: Increased phenytoin levels. Reduced dose of phenytoin may be required (7.1) Carbamazepine, Phenytoin, Phenobarbital: Decreased plasma levels of MHD (the active metabolite). Dose adjustments may be necessary (7.1) Oral Contraceptive: TRILEPTAL may decrease the effectiveness of hormonal contraceptives (7.2) 7.1 Effect of TRILEPTAL on Other Drugs Phenytoin levels have been shown to increase with concomitant use of TRILEPTAL at doses greater than 1200 mg/day [see Clinical Pharmacology (12.3)]. Therefore, it is recommended that the plasma levels of phenytoin be monitored during the period of TRILEPTAL titration and dosage modification. A decrease in the dose of phenytoin may be required. 7.2 Effect of Other Drugs on TRILEPTAL Strong inducers of cytochrome P450 enzymes and/or inducers of UGT (e.g., rifampin, carbamazepine, phenytoin and phenobarbital) have been shown to decrease the plasma/serum levels of MHD, the active metabolite of TRILEPTAL (25% to 49%) [see Clinical Pharmacology (12.3)]. If TRILEPTAL and strong CYP3A4 inducers or UGT inducers are administered concurrently, it is recommended that the plasma levels of MHD be monitored during the period of TRILEPTAL titration. Dose adjustment of TRILEPTAL may be required after initiation, dosage modification, or discontinuation of such inducers. 7.3 Hormonal Contraceptives Concurrent use of TRILEPTAL with hormonal contraceptives may render these contraceptives less effective [see Clinical Pharmacology (12.3)]. Studies with other oral or implant contraceptives have not been conducted.

More information

Category Value
Authorisation number NDA021014
Agency product number VZI5B1W380
Orphan designation No
Product NDC 0078-0456,0078-0457,0078-0357,0078-0337
Date Last Revised 22-03-2018
Type HUMAN PRESCRIPTION DRUG
Marketing authorisation holder Novartis Pharmaceuticals Corporation