Lamictal Odt Starter (GREEN) (lamotrigine)

The manufacturers state that lamotrigine should be used with caution in patients with severe renal impairment because there is insufficient information from controlled clinical studies to establish the safety and efficacy of the drug in such patients. The initial dosage of lamotrigine in patients with renal impairment should be based on the patient's existing anticonvulsant drug regimen. The manufacturers state that a reduced maintenance dosage of lamotrigine may be effective in patients with substantial renal impairment.

The manufacturers state that experience with lamotrigine therapy in patients with hepatic impairment is limited. Based on a clinical pharmacology study of the drug in a small number of patients with moderate to severe hepatic dysfunction, the manufacturers make the general recommendation that initial, escalation, and maintenance dosages of lamotrigine therapy should be decreased by approximately 25% in patients with moderate (e.g., Child-Pugh class B) or severe (e.g., Child-Pugh class C) hepatic impairment without ascites and by 50% in patients with severe hepatic impairment with ascites. Escalation and maintenance dosages should be adjusted according to clinical response. Dosage adjustment is not necessary in patients with mild (e.g., Child-Pugh class A) hepatic impairment.

Lamotrigine is administered orally as immediate-release formulations (conventional tablets, tablets for oral suspension, orally disintegrating tablets) or as extended-release tablets. Immediate-release formulations of the drug (Lamictal(R), generics) are administered once or twice daily; the extended-release tablets (Lamictal(R) XR) are administered once daily. Lamotrigine may be administered without regard to meals.

Lamotrigine conventional tablets should be swallowed whole.

Lamotrigine tablets for oral suspension may be swallowed whole, chewed (and consumed with a small amount of water or diluted fruit juice to aid swallowing), or dispersed in water or diluted fruit juice. To disperse the tablets, they should be added to a small volume (i.e., 5 mL or enough to cover the tablet) of liquid and allowed to disperse completely (over approximately 1 minute); the solution should then be swirled and consumed immediately. Administration of partial quantities of the dispersed tablets should not be attempted; calculated doses that do not correspond to available strengths of whole tablets should be rounded down to the nearest whole tablet.

Lamotrigine orally disintegrating tablets should be placed on the tongue and moved around in the mouth; the tablets should disintegrate rapidly in saliva, and then subsequently swallowed with or without water.

Lamotrigine extended-release tablets should be swallowed whole and not chewed, crushed, or divided.

Patients who are currently receiving or beginning therapy with lamotrigine and/or any other anticonvulsant for any indication should be closely monitored for the emergence or worsening of depression, suicidal thoughts or behavior (suicidality), and/or any unusual changes in mood or behavior. (See Suicidality Risk under Cautions.)

There is no enhanced messaging for this drug.

Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

Lamotrigine/Dofetilide

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: The active tubular secretion via organic cationic transporter 2 (OCT2) of dofetilide may be inhibited by lamotrigine.(1,2)

CLINICAL EFFECTS: The concurrent administration of dofetilide with lamotrigine may result in elevated levels and increased effects of dofetilide including QT prolongation or torsades de pointes.(1,2)

PREDISPOSING FACTORS: Renal impairment may increase risk for excessive QTc prolongation as dofetilide is primarily renally eliminated. To prevent increased serum levels and risk for ventricular arrhythmias, dofetilide must be dose adjusted for creatinine clearance < or = to 60 mL/min.(1) The risk of QT prolongation or torsades de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsades de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(3) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsades de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(3)

PATIENT MANAGEMENT: The manufacturer of dofetilide states that the concurrent administration of dofetilide with known inhibitors of the renal cation transport system should not be used. If dofetilide is to be discontinued, a washout of at least 2 days is recommended prior to starting lamotrigine.(1) The manufacturer of lamotrigine states the concurrent administration of lamotrigine with organic cationic transporter 2 (OCT2) substrates with a narrow therapeutic index, such as dofetilide, is not recommended.(2)

DISCUSSION: Dofetilide is primarily excreted in the urine via both glomerular filtration and active tubular secretion via the cation transport system. Lamotrigine is believed to inhibit the cation transport system (OCT2).(1,2)

Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

Brivaracetam; Lamotrigine; Perampanel/Rifampin; Rifapentine

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Rifampin and rifapentine may induce the metabolism of brivaracetam by CYP2C19(1) and lamotrigine(2,3) and perampanel(4) by CYP3A4.

CLINICAL EFFECTS: The concurrent use of rifampin or rifapentine with brivaracetam,(1) lamotrigine,(2,3) or perampanel(4) may result in decreased levels and clinical effectiveness of the anticonvulsant.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Patients receiving rifampin or rifapentine concurrently with brivaracetam, lamotrigine, or perampanel should be observed for decreased anticonvulsant levels and clinical effectiveness. The dose of the anticonvulsant may need to be adjusted if the rifamycin is added to or removed from therapy. Refer to the current anticonvulsant prescribing information for information on dosage adjustments.

DISCUSSION: Concurrent rifampin decreases brivaracetam levels by 45%.(1) A study in 10 healthy subjects examined the effects of rifampin (600 mg daily for five days) on a single dose of lamotrigine (25 mg). Pretreatment with rifampin decreased the lamotrigine area-under-curve (AUC) and half-life (T1/2) by 43.7% and 40.8%, respectively. Lamotrigine clearance over bioavailability increased 98.3%. The amount of lamotrigine excreted as the glucuronide metabolite increased 36%.(2) A study in 10 healthy subjects examining the effects of rifampin (600 mg daily for 5 days) on a single dose of lamotrigine (25 mg) showed that rifampin increased the apparent clearance of lamotrigine by approximately 2-fold and decreased the AUC by 40%.(3) Rifampin and rifapentine are expected to decrease perampanel concentrations.(4)

Lamotrigine/Estrogen Replacement Therapy

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Estrogens increase glucuronidation mediated metabolism of lamotrigine. Lamotrigine may modestly induce the metabolism of estrogens.(1,2)

CLINICAL EFFECTS: Concurrent use of lamotrigine and estrogens may result in decreased levels and effectiveness of both agents. Increased seizure rates have been reported in patients taking lamotrigine for epilepsy.(1,2)

PREDISPOSING FACTORS: Increased seizure risk is more likely in when lamotrigine is used as monotherapy for treatment of epilepsy. The risk for an increase in seizure rate is lower in patients already stabilized on a combination of lamotrigine and an enzyme inducing agent such as carbamazepine, phenytoin, phenobarbital, or primidone.

PATIENT MANAGEMENT: Monitor closely the clinical effectiveness of lamotrigine with concurrent use of estrogen replacement therapy. Dose adjustment may be necessary.(1) During initiation of lamotrigine therapy, no adjustments to the recommended lamotrigine dose escalation guidelines are recommended in patients taking estrogen.(1) Dose adjustments will be necessary in most patients who start or stop an estrogen in patients taking maintenance doses of lamotrigine. The lamotrigine dosage may need to be increased by as much as 2-fold according to clinical response when estrogen or estrogen-containing contraceptives are initiated in patients NOT taking other drugs which induce glucuronidation such as carbamazepine, phenytoin, phenobarbital, primidone, lopinavir/ritonavir, atazanavir/ritonavir, or rifampin. If estrogen is discontinued, the dosage of lamotrigine may need to be decreased by 50%.(1) Initiate changes in lamotrigine dosage at the same time estrogen containing products are started or stopped.(1) In patients also taking carbamazepine, phenytoin, phenobarbital, primidone, lopinavir/ritonavir, atazanavir/ritonavir, or rifampin, no lamotrigine maintenance dosage adjustments should be necessary if estrogen is initiated or discontinued.(1)

DISCUSSION: In a study in 16 females, concurrent ethinylestradiol (30 mcg) and levonorgestrel (150 mcg) with lamotrigine (300 mg per day) increased lamotrigine clearance by 2-fold, with a mean decrease in lamotrigine area-under-curve (AUC) and maximum concentration (Cmax) by 52% and 39%, respectively. Serum trough lamotrigine levels were two-fold higher at the end of the week of inactive tablets when compared to lamotrigine levels at the end of the active hormonal cycle. This effect should be expected in women not taking carbamazepine, phenytoin, phenobarbital, primidone, or rifampin.(1) In a study in 16 females, concurrent ethinylestradiol (30 mcg) and levonorgestrel (150 mcg) with lamotrigine (300 mg per day) had no effect on ethinylestradiol levels. Levonorgestrel AUC and Cmax decreased by 19% and 12%, respectively. Though there was no hormonal evidence of ovulation, there was some loss of suppression of the hypothalamic-pituitary-ovarian axis.(1) In a study, mean steady-state lamotrigine levels were 13 micro mol/L in 22 women taking oral contraceptives compared to 28 micro mol/L in 30 women who were not taking oral contraceptives. The lamotrigine dose/body weight/ plasma concentration was 2.1 L/kg/day in patients taking oral contraceptives compared to 0.8 L/kg/day in patients without oral contraceptives.(3) One set of authors reported seven cases of decreased lamotrigine levels in patients receiving oral contraceptives. Lamotrigine levels were decreased by 41% to 64%, average 49%. Most patients either experienced increased seizure frequency or recurrence of seizures after the addition of the oral contraceptive, or increased lamotrigine adverse effects following the discontinuation of the oral contraceptive.(4) A study in 45 females compared lamotrigine pharmacokinetics in patients taking an ethinyl estradiol-containing contraceptive (n=11) to patients taking a progestin-only contraceptive (n=16) and to patients taking no contraceptives (n=18). The lamotrigine serum concentration to dose ratio was significantly lower in patients taking ethinyl estradiol-containing contraceptives. There was no significant difference between patients taking progestin-only contraceptives and those using no contraceptives.(5) In a double-blind, placebo-controlled study, women with epilepsy were treated with lamotrigine monotherapy, or lamotrigine plus oral contraceptive. After 21 days, the mean dose-corrected lamotrigine concentration was 84% higher in the monotherapy group verses the combined treatment group.(6) Another study in 8 epileptic females assessed the pharmacokinetics of lamotrigine in combination with hormonal contraceptives. Serum samples were drawn on days 18 and 21 of hormonal contraceptive therapy and during days 5 and 7 of the placebo week (hormonal contraceptive free week). Analysis found statistically significant elevations (approximately 27%) in lamotrigine plasma concentrations during the hormone-free week, than during cycle intake.(7) In a study, 22 enrolled females took lamotrigine titrated up to 300 mg/d for a period of 130 days and either combined it with an oral contraceptive or took lamotrigine monotherapy. Both ethinyl estradiol and lamotrigine serum levels were drawn in the presence or absence of combined therapy. Laboratory serum data showed the ratios of lamotrigine AUC (0-24h) and Cmax at 0.48 for coadministration (lamotrigine plus oral contraceptive) and a ratio of 0.61 for lamotrigine monotherapy.(8)

Lamotrigine/Estrogen-Containing Contraceptives

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Estrogens increase glucuronidation mediated metabolism of lamotrigine. Lamotrigine may modestly induce the metabolism of hormonal contraceptives.(1,2)

CLINICAL EFFECTS: Concurrent use of lamotrigine and estrogen-containing contraceptives may result in decreased levels and effectiveness of both agents. Increased seizure rates have been reported in patients taking lamotrigine for epilepsy.(1,2)

PREDISPOSING FACTORS: Increased seizure risk is more likely when lamotrigine is used as monotherapy for treatment of epilepsy. The risk for an increase in seizure rate is lower in patients already stabilized on a combination of lamotrigine and an enzyme inducing agent such as carbamazepine, phenytoin, phenobarbital, or primidone. The risk for contraceptive failure may be greater in patients also taking other enzyme inducing agents such as carbamazepine, phenytoin, phenobarbital, primidone, or rifampin.

PATIENT MANAGEMENT: During initiation of lamotrigine therapy, no adjustments to the recommended lamotrigine dose escalation guidelines are recommended in patients taking estrogen-containing contraceptives.(1) Dose adjustments will be necessary in most patients who start or stop an estrogen-containing oral contraceptive in patients taking maintenance doses of lamotrigine. The lamotrigine dosage may need to be increased by as much as 2-fold according to clinical response when estrogen-containing contraceptives are initiated in patients NOT taking other drugs which induce glucuronidation such as carbamazepine, phenytoin, phenobarbital, primidone, lopinavir/ritonavir, atazanavir/ritonavir, or rifampin. If estrogen-containing contraceptives are discontinued, the dosage of lamotrigine may need to be decreased by 50%.(1) Initiate changes in lamotrigine dosage at the same time estrogen containing products are started or stopped.(1) In patients also taking carbamazepine, phenytoin, phenobarbital, primidone, lopinavir/ritonavir, atazanavir/ritonavir, or rifampin, no lamotrigine maintenance dosage adjustments should be necessary if estrogen-containing contraceptives are initiated or discontinued.(1) Patients should be instructed to promptly report any changes in their menstrual cycle, such as break-through bleeding.(1)

DISCUSSION: In a study in 16 females, concurrent ethinylestradiol (30 mcg) and levonorgestrel (150 mcg) with lamotrigine (300 mg per day) increased lamotrigine clearance by 2-fold, with a mean decrease in lamotrigine area-under-curve (AUC) and maximum concentration (Cmax) by 52% and 39%, respectively. Serum trough lamotrigine levels were two-fold higher at the end of the week of inactive tablets when compared to lamotrigine levels at the end of the active hormonal cycle. This effect should be expected in women not taking carbamazepine, phenytoin, phenobarbital, primidone, or rifampin.(1) In a study in 16 females, concurrent ethinylestradiol (30 mcg) and levonorgestrel (150 mcg) with lamotrigine (300 mg per day) had no effect on ethinylestradiol levels. Levonorgestrel AUC and Cmax decreased by 19% and 12%, respectively. Though there was no hormonal evidence of ovulation, there was some loss of suppression of the hypothalamic-pituitary-ovarian axis.(1) In a study, mean steady-state lamotrigine levels were 13 micro mol/L in 22 women taking oral contraceptives compared to 28 micro mol/L in 30 women who were not taking oral contraceptives. The lamotrigine dose/body weight/ plasma concentration was 2.1 L/kg/day in patients taking oral contraceptives compared to 0.8 L/kg/day in patients without oral contraceptives.(3) One set of authors reported seven cases of decreased lamotrigine levels in patients receiving oral contraceptives. Lamotrigine levels were decreased by 41% to 64%, average 49%. Most patients either experienced increased seizure frequency or recurrence of seizures after the addition of the oral contraceptive, or increased lamotrigine adverse effects following the discontinuation of the oral contraceptive.(4) A study in 45 females compared lamotrigine pharmacokinetics in patients taking an ethinyl estradiol-containing contraceptive (n=11) to patients taking a progestin-only contraceptive (n=16) and to patients taking no contraceptives (n=18). The lamotrigine serum concentration to dose ratio was significantly lower in patients taking ethinyl estradiol-containing contraceptives. There was no significant difference between patients taking progestin-only contraceptives and those using no contraceptives.(5) In a double-blind, placebo-controlled study, women with epilepsy were treated with lamotrigine monotherapy, or lamotrigine plus oral contraceptive. After 21 days, the mean dose-corrected lamotrigine concentration was 84% higher in the monotherapy group verses the combined treatment group.(6) Another study in 8 epileptic females assessed the pharmacokinetics of lamotrigine in combination with hormonal contraceptives. Serum samples were drawn on days 18 and 21 of hormonal contraceptive therapy and during days 5 and 7 of the placebo week (hormonal contraceptive free week). Analysis found statistically significant elevations (approximately 27%) in lamotrigine plasma concentrations during the hormone-free week, than during cycle intake.(7) In a study, 22 enrolled females took lamotrigine titrated up to 300 mg/d for a period of 130 days and either combined it with an oral contraceptive or took lamotrigine monotherapy. Both ethinyl estradiol and lamotrigine serum levels were drawn in the presence or absence of combined therapy. Laboratory serum data showed the ratios of lamotrigine AUC (0-24h) and Cmax at 0.48 for coadministration (lamotrigine plus oral contraceptive) and a ratio of 0.61 for lamotrigine monotherapy. There were no changes in ethinyl estradiol levels. Levonorgestrel levels decreased 19% and 7 of 22 patients reported break-through bleeding; however, suppression of ovulation was maintained.(8) In an interaction study, lamotrigine decreased exposure to the progestin component (levonorgestrel) of an oral contraceptive by 19%, but suppression of ovulation was not affected. The manufacturer of lamotrigine states that the possibility of decreased contraceptive efficacy in some patients cannot be excluded.(1) The 2010 CDC and 2015 WHO contraceptive guidelines do not mention evidence of reduced contraceptive efficacy with concurrent therapy with lamotrigine.(9,10) The 2018 Faculty of Sexual and Reproductive Healthcare contraceptive guidelines state that lamotrigine is not thought to be an enzyme-inducing drug but that contraceptive efficacy may be reduced by concurrent use with lamotrigine. The clinical significance of this effect is unknown. The guideline recommends caution when administering lamotrigine and contraceptives concurrently.(11)

Lamotrigine/Selected Barbiturates

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Phenobarbital and perhaps other barbiturates induce glucuronidation (UGT) pathways. Lamotrigine is primarily metabolized by glucuronidation.

CLINICAL EFFECTS: Lower lamotrigine concentrations may lead to diminished efficacy, e.g loss of seizure control.

PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks.

PATIENT MANAGEMENT: Patients receiving concurrent therapy with lamotrigine and barbiturates without valproate should be observed for decreased lamotrigine levels and clinical effectiveness. The dose of lamotrigine may need to be adjusted if these agents are added to or removed from lamotrigine therapy. Refer to the current lamotrigine prescribing information for information on dosage adjustments. Lamotrigine levels for patients whose therapeutic regimens include coadministration of lamotrigine with barbiturates and valproic acid should be monitored for elevation. The dose of lamotrigine should be adjusted accordingly while the medication is being coadministered with valproic acid and other antiepileptic drugs. If the barbiturate is discontinued in a patient stabilized on lamotrigine therapy, lamotrigine concentrations will increase over 1 to 4 weeks. Monitor serum levels and adjust dosages as needed.

DISCUSSION: In 24 epileptic adults taking carbamazepine, phenytoin, phenobarbital, or primidone, the time to maximum concentration (Tmax), half-life, and apparent plasma clearance for a single dose of lamotrigine were 2.3 hours, 14.4 hours, and 1.10 ml/min/kg, respectively. In 179 healthy adults taking no other medications, these values were 2.2 hours, 32.8 hours, and 0.44 ml/min/kg, respectively. In 17 epileptic adults taking carbamazepine, phenytoin, phenobarbital, or primidone, the Tmax, half-life, and apparent plasma clearance of multiple dose lamotrigine were 2.0 hours, 12.6 hours, and 1.21 ml/min/kg. These values were 1.7 hours, 25.4 hours, and 0.58 ml/min/kg, respectively, in 36 healthy adults taking no other medications. In 10 pediatric patients with epilepsy aged 10 months to 5.3 years who were taking carbamazepine, phenytoin, phenobarbital, or primidone, lamotrigine Tmax, half-life, and apparent plasma clearance were 3.0 hours, 7.7 hours, and 3.62 ml/min/kg, respectively. In 7 patients in the same age range who where not taking other medications known to affect lamotrigine clearance, these values were 5.2 hours, 19.0 hours, and 1.2 ml/min/kg, respectively. In 527 adult patients with epilepsy, the mean oral clearance of lamotrigine in patients receiving one concomitant enzyme-inducing anti-epileptic agent and not valproic acid was estimated to be 1 ml/min/kg.(3) One study of 302 patients looked at the results of combining lamotrigine with carbamazepine, phenytoin, or phenobarbital with or without valproic acid. The study found when the lamotrigine combinations contained valproic acid that lamotrigine concentrations were two times higher when compared to patients taking either lamotrigine alone or in combination with one of the other antiepileptic drugs even when the lamotrigine doses were halved.

Lamotrigine/Valproic Acid

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Valproic acid decreases the clearance of lamotrigine.(1)

CLINICAL EFFECTS: Concurrent therapy results in increased levels of lamotrigine, requiring dosage adjustments. Valproic acid levels may also decrease over the first three weeks of therapy. Coadministration of valproic acid may increase the risk of potentially life-threatening lamotrigine-induced rashes.(1)

PREDISPOSING FACTORS: The incidence of lamotrigine-induced rash has been shown to be higher in pediatric patients. Although yet to proven, exceeding the recommended dosage for lamotrigine, exceeding the recommended dose escalation for lamotrigine, or being positive for the HLA-B*1502 allele may also increase the risk for lamotrigine-induced rash.(1)

PATIENT MANAGEMENT: The dosage of lamotrigine should be reduced during concurrent administration of valproic acid. Refer to the current manufacturer's prescribing information for lamotrigine for dosing guidelines for patients receiving concurrent lamotrigine and valproic acid therapy.(1) All patients receiving lamotrigine should be instructed to immediately report the development of a rash of any kind to their physician. The dosage of valproic acid may also need to be adjusted.

DISCUSSION: In clinical trials, 6 of 584 (1%) of patients who received lamotrigine with valproate were hospitalized with rash. Only 4 of 2398 patients who received lamotrigine without valproate were hospitalized. In pediatric patients receiving concurrent valproate, 1.2% experienced a serious rash compared with 0.6% of those not receiving concurrent therapy. (1) In a study in 103 adult patients with epilepsy, 30% of patients receiving concurrent lamotrigine with valproate developed a rash, while only 8% of patients receiving lamotrigine alone developed a rash.(2) In a study in 56 pediatric patients, the addition of lamotrigine to valproate resulted in rash in five patients. When lamotrigine was resumed without concurrent valproate therapy, there was no recurrence of rash.(3) In a study in 18 healthy subjects, the administration of lamotrigine and valproic acid decreased the trough stead-state levels of valproate by 25% over a 3 week period. Valproate levels then stabilized.(4) Valproate increases lamotrigine levels by slightly more than 2-fold.(1)

Moderate Interaction: Assess the risk to the patient and take action as needed.

Agents With Hyponatremia Risk/Desmopressin

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Carbamazepine, chlorpromazine, lamotrigine, NSAIDs, opioids, SSRIs, thiazide diuretics, and/or tricyclic antidepressants increase the risk of hyponatremia.(1-3)

CLINICAL EFFECTS: Concurrent use may increase the risk of hyponatremia with desmopressin.(1-3)

PREDISPOSING FACTORS: Predisposing factors for hyponatremia include: polydipsia, renal impairment (eGFR < 50 ml/min/1.73m2), illnesses that can cause fluid/electrolyte imbalances, age >=65, medications that cause water retention and/or increase the risk of hyponatremia (glucocorticoids, loop diuretics).

PATIENT MANAGEMENT: The concurrent use of agents with a risk of hyponatremia with desmopressin may increase the risk of hyponatremia. If concurrent use is deemed medically necessary, make sure serum sodium levels are normal before beginning therapy and consider using the desmopressin nasal 0.83 mcg dose. Consider measuring serum sodium levels more frequently than the recommended intervals of: within 7 days of concurrent therapy initiation, one month after concurrent therapy initiation and periodically during treatment. Counsel patients to report symptoms of hyponatremia, which may include: headache, nausea/vomiting, feeling restless, fatigue, drowsiness, dizziness, muscle cramps, changes in mental state (confusion, decreased awareness/alertness), seizures, coma, and trouble breathing. Counsel patients to limit the amount of fluids they drink in the evening and night-time and to stop taking desmopressin if they develop a stomach/intestinal virus with nausea/vomiting or any nose problems (blockage, stuffy/runny nose, drainage).(1)

DISCUSSION: In clinical trials of desmopressin for the treatment of nocturia, 4 of 5 patients who developed severe hyponatremia (serum sodium <= 125 mmol/L) were taking systemic or inhaled glucocorticoids. Three of these patients were also taking NSAIDs and one was receiving a thiazide diuretic.(2) Drugs associated with hyponatremia may increase the risk, including loop diuretics, carbamazepine, chlorpromazine, glucocorticoids, lamotrigine, NSAIDs, opioids, SSRIs, thiazide diuretics, and/or tricyclic antidepressants.(1,3-4)

Lamotrigine/Carbamazepine

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Carbamazepine may induce the metabolism of lamotrigine.(1)

CLINICAL EFFECTS: The concurrent use of carbamazepine with lamotrigine without valproate and without dosage adjustments may result in decreased levels and clinical effectiveness of lamotrigine.(1) Coadministration of lamotrigine and valproic acid with carbamazepine may result in elevated lamotrigine concentrations.(2)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Patients receiving concurrent therapy with lamotrigine and carbamazepine without valproate should be observed for decreased lamotrigine levels and clinical effectiveness. The dose of lamotrigine may need to be adjusted if carbamazepine is added to or removed from lamotrigine therapy. Refer to the current lamotrigine prescribing information for information on dosage adjustments. Lamotrigine levels for patients whose therapeutic regimens include coadministration of lamotrigine with carbamazepine should be monitored for elevation. The dose of lamotrigine should be adjusted accordingly while the medication is being coadministered with valproic acid and other antiepileptic drugs.

DISCUSSION: In 24 epileptic adults taking carbamazepine, phenytoin, phenobarbital, or primidone, the time to maximum concentration (Tmax), half-life, and apparent plasma clearance for a single dose of lamotrigine were 2.3 hours, 14.4 hours, and 1.10 ml/min/kg, respectively. In 179 healthy adults taking no other medications, these values were 2.2 hours, 32.8 hours, and 0.44 ml/min/kg, respectively.(1) In 17 epileptic adults taking carbamazepine, phenytoin, phenobarbital, or primidone, the Tmax, half-life, and apparent plasma clearance of multiple dose lamotrigine were 2.0 hours, 12.6 hours, and 1.21 ml/min/kg. These values were 1.7 hours, 25.4 hours, and 0.58 ml/min/kg, respectively, in 36 healthy adults taking no other medications.(1) In 10 pediatric patients with epilepsy aged 10 months to 5.3 years who were taking carbamazepine, phenytoin, phenobarbital, or primidone, lamotrigine Tmax, half-life, and apparent plasma clearance were 3.0 hours, 7.7 hours, and 3.62 ml/min/kg, respectively. In 7 patients in the same age range who where not taking other medications known to affect lamotrigine clearance, these values were 5.2 hours, 19.0 hours, and 1.2 ml/min/kg, respectively.(1) In 527 adult patients with epilepsy, the mean oral clearance of lamotrigine in patients receiving one concomitant enzyme-inducing anti-epileptic agent and not valproic acid was estimated to be 1 ml/min/kg.(3) One study of 302 patients looked at the results of combining lamotrigine with carbamazepine, phenytoin, or phenobarbital with or without valproic acid. The study found when the lamotrigine combinations contained valproic acid that lamotrigine concentrations were two times higher when compared to patients taking either lamotrigine alone or in combination with one of the other antiepileptic drugs even when the lamotrigine doses were halved.(2)

Lamotrigine/Hydantoins; Anticonvulsant Barbiturates

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Phenobarbital, phenytoin, primidone and perhaps other barbiturates and hydantoins induce glucuronidation (UGT) pathways. Lamotrigine is primarily metabolized by glucuronidation.

CLINICAL EFFECTS: Lower lamotrigine concentrations may lead to diminished efficacy, e.g loss of seizure control.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Patients receiving concurrent therapy with lamotrigine and carbamazepine, phenytoin, phenobarbital, or primidone without valproate should be observed for decreased lamotrigine levels and clinical effectiveness. The dose of lamotrigine may need to be adjusted if these agents are added to or removed from lamotrigine therapy. Refer to the current lamotrigine prescribing information for information on dosage adjustments. Lamotrigine levels for patients whose therapeutic regimens include coadministration of lamotrigine with either carbamazepine, phenytoin, or phenobarbital and valproic acid should be monitored for elevation. The dose of lamotrigine should be adjusted accordingly while the medication is being coadministered with valproic acid and other antiepileptic drugs. If the barbiturate or hydantoin is discontinued in a patient stabilized on lamotrigine therapy, lamotrigine concentrations will increase over 1 to 4 weeks. Monitor serum levels and adjust dosages as needed.

DISCUSSION: In 24 epileptic adults taking carbamazepine, phenytoin, phenobarbital, or primidone, the time to maximum concentration (Tmax), half-life, and apparent plasma clearance for a single dose of lamotrigine were 2.3 hours, 14.4 hours, and 1.10 ml/min/kg, respectively. In 179 healthy adults taking no other medications, these values were 2.2 hours, 32.8 hours, and 0.44 ml/min/kg, respectively. In 17 epileptic adults taking carbamazepine, phenytoin, phenobarbital, or primidone, the Tmax, half-life, and apparent plasma clearance of multiple dose lamotrigine were 2.0 hours, 12.6 hours, and 1.21 ml/min/kg. These values were 1.7 hours, 25.4 hours, and 0.58 ml/min/kg, respectively, in 36 healthy adults taking no other medications. In 10 pediatric patients with epilepsy aged 10 months to 5.3 years who were taking carbamazepine, phenytoin, phenobarbital, or primidone, lamotrigine Tmax, half-life, and apparent plasma clearance were 3.0 hours, 7.7 hours, and 3.62 ml/min/kg, respectively. In 7 patients in the same age range who where not taking other medications known to affect lamotrigine clearance, these values were 5.2 hours, 19.0 hours, and 1.2 ml/min/kg, respectively. In 527 adult patients with epilepsy, the mean oral clearance of lamotrigine in patients receiving one concomitant enzyme-inducing anti-epileptic agent and not valproic acid was estimated to be 1 ml/min/kg.(3) One study of 302 patients looked at the results of combining lamotrigine with carbamazepine, phenytoin, or phenobarbital with or without valproic acid. The study found when the lamotrigine combinations contained valproic acid that lamotrigine concentrations were two times higher when compared to patients taking either lamotrigine alone or in combination with one of the other antiepileptic drugs even when the lamotrigine doses were halved.

Lamotrigine/Lopinavir; Ritonavir

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Lopinavir and ritonavir may induce the glucuronidation of lamotrigine.(1,2)

CLINICAL EFFECTS: Concurrent use of ritonavir or lopinavir-ritonavir may result in decreased levels and effectiveness of lamotrigine.(1,2)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: A dosage increase of lamotrigine may be required in patients receiving concurrent ritonavir or lopinavir-ritonavir. Monitor lamotrigine levels and adjust the dose as necessary. One set of authors suggested doubling the dose of lamotrigine with concurrent lopinavir-ritonavir.(1) The American Academy of Neurology (AAN) and International League Against Epilepsy (ILAE) clinical practice guidelines recommend considering a dose increase of lamotrigine of 50% in patients receiving atazanavir-ritonavir or lopinavir-ritonavir.(3,4) The NIH Covid-19 treatment guidelines state when extended-course (>= 10 days of therapy) nirmatrelvir-ritonavir is warranted, lamotrigine levels may decrease. Closely monitor lamotrigine levels and adjust lamotrigine dosing to maintain therapeutic lamotrigine levels. Short-course (5 days of therapy) nirmatrelvir-ritonavir is not expected to cause a clinically significant decrease in lamotrigine levels.(5)

DISCUSSION: In a study in 24 healthy subjects, administration of lopinavir-ritonavir (400/100 mg twice daily) decreased the minimum concentration (Cmin) of lamotrigine (50 mg daily on Days 1-2, then 100 mg twice daily) by 55.4%. Increasing the dose of lamotrigine to 200 mg daily with concurrent lopinavir-ritonavir resulted in bioequivalent levels to those seen with lamotrigine alone at a dosage of 100 mg twice daily.(1) In a study in 21 healthy subjects, atazanavir (400 mg daily) had no effect on the pharmacokinetics of a single dose of lamotrigine (100 mg). Concurrent atazanavir/ritonavir (300/100 mg daily) decreased the area-under-curve (AUC) and maximum concentration (Cmax) of a single dose of lamotrigine (100 mg) by 32% and 6%, respectively.(2)

Lamotrigine/Selected Progestin-Only Contraceptives

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Lamotrigine may induce the metabolism of levonorgestrel and norethindrone.(1-4)

CLINICAL EFFECTS: Concurrent use of lamotrigine and levonorgestrel or norethindrone-only contraceptives may result in decreased levels and effectiveness of the contraceptive. Agents linked to this monograph contain only levonorgestrel or norethindrone.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Lamotrigine may decrease progestin concentration by approximately 20%. While this modest decrease does not appear to affect the efficacy of estrogen-progestin contraceptive combinations, it may be important in progestin-only oral or implanted contraceptives. Thus, contraceptive efficacy may be lower than described in prescribing information. Patients receiving lamotrigine may have a progestin-only contraceptive prescribed to avoid the effects of estrogens on lamotrigine concentrations. Although studies have not been performed to evaluate this interaction, it would be prudent to counsel patients on the importance of not missing doses of oral contraceptives. Theoretically, the efficacy of implanted progestins may be lower than expected at the end of the dosing interval as progestin concentrations wane.

DISCUSSION: Lamotrigine induces glucuronidation pathways including UGT1A4, a pathway associated with progestin metabolism.(3,4) In a study, 16 females took lamotrigine titrated up to 300 mg/d for a period of 130 days and either combined it with an estrogen-progestin oral contraceptive or took lamotrigine monotherapy. Levonorgestrel and lamotrigine serum levels were drawn in the presence or absence of combined therapy. Levonorgestrel AUC and Cmax decreased by 19% and 12%, respectively.(1,2)

Sodium Channel Blocker; Potassium Channel Blocker/Lacosamide

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Lacosamide may enhance the slow inactivation of voltage-gated sodium channels and may cause dose-dependent bradycardia, prolongation of the PR interval, atrioventricular (AV) block, or ventricular tachyarrhythmia.(1)

CLINICAL EFFECTS: Concurrent use of lacosamide and agents that affect cardiac conduction (sodium channel blockers and potassium channel blockers) may increase the risk of bradycardia, prolongation of the PR interval, atrioventricular (AV) block, or ventricular tachyarrhythmia.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Lacosamide should be used with caution in patients on concomitant medications that affect cardiac conduction, including sodium channel blockers and potassium channel blockers.(1) If concurrent use is needed, obtain an ECG before lacosamide therapy and after lacosamide dose is titrated to steady-state.(1) Patients should be monitored closely when lacosamide is given intravenously.(1)

DISCUSSION: In a clinical trial in patients with partial-onset seizures, asymptomatic first-degree atrioventricular (AV) block occurred in 4/944 (0.4%) of patient who received lacosamide compared to 0/364 (0%) with placebo.(1) In a clinical trial in patients with diabetic neuropathy, asymptomatic first-degree AV block occurred in 5/1023 (0.5%) of patients who received lacosamide compared to 0/291 (0%) with placebo.(1) Second-degree and complete AV block have been reported in patients with seizures.(1) One case of profound bradycardia was observed in a patient during a 15-minute infusion of 150 mg of lacosamide.(1) A case report of a 49 year old male with refractory complex partial and generalized seizures described the development of ventricular tachycardia four months after addition of lacosamide 400 mg/day to the existing regimen of carbamazepine, lamotrigine, clonazepam, and valproate. The patient's ECG showed first-degree AV block, posterior left fascicular block, and severe widening of the QRS complex, all of which resolved upon discontinuation of lacosamide.(2)

Lamotrigine is contraindicated in patients with known hypersensitivity to the drug or any ingredient in the formulation.

There are no contraindication contraindications for this drug.

• Child-pugh class B hepatic impairment
• Child-pugh class C hepatic impairment
• Chronic heart failure
• Complete atrioventricular block
• Disease of liver
• HLa-B *15:02 positive
• Myocardial ischemia
• Non-infective meningitis
• Second degree atrioventricular heart block
• Structural disorder of heart
• Suicidal ideation

• Anemia
• Aplastic anemia
• Brugada syndrome
• Chronic kidney disease stage 4 (severe) GFR 15-29 ml/min
• Depression
• Kidney disease with likely reduction in glomerular filtration rate (GFr)
• Neutropenic disorder
• Thrombocytopenic disorder

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More Frequent

• Fever
• Skin rash

Less Frequent

• Accidental injury
• Altered mental status
• Hemorrhage
• Irritability

Rare or Very Rare

• Abnormal hepatic function tests
• Acute eruptions of skin
• Acute renal failure
• Agranulocytosis
• Alcohol intolerance
• Anemia
• Angioedema
• Aplastic anemia
• Apnea
• Blood dyscrasias
• DRESS syndrome
• Dyskinesia
• Eosinophilia
• Epididymitis
• Erythema multiforme
• Esophagitis
• Exfoliative dermatitis
• Gastrointestinal hemorrhage
• Hearing loss
• Hemolytic anemia
• Hemophagocytic lymphohistiocytosis
• Hemorrhagic colitis
• Hyperbilirubinemia
• Hypersensitivity drug reaction
• Hypertension
• Hypogammaglobulinemia
• Immunosuppression
• Increased alanine transaminase
• Increased aspartate transaminase
• Interstitial nephritis
• Intraventricular conduction delay
• Leukopenia
• Lupus-like syndrome
• Multiple organ failure
• Neoplasm of breast
• Neutropenic disorder
• Non-infective meningitis
• Orthostatic hypotension
• Pancreatitis
• Pancytopenia
• Petechiae
• Pure red cell aplasia
• Rhabdomyolysis
• ST segment changes
• Status epilepticus
• Stevens-johnson syndrome
• Suicidal
• Suicidal ideation
• Thrombocytopenic disorder
• Tongue swelling
• Toxic epidermal necrolysis
• Uveitis
• Vasculitis
• Ventricular arrhythmias

More Frequent

• Acute abdominal pain
• Ataxia
• Back pain
• Blurred vision
• Chest pain
• Diplopia
• Dizziness
• Drowsy
• Fatigue
• Headache disorder
• Infection
• Insomnia
• Nausea
• Pharyngitis
• Rhinitis
• Tremor
• Vomiting
• Xerostomia

Less Frequent

• Acute cognitive impairment
• Anorexia
• Arthralgia
• Constipation
• Depression
• Diarrhea
• Dysmenorrhea
• Dyspepsia
• Mood changes
• Neck pain
• Nystagmus
• Pain
• Symptoms of anxiety
• Vaginitis
• Visual changes
• Weight loss

Rare or Very Rare

• Accidental fall
• Acne vulgaris
• Aggressive behavior
• Alopecia
• Aphthous stomatitis
• Arthritis
• Blepharoptosis
• Bloody vomit
• Bullous dermatitis
• Bursitis
• Chills
• Cramps in legs
• Cystitis
• Drug-induced hot flash
• Dry eye
• Dysarthria
• Dyschromia
• Dysgeusia
• Dysphagia
• Dysuria
• Earache
• Ecchymosis
• Eructation
• Erythema
• Flushing
• Galactorrhea not associated with childbirth
• Gastritis
• General weakness
• Gingival hyperplasia
• Gingivitis
• Glossitis
• Goiter
• Hallucinations
• Herpes zoster
• Hiccups
• Hirsutism
• Hostility
• Hyperglycemia
• Hyperkinesis
• Hyperventilation
• Hypothyroidism
• Increased appetite
• Loss of taste
• Lymphadenopathy
• Maculopapular rash
• Malaise
• Memory impairment
• Motor tic disorder
• Muscle atrophy
• Muscle fasciculation
• Muscle weakness
• Nocturia
• Orgasm disorder
• Palpitations
• Panic disorder
• Paresthesia
• Parosmia
• Photophobia
• Pruritus of skin
• Sinusitis
• Skin hypopigmentation
• Skin photosensitivity
• Sleep disorder
• Stomatitis
• Syncope
• Tachycardia
• Tinnitus
• Toxic amblyopia
• Urinary retention
• Urinary urgency
• Urticaria
• Vasodilation of blood vessels
• Yawning

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There are no adequate and well-controlled studies of lamotrigine in pregnant women. Women who are pregnant while receiving lamotrigine should be encouraged to enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry at 888-233-2334 or http://www.aedpregnancyregistry.org/.

Data from several prospective pregnancy exposure registries and epidemiological studies of pregnant women have not detected an increased frequency of major congenital malformations or a consistent pattern of malformations among women exposed to lamotrigine compared with the general population. The majority of lamotrigine pregnancy exposure data are from women with epilepsy.

In animal reproduction studies, lamotrigine produced developmental toxicity (e.g., increased mortality, decreased body weight, increased structural variation, neurobehavioral abnormalities) when administered to pregnant animals at doses lower than those used clinically.

Lamotrigine decreased fetal folate concentrations in rats, an effect known to be associated with adverse pregnancy outcomes in animals and humans.

Although preliminary information from the NAAED Pregnancy Registry suggested a possible association between exposure to lamotrigine monotherapy during the first trimester of pregnancy and an increased incidence of cleft lip or cleft palate in infants, this finding has not be observed in other international registries.

The effect of lamotrigine on labor and delivery in humans is unknown.

Physiologic changes during pregnancy may affect plasma lamotrigine concentrations and/or therapeutic effect. Decreased lamotrigine concentrations during pregnancy and restoration of prepartum concentrations after delivery have been reported. Dosage adjustment of lamotrigine may be necessary to maintain clinical response.

Lamotrigine is distributed into human milk. There is some evidence that lamotrigine plasma concentrations in breast-fed infants may be as high as 50% of maternal serum levels. Exposure to lamotrigine in these infants may be further increased due to the immaturity of the infant glucuronidation process required for drug clearance. Apnea, drowsiness, and poor sucking have been reported in nursing infants whose mothers were receiving lamotrigine, although it is not known whether these effects were caused by lamotrigine. It is not known whether lamotrigine can affect milk production.

The known benefits of breast-feeding should be considered along with the mother's clinical need for lamotrigine and any potential adverse effects on the breast-fed infant from the drug or underlying condition.

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