Lamotrigine

Class: Anticonvulsants, Miscellaneous
VA Class: CN400
Chemical Name: 6-(2,3-Dichlorophenyl)-1,2,4-triazine-3,5-diamine
Molecular Formula: C₉H₇C_l2N₅
CAS Number: 84057-84-1
Brands: Lamictal

• Dermatologic Reactions


• 
  

  Can cause serious and potentially life-threatening rash, including Stevens-Johnson syndrome, toxic epidermal necrolysis, and/or rash-related death.^{1 6 9 11 43 a} (See Dermatologic Reactions under Cautions.)

  
  


• 
  

  Risk of serious rash is greater in pediatric patients than in adults (see Pediatric Use under Cautions) and may be increased by concomitant use of valproic acid (valproate, divalproex sodium)^{a 43} or by exceeding the recommended initial dosage or dosage escalation schedule for lamotrigine.^{1 5 9 43}

  
  


• 
  

  Cases of life-threatening rash associated with immediate-release lamotrigine almost always have occurred within 2–8 weeks of treatment initiation;^{1 43} however, isolated cases have been reported following prolonged treatment (e.g., 6 months).^{1 43}

  
  


• 
  

  Can also cause benign rashes; however, it is not possible to predict which rashes will become serious or life-threatening.⁴³ Discontinue therapy at the first sign of rash (unless the rash is clearly not drug related).^{1 43}

  
  


• 
  

  Discontinuance of therapy may not prevent rash from becoming life-threatening or permanently disabling or disfiguring.^{1 43}

  
  

REMS:

FDA approved a REMS for lamotrigine to ensure that the benefits of a drug outweigh the risks. However, FDA later rescinded REMS requirements. See the FDA REMS page () or the ASHP REMS Resource Center ().

Introduction

Phenyltriazine anticonvulsant;^{1 2 4 5 6 7 10 13 14 20} structurally unrelated to other currently available anticonvulsants.^{1 3 4 5 6 9 10 12 13 14 15 17 20}

Uses for Lamotrigine

Seizure Disorders

Immediate-release formulations (e.g., conventional tablets, chewable/dispersible tablets, orally disintegrating tablets): Management (in combination with other anticonvulsants) of partial seizures, with or without secondary generalization, or primary generalized tonic-clonic seizures in adults and children ≥2 years of age.^{2 6 9 10 11 12 20 38 39 45}

Adults and adolescents ≥16 years of age with partial seizures who are receiving a hepatic enzyme-inducing anticonvulsant (e.g., carbamazepine, phenobarbital, phenytoin, primidone) or valproic acid as monotherapy may be converted to immediate-release lamotrigine monotherapy.^{2 6 9 10 11 12 20 38 45}

Extended-release tablets: Management (in combination with other anticonvulsants) of partial seizures, with or without secondary generalization, or primary generalized tonic-clonic seizures in adults and adolescents ≥13 years of age.^{43 52}

Immediate-release formulations: Management (in combination with other anticonvulsants) of generalized seizures associated with Lennox-Gastaut syndrome in adults and children ≥2 years of age.^{28 38 45}

Safety and efficacy of lamotrigine not established as initial monotherapy; for conversion from monotherapy with anticonvulsants other than hepatic enzyme-inducing anticonvulsants (e.g., carbamazepine, phenobarbital, phenytoin, primidone) or valproic acid; or for simultaneous conversion to monotherapy from ≥2 concomitant anticonvulsants.^{38 45}

Bipolar Disorder

Immediate-release formulations: Maintenance therapy of bipolar 1 disorder to prevent or attenuate recurrences of bipolar episodes in adult patients who remain at high risk of relapse following treatment of an acute depressive or manic episode.^{30 38 40 41 45} Considered by the American Psychiatric Association (APA) to be an alternative to first-line maintenance therapies (e.g., lithium, valproic acid, divalproex).³⁰ May be more effective in preventing depressive episodes than manic episodes.³⁰

Efficacy in the acute treatment of mood episodes has yet to be fully established,^{38 45} but lamotrigine is considered a first-line agent by the APA for the management of acute depressive episodes in patients with bipolar disorder† and an alternative to lithium, valproic acid, or divalproex in the management of patients with rapid cycling bipolar disorder†, particularly in those with the bipolar 2 form of rapid cycling.³⁰

Lamotrigine Dosage and Administration

General

• 
  

  Therapeutic plasma concentration range has not been established for treatment of seizure disorders; base dosage on clinical response.^a

  
  


• 
  

  To minimize the possibility of developing a serious rash, adhere to manufacturer-recommended initial dosages and dosage escalation regimens.^{1 2 3 6 9} Discontinue therapy at the first sign of rash (unless the rash is known not to be drug related).¹ (See Boxed Warning and see also Dermatologic Reactions under Cautions.)

  
  


• 
  

  Do not discontinue abruptly, particularly in patients with preexisting seizure disorders.^{1 2 4 9 10 31 43} To minimize the possibility of increasing seizure frequency, reduce dosage in a step-wise fashion over ≥2 weeks (e.g., achieving a 50% reduction in the daily dosage of lamotrigine each week) unless safety concerns require more rapid withdrawal.^{1 2 10 43}

  
  


• 
  

  Closely monitor for notable changes in behavior that could indicate emergence or worsening of suicidal thoughts or behavior or depression.^{35 36 37 38 42 43} (See Suicidality Risk under Cautions.)

  
  

Administration

Oral Administration

Conventional Tablets

Administer orally in 1 dose or 2 divided doses daily without regard to meals.^{1 2 3 4 5 6 9 10 12}

Swallow whole.³⁸

Chewable/Dispersible Tablets

Administer orally in 1 dose or 2 divided doses daily without regard to meals.^{1 2 3 4 5 6 9 10 12}

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.¹

To disperse the tablets, add to a small volume (i.e., 5 mL or enough to cover the tablet) of liquid and allow to disperse completely (over approximately 1 minute); swirl the solution and consume immediately.¹

Do not administer partial quantities of chewable/dispersible tablets; calculated doses that do not correspond to available strength of whole tablets should be rounded down to the nearest whole tablet.¹ The smallest commercially available strength of chewable/dispersible tablets is 2 mg.¹

Extended-release Tablets

Administer orally once daily without regard to meals.⁴³

Swallow whole; do not chew, crush, or divide.⁴³

Orally-disintegrating Tablets

Administer orally in 1 dose or 2 divided doses daily without regard to meals.³⁸

Place orally disintegrating tablet on tongue and move around in mouth to disintegrate; then swallow with or without water.³⁸

Dosage

When adding lamotrigine to an existing anticonvulsant regimen, add gradually while maintaining or gradually adjusting dosage of the other anticonvulsant(s).^{1 4 21}

Addition of other anticonvulsants (e.g., carbamazepine, phenobarbital, phenytoin, primidone, valproic acid) to, or their discontinuance from, an anticonvulsant regimen including lamotrigine may require modification of the dosage of lamotrigine and/or the other anticonvulsant(s).^{1 4 a} (See Specific Drugs under Interactions.)

If lamotrigine therapy is interrupted for >5 half-lives (see Half-life under Pharmacokinetics) for any reason and reinitiation of the drug is not contraindicated, resume therapy using recommended initial dosage and dosage escalation regimens.^a

Pediatric Patients

Seizure Disorders

Adjunctive Therapy with Immediate-release Formulations

Oral

Recommended initial dosages and dosage escalations for lamotrigine given as immediate-release formulations (e.g., conventional tablets, chewable/dispersible tablets, orally disintegrating tablets) when added to an anticonvulsant regimen containing valproic acid; containing anticonvulsant(s) other than carbamazepine, phenobarbital, phenytoin, or primidone (without valproic acid); or containing carbamazepine, phenobarbital, phenytoin, or primidone (without valproic acid) are summarized in Table 1, Table 2, and Table 3, respectively.^{38 45}

May take several weeks to months to achieve an individualized maintenance dosage.³⁸ May need to increase maintenance dosage by as much as 50%, based on clinical response, in patients weighing <30 kg, regardless of age or concomitant anticonvulsant(s).^{38 45}

Round dosage down to the nearest whole tablet.^{38 45}

May need to increase maintenance dosage by as much as 50%, based on clinical response, in patients weighing <30 kg, regardless of age or concomitant anticonvulsant(s).^{38 45}

Table 1: Recommended Pediatric Dosages of Immediate-release Lamotrigine When Added to Anticonvulsant Regimens Containing Valproic Acid3845

Week of Therapy	Children 2–12 Years of Age	Children >12 Years of Age
Weeks 1 and 2	0.15 mg/kg daily in 1 dose or 2 divided doses	25 mg every other day
Weeks 3 and 4	0.3 mg/kg daily in 1 dose or 2 divided doses	25 mg daily
Week 5 onward	Increase dosage in increments of 0.3 mg/kg daily every 1–2 weeks until an effective maintenance dosage is reached	Increase dosage in increments of 25–50 mg daily every 1–2 weeks until an effective maintenance dosage is reached
Usual maintenance dosage	1–5 mg/kg daily (maximum 200 mg daily in 1 dose or 2 divided doses)	100–400 mg daily in 1 dose or 2 divided doses
1–3 mg/kg daily if added to anticonvulsant regimen containing valproic acid alone	100–200 mg daily if added to anticonvulsant regimen containing valproic acid alone

Round dosage down to the nearest whole tablet.^{38 45}

May need to increase maintenance dosage by as much as 50%, based on clinical response, in patients weighing <30 kg, regardless of age or concomitant anticonvulsant(s).^{38 45}

Table 2: Recommended Pediatric Dosages of Immediate-release Lamotrigine When Added to Anticonvulsant Regimens Containing Anticonvulsants Other Than Carbamazepine, Phenobarbital, Phenytoin, or Primidone (Without Valproic Acid)3845

Week of Therapy	Children 2–12 Years of Age	Children >12 Years of Age
Weeks 1 and 2	0.3 mg/kg daily in 1 dose or 2 divided doses	25 mg daily
Weeks 3 and 4	0.6 mg/kg daily in 2 divided doses	50 mg daily
Week 5 onward	Increase dosage in increments of 0.6 mg/kg daily every 1–2 weeks until an effective maintenance dosage is reached	Increase dosage in increments of 50 mg daily every 1–2 weeks until an effective maintenance dosage is reached
Usual maintenance dosage	4.5–7.5 mg/kg daily (maximum 300 mg daily in 2 divided doses)	225–375 mg daily in 2 divided doses

Round dosage down to the nearest whole tablet.^{38 45}

May need to increase maintenance dosage by as much as 50%, based on clinical response, in patients weighing <30 kg, regardless of age or concomitant anticonvulsant(s).^{38 45}

Table 3: Recommended Pediatric Dosages of Immediate-release Lamotrigine When Added to Anticonvulsant Regimens Containing Carbamazepine, Phenobarbital, Phenytoin, or Primidone (Without Valproic Acid)3845

Week of Therapy	Children 2–12 Years of Age	Children >12 Years of Age
Weeks 1 and 2	0.6 mg/kg daily in 2 divided doses	50 mg daily
Weeks 3 and 4	1.2 mg/kg daily in 2 divided doses	100 mg daily in 2 divided doses
Week 5 onward	Increase dosage in increments of 1.2 mg/kg daily every 1–2 weeks until an effective maintenance dosage is reached	Increase dosage in increments of 100 mg daily every 1–2 weeks until an effective maintenance dosage is reached
Usual maintenance dosage	5–15 mg/kg daily (maximum 400 mg daily in 2 divided doses)	300–500 mg daily in 2 divided doses

Patients receiving rifampin or other drugs that induce lamotrigine glucuronidation and increase clearance, but not receiving valproic acid, should receive lamotrigine dosages recommended for individuals receiving carbamazepine, phenobarbital, phenytoin, or primidone (without valproic acid).^{38 45} For dosage adjustments in patients receiving other concomitant therapy, including estrogen-containing oral contraceptives, see Interactions.

Adjunctive Therapy with Extended-release Formulations

Oral

Adolescents ≥13 years of age should receive extended-release dosage recommended for adults.⁴³ (See Adults under Dosage and Administration.)

Conversion to Immediate-release Lamotrigine Monotherapy

Oral

Adolescents ≥16 years of age should receive immediate-release dosage recommended for adults.^a (See Adults under Dosage and Administration.)

Conversion from Immediate-release Lamotrigine to Extended-release Lamotrigine

Oral

May convert patients directly from immediate-release formulations to extended-release tablets (Lamictal XR).⁴³ Initial dosage of extended-release lamotrigine should be the same as the total daily dosage of immediate-release lamotrigine.⁴³

Monitor all patients closely for effective seizure control following conversion, particularly those receiving concomitant therapy with enzyme-inducing drugs since they may have lower plasma lamotrigine concentrations.⁴³

Depending on therapeutic response following conversion, adjust total daily dosage of extended-release lamotrigine within recommended dosing guidelines if necessary.⁴³

Adults

Seizure Disorders

Adjunctive Therapy with Immediate-release Formulations

Oral

Recommended initial dosages and dosage escalations for lamotrigine given as immediate-release formulations (e.g., conventional tablets, chewable/dispersible tablets, orally disintegrating tablets) when added to an anticonvulsant regimen containing valproic acid; containing anticonvulsant(s) other than carbamazepine, phenobarbital, phenytoin, or primidone (without valproic acid); or containing carbamazepine, phenobarbital, phenytoin, or primidone (without valproic acid) are summarized in Table 4.^{38 45}

Maintenance dosages usually are achieved after several weeks to months of therapy and should be individualized.¹

Table 4: Recommended Adult Dosage of Immediate-release Lamotrigine When Added to Existing Anticonvulsant Regimens3845

Week of Therapy	Regimens Containing Valproic Acid	Regimens Containing Anticonvulsants Other Than Carbamazepine, Phenobarbital, Phenytoin, or Primidone (Without Valproic Acid)	Regimens Containing Carbamazepine, Phenobarbital, Phenytoin, or Primidone (Without Valproic Acid)
Weeks 1 and 2	25 mg every other day	25 mg daily	50 mg daily
Weeks 3 and 4	25 mg daily	50 mg daily	100 mg daily in 2 divided doses
Week 5 onward	Increase dosage in increments of 25–50 mg daily every 1–2 weeks until an effective maintenance dosage is reached	Increase dosage in increments of 50 mg daily every 1–2 weeks until an effective maintenance dosage is reached	Increase dosage in increments of 100 mg daily every 1–2 weeks until an effective maintenance dosage is reached
Usual maintenance dosage	100–400 mg daily in 1 dose or 2 divided doses	225–375 mg daily in 2 divided doses	300–500 mg daily in 2 divided doses
100–200 mg daily if added to anticonvulsant regimen containing valproic acid alone

Patients receiving rifampin or other drugs that induce lamotrigine glucuronidation and increase clearance, but not receiving valproic acid, should receive lamotrigine dosages recommended for individuals receiving carbamazepine, phenobarbital, phenytoin, or primidone (without valproic acid).^{38 45} For dosage adjustments in patients receiving other concomitant therapy, including estrogen-containing oral contraceptives, see Interactions.

Adjunctive Therapy with Extended-release Formulations

Oral

Recommended initial dosages and dosage escalations for lamotrigine given as extended-release tablets (e.g., Lamictal XR) when added to an anticonvulsant regimen containing valproic acid; containing anticonvulsant(s) other than carbamazepine, phenobarbital, phenytoin, or primidone (without valproic acid); or containing carbamazepine, phenobarbital, phenytoin, or primidone (without valproic acid) are summarized in Table 5.⁴³

Dosage increases from week 8 or later should not exceed 100 mg daily at weekly intervals.⁴³

Table 5: Recommended Adult Dosage of Extended-release Lamotrigine When Added to Existing Anticonvulsant Regimens43

Week of Therapy	Regimens Containing Valproic Acid	Regimens Containing Anticonvulsants Other Than Carbamazepine, Phenobarbital, Phenytoin, or Primidone (Without Valproic Acid)	Regimens Containing Carbamazepine, Phenobarbital, Phenytoin, or Primidone (Without Valproic Acid)
Weeks 1 and 2	25 mg every other day	25 mg daily	50 mg daily
Weeks 3 and 4	25 mg daily	50 mg daily	100 mg daily
Week 5	50 mg daily	100 mg daily	200 mg daily
Week 6	100 mg daily	150 mg daily	300 mg daily
Week 7	150 mg daily	200 mg daily	400 mg daily
Usual maintenance dosage (Week 8 onward)	200–250 mg daily	300–400 mg daily	400–600 mg daily

Patients receiving rifampin or other drugs that induce lamotrigine glucuronidation and increase clearance, but not receiving valproic acid, should receive lamotrigine dosages recommended for individuals receiving carbamazepine, phenobarbital, phenytoin, or primidone (without valproic acid).⁴³ For dosage adjustments in patients receiving other concomitant therapy, including estrogen-containing oral contraceptives, see Interactions.

Conversion to Immediate-release Lamotrigine Monotherapy

Oral

Conversion from adjunctive therapy with carbamazepine, phenobarbital, phenytoin, or primidone: Titrate dosage until a maintenance lamotrigine dosage of 500 mg daily (given in 2 divided doses daily) is reached (see dosage guidelines in Table 4),^{38 45} then withdraw concomitant anticonvulsant by 20% decrements each week over a 4-week period.^{38 45}

Conversion from adjunctive therapy with valproic acid: Follow the manufacturer-recommended 4-step conversion regimen in Table 6.^{38 45}

Table 6: Conversion from Adjunctive Therapy with Valproic Acid to Immediate-release Lamotrigine Monotherapy3845

Step	Lamotrigine	Valproic Acid
1	Achieve a dosage of 200 mg daily according to guidelines in Table 4 (if not already receiving 200 mg daily)	Maintain previous stable dosage
2	Maintain at 200 mg daily	Decrease to 500 mg daily in decrements no greater than 500 mg daily every week and then maintain dosage of 500 mg daily for 1 week
3	Increase to 300 mg daily and maintain for 1 week	Simultaneously decrease to 250 mg daily and maintain for 1 week
4	Increase in increments of 100 mg daily every week to achieve maintenance dosage of 500 mg daily	Discontinue

Manufacturers make no specific dosage recommendations for conversion to lamotrigine monotherapy in patients receiving anticonvulsants other than carbamazepine, phenobarbital, phenytoin, primidone, or valproic acid.^{38 45}

Conversion from Immediate-release Lamotrigine to Extended-release Lamotrigine

Oral

May convert patients directly from immediate-release formulations to extended-release tablets (Lamictal XR).⁴³ Initial dosage of extended-release lamotrigine should be the same as the total daily dosage of immediate-release lamotrigine.⁴³

Monitor all patients closely for effective seizure control following conversion, particularly those receiving concomitant therapy with enzyme-inducing drugs since they may have lower plasma lamotrigine concentrations.⁴³

Depending on therapeutic response following conversion, adjust total daily dosage of extended-release lamotrigine within recommended dosing guidelines if necessary.⁴³

Bipolar Disorder

Maintenance Therapy with Immediate-release Formulations

Oral

Recommended initial dosages and dosage escalations for immediate-release lamotrigine in patients not receiving carbamazepine, phenobarbital, phenytoin, primidone, rifampin, or valproic acid; receiving valproic acid; or receiving carbamazepine, phenobarbital, phenytoin, primidone, or rifampin (without valproic acid) are summarized in Table 7.^{38 45}

Optimum duration of therapy has not been established; periodically reevaluate the usefulness of the drug during prolonged therapy (i.e., >18 months).^{38 45}

Table 7: Immediate-release Lamotrigine Dosage Titration Regimen for Patients with Bipolar Disorder3845

Week of Therapy	For Patients Not Receiving Carbamazepine, Phenobarbital, Phenytoin, Primidone, Rifampin, or Valproic Acid	For Patients Receiving Valproic Acid	For Patients Receiving Carbamazepine, Phenobarbital, Phenytoin, Primidone, or Rifampin (Without Valproic Acid)
Weeks 1 and 2	25 mg daily	25 mg every other day	50 mg daily
Weeks 3 and 4	50 mg daily	25 mg daily	100 mg daily in divided doses
Week 5	100 mg daily	50 mg daily	200 mg daily in divided doses
Week 6	200 mg daily	100 mg daily	300 mg daily in divided doses
Week 7 (target dosages)	200 mg daily	100 mg daily	Up to 400 mg daily in divided doses

Recommended adjustments to lamotrigine dosage following discontinuance of rifampin or concomitantly administered psychotropic agents are summarized in Table 8.^{38 45}

Table 8: Immediate-release Lamotrigine Dosage Adjustments for Patients with Bipolar Disorder following Discontinuance of Rifampin or Concomitantly Administered Psychotropic Agents3845

Week of Therapy	Lamotrigine Dosage after Discontinuance of Psychotropic Agents Excluding Carbamazepine, Phenobarbital, Phenytoin, Primidone, or Valproic Acid	Lamotrigine Dosage after Discontinuance of Valproic Acid (when current lamotrigine dosage = 100 mg daily)	Lamotrigine Dosage after Discontinuance of Carbamazepine, Phenobarbital, Phenytoin, Primidone, or Rifampin (when current lamotrigine dosage = 400 mg daily)
Week 1	Maintain current lamotrigine dosage	150 mg daily	400 mg daily
Week 2	Maintain current lamotrigine dosage	200 mg daily	300 mg daily
Week 3 onward	Maintain current lamotrigine dosage	200 mg daily	200 mg daily

Prescribing Limits

Pediatric Patients

Seizure Disorders

Adjunctive Therapy with Immediate-release Formulations

Oral

Children 2–12 years of age: Maximum 200 mg daily when added to an anticonvulsant regimen containing valproic acid.^{38 45}

Children 2–12 years of age: Maximum 300 mg daily when added to an anticonvulsant regimen not containing carbamazepine, phenobarbital, phenytoin, or primidone (without valproic acid).^{38 45}

Children 2–12 years of age: Maximum 400 mg daily when added to an anticonvulsant regimen containing carbamazepine, phenobarbital, phenytoin, or primidone (without valproic acid).^{38 45}

Children >12 years of age: See recommended dosage ranges in Pediatric Patients under Dosage. ^{38 45}

Adults

Bipolar Disorder

Maintenance Therapy with Immediate-release Formulations

Oral

Maximum 200 mg daily in patients not receiving concomitant therapy with carbamazepine, phenobarbital, phenytoin, primidone, rifampin, or valproic acid.^a

Special Populations

Hepatic Impairment

Manufacturers generally recommend reducing initial, escalation, and maintenance dosages by approximately 25% in patients with moderate (Child-Pugh class B) or severe (Child-Pugh class C) hepatic impairment without ascites and by 50% in patients with severe hepatic impairment with ascites.^{38 43 45} Adjust escalation and maintenance dosage according to clinical response.^{38 43 45} Dosage adjustment not necessary in patients with mild (Child-Pugh class A) hepatic impairment.^{38 43 45}

Renal Impairment

In patients with renal impairment, base initial dosage on patient's existing anticonvulsant drug regimen.^{10 38 43 45} (See Dosage under Dosage and Administration.) A reduced maintenance dosage may be effective in patients with substantial renal impairment;^{10 38 43 45} however, manufacturers make no specific recommendation for dosage adjustment in such patients.^{38 43 45}

Geriatric Patients

Initiate therapy with dosages at the lower end of the usual range because of possible age-related decreases in hepatic, renal, and/or cardiac function and potential for concomitant disease and drug therapy.^{38 43 45} Titrate dosage carefully.^{38 43 45}

Cautions for Lamotrigine

Contraindications

• 
  

  Known hypersensitivity to lamotrigine or any ingredient in the formulation.^{38 43 45}

  
  

Warnings/Precautions

Warnings

Acute Multiorgan Failure

Multiorgan failure, in some cases fatal or irreversible, reported rarely.^{1 2 6 13 22 24 43}

Majority of deaths caused by multiorgan failure occurred in association with other serious medical events, including status epilepticus, overwhelming sepsis, and hantavirus infection, making it difficult to identify the initiating cause.^{1 43 a}

Consider possibility of potentially fatal adverse effects in patients who exhibit signs and symptoms of multiorgan failure and/or hepatic impairment following initiation of lamotrigine.^{21 22}

Blood Dyscrasias

Neutropenia, leukopenia, anemia, thrombocytopenia, pancytopenia, and, rarely, aplastic anemia and pure red cell aplasia have been reported.^{26 a} Such blood dyscrasias may or may not be associated with a hypersensitivity syndrome.^a (See Hypersensitivity Reactions under Cautions.)

Suicidality Risk

Increased risk of suicidality (suicidal ideation or behavior) observed in an analysis of studies using various anticonvulsants in patients with epilepsy, psychiatric disorders (e.g., bipolar disorder, depression, anxiety), and other conditions (e.g., migraine, neuropathic pain); risk in patients receiving anticonvulsants (0.43%) was approximately twice that in patients receiving placebo (0.24%).^{35 36 37 38 43} Increased suicidality risk was observed ≥1 week after initiation of anticonvulsant therapy and continued through 24 weeks.^{35 36 37 38 43} Risk was higher for patients with epilepsy compared with those receiving anticonvulsants for other conditions.^{35 37}

Closely monitor all patients currently receiving or beginning anticonvulsant therapy for changes in behavior that may indicate emergence or worsening of suicidal thoughts or behavior or depression.^{35 36 37 38 42} Anxiety, agitation, hostility, hypomania, and mania may be precursors to emerging suicidality.³⁵

Balance risk of suicidality with the risk of untreated illness.³⁵ Epilepsy and other illnesses treated with anticonvulsants are themselves associated with morbidity and mortality and an increased risk of suicidality.³⁸ If suicidal thoughts or behavior emerge during anticonvulsant therapy, consider whether these symptoms may be related to the illness itself.³⁸ (See Advice to Patients.)

Aseptic Meningitis

Risk of aseptic meningitis.^{43 44 46 47 48 49 50 51} In postmarketing cases, symptoms included headache, fever, nausea, vomiting, and nuchal rigidity; rash, photophobia, myalgia, chills, altered consciousness, and somnolence also reported.^{43 44 46 47 48 49 50} In most cases, symptoms resolved following discontinuance of lamotrigine.^{43 44 46 47 48 49 50}

Some patients had underlying diagnoses of systemic lupus erythematosus or other autoimmune diseases.^{43 44 47 48 50} Some patients also had new onset of signs and symptoms of other organ involvement (predominantly hepatic and renal), possibly suggesting that the aseptic meningitis was part of a hypersensitivity or generalized drug reaction.^{43 44 46 47 48 50} (See Sensitivity Reactions under Cautions.)

Because of the potential for serious outcomes with untreated meningitis due to other causes, evaluate patients for other causes of meningitis and treat appropriately.^{43 44} Discontinue lamotrigine if no other clear cause of meningitis is identified.^{43 44}

Withdrawal Seizures

Abrupt withdrawal may result in increased seizure frequency, particularly in patients with preexisting seizure disorders;^{1 2 31 43} withdraw gradually (e.g., over a period of ≥2 weeks) and slowly reduce dosage unless safety concerns dictate more rapid withdrawal of the drug.^{1 2 43} (See General under Dosage and Administration.)

Possible Prescribing and Dispensing Errors

Ensure accuracy of prescription; similarity in spelling of Lamictal (lamotrigine), Lamisil (terbinafine hydrochloride), lamivudine, labetalol hydrochloride, Lomotil (the fixed combination of atropine sulfate and diphenoxylate hydrochloride), and Ludiomil (maprotiline hydrochloride; no longer commercially available under this trade name in the US) may result in errors.^{27 29} Medication errors also may occur between the different formulations of lamotrigine.^{38 43 45} Advise patients to visually inspect their tablets to verify that they are lamotrigine as well as the correct formulation of the drug each time they fill their prescription.^{38 43 45}

Sensitivity Reactions

Dermatologic Reactions

Rashes severe enough to result in discontinuance of therapy and hospitalization (e.g., Stevens-Johnson syndrome,^{1 3 5 6 9 11 43} toxic epidermal necrolysis,^{1 5 6 9 43} angioedema,^{1 3 5 6 9 43} rash associated with systemic manifestations)^{1 5 6 9 43} reported in adults and pediatric patients receiving immediate-release lamotrigine.^{1 6 9 11 43} Risk caused by extended-release lamotrigine not fully characterized but not expected to differ from risk associated with immediate-release formulations.⁴³ (See Boxed Warning and see Pediatric Use under Cautions.)

Discontinue therapy at the first sign of rash (unless the rash is known not to be drug related).¹

Hypersensitivity Reactions

Potentially fatal or life-threatening hypersensitivity reactions may occur; manifestations may include multiorgan failure or dysfunction, including hepatic abnormalities and disseminated intravascular coagulation.^{1 43}

If early signs of a possible hypersensitivity reaction (e.g., fever and lymphadenopathy, with or without rash) occur, immediately evaluate the patient.^{1 43} Unless another cause for the signs or symptoms is found, discontinue lamotrigine.^{1 43}

General Precautions

REMS Program

FDA required and approved a Risk Evaluation and Mitigation Strategy (REMS) for lamotrigine.^{54 55} Goal is to inform patients about serious risks (e.g., suicidality) associated with use of the drug.^{54 55} (See Cautions.) The REMS program consists of a medication guide.^{54 55} (See Advice to Patients.)

Suicide

Attendant risk with bipolar disorder; closely supervise patients and prescribe drug in the smallest quantity consistent with good patient management to reduce the risk of overdosage.^a Overdosages of lamotrigine (including fatalities) have been reported.^a

Nervous System Effects

Seizure exacerbation and/or treatment-emergent status epilepticus have been reported in patients receiving lamotrigine as adjunctive therapy for seizure disorders; the incidence has been difficult to determine conclusively.^{1 21}

If a change in seizure control or appearance or worsening of adverse effects occurs, reevaluate the use and dosage of all anticonvulsants in the regimen.¹

Sudden, Unexplained Deaths in Epilepsy

Higher incidence of sudden and unexplained deaths reported with immediate-release lamotrigine than would be expected in a healthy (nonepileptic) population; however, incidence is within range of estimates for patients with epilepsy or refractory epilepsy receiving a chemically unrelated anticonvulsant drug.^{1 6 43}

Concomitant Diseases

Experience in patients with concomitant diseases is limited.^a Use with caution in patients with conditions that could affect metabolism or elimination of the drug (e.g., renal, hepatic, or cardiac impairment).^{22 a}

Binding To Melanin-Rich Tissues

Potential accumulation of lamotrigine in melanin-rich tissues (e.g., eye, pigmented skin) over time, resulting in potential toxicity in these tissues with extended use.¹

Manufacturers make no specific recommendations for periodic ophthalmologic monitoring; however, clinicians should be aware of possible long-term adverse ophthalmologic effects.^{1 43 45}

Specific Populations

Pregnancy

Category C.^{1 43 45}

Lamotrigine pregnancy registry (for clinicians) at 800-336-2176.^{38 43} North American Antiepileptic Drug (NA

Lamisil Topical

Generic Name: terbinafine topical (ter BIN a feen TOP i kal)

Brand Names: Athlete's Foot Cream, LamISIL AT, LamISIL AT Athletes Foot, LamISIL AT Jock Itch, LamISIL Topical

What is Lamisil Topical (terbinafine topical)?

Terbinafine is an antifungal medication. Terbinafine topical prevents fungus from growing on the skin.

Terbinafine topical (for the skin) is used to treat skin infections such as athlete's foot, jock itch, and ringworm infections.

Terbinafine topical may also be used for other purposes not listed in this medication guide.

What is the most important information I should know about Lamisil Topical (terbinafine topical)?

Use this medication for the full prescribed length of time. Your symptoms may improve before the infection is completely cleared.

Do not cover treated skin areas with a bandage or other covering unless your doctor has told you to.

Avoid getting this medication in your mouth or eyes.

What should I discuss with my healthcare provider before using Lamisil Topical (terbinafine topical)?

You should not use this medication if you are allergic to it. It is not known whether terbinafine topical will be harmful to an unborn baby. Do not use terbinafine topical without first talking to your doctor if you are pregnant. It is not known whether terbinafine topical passes into breast milk or if it could harm a nursing baby. Do not use this medication without telling your doctor if you are breast-feeding a baby.

How should I use Lamisil Topical (terbinafine topical)?

Use this medication exactly as prescribed by your doctor. Do not use it in larger amounts or for longer than recommended. Follow the directions on your prescription label.

Wash your hands before and after using this medication.

Clean and dry the affected area. Apply the medication as directed.

Use this medication for the full prescribed length of time. Your symptoms may improve before the infection is completely cleared.

For best results, keep using the medication as directed. Talk with your doctor if your symptoms do not improve after a few weeks of treatment.

Do not cover treated skin areas with a bandage or other covering unless your doctor has told you to.

Store terbinafine topical at room temperature away from moisture and heat.

What happens if I miss a dose?

Apply the missed dose as soon as you remember. If it is almost time for your next dose, wait until then to use the medicine and skip the missed dose. Do not apply extra medicine to make up the missed dose.

What happens if I overdose?

Seek emergency medical attention if you think you have used too much of this medicine.

An overdose of terbinafine topical is not likely to cause life-threatening symptoms.

What should I avoid while using Lamisil Topical (terbinafine topical)?

Avoid getting this medication in your mouth or eyes. If it does get into any of these areas, rinse with water.

Avoid using other medications on the areas you treat with terbinafine topical unless your doctor has told you to.

Avoid wearing tight-fitting, synthetic clothing that doesn't allow air circulation. Wear loose-fitting clothing made of cotton and other natural fibers until your infection is healed.

Lamisil Topical (terbinafine topical) side effects

Get emergency medical help if you have any of these signs of an allergic reaction: hives; difficult breathing; swelling of your face, lips, tongue, or throat. Stop using terbinafine topical and call your doctor at once if you have a serious side effect such as severe blistering, itching, redness, peeling, dryness, or irritation of the skin.

Less serious side effects are more likely, and you may have none at all.

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

What other drugs will affect Lamisil Topical (terbinafine topical)?

It is not likely that other drugs you take orally or inject will have an effect on topically applied terbinafine topical. But many drugs can interact with each other. Tell your doctor about all your prescription and over-the-counter medications, vitamins, minerals, herbal products, and drugs prescribed by other doctors. Do not start a new medication without telling your doctor.

More Lamisil Topical resources

• Lamisil Topical Side Effects (in more detail)
• Lamisil Topical Use in Pregnancy & Breastfeeding
• Lamisil Topical Support Group
• 0 Reviews for Lamisil Topical - Add your own review/rating

• Lamisil AT Prescribing Information (FDA)


• Lamisil AT Topical Advanced Consumer (Micromedex) - Includes Dosage Information


• Lamisil AT Cream MedFacts Consumer Leaflet (Wolters Kluwer)


• Lamisil AT Jock Itch Prescribing Information (FDA)

Compare Lamisil Topical with other medications

• Tinea Versicolor

Where can I get more information?

• Your pharmacist has additional information about terbinafine topical written for health professionals that you may read.

See also: Lamisil Topical side effects (in more detail)

Levothyroxine Sodium

Class: Thyroid Agents
VA Class: HS851
CAS Number: 25416-65-3
Brands: Levothroid, Levoxyl, Synthroid, Unithroid

Introduction

Thyroid agent; sodium salt of thel-isomer of thyroxine (tetraiodothyronine, T₄).

Uses for Levothyroxine Sodium

Hypothyroidism

Used orally as replacement or supplemental therapy in congenital or acquired hypothyroidism of any etiology, except transient hypothyroidism during the recovery phase of subacute thyroiditis.^{140 141 142 143 161 160} Specific indications include subclinical hypothyroidism and primary (thyroidal), secondary (pituitary), and tertiary (hypothalamic) hypothyroidism.^{140 141 142 143 161 160}

Considered drug of choice for the treatment of congenital hypothyroidism (cretinism).^a

Used IV for treatment of myxedema coma or other conditions when rapid thyroid replacement is required.^{140 141 142 155 161 160}

Pituitary TSH Suppression

Treatment or prevention of various types of euthyroid goiters, including thyroid nodules, subacute or chronic lymphocytic thyroiditis (Hashimoto’s thyroiditis), and multinodular goiter.^{140 141 142 161 160}

Adjunct to surgery and radioiodine therapy in the management of thyrotropin-dependent well-differentiated thyroid cancer.^{140 141 142 161 160}

Efficacy of TSH suppression for benign nodular disease remains controversial.^{141 142 160}

Other Uses

See Unlabeled Uses under Cautions.

Levothyroxine Sodium Dosage and Administration

General

• 
  

  Approved levothyroxine sodium oral preparations¹⁵⁷ should be considered therapeutically inequivalent unless equivalence has been established and noted in the FDA’s Approved Drug Products with Therapeutic Equivalence Evaluations (Orange Book).¹⁴⁴ The following are considered to be therapeutically equivalent to at least 1 reference listed drug: Levoxyl, Synthroid, Unithroid, and nonproprietary (generic) levothyroxine sodium preparations manufactured by Mylan, Sandoz, or Lannett.^{162 163 164} Check Orange Book at for more current information on preparations designated therapeutically equivalent by the FDA.

  
  


• 
  

  Due to narrow therapeutic index, American Thyroid Association (ATA) and American Association of Clinical Endocrinologists (AACE) recommend not to use levothyroxine sodium preparations interchangeably.^{157 163} When switching preparations (e.g., from brand to generic), pharmacists should notify the patient and prescriber.^{162 163} In addition, clinicians should measure serum TSH concentration about 4–8 weeks after starting the new preparation and adjust dosage if needed.^{162 163}

  
  


• 
  

  Initially, monitor response to therapy about every 6–8 weeks.^{135 140 141 142} Once normalization of thyroid function and serum TSH concentrations has been achieved, patients may be evaluated less frequently (i.e., every 6–12 months).¹³⁵ However, if dosage of levothyroxine is changed, measure serum TSH concentrations after 8–12 weeks.^{135 140 141 142 160}

  
  

Administration

Administer orally or by IV or IM injection.^{140 141 142 143 161 160} IV is preferred over IM since absorption may be variable following IM administration.^a

Oral Administration

Administer orally on an empty stomach, preferably one-half to one hour before breakfast or the first food of the day.^{140 141 142 143 160} Administer Levoxyl tablets with a full glass of water to avoid choking, gagging, or difficulty in swallowing the tablet.¹⁴¹

In individuals who are unable to swallow intact tablets (e.g., pediatric patients), may crush appropriate dose of levothyroxine tablets and place in a small amount (5–10 mL) of water; immediately administer resultant suspension by spoon or dropper (do not store).^{140 141 142 152}

Foods that decrease absorption of levothyroxine (e.g., soybean infant formula, soybean flour, cotton seed meal) should not be used for administering levothyroxine.^{140 141 142 160}

IV Administration

For solution compatibility information, see Compatibility under Stability.

Reconstitution

Reconstitute Synthroid powder for injection by adding 5 mL of 0.9% sodium chloride injection to vial containing 200 or 500 mcg levothyroxine sodium; shake until clear solution is obtained.¹⁶¹ Resultant solutions contain approximately 40 or 100 mcg/mL, respectively.^a

Alternatively, to produce Synthroid solutions containing approximately 100 mcg/mL, add 2 mL 0.9% sodium chloride injection to vial containing 200 mcg.^a

Use reconstituted solutions immediately and discard any unused portions; do not admix with IV infusion solutions.¹⁶¹

Dosage

Available as levothyroxine sodium; dosage is expressed in terms of the salt.^{140 141 142}

Adjust dosage carefully according to clinical and laboratory response to treatment.^{140 141 142 160} Avoid undertreatment or overtreatment.^{140 141 142 161 160} (See Therapy Monitoring under Cautions.)

Initiate dosage at a lower level in geriatric patients, in patients with functional or ECG evidence of cardiovascular disease, and in patients with severe, long-standing hypothyroidism.^{145 146 147}

Pediatric Patients

Hypothyroidism

Oral

Initiate therapy at full replacement dosages as soon as possible after diagnosis of hypothyroidism to prevent deleterious effects on intellectual and physical growth and development; initiate dosage at a lower level in children with long-standing or severe hypothyroidism.^{140 141 142 160} The following dosages have been recommended:

Dosage for Management of Hypothyroidism in Pediatric Patients140141142152a160

Age	Daily Dose
0–3 months	10–15 mcg/kg
3–6 months	25–50 mcg or 8–10 mcg/kg
6–12 months	50–75 mcg or 6–8 mcg/kg
1–5 years	75–100 mcg or 5–6 mcg/kg
6–12 years	100–150 mcg or 4–5 mcg/kg
Older than 12 years (growth and puberty incomplete)	>150 mcg or 2–3 mcg/kg
Growth and puberty complete	1.6–1.7 mcg/kg

Alternatively, 25–50 mcg once daily has been recommended for otherwise healthy children <1 year of age; after 1 year of age, children may be given 3–5 mcg/kg daily until the adult dosage of about 150 mcg daily is reached in early or mid-adolescence.^a

In neonates at risk of cardiac failure, initiate at a lower dosage (e.g., 25 mcg daily); increase dosage at intervals of 4–6 weeks as needed based on clinical and laboratory response to treatment.^{140 141 142 143 160} In neonates with very low (<5 mcg/dL) or undetectable serum T₄ concentrations, usual initial dosage is 50 mcg daily.^{140 141 142 152 160}

When transient hypothyroidism is suspected, therapy may be temporarily discontinued when the child is older than 3 years of age to reassess the condition.^{140 141 142 161 160} (See Pediatric Use under Cautions.)

Hyperactivity in an older child may be minimized by initiating therapy at a dosage approximately one-fourth of the recommended full replacement dosage; increase dosage by an amount equal to one-fourth the full recommended replacement dosage at weekly intervals until the full recommended replacement dosage is reached.^{140 141 142 160}

For treatment of severe or long-standing hypothyroidism, usual initial dosage is 25 mcg daily.^{140 141 142 160} Increase dosage in increments of 25 mcg at intervals of 2–4 weeks until desired response is obtained.^{140 141 142 160}

IV or IM

Replacement therapy: initially about one-half previously established oral dosage.¹⁶¹ Monitor patients closely and adjust dosage according to patient’s tolerance and therapeutic response.¹⁶¹

Adults

Hypothyroidism

Oral

In otherwise healthy individuals <50 years of age and in those >50 years of age who have been recently treated for hyperthyroidism or who have been hypothyroid for only a short time (i.e., several months), usual initial oral dosage (full replacement dosage) is 1.7 mcg/kg daily (e.g., 100–125 mcg daily for a 70-kg adult) given as a single dose.^{135 140 141 142 143 160} Older patients may require <1 mcg/kg daily.^{135 140 141 142}

Dosages >200 mcg daily seldom required; failure to respond adequately to oral dosages ≥ 300 mcg daily is rare and should prompt reevaluation of the diagnosis, or suggest presence of malabsorption, patient noncompliance, and/or drug interactions.^{140 141 142 160}

For most patients >50 years of age, usual initial dosage is 25–50 mcg daily given as a single dose;^{135 140 141 142 143 146 147 150 160} increase dosage at intervals of 6–8 weeks.^{140 141 142 143}

For management of severe or long-standing hypothyroidism, usual initial dosage is 12.5–25 mcg daily given as a single dose.^{140 141 142 160} Increase by increments of 25 mcg at intervals of 2–4 weeks until serum TSH concentrations return to normal;^{140 141 142 160} some clinicians suggest that dosage be adjusted at intervals of 4–8 weeks.^{143 145 147}

For management of subclinical hypothyroidism (if considered necessary), initiate at lower dosages (e.g., 1 mcg/kg daily).^{140 141 142 160} If levothyroxine therapy is not initiated, monitor patients annually for changes in clinical status and thyroid laboratory parameters.^{140 141 142 160}

IV and IM

Replacement therapy: about one-half previously established oral dosage.¹⁶¹ Usual parenteral maintenance dosage is 50–100 mcg daily.¹⁶¹

Monitor patients closely and adjust dosage according to patient’s tolerance and therapeutic response.¹⁶¹

Myxedema Coma

IV

In patients who do not have severe cardiovascular disease, usual initial dose is 200–500 mcg;¹⁶¹ some clinicians recommend an initial dose of 100–500 mcg.¹⁵⁵ If substantial and progressive improvements have not been achieved, administer 100–300 mcg or greater IV on the second day.¹⁶¹ Lower daily IV dosages should then be administered as needed until patient’s condition stabilizes and drug can be given orally.¹⁶¹

Pituitary TSH Suppression

Individualize dosage based on patient characteristics and nature of the disease.^{141 142 160} Target level for TSH suppression in management of well-differentiated thyroid cancer and thyroid nodules not established.^{141 142 160}

Thyroid Cancer

Oral

Dosages >2 mcg/kg daily given as a single dose usually required to suppress TSH concentrations to <0.1 mU/L.^{140 141 142 160} In patients with high-risk tumors, target level for TSH suppression may be <0.01 mU/L.^{141 160}

Benign Nodules or Nontoxic Multinodular Goiter

Oral

Suppress TSH concentrations to 0.1–0.5 mU/L for nodules and to 0.5–1 mU/L for multinodular goiter.^{140 142 143 160}

Special Populations

Patients with Cardiovascular Disease

Hypothyroidism

Initiate therapy at lower doses than those recommended in patients without cardiovascular disease.^{140 141 142 161 160} For patients <50 years of age with underlying cardiovascular disease, usual initial dosage is 25–50 mcg daily given as a single dose;^{135 140 141 142 143 146 147 150 160} increase dosage at intervals of 6–8 weeks.^{140 141 142 143}

If cardiac symptoms develop or worsen, reduce dosage or withhold therapy for 1 week and then cautiously restart therapy at a lower dose.^{140 141 142 161 160}

Myxedema Coma

IV

If levothyroxine therapy is clinically indicated, smaller initial IV doses may be necessary.¹⁶¹ Consider risks of adverse cardiovascular effects associated with sudden IV administration of large doses of levothyroxine sodium against risks of withholding therapy.¹⁶¹

Geriatric Patients

Hypothyroidism

Initiate therapy at lower doses than those recommended in younger patients.^{140 141 142 161 160}

In geriatric patients with underlying cardiovascular disease, usual initial dosage is 12.5–25 mcg daily; increase dosage by increments of 12.5–25 mcg at intervals of 4–6 weeks until patient becomes euthyroid and serum TSH concentrations return to normal.^{140 141 142 160} If cardiac symptoms develop or worsen, reduce dosage or withhold therapy for 1 week and then cautiously restart therapy at a lower dose.^{140 141 142 161 160}

Myxedema Coma

Reduced initial dose may be appropriate in geriatric patients.^{155 161}

Cautions for Levothyroxine Sodium

Contraindications

• 
  

  Untreated subclinical (suppressed serum TSH concentrations with normal T₃ [triiodothyronine] and T₄ concentrations) or overt thyrotoxicosis of any etiology.^{140 141 142 160 161}

  
  


• 
  

  AMI.^{140 141 142 161 160}

  
  


• 
  

  Untreated adrenal insufficiency.^{140 141 142 161 160}

  
  


• 
  

  Known hypersensitivity to any ingredient in the formulation.^{140 141 142 161 160} (See Sensitivity Reactions under Cautions.)

  
  

Warnings/Precautions

Warnings

Unlabeled Uses

Should not be used for the treatment of obesity or for weight loss either alone or with other therapeutic agents.^{140 141 142 161 160} In euthyroid patients, doses within the range of daily hormonal requirements are ineffective for weight reduction.^{140 141 142 161 160} Larger doses may produce serious or life-threatening toxicity, particularly when given in conjunction with sympathomimetic amines (e.g., anorectic agents).^{140 141 142 161 160}

Should not be used in the treatment of male or female infertility unless this condition is associated with hypothyroidism.^{140 141 142 161 160}

Thyrotoxicosis

Because of risk of precipitating overt thyrotoxicosis, levothyroxine is contraindicated in patients with nontoxic diffuse goiter or nodular thyroid disease (particularly geriatric patients or those with underlying cardiovascular disease) in whom serum TSH level is already suppressed.^{141 142 161 160}

If serum TSH level is not suppressed, use with caution and monitor clinical (e.g., adverse cardiovascular effects) and laboratory (i.e., thyroid function) parameters for evidence of hyperthyroidism.^{141 142 161 160}

Sensitivity Reactions

Hypersensitivity to levothyroxine is not known to occur.^{140 141 142 161 160} However, hypersensitivity reactions to inactive ingredients of thyroid hormone products have been reported and include urticaria, pruritus, rash, flushing, angioedema, abdominal pain, nausea, vomiting, diarrhea, fever, arthralgia, serum sickness, and wheezing.^{140 141 142 161 160}

Major Toxicities

Effects on Bone Mineral Density

In women, long-term therapy has been associated with decreased bone mineral density, especially in postmenopausal women receiving greater than replacement doses or in women who are receiving suppressive doses.^{140 141 142 161 160} Use lowest dose necessary to achieve desired clinical and biochemical response.^{140 141 142 161 160}

GI Effects

Choking, gagging, dysphagia, or lodging of a tablet in the throat reported with Levoxyl, particularly when administered without water.¹⁴¹ Administer Levoxyl tablets with a full glass of water.¹⁴¹

General Precautions

Therapy Monitoring

Levothyroxine has a narrow therapeutic index.^{140 141 142 161 160} Avoid undertreatment or overtreatment, which may result in adverse effects on growth and development in pediatric patients, cardiovascular function, bone metabolism, reproductive function, cognitive function, emotional state, GI function, and glucose and lipid metabolism.^{140 141 142 161 160}

Periodically perform appropriate laboratory tests (e.g., serum TSH, total or free T₄) and clinical evaluations to monitor adequacy of therapy.^{140 141 142 161 160}

Preexisting Cardiovascular Disease

Use with caution.^{140 141 142 161 160} (See Patients with Cardiovascular Disease under Dosage and Administration.) Patients with CHD should be monitored closely during surgical procedures due to increased risk of arrhythmias.^{140 141 142 161 160}

Associated Endocrine Disorders

In patients with secondary or tertiary hypothyroidism, consider possibility of additional hypothalamic/pituitary hormone deficiencies and treat if diagnosed.^{140 141 142 161 160}

Chronic autoimmune thyroiditis may occur in association with other autoimmune disorders (e.g., adrenal insufficiency, pernicious anemia, and insulin-dependent diabetes mellitus).^{140 141 142 161 160}

Patients with concomitant adrenal insufficiency should be treated with replacement glucocorticoids prior to initiation of levothyroxine.^{140 141 142 161 160} Failure to do so may precipitate an acute adrenal crisis due to increased metabolic clearance of glucocorticoids when levothyroxine is initiated.^{140 141 142 161 160}

Patients with diabetes mellitus may require increased dosages of antidiabetic agents when treated with levothyroxine.^{140 141 142 161 160}

Lactose Intolerance

Lactose is used in manufacture of Synthroid and Unithroid tablets.^{140 142}

Specific Populations

Pregnancy

Category A.^{140 141 142 161 160}

During pregnancy, serum T₄ levels may decrease and serum TSH levels increase to values outside the normal range.^{140 141 142 161 160} Elevations in serum TSH may occur at 4 weeks gestation; monitor TSH levels during each trimester and adjust levothyroxine dosage accordingly.^{140 141 142 161 160} Reduce dosage to pre-pregnancy level immediately after delivery, since postpartum TSH concentrations are similar to preconception levels; measure serum TSH concentrations 6–8 weeks postpartum.^{140 141 142 161 160}

Lactation

Although thyroid hormones are distributed minimally into human milk, exercise caution when administering to a nursing woman.^{140 141 142 161 160} However, adequate replacement dosages generally are needed to maintain normal lactation.^{140 141 142 161 160}

Pediatric Use

The goal of treatment in pediatric patients with hypothyroidism is to achieve and maintain normal intellectual and physical growth and development.^{140 141 142 161 160} Initiate therapy immediately upon diagnosis and maintain for life, unless transient hypothyroidism is suspected.^{140 141 142 161 160}

Neonates with suspected hypothyroidism should receive thyroid agent therapy pending results of confirmative tests. If a positive diagnosis cannot be made on the basis of laboratory findings but there is a strong clinical suspicion of congenital hypothyroidism, initiate replacement therapy to achieve euthyroidism until the child is 1–2 years of age. During first 2 weeks of therapy, closely monitor infants for cardiac overload, arrhythmias, and aspiration resulting from avid suckling.^{140 141 142 161 160} Evaluate infant’s clinical response to therapy about 6 weeks after initiation of levothyroxine and at least at 6 and 12 months of age and yearly thereafter.

When transient hypothyroidism is suspected, temporarily discontinue therapy for 4–8 weeks to reassess the condition when the child is >3 years of age.^{140 141 142 161 160} If the diagnosis of permanent hypothyroidism is confirmed, reinstitute full replacement therapy.^{140 141 142 161 160} However, if serum concentrations of T₄ and TSH are normal, discontinue levothyroxine and monitor carefully; repeat thyroid function tests if manifestations of hypothyroidism develop.^{140 141 142 161 160}

In pediatric patients with transient severe hypothyroidism, reduce replacement dose by half for 30 days.^{140 141 142 161 160} If, after 30 days, serum TSH >20 mU/L, consider the hypothyroidism permanent and reinstitute full replacement therapy.^{140 141 142 161 160} However, if serum TSH ≤ 20 mU/L, temporarily discontinue levothyroxine for 30 days, then repeat serum T₄ and TSH measurements.^{140 141 142 161 160} Reinstitute or discontinue replacement therapy based on laboratory findings.^{140 141 142 161 160}

Monitor patients closely to avoid undertreatment or overtreatment.^{140 141 142 161 160} Undertreatment may result in impaired intellectual development, poor school performance (due to impaired concentration and slowed mentation), and reduced adult height.^{140 141 142 161 160} Overtreatment may result in craniosynostosis in infants and accelerate aging of bones, resulting in premature epiphyseal closure and compromised adult stature.^{140 141 142 161 160}

Treated children may manifest a period of catch-up growth, which may be adequate in some cases to achieve normal adult height. In children with severe or long-standing hypothyroidism, catch-up growth may not be adequate to achieve normal adult height.^{140 141 142 161 160}

Pseudotumor cerebri and slipped capital femoral epiphysis have been reported in children receiving levothyroxine.^{140 141 142 161 160}

Geriatric Use

Because of the increased risk of cardiovascular disease among geriatric patients, levothyroxine therapy should not be initiated at the full replacement dose.^{140 141 142 161 160}

Common Adverse Effects

Adverse reactions result from overdosage and resemble manifestations of hyperthyroidism, including fatigue, increased appetite, weight loss, heat intolerance, fever, excessive sweating, headache, hyperactivity, nervousness, anxiety, irritability, emotional lability, insomnia, tremor, muscle weakness, palpitations, tachycardia, arrhythmias, increased heart rate and BP, heart failure, angina, AMI, cardiac arrest, dyspnea, diarrhea, vomiting, abdominal cramps, elevations in liver function tests, hair loss, flushing, decreased bone mineral density, menstrual irregularities, and impaired fertility.^{141 142 161 160}

Interactions for Levothyroxine Sodium

Drugs Affecting Hepatic Microsomal Enzymes

Potential increased levothyroxine metabolism and decreased plasma levothyroxine concentrations with drugs that induce general hepatic metabolic activity resulting in increased levothyroxine dosage requirements.^{141 142 161 160}

Drugs That May Decrease T₄ 5’-Deiodinase Activity

Inhibitors of T₄ 5’-deiodinase decrease peripheral conversion of T₄ to T₃, resulting in decreased T₃ concentrations.^{140 141 142 161 160} However, serum T₄ concentrations usually remain within normal range but may occasionally be slightly increased.^{140 141 142 161 160}

Specific Drugs and Foods

Drug or Food	Interaction	Comment
Amiodarone	Decreased metabolism of T4 to T3140 141 142 161 160
Anticoagulants, oral (e.g., coumarins)	Potentiation of anticoagulant activity140 141 142 161 160	Carefully monitor PT and adjust anticoagulant dosage accordingly140 141 142 161 160
Antidepressants (tricyclics, tetracyclics, SSRIs)	Increased risk of cardiac arrhythmias and CNS stimulation when used with tricyclics or tetracyclics140 141 142 161 160 Faster onset of action of tricyclics140 141 142 161 160 Sertraline may increase levothyroxine requirements140 141 142 161 160
Antidiabetic agents (biguanides, meglitinides, sulfonylureas, thiazolidediones, insulin)	Levothyroxine may cause increased antidiabetic agent or insulin requirements140 141 142 161 160	Carefully monitor diabetic control, especially when thyroid therapy is initiated, changed, or discontinued140 141 142 161 160
β-Adrenergic blocking agents (e.g., propranolol hydrochloride dosages >160 mg daily)	Decreased metabolism of T4 to T3140 141 142 161 160 Impaired antihypertensive effects when hypothyroid patient is converted to euthyroid state140 141 142 161 160
Bile acid sequestrants (e.g., cholestyramine, colestipol)	Delayed or impaired levothyroxine absorption140 141 142 161 160	Administer levothyroxine at least 4 hours apart from these agents140 141 142 154 161 160
Carbamazepine	Potential increased levothyroxine metabolism140 141 142 161 160 Reduced levothyroxine serum protein binding140 141 142 161 160	May require levothyroxine dosage increase140 141 142 161 160
Cardiac glycosides	Decreased serum digitalis glycoside concentrations in patients with hyperthyroidism or in patients with hypothyroidism in whom a euthyroid state has been achieved; potential for reduced therapeutic effects of digitalis glycosides with levothyroxine140 141 142 161 160	May need to increase dosage of digitalis glycoside when hypothyroidism has been corrected140 141 142 161 160
Corticosteroids (e.g., dexamethasone at dosages >4 mg daily)	Decreased metabolism of T4 to T3140 141 142 161 160 . Short-term administration of large doses of corticosteroids may decrease serum T3 concentrations by 30% with minimal change in serum T4 levels140 141 142 161 160
Ferrous sulfate	Delayed or impaired levothyroxine absorption140 141 142 161 160	Administer levothyroxine at least 4 hours apart from this agent140 141 142 154 161 160
Food with large amounts of fiber (e.g., cotton seed meal, infant soybean formula, soybean flour, walnuts)	Delayed or impaired levothyroxine absorption140 141 142 161 160
Fusosemide (at IV dosages >80 mg)	Concomitant use with levothyroxine produces transient increases in serum free T4 concentrations; continued administration results in a decrease in serum T4 and normal free T4 and TSH concentrations, and therefore, patients are clinically euthyroid140 141 142 161 160
GI drugs (e.g., antacids [aluminum hydroxide, magnesium hydroxide, calcium carbonate], simethicone, sucralfate)	Delayed or impaired levothyroxine absorption140 141 142 161 160	Administer levothyroxine at least 4 hours apart from these agents140 141 142 154 161 160
Growth hormones (e.g., somatropin)	Excessive levothyroxine use with growth hormones may accelerate epiphyseal closure; however, untreated hypothyroidism may interfere with growth response to growth hormone140 141 142 161 160