Author: druginteractionchecker_lgaiz4

DOSAGE AND ADMINISTRATION

2 Take Amitiza orally with food and water.

Swallow capsules whole and do not break apart or chew.

Physicians and patients should periodically assess the need for continued therapy.

Capsules should be swallowed whole and should not be broken apart or chewed ( ) 2 Chronic Idiopathic Constipation and Opioid -induced Constipation 24 mcg taken twice daily orally with food and water • (2.1) Reduce the dosage in patients with moderate and severe hepatic impairment ( ) 2.1 Irritable Bowel Syndrome with Constipation 8 mcg taken twice daily orally with food and water • (2.2) Reduce the dosage in patients with severe hepatic impairment ( ) 2.2 2.1 Chronic Idiopathic Constipation and Opioid-induced Constipation The recommended dose is 24 mcg twice daily orally with food and water.

Dosage in patients with hepatic impairment For patients with moderately impaired hepatic function (Child-Pugh Class B), the recommended starting dose is 16 mcg twice daily.

For patients with severely impaired hepatic function (Child-Pugh Class C), the recommended starting dose is 8 mcg twice daily.

If this dose is tolerated and an adequate response has not been obtained after an appropriate interval, doses can then be escalated to full dosing with appropriate monitoring of patient response and .

[see Use in Specific Populations ( ) 8.7 Clinical Pharmacology ( )] 12.3 2.2 Irritable Bowel Syndrome with Constipation The recommended dose is 8 mcg twice daily orally with food and water.

Dosage in patients with hepatic impairment For patients with severely impaired hepatic function (Child-Pugh Class C), the recommended starting dose is 8 mcg once daily.

If this dose is tolerated and an adequate response has not been obtained after an appropriate interval, doses can then be escalated to full dosing with appropriate monitoring of patient response.

Dosage adjustment is not required for patients with moderately impaired hepatic function (Child-Pugh Class B) .

[see Use in Specific Populations ( ) and Clinical Pharmacology ( )] 8.7 12.3

DOSAGE AND ADMINISTRATION

Gently massage sufficient Clotrimazole and Betamethasone Dipropionate Cream or Lotion into the affected skin areas twice a day, in the morning and evening.

Clotrimazole and Betamethasone Dipropionate Cream or Lotion should not be used longer than 2 weeks in the treatment of tinea corporis or tinea cruris, and amounts greater than 45 g per week of Clotrimazole and Betamethasone Dipropionate Cream, USP or amounts greater than 45 mL per week of Clotrimazole and Betamethasone Dipropionate Lotion should not be used.

If a patient with tinea corporis or tinea cruris shows no clinical improvement after one week of treatment with Clotrimazole and Betamethasone Dipropionate Cream or Lotion, the diagnosis should be reviewed.

Clotrimazole and Betamethasone Dipropionate Cream or Lotion should not be used longer than 4 weeks in the treatment of tinea pedis, and amounts greater than 45 g per week of Clotrimazole and Betamethasone Dipropionate Cream, USP or amounts greater than 45 mL per week of Clotrimazole and Betamethasone Dipropionate Lotion should not be used.

If a patient with tinea pedis shows no clinical improvement after 2 weeks of treatment with Clotrimazole and Betamethasone Dipropionate Cream or Lotion, the diagnosis should be reviewed.

Clotrimazole and Betamethasone Dipropionate Cream or Lotion should not be used with occlusive dressings.

DOSAGE AND ADMINISTRATION

The patient’s pretreatment body weight should be obtained for calculation of correct dosage.

Amikacin Sulfate Injection may be given intramuscularly or intravenously.

The status of renal function should be estimated by measurement of the serum creatinine concentration or calculation of the endogenous creatinine clearance rate.

The blood urea nitrogen (BUN) is much less reliable for this purpose.

Reassessment of renal function should be made periodically during therapy.

Whenever possible, amikacin concentrations in serum should be measured to assure adequate but not excessive levels.

It is desirable to measure both peak and trough serum concentrations intermittently during therapy.

Peak concentrations (30 to 90 minutes after injection) above 35 micrograms per mL and trough concentrations (just prior to the next dose) above 10 micrograms per mL should be avoided.

Dosage should be adjusted as indicated.

Intramuscular Administration for Patients with Normal Renal Function The recommended dosage for adults, children and older infants (see WARNINGS box) with normal renal function is 15 mg/kg/day divided into 2 or 3 equal doses administered at equally-divided intervals, i.e., 7.5 mg/kg q12h or 5 mg/kg q8h.

Treatment of patients in the heavier weight classes should not exceed 1.5 gram/day.

When amikacin is indicated in newborns (see WARNINGS box), it is recommended that a loading dose of 10 mg/kg be administered initially to be followed with 7.5 mg/kg every 12 hours.

The usual duration of treatment is 7 to 10 days.

It is desirable to limit the duration of treatment to short term whenever feasible.

The total daily dose by all routes of administration should not exceed 15 mg/kg/day.

In difficult and complicated infections where treatment beyond 10 days is considered, the use of amikacin should be reevaluated.

If continued, amikacin serum levels, and renal, auditory, and vestibular functions should be monitored.

At the recommended dosage level, uncomplicated infections due to amikacin-sensitive organisms should respond in 24 to 48 hours.

If definite clinical response does not occur within 3 to 5 days, therapy should be stopped and the antibiotic susceptibility pattern of the invading organism should be rechecked.

Failure of the infection to respond may be due to resistance of the organism or to the presence of septic foci requiring surgical drainage.

When amikacin is indicated in uncomplicated urinary tract infections, a dose of 250 mg twice daily may be used.

DOSAGE GUIDELINES ADULTS AND CHILDREN WITH NORMAL RENAL FUNCTION Patient Weight Dosage lbs kg 7.5 mg/kg q12h OR 5 mg/kg q8h 99 45 337.5 mg 225 mg 110 50 375 mg 250 mg 121 55 412.5 mg 275 mg 132 60 450 mg 300 mg 143 65 487.5 mg 325 mg 154 70 525 mg 350 mg 165 75 562.5 mg 375 mg 176 80 600 mg 400 mg 187 85 637.5 mg 425 mg 198 90 675 mg 450 mg 209 95 712.5 mg 475 mg 220 100 750 mg 500 mg Intramuscular Administration for Patients with Impaired Renal Function Whenever possible, serum amikacin concentrations should be monitored by appropriate assay procedures.

Doses may be adjusted in patients with impaired renal function either by administering normal doses at prolonged intervals or by administering reduced doses at a fixed interval.

Both methods are based on the patient’s creatinine clearance or serum creatinine values since these have been found to correlate with aminoglycoside half-lives in patients with diminished renal function.

These dosage schedules must be used in conjunction with careful clinical and laboratory observations of the patient and should be modified as necessary.

Neither method should be used when dialysis is being performed.

Normal Dosage at Prolonged Intervals If the creatinine clearance rate is not available and the patient’s condition is stable, a dosage interval in hours for the normal dose can be calculated by multiplying the patient’s serum creatinine by 9, e.g., if the serum creatinine concentration is 2 mg/100 mL, the recommended single dose (7.5 mg/kg) should be administered every 18 hours.

Reduced Dosage at Fixed Time Intervals When renal function is impaired and it is desirable to administer amikacin at a fixed time interval, dosage must be reduced.

In these patients, serum amikacin concentrations should be measured to assure accurate administration of amikacin and to avoid concentrations above 35 mcg/mL.

If serum assay determinations are not available and the patient’s condition is stable, serum creatinine and creatinine clearance values are the most readily available indicators of the degree of renal impairment to use as a guide for dosage.

First, initiate therapy by administering a normal dose, 7.5 mg/kg, as a loading dose.

This loading dose is the same as the normally recommended dose which would be calculated for a patient with a normal renal function as described above.

To determine the size of maintenance doses administered every 12 hours, the loading dose should be reduced in proportion to the reduction in the patient’s creatinine clearance rate: Maintenance Dose Every 12 hours = observed CC in mL/min X Calculated loading dose in mg normal CC in mL/min (CC – creatinine clearance rate) An alternate rough guide for determining reduced dosage at 12-hour intervals (for patients whose steady state serum creatinine values are known) is to divide the normally recommended dose by the patient’s serum creatinine.

The above dosage schedules are not intended to be rigid recommendations but are provided as guides to dosage when the measurement of amikacin serum levels is not feasible.

Intravenous Administration The individual dose, the total daily dose, and the total cumulative dose of amikacin sulfate are identical to the dose recommended for intramuscular administration.

The solution for intravenous use is prepared by adding the contents of a 500 mg vial to 100 or 200 mL of sterile diluent such as 0.9% sodium chloride injection or 5% dextrose injection or any of the compatible solutions listed below.

The solution is administered to adults over a 30 to 60 minute period.

The total daily dose should not exceed 15 mg/kg/day and may be divided into either 2 or 3 equally-divided doses at equally-divided intervals.

In pediatric patients the amount of fluid used will depend on the amount of amikacin ordered for the patient.

It should be a sufficient amount to infuse the Amikacin Sulfate Injection over a 30 to 60 minute period.

Infants should receive a 1 to 2 hour infusion.

Amikacin should not be physically premixed with other drugs but should be administered separately according to the recommended dose and route.

Stability in IV Fluids Amikacin sulfate is stable for 24 hours at room temperature at concentrations of 0.25 and 5 mg/mL in the following solutions: 5% Dextrose Injection 5% Dextrose and 0.2% Sodium Chloride Injection 5% Dextrose and 0.45% Sodium Chloride Injection 0.9% Sodium Chloride Injection Lactated Ringer’s Injection Normosol ® M in 5% Dextrose Injection (or Plasma-Lyte 56 Injection in 5% Dextrose in Water) Normosol ® R in 5% Dextrose Injection (or Plasma-Lyte 148 Injection in 5% Dextrose in Water) In the above solutions with Amikacin Sulfate Injection concentrations of 0.25 and 5 mg/mL, solutions aged for 60 days at 4°C and then stored at 25°C had utility times of 24 hours.

At the same concentrations, solutions frozen and aged for 30 days at -15°C, thawed, and stored at 25°C had utility times of 24 hours.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit.

Aminoglycosides administered by any of the above routes should not be physically premixed with other drugs but should be administered separately.

Because of the potential toxicity of aminoglycosides, “fixed dosage” recommendations which are not based upon body weight are not advised.

Rather, it is essential to calculate the dosage to fit the needs of each patient.

DOSAGE AND ADMINISTRATION

DOSAGE & ADMINISTRATION The dose is dependent on the requirements of the individual patient.

Intravenous calcium gluconate injection must be administered slowly.

Adults —500 mg to 2 g (5 to 20 mL) Pediatric patients —200 to 500 mg (2 to 5 mL) Infants —Not more than 200 mg (not more than 2 mL) Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

DOSAGE AND ADMINISTRATION

DOSAGE AND ADMlNlSTRATION Gabapentin is given orally with or without food.

If gabapentin dose is reduced, discontinued, or substituted with an alternative medication, this should be done gradually over a minimum of 1 week (a longer period may be needed at the discretion of the prescriber).

Postherpetic Neuralgia In adults with postherpetic neuralgia, gabapentin therapy may be initiated as a single 300-mg dose on Day 1, 600 mg/day on Day 2 (divided BID), and 900 mg/day on Day 3 (divided TID).

The dose can subsequently be titrated up as needed for pain relief to a daily dose of 1800 mg (divided TID).

In clinical studies, efficacy was demonstrated over a range of doses from 1800 mg/day to 3600 mg/day with comparable effects across the dose range.

Additional benefit of using doses greater than 1800 mg/day was not demonstrated.

Epilepsy Gabapentin is recommended for add-on therapy in patients 3 years of age and older.

Effectiveness in pediatric patients below the age of 3 years has not been established.

Patients >12 years of age The effective dose of gabapentin is 900 to 1800 mg/day and given in divided doses (three times a day) using 300 or 400 mg capsules.

The starting dose is 300 mg three times a day.

If necessary, the dose may be increased using 300 or 400 mg capsules three times a day up to 1800 mg/day.

Dosages up to 2400 mg/day have been well tolerated in long-term clinical studies.

Doses of 3600 mg/day have also been administered to a small number of patients for a relatively short duration, and have been well tolerated.

The maximum time between doses in the TID schedule should not exceed 12 hours.

Pediatric Patients Age 3 to 12 years The starting dose should range from 10 to 15 mg/kg/day in 3 divided doses, and the effective dose reached by upward titration over a period of approximately 3 days.

The effective dose of gabapentin in patients 5 years of age and older is 25 to 35 mg/kg/day and given in divided doses (three times a day).

The effective dose in pediatric patients ages 3 and 4 years is 40 mg/kg/day and given in divided doses (three times a day) (see CLINICAL PHARMACOLOGY, Pediatric ).

Dosages up to 50 mg/kg/day have been well tolerated in a long-term clinical study.

The maximum time interval between doses should not exceed 12 hours.

It is not necessary to monitor gabapentin plasma concentrations to optimize gabapentin therapy.

Further, because there are no significant pharmacokinetic interactions among gabapentin and other commonly used antiepileptic drugs, the addition of gabapentin does not alter the plasma levels of these drugs appreciably.

If gabapentin is discontinued and/or an alternate anticonvulsant medication is added to the therapy, this should be done gradually over a minimum of 1 week.

Dosage in Renal Impairment Creatinine clearance is difficult to measure in outpatients.

In patients with stable renal function, creatinine clearance (C Cr ) can be reasonably well estimated using the equation of Cockcroft and Gault: for females C Cr = (0.85)(140-age)(weight)/[(72)(S Cr )] for males C Cr = (140-age)(weight)/[(72)(S Cr )] in which age is in years, weight is in kilograms, and S Cr is serum creatinine in mg/dL.

Dosage adjustment in patients ≥ 12 years of age with compromised renal function or undergoing hemodialysis is recommended as follows (see dosing recommendations above for effective doses in each indication).

TABLE 6.

Gabapentin Dosage Based on Renal Function Renal Function Creatinine Clearance (mL/min) Total Daily Dose Range (mg/day) Dose Regimen (mg) ≥60 900 to 3600 300 TID 400 TID 600 TID 800 TID 1200 TID >30 to 59 400 to 1400 200 BID 300 BID 400 BID 500 BID 700 BID >15 to 29 200 to 700 200 QD 300 QD 400 QD 500 QD 700 QD 15 For patients with creatinine clearance <15 mL/min, reduce daily dose in proportion to creatinine clearance (e.g., patients with a creatinine clearance of 7.5 mL/min should receive one-half the daily dose that patients with a creatinine clearance of 15 mL/min receive).

100 to 300 100 QD 125 QD 150 QD 200 QD 300 QD Post-Hemodialysis Supplemental Dose (mg) Patients on hemodialysis should receive maintenance doses based on estimates of creatinine clearance as indicated in the upper portion of the table and a supplemental post-hemodialysis dose administered after each 4 hours of hemodialysis as indicated in the lower portion of the table.

Hemodialysis 125 150 200 250 350 The use of gabapentin in patients <12 years of age with compromised renal function has not been studied.

Dosage in Elderly Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and dose should be adjusted based on creatinine clearance values in these patients.

DOSAGE AND ADMINISTRATION

• Therapy with TIKOSYN must be initiated (and, if necessary, re-initiated) in a setting that provides continuous electrocardiographic (ECG) monitoring and in the presence of personnel trained in the management of serious ventricular arrhythmias.

Patients should continue to be monitored in this way for a minimum of three days.

Additionally, patients should not be discharged within 12 hours of electrical or pharmacological conversion to normal sinus rhythm.

• The dose of TIKOSYN must be individualized according to calculated creatinine clearance and QTc.

(QT interval should be used if the heart rate is <60 beats per minute.

There are no data on use of TIKOSYN when the heart rate is <50 beats per minute.) The usual recommended dose of TIKOSYN is 500 mcg BID, as modified by the dosing algorithm described below.

For consideration of a lower dose, see Special Considerations below.

• Serum potassium should be maintained within the normal range before TIKOSYN treatment is initiated and should be maintained within the normal range while the patient remains on TIKOSYN therapy.

(See WARNINGS, Hypokalemia and Potassium-Depleting Diuretics ).

In clinical trials, potassium levels were generally maintained above 3.6–4.0 mEq/L.

• Patients with atrial fibrillation should be anticoagulated according to usual medical practice prior to electrical or pharmacological cardioversion.

Anticoagulant therapy may be continued after cardioversion according to usual medical practice for the treatment of people with AF.

Hypokalemia should be corrected before initiation of TIKOSYN therapy (see WARNINGS, Ventricular Arrhythmia ).

• Patients to be discharged on TIKOSYN therapy from an inpatient setting as described above must have an adequate supply of TIKOSYN, at the patient’s individualized dose, to allow uninterrupted dosing until the patient can fill a TIKOSYN prescription.

Instructions for Individualized Dose Initiation Initiation of TIKOSYN Therapy Step 1.

Electrocardiographic assessment: Prior to administration of the first dose, the QTc or QT must be checked using an average of 5–10 beats.

If the QTc or QT is greater than 440 msec (500 msec in patients with ventricular conduction abnormalities), TIKOSYN is contraindicated.

If heart rate is less than 60 beats per minute, QT interval should be used.

Proceed to Step 2 if the QTc or QT is 440 msec.

Patients with heart rates <50 beats per minute have not been studied.

Step 2.

Calculation of creatinine clearance: Prior to the administration of the first dose, the patient’s creatinine clearance must be calculated using the following formula: creatinine clearance (male) = (140-age) × actual body weight in kg 72 × serum creatinine (mg/dL) creatinine clearance (female) = (140-age) × actual body weight in kg × 0.85 72 × serum creatinine (mg/dL) When serum creatinine is given in µmol/L, divide the value by 88.4 (1 mg/dL = 88.4 µmol/L).

Step 3.

Starting Dose: The starting dose of TIKOSYN is determined as follows: Calculated Creatinine Clearance TIKOSYN Dose >60 mL/min 500 mcg twice daily 40 to 60 mL/min 250 mcg twice daily 20 to <40 mL/min 125 mcg twice daily <20 mL/min Tikosyn is contraindicated in these patients Step 4.

Administer the adjusted TIKOSYN dose and begin continuous ECG monitoring.

Step 5.

At 2–3 hours after administering the first dose of Tikosyn, determine the QTc or QT (if heart rate is less than 60 beats per minute).

If the QTc or QT has increased by greater than 15% compared to the baseline established in Step 1 OR if the QTc or QT is greater than 500 msec (550 msec in patients with ventricular conduction abnormalities), subsequent dosing should be adjusted as follows: If the Starting Dose Based on Creatinine Clearance is: Then the Adjusted Dose (for QTc or QT Prolongation) is: 500 mcg twice daily 250 mcg twice daily 250 mcg twice daily 125 mcg twice daily 125 mcg twice daily 125 mcg once a day Step 6.

At 2–3 hours after each subsequent dose of Tikosyn, determine the QTc or QT (if heart rate is less than 60 beats per minute) (for in-hospital doses 2–5).

No further down titration of Tikosyn based on QTc or QT is recommended.

NOTE: If at any time after the second dose of Tikosyn is given the QTc or QT is greater than 500 msec (550 msec in patients with ventricular conduction abnormalities), Tikosyn should be discontinued.

Step 7.

Patients are to be continuously monitored by ECG for a minimum of three days, or for a minimum of 12 hours after electrical or pharmacological conversion to normal sinus rhythm, whichever is greater.

The steps described above are summarized in the following diagram: flow chart Maintenance of TIKOSYN Therapy Renal function and QTc or QT (if heart rate is less than 60 beats per minute) should be re-evaluated every three months or as medically warranted.

If QTc or QT exceeds 500 milliseconds (550 msec in patients with ventricular conduction abnormalities), TIKOSYN therapy should be discontinued and patients should be carefully monitored until QTc or QT returns to baseline levels.

If renal function deteriorates, adjust dose as described in Initiation of TIKOSYN Therapy, Step 3.

Special Considerations Consideration of a Dose Lower than that Determined by the Algorithm: The dosing algorithm shown above should be used to determine the individualized dose of TIKOSYN.

In clinical trials (see CLINICAL STUDIES ), the highest dose of 500 mcg BID of TIKOSYN as modified by the dosing algorithm led to greater effectiveness than lower doses of 125 or 250 mcg BID as modified by the dosing algorithm.

The risk of Torsade de Pointes, however, is related to dose as well as to patient characteristics (see WARNINGS ).

Physicians, in consultation with their patients, may therefore in some cases choose doses lower than determined by the algorithm.

It is critically important that if at any time this lower dose is increased, the patient needs to be rehospitalized for three days.

Previous toleration of higher doses does not eliminate the need for rehospitalization.

The maximum recommended dose in patients with a calculated creatinine clearance greater than 60 mL/min is 500 mcg BID; doses greater than 500 mcg BID have been associated with an increased incidence of Torsade de Pointes.

A patient who misses a dose should NOT double the next dose.

The next dose should be taken at the usual time.

Cardioversion: If patients do not convert to normal sinus rhythm within 24 hours of initiation of TIKOSYN therapy, electrical conversion should be considered.

Patients continuing on TIKOSYN after successful electrical cardioversion should continue to be monitored by electrocardiography for 12 hours post cardioversion, or a minimum of 3 days after initiation of TIKOSYN therapy, whichever is greater.

Switch to TIKOSYN from Class I or other Class III Antiarrhythmic Therapy Before initiating TIKOSYN therapy, previous antiarrhythmic therapy should be withdrawn under careful monitoring for a minimum of three (3) plasma half-lives.

Because of the unpredictable pharmacokinetics of amiodarone, TIKOSYN should not be initiated following amiodarone therapy until amiodarone plasma levels are below 0.3 mcg/mL or until amiodarone has been withdrawn for at least three months.

Stopping TIKOSYN Prior to Administration of Potentially Interacting Drugs If TIKOSYN needs to be discontinued to allow dosing of other potentially interacting drug(s), a washout period of at least two days should be followed before starting the other drug(s).

DOSAGE AND ADMINISTRATION

2 Oxybutynin chloride extended-release tablets must be swallowed whole with the aid of liquids, and must not be chewed, divided, or crushed.

Oxybutynin chloride extended-release tablets may be administered with or without food.

Oxybutynin chloride extended-release tablets must be swallowed whole with the aid of liquids, and must not be chewed, divided, or crushed.

Oxybutynin chloride extended-release tablets may be administered with or without food.

( 2 ) Adults: Start with 5 mg or 10 mg, once daily at approximately the same time every day.

Dose should not exceed 30 mg per day.

( 2.1 ) Pediatric patients (6 years of age or older): Start with 5 mg, once daily at approximately the same time every day.

Dose should not exceed 20 mg per day.

( 2.2 ) 2.1 Adults The recommended starting dose of oxybutynin chloride extended-release tablets is 5 or 10 mg once daily at approximately the same time each day.

Dosage may be adjusted in 5-mg increments to achieve a balance of efficacy and tolerability (up to a maximum of 30 mg/day).

In general, dosage adjustment may proceed at approximately weekly intervals.

2.2 Pediatric Patients Aged 6 Years of Age and Older The recommended starting dose of oxybutynin chloride extended-release tablets is 5 mg once daily at approximately the same time each day.

Dosage may be adjusted in 5-mg increments to achieve a balance of efficacy and tolerability (up to a maximum of 20 mg/day).

DOSAGE AND ADMINISTRATION

2 The recommended starting dose and highest recommended dose of budesonide inhalation suspension, based on prior asthma therapy, are listed in the following table.

Previous Therapy Recommended Starting Dose Highest Recommended Dose Bronchodilators alone 0.5 mg total daily dose administered either once daily or twice daily in divided doses 0.5 mg total daily dose Inhaled Corticosteroids 0.5 mg total daily dose administered either once daily or twice daily in divided doses 1 mg total daily dose Oral Corticosteroids 1 mg total daily dose administered either as 0.5 mg twice daily or 1 mg once daily 1 mg total daily dose Recommended dosing based on previous therapy ( 2 ).

Start with the lowest recommended dose: • Bronchodilators alone: 0.5 mg once daily or 0.25 mg twice daily • Inhaled corticosteroids: 0.5 mg once daily or 0.25 mg twice daily up to 0.5 mg twice daily • Oral corticosteroids: 0.5 mg twice daily or 1 mg once daily • In symptomatic children not responding to non-steroidal therapy, a starting dose of 0.25 mg once daily may be considered.

• If once-daily treatment does not provide adequate control, the total daily dose should be increased and/or administered as a divided dose.

Once asthma stability is achieved, titrate the dose downwards.

• For inhalation use via compressed air driven jet nebulizers only (not for use with ultrasonic devices).

Not for injection.

( 2.2 ) 2.1 Dosing Recommendations Dosing recommendations based on previous therapy are as follows: • Bronchodilators alone: 0.5 mg once daily or 0.25 mg twice daily • Inhaled corticosteroids: 0.5 mg once daily or 0.25 mg twice daily up to 0.5 mg twice daily • Oral corticosteroids: 0.5 mg twice daily or 1 mg once daily In symptomatic children not responding to non-steroidal therapy, a starting dose of 0.25 mg once daily may be considered.

If once-daily treatment does not provide adequate control, the total daily dose should be increased and/or administered as a divided dose.

In all patients, it is desirable to downward-titrate to the lowest effective dose once asthma stability is achieved.

2.2 Directions for Use Budesonide inhalation suspension should be administered via jet nebulizer connected to an air compressor with an adequate air flow, equipped with a mouthpiece or suitable face mask.

Ultrasonic nebulizers are not suitable for the adequate administration of budesonide inhalation suspension and, therefore, are NOT recommended.

The effects of mixing budesonide inhalation suspension with other nebulizable medications have not been adequately assessed.

Budesonide inhalation suspension should be administered separately in the nebulizer [see PATIENT COUNSELING INFORMATION , Administration with a jet nebulizer ( 17.1 )].

A Pari-LC-Jet Plus Nebulizer (with face mask or mouthpiece) connected to a Pari Master compressor was used to deliver budesonide inhalation suspension to each patient in 3 U.S.

controlled clinical studies.

The safety and efficacy of budesonide inhalation suspension delivered by other nebulizers and compressors have not been established.

DOSAGE AND ADMINISTRATION

2 Dosing is based on concomitant medications, indication, and patient age.

( 2.1 , 2.2 , 2.3 , 2.4 ) To avoid an increased risk of rash, the recommended initial dose and subsequent dose escalations should not be exceeded.

Lamotrigine Starter Kits and Lamotrigine Orally Disintegrating Tablets Patient Titration Kits are available for the first 5 weeks of treatment.

( 2.1 , 16 ) Do not restart lamotrigine orally disintegrating tablets in patients who discontinued due to rash unless the potential benefits clearly outweigh the risks.

( 2.1 , 5.1 ) Adjustments to maintenance doses will be necessary in most patients starting or stopping estrogen-containing oral contraceptives.

( 2.1 , 5.9 ) Discontinuation: Taper over a period of at least 2 weeks (approximately 50% dose reduction per week).

( 2.1 , 5.10 ) Epilepsy : Adjunctive therapy—See Table 1 for patients older than 12 years and Tables 2 and 3 for patients aged 2 to 12 years.

( 2.2 ) Conversion to monotherapy—See Table 4.

( 2.3 ) Bipolar disorder : See Tables 5 and 6.

( 2.4 ) 2.1 General Dosing Considerations Rash There are suggestions, yet to be proven, that the risk of severe, potentially life-threatening rash may be increased by (1) coadministration of lamotrigine with valproate, (2) exceeding the recommended initial dose of lamotrigine, or (3) exceeding the recommended dose escalation for lamotrigine.

However, cases have occurred in the absence of these factors [see Boxed Warning ].

Therefore, it is important that the dosing recommendations be followed closely.

The risk of nonserious rash may be increased when the recommended initial dose and/or the rate of dose escalation for lamotrigine orally disintegrating tablets are exceeded and in patients with a history of allergy or rash to other AEDs.

Lamotrigine ODT Patient Titration Kits provide lamotrigine at doses consistent with the recommended titration schedule for the first 5 weeks of treatment, based upon concomitant medications, for patients with epilepsy (older than 12 years) and bipolar I disorder (adults) and are intended to help reduce the potential for rash.

The use of lamotrigine ODT Patient Titration Kits is recommended for appropriate patients who are starting or restarting lamotrigine orally disintegrating tablets [see How Supplied/Storage and Handling (16) ].

It is recommended that lamotrigine orally disintegrating tablets not be restarted in patients who discontinued due to rash associated with prior treatment with lamotrigine unless the potential benefits clearly outweigh the risks.

If the decision is made to restart a patient who has discontinued lamotrigine orally disintegrating tablets, the need to restart with the initial dosing recommendations should be assessed.

The greater the interval of time since the previous dose, the greater consideration should be given to restarting with the initial dosing recommendations.

If a patient has discontinued lamotrigine for a period of more than 5 half-lives, it is recommended that initial dosing recommendations and guidelines be followed.

The half-life of lamotrigine is affected by other concomitant medications [see Clinical pharmacology (12.3) ].

Lamotrigine Added to Drugs Known to Induce or Inhibit Glucuronidation Because lamotrigine orally disintegrating tablets are metabolized predominantly by glucuronic acid conjugation, drugs that are known to induce or inhibit glucuronidation may affect the apparent clearance of lamotrigine.

Drugs that induce glucuronidation include carbamazepine, phenytoin, phenobarbital, primidone, rifampin, estrogen-containing oral contraceptives, and the protease inhibitors lopinavir/ritonavir and atazanavir/ritonavir.

Valproate inhibits glucuronidation.

For dosing considerations for lamotrigine orally disintegrating tablets in patients on estrogen-containing contraceptives and atazanavir/ritonavir, see below and Table 13.

For dosing considerations for lamotrigine orally disintegrating tablets in patients on other drugs known to induce or inhibit glucuronidation, see Tables 1, 2, 5 to 6, and 13.

Target Plasma Levels for Patients with Epilepsy or Bipolar Disorder A therapeutic plasma concentration range has not been established for lamotrigine.

Dosing of lamotrigine orally disintegrating tablets should be based on therapeutic response [see Clinical Pharmacology (12.3) ].

Women Taking Estrogen-Containing Oral Contraceptives Starting Lamotrigine orally disintegrating tablets in Women Taking Estrogen-Containing Oral Contraceptives: Although estrogen-containing oral contraceptives have been shown to increase the clearance of lamotrigine [see Clinical Pharmacology (12.3) ], no adjustments to the recommended dose-escalation guidelines for lamotrigine orally disintegrating tablets should be necessary solely based on the use of estrogen-containing oral contraceptives.

Therefore, dose escalation should follow the recommended guidelines for initiating adjunctive therapy with lamotrigine orally disintegrating tablets based on the concomitant AED or other concomitant medications (see Tables 1, 5, and 7).

See below for adjustments to maintenance doses of lamotrigine orally disintegrating tablets in women taking estrogen-containing oral contraceptives.

Adjustments to the Maintenance Dose of Lamotrigine in Women Taking Estrogen-Containing Oral Contraceptives: (1) Taking Estrogen-Containing Oral Contraceptives : In women not taking carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin and the protease inhibitors lopinavir/ritonavir and atazanavir/ritonavir that induce lamotrigine glucuronidation [see Drug Interactions (7) , Clinical Pharmacology (12.3) ], the maintenance dose of lamotrigine orally disintegrating tablets will in most cases need to be increased by as much as 2-fold over the recommended target maintenance dose to maintain a consistent lamotrigine plasma level.

(2) Starting Estrogen-Containing Oral Contraceptives: In women taking a stable dose of lamotrigine orally disintegrating tablets and not taking carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin and the protease inhibitors lopinavir/ritonavir and atazanavir/ritonavir that induce lamotrigine glucuronidation [see Drug Interactions (7) , Clinical Pharmacology (12.3) ], the maintenance dose will in most cases need to be increased by as much as 2-fold to maintain a consistent lamotrigine plasma level.

The dose increases should begin at the same time that the oral contraceptive is introduced and continue, based on clinical response, no more rapidly than 50 to 100 mg/day every week.

Dose increases should not exceed the recommended rate (see Tables 1 and 5) unless lamotrigine plasma levels or clinical response support larger increases.

Gradual transient increases in lamotrigine plasma levels may occur during the week of inactive hormonal preparation (pill-free week), and these increases will be greater if dose increases are made in the days before or during the week of inactive hormonal preparation.

Increased lamotrigine plasma levels could result in additional adverse reactions, such as dizziness, ataxia, and diplopia.

If adverse reactions attributable to lamotrigine orally disintegrating tablets consistently occur during the pill-free week, dose adjustments to the overall maintenance dose may be necessary.

Dose adjustments limited to the pill-free week are not recommended.

For women taking lamotrigine orally disintegrating tablets in addition to carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin and the protease inhibitors lopinavir/ritonavir and atazanavir/ritonavir that induce lamotrigine glucuronidation [see Drug Interactions (7) , Clinical Pharmacology (12.3) ], no adjustment to the dose of lamotrigine orally disintegrating tablets should be necessary.

(3) Stopping Estrogen-Containing Oral Contraceptives : In women not taking carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin and the protease inhibitors lopinavir/ritonavir and atazanavir/ritonavir that induce lamotrigine glucuronidation [see Drug Interactions (7) , Clinical Pharmacology (12.3) ], the maintenance dose of lamotrigine orally disintegrating tablets will in most cases need to be decreased by as much as 50% in order to maintain a consistent lamotrigine plasma level.

The decrease in dose of lamotrigine orally disintegrating tablets should not exceed 25% of the total daily dose per week over a 2-week period, unless clinical response or lamotrigine plasma levels indicate otherwise [see Clinical Pharmacology (12.3) ].

In women taking lamotrigine orally disintegrating tablets in addition to carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin and the protease inhibitors lopinavir/ritonavir and atazanavir/ritonavir that induce lamotrigine glucuronidation [see Drug Interactions (7) , Clinical Pharmacology (12.3) ], no adjustment to the dose of lamotrigine orally disintegrating tablets should be necessary.

Women and Other Hormonal Contraceptive Preparations or Hormone Replacement Therapy The effect of other hormonal contraceptive preparations or hormone replacement therapy on the pharmacokinetics of lamotrigine has not been systematically evaluated.

It has been reported that ethinylestradiol, not progestogens, increased the clearance of lamotrigine up to 2-fold, and the progestin-only pills had no effect on lamotrigine plasma levels.

Therefore, adjustments to the dosage of lamotrigine orally disintegrating tablets in the presence of progestogens alone will likely not be needed.

Patients Taking Atazanavir/Ritonavir While atazanavir/ritonavir does reduce the lamotrigine plasma concentration, no adjustments to the recommended dose-escalation guidelines for lamotrigine orally disintegrating tablets should be necessary solely based on the use of atazanavir/ritonavir.

Dose escalation should follow the recommended guidelines for initiating adjunctive therapy with lamotrigine orally disintegrating tablets based on concomitant AED or other concomitant medications (see Tables 1, 2, and 5).

In patients already taking maintenance doses of lamotrigine orally disintegrating tablets and not taking glucuronidation inducers, the dose of lamotrigine orally disintegrating tablets may need to be increased if atazanavir/ritonavir is added or decreased if atazanavir/ritonavir is discontinued [see Clinical Pharmacology (12.3) ].

Patients with Hepatic Impairment Experience in patients with hepatic impairment is limited.

Based on a clinical pharmacology study in 24 subjects with mild, moderate, and severe liver impairment [see Use in Specific Populations (8.6) , Clinical Pharmacology (12.3) ], the following general recommendations can be made.

No dosage adjustment is needed in patients with mild liver impairment.

Initial, escalation, and maintenance doses should generally be reduced by approximately 25% in patients with moderate and severe liver impairment without ascites and 50% in patients with severe liver impairment with ascites.

Escalation and maintenance doses may be adjusted according to clinical response.

Patients with Renal Impairment Initial doses of lamotrigine orally disintegrating tablets should be based on patients’ concomitant medications (see Tables 1 to 3 and 5); reduced maintenance doses may be effective for patients with significant renal impairment [see Use in Specific Populations (8.7) , Clinical Pharmacology (12.3) ].

Few patients with severe renal impairment have been evaluated during chronic treatment with lamotrigine orally disintegrating tablets.

Because there is inadequate experience in this population, lamotrigine orally disintegrating tablets should be used with caution in these patients.

Discontinuation Strategy Epilepsy : For patients receiving lamotrigine orally disintegrating tablets in combination with other AEDs, a re-evaluation of all AEDs in the regimen should be considered if a change in seizure control or an appearance or worsening of adverse reactions is observed.

If a decision is made to discontinue therapy with lamotrigine orally disintegrating tablets, a step-wise reduction of dose over at least 2 weeks (approximately 50% per week) is recommended unless safety concerns require a more rapid withdrawal [see Warnings and Precautions (5.10) ].

Discontinuing carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin and the protease inhibitors lopinavir/ritonavir and atazanavir/ritonavir that induce lamotrigine glucuronidation should prolong the half-life of lamotrigine; discontinuing valproate should shorten the half-life of lamotrigine.

Bipolar Disorder: In the controlled clinical trials, there was no increase in the incidence, type, or severity of adverse reactions following abrupt termination of lamotrigine orally disintegrating tablets.

In the clinical development program in adults with bipolar disorder, 2 patients experienced seizures shortly after abrupt withdrawal of lamotrigine orally disintegrating tablets.

Discontinuation of lamotrigine orally disintegrating tablets should involve a step-wise reduction of dose over at least 2 weeks (approximately 50% per week) unless safety concerns require a more rapid withdrawal [see Warnings and Precautions (5.10) ].

2.2 Epilepsy – Adjunctive Therapy This section provides specific dosing recommendations for patients older than 12 years and patients aged 2 to 12 years.

Within each of these age-groups, specific dosing recommendations are provided depending upon the concomitant AEDs or other concomitant medications (see Table 1 for patients older than 12 years and Table 2 for patients aged 2 to 12 years).

A weight-based dosing guide for patients aged 2 to 12 years on concomitant valproate is provided in Table 3.

Patients Older than 12 Years Recommended dosing guidelines are summarized in Table 1.

Table 1.

Escalation Regimen for Lamotrigine Orally Disintegrating Tablets in Patients Older than 12 Years with Epilepsy In Patients TAKING Valproate a In Patients NOT TAKING Carbamazepine, Phenytoin, Phenobarbital, Primidone, b or Valproate a In Patients TAKING Carbamazepine, Phenytoin, Phenobarbital, or Primidone b and NOT TAKING Valproate a Weeks 1 and 2 25 mg every other day 25 mg every day 50 mg/day Weeks 3 and 4 25 mg every day 50 mg/day 100 mg/day (in 2 divided doses) Week 5 onward to maintenance Increase by 25 to 50 mg/day every 1 to 2 weeks.

Increase by 50 mg/day every 1 to 2 weeks.

Increase by 100 mg/day every 1 to 2 weeks.

Usual maintenance dose 100 to 200 mg/day with valproate alone 100 to 400 mg/day with valproate and other drugs that induce glucuronidation (in 1 or 2 divided doses) 225 to 375 mg/day (in 2 divided doses) 300 to 500 mg/day (in 2 divided doses) a Valproate has been shown to inhibit glucuronidation and decrease the apparent clearance of lamotrigine [see Drug Interactions (7) , Clinical Pharmacology (12.3) ].

b Drugs that induce lamotrigine glucuronidation and increase clearance, other than the specified antiepileptic drugs, include estrogen-containing oral contraceptives, rifampin, and the protease inhibitors lopinavir/ritonavir and atazanavir/ritonavir.

Dosing recommendations for oral contraceptives and the protease inhibitor atazanavir/ritonavir can be found in General Dosing Considerations [see Dosage and Administration (2.1)].

Patients on rifampin and the protease inhibitor lopinavir/ritonavir should follow the same dosing titration/maintenance regimen used with antiepileptic drugs that induce glucuronidation and increase clearance [see Dosage and Administration (2.1) , Drug Interactions (7) , Clinical Pharmacology (12.3) ].

Patients Aged 2 to 12 Years Recommended dosing guidelines are summarized in Table 2.

Lower starting doses and slower dose escalations than those used in clinical trials are recommended because of the suggestion that the risk of rash may be decreased by lower starting doses and slower dose escalations.

Therefore, maintenance doses will take longer to reach in clinical practice than in clinical trials.

It may take several weeks to months to achieve an individualized maintenance dose.

Maintenance doses in patients weighing <30 kg, regardless of age or concomitant AED, may need to be increased as much as 50%, based on clinical response.

Table 2.

Escalation Regimen for Lamotrigine Orally Disintegrating Tablets in Patients Aged 2 to 12 Years with Epilepsy In Patients TAKING Valproate a In Patients NOT TAKING Carbamazepine, Phenytoin, Phenobarbital, Primidone, b or Valproate a In Patients TAKING Carbamazepine, Phenytoin, Phenobarbital, or Primidone b and NOT TAKING Valproate a Weeks 1 and 2 0.15 mg/kg/day in 1 or 2 divided doses, rounded down to the nearest whole tablet (see Table 3 for weight-based dosing guide) 0.3 mg/kg/day in 1 or 2 divided doses, rounded down to the nearest whole tablet 0.6 mg/kg/day in 2 divided doses, rounded down to the nearest whole tablet Weeks 3 and 4 0.3 mg/kg/day in 1 or 2 divided doses, rounded down to the nearest whole tablet (see Table 3 for weight-based dosing guide) 0.6 mg/kg/day in 2 divided doses, rounded down to the nearest whole tablet 1.2 mg/kg/day in 2 divided doses, rounded down to the nearest whole tablet Week 5 onward to maintenance The dose should be increased every 1 to 2 weeks as follows: calculate 0.3 mg/kg/day, round this amount down to the nearest whole tablet, and add this amount to the previously administered daily dose.

The dose should be increased every 1 to 2 weeks as follows: calculate 0.6 mg/kg/day, round this amount down to the nearest whole tablet, and add this amount to the previously administered daily dose.

The dose should be increased every 1 to 2 weeks as follows: calculate 1.2 mg/kg/day, round this amount down to the nearest whole tablet, and add this amount to the previously administered daily dose.

Usual maintenance dose 1 to 5 mg/kg/day (maximum 200 mg/day in 1 or 2 divided doses) 1 to 3 mg/kg/day with valproate alone 4.5 to 7.5 mg/kg/day (maximum 300 mg/day in 2 divided doses) 5 to 15 mg/kg/day (maximum 400 mg/day in 2 divided doses) Maintenance dose in patients <30 kg May need to be increased by as much as 50%, based on clinical response.

May need to be increased by as much as 50%, based on clinical response.

May need to be increased by as much as 50%, based on clinical response.

Note: Only whole tablets should be used for dosing.

a Valproate has been shown to inhibit glucuronidation and decrease the apparent clearance of lamotrigine [see Drug Interactions (7) , Clinical Pharmacology (12.3) ].

b Drugs that induce lamotrigine glucuronidation and increase clearance, other than the specified antiepileptic drugs, include estrogen-containing oral contraceptives, rifampin, and the protease inhibitors lopinavir/ritonavir and atazanavir/ritonavir.

Dosing recommendations for oral contraceptives and the protease inhibitor atazanavir/ritonavir can be found in General Dosing Considerations [see Dosage and Administration (2.1) ].

Patients on rifampin and the protease inhibitor lopinavir/ritonavir should follow the same dosing titration/maintenance regimen used with antiepileptic drugs that induce glucuronidation and increase clearance [see Dosage and Administration (2.1) , Drug Interactions (7) , Clinical Pharmacology (12.3) ].

Table 3.

The Initial Weight-Based Dosing Guide for Patients Aged 2 to 12 Years Taking Valproate (Weeks 1 to 4) with Epilepsy If the patient’s weight is Give this daily dose, using the most appropriate combination of lamotrigine 2- and 5-mg tablets Greater than And less than Weeks 1 and 2 Weeks 3 and 4 6.7 kg 14 kg 2 mg every other day 2 mg every day 14.1 kg 27 kg 2 mg every day 4 mg every day 27.1 kg 34 kg 4 mg every day 8 mg every day 34.1 kg 40 kg 5 mg every day 10 mg every day Usual Adjunctive Maintenance Dose for Epilepsy The usual maintenance doses identified in Tables 1 and 2 are derived from dosing regimens employed in the placebo-controlled adjunctive trials in which the efficacy of lamotrigine orally disintegrating tablet was established.

In patients receiving multidrug regimens employing carbamazepine, phenytoin, phenobarbital, or primidone without valproate , maintenance doses of adjunctive lamotrigine orally disintegrating tablets as high as 700 mg/day have been used.

In patients receiving valproate alone , maintenance doses of adjunctive lamotrigine orally disintegrating tablets as high as 200 mg/day have been used.

The advantage of using doses above those recommended in Tables 1 to 4 has not been established in controlled trials.

2.3 Epilepsy – Conversion from Adjunctive Therapy to Monotherapy The goal of the transition regimen is to attempt to maintain seizure control while mitigating the risk of serious rash associated with the rapid titration of lamotrigine orally disintegrating tablets.

The recommended maintenance dose of lamotrigine orally disintegrating tablets as monotherapy is 500 mg/day given in 2 divided doses.

To avoid an increased risk of rash, the recommended initial dose and subsequent dose escalations for lamotrigine should not be exceeded [see Boxed Warning ].

Conversion from Adjunctive Therapy with Carbamazepine, Phenytoin, Phenobarbital, or Primidone to Monotherapy with Lamotrigine Orally Disintegrating Tablets After achieving a dose of 500 mg/day of lamotrigine orally disintegrating tablets using the guidelines in Table 1, the concomitant enzyme-inducing AED should be withdrawn by 20% decrements each week over a 4-week period.

The regimen for the withdrawal of the concomitant AED is based on experience gained in the controlled monotherapy clinical trial.

Conversion from Adjunctive Therapy with Valproate to Monotherapy with Lamotrigine Orally Disintegrating Tablets The conversion regimen involves the 4 steps outlined in Table 4.

Table 4.

Conversion from Adjunctive Therapy with Valproate to Monotherapy with Lamotrigine Orally Disintegrating Tablets in Patients Aged 16 Years and Older with Epilepsy Lamotrigine Orally Disintegrating Tablets Valproate Step 1 Achieve a dose of 200 mg/day according to guidelines in Table 1.

Maintain established stable dose.

Step 2 Maintain at 200 mg/day.

Decrease dose by decrements no greater than 500 mg/day/week to 500 mg/day and then maintain for 1 week.

Step 3 Increase to 300 mg/day and maintain for 1 week.

Simultaneously decrease to 250 mg/day and maintain for 1 week.

Step 4 Increase by 100 mg/day every week to achieve maintenance dose of 500 mg/day.

Discontinue.

Conversion from Adjunctive Therapy with Antiepileptic Drugs other than Carbamazepine, Phenytoin, Phenobarbital, Primidone, or Valproate to Monotherapy with Lamotrigine Orally Disintegrating Tablets No specific dosing guidelines can be provided for conversion to monotherapy with lamotrigine orally disintegrating tablets with AEDs other than carbamazepine, phenytoin, phenobarbital, primidone, or valproate.

2.4 Bipolar Disorder The goal of maintenance treatment with lamotrigine orally disintegrating tablet is to delay the time to occurrence of mood episodes (depression, mania, hypomania, mixed episodes) in patients treated for acute mood episodes with standard therapy [see Indications and Usage (1.2) ] .

Patients taking lamotrigine orally disintegrating tablets for more than 16 weeks should be periodically reassessed to determine the need for maintenance treatment.

Adults The target dose of lamotrigine orally disintegrating tablet is 200 mg/day (100 mg/day in patients taking valproate, which decreases the apparent clearance of lamotrigine, and 400 mg/day in patients not taking valproate and taking either carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin and the protease inhibitor lopinavir/ritonavir that increase the apparent clearance of lamotrigine).

In the clinical trials, doses up to 400 mg/day as monotherapy were evaluated; however, no additional benefit was seen at 400 mg/day compared with 200 mg/day [see Clinical Studies (14.2) ] .

Accordingly, doses above 200 mg/day are not recommended.

Treatment with lamotrigine orally disintegrating tablets are introduced, based on concurrent medications, according to the regimen outlined in Table 5.

If other psychotropic medications are withdrawn following stabilization, the dose of lamotrigine orally disintegrating tablets should be adjusted.

In patients discontinuing valproate, the dose of lamotrigine orally disintegrating tablets should be doubled over a 2-week period in equal weekly increments (see Table 6).

In patients discontinuing carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin and the protease inhibitors lopinavir/ritonavir and atazanavir/ritonavir that induce lamotrigine glucuronidation, the dose of lamotrigine orally disintegrating tablets should remain constant for the first week and then should be decreased by half over a 2-week period in equal weekly decrements (see Table 6).

The dose of lamotrigine orally disintegrating tablets may then be further adjusted to the target dose (200 mg) as clinically indicated.

If other drugs are subsequently introduced, the dose of lamotrigine orally disintegrating tablets may need to be adjusted.

In particular, the introduction of valproate requires reduction in the dose of lamotrigine orally disintegrating tablets [see Drug Interactions (7) , Clinical Pharmacology (12.3) ].

To avoid an increased risk of rash, the recommended initial dose and subsequent dose escalations of lamotrigine orally disintegrating tablets should not be exceeded [see Boxed Warning ].

Table 5.

Escalation Regimen for Lamotrigine Orally Disintegrating Tablets in Adults with Bipolar Disorder In Patients TAKING Valproate a In Patients NOT TAKING Carbamazepine, Phenytoin, Phenobarbital, Primidone, b or Valproate a In Patients TAKING Carbamazepine, Phenytoin, Phenobarbital, or Primidone b and NOT TAKING Valproate a 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 divided doses Week 5 50 mg daily 100 mg daily 200 mg daily, in divided doses Week 6 100 mg daily 200 mg daily 300 mg daily, in divided doses Week 7 100 mg daily 200 mg daily up to 400 mg daily, in divided doses a Valproate has been shown to inhibit glucuronidation and decrease the apparent clearance of lamotrigine [see Drug Interactions (7) , Clinical Pharmacology (12.3) ] .

b Drugs that induce lamotrigine glucuronidation and increase clearance, other than the specified antiepileptic drugs, include estrogen-containing oral contraceptives, rifampin, and the protease inhibitors lopinavir/ritonavir and atazanavir/ritonavir.

Dosing recommendations for oral contraceptives and the protease inhibitor atazanavir/ritonavir can be found in General Dosing Considerations [see Dosage and Administration (2.1) ] .

Patients on rifampin and the protease inhibitor lopinavir/ritonavir should follow the same dosing titration/maintenance regimen used with antiepileptic drugs that induce glucuronidation and increase clearance [see Dosage and Administration (2.1) , Drug Interactions (7) , Clinical Pharmacology (12.3) ].

Table 6.

Dosage Adjustments to Lamotrigine Orally Disintegrating Tablets in Adults with Bipolar Disorder following Discontinuation of Psychotropic Medications Discontinuation of Psychotropic Drugs (excluding Valproate, a Carbamazepine, Phenytoin, Phenobarbital, or Primidone b ) After Discontinuation of Valproate a After Discontinuation of Carbamazepine, Phenytoin, Phenobarbital, or Primidone b Current Dose of Lamotrigine Orally Disintegrating Tablets (mg/day) 100 Current Dose of Lamotrigine Orally Disintegrating Tablets(mg/day) 400 Week 1 Maintain current dose of lamotrigine orally disintegrating tablets 150 400 Week 2 Maintain current dose of lamotrigine orally disintegrating tablets 200 300 Week 3 onward Maintain current dose of lamotrigine orally disintegrating tablets 200 200 a Valproate has been shown to inhibit glucuronidation and decrease the apparent clearance of lamotrigine [see Drug Interactions (7) , Clinical Pharmacology (12.3) ].

b Drugs that induce lamotrigine glucuronidation and increase clearance, other than the specified antiepileptic drugs, include estrogen-containing oral contraceptives, rifampin, and the protease inhibitors lopinavir/ritonavir and atazanavir/ritonavir.

Dosing recommendations for oral contraceptives and the protease inhibitor atazanavir/ritonavir can be found in General Dosing Considerations [see Dosage and Administration (2.1) ] .

Patients on rifampin and the protease inhibitor lopinavir/ritonavir should follow the same dosing titration/maintenance regimen used with antiepileptic drugs that induce glucuronidation and increase clearance [see Dosage and Administration (2.1) , Drug Interactions (7) , Clinical Pharmacology (12.3) ].

2.6 Administration of Lamotrigine Orally Disintegrating Tablets Lamotrigine orally disintegrating tablets should be placed onto the tongue and moved around in the mouth.

The tablet will disintegrate rapidly, can be swallowed with or without water, and can be taken with or without food.