LAMORIG

Lamotrigine is an antiepileptic drug belonging in the phenyltriazine class.

It is used in the treatment of both epilepsy and as a mood stabilizer in bipolar disorder.

Lamotrigine is the first medication since lithium granted Food and Drug Administration (FDA) approval for the maintenance treatment of bipolar type I. It is approved for use in more than 30 countries.

Lamotrigine has relatively few side-effects and does not require laboratory monitoring.

While it is indicated for epilepsy and bipolar disorders, there is evidence that lamotrigine could have some clinical efficacy in certain neuropathic pain states. 3, 4.

Lamotrigine is indicated as adjunctive therapy for the following seizure types in patients ≥2 years of age: partial seizures, primary generalized tonic-clonic seizures, and generalized seizures due to Lennox-Gastaut syndrome.

It is also indicated for the process of conversion to drug monotherapy for those at least 16 years of age or older with partial seizures and currently are receiving treatment with carbamazepine, phenytoin, phenobarbital, primidone, or valproate as the single antiepileptic drug (AED).

In addition to the above, lamotrigine is also indicated for the maintenance treatment of bipolar I disorder, delaying the time to mood episodes (which may include mania, hypomania, depression, mixed episodes) in adults at least 18 years or older, who have been treated for acute mood symptoms with standard therapy.

Limitations of use

It is important to note that lamotirigine should not be used in the treatment of acute mood episodes, as efficacy has not been established in this context.

Lamotrigine likely prevents seizures and prevents mood symptoms via stabilizing presynaptic neuronal membranes and preventing the release of excitatory neurotransmitters such as glutamate, which contribute to seizure activity. 10, 14 A note on cardiovascular effects The metabolite of lamotrigine, 2-N-methyl metabolite (formed by glucuronidation), is reported to cause dose-dependent prolongations of the PR interval, widening of the QRS complex, and at higher doses, complete AV block.

Although this harmful metabolite is only found in trace amounts in humans, plasma concentrations may increase in conditions that cause decreased drug glucuronidation, such as liver disease. 7, 14, 15.

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Lamotrigine is rapidly and entirely absorbed with minimal first-pass metabolism effects, with a bioavailability estimated at 98%.

Cmax is reached in the range of 1.4-4.8 hours post-dose, but this depends on the dose administered, concomitant medications, and epileptic status.

The rate and extent of lamictal absorption is considered equivalent between the compressed tablet form taken with water to that of the chewable dispersible tablets, taken with or without water. 14, 15.

The mean apparent volume of distribution (Vd/F) of lamotrigine following oral administration ranges from 0.9-1.3 L/kg and is independent of dose administered.

Lamotrigine accumulated in the kidney of the male rat, and likely behaves in a similar fashion in humans.

Lamotrigine also binds to tissues containing melanin, such as the eyes and pigmented skin. 14, 15.

Lamotrigine is mainly glucuronidated, forming 2-N-glucuronide conjugate, a pharmacologically inactive metabolite.

The total radioactivity detected after a 240 mg radiolabeled dose of lamotrigine during clinical trials were as follows: lamotrigine as unchanged drug(10%), a 2-N-glucuronide (76%), a 5-N-glucuronide (10%), a 2-N-methyl metabolite (0.14%), as well as various other minor metabolites (4%).

Hover over products below to view reaction partners Lamotrigine lamotrigine-2-N-glucuronide.

Lamotrigine is excreted in both the urine and feces.

Following oral administration of 240 mg radiolabelled lamotrigine, about 94% of total drug and its metabolites administered is recovered in the urine and 2% is recovered in the feces.

One pharmacokinetic study recovered 43-87% of a lamotrigine dose in the urine mainly as glucuronidated metabolites. 11 2-N-glucuronide is mainly excreted in the urine.

The average elimination half-life of lamotrigine ranges from approximately 14-59 hours.

The value is dependent on the dose administered, concomitant drug therapy, as well as disease status. 11, 15 One pharmacokinetic study revealed a half-life of 22.8-37.4 hours in healthy volunteers.

It also reported that enzyme-inducing antiepileptic drugs such as pheobarbital, phenytoin, or carbamazepine decrease the half-life of lamotrigine.

On the other hand, valproic acid increases the half-life of lamotrigine (in the range of 48-59 hours).

The mean apparent plasma clearance (Cl/F) ranges from 0.18-1.21 mL/min/kg. The values vary depending on dosing regimen, concomitant antiepileptic medications, and disease state of the individual.

In one study, healthy volunteers on lamictal monotherapy showed a clearance of about 0.44 mL/min/kg after a single dose.

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The oral

LD50 in mouse and rat is 205 mg/kg and 245 mg/kg, respectively.

Fatal cases of overdose of up to 15 g of lamotrigine have been reported.

Overdose with lamotrigine has been manifested by ataxia, nystagmus, increased seizures, decreased level of consciousness, coma, and intraventricular conduction delay.

Though no known antidote exists for lamotrigine, hospitalization and general supportive measures should be employed in the case of a suspected lamotrigine overdose.

Gastric lavage and emesis may be warranted with simultaneous protection of the airway.

It is uncertain at this time whether hemodialysis is an effective means of removing lamotrigine from the sytemic circulation. 15, 14.

Lamotrigine is contraindicated in patients who have demonstrated hypersensitivity (e.g., rash, angioedema, acute urticaria, extensive pruritus, mucosal ulceration) to the drug or its ingredients.

Hypersensitivity to the drug or its ingredients. ( Boxed Warning, 4 ).

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

To avoid an increased risk of rash, the recommended initial dose and subsequent dose escalations should not be exceeded.

Lamotrigine Orally Disintegrating Tablets Patient Titration

Kits are available for the first 5 weeks of treatment.

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

Adjustments to maintenance doses will be necessary in most patients starting or stopping estrogen-containing products, including oral contraceptives.

Taper over a period of at least 2 weeks (approximately 50% dose reduction per week).

Adjunctive therapy—See Table for patients older than 12 years and Tables and 3 for patients aged to 12 years.

Conversion to monotherapy—See Table 4.

Bipolar disorde r

See Tables and 6. 2.1 General Dosing Considerations Rash There are suggestions that the risk of severe, potentially life-threatening rash may be increased by coadministration of lamotrigine with valproate, exceeding the recommended initial dose of lamotrigine, or exceeding the recommended dose escalation for lamotrigine.

However, cases have occurred in the absence of these factors.

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.

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.

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.

Lamotrigine Added to Drugs Known to Induce or Inhibit Glucuronidation Because lamotrigine is 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 products, including 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 products, including 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 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.

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, 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 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: 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, 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.

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, 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 to 100 mg/day every week.

Dose increases should not exceed the recommended rate 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, no adjustment to the dose of lamotrigine orally disintegrating tablets should be necessary.

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, 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.

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, 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 (HRT) on the pharmacokinetics of lamotrigine has not been systematically evaluated.

Other estrogen-containing therapies, such as HRT, may interfere with lamotrigine.

Therefore, close clinical monitoring on effectiveness of lamotrigine orally disintegrating tablets with dose adjustment may be necessary.

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.

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.

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.

Experience in patients with hepatic impairment is limited.

Based on a clinical pharmacology study in 24 subjects with mild, moderate, and severe liver impairment, 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.

Initial doses of lamotrigine orally disintegrating tablets should be based on patients’ concomitant medications; reduced maintenance doses may be effective for patients with significant renal impairment.

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.

Tablets 25-mg, white colored, round shaped, flat-faced, bevel-edged tablets debossed with “NT” on one side and “123” on the other side.

Packs of 30 (NDC 49884-484-11). 50-mg, white colored, round shaped, flat-faced, bevel-edged tablets debossed with “EP” on one side and “191” on the other side.

Packs of 30 (NDC 49884-485-11). 100-mg, Peach colored, round shaped, flat-faced, bevel-edged tablets debossed with “E” on one side and “432” on the other side.

Packs of 30 (NDC 49884-486-11). 200-mg, White colored, round shaped, flat-faced, bevel-edged tablets debossed with “EP” on one side and “433” on the other side.

Packs of 30 (NDC 49884-487-11).

Store at 20° to 25°C (68° to 77°F); with excursions permitted to 15° to 30°C (59° to 86°F). .

Lamotrigine Orally Disintegrating Tablets Patient Titration Kit for Patients Taking Valproate (Blue ODT Kit) 25-mg, white colored, round shaped, flat-faced, bevel-edged tablets debossed with “NT” on one side and “123” on the other side and 50 mg, white colored, round shaped, flat-faced, bevel-edged tablets debossed with “EP” on one side and “191” on the other side, blister pack of 28 tablets (21/25-mg tablets and 7/50-mg tablets) (NDC 49884-880-99).

Lamotrigine Orally Disintegrating Tablets Patient Titration Kit for Patients Taking Carbamazepine, Phenytoin, Phenobarbital, or Primidone and Not Taking Valproate (Green ODT Kit) 50-mg, white colored, round shaped, flat-faced, bevel-edged tablets debossed with “EP” on one side and “191” on the other side and 100 mg, Peach colored, round shaped, flat-faced, bevel-edged tablets debossed with “E” on one side and “432” on the other side, blister pack of 56 tablets (42/50-mg tablets and 14/100-mg tablets) (NDC 49884-881-99).

Lamotrigine Orally Disintegrating Tablets Patient Titration Kit for Patients Not Taking Carbamazepine, Phenytoin, Phenobarbital, Primidone, or Valproate (Orange ODT Kit) 25-mg, white colored, round shaped, flat-faced, bevel-edged tablets debossed with “NT” on one side and “123” on the other side, 50 mg, white colored, round shaped, flat-faced, bevel-edged tablets debossed with “EP” on one side and “191” on the other side, and 100 mg, Peach colored, round shaped, flat-faced, bevel-edged tablets debossed with “E” on one side and “432” on the other side, blister pack of 35 tablets (14/25-mg tablets, 14/50-mg tablets, and 7/100-mg tablets) (NDC 49884-882-99).

If the product is dispensed in a blister pack, the patient should be advised to examine the blister pack before use and not use if blisters are torn, broken, or missing.

There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to AEDs, including lamotrigine, during pregnancy.

Encourage women who are taking lamotrigine during pregnancy to enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry by calling 1-888-233-2334 or visiting.

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

The majority of lamotrigine pregnancy exposure data are from women with epilepsy.

In animal studies, administration of lamotrigine during pregnancy resulted in developmental toxicity (increased mortality, decreased body weight, increased structural variation, neurobehavioral abnormalities) at doses lower than those administered clinically.

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

In the

U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Maternal and/or Embryofetal Risk Epilepsy, with or without exposure to antiepileptic drugs, has been associated with several adverse outcomes during pregnancy, including preeclampsia, preterm labor, antepartum and postpartum hemorrhage, placental abruption, poor fetal growth, prematurity, fetal death, and maternal mortality.

The risk of maternal or fetal injury may be greatest for patients with untreated or poorly controlled convulsive seizures.

Women with epilepsy who become pregnant should not abruptly discontinue antiepileptic drugs, including lamotrigine, due to the risk of status epilepticus or severe seizures, which may be life-threatening.

Dose Adjustments During Pregnancy and the Postpartum Period As with other AEDs, physiological changes during pregnancy may affect lamotrigine concentrations and/or therapeutic effect.

There have been reports of decreased lamotrigine concentrations during pregnancy and restoration of pre-pregnancy concentrations after delivery.

Dose adjustments may be necessary to maintain clinical response.

Data from several international pregnancy registries have not shown an increased risk for malformations overall.

Registry reported major congenital malformations in 2.2% (95% CI: 1.6%, 3.1%) of 1,558 infants exposed to lamotrigine monotherapy in the first trimester of pregnancy.

Registry reported major congenital malformations among 2% of 1,562 infants exposed to lamotrigine monotherapy in the first trimester.

EURAP, a large international pregnancy registry focused outside of North America, reported major birth defects in 2.9% (95% CI: 2.3%, 3.7%) of 2,514 exposures to lamotrigine monotherapy in the first trimester.

The frequency of major congenital malformations was similar to estimates from the general population.

Registry observed an increased risk of isolated oral clefts: among 2,200 infants exposed to lamotrigine early in pregnancy, the risk of oral clefts was 3.2 per 1,000 (95% CI: 1.4, 6.3), a 3-fold increased risk versus unexposed healthy controls.

This finding has not been observed in other large international pregnancy registries.

Furthermore, a case-control study based on 21 congenital anomaly registries covering over 10 million births in Europe reported an adjusted odds ratio for isolated oral clefts with lamotrigine exposure of 1.45 (95% CI: 0.8, 2.63).

Several meta-analyses have not reported an increased risk of major congenital malformations following lamotrigine exposure in pregnancy compared with healthy and disease-matched controls.

No patterns of specific malformation types were observed.

The same meta-analyses evaluated the risk of additional maternal and infant outcomes including fetal death, stillbirth, preterm birth, small for gestational age, and neurodevelopmental delay.

Although there are no data suggesting an increased risk of these outcomes with lamotrigine monotherapy exposure, differences in outcome definition, ascertainment methods, and comparator groups limit the conclusions that can be drawn.

When lamotrigine was administered to pregnant mice, rats, or rabbits during the period of organogenesis (oral doses of up to 125, 25, and 30 mg/kg, respectively), reduced fetal body weight and increased incidences of fetal skeletal variations were seen in mice and rats at doses that were also maternally toxic.

The no-effect doses for embryofetal developmental toxicity in mice, rats, and rabbits (75, 6.25, and 30 mg/kg, respectively) are similar to (mice and rabbits) or less than (rats) the human dose of 400 mg/day on a body surface area (mg/m 2 ) basis.

In a study in which pregnant rats were administered lamotrigine (oral doses of 0, 5, or 25 mg/kg) during the period of organogenesis and offspring were evaluated postnatally, neurobehavioral abnormalities were observed in exposed offspring at both doses.

The lowest effect dose for developmental neurotoxicity in rats is less than the human dose of 400 mg/day on a mg/m 2 basis.

Maternal toxicity was observed at the higher dose tested.

When pregnant rats were administered lamotrigine (oral doses of 0, 5, 10, or 20 mg/kg) during the latter part of gestation and throughout lactation, increased offspring mortality (including stillbirths) was seen at all doses.

The lowest effect dose for pre.

• and post-natal developmental toxicity in rats is less than the human dose of 400 mg/day on a mg/m 2 basis.

Maternal toxicity was observed at the 2 highest doses tested.

When administered to pregnant rats, lamotrigine decreased fetal folate concentrations at doses greater than or equal to 5 mg/kg/day, which is less than the human dose of 400 mg/day on a mg/m 2 basis.

Lamotrigine is indicated as adjunctive therapy in patients aged 2 years and older for partial-onset seizures, the generalized seizures of Lennox-Gastaut syndrome, and PGTC seizures.

Safety and efficacy of lamotrigine used as adjunctive treatment for partial-onset seizures were not demonstrated in a small, randomized, double-blind, placebo-controlled withdrawal trial in very young pediatric patients (aged to 24 months).

Lamotrigine was associated with an increased risk for infectious adverse reactions (lamotrigine 37%, placebo 5%), and respiratory adverse reactions (lamotrigine 26%, placebo 5%).

Infectious adverse reactions included bronchiolitis, bronchitis, ear infection, eye infection, otitis externa, pharyngitis, urinary tract infection, and viral infection.

Respiratory adverse reactions included nasal congestion, cough, and apnea.

Safety and efficacy of lamotrigine for the maintenance treatment of bipolar disorder were not established in a double-blind, randomized withdrawal, placebo-controlled trial that evaluated 301 pediatric patients aged to 17 years with a current manic/hypomanic, depressed, or mixed mood episode as defined by DSM-IV-TR.

In the randomized phase of the trial, adverse reactions that occurred in at least 5% of patients taking lamotrigine (n = 87) and were twice as common compared with patients taking placebo (n = 86) were influenza (lamotrigine 8%, placebo 2%), oropharyngeal pain (lamotrigine 8%, placebo 2%), vomiting (lamotrigine 6%, placebo 2%), contact dermatitis (lamotrigine 5%, placebo 2%), upper abdominal pain (lamotrigine 5%, placebo 1%), and suicidal ideation (lamotrigine 5%, placebo 0%).

In a juvenile animal study in which lamotrigine (oral doses of 0, 5, 15, or 30 mg/kg) was administered to young rats from postnatal day to 62, decreased viability and growth were seen at the highest dose tested and long-term neurobehavioral abnormalities (decreased locomotor activity, increased reactivity, and learning deficits in animals tested as adults) were observed at the 2 highest doses.

The no-effect dose for adverse developmental effects in juvenile animals is less than the human dose of 400 mg/day on a mg/m 2 basis.

Clinical trials of lamotrigine for epilepsy and bipolar disorder did not include sufficient numbers of patients aged 65 years and older to determine whether they respond differently from younger patients or exhibit a different safety profile than that of younger patients.

In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or other drug therapy.