Lamotrigine 200mg Tablets

1. Name Of The Medicinal Product

LAMOTRIGINE 200mg TABLETS

2. Qualitative And Quantitative Composition

Each tablet contains 200mg Lamotrigine.

For excipients, see 6.1

3. Pharmaceutical Form

Tablet.

Light yellow, round, flat, uncoated tablets with a score line on one side.

4. Clinical Particulars

4.1 Therapeutic Indications

Epilepsy

Adults and adolescents aged 13 years and above

− Adjunctive or monotherapy treatment of partial seizures and generalised seizures, including tonic-clonic seizures.

− Seizures associated with Lennox-Gastaut syndrome. Lamotrigine Tablets is given as adjunctive therapy but may be the initial antiepileptic drug (AED) to start with in Lennox-Gastaut syndrome.

Children and adolescents aged 2 to 12 years

− Adjunctive treatment of partial seizures and generalised seizures, including tonic-clonic seizures and the seizures associated with Lennox-Gastaut syndrome.

− Monotherapy of typical absence seizures.

Bipolar disorder

Adults aged 18 years and above

− Prevention of depressive episodes in patients with bipolar I disorder who experience predominantly depressive episodes (see section 5.1).

Lamotrigine Tablets is not indicated for the acute treatment of manic or depressive episodes.

4.2 Posology And Method Of Administration

Method of Administration

Lamotrigine Tablets should be swallowed whole with a little water and should not be chewed or crushed.

Posology

Restarting therapy

Prescribers should assess the need for escalation to maintenance dose when restarting Lamotrigine Tablets in patients who have discontinued Lamotrigine Tablets for any reason, since the risk of serious rash is associated with high initial doses and exceeding the recommended dose escalation for lamotrigine (see section 4.4). The greater the interval of time since the previous dose, the more consideration should be given to escalation to the maintenance dose. When the interval since discontinuing lamotrigine exceeds five half-lives (see section 5.2), Lamotrigine Tablets should generally be escalated to the maintenance dose according to the appropriate schedule.

It is recommended that Lamotrigine Tablets not be restarted in patients who have discontinued due to rash associated with prior treatment with lamotrigine unless the potential benefit clearly outweighs the risk.

Epilepsy

The recommended dose escalation and maintenance doses for adults and adolescents aged 13 years and above (Table 1) and for children and adolescents aged 2 to 12 years (Table 2) are given below. Because of a risk of rash the initial dose and subsequent dose escalation should not be exceeded (see section 4.4).

When concomitant AEDs are withdrawn or other AEDs/medicinal products are added on to treatment regimes containing lamotrigine, consideration should be given to the effect this may have on lamotrigine pharmacokinetics (see section 4.5).

Table 1: Adults and adolescents aged 13 years and above - recommended treatment regimen in epilepsy

Treatment regimen	Weeks 1 + 2	Weeks 3 + 4	Usual maintenance dose
Monotherapy:	25mg/day (once a day)	50mg/day (once a day)	100 - 200mg/day (once a day or two divided doses) To achieve maintenance, doses may be increased by maximum of 50 - 100mg everyone to two weeks until optimal response is achieved 500mg/day has been required by some patients to achieve desired response
Adjunctive therapy WITH valproate (inhibitor of lamotrigine glucuronidation - see section 4.5):
This dosage regimen should be used with valproate regardless of any concomitant medicinal products	12.5mg/day (given as 25mg on alternate days)	25mg/day (once a day)	100 - 200mg/day (once a day or two divided doses) To achieve maintenance, doses may be increased by maximum of 25 - 50mg every one to two weeks until optimal response is achieved
Adjunctive therapy WITHOUT valproate and WITH inducers of lamotrigine glucuronidation (see section 4.5):
This dosage regimen should be used without valproate but with: phenytoin carbamazepine phenobarbital primidone rifampicin lopinavir/ritonavir	50mg/day (once a day)	100mg/day (two divided doses)	200 - 400mg/day (two divided doses) To achieve maintenance, doses may be increased by maximum of 100mg every one to two weeks until optimal response is achieved 700mg/day has been required by some patients to achieve desired response
Adjunctive therapy WITHOUT valproate and WITHOUT inducers of lamotrigine glucuronidation (see section 4.5):
This dosage regimen should be used with other medicinal products that do not significantly inhibit or induce lamotrigine glucuronidation	25mg/day (once a day)	50mg/day (once a day)	100 - 200mg/day (once a day or two divided doses) To achieve maintenance, doses may be increased by maximum of 50 - 100mg every one to two weeks until optimal response is achieved
In patients taking medicinal products where the pharmacokinetic interaction with lamotrigine is currently not known (see section 4.5), the treatment regimen as recommended for lamotrigine with concurrent valproate should be used.

Table 2: Children and adolescents aged 2 to 12 years - recommended treatment regimen in epilepsy (total daily dose in mg/kg body weight/day)

Treatment regimen	Weeks 1 + 2	Weeks 3 + 4	Usual maintenance dose
Monotherapy of typical absence seizures:	0.3mg/kg/day (once a day or two divided doses)	0.6mg/kg/day (once a day or two divided doses)	1 - 10mg/kg/day, although some patients have required higher doses (up to 15mg/kg/day) to achieve desired response (once a day or two divided doses) To achieve maintenance, doses may be increased by maximum of 0.6mg/kg/day every one to two weeks until optimal response is achieved
Adjunctive therapy WITH valproate (inhibitor of lamotrigine glucuronidation - see section 4.5):
This dosage regimen should be used with valproate regardless of any other concomitant medicinal products	0.15mg/kg/day * (once a day)	0.3mg/kg/day (once a day)	1 - 5mg/kg/day (once a day or two divided doses) To achieve maintenance, doses may be increased by maximum of 0.3mg/kg every one to two weeks until optimal response is achieved, with a maximum maintenance dose of 200mg/day
Adjunctive therapy WITHOUT valproate and WITH inducers of lamotrigine glucuronidation (see section 4.5):
This dosage regimen should be used without valproate but with: phenytoin carbamazepine phenobarbital primidone rifampicin lopinavir/ritonavir	0.6mg/kg/day (two divided doses)	1.2mg/kg/day (two divided doses)	5 - 15mg/kg/ day (once a day or two divided doses) To achieve maintenance, doses may be increased by maximum of 1.2mg/kg every one to two weeks until optimal response is achieved, with a maximum maintenance dose of 400mg/day
Adjunctive therapy WITHOUT valproate and WITHOUT inducers of lamotrigine glucuronidation (see section 4.5):
This dosage regimen should be used with other medicinal products that do not significantly inhibit or induce lamotrigine glucuronidation	0.3mg/kg/day (once a day or two divided doses)	0.6mg/kg/day (once a day or two divided doses)	1 - 10mg/kg/day (once a day or two divided doses) To achieve maintenance, doses may be increased by maximum of 0.6mg/kg every one to two weeks until optimal response is achieved, with a maximum of maintenance dose of 200mg/day
In patients taking medicinal products where the pharmacokinetic interaction with lamotrigine is currently not known (see section 4.5), the treatment regimen as recommended for lamotrigine with concurrent valproate should be used.

To ensure a therapeutic dose is maintained the weight of a child must be monitored and the dose reviewed as weight changes occur. It is likely that patients aged two to six years will require a maintenance dose at the higher end of the recommended range.

If epileptic control is achieved with adjunctive treatment, concomitant AEDs may be withdrawn and patients continued on Lamotrigine Tablets monotherapy.

Children below 2 years

There are limited data on the efficacy and safety of lamotrigine for adjunctive therapy of partial seizures in children aged 1 month to 2 years (see section 4.4). There are no data in children below 1 month of age. Thus Lamotrigine Tablets is not recommended for use in children below 2 years of age. If, based on clinical need, a decision to treat is nevertheless taken, see sections 4.4, 5.1 and 5.2.

Bipolar disorder

The recommended dose escalation and maintenance doses for adults of 18 years of age and above are given in the tables below. The transition regimen involves escalating the dose of lamotrigine to a maintenance stabilisation dose over six weeks (Table 3) after which other psychotropic medicinal products and/or AEDs can be withdrawn, if clinically indicated (Table 4). The dose adjustments following addition of other psychotropic medicinal products and/or AEDs are also provided below (Table 5). Because of the risk of rash the initial dose and subsequent dose escalation should not be exceeded (see section 4.4).

Table 3: Adults aged 18 years and above - recommended dose escalation to the maintenance total daily stabilisation dose in treatment of bipolar disorder

Treatment Regimen	Weeks 1 + 2	Weeks 3 + 4	Week 5	Target Stabilisation Dose (Week 6)*
Monotherapy with lamotrigine OR adjunctive therapy WITHOUT valproate and WITHOUT inducers of lamotrigine glucuronidation (see section 4.5):
This dosage regimen should be used with other medicinal products that do not significantly inhibit or induce lamotrigine glucuronidation	25mg/day (once a day)	50mg/day (once a day or two divided doses	100mg/day (once a day or two divided doses)	200mg/day – usual target dose for optimal response (once a day or two divided doses) Doses In the range 100 - 400mg/day used in clinical trials
Adjunctive therapy WITH valproate (inhibitor of lamotrigine glucuronidation - see section 4.5):
This dosage regimen should be used with valproate regardless of any concomitant medicinal products	12.5mg/day (given as 25mg on alternate days)	25mg/day (once a day)	50mg/day (once a day or two divided doses)	100mg/day – usual target dose for optimal response (once a day or two divided doses) Maximum dose of 200mg/day can be used depending on clinical response
Adjunctive therapy WITHOUT valproate and WITH inducers of lamotrigine glucuronidation (see section 4.5):
This dosage regimen should be used without valproate but with: phenytoin carbamazepine phenobarbital primidone rifampicin lopinavir/ritonavir	50mg/day (once a day)	100mg/day (two divided doses)	200mg/day (two divided doses)	300mg/day in week 6, if necessary increasing to usual target dose of 400mg/day in week 7, to achieve optimal response (two divided doses)
In patients taking medicinal products where the pharmacokinetic interaction with lamotrigine is currently not known (see section 4.5), the dose escalation as recommended for lamotrigine with concurrent valproate, should be used.

* The Target stabilisation dose will alter depending on clinical response

Table 4: Adults aged 18 years and above - maintenance stabilsation total daily dose following withdrawal of concomitant medicinal products in treatment of bipolar disorder

Once the target daily maintenance stabilisation dose has been achieved, other medicinal products may be withdrawn as shown below.

Treatment Regimen	Current lamotrigine stabilisation dose (prior to withdrawal)	Week 1 (beginning with withdrawal)	Week 2	Week 3 onwards *
Withdrawal of valproate (inhibitor of lamotrigine glucuronidation - see section 4.5), depending on original dose of lamotrigine:
When valproate is withdrawn, double the stabilisation dose, not exceeding an increase of more than 100mg/week	100mg/day	200mg/day	Maintain this dose (200mg/day) (two divided doses)
200mg/day	300mg/day	400mg/day	Maintain this dose (400mg/day)
Withdrawal of inducers of lamotrigine glucuronidation (see section 4.5), depending on original dose of lamotrigine:
This dosage regimen should be used when the following are withdrawn: phenytoin carbamazepine phenobarbital primidone rifampicin lopinavir/ritonavir	400mg/day	400mg/day	300mg/day	200mg/day
300mg/day	300mg/day	225mg/day	150mg/day
200mg/day	200mg/day	150mg/day	100mg/day
Withdrawal of medicinal products that do NOT signifcantly inhibit or induce lamotrigine glucuronidation (see section 4.5):
This dosage regimen should be used when other medicinal products that do not significantly inhibit or induce lamotrigine glucuronidation are withdrawn	Maintain target dose achieved in dose escalation (200mg/day; two divided doses) (dose range 100 - 400mg/day)
In patients taking medicinal products where the pharmacokinetic interaction with lamotrigine is currently not known (see section 4.5), the treatment regimen as recommended for lamotrigine with concurrent valproate should be used.

* Dose may be increased to 400mg/day as needed

Table 5: Adults aged 18 years and above - adjustment of lamotrigine daily dosing following the addition of other medicinal products in treatment of bipolar disorder

There is no clinical experience in adjusting the lamotrigine daily dose following the addition of other medicinal products. However, based on interaction studies with other medicinal products, the following recommendations can be made:

Treatment Regimen	Current lamotrigine stabilisation dose (prior to addition)	Week 1 (beginning with addition)	Week 2	Week 3 onwards
Addition of valproate (inhibitor of lamotrigine glucuronidation - see section 4.5), depending on original dose of lamotrigine:
This dosage regimen should be used when valproate is added regardless of any concomitant medicinal products	200mg/day	100mg/day	Maintain this dose (100mg/day)
300mg/day	150mg/day	Maintain this dose (150mg/day)
400mg/day	200mg/day	Maintain this dose (200mg/day)
Addition of inducers of lamotrigine glucuronidation in patients NOT taking valproate (see section 4.5), depending on original dose of lamotrigine:
This dosage regimen should be used when the following are added without valproate: phenytoin carbamazepine phenobarbital primidone rifampicin lopinavir/ritonavir	200mg/day	200mg/day	300mg/day	400mg/day
150mg/day	150mg/day	225mg/day	300mg/day
100mg/day	100mg/day	150mg/day	200mg/day
Addition of medicinal products that do NOT significantly inhibit or induce lamotrigine glucuronidation (see section 4.5):
This dosage regimen should be used when other medicinal products that do not significantly inhibit or induce lamotrigine glucuronidation are added	Maintain target dose achieved in dose escalation (200mg/day; dose range 100-400mg/day)
In patients taking medicinal products where the pharmacokinetic interaction with lamotrigine is currently not known (see section 4.5), the treatment regimen as recommended for lamotrigine with concurrent valproate, should be used.

Discontinuation of Lamotrigine Tablets in patients with bipolar disorder

In clinical trials, there was no increase in the incidence, severity or type of adverse reactions following abrupt termination of lamotrigine versus placebo. Therefore, patients may terminate Lamotrigine Tablets without a step-wise reduction of dose.

Children and adolescents below 18 years

Lamotrigine Tablets is not recommended for use in children below 18 years of age due to a lack of data on safety and efficacy (see section 4.4).

General dosing recommendations for Lamotrigine Tablets in special patient populations

Women taking hormonal contraceptives

The use of an ethinyloestradiol/levonorgestrel (30µg/150µg) combination increases the clearance of lamotrigine by approximately two-fold, resulting in decreased lamotrigine levels. Following titration, higher maintenance doses of lamotrigine (by as much as two-fold) may be needed to attain a maximal therapeutic response. During the pill-free week, a two-fold increase in lamotrigine levels has been observed. Dose-related adverse events cannot be excluded. Therefore, consideration should be given to using contraception without a pill-free week, as first-line therapy (for example, continuous hormonal contraceptives or non-hormonal methods; see sections 4.4 and 4.5).

Starting hormonal contraceptives in patients already taking maintenance doses of lamotrigine and NOT taking inducers of lamotrigine glucuronidation

The maintenance dose of lamotrigine will in most cases need to be increased by as much as two-fold (see sections 4.4 and 4.5). It is recommended that from the time that the hormonal contraceptive is started, the lamotrigine dose is increased by 50 to 100mg/day every week, according to the individual clinical response. Dose increases should not exceed this rate, unless the clinical response supports larger increases. Measurement of serum lamotrigine concentrations before and after starting hormonal contraceptives may be considered, as confirmation that the baseline concentration of lamotrigine is being maintained. If necessary, the dose should be adapted. In women taking a hormonal contraceptive that includes one week of inactive treatment ("pill-free week"), serum lamotrigine level monitoring should be conducted during week 3 of active treatment, i.e. on days 15 to 21 of the pill cycle. Therefore, consideration should be given to using contraception without a pill-free week, as first-line therapy (for example, continuous hormonal contraceptives or non-hormonal methods; see sections 4.4 and 4.5).

Stopping hormonal contraceptives in patients already taking maintenance doses of lamotrigine and NOT taking inducers of lamotrigine glucuronidation

The maintenance dose of lamotrigine will in most cases need to be decreased by as much as 50% (see sections 4.4 and 4.5). It is recommended to gradually decrease the daily dose of lamotrigine by 50-100mg each week (at a rate not exceeding 25% of the total daily dose per week) over a period of 3 weeks, unless the clinical response indicates otherwise. Measurement of serum lamotrigine concentrations before and after stopping hormonal contraceptives may be considered, as confirmation that the baseline concentration of lamotrigine is being maintained. In women who wish to stop taking a hormonal contraceptive that includes one week of inactive treatment ("pill-free week"), serum lamotrigine level monitoring should be conducted during week 3 of active treatment, i.e. on days 15 to 21 of the pill cycle. Samples for assessment of lamotrigine levels after permanently stopping the contraceptive pill should not be collected during the first week after stopping the pill.

Starting lamotrigine in patients already taking hormonal contraceptives

Dose escalation should follow the normal dose recommendation described in the tables.

Starting and stopping hormonal contraceptives in patients already taking maintenancedoses of lamotrigine and TAKING inducers of lamotrigine glucuronidation

Adjustment to the recommended maintenance dose of lamotrigine may not be required.

If the doses calculated for children, according to bodyweight, do not equate to whole tablets the dose to be administered is that equal to the lower number of whole tablets.

Elderly (above 65 years)

No dosage adjustment from recommended schedule is required. The pharmacokinetics of lamotrigine in this age group do not differ significantly from a non elderly adult population (see section 5.2).

Renal impairment

Caution should be exercised when administering Lamotrigine Tablets to patients with renal failure. For patients with end-stage renal failure, initial doses of lamotrigine should be based on patients' concomitant medicinal products; reduced maintenance doses may be effective for patients with significant renal functional impairment (see sections 4.4 and 5.2).

Hepatic impairment

Initial, escalation and maintenance doses should generally be reduced by approximately 50% in patients with moderate (Child-Pugh grade B) and 75% in severe (Child-Pugh grade C) hepatic impairment. Escalation and maintenance doses should be adjusted according to clinical response (see section 5.2).

4.3 Contraindications

Lamotrigine is contraindicated in individuals with known hypersensitivity to lamotrigine.

Lamotrigine is cleared primarily by metabolism in the liver. No studies have been carried out in patients with significant impairment of hepatic function. Until such data become available Lamotrigine cannot be recommended in this condition.

4.4 Special Warnings And Precautions For Use

Skin rash

There have been reports of adverse skin reactions, which have generally occurred within the first 8 weeks after initiation of lamotrigine treatment. The majority of rashes are mild and self limiting, however rarely, serious potentially life threatening skin rashes including Stevens Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) have been reported (see section 4.8).

In adults enrolled in studies utilizing the current lamotrigine dosing recommendations the incidence of serious skin rashes is approximately 1 in 500 in epilepsy patients (see section 4.8).

The approximate incidence of serious skin rashes reported as SJS in adults and children over the age of 12 is 1 in 1000. The risk is higher in children under the age of 12 than in adults. Available data from a number of studies suggest the incidence in children under the age of 12 requiring hospitalisation due to rash ranges from 1 in 300 to 1 in 100 (see section 4.8).

In children, the initial presentation of a rash can be mistaken for an infection, physicians should consider the possibility of a drug reaction in children that develop symptoms of rash and fever during the first eight weeks of therapy.

Additionally the overall risk of rash appears to be strongly associated with:-

-	High initial doses of lamotrigine and exceeding the recommended dose escalation of lamotrigine therapy (see section 4.2).
-	Concomitant use of valproate, which increases the mean half life of lamotrigine nearly two fold (see section 4.2).

Approximately half of these cases have been reported as Stevens-Johnson syndrome (1 in 1000). In clinical trials in patients with bipolar disorder, the incidence of serious rash is approximately 1 in 1000.

The risk of serious skin rashes in children is higher than in adults. Available data from a number of studies suggest the incidence of rashes associated with hospitalisation in epileptic children is from 1 in 300 to 1 in 100.

In children, the initial presentation of a rash can be mistaken for an infection, physicians should consider the possibility of a reaction to lamotrigine treatment in children that develop symptoms of rash and fever during the first eight weeks of therapy.

Additionally the overall risk of rash appears to be strongly associated with:

− high initial doses of lamotrigine and exceeding the recommended dose escalation of lamotrigine therapy (see section 4.2)

− concomitant use of valproate (see section 4.2).

Caution is also required when treating patients with a history of allergy or rash to other AEDs as the frequency of non-serious rash after treatment with lamotrigine was approximately three times higher in these patients than in those without such history.

All patients (adults and children) who develop a rash should be promptly evaluated and lamotrigine withdrawn immediately unless the rash is clearly not drug related to lamotrigine treatment. It is recommended that Lamotrigine Tablets not be restarted in patients who have discontinued due to rash associated with prior treatment with lamotrigine unless the potential benefit clearly outweighs the risk.

Rash has also been reported as part of a hypersensitivity syndrome associated with a variable pattern of systemic symptoms including fever, lymphadenopathy, facial oedema and abnormalities of the blood and liver (see section 4.8). The syndrome shows a wide spectrum of clinical severity and may, rarely, lead to disseminated intravascular coagulation (DIC) and multiorgan failure. It is important to note that early manifestations of hypersensitivity (e.g., fever, lymphadenopathy) may be present even though rash is not evident. Patients should be warned to seek immediate medical advice if signs and symptoms develop. If such signs and symptoms are present the patient should be evaluated immediately and lamotrigine discontinued if an alternative aetiology cannot be established.

Clinical worsening and suicide risk

Suicidal ideation and behaviour have been reported in patients treated with AEDs in several indications. A meta-analysis of randomised placebo-controlled trials of AEDs has also shown a small increased risk of suicidal ideation and behaviour. The mechanism of this risk is not known and the available data do not exclude the possibility of an increased risk for lamotrigine.

Therefore patients should be monitored for signs of suicidal ideation and behaviours and appropriate treatment should be considered. Patients (and caregivers of patients) should be advised to seek medical advice should signs of suicidal ideation or behaviour emerge.

In patients with bipolar disorder, worsening of depressive symptoms and/or the emergence of suicidality may occur whether or not they are taking medications for bipolar disorder, including Lamotrigine Tablets. Therefore patients receiving Lamotrigine Tablets for bipolar disorder should be closely monitored for clinical worsening (including development of new symptoms) and suicidality, especially at the beginning of a course of treatment, or at the time of dose changes. Certain patients, such as those with a history of suicidal behaviour or thoughts, young adults, and those patients exhibiting a significant degree of suicidal ideation prior to commencement of treatment, may be at a greater risk of suicidal thoughts or suicide attempts, and should receive careful monitoring during treatment.

Consideration should be given to changing the therapeutic regimen, including possibly discontinuing the medication, in patients who experience clinical worsening (including development of new symptoms) and/or the emergence of suicidal ideation/behaviour, especially if these symptoms are severe, abrupt in onset, or were not part of the patient's presenting symptoms.

Hormonal contraceptives

Effects of hormonal contraceptives on lamotrigine efficacy

The use of an ethinyloestradiol/levonorgestrel (30µg/150µg) combination increases the clearance of lamotrigine by approximately two-fold resulting in decreased lamotrigine levels (see section 4.5). A decrease in lamotrigine levels has been associated with loss of seizure control. Following titration, higher maintenance doses of lamotrigine (by as much as two-fold) will be needed in most cases to attain a maximal therapeutic response. When stopping hormonal contraceptives, the clearance of lamotrigine may be halved. Increases in lamotrigine concentrations may be associated with dose-related adverse events.

Patients should be monitored with respect to this.

In women not already taking an inducer of lamotrigine glucuronidation and taking a hormonal contraceptive that includes one week of inactive treatment (for example "pill-free week"), gradual transient increases in lamotrigine levels will occur during the week of inactive treatment (see section 4.2). Variations in lamotrigine levels of this order may be associated with adverse effects. Therefore, consideration should be given to using contraception without a pill-free week, as first-line therapy (for example, continuous hormonal contraceptives or non-hormonal methods).

The interaction between other oral contraceptive or HRT treatments and lamotrigine have not been studied, though they may similarly affect lamotrigine pharmacokinetic parameters.

Effects of lamotrigine on hormonal contraceptive efficacy

An interaction study in 16 healthy volunteers has shown that when lamotrigine and a hormonal contraceptive (ethinyloestradiol/levonorgestrel combination) are administered in combination, there is a modest increase in levonorgestrel clearance and changes in serum FSH and LH (see section 4.5). The impact of these changes on ovarian ovulatory activity is unkown. However, the possibility of these changes resulting in decreased contraceptive efficacy in some patients taking hormonal preparations with lamotrigine cannot be excluded. Therefore, women should have a review of their contraception when starting lamotrigine, and the use of alternative non-hormonal methods of contraception should be encouraged. A hormonal contraceptive should only be used as the sole method of contraception if there is no other alternative. If the oral contraceptive pill is chosen as the sole method of contraception, women should be advised to promptly notify their physician if they experience changes in menstrual pattern (e.g. breakthrough bleeding) while taking lamotrigine as this may be an indication of decreased contraceptive efficacy. Women taking lamotrigine should notify their physician if they plan to start or stop use of oral contraceptives or other female hormonal preparations.

Dihydrofolate reductase

Lamotrigine is a weak inhibitor of dihydrofolate reductase hence there is a possibility of interference with folate metabolism during long-term therapy (see section 4.6). However, during prolonged human dosing, lamotrigine did not induce significant changes in the haemoglobin concentration, mean corpuscular volume, or serum or red blood cell folate concentrations up to 1 year or red blood cell folate concentrations for up to 5 years.

Renal failure

In single dose studies in subjects with end stage renal failure, plasma concentrations of lamotrigine were not significantly altered. However, accumulation of the glucuronide metabolite is to be expected; caution should therefore be exercised in treating patients with renal failure.

Patients taking other preparations containing lamotrigine

Lamotrigine Tablets should not be administered to patients currently being treated with any other preparation containing lamotrigine without consulting a doctor.

Development in children

There are no data on the effect of lamotrigine on growth, sexual maturation and cognitive, emotional and behavioural developments in children.

Precautions relating to epilepsy

As with other AEDs, abrupt withdrawal of lamotrigine may provoke rebound seizures. Unless safety concerns (for example rash) require an abrupt withdrawal, the dose of lamotrigine should be gradually decreased over a period of 2 weeks.

There are reports in the literature that

Quetiapine Fumarate

Class: Atypical Antipsychotics
VA Class: CN709
Chemical Name: (E)-2-Butenedioate-2-[2-(4-dibenzo[b,f] [1,4]thiazepin-11-yl-1-piperazinyl)ethoxy]-ethanol (2:1) (salt)
Molecular Formula: (C₂₁H₂₅N₃O₂S)₂^•C₄H₄O₄
CAS Number: 111974-72-2
Brands: Seroquel

Special Alerts:

[Posted 02/22/2011] ISSUE: FDA notified healthcare professionals that the Pregnancy section of drug labels for the entire class of antipsychotic drugs has been updated. The new drug labels now contain more and consistent information about the potential risk for abnormal muscle movements (extrapyramidal signs or EPS) and withdrawal symptoms in newborns whose mothers were treated with these drugs during the third trimester of pregnancy.

The symptoms of EPS and withdrawal in newborns may include agitation, abnormally increased or decreased muscle tone, tremor, sleepiness, severe difficulty breathing, and difficulty in feeding. In some newborns, the symptoms subside within hours or days and do not require specific treatment; other newborns may require longer hospital stays.

BACKGROUND: Antipsychotic drugs are used to treat symptoms of psychiatric disorders such as schizophrenia and bipolar disorder.

RECOMMENDATION: Healthcare professionals should be aware of the effects of antipsychotic medications on newborns when the medications are used during pregnancy. Patients should not stop taking these medications if they become pregnant without talking to their healthcare professional, as abruptly stopping antipsychotic medications can cause significant complications for treatment. For more information visit the FDA website at: and .

[Posted 05/02/2007] FDA notified healthcare professionals that the Agency proposed that makers of all antidepressant medications update the existing black box warning on the prescribing information for their products to include warnings about the increased risks of suicidal thinking and behavior in young adults ages 18 to 24 years old during the first one to two months of treatment. The proposed labeling changes also state that scientific data did not show this increased risk in adults older than 24 years of age and that adults 65 years of age and older taking antidepressants have a decreased risk of suicidality. The proposed updates apply to the entire category of antidepressants. Individuals currently taking prescribed antidepressant medications should not stop taking them and should notify their healthcare professional if they have concerns. Manufacturers of antidepressant medications will have 30 days to submit their revised product labeling and revised Medication Guides to FDA for review. See the FDA press release for the list of products affected by the proposed antidepressant product labeling changes. For more information visit the FDA website at: , and .

REMS:

FDA approved a REMS for quetiapine to ensure that the benefits of a drug outweigh the risks. The REMS may apply to one or more preparations of quetiapine and consists of the following: medication guide. See the FDA REMS page () or the ASHP REMS Resource Center ().

• Increased Mortality in Geriatric Patients


• 
  

  Substantially higher mortality rate (4.5%) in geriatric patients with dementia-related psychosis† receiving atypical antipsychotic agents (e.g., quetiapine, aripiprazole, olanzapine, risperidone) compared with those receiving placebo (2.6%).^{a 97 98}

  
  


• 
  

  Most fatalities resulted from cardiac-related events (e.g., heart failure, sudden death) or infections (mostly pneumonia).^{a 97 98}

  
  


• 
  

  Atypical antipsychotics are not approved for the treatment of dementia-related psychosis.^{a 97 98} (See Increased Mortality in Geriatric Patients with Dementia-related Psychosis under Cautions.)

  
  

Introduction

Atypical or second-generation antipsychotic agent.^{1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 21 22 23 26 27 28}

Uses for Quetiapine Fumarate

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

Schizophrenia

Symptomatic management of schizophrenia.^{1 2 3 4 5 6 18 22 23 26}

Bipolar Disorder

Management (alone or in combination with lithium or divalproex sodium) of acute manic episodes associated with bipolar I disorder.^{1 a}

Quetiapine Fumarate Dosage and Administration

Administration

Oral Administration

Administer orally, generally 2–3 times daily without regard to meals.^{1 25}

When switching from other antipsychotic agents to quetiapine, abrupt discontinuance of previous agent may be acceptable for some patients with schizophrenia, but gradual discontinuance may be appropriate for others.¹ In all cases, minimize period of overlapping antipsychotic administration.¹

In patients being switched from long-acting (depot) parenteral antipsychotic therapy to oral quetiapine therapy, administer first oral dose in place of next scheduled depot injection of the long-acting preparation.¹

Periodically reevaluate need for continuing any existing drug therapy for symptomatic relief of adverse extrapyramidal effects.¹

Dosage

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

Available as quetiapine fumarate; dosage is expressed in terms of quetiapine.¹

Reinitiating therapy: In patients previously treated with quetiapine, dosage titration is not necessary if reinitiated after a drug-free period <1 week;¹ if reinitiated after a drug-free period >1 week, generally titrate dosage as with initial therapy.¹

Adults

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

Schizophrenia

Oral

Initially, 25 mg twice daily.^{1 23}

Increase dosage in increments of 25–50 mg 2 or 3 times daily on the second or third day, as tolerated, to a target dosage of 300–400 mg daily in 2 or 3 divided doses by the fourth day.^{1 23}

Make subsequent dosage adjustments at intervals of not less than 2 days, usually in increments or decrements of 25–50 mg twice daily.^{1 20}

Dosages ranging from 150–750 mg daily were effective in clinical trials.^{1 4 5 6 7 8 11 18 22} Dosages >300 mg daily usually do not result in greater efficacy, but dosages of 400–500 mg daily have been required in some patients.¹

Optimum duration of therapy currently not known, but efficacy of maintenance therapy with antipsychotics is well established.^{1 22} Continue therapy in responsive patients as long as clinically necessary and tolerated but at lowest possible effective dosage; reassess need for continued therapy and optimal dosage periodically (e.g., at least annually).^{1 22}

If discontinuance is considered, precautions include slow, gradual dose reduction over many months, more frequent clinician visits, and use of early intervention strategies.²²

Bipolar Disorder

Acute Mania

Oral

Initially, 100 mg daily in 2 divided doses.¹ Increase dosage (in increments of ≤100 mg daily in 2 divided doses) to 400 mg daily on the fourth day of therapy.¹ Make subsequent adjustments in increments of ≤200 mg daily to reach a dosage of up to 800 mg daily by the sixth day of therapy.¹

Majority of patients respond to 400–800 mg daily.¹

Optimum duration not established; efficacy has been demonstrated in two 12-week monotherapy trials and one 3-week adjunct therapy trial.^a If used for extended periods, periodically reevaluate long-term risks and benefits for the individual patient.^{1 a}

Prescribing Limits

Adults

Schizophrenia

Oral

Safety of dosages >800 mg daily not established.¹

Bipolar Disorder

Acute Mania

Oral

Safety of dosages >800 mg daily not established.¹

Special Populations

Hepatic Impairment

Initially, 25 mg daily; increase dosage by 25–50 mg daily according to clinical response and tolerability until an effective dosage is reached.¹

Renal Impairment

No dosage adjustment necessary.¹

Patients at Risk of Orthostatic Hypotension

Consider a slower rate of dosage titration and a lower target dosage in geriatric patients and in patients who are debilitated or have a predisposition to hypotensive reactions.¹ Adjust dosage with caution.¹

Initially, 25 mg twice daily to minimize risk of orthostatic hypotension and associated syncope.¹ If hypotension occurs during dosage titration, return to previous dosage in titration schedule.¹

Cautions for Quetiapine Fumarate

Contraindications

• 
  

  Known hypersensitivity to quetiapine or any ingredient in the formulation.¹

  
  

Warnings/Precautions

Warnings

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

Increased Mortality in Geriatric Patients with Dementia-related Psychosis

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

Possible increased risk of death with use of atypical antipsychotics in geriatric patients with dementia-related psychosis.^{a 97 98}

Atypical antipsychotics are not approved for the treatment of dementia-related psychosis.^{a 97 98} (See Boxed Warning and see Geriatric Use under Cautions.)

Neuroleptic Malignant Syndrome

Neuroleptic malignant syndrome (NMS), a potentially fatal syndrome requiring immediate discontinuance of the drug and intensive symptomatic treatment, reported rarely.¹

Tardive Dyskinesia

Tardive dyskinesia, a syndrome of potentially irreversible, involuntary dyskinetic movements, reported infrequently.¹ Consider discontinuance of quetiapine.¹

Hyperglycemia and Diabetes Mellitus

Severe hyperglycemia, sometimes associated with ketoacidosis, hyperosmolar coma, or death, reported in patients receiving atypical antipsychotic agents, including quetiapine.^{1 34 35 36 37 38 39 40 41 42 43 44 45 47 60 61 62 63 67 87} Closely monitor patients with preexisting diabetes mellitus for worsening of glucose control and perform fasting glucose tests at baseline and periodically for patients with risk factors for diabetes (e.g., obesity, family history of diabetes).^{1 34 35 36 37 38 39 40 41 42 43 44 45} If manifestations of hyperglycemia occur in any patient, test for diabetes mellitus.^{1 34 35 36 37 38 39 40 41 42 43 44 45}

General Precautions

Orthostatic Hypotension

Orthostatic hypotension reported.¹ Use with caution in patients with known cardiovascular or cerebrovascular disease and/or conditions that would predispose patients to hypotension (e.g., dehydration, hypovolemia, concomitant antihypertensive therapy).¹ (See Patients at Risk of Orthostatic Hypotension under Dosage and Administration.)

Ocular Effects

Possible lenticular changes; ophthalmologic examination of the lens by methods adequate to detect cataract formation (e.g., slit lamp exam) recommended at initiation of therapy, or shortly thereafter, and at 6-month intervals during chronic therapy.¹

Nervous System Effects

Possible risk of seizures; use with caution in patients with a history of seizures or with conditions known to lower the seizure threshold (e.g., dementia of the Alzheimer’s type, geriatric patients).¹

Disruption of ability to reduce core body temperature possible; use with caution in patients exposed to conditions that may contribute to an elevation in core body temperature (e.g., dehydration, extreme heat, strenuous exercise, concomitant use of anticholinergic agents).¹

Somnolence reported.¹ Potential impairment of judgment, thinking, or motor skills.¹

Endocrine Effects

Hypothyroidism possible.¹

Elevated prolactin concentrations reported with some atypical antipsychotic agents; not observed in clinical trials with quetiapine but reported in animals.¹

Metabolic Effects

Weight gain possible.¹

Increases in cholesterol and triglyceride concentrations possible; weakly related to weight gain.¹

Hepatic Effects

Asymptomatic, transient, and reversible increases in serum transaminases (principally ALT) reported; usually occurred within first 3 weeks and resolved despite continued quetiapine therapy.¹

Sexual Dysfunction

Priapism possible.¹

GI Effects

Esophageal dysmotility and aspiration possible; use with caution in patients at risk for aspiration pneumonia (e.g., geriatric patients, those with advanced Alzheimer’s dementia).¹

Suicide

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

Attendant risk with psychotic illnesses; closely supervise high-risk patients.¹ Prescribe in the smallest quantity consistent with good patient management to reduce the risk of overdosage.¹

Possible Prescribing and Dispensing Precautions

Ensure accuracy of prescription; similarity in spelling of Seroquel (quetiapine) and Serzone (former trade name for nefazodone hydrochloride, an antidepressant agent) may result in errors associated with adverse CNS (e.g., mental status deterioration, hallucination, paranoia, muscle weakness, lethargy, dizziness) and GI (e.g., nausea, vomiting, diarrhea) effects.^{29 30 31}

Specific Populations

Pregnancy

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

Category C.¹

Lactation

Distributed into milk in animals; not known whether distributed into human milk.¹ Women receiving quetiapine should not breast-feed.¹

Pediatric Use

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

Safety and efficacy not established in children <18 years of age.¹

Geriatric Use

No substantial differences in safety relative to younger adults, but factors that decrease pharmacokinetic clearance, increase the pharmacodynamic response, or cause poorer tolerance or orthostasis may be present.¹ (See Patients at Risk of Orthostatic Hypotension under Dosage and Administration.)

Possible increased risk of death in geriatric patients with dementia-related psychosis.^{a 97 98} Substantial (1.6- to 1.7-fold) increase in mortality rate reported in geriatric patients with dementia who received atypical antipsychotic agents (e.g., aripiprazole, olanzapine, quetiapine, risperidone) for treatment of behavioral disorders; most fatalities resulted from cardiac-related events (e.g., heart failure, sudden death) or infections (mostly pneumonia).^{a 97 98}

Atypical antipsychotics are not approved for the treatment of dementia-related psychosis.^{a 97 98} (See Boxed Warning and see Increased Mortality in Geriatric Patients with Dementia-related Psychosis under Cautions.)

Hepatic Impairment

Increased plasma concentrations expected in patients with hepatic impairment; dosage adjustment may be necessary.¹

Renal Impairment

Clearance may be decreased in severe renal impairment, but dosage adjustment not necessary.¹

Common Adverse Effects

Somnolence, dizziness, dry mouth, constipation, increased ALT, weight gain, dyspepsia.^a

Interactions for Quetiapine Fumarate

Metabolized principally by CYP3A4.^{1 b} Does not appear to inhibit CYP1A2, CYP2C9, CYP2C19, CYP2D6, or CYP3A4 in vitro; pharmacokinetic interaction with substrates of these isoenzymes unlikely.^{1 b}

Drugs Affecting Hepatic Microsomal Enzymes

Inhibitors or inducers of CYP3A4; potential pharmacokinetic interaction (altered quetiapine metabolism).^{1 b}

Specific Drugs

Drug	Interaction	Comments
Alcohol	Potentiation of cognitive and motor effects of alcohol1	Avoid alcohol during therapy with quetiapine1
Antifungals, azole (e.g., fluconazole, itraconazole, ketoconazole)	Substantial decrease in quetiapine clearance with concomitant use of ketoconazole, resulting in increased peak plasma quetiapine concentrations1	Use concomitantly with caution; dosage adjustment of quetiapine may be necessary1
Barbiturates	Possible increased quetiapine clearance1	Increased quetiapine dosage may be required1
Carbamazepine	Possible increased quetiapine clearance1	Increased quetiapine dosage may be required1
Cimetidine	Decreased quetiapine mean clearance1	No dosage adjustment of quetiapine required1
CNS agents	Possible additive CNS effects1	Use with caution1
Divalproex sodium	Increased peak plasma quetiapine concentrations, with no effect on extent of absorption or mean quetiapine clearance; decreased peak plasma valproic acid concentrations and extent of absorption, but not significant1
Dopamine agonists	Antagonistic effects1
Erythromycin	Decreased quetiapine clearance1	Use concomitantly with caution1
Fluoxetine	No effect on quetiapine pharmacokinetics1
Glucocorticoids	Possible increased quetiapine clearance1	Increased quetiapine dosage may be required1
Haloperidol	No effect on quetiapine pharmacokinetics1
Hypotensive agents	Additive hypotensive effects1
Imipramine	No effect on quetiapine pharmacokinetics1
Levodopa	Antagonistic effects1
Lithium	No effect on lithium pharmacokinetics1
Lorazepam	Decreased lorazepam clearance1
Phenytoin	Substantially increased quetiapine clearance1	Increased quetiapine dosage may be required;1 23 caution advised if phenytoin is withdrawn and replaced with a non-inducer (e.g., valproate)1
Rifampin	Possible increased quetiapine clearance1	Increased quetiapine dosage may be required1
Risperidone	No effect on quetiapine pharmacokinetics1
Thioridazine	Substantially increased quetiapine clearance1

Quetiapine Fumarate Pharmacokinetics

Absorption

Bioavailability

Rapidly absorbed after oral administration, with peak plasma concentrations attained within 1.5 hours.^{1 b} Bioavailability of tablet formulation is 100% relative to an oral solution (not commercially available in US).^{1 b}

Food

Bioavailability is marginally affected by food.^{1 b}

Distribution

Extent

Widely distributed throughout the body.¹

Distributed into milk in animals; not known whether distributed into human milk.¹

Plasma Protein Binding

83%.^{1 b}

Elimination

Metabolism

Extensively metabolized to inactive metabolites, principally via CYP3A4.^{1 b}

Elimination Route

Excreted in urine (73%) and feces (20%), with <1% of the drug excreted unchanged.^{1 b}

Half-life

Approximately 6 hours.^{1 b}

Special Populations

In patients with hepatic impairment, clearance is 30% lower and AUC and peak plasma concentrations are 3 times higher than those of healthy individuals.¹

In patients with severe renal impairment (Cl_cr 10–30 mL/minute), clearance may be reduced by 25% compared with healthy individuals; however, plasma concentrations in patients with renal impairment were within the range of those seen in healthy patients.¹

In geriatric patients, clearance is decreased by about 40% compared with younger patients.¹

Stability

Storage

Oral

Tablets

25°C (may be exposed to 15–30°C).¹

Actions

• 
  

  Exact mechanism of antipsychotic action is not known; may involve antagonism at serotonin type 1 (5-hydroxytryptamine [5-HT_1A]),^{1 6 7 15 17} type 2 (5-HT_2A, 5-HT_2C),^{1 2 3 4 5 6 7 8 9 10 11 12 14 15 16 17 23} and type 6 (5-HT₆) receptors,¹⁷ and at dopamine receptors.^{1 2 3 4 5 6 7 8 9 10 11 12 14 15 16 17 26 28}

  
  


• 
  

  Antagonism at other receptors (e.g., α₁-adrenergic receptors, histamine H₁ receptors) may contribute to other therapeutic and adverse effects (e.g., orthostatic hypotension, somnolence).¹

  
  

Advice to Patients

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

• 
  

  Risk of orthostatic hypotension, especially during initial dosage titration and at times of re-initiation of therapy or increases in dosage.¹

  
  


• 
  

  Risk of somnolence and impairment of judgment, thinking, or motor skills; avoid driving, operating machinery, or performing hazardous tasks until effects on the individual are known.¹

  
  


• 
  

  Importance of avoiding alcohol during quetiapine therapy.¹

  
  


• 
  

  Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.¹

  
  


• 
  

  Importance of avoiding overheating or dehydration.¹

  
  


• 
  

  Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses (e.g., diabetes mellitus, seizures, dementia).¹

  
  


• 
  

  Importance of informing patients of other important precautionary information. (See Cautions.)

  
  

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Quetiapine Fumarate

Routes	Dosage Forms	Strengths	Brand Names	Manufacturer
Oral	Tablets, film-coated	25 mg (of quetiapine)	Seroquel (with povidone)	AstraZeneca
		50 mg (of quetiapine)	Seroquel (with povidone)	AstraZeneca
		100 mg (of quetiapine)	Seroquel (with povidone)	AstraZeneca
		200 mg (of quetiapine)	Seroquel (with povidone)	AstraZeneca
		300 mg (of quetiapine)	Seroquel (with povidone)	AstraZeneca
		400 mg (of quetiapine)	Seroquel (with povidone)	AstraZeneca

Comparative Pricing

This pricing information is subject to change at the sole discretion of DS Pharmacy. This pricing information was updated 10/2011. Actual costs to patients will vary depending on the use of specific retail or mail-order locations and health insurance copays.

SEROquel 100MG Tablets (ASTRAZENECA): 60/$364.98 or 180/$1,063.93

SEROquel 200MG Tablets (ASTRAZENECA): 60/$683.97 or 180/$2,012.08

SEROquel 25MG Tablets (ASTRAZENECA): 60/$212.09 or 180/$607.90

SEROquel 300MG Tablets (ASTRAZENECA): 60/$902.01 or 180/$2,652.93

SEROquel 400MG Tablets (ASTRAZENECA): 30/$551.01 or 90/$1,506.89

SEROquel 50MG Tablets (ASTRAZENECA): 100/$584.01 or 300/$1,709.97

SEROquel XR 150MG 24-hr Tablets (ASTRAZENECA): 60/$597.99 or 180/$1,685.97

SEROquel XR 200MG 24-hr Tablets (ASTRAZENECA): 60/$673.96 or 180/$1,980.98

SEROquel XR 400MG 24-hr Tablets (ASTRAZENECA): 60/$983.96 or 180/$2,893.85

SEROquel XR 50MG 24-hr Tablets (ASTRAZENECA): 60/$337.99 or 180/$953.01

Disclaimer

This report on medications is for your information only, and is not considered individual patient advice. Because of the changing nature of drug information, please consult your physician or pharmacist about specific clinical use.

The American Society of Health-System Pharmacists, Inc. and Drugs.com represent that the information provided hereunder was formulated with a reasonable standard of care, and in conformity with professional standards in the field. The American Society of Health-System Pharmacists, Inc. and Drugs.com make no representations or warranties, express or implied, including, but not limited to, any implied warranty of merchantability and/or fitness for a particular purpose, with respect to such information and specifically disclaims all such warranties. Users are advised that decisions regarding drug therapy are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and the information is provided for informational purposes only. The entire monograph for a drug should be reviewed for a thorough understanding of the drug's actions, uses and side effects. The American Society of Health-System Pharmacists, Inc. and Drugs.com do not endorse or recommend the use of any drug. The information is not a substitute for medical care.

AHFS Drug Information. © Copyright, 1959-2011, Selected Revisions October 27, 2011. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

† Use is not currently included in the labeling approved by the US Food and Drug Administration.

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39. Lewis-Hall F. Dear health care professional letter regarding class labeling for atypical antipsychotics and risk of hyperglycemia and diabetes. Princeton, NJ: Briston-Myers Squibb Company; 2004 Mar 25. From FDA website.

40. Bess AL, Cunningham SR. Dear health care professional letter regarding class labeling for atypical antipsychotics and risk of hyperglycemia and diabetes. East Hanover, NJ: Novartis Pharmaceuticals Corporation; 2004 Apr 1. From the FDA website.

41. Eli Lilly and Company. Lilly announces FDA notification of class labeling for atypical antipsychotics regarding hyperglycemia and diabetes. Indianapolis, IN; 2003 Sep 17. Press release.

42. Eisenberg P. Dear health care professional letter regarding safety data on Zyprexa (olanzapine) – hyperglycemia and diabetes. Indianapolis, IN: Eli Lilly and Company; 2004 Mar 1. From the FDA website.

43. Macfadden W. Dear health care professional letter regarding class labeling for atypical antipsychotics and risk of hyperglycemia and diabetes. Wilmington, DE: AstraZeneca Pharmaceuticals; 2004 Apr 22. From the FDA website.

44. Mahmoud RA. Dear health care professional letter regarding class labeling for atypical antipsychotics and risk of hyperglycemia and diabetes. Titusville, NJ: Janssen Pharmaceutica, Inc; 2004. From the FDA website.

45. Clary CM. Dear health care practitioner letter regarding class labeling for atypical antipsychotics and risk of hyperglycemia and diabetes. New York NY: Pfizer Global Pharmaceuticals; 2004 Aug. From the FDA website.

46. Cunningham F, Lambert B, Miller DR et al. Antipsychotic induced diabetes in veteran schizophrenic patients. In: Abstracts of the 1st International Conference on Therapeutic Risk Management and 19th International Conference on Pharmacoepidemiology, Philadelphia, PA, 2003 Aug 21-24. Pharmacoepidemiol Drug Saf. 2003; 12(suppl 1): S154-5.

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48. Melkersson K, Dahl ML. Adverse metabolic effects associated with atypical antipsychotics. Drugs. 2004; 64:701-23. [PubMed 15025545]

49. Citrome LL, Jaffe AB. Relationship of atypical antipsychotics with development of diabetes mellitus. Ann Pharmacother. 2003; 37:1849-57. [IDIS 510453] [PubMed 14632602]

50. Sumiyoshi T, Roy A, Anil AE et al. A comparison of incidence of diabetes mellitus between atypical antipsychotic drugs. J Clin Psychopharmacol. 2004; 24:345-8. [IDIS 515736] [PubMed 15118492]

51. Expert Group. ’Schizophrenia and Diabetes 2003’ expert consensus meeting, Dublin, 3–4 October 2003: consensus summary. Br J Psychiatry. 2004; 47(Suppl):S112-4.

52. Marder SR, Essock SM, Miller AL et al.