Author: druginteractionchecker_lgaiz4

WARNING AND CAUTIONS

5 WARNINGS AND PRECAUTIONS Niacin extended-release tablet preparations should not be substituted for equivalent doses of immediate-release (crystalline) niacin.

For patients switching from immediate-release niacin to niacin extended-release tablets, therapy with niacin extended-release tablets should be initiated with low doses (i.e., 500 mg at bedtime) and the niacin extended-release tablet dose should then be titrated to the desired therapeutic response [see Dosage and Administration ( 2 )] .

Caution should also be used when niacin extended-release tablets are used in patients with unstable angina or in the acute phase of an MI, particularly when such patients are also receiving vasoactive drugs such as nitrates, calcium channel blockers, or adrenergic blocking agents.

Niacin is rapidly metabolized by the liver, and excreted through the kidneys.

Niacin extended-release tablets are contraindicated in patients with significant or unexplained hepatic impairment [see Contraindications ( 4 ) and Warnings and Precautions ( 5.3 )] and should be used with caution in patients with renal impairment.

Patients with a past history of jaundice, hepatobiliary disease, or peptic ulcer should be observed closely during niacin extended-release tablet therapy.

• Severe hepatic toxicity has occurred in patients substituting sustained-release niacin for immediate-release niacin at equivalent doses.

( 5.3 ) • Myopathy has been reported in patients taking niacin extended-release tablets.

The risk for myopathy and rhabdomyolysis are increased among elderly patients; patients with diabetes, renal failure, or uncontrolled hypothyroidism; and patients being treated with a statin.

( 5.2 ) • Liver enzyme abnormalities and monitoring: Persistent elevations in hepatic transaminase can occur.

Monitor liver enzymes before and during treatment.

( 5.3 ) • Use with caution in patients with unstable angina or in the acute phase of an MI.

( 5 ) • Niacin extended-release tablets can increase serum glucose levels.

Glucose levels should be closely monitored in diabetic or potentially diabetic patients particularly during the first few months of use or dose adjustment.

( 5.4 ) 5.1 Mortality and Coronary Heart Disease Morbidity Niacin extended-release tablets have not been shown to reduce cardiovascular morbidity or mortality among patients already treated with a statin.

The Atherothrombosis Intervention in Metabolic Syndrome with Low HDL/High Triglycerides: Impact on Global Health Outcomes (AIM-HIGH) trial was a randomized placebo-controlled trial of 3414 patients with stable, previously diagnosed cardiovascular disease.

Mean baseline lipid levels were LDL-C 74 mg/dL, HDL-C 35 mg/dL, non-HDL-C 111 mg/dL and median triglyceride level of 163 to 177 mg/dL.

Ninety-four percent of patients were on background statin therapy prior to entering the trial.

All participants received simvastatin, 40 to 80 mg per day, plus ezetimibe 10 mg per day if needed, to maintain an LDL-C level of 40 to 80 mg/dL, and were randomized to receive niacin extended-release tablets 1500 to 2000 mg/day (n = 1718) or matching placebo (IR Niacin, 100 to 150 mg, n = 1696).

On-treatment lipid changes at two years for LDL-C were -12% for the simvastatin plus niacin extended-release tablets group and -5.5% for the simvastatin plus placebo group.

HDL-C increased by 25% to 42 mg/dL in the simvastatin plus niacin extended-release tablets group and by 9.8% to 38 mg/dL in the simvastatin plus placebo group (P < 0.001).

Triglyceride levels decreased by 28.6% in the simvastatin plus niacin extended-release tablets group and by 8.1% in the simvastatin plus placebo group.

The primary outcome was an ITT composite of the first study occurrence of coronary heart disease death, nonfatal myocardial infarction, ischemic stroke, hospitalization for acute coronary syndrome or symptom-driven coronary or cerebral revascularization procedures.

The trial was stopped after a mean follow-up period of 3 years owing to a lack of efficacy.

The primary outcome occurred in 282 patients in the simvastatin plus niacin extended-release tablets group (16.4%) and in 274 patients in the simvastatin plus placebo group (16.2%) (HR 1.02 [95% CI, 0.87 to 1.21], P = 0.79.

In an ITT analysis, there were 42 cases of first occurrence of ischemic stroke reported, 27 (1.6%) in the simvastatin plus niacin extended-release tablets group and 15 (0.9%) in the simvastatin plus placebo group, a non-statistically significant result (HR 1.79, [95%CI = 0.95 to 3.36], p = 0.071).

The on-treatment ischemic stroke events were 19 for the simvastatin plus niacin extended-release tablets group and 15 for the simvastatin plus placebo group [see Adverse Reactions ( 6.1 )] .

5.2 Skeletal Muscle Cases of rhabdomyolysis have been associated with concomitant administration of lipid-altering doses (≥ 1 g/day) of niacin and statins.

Elderly patients and patients with diabetes, renal failure, or uncontrolled hypothyroidism are particularly at risk.

Monitor patients for any signs and symptoms of muscle pain, tenderness, or weakness, particularly during the initial months of therapy and during any periods of upward dosage titration.

Periodic serum creatine phosphokinase (CPK) and potassium determinations should be considered in such situations, but there is no assurance that such monitoring will prevent the occurrence of severe myopathy.

5.3 Liver Dysfunction Cases of severe hepatic toxicity, including fulminant hepatic necrosis, have occurred in patients who have substituted sustained-release (modified-release, timed-release) niacin products for immediate-release (crystalline) niacin at equivalent doses.

Niacin extended-release tablets should be used with caution in patients who consume substantial quantities of alcohol and/or have a past history of liver disease.

Active liver diseases or unexplained transaminase elevations are contraindications to the use of niacin extended-release tablets.

Niacin preparations have been associated with abnormal liver tests.

In three placebo-controlled clinical trials involving titration to final daily niacin extended-release tablet doses ranging from 500 to 3000 mg, 245 patients received niacin extended-release tablets for a mean duration of 17 weeks.

No patient with normal serum transaminase levels (AST, ALT) at baseline experienced elevations to more than 3 times the upper limit of normal (ULN) during treatment with niacin extended-release tablets.

In these studies, fewer than 1% (2/245) of niacin extended-release tablet patients discontinued due to transaminase elevations greater than 2 times the ULN.

Liver-related tests should be performed on all patients during therapy with niacin extended-release tablets.

Serum transaminase levels, including AST and ALT (SGOT and SGPT), should be monitored before treatment begins, every 6 to 12 weeks for the first year, and periodically thereafter (e.g., at approximately 6 month intervals).

Special attention should be paid to patients who develop elevated serum transaminase levels, and in these patients, measurements should be repeated promptly and then performed more frequently.

If the transaminase levels show evidence of progression, particularly if they rise to 3 times ULN and are persistent, or if they are associated with symptoms of nausea, fever, and/or malaise, the drug should be discontinued.

5.4 Laboratory Abnormalities Increase in Blood Glucose: Niacin treatment can increase fasting blood glucose.

Frequent monitoring of blood glucose should be performed to ascertain that the drug is producing no adverse effects.

Diabetic patients may experience a dose-related increase in glucose intolerance.

Diabetic or potentially diabetic patients should be observed closely during treatment with niacin extended-release tablets, particularly during the first few months of use or dose adjustment; adjustment of diet and/or hypoglycemic therapy may be necessary.

Reduction in Platelet Count: Niacin extended-release tablets have been associated with small but statistically significant dose-related reductions in platelet count (mean of -11% with 2000 mg).

Caution should be observed when niacin extended-release tablets are administered concomitantly with anticoagulants; platelet counts should be monitored closely in such patients.

Increase in Prothrombin Time (PT): Niacin extended-release tablets have been associated with small but statistically significant increases in prothrombin time (mean of approximately +4%); accordingly, patients undergoing surgery should be carefully evaluated.

Caution should be observed when niacin extended-release tablets are administered concomitantly with anticoagulants; prothrombin time should be monitored closely in such patients.

Increase in Uric Acid: Elevated uric acid levels have occurred with niacin therapy, therefore use with caution in patients predisposed to gout.

Decrease in Phosphorus: In placebo-controlled trials, niacin extended-release tablets have been associated with small but statistically significant, dose-related reductions in phosphorus levels (mean of -13% with 2000 mg).

Although these reductions were transient, phosphorus levels should be monitored periodically in patients at risk for hypophosphatemia.

WARNING AND CAUTIONS

5 WARNINGS AND PRECAUTIONS • Gastric Malignancy: In adults, symptomatic response does not preclude presence of gastric malignancy.

Consider additional follow-up and diagnostic testing.

( 5.1 ) • Acute Tubulointerstitial Nephritis : Discontinue treatment and evaluate patients.

( 5.2 ) • Clostridium difficile- Associated Diarrhea : PPI therapy may be associated with increased risk of Clostridium difficile- associated diarrhea.

( 5.3 ) • Bone Fracture : Long-term and multiple daily dose PPI therapy may be associated with an increased risk for osteoporosis-related fractures of the hip, wrist or spine.

( 5.4 ) • Severe Cutaneous Adverse Reactions : Discontinue at the first signs or symptoms of severe cutaneous adverse reactions or other signs of hypersensitivity and consider further evaluation.

( 5.5 ) • Cutaneous and Systemic Lupus Erythematosus : Mostly cutaneous; new onset or exacerbation of existing disease; discontinue PROTONIX and refer to specialist for evaluation.

( 5.6 ) • Cyanocobalamin (Vitamin B-12) Deficiency : Daily long-term use (e.g., longer than 3 years) may lead to malabsorption or a deficiency of cyanocobalamin.

( 5.7 ) • Hypomagnesemia and Mineral Metabolism : Reported rarely with prolonged treatment with PPIs.

( 5.8 ) • Fundic Gland Polyps: Risk increases with long-term use, especially beyond one year.

Use the shortest duration of therapy.

( 5.10 ) 5.1 Presence of Gastric Malignancy In adults, symptomatic response to therapy with PROTONIX does not preclude the presence of gastric malignancy.

Consider additional follow-up and diagnostic testing in adult patients who have a suboptimal response or an early symptomatic relapse after completing treatment with a PPI.

In older patients, also consider an endoscopy.

5.2 Acute Tubulointerstitial Nephritis Acute tubulointerstitial nephritis (TIN) has been observed in patients taking PPIs and may occur at any point during PPI therapy.

Patients may present with varying signs and symptoms from symptomatic hypersensitivity reactions to non-specific symptoms of decreased renal function (e.g., malaise, nausea, anorexia).

In reported case series, some patients were diagnosed on biopsy and in the absence of extra-renal manifestations (e.g., fever, rash or arthralgia).

Discontinue PROTONIX and evaluate patients with suspected acute TIN [see Contraindications (4) ].

5.3 Clostridium difficile- Associated Diarrhea Published observational studies suggest that PPI therapy like PROTONIX may be associated with an increased risk of Clostridium difficile associated diarrhea, especially in hospitalized patients.

This diagnosis should be considered for diarrhea that does not improve [see Adverse Reactions (6.2) ] .

Patients should use the lowest dose and shortest duration of PPI therapy appropriate to the condition being treated.

5.4 Bone Fracture Several published observational studies suggest that PPI therapy may be associated with an increased risk for osteoporosis-related fractures of the hip, wrist, or spine.

The risk of fracture was increased in patients who received high-dose, defined as multiple daily doses, and long-term PPI therapy (a year or longer).

Patients should use the lowest dose and shortest duration of PPI therapy appropriate to the condition being treated.

Patients at risk for osteoporosis-related fractures should be managed according to established treatment guidelines [see Dosage and Administration (2) , Adverse Reactions (6.2) ].

5.5 Severe Cutaneous Adverse Reactions Severe cutaneous adverse reactions, including erythema multiforme, Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), drug reaction with eosinophilia and systemic symptoms (DRESS), and acute generalized exanthematous pustulosis (AGEP) have been reported in association with the use of PPIs [see Adverse Reactions (6.2) ] .

Discontinue PROTONIX at the first signs or symptoms of severe cutaneous adverse reactions or other signs of hypersensitivity and consider further evaluation.

5.6 Cutaneous and Systemic Lupus Erythematosus Cutaneous lupus erythematosus (CLE) and systemic lupus erythematosus (SLE) have been reported in patients taking PPIs, including pantoprazole sodium.

These events have occurred as both new onset and an exacerbation of existing autoimmune disease.

The majority of PPI-induced lupus erythematous cases were CLE.

The most common form of CLE reported in patients treated with PPIs was subacute CLE (SCLE) and occurred within weeks to years after continuous drug therapy in patients ranging from infants to the elderly.

Generally, histological findings were observed without organ involvement.

Systemic lupus erythematosus (SLE) is less commonly reported than CLE in patients receiving PPIs.

PPI associated SLE is usually milder than non-drug induced SLE.

Onset of SLE typically occurred within days to years after initiating treatment primarily in patients ranging from young adults to the elderly.

The majority of patients presented with rash; however, arthralgia and cytopenia were also reported.

Avoid administration of PPIs for longer than medically indicated.

If signs or symptoms consistent with CLE or SLE are noted in patients receiving PROTONIX, discontinue the drug and refer the patient to the appropriate specialist for evaluation.

Most patients improve with discontinuation of the PPI alone in 4 to 12 weeks.

Serological testing (e.g., ANA) may be positive and elevated serological test results may take longer to resolve than clinical manifestations.

5.7 Cyanocobalamin (Vitamin B-12) Deficiency Generally, daily treatment with any acid-suppressing medications over a long period of time (e.g., longer than 3 years) may lead to malabsorption of cyanocobalamin (Vitamin B-12) caused by hypo- or achlorhydria.

Rare reports of cyanocobalamin deficiency occurring with acid-suppressing therapy have been reported in the literature.

This diagnosis should be considered if clinical symptoms consistent with cyanocobalamin deficiency are observed.

5.8 Hypomagnesemia and Mineral Metabolism Hypomagnesemia, symptomatic and asymptomatic, has been reported rarely in patients treated with PPIs for at least three months, and in most cases after a year of therapy.

Serious adverse events include tetany, arrhythmias, and seizures.

Hypomagnesemia may lead to hypocalcemia and/or hypokalemia and may exacerbate underlying hypocalcemia in at-risk patients.

In most patients, treatment of hypomagnesemia required magnesium replacement and discontinuation of the PPI.

For patients expected to be on prolonged treatment or who take PPIs with medications such as digoxin or drugs that may cause hypomagnesemia (e.g., diuretics), health care professionals may consider monitoring magnesium levels prior to initiation of PPI treatment and periodically [see Adverse Reactions (6.2) ] .

Consider monitoring magnesium and calcium levels prior to initiation of PROTONIX and periodically while on treatment in patients with a preexisting risk of hypocalcemia (e.g., hypoparathyroidism).

Supplement with magnesium and/or calcium as necessary.

If hypocalcemia is refractory to treatment, consider discontinuing the PPI.

5.9 Tumorigenicity Due to the chronic nature of GERD, there may be a potential for prolonged administration of PROTONIX.

In long-term rodent studies, pantoprazole was carcinogenic and caused rare types of gastrointestinal tumors.

The relevance of these findings to tumor development in humans is unknown [see Nonclinical Toxicology (13.1) ] .

5.10 Fundic Gland Polyps PPI use is associated with an increased risk of fundic gland polyps that increases with long-term use, especially beyond one year.

Most PPI users who developed fundic gland polyps were asymptomatic and fundic gland polyps were identified incidentally on endoscopy.

Use the shortest duration of PPI therapy appropriate to the condition being treated.

5.11 Interference with Investigations for Neuroendocrine Tumors Serum chromogranin A (CgA) levels increase secondary to drug-induced decreases in gastric acidity.

The increased CgA level may cause false positive results in diagnostic investigations for neuroendocrine tumors.

Healthcare providers should temporarily stop PROTONIX treatment at least 14 days before assessing CgA levels and consider repeating the test if initial CgA levels are high.

If serial tests are performed (e.g., for monitoring), the same commercial laboratory should be used for testing, as reference ranges between tests may vary [see Clinical Pharmacology (12.2) ] .

5.12 Interference with Urine Screen for THC There have been reports of false-positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving PPIs, including PROTONIX [see Drug Interactions (7) ] .

5.13 Concomitant Use of PROTONIX with Methotrexate Literature suggests that concomitant use of PPIs with methotrexate (primarily at high dose; see methotrexate prescribing information) may elevate and prolong serum levels of methotrexate and/or its metabolite, possibly leading to methotrexate toxicities.

In high-dose methotrexate administration, a temporary withdrawal of the PPI may be considered in some patients [see Drug Interactions (7) ].

WARNING AND CAUTIONS

5 WARNINGS AND PRECAUTIONS Observe for signs and symptoms of hypotension ( ) 5.2 Monitor renal function and potassium in susceptible patients ( , ) 5.3 5.4 5.1 Fetal Toxicity Pregnancy Category D Use of drugs that act on the renin-angiotensin system during the second and third trimesters of pregnancy reduces fetal renal function and increases fetal and neonatal morbidity and death.

Resulting oligohydramnios can be associated with fetal lung hypoplasia and skeletal deformations.

Potential neonatal adverse effects include skull hypoplasia, anuria, hypotension, renal failure, and death.

When pregnancy is detected, discontinue Diovan as soon as possible .

[see Use in Specific Populations (8.1)] 5.2 Hypotension Excessive hypotension was rarely seen (0.1%) in patients with uncomplicated hypertension treated with Diovan alone.

In patients with an activated renin-angiotensin system, such as volume- and/or salt-depleted patients receiving high doses of diuretics, symptomatic hypotension may occur.

This condition should be corrected prior to administration of Diovan, or the treatment should start under close medical supervision.

Caution should be observed when initiating therapy in patients with heart failure or post-myocardial infarction patients.

Patients with heart failure or post-myocardial infarction patients given Diovan commonly have some reduction in blood pressure, but discontinuation of therapy because of continuing symptomatic hypotension usually is not necessary when dosing instructions are followed.

In controlled trials in heart failure patients, the incidence of hypotension in valsartan-treated patients was 5.5% compared to 1.8% in placebo-treated patients.

In the Valsartan in Acute Myocardial Infarction Trial (VALIANT), hypotension in post-myocardial infarction patients led to permanent discontinuation of therapy in 1.4% of valsartan-treated patients and 0.8% of captopril-treated patients.

If excessive hypotension occurs, the patient should be placed in the supine position and, if necessary, given an intravenous infusion of normal saline.

A transient hypotensive response is not a contraindication to further treatment, which usually can be continued without difficulty once the blood pressure has stabilized.

5.3 Impaired Renal Function Changes in renal function including acute renal failure can be caused by drugs that inhibit the renin-angiotensin system and by diuretics.

Patients whose renal function may depend in part on the activity of the renin-angiotensin system (e.g., patients with renal artery stenosis, chronic kidney disease, severe congestive heart failure, or volume depletion) may be at particular risk of developing acute renal failure on Diovan.

Monitor renal function periodically in these patients.

Consider withholding or discontinuing therapy in patients who develop a clinically significant decrease in renal function on Diovan .

[see Drug Interactions (7)] 5.4 Hyperkalemia Some patients with heart failure have developed increases in potassium.

These effects are usually minor and transient, and they are more likely to occur in patients with pre-existing renal impairment.

Dosage reduction and/or discontinuation of Diovan may be required .

[see Adverse Reactions (6.1)]

WARNING AND CAUTIONS

5 WARNINGS AND PRECAUTIONS Monitor patients for new or worsening depression, suicidal thoughts/behavior, and unusual changes in mood or behavior ( 5.1 ) Central nervous system reactions can occur ( 5.2 ) Use caution when administering BANZEL with other drugs that shorten the QT interval ( 5.3 ) Discontinue BANZEL if multi-organ hypersensitivity reaction occurs ( 5.4 ) Withdraw BANZEL gradually to minimize the risk of precipitating seizures, seizure exacerbation, or status epilepticus ( 5.5 ) 5.1 Suicidal Behavior and Ideation Antiepileptic drugs (AEDs), including BANZEL, increase the risk of suicidal thoughts or behavior in patients taking these drugs for any indication.

Patients treated with any AED for any indication should be monitored for the emergence or worsening of depression, suicidal thoughts or behavior, and/or any unusual changes in mood or behavior.

Pooled analyses of 199 placebo-controlled clinical trials (mono- and adjunctive therapy) of 11 different AEDs showed that patients randomized to one of the AEDs had approximately twice the risk (adjusted Relative Risk 1.8, 95% CI:1.2, 2.7) of suicidal thinking or behavior compared to patients randomized to placebo.

In these trials, which had a median treatment duration of 12 weeks, the estimated incidence rate of suicidal behavior or ideation among 27,863 AED-treated patients was 0.43%, compared to 0.24% among 16,029 placebo-treated patients, representing an increase of approximately one case of suicidal thinking or behavior for every 530 patients treated.

There were four suicides in drug-treated patients in the trials and none in placebo-treated patients, but the number is too small to allow any conclusion about drug effect on suicide.

The increased risk of suicidal thoughts or behavior with AEDs was observed as early as 1 week after starting drug treatment with AEDs and persisted for the duration of treatment assessed.

Because most trials included in the analysis did not extend beyond 24 weeks, the risk of suicidal thoughts or behavior beyond 24 weeks could not be assessed.

The risk of suicidal thoughts or behavior was generally consistent among drugs in the data analyzed.

The finding of increased risk with AEDs of varying mechanisms of action and across a range of indications suggests that the risk applies to all AEDs used for any indication.

The risk did not vary substantially by age (5-100 years) in the clinical trials analyzed.

Table 1 shows absolute and relative risk by indication for all evaluated AEDs.

Table 1: Absolute and Relative Risk of Suicidal Behavior and Ideation Indication Placebo Patients with Events Per 1000 Patients Drug Patients with Events Per 1000 Patients Relative Risk: Incidence of Events in Drug Patients/Incidence in Placebo Patients Risk Difference: Additional Drug Patients with Events Per 1000 Patients Epilepsy 1.0 3.4 3.5 2.4 Psychiatric 5.7 8.5 1.5 2.9 Other 1.0 1.8 1.9 0.9 Total 2.4 4.3 1.8 1.9 The relative risk for suicidal thoughts or behavior was higher in clinical trials for epilepsy than in clinical trials for psychiatric or other conditions, but the absolute risk differences were similar for the epilepsy and psychiatric indications.

Anyone considering prescribing BANZEL or any other AED must balance the risk of suicidal thoughts or behavior with the risk of untreated illness.

Epilepsy and many other illnesses for which AEDs are prescribed are themselves associated with morbidity and mortality and an increased risk of suicidal thoughts and behavior.

Should suicidal thoughts and behavior emerge during treatment, consider whether the emergence of these symptoms in any given patient may be related to the illness being treated.

5.2 C entral Nervous System Reactions Use of BANZEL has been associated with central nervous system-related adverse reactions in the controlled clinical trial of patients 4 years or older with Lennox-Gastaut Syndrome.

The most significant of these can be classified into two general categories: 1) somnolence or fatigue, and 2) coordination abnormalities, dizziness, gait disturbances, and ataxia.

Somnolence was reported in 24% of BANZEL-treated patients compared to 13% of patients on placebo, and led to study discontinuation in 3% of BANZEL-treated patients compared to 0% of patients on placebo.

Fatigue was reported in 10% of BANZEL-treated patients compared to 8% of patients on placebo.

It led to study discontinuation in 1% of BANZEL-treated patients and 0% of patients on placebo.

Dizziness was reported in 2.7% of BANZEL-treated patients compared to 0% of patients on placebo, and did not lead to study discontinuation.

Ataxia and gait disturbance were reported in 5.4% and 1.4% of BANZEL-treated patients, respectively, compared to no patient on placebo.

None of these reactions led to study discontinuation.

Accordingly, patients should be advised not to drive or operate machinery until they have gained sufficient experience on BANZEL to gauge whether it adversely affects their ability to drive or operate machinery.

5.3 QT Shortening Formal cardiac ECG studies demonstrated shortening of the QT interval (mean = 20 msec, for doses > 2400 mg twice daily) with BANZEL.

In a placebo-controlled study of the QT interval, a higher percentage of BANZEL-treated subjects (46% at 2400 mg, 46% at 3200 mg, and 65% at 4800 mg) had a QT shortening of greater than 20 msec at T max compared to placebo (5-10%).

Reductions of the QT interval below 300 msec were not observed in the formal QT studies with doses up to 7200 mg per day.

Moreover, there was no signal for drug-induced sudden death or ventricular arrhythmias.

The degree of QT shortening induced by BANZEL is without any known clinical risk.

Familial Short QT syndrome is associated with an increased risk of sudden death and ventricular arrhythmias, particularly ventricular fibrillation.

Such events in this syndrome are believed to occur primarily when the corrected QT interval falls below 300 msec.

Non-clinical data also indicate that QT shortening is associated with ventricular fibrillation.

Patients with Familial Short QT syndrome should not be treated with BANZEL.

Caution should be used when administering BANZEL with other drugs that shorten the QT interval [ see Contraindications ( 4 ) ] .

5.4 Multi-organ Hypersensitivity /Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), also known as multi-organ hypersensitivity, has been reported in patients taking antiepileptic drugs, including BANZEL.

DRESS may be fatal or life-threatening.

DRESS typically, although not exclusively, presents with fever, rash, and/or lymphadenopathy, and/or facial swelling, in association with other organ system involvement, such as hepatitis, nephritis, hematological abnormalities, myocarditis, or myositis, sometimes resembling an acute viral infection.

Eosinophilia is often present.

It is important to note that early manifestations of hypersensitivity, such as fever or lymphadenopathy, may be present even though rash is not evident.

Because this disorder is variable in its expression, other organ systems not noted here may be involved.

All cases of DRESS identified in clinical trials with BANZEL occurred in pediatric patients less than 12 years of age, occurred within 4 weeks of treatment initiation, and resolved or improved with BANZEL discontinuation.

DRESS has also been reported in adult and pediatric patients taking BANZEL in the postmarketing setting.

If DRESS is suspected, the patient should be evaluated immediately, BANZEL should be discontinued, and alternative treatment should be started.

5.5 Withdrawal of AEDs As with all antiepileptic drugs, BANZEL should be withdrawn gradually to minimize the risk of precipitating seizures, seizure exacerbation, or status epilepticus.

If abrupt discontinuation of the drug is medically necessary, the transition to another AED should be made under close medical supervision.

In clinical trials, BANZEL discontinuation was achieved by reducing the dose by approximately 25% every 2 days.

5.6 Status Epilepticus Estimates of the incidence of treatment emergent status epilepticus among patients treated with BANZEL are difficult because standard definitions were not employed.

In a controlled Lennox-Gastaut Syndrome trial, 3 of 74 (4.1%) BANZEL-treated patients had episodes that could be described as status epilepticus in the BANZEL-treated patients compared with none of the 64 patients in the placebo-treated patients.

In all controlled trials that included patients with different epilepsies, 11 of 1240 (0.9%) BANZEL-treated patients had episodes that could be described as status epilepticus compared with none of 635 patients in the placebo-treated patients.

5.7 Leukopenia BANZEL has been shown to reduce white cell count.

Leukopenia (white cell count < 3X10 9 L) was more commonly observed in BANZEL-treated patients 43 of 1171 (3.7%) than placebo-treated patients, 7 of 579 (1.2%) in all controlled trials.

WARNING AND CAUTIONS

5 WARNINGS AND PRECAUTIONS • Cerebrovascular Adverse Reactions: Increased incidence of cerebrovascular adverse reactions (e.g., stroke, transient ischemic attack) has been seen in elderly patients with dementia-related psychoses treated with atypical antipsychotic drugs (5.3) • Neuroleptic Malignant Syndrome (NMS): Manage with immediate discontinuation and close monitoring (5.4) • Metabolic Changes: Atypical antipsychotics have been associated with metabolic changes.

These metabolic changes include hyperglycemia, dyslipidemia, and weight gain (5.5) ∘ Hyperglycemia and Diabetes Mellitus: Monitor patients for symptoms of hyperglycemia including polydipsia, polyuria, polyphagia, and weakness.

Monitor glucose regularly in patients with diabetes or at risk for diabetes ∘ Dyslipidemia: Undesirable alterations have been observed in patients treated with atypical antipsychotics.

Appropriate clinical monitoring is recommended, including fasting blood lipid testing at the beginning of, and periodically, during treatment ∘ Weight Gain: Gain in body weight has been observed; clinical monitoring of weight is recommended • Tardive Dyskinesia: Discontinue if clinically appropriate (5.6) • Hypotension: Use with caution in patients with known cardiovascular or cerebrovascular disease (5.7) • Increased Blood Pressure in Children and Adolescents: Monitor blood pressure at the beginning of, and periodically during treatment in children and adolescents (5.9) • Leukopenia, Neutropenia and Agranulocytosis: Monitor complete blood count frequently during the first few months of treatment in patients with a pre-existing low white cell count or a history of leukopenia/neutropenia and discontinue SEROQUEL at the first sign of a decline in WBC in absence of other causative factors (5.10) • Cataracts: Lens changes have been observed in patients during long-term quetiapine treatment.

Lens examination is recommended when starting treatment and at 6-month intervals during chronic treatment (5.11) • Anticholinergic(antimuscarinic) Effects : Use with caution with other anticholinergic drugs and in patients with urinary retention, prostatic hypertrophy, or constipation (5.20) 5.1 Increased Mortality in Elderly Patients with Dementia-Related Psychosis Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death.

Analysis of 17 placebo-controlled trials (modal duration of 10 weeks), largely in patients taking atypical antipsychotic drugs, revealed a risk of death in drug-treated patients of between 1.6 to 1.7 times the risk of death in placebo-treated patients.

Over the course of a typical 10-week controlled trial, the rate of death in drug-treated patients was about 4.5%, compared to a rate of about 2.6% in the placebo group.

Although the causes of death were varied, most of the deaths appeared to be either cardiovascular (e.g., heart failure, sudden death) or infectious (e.g., pneumonia) in nature.

Observational studies suggest that, similar to atypical antipsychotic drugs, treatment with conventional antipsychotic drugs may increase mortality.

The extent to which the findings of increased mortality in observational studies may be attributed to the antipsychotic drug as opposed to some characteristic(s) of the patients is not clear.

SEROQUEL is not approved for the treatment of patients with dementia-related psychosis [see Boxed Warning ] .

5.2 Suicidal Thoughts and Behaviors in Adolescents and Young Adults Patients with major depressive disorder (MDD), both adult and pediatric, may experience worsening of their depression and/or the emergence of suicidal ideation and behavior (suicidality) or unusual changes in behavior, whether or not they are taking antidepressant medications, and this risk may persist until significant remission occurs.

Suicide is a known risk of depression and certain other psychiatric disorders, and these disorders themselves are the strongest predictors of suicide.

There has been a long-standing concern, however, that antidepressants may have a role in inducing worsening of depression and the emergence of suicidality in certain patients during the early phases of treatment.

Pooled analyses of short-term placebo-controlled trials of antidepressant drugs (SSRIs and others) showed that these drugs increase the risk of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults (ages 18-24) with major depressive disorder (MDD) and other psychiatric disorders.

Short-term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults beyond age 24; there was a reduction with antidepressants compared to placebo in adults aged 65 and older.

The pooled analyses of placebo-controlled trials in children and adolescents with MDD, obsessive-compulsive disorder (OCD), or other psychiatric disorders included a total of 24 short-term trials of 9 antidepressant drugs in over 4400 patients.

The pooled analyses of placebo-controlled trials in adults with MDD or other psychiatric disorders included a total of 295 short-term trials (median duration of 2 months) of 11 antidepressant drugs in over 77,000 patients.

There was considerable variation in risk of suicidality among drugs, but a tendency toward an increase in the younger patients for almost all drugs studied.

There were differences in absolute risk of suicidality across the different indications, with the highest incidence in MDD.

The risk differences (drug vs.

placebo), however, were relatively stable within age strata and across indications.

These risk differences (drug-placebo difference in the number of cases of suicidality per 1000 patients treated) are provided in Table 2.

Table 2: Drug-Placebo Difference in Number of Cases of Suicidality per 1000 Patients Treated Age Range Drug-Placebo Difference in Number of Cases of Suicidality per 1000 Patients Treated Increases Compared to Placebo <18 14 additional cases 18-24 5 additional cases Decreases Compared to Placebo 25-64 1 fewer case ≥65 6 fewer cases No suicides occurred in any of the pediatric trials.

There were suicides in the adult trials, but the number was not sufficient to reach any conclusion about drug effect on suicide.

It is unknown whether the suicidality risk extends to longer-term use, i.e., beyond several months.

However, there is substantial evidence from placebo-controlled maintenance trials in adults with depression that the use of antidepressants can delay the recurrence of depression.

All patients being treated with antidepressants for any indication should be monitored appropriately and observed closely for clinical worsening, suicidality, and unusual changes in behavior, especially during the initial few months of a course of drug therapy, or at times of dose changes, either increases or decreases.

The following symptoms, anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, and mania, have been reported in adult and pediatric patients being treated with antidepressants for major depressive disorder as well as for other indications, both psychiatric and non-psychiatric.

Although a causal link between the emergence of such symptoms and either the worsening of depression and/or the emergence of suicidal impulses has not been established, there is concern that such symptoms may represent precursors to emerging suicidality.

Consideration should be given to changing the therapeutic regimen, including possibly discontinuing the medication, in patients whose depression is persistently worse, or who are experiencing emergent suicidality or symptoms that might be precursors to worsening depression or suicidality, especially if these symptoms are severe, abrupt in onset, or were not part of the patient’s presenting symptoms.

Families and caregivers of patients being treated with antidepressants for major depressive disorder or other indications, both psychiatric and non-psychiatric, should be alerted about the need to monitor patients for the emergence of agitation, irritability, unusual changes in behavior, and the other symptoms described above, as well as the emergence of suicidality, and to report such symptoms immediately to healthcare providers.

Such monitoring should include daily observation by families and caregivers.

Prescriptions for SEROQUEL should be written for the smallest quantity of tablets consistent with good patient management, in order to reduce the risk of overdose.

Screening Patients for Bipolar Disorder: A major depressive episode may be the initial presentation of bipolar disorder.

It is generally believed (though not established in controlled trials) that treating such an episode with an antidepressant alone may increase the likelihood of precipitation of a mixed/manic episode in patients at risk for bipolar disorder.

Whether any of the symptoms described above represent such a conversion is unknown.

However, prior to initiating treatment with an antidepressant, including SEROQUEL, patients with depressive symptoms should be adequately screened to determine if they are at risk for bipolar disorder; such screening should include a detailed psychiatric history, including a family history of suicide, bipolar disorder, and depression.

5.3 Cerebrovascular Adverse Reactions, Including Stroke, in Elderly Patients with Dementia-Related Psychosis In placebo-controlled trials with risperidone, aripiprazole, and olanzapine in elderly subjects with dementia, there was a higher incidence of cerebrovascular adverse reactions (cerebrovascular accidents and transient ischemic attacks) including fatalities compared to placebo-treated subjects.

SEROQUEL is not approved for the treatment of patients with dementia-related psychosis [see also Boxed Warning and Warnings and Precautions (5.1) ].

5.4 Neuroleptic Malignant Syndrome (NMS) A potentially fatal symptom complex sometimes referred to as Neuroleptic Malignant Syndrome (NMS) has been reported in association with administration of antipsychotic drugs, including SEROQUEL.

Rare cases of NMS have been reported with SEROQUEL.

Clinical manifestations of NMS are hyperpyrexia, muscle rigidity, altered mental status, and evidence of autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis, and cardiac dysrhythmia).

Additional signs may include elevated creatinine phosphokinase, myoglobinuria (rhabdomyolysis) and acute renal failure.

The diagnostic evaluation of patients with this syndrome is complicated.

In arriving at a diagnosis, it is important to exclude cases where the clinical presentation includes both serious medical illness (e.g., pneumonia, systemic infection, etc.) and untreated or inadequately treated extrapyramidal signs and symptoms (EPS).

Other important considerations in the differential diagnosis include central anticholinergic toxicity, heat stroke, drug fever, and primary central nervous system (CNS) pathology.

The management of NMS should include: 1) immediate discontinuation of antipsychotic drugs and other drugs not essential to concurrent therapy; 2) intensive symptomatic treatment and medical monitoring; and 3) treatment of any concomitant serious medical problems for which specific treatments are available.

There is no general agreement about specific pharmacological treatment regimens for NMS.

If a patient requires antipsychotic drug treatment after recovery from NMS, the potential reintroduction of drug therapy should be carefully considered.

The patient should be carefully monitored since recurrences of NMS have been reported.

5.5 Metabolic Changes Atypical antipsychotic drugs have been associated with metabolic changes that include hyperglycemia/diabetes mellitus, dyslipidemia, and body weight gain.

While all of the drugs in the class have been shown to produce some metabolic changes, each drug has its own specific risk profile.

In some patients, a worsening of more than one of the metabolic parameters of weight, blood glucose, and lipids was observed in clinical studies.

Changes in these metabolic profiles should be managed as clinically appropriate.

Hyperglycemia and Diabetes Mellitus Hyperglycemia, in some cases extreme and associated with ketoacidosis or hyperosmolar coma or death, has been reported in patients treated with atypical antipsychotics, including quetiapine.

Assessment of the relationship between atypical antipsychotic use and glucose abnormalities is complicated by the possibility of an increased background risk of diabetes mellitus in patients with schizophrenia and the increasing incidence of diabetes mellitus in the general population.

Given these confounders, the relationship between atypical antipsychotic use and hyperglycemia-related adverse reactions is not completely understood.

However, epidemiological studies suggest an increased risk of hyperglycemia-related adverse reactions in patients treated with the atypical antipsychotics.

Precise risk estimates for hyperglycemia-related adverse reactions in patients treated with atypical antipsychotics are not available.

Patients with an established diagnosis of diabetes mellitus who are started on atypical antipsychotics should be monitored regularly for worsening of glucose control.

Patients with risk factors for diabetes mellitus (e.g., obesity, family history of diabetes) who are starting treatment with atypical antipsychotics should undergo fasting blood glucose testing at the beginning of treatment and periodically during treatment.

Any patient treated with atypical antipsychotics should be monitored for symptoms of hyperglycemia including polydipsia, polyuria, polyphagia, and weakness.

Patients who develop symptoms of hyperglycemia during treatment with atypical antipsychotics should undergo fasting blood glucose testing.

In some cases, hyperglycemia has resolved when the atypical antipsychotic was discontinued; however, some patients required continuation of anti-diabetic treatment despite discontinuation of the suspect drug.

Adults: Table 3: Fasting Glucose – Proportion of Patients Shifting to ≥126 mg/dL in Short-Term (≤12 weeks) Placebo-Controlled Studies Includes SEROQUEL and SEROQUEL XR data.

Laboratory Analyte Category Change (At Least Once) from Baseline Treatment Arm N Patients n (%) Fasting Glucose Normal to High (<100 mg/dL to ≥126 mg/dL) Quetiapine 2907 71 (2.4%) Placebo 1346 19 (1.4%) Borderline to High (≥100 mg/dL and <126 mg/dL to ≥126 mg/dL) Quetiapine 572 67 (11.7%) Placebo 279 33 (11.8%) In a 24-week trial (active-controlled, 115 patients treated with SEROQUEL) designed to evaluate glycemic status with oral glucose tolerance testing of all patients, at Week 24 the incidence of a post-glucose challenge glucose level ≥200 mg/dL was 1.7% and the incidence of a fasting blood glucose level ≥126 mg/dL was 2.6%.

The mean change in fasting glucose from baseline was 3.2 mg/dL and mean change in 2-hour glucose from baseline was -1.8 mg/dL for quetiapine.

In 2 long-term placebo-controlled randomized withdrawal clinical trials for bipolar I disorder maintenance, mean exposure of 213 days for SEROQUEL (646 patients) and 152 days for placebo (680 patients), the mean change in glucose from baseline was +5.0 mg/dL for SEROQUEL and –0.05 mg/dL for placebo.

The exposure-adjusted rate of any increased blood glucose level (≥126 mg/dL) for patients more than 8 hours since a meal (however, some patients may not have been precluded from calorie intake from fluids during fasting period) was 18.0 per 100 patient years for SEROQUEL (10.7% of patients; n=556) and 9.5 for placebo per 100 patient years (4.6% of patients; n=581).

Children and Adolescents: In a placebo-controlled SEROQUEL monotherapy study of adolescent patients (13–17 years of age) with schizophrenia (6 weeks duration), the mean change in fasting glucose levels for SEROQUEL (n=138) compared to placebo (n=67) was –0.75 mg/dL versus –1.70 mg/dL.

In a placebo-controlled SEROQUEL monotherapy study of children and adolescent patients (10–17 years of age) with bipolar mania (3 weeks duration), the mean change in fasting glucose level for SEROQUEL (n=170) compared to placebo (n=81) was 3.62 mg/dL versus –1.17 mg/dL.

No patient in either study with a baseline normal fasting glucose level (<100 mg/dL) or a baseline borderline fasting glucose level (≥100 mg/dL and <126 mg/dL) had a blood glucose level of ≥126 mg/dL.

In a placebo-controlled SEROQUEL XR monotherapy study (8 weeks duration) of children and adolescent patients (10-17 years of age) with bipolar depression, in which efficacy was not established, the mean change in fasting glucose levels for SEROQUEL XR (n=60) compared to placebo (n=62) was 1.8 mg/dL versus 1.6 mg/dL.

In this study, there were no patients in the SEROQUEL XR or placebo-treated groups with a baseline normal fasting glucose level (126 mg/dL.

There was one patient in the SEROQUEL XR group with a baseline borderline fasting glucose level (>100 mg/dL and 126 mg/dL compared to zero patients in the placebo group.

Dyslipidemia Adults: Table 4 shows the percentage of adult patients with changes in total cholesterol, triglycerides, LDL-cholesterol, and HDL-cholesterol from baseline by indication in clinical trials with SEROQUEL.

Table 4: Percentage of Adult Patients with Shifts in Total Cholesterol, Triglycerides, LDL-Cholesterol, and HDL-Cholesterol from Baseline to Clinically Significant Levels by Indication Laboratory Analyte Indication Treatment Arm N Patients n (%) Total Cholesterol ≥240 mg/dL Schizophrenia 6 weeks duration SEROQUEL 137 24 (18%) Placebo 92 6 (7%) Bipolar Depression 8 weeks duration SEROQUEL 463 41 (9%) Placebo 250 15 (6%) Triglycerides ≥200 mg/dL Schizophrenia SEROQUEL 120 26 (22%) Placebo 70 11 (16%) Bipolar Depression SEROQUEL 436 59 (14%) Placebo 232 20 (9%) LDL- Cholesterol ≥160 mg/dL Schizophrenia SEROQUEL na Parameters not measured in the SEROQUEL registration studies for schizophrenia.

na Placebo na na Bipolar Depression SEROQUEL 465 29 (6%) Placebo 256 12 (5%) HDL- Cholesterol ≤40 mg/dL Schizophrenia SEROQUEL na na Placebo na na Bipolar Depression SEROQUEL 393 56 (14%) Placebo 214 29 (14%) Children and Adolescents: Table 5 shows the percentage of children and adolescents with changes in total cholesterol, triglycerides, LDL-cholesterol, and HDL-cholesterol from baseline in clinical trials with SEROQUEL.

Table 5: Percentage of Children and Adolescents with Shifts in Total Cholesterol, Triglycerides, LDL-Cholesterol, and HDL-Cholesterol from Baseline to Clinically Significant Levels Laboratory Analyte Indication Treatment Arm N Patients n (%) Total Cholesterol ≥200 mg/dL Schizophrenia 13-17 years, 6 weeks duration SEROQUEL 107 13 (12%) Placebo 56 1 (2%) Bipolar Mania 10-17 years, 3 weeks duration SEROQUEL 159 16 (10%) Placebo 66 2 (3%) Triglycerides ≥150 mg/dL Schizophrenia SEROQUEL 103 17 (17%) Placebo 51 4 (8%) Bipolar Mania SEROQUEL 149 32 (22%) Placebo 60 8 (13%) LDL-Cholesterol ≥130 mg/dL Schizophrenia SEROQUEL 112 4 (4%) Placebo 60 1 (2%) Bipolar Mania SEROQUEL 169 13 (8%) Placebo 74 4 (5%) HDL-Cholesterol ≤40 mg/dL Schizophrenia SEROQUEL 104 16 (15%) Placebo 54 10 (19%) Bipolar Mania SEROQUEL 154 16 (10%) Placebo 61 4 (7%) In a placebo-controlled SEROQUEL XR monotherapy study (8 weeks duration) of children and adolescent patients (10 to 17 years of age) with bipolar depression, in which efficacy was not established, the percentage of children and adolescents with shifts in total cholesterol (≥200 mg/dL), triglycerides (≥150 mg/dL), LDL-cholesterol (≥ 130 mg/dL), and HDL-cholesterol (≤40 mg/dL) from baseline to clinically significant levels were: total cholesterol 8% (7/83) for SEROQUEL XR vs.

6% (5/84) for placebo; triglycerides 28% (22/80) for SEROQUEL XR vs.

9% (7/82) for placebo; LDL-cholesterol 2% (2/86) for SEROQUEL XR vs.

4% (3/85) for placebo and HDL-cholesterol 20% (13/65) for SEROQUEL XR vs.

15% (11/74) for placebo.

Weight Gain Increases in weight have been observed in clinical trials.

Patients receiving quetiapine should receive regular monitoring of weight.

Adults : In clinical trials with SEROQUEL the following increases in weight have been reported.

Table 6: Proportion of Patients with Weight Gain ≥7% of Body Weight (Adults) Vital Sign Indication Treatment Arm N Patients n (%) Weight Gain ≥7% of Body Weight Schizophrenia up to 6 weeks duration SEROQUEL 391 89 (23%) Placebo 206 11 (6%) Bipolar Mania (monotherapy) up to 12 weeks duration SEROQUEL 209 44 (21%) Placebo 198 13 (7%) Bipolar Mania (adjunct therapy) up to 3 weeks duration SEROQUEL 196 25 (13%) Placebo 203 8 (4%) Bipolar Depression up to 8 weeks duration SEROQUEL 554 47 (8%) Placebo 295 7 (2%) Children and Adolescents: In two clinical trials with SEROQUEL, one in bipolar mania and one in schizophrenia, reported increases in weight are included in Table 7.

Table 7: Proportion of Patients with Weight Gain ≥7% of Body Weight (Children and Adolescents) Vital Sign Indication Treatment Arm N Patients n (%) Weight Gain ≥7% of Body Weight Schizophrenia 6 weeks duration SEROQUEL 111 23 (21%) Placebo 44 3 (7%) Bipolar Mania 3 weeks duration SEROQUEL 157 18 (12%) Placebo 68 0 (0%) The mean change in body weight in the schizophrenia trial was 2.0 kg in the SEROQUEL group and -0.4 kg in the placebo group and in the bipolar mania trial, it was 1.7 kg in the SEROQUEL group and 0.4 kg in the placebo group.

In an open-label study that enrolled patients from the above two pediatric trials, 63% of patients (241/380) completed 26 weeks of therapy with SEROQUEL.

After 26 weeks of treatment, the mean increase in body weight was 4.4 kg.

Forty-five percent of the patients gained ≥7% of their body weight, not adjusted for normal growth.

In order to adjust for normal growth over 26 weeks, an increase of at least 0.5 standard deviation from baseline in BMI was used as a measure of a clinically significant change; 18.3% of patients on SEROQUEL met this criterion after 26 weeks of treatment.

In a clinical trial for SEROQUEL XR in children and adolescents (10-17 years of age) with bipolar depression, in which efficacy was not established, the percentage of patients with weight gain ≥7% of body weight at any time was 15% (14/92) for SEROQUEL XR vs.

10% (10/100) for placebo.

The mean change in body weight was 1.4 kg in the SEROQUEL XR group vs.

0.6 kg in the placebo group.

When treating pediatric patients with SEROQUEL for any indication, weight gain should be assessed against that expected for normal growth.

5.6 Tardive Dyskinesia A syndrome of potentially irreversible, involuntary, dyskinetic movements may develop in patients treated with antipsychotic drugs, including quetiapine.

Although the prevalence of the syndrome appears to be highest among the elderly, especially elderly women, it is impossible to rely upon prevalence estimates to predict, at the inception of antipsychotic treatment, which patients are likely to develop the syndrome.

Whether antipsychotic drug products differ in their potential to cause tardive dyskinesia is unknown.

The risk of developing tardive dyskinesia and the likelihood that it will become irreversible are believed to increase as the duration of treatment and the total cumulative dose of antipsychotic drugs administered to the patient increase.

However, the syndrome can develop, although much less commonly, after relatively brief treatment periods at low doses or may even arise after discontinuation of treatment.

Tardive dyskinesia may remit, partially or completely, if antipsychotic treatment is withdrawn.

Antipsychotic treatment, itself, however, may suppress (or partially suppress) the signs and symptoms of the syndrome and thereby may possibly mask the underlying process.

The effect that symptomatic suppression has upon the long-term course of the syndrome is unknown.

Given these considerations, SEROQUEL should be prescribed in a manner that is most likely to minimize the occurrence of tardive dyskinesia.

Chronic antipsychotic treatment should generally be reserved for patients who appear to suffer from a chronic illness that (1) is known to respond to antipsychotic drugs, and (2) for whom alternative, equally effective, but potentially less harmful treatments are not available or appropriate.

In patients who do require chronic treatment, the smallest dose and the shortest duration of treatment producing a satisfactory clinical response should be sought.

The need for continued treatment should be reassessed periodically.

If signs and symptoms of tardive dyskinesia appear in a patient on SEROQUEL, drug discontinuation should be considered.

However, some patients may require treatment with SEROQUEL despite the presence of the syndrome.

5.7 Hypotension Quetiapine may induce orthostatic hypotension associated with dizziness, tachycardia and, in some patients, syncope, especially during the initial dose-titration period, probably reflecting its α 1 -adrenergic antagonist properties.

Syncope was reported in 1% (28/3265) of the patients treated with SEROQUEL, compared with 0.2% (2/954) on placebo and about 0.4% (2/527) on active control drugs.

Orthostatic hypotension, dizziness, and syncope may lead to falls.

SEROQUEL should be used with particular caution in patients with known cardiovascular disease (history of myocardial infarction or ischemic heart disease, heart failure, or conduction abnormalities), cerebrovascular disease or conditions which would predispose patients to hypotension (dehydration, hypovolemia, and treatment with antihypertensive medications).

The risk of orthostatic hypotension and syncope may be minimized by limiting the initial dose to 25 mg twice daily [see Dosage and Administration (2.2) ].

If hypotension occurs during titration to the target dose, a return to the previous dose in the titration schedule is appropriate.

5.8 Falls Atypical antipsychotic drugs, including SEROQUEL, may cause somnolence, postural hypotension, motor, and sensory instability, which may lead to falls and, consequently, fractures or other injuries.

For patients with diseases, conditions, or medications that could exacerbate these effects, complete fall risk assessments when initiating antipsychotic treatment and recurrently for patients on long-term antipsychotic therapy.

5.9 Increases in Blood Pressure (Children and Adolescents) In placebo-controlled trials in children and adolescents with schizophrenia (6-week duration) or bipolar mania (3-week duration), the incidence of increases at any time in systolic blood pressure (≥20 mmHg) was 15.2% (51/335) for SEROQUEL and 5.5% (9/163) for placebo; the incidence of increases at any time in diastolic blood pressure (≥10 mmHg) was 40.6% (136/335) for SEROQUEL and 24.5% (40/163) for placebo.

In the 26-week open-label clinical trial, one child with a reported history of hypertension experienced a hypertensive crisis.

Blood pressure in children and adolescents should be measured at the beginning of, and periodically during treatment.

In a placebo-controlled SEROQUEL XR clinical trial (8 weeks duration) in children and adolescents (10-17 years of age) with bipolar depression, in which efficacy was not established, the incidence of increases at any time in systolic blood pressure (≥20 mmHg) was 6.5% (6/92) for SEROQUEL XR and 6.0% (6/100) for placebo; the incidence of increases at any time in diastolic blood pressure (≥10 mmHg) was 46.7% (43/92) for SEROQUEL XR and 36.0% (36/100) for placebo.

5.10 Leukopenia, Neutropenia, and Agranulocytosis In clinical trial and postmarketing experience, events of leukopenia/neutropenia have been reported temporally related to atypical antipsychotic agents, including SEROQUEL.

Agranulocytosis has been reported.

Agranulocytosis (defined as absolute neutrophil count <500/mm3) has been reported with quetiapine, including fatal cases and cases in patients without pre-existing risk factors.

Neutropenia should be considered in patients presenting with infection, particularly in the absence of obvious predisposing factor(s), or in patients with unexplained fever, and should be managed as clinically appropriate.

Possible risk factors for leukopenia/neutropenia include pre-existing low white cell count (WBC) and history of drug induced leukopenia/neutropenia.

Patients with a pre-existing low WBC or a history of drug induced leukopenia/neutropenia should have their complete blood count (CBC) monitored frequently during the first few months of therapy and should discontinue SEROQUEL at the first sign of a decline in WBC in absence of other causative factors.

Patients with neutropenia should be carefully monitored for fever or other symptoms or signs of infection and treated promptly if such symptoms or signs occur.

Patients with severe neutropenia (absolute neutrophil count <1000/mm3) should discontinue SEROQUEL and have their WBC followed until recovery.

5.11 Cataracts The development of cataracts was observed in association with quetiapine treatment in chronic dog studies [see Nonclinical Toxicology (13.2) ] .

Lens changes have also been observed in adults, children, and adolescents during long-term SEROQUEL treatment, but a causal relationship to SEROQUEL use has not been established.

Nevertheless, the possibility of lenticular changes cannot be excluded at this time.

Therefore, examination of the lens by methods adequate to detect cataract formation, such as slit lamp exam or other appropriately sensitive methods, is recommended at initiation of treatment or shortly thereafter, and at 6-month intervals during chronic treatment.

5.12 QT Prolongation In clinical trials, quetiapine was not associated with a persistent increase in QT intervals.

However, the QT effect was not systematically evaluated in a thorough QT study.

In post marketing experience, there were cases reported of QT prolongation in patients who overdosed on quetiapine [see Overdosage (10.1) ], in patients with concomitant illness, and in patients taking medicines known to cause electrolyte imbalance or increase QT interval [see Drug Interactions (7.1) ] .

The use of quetiapine should be avoided in combination with other drugs that are known to prolong QTc including Class 1A antiarrythmics (e.g., quinidine, procainamide) or Class III antiarrythmics (e.g., amiodarone, sotalol), antipsychotic medications (e.g., ziprasidone, chlorpromazine, thioridazine), antibiotics (e.g., gatifloxacin, moxifloxacin), or any other class of medications known to prolong the QTc interval (e.g., pentamidine, levomethadyl acetate, methadone).

Quetiapine should also be avoided in circumstances that may increase the risk of occurrence of torsade de pointes and/or sudden death including (1) a history of cardiac arrhythmias such as bradycardia; (2) hypokalemia or hypomagnesemia; (3) concomitant use of other drugs that prolong the QTc interval; and (4) presence of congenital prolongation of the QT interval.

Caution should also be exercised when quetiapine is prescribed in patients with increased risk of QT prolongation (e.g., cardiovascular disease, family history of QT prolongation, the elderly, congestive heart failure, and heart hypertrophy).

5.13 Seizures During clinical trials, seizures occurred in 0.5% (20/3490) of patients treated with SEROQUEL compared to 0.2% (2/954) on placebo and 0.7% (4/527) on active control drugs.

As with other antipsychotics, SEROQUEL should be used cautiously in patients with a history of seizures or with conditions that potentially lower the seizure threshold, e.g., Alzheimer’s dementia.

Conditions that lower the seizure threshold may be more prevalent in a population of 65 years or older.

5.14 Hypothyroidism Adults: Clinical trials with quetiapine demonstrated dose-related decreases in thyroid hormone levels.

The reduction in total and free thyroxine (T 4 ) of approximately 20% at the higher end of the therapeutic dose range was maximal in the first six weeks of treatment and maintained without adaptation or progression during more chronic therapy.

In nearly all cases, cessation of quetiapine treatment was associated with a reversal of the effects on total and free T 4 , irrespective of the duration of treatment.

The mechanism by which quetiapine effects the thyroid axis is unclear.

If there is an effect on the hypothalamic-pituitary axis, measurement of TSH alone may not accurately reflect a patient’s thyroid status.

Therefore, both TSH and free T 4 , in addition to clinical assessment, should be measured at baseline and at follow-up.

In the mania adjunct studies, where SEROQUEL was added to lithium or divalproex, 12% (24/196) of SEROQUEL treated patients compared to 7% (15/203) of placebo-treated patients had elevated TSH levels.

Of the SEROQUEL treated patients with elevated TSH levels, 3 had simultaneous low free T 4 levels (free T 4 <0.8 LLN).

About 0.7% (26/3489) of SEROQUEL patients did experience TSH increases in monotherapy studies.

Some patients with TSH increases needed replacement thyroid treatment.

In all quetiapine trials, the incidence of shifts in thyroid hormones and TSH were 1 : decrease in free T 4 (<0.8 LLN), 2.0% (357/17513); decrease in total T 4 (<0.8LLN), 4.0% (75/1861); decrease in free T 3 (<0.8 LLN), 0.4% (53/13766); decrease in total T 3 (5mIU/L), 4.9% (956/19412).

In eight patients, where TBG was measured, levels of TBG were unchanged.

Table 8 shows the incidence of these shifts in short-term placebo-controlled clinical trials.

____________ 1 Based on shifts from normal baseline to potentially clinically important value at anytime post-baseline.

Shifts in total T4, free T4, total T3 and free T3 are defined as 5 mlU/L at any time.

Table 8: Incidence of Shifts in Thyroid Hormone Levels and TSH in Short-Term Placebo-Controlled Clinical Trials Based on shifts from normal baseline to potentially clinically important value at any time post-baseline.

Shifts in total T 4 , free T 4 , total T 3 , and free T 3 are defined as 5 mlU/L at any time.

Includes SEROQUEL and SEROQUEL XR data.

Total T 4 Free T 4 Total T 3 Free T 3 TSH Quetiapine Placebo Quetiapine Placebo Quetiapine Placebo Quetiapine Placebo Quetiapine Placebo 3.4 % (37/1097) 0.6% (4/651) 0.7% (52/7218) 0.1% (4/3668) 0.5% (2/369) 0.0% (0/113) 0.2% (11/5673) 0.0% (1/2679) 3.2% (240/7587) 2.7% (105/3912) In short-term placebo-controlled monotherapy trials, the incidence of reciprocal, shifts in T 3 and TSH was 0.0 % for both quetiapine (1/4800) and placebo (0/2190) and for T 4 and TSH the shifts were 0.1% (7/6154) for quetiapine versus 0.0% (1/3007) for placebo.

Children and Adolescents: In acute placebo-controlled trials in children and adolescent patients with schizophrenia (6-week duration) or bipolar mania (3-week duration), the incidence of shifts for thyroid function values at any time for SEROQUEL treated patients and placebo-treated patients for elevated TSH was 2.9% (8/280) vs.

0.7% (1/138), respectively, and for decreased total thyroxine was 2.8% (8/289) vs.

0% (0/145), respectively.

Of the SEROQUEL treated patients with elevated TSH levels, 1 had simultaneous low free T 4 level at end of treatment.

5.15 Hyperprolactinemia Adults : During clinical trials with quetiapine, the incidence of shifts in prolactin levels to a clinically significant value occurred in 3.6% (158/4416) of patients treated with quetiapine compared to 2.6% (51/1968) on placebo.

Children and Adolescents: In acute placebo-controlled trials in children and adolescent patients with bipolar mania (3-week duration) or schizophrenia (6-week duration), the incidence of shifts in prolactin levels to a value (>20 µg/L males; >26 µg/L females at any time) was 13.4% (18/134) for SEROQUEL compared to 4% (3/75) for placebo in males and 8.7% (9/104) for SEROQUEL compared to 0% (0/39) for placebo in females.

Like other drugs that antagonize dopamine D 2 receptors, SEROQUEL elevates prolactin levels in some patients and the elevation may persist during chronic administration.

Hyperprolactinemia, regardless of etiology, may suppress hypothalamic GnRH, resulting in reduced pituitary gonadotrophin secretion.

This, in turn, may inhibit reproductive function by impairing gonadal steroidogenesis in both female and male patients.

Galactorrhea, amenorrhea, gynecomastia, and impotence have been reported in patients receiving prolactin-elevating compounds.

Long-standing hyperprolactinemia when associated with hypogonadism may lead to decreased bone density in both female and male subjects.

Tissue culture experiments indicate that approximately one-third of human breast cancers are prolactin dependent in vitro , a factor of potential importance if the prescription of these drugs is considered in a patient with previously detected breast cancer.

As is common with compounds which increase prolactin release, mammary gland, and pancreatic islet cell neoplasia (mammary adenocarcinomas, pituitary, and pancreatic adenomas) was observed in carcinogenicity studies conducted in mice and rats.

Neither clinical studies nor epidemiologic studies conducted to date have shown an association between chronic administration of this class of drugs and tumorigenesis in humans, but the available evidence is too limited to be conclusive [see Nonclinical Toxicology (13.1) ].

5.16 Potential for Cognitive and Motor Impairment Somnolence was a commonly reported adverse event reported in patients treated with SEROQUEL especially during the 3-5 day period of initial dose-titration.

In schizophrenia trials, somnolence was reported in 18% (89/510) of patients on SEROQUEL compared to 11% (22/206) of placebo patients.

In acute bipolar mania trials using SEROQUEL as monotherapy, somnolence was reported in 16% (34/209) of patients on SEROQUEL compared to 4% of placebo patients.

In acute bipolar mania trials using SEROQUEL as adjunct therapy, somnolence was reported in 34% (66/196) of patients on SEROQUEL compared to 9% (19/203) of placebo patients.

In bipolar depression trials, somnolence was reported in 57% (398/698) of patients on SEROQUEL compared to 15% (51/347) of placebo patients.

Since SEROQUEL has the potential to impair judgment, thinking, or motor skills, patients should be cautioned about performing activities requiring mental alertness, such as operating a motor vehicle (including automobiles) or operating hazardous machinery until they are reasonably certain that SEROQUEL therapy does not affect them adversely.

Somnolence may lead to falls.

5.17 Body Temperature Regulation Although not reported with SEROQUEL, disruption of the body’s ability to reduce core body temperature has been attributed to antipsychotic agents.

Appropriate care is advised when prescribing SEROQUEL for patients who will be experiencing conditions which may contribute to an elevation in core body temperature, e.g., exercising strenuously, exposure to extreme heat, receiving concomitant medication with anticholinergic activity, or being subject to dehydration.

5.18 Dysphagia Esophageal dysmotility and aspiration have been associated with antipsychotic drug use.

Aspiration pneumonia is a common cause of morbidity and mortality in elderly patients, in particular those with advanced Alzheimer’s dementia.

SEROQUEL and other antipsychotic drugs should be used cautiously in patients at risk for aspiration pneumonia.

5.19 Discontinuation Syndrome Acute withdrawal symptoms, such as insomnia, nausea, and vomiting have been described after abrupt cessation of atypical antipsychotic drugs, including SEROQUEL.

In short-term placebo-controlled, monotherapy clinical trials with SEROQUEL XR that included a discontinuation phase which evaluated discontinuation symptoms, the aggregated incidence of patients experiencing one or more discontinuation symptoms after abrupt cessation was 12.1% (241/1993) for SEROQUEL XR and 6.7% (71/1065) for placebo.

The incidence of the individual adverse reactions (i.e., insomnia, nausea, headache, diarrhea, vomiting, dizziness, and irritability) did not exceed 5.3% in any treatment group and usually resolved after 1 week post-discontinuation.

Gradual withdrawal is advised [see Use in Specific Populations (8.1) ] .

5.20 Anticholinergic (antimuscarinic) Effects Norquetiapine, an active metabolite of quetiapine, has moderate to strong affinity for several muscarinic receptor subtypes.

This contributes to anticholinergic adverse reactions when SEROQUEL is used at therapeutic doses, taken concomitantly with other anticholinergic medications, or taken in overdose.

SEROQUEL should be used with caution in patients receiving medications having anticholinergic (antimuscarinic) effects [see Drug Interactions (7.1) , Overdosage (10.1) , and Clinical Pharmacology (12.1) ] .

Constipation was a commonly reported adverse event in patients treated with quetiapine and represents a risk factor for intestinal obstruction.

Intestinal obstruction has been reported with quetiapine, including fatal reports in patients who were receiving multiple concomitant medications that decrease intestinal motility.

SEROQUEL should be used with caution in patients with a current diagnosis or prior history of urinary retention, clinically significant prostatic hypertrophy, or constipation.

WARNING AND CAUTIONS

5 WARNINGS AND PRECAUTIONS May cause new or worsened arrhythmias.

Evaluate patients via ECG prior to and during therapy.

( 5.1 ) Propafenone hydrochloride may unmask Brugada or Brugada-like Syndrome.

( 4 , 5.2 ) Avoid use with other drugs that prolong the QT interval.

( 5.3 ) Avoid simultaneous use of propafenone with both a cytochrome P450 2D6 inhibitor and a 3A4 inhibitor.

( 5.4 ) May provoke overt heart failure.

( 5.5 ) May cause dose-related first degree AV block or other conduction disturbances.

Only use in patients with conduction disorders who have pacemakers.

( 5.6 ) May affect artificial pacemakers.

Monitor pacemaker function.

( 5.7 ) Agranulocytosis: Patients should report signs of infection.

( 5.8 ) May exacerbate myasthenia gravis.

( 5.11 ) 5.1 Proarrhythmic Effects Propafenone has caused new or worsened arrhythmias.

Such proarrhythmic effects include sudden death and life-threatening ventricular arrhythmias such as ventricular fibrillation, ventricular tachycardia, asystole and torsade de pointes.

It may also worsen premature ventricular contractions or supraventricular arrhythmias, and it may prolong the QT interval.

It is therefore essential that each patient given propafenone hydrochloride be evaluated electrocardiographically prior to and during therapy to determine whether the response to propafenone hydrochloride supports continued treatment.

Because propafenone prolongs the QRS interval in the electrocardiogram, changes in the QT interval are difficult to interpret [see Clinical Pharmacology (12.2) ].

In a U.S.

uncontrolled, open label, multicenter trial in patients with symptomatic supraventricular tachycardia (SVT), 1.9% (9/474) of these patients experienced ventricular tachycardia (VT) or ventricular fibrillation (VF) during the study.

However, in 4 of the 9 patients, the ventricular tachycardia was of atrial origin.

Six of the nine patients that developed ventricular arrhythmias did so within 14 days of onset of therapy.

About 2.3% (11/474) of all patients had a recurrence of SVT during the study which could have been a change in the patients’ arrhythmia behavior or could represent a proarrhythmic event.

Case reports in patients treated with propafenone for atrial fibrillation/flutter have included increased premature ventricular contractions (PVCs), VT, VF, torsade de pointes, asystole, and death.

Overall in clinical trials with propafenone hydrochloride (which included patients treated for ventricular arrhythmias, atrial fibrillation/flutter, and PSVT), 4.7% of all patients had new or worsened ventricular arrhythmia possibly representing a proarrhythmic event (0.7% was an increase in PVCs; 4.0% a worsening, or new appearance, of VT or VF).

Of the patients who had worsening of VT (4%), 92% had a history of VT and/or VT/VF, 71% had coronary artery disease, and 68% had a prior myocardial infarction.

The incidence of proarrhythmia in patients with less serious or benign arrhythmias, which include patients with an increase in frequency of PVCs, was 1.6%.

Although most proarrhythmic events occurred during the first week of therapy, late events also were seen and the CAST study [see Boxed Warning: Mortality ] suggests that an increased risk of proarrythmia is present throughout treatment.

In a study of sustained-release propafenone, there were too few deaths to assess the long term risk to patients.

There were 5 deaths, 3 in the pooled sustained-release propafenone group (0.8%) and 2 in the placebo group (1.6%).

In the overall sustained-release propafenone and propafenone hydrochloride immediate-release database of 8 studies, the mortality rate was 2.5% per year on propafenone and 4.0% per year on placebo.

Concurrent use of propafenone with other antiarrhythmic agents has not been well studied.

5.2 Unmasking Brugada Syndrome Brugada Syndrome may be unmasked after exposure to propafenone hydrochloride.

Perform an ECG after initiation of propafenone hydrochloride, and discontinue the drug if changes are suggestive of Brugada Syndrome [see Contraindications (4) ] .

5.3 Use with Drugs that Prolong the QT Interval and Antiarrhythmic Agents The use of propafenone hydrochloride in conjunction with other drugs that prolong the QT interval has not been extensively studied.

Such drugs may include many antiarrhythmics, some phenothiazines, tricyclic antidepressants, and oral macrolides.

Withhold Class IA and III antiarrhythmic agents for at least 5 half-lives prior to dosing with propafenone hydrochloride.

Avoid the use of propafenone with Class IA and III antiarrhythmic agents (including quinidine and amiodarone).

There is only limited experience with the concomitant use of Class IB or IC antiarrhythmics.

5.4 Drug Interactions: Simultaneous Use with Inhibitors of Cytochrome P450 Isoenzymes 2D6 and 3A4 Propafenone is metabolized by CYP2D6, CYP3A4, and CYP1A2 isoenzymes.

Approximately 6% of Caucasians in the U.S.

population are naturally deficient in CYP2D6 activity and to a somewhat lesser extent in other demographic groups.

Drugs that inhibit these CYP pathways (such as desipramine, paroxetine, ritonavir, sertraline for CYP2D6; ketoconazole, erythromycin, saquinavir, and grapefruit juice for CYP3A4; and amiodarone and tobacco smoke for CYP1A2) can be expected to cause increased plasma levels of propafenone.

Increased exposure to propafenone may lead to cardiac arrhythmias and exaggerated beta-adrenergic blocking activity.

Because of its metabolism, the combination of CYP3A4 inhibition and either CYP2D6 deficiency or CYP2D6 inhibition in users of propafenone is potentially hazardous.

Therefore, avoid simultaneous use of propafenone hydrochloride with both a CYP2D6 inhibitor and a CYP3A4 inhibitor.

5.5 Use in Patients with a History of Heart Failure Propafenone exerts a negative inotropic activity on the myocardium as well as beta blockade effects and may provoke overt heart failure.

In clinical trial experience with propafenone hydrochloride, new or worsened congestive heart failure (CHF) has been reported in 3.7% of patients with ventricular arrhythmia; of those 0.9% were considered probably or definitely related to propafenone HCl.

Of the patients with CHF probably related to propafenone, 80% had preexisting heart failure and 85% had coronary artery disease.

CHF attributable to propafenone HCl developed rarely (< 0.2%) in ventricular arrhythmia patients who had no previous history of CHF.

CHF occurred in 1.9% of patients studied with PAF or PSVT.

In a U.S.

trial of sustained-release propafenone in patients with symptomatic AF, heart failure was reported in 4 (1.0%) patients receiving sustained-release propafenone (all doses), compared to 1 (0.8%) patient receiving placebo.

5.6 Conduction Disturbances Propafenone slows atrioventricular conduction and may also cause dose-related first degree AV block.

Average PR interval prolongation and increases in QRS duration are also dose-related.

Do not give propafenone to patients with atrioventricular and intraventricular conduction defects in the absence of a pacemaker [see Contraindications (4) and Clinical Pharmacology (12.2) ].

The incidence of first degree, second degree, and third degree AV block observed in 2,127 ventricular arrhythmia patients was 2.5%, 0.6%, and 0.2%, respectively.

Development of second or third degree AV block requires a reduction in dosage or discontinuation of propafenone HCl.

Bundle branch block (1.2%) and intraventricular conduction delay (1.1%) have been reported in patients receiving propafenone.

Bradycardia has also been reported (1.5%).

Experience in patients with sick sinus node syndrome is limited and these patients should not be treated with propafenone.

In a U.S.

trial in 523 patients with a history of symptomatic AF treated with sustained-release propafenone, sinus bradycardia (rate <50 beats/min) was reported with the same frequency with sustained-release propafenone and placebo.

5.7 Effects on Pacemaker Threshold Propafenone may alter both pacing and sensing thresholds of implanted pacemakers and defibrillators.

During and after therapy, monitor and re-program these devices accordingly.

5.8 Agranulocytosis Agranulocytosis has been reported in patients receiving propafenone.

Generally, the agranulocytosis occurred within the first 2 months of propafenone therapy and upon discontinuation of therapy, the white count usually normalized by 14 days.

Unexplained fever or decrease in white cell count, particularly during the initial 3 months of therapy, warrant consideration of possible agranulocytosis or granulocytopenia.

Instruct patients to report promptly any signs of infection such as fever, sore throat, or chills.

5.9 Use in Patients with Hepatic Dysfunction Propafenone is highly metabolized by the liver.

Severe liver dysfunction increases the bioavailability of propafenone to approximately 70% compared to 3 to 40% in patients with normal liver function.

In 8 patients with moderate to severe liver disease, the mean half-life was approximately 9 hours.

Increased bioavailability of propafenone in these patients may result in excessive accumulation.

Carefully monitor patients with impaired hepatic function for excessive pharmacological effects [see Overdosage (10) ] .

5.10 Use in Patients with Renal Dysfunction Approximately 50% of propafenone metabolites are excreted in the urine following administration of propafenone hydrochloride.

In patients with impaired renal function, monitor for signs of overdosage [see Overdosage (10) ].

5.11 Use in Patients with Myasthenia Gravis Exacerbation of myasthenia gravis has been reported during propafenone therapy.

5.12 Elevated ANA Titers Positive ANA titers have been reported in patients receiving propafenone.

They have been reversible upon cessation of treatment and may disappear even in the face of continued propafenone therapy.

These laboratory findings were usually not associated with clinical symptoms, but there is one published case of drug-induced lupus erythematosis (positive rechallenge); it resolved completely upon discontinuation of therapy.

Carefully evaluate patients who develop an abnormal ANA test and, if persistent or worsening elevation of ANA titers is detected, consider discontinuing therapy.

5.13 Impaired Spermatogenesis Reversible disorders of spermatogenesis have been demonstrated in monkeys, dogs and rabbits after high dose intravenous administration of propafenone.

Evaluation of the effects of short-term propafenone hydrochloride administration on spermatogenesis in 11 normal subjects suggested that propafenone produced a reversible, short-term drop (within normal range) in sperm count.

WARNING AND CAUTIONS

5 WARNINGS AND PRECAUTIONS Atovaquone absorption may be reduced in patients with diarrhea or vomiting.

If used in patients who are vomiting, parasitemia should be closely monitored and the use of an antiemetic considered.

In patients with severe or persistent diarrhea or vomiting, alternative antimalarial therapy may be required.

( ) • 5.1 In mixed and infection, relapse occurred commonly when patients were treated with MALARONE alone.

( ) • P.

falciparum Plasmodium vivax P.

vivax 5.2 In the event of recrudescent infections after treatment or prophylaxis failure, patients should be treated with a different blood schizonticide.

( ) • P.

falciparum 5.2 Elevated liver laboratory tests and cases of hepatitis and hepatic failure requiring liver transplantation have been reported with prophylactic use.

( ) • 5.3 MALARONE has not been evaluated for the treatment of cerebral malaria or other severe manifestations of complicated malaria.

Patients with severe malaria are not candidates for oral therapy.

( ) • 5.4 5.1 Vomiting and Diarrhea Absorption of atovaquone may be reduced in patients with diarrhea or vomiting.

If MALARONE is used in patients who are vomiting, parasitemia should be closely monitored and the use of an antiemetic considered.

Vomiting occurred in up to 19% of pediatric patients given treatment doses of MALARONE.

In the controlled clinical trials, 15.3% of adults received an antiemetic when they received atovaquone/proguanil and 98.3% of these patients were successfully treated.

In patients with severe or persistent diarrhea or vomiting, alternative antimalarial therapy may be required.

[See Dosage and Administration (2).] 5.2 Relapse of Infection In mixed and infections, parasite relapse occurred commonly when patients were treated with MALARONE alone.

P.

falciparum Plasmodium vivax P.

vivax In the event of recrudescent infections after treatment with MALARONE or failure of chemoprophylaxis with MALARONE, patients should be treated with a different blood schizonticide.

P.

falciparum 5.3 Hepatotoxicity Elevated liver laboratory tests and cases of hepatitis and hepatic failure requiring liver transplantation have been reported with prophylactic use of MALARONE.

5.4 Severe or Complicated Malaria MALARONE has not been evaluated for the treatment of cerebral malaria or other severe manifestations of complicated malaria, including hyperparasitemia, pulmonary edema, or renal failure.

Patients with severe malaria are not candidates for oral therapy.