Author: druginteractionchecker_lgaiz4

WARNING AND CAUTIONS

5 WARNINGS AND PRECAUTIONS Hypotension: Correct volume depletion prior to initiation ( 5.2 ) Observe for signs of fluid or electrolyte imbalance ( 5.9 ) Monitor renal function and potassium in susceptible patients ( 5.3 , 5.7 ) Exacerbation or activation of systemic lupus erythematosus ( 5.5 ) Acute angle-closure glaucoma ( 5.8 ) 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 valsartan and hydrochlorothiazide as soon as possible [see Use in Specific Populations (8.1) ] .

Intrauterine exposure to thiazide diuretics is associated with fetal or neonatal jaundice, thrombocytopenia, and possibly other adverse reactions that have occurred in adults.

5.2 Hypotension in Volume- and/or Salt-Depleted Patients Excessive reduction of blood pressure was rarely seen (0.7%) in patients with uncomplicated hypertension treated with valsartan and hydrochlorothiazide in controlled trials.

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 valsartan and hydrochlorothiazide, or the treatment should start under close medical supervision.

If 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 valsartan and hydrochlorothiazide.

Monitor renal function periodically in these patients.

Consider withholding or discontinuing therapy in patients who develop a clinically significant decrease in renal function on valsartan and hydrochlorothiazide [see Drug Interactions (7) ] .

5.4 Hypersensitivity Reaction Hydrochlorothiazide Hypersensitivity reactions to hydrochlorothiazide may occur in patients with or without a history of allergy or bronchial asthma, but are more likely in patients with such a history.

5.5 Systemic Lupus Erythematosus Hydrochlorothiazide Thiazide diuretics have been reported to cause exacerbation or activation of systemic lupus erythematosus.

5.6 Lithium Interaction Increases in serum lithium concentrations and lithium toxicity have been reported with concomitant use of valsartan or thiazide diuretics.

Monitor lithium levels in patients receiving valsartan and hydrochlorothiazide and lithium [see Drug Interactions (7) ] .

5.7 Potassium Abnormalities Valsartan and Hydrochlorothiazide In the controlled trials of various doses of valsartan and hydrochlorothiazide the incidence of hypertensive patients who developed hypokalemia (serum potassium 5.7 mEq/L) was 0.4%.

Hydrochlorothiazide can cause hypokalemia and hyponatremia.

Hypomagnesemia can result in hypokalemia which appears difficult to treat despite potassium repletion.

Drugs that inhibit the renin-angiotensin system can cause hyperkalemia.

Monitor serum electrolytes periodically.

If hypokalemia is accompanied by clinical signs (e.g., muscular weakness, paresis or ECG alterations), valsartan and hydrochlorothiazide should be discontinued.

Correction of hypokalemia and any coexisting hypomagnesemia is recommended prior to the initiation of thiazides.

Some patients with heart failure have developed increases in potassium with valsartan therapy.

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

Dosage reduction and/or discontinuation of the diuretic and/or valsartan may be required [see Adverse Reactions (6.1) ].

5.8 Acute Myopia and Secondary Angle-Closure Glaucoma Hydrochlorothiazide, a sulfonamide, can cause an idiosyncratic reaction, resulting in acute transient myopia and acute angle-closure glaucoma.

Symptoms include acute onset of decreased visual acuity or ocular pain and typically occur within hours to weeks of drug initiation.

Untreated acute angle-closure glaucoma can lead to permanent vision loss.

The primary treatment is to discontinue hydrochlorothiazide as rapidly as possible.

Prompt medical or surgical treatments may need to be considered if the intraocular pressure remains uncontrolled.

Risk factors for developing acute angle-closure glaucoma may include a history of sulfonamide or penicillin allergy.

5.9 Metabolic Disturbances Hydrochlorothiazide Hydrochlorothiazide may alter glucose tolerance and raise serum levels of cholesterol and triglycerides.

Hydrochlorothiazide may raise the serum uric acid level due to reduced clearance of uric acid and may cause or exacerbate hyperuricemia and precipitate gout in susceptible patients.

Hydrochlorothiazide decreases urinary calcium excretion and may cause elevations of serum calcium.

Monitor calcium levels in patients with hypercalcemia receiving valsartan and hydrochlorothiazide.

WARNING AND CAUTIONS

5 WARNINGS AND PRECAUTIONS Falling Asleep During Activities of Daily Living: Sudden onset of sleep may occur without warning; advise patients to report symptoms.

(5.1) Symptomatic Orthostatic Hypotension: Monitor closely especially during dose escalation (5.2) Impulse Control/Compulsive Behaviors: Patients may experience compulsive behaviors and other intense urges (5.3) Hallucinations and Psychotic-like Behavior: May occur.

Risk increases with age (5.4) Dyskinesia: May be caused or exacerbated by pramipexole dihydrochloride extended-release (5.5) Postural Deformity: Consider reducing the dose or discontinuing pramipexole dihydrochloride extended-release tablets if postural deformity occurs (5.6) 5.1 Falling Asleep During Activities of Daily Living and Somnolence Patients treated with pramipexole have reported falling asleep while engaged in activities of daily living, including the operation of motor vehicles, which sometimes resulted in accidents.

Although many of these patients reported somnolence while on pramipexole tablets, some perceived that they had no warning signs (sleep attack) such as excessive drowsiness, and believed that they were alert immediately prior to the event.

Some of these events had been reported as late as one year after the initiation of treatment.

In placebo-controlled clinical trials in Parkinson’s disease, the sudden onset of sleep or sleep attacks were reported in 8 of 387 (2%) patients treated with pramipexole dihydrochloride extended-release tablets compared to 2 of 281 (1%) patients on placebo.

In early Parkinson’s disease, somnolence was reported in 36% of 223 patients treated with pramipexole dihydrochloride extended-release, median dose 3 mg/day, compared to 15% of 103 patients on placebo.

In advanced Parkinson’s disease, somnolence was reported in 15% of 164 patients treated with pramipexole dihydrochloride extended-release tablets, median dose 3 mg/day, compared to 16% of 178 patients on placebo.

It has been reported that falling asleep while engaged in activities of daily living usually occurs in a setting of preexisting somnolence, although patients may not give such a history.

For this reason, prescribers should reassess patients for drowsiness or sleepiness, especially since some of the events occur well after the start of treatment.

Prescribers should also be aware that patients may not acknowledge drowsiness or sleepiness until directly questioned about drowsiness or sleepiness during specific activities.

Before initiating treatment with pramipexole dihydrochloride extended-release tablets, advise patients of the potential to develop drowsiness, and specifically ask about factors that may increase the risk for somnolence such as the use of concomitant sedating medications or alcohol, the presence of sleep disorders, and concomitant medications that increase pramipexole plasma levels (e.g., cimetidine) [see Clinical Pharmacology (12.3) ].

If a patient develops significant daytime sleepiness or episodes of falling asleep during activities that require active participation (e.g., conversations, eating, etc.), pramipexole dihydrochloride extended-release tablets should ordinarily be discontinued.

If a decision is made to continue pramipexole dihydrochloride extended-release tablets, advise patients not to drive and to avoid other potentially dangerous activities that might result in harm if the patients become somnolent.

While dose reduction reduces the degree of somnolence, there is insufficient information to establish that dose reduction will eliminate episodes of falling asleep while engaged in activities of daily living.

5.2 Symptomatic Orthostatic Hypotension Dopamine agonists, in clinical studies and clinical experience, appear to impair the systemic regulation of blood pressure, with resulting orthostatic hypotension, especially during dose escalation.

Parkinson’s disease patients, in addition, appear to have an impaired capacity to respond to an orthostatic challenge.

For these reasons, Parkinson’s disease patients being treated with dopaminergic agonists, including pramipexole dihydrochloride extended-release, ordinarily require careful monitoring for signs and symptoms of orthostatic hypotension, especially during dose escalation, and should be informed of this risk.

In placebo-controlled clinical trials in Parkinson’s disease, symptomatic orthostatic hypotension was reported in 10 of 387 (3%) patients treated with pramipexole dihydrochloride extended-release tablets compared to 3 of 281 (1%) patients on placebo.

One patient of 387 on pramipexole dihydrochloride extended-release tablets discontinued treatment due to hypotension.

5.3 Impulse Control/Compulsive Behaviors Case reports and the results of cross-sectional studies suggest that patients can experience intense urges to gamble, increased sexual urges, intense urges to spend money, binge eating, and/or other intense urges, and the inability to control these urges while taking one or more of the medications, including pramipexole dihydrochloride extended-release, that increase central dopaminergic tone.

In some cases, although not all, these urges were reported to have stopped when the dose was reduced or the medication was discontinued.

Because patients may not recognize these behaviors as abnormal, it is important for prescribers to specifically ask patients or their caregivers about the development of new or increased gambling urges, sexual urges, uncontrolled spending or other urges while being treated with pramipexole dihydrochloride extended-release for Parkinson’s disease.

Physicians should consider dose reduction or stopping the medication if a patient develops such urges while taking pramipexole dihydrochloride extended-release.

A total of 1056 patients with Parkinson’s disease who participated in two pramipexole dihydrochloride extended-release placebo-controlled studies of up to 33 weeks duration were specifically asked at each visit about the occurrence of these symptoms.

A total of 14 of 387 (4%) treated with pramipexole dihydrochloride extended-release tablets, 12 of 388 (3%) treated with immediate-release pramipexole tablets, and 4 of 281 (1%) treated with placebo reported compulsive behaviors, including pathological gambling, hypersexuality, and/or compulsive buying.

5.4 Hallucinations and Psychotic-like Behavior In placebo-controlled clinical trials in Parkinson’s disease, hallucinations (visual or auditory or mixed) were reported in 25 of 387 (6%) patients treated with pramipexole dihydrochloride extended-release tablets compared to 5 of 281 (2%) patients receiving placebo.

Hallucinations led to discontinuation of treatment in 5 of 387 (1%) patients on pramipexole dihydrochloride extended-release tablets.

Age appears to increase the risk of hallucinations attributable to pramipexole.

In placebo-controlled clinical trials in Parkinson’s disease, hallucinations were reported in 15 of 162 (9%)patients ≥ 65 years of age taking pramipexole dihydrochloride extended-release tablets compared to 10 of 225 (4%)patients <65 years of age taking pramipexole dihydrochloride extended-release tablets.

Postmarketing reports with dopamine agonists, including pramipexole dihydrochloride extended-release, indicate that patients with Parkinson’s disease may experience new or worsening mental status and behavioral changes, which may be severe, including psychotic-like behavior during treatment with pramipexole dihydrochloride extended-release or after starting or increasing the dose of pramipexole dihydrochloride extended-release.

Other drugs prescribed to improve the symptoms of Parkinson’s disease can have similar effects on thinking and behavior.

This abnormal thinking and behavior can consist of one or more of a variety of manifestations including paranoid ideation, delusions, hallucinations, confusion, psychotic-like behavior, symptoms of mania (e.g., insomnia, psychomotor agitation), disorientation, aggressive behavior, agitation, and delirium.

Patients with a major psychotic disorder should ordinarily not be treated with dopamine agonists, including pramipexole dihydrochloride extended-release, because of the risk of exacerbating the psychosis.

In addition, certain medications used to treat psychosis may exacerbate the symptoms of Parkinson’s disease and may decrease the effectiveness of pramipexole dihydrochloride extended-release [see Drug Interactions ( 7.1 )].

5.5 Dyskinesia Pramipexole dihydrochloride extended-release tablets may cause or exacerbate preexisting dyskinesia.

5.6 Postural Deformity Postural deformities, including antecollis, camptocormia (Bent Spine Syndrome), and pleurothotonus (Pisa Syndrome), have been reported in patients after starting or increasing the dose of pramipexole dihydrochloride extended-release tablets.

Postural deformity may occur several months after starting treatment or increasing the dose.

Reducing the dose or discontinuing pramipexole dihydrochloride extended-release tablets has been reported to improve postural deformity in some patients, and should be considered if postural deformity occurs.

5.7 Renal Impairment The elimination of pramipexole is dependent on renal function [see Clinical Pharmacology (12.3) ].

Patients with mild renal impairment (a creatinine clearance above 50 mL/min) require no reduction in daily dose.

Pramipexole dihydrochloride extended-release tablets have not been studied in patients with moderate to severe renal impairment (creatinine clearance <50 mL/min) or on hemodialysis [see Dosage and Administration (2.2) , Use in Specific Populations (8.6) , and Clinical Pharmacology (12.3) ].

5.8 Rhabdomyolysis In the clinical development program for immediate-release pramipexole tablets, a single case of rhabdomyolysis occurred in a 49 year old male with advanced Parkinson’s disease.

The patient was hospitalized with an elevated CPK (10,631 IU/L).

The symptoms resolved with discontinuation of the medication.

Advise patients to contact a physician if they experience any unexplained muscle pain, tenderness, or weakness, as these may be symptoms of rhabdomyolysis.

5.9 Retinal Pathology Human Data A two-year open-label, randomized, parallel-group safety study of retinal deterioration and vision compared immediate-release pramipexole tablets and immediate-release ropinirole.

Two hundred thirty four Parkinson’s disease patients (115 on pramipexole, mean dose 3 mg/day and 119 on ropinirole, mean dose 9.5 mg/day) were evaluated using a panel of clinical ophthalmological assessments.

Of 234 patients who were evaluable, 196 had been treated for two years and 29 were judged to have developed clinical abnormalities that were considered meaningful (19 patients in each treatment arm had received treatment for less than two years).

There was no statistical difference in retinal deterioration between the treatment arms; however, the study was only capable of detecting a very large difference between treatments.

In addition, because the study did not include an untreated comparison group (placebo treated), it is unknown whether the findings reported in patients treated with either drug are greater than the background rate in an aging population.

Animal Data Pathologic changes (degeneration and loss of photoreceptor cells) were observed in the retina of albino rats in a 2 year carcinogenicity study.

While retinal degeneration was not diagnosed in pigmented rats treated for 2 years, a thinning in the outer nuclear layer of the retina was slightly greater in rats given drug compared with controls.

Evaluation of the retinas of albino mice, monkeys, and minipigs did not reveal similar changes.

The potential significance of this effect for humans has not been established, but cannot be disregarded because disruption of a mechanism that is universally present in vertebrates (i.e., disk shedding) may be involved [see Nonclinical Toxicology (13.2) ].

5.10 Events Reported with Dopaminergic Therapy Although the events enumerated below may not have been reported with the use of pramipexole in its development program, they are associated with the use of other dopaminergic drugs.

The expected incidence of these events, however, is so low that even if pramipexole caused these events at rates similar to those attributable to other dopaminergic therapies, it would be unlikely that even a single case would have occurred in a cohort of the size exposed to pramipexole in studies to date.

Hyperpyrexia and Confusion Although not reported with pramipexole in the clinical development program, a symptom complex resembling the neuroleptic malignant syndrome (characterized by elevated temperature, muscular rigidity, altered consciousness, and autonomic instability), with no other obvious etiology, has been reported in association with rapid dose reduction, withdrawal of, or changes in dopaminergic therapy.

If possible, avoid sudden discontinuation or rapid dose reduction in patients taking pramipexole dihydrochloride extended-release tablets.

If the decision is made to discontinue pramipexole dihydrochloride extended-release tablets, the dose should be tapered to reduce the risk of hyperpyrexia and confusion [see Dosage and Administration ( 2.2 ) ].

Fibrotic Complications Cases of retroperitoneal fibrosis, pulmonary infiltrates, pleural effusion, pleural thickening, pericarditis, and cardiac valvulopathy have been reported in patients treated with ergot-derived dopaminergic agents.

While these complications may resolve when the drug is discontinued, complete resolution does not always occur.

Although these adverse events are believed to be related to the ergoline structure of these compounds, whether other, non-ergot derived dopamine agonists can cause them is unknown.

Cases of possible fibrotic complications, including peritoneal fibrosis, pleural fibrosis, and pulmonary fibrosis have been reported in the postmarketing experience with immediate-release pramipexole tablets.

While the evidence is not sufficient to establish a causal relationship between pramipexole and these fibrotic complications, a contribution of pramipexole cannot be completely ruled out.

5.11 Withdrawal Symptoms Symptoms including apathy, anxiety, depression, fatigue, insomnia, sweating, and pain have been reported during taper or after discontinuation of dopamine agonists, including pramipexole dihydrochloride extended-release tablets.

These symptoms generally do not respond to levodopa.

Prior to discontinuation of pramipexole dihydrochloride extended-release tablets, patients should be informed about potential withdrawal symptoms, and monitored during and after discontinuation.

In case of severe withdrawal symptoms, a trial re-administration of a dopamine agonist at the lowest effective dose may be considered.

WARNING AND CAUTIONS

Serious psychiatric symptoms: Immediate medical evaluation is recommended.

( 5.5 , 6.1 ) Nervous system symptoms (NSS): NSS are frequent, usually begin 1–2 days after initiating therapy and resolve in 2–4 weeks.

Dosing at bedtime may improve tolerability.

NSS are not predictive of onset of psychiatric symptoms.

( 2 , 5.6 ) New onset or worsening renal impairment: Can include acute renal failure and Fanconi syndrome.

Assess creatinine clearance (CrCl) before initiating treatment with ATRIPLA.

Monitor CrCl and serum phosphorus in patients at risk.

Avoid administering ATRIPLA with concurrent or recent use of nephrotoxic drugs.

( 5.7 ) Pregnancy: Fetal harm can occur when administered to a pregnant woman during the first trimester.

Women should be apprised of the potential harm to the fetus.

( 5.8 ) Rash: Discontinue if severe rash develops.

( 5.9 , 6.1 ) Hepatotoxicity: Monitor liver function tests before and during treatment in patients with underlying hepatic disease, including hepatitis B and C, or marked transaminase elevations.

( 5.10 , 8.6 ) Decreases in bone mineral density (BMD): Consider monitoring BMD in patients with a history of pathological fracture or who are at risk for osteopenia.

( 5.11 ) Convulsions: Use caution in patients with a history of seizures.

( 5.12 ) Immune reconstitution syndrome: May necessitate further evaluation and treatment.

( 5.13 ) Redistribution/accumulation of body fat: Observed in patients receiving antiretroviral therapy.

( 5.14 ) Coadministration with other products: Do not use with drugs containing efavirenz, emtricitabine or tenofovir disoproxil fumarate including SUSTIVA, TRUVADA, EMTRIVA, VIREAD; or with drugs containing lamivudine.

Do not administer in combination with HEPSERA.

( 5.4 ) 5.1 Lactic Acidosis/Severe Hepatomegaly with Steatosis Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogs including tenofovir DF, a component of ATRIPLA, in combination with other antiretrovirals.

A majority of these cases have been in women.

Obesity and prolonged nucleoside exposure may be risk factors.

Particular caution should be exercised when administering nucleoside analogs to any patient with known risk factors for liver disease; however, cases have also been reported in patients with no known risk factors.

Treatment with ATRIPLA should be suspended in any patient who develops clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity (which may include hepatomegaly and steatosis even in the absence of marked transaminase elevations).

5.2 Patients Coinfected with HIV-1 and HBV It is recommended that all patients with HIV-1 be tested for the presence of chronic HBV before initiating antiretroviral therapy.

ATRIPLA is not approved for the treatment of chronic HBV infection, and the safety and efficacy of ATRIPLA have not been established in patients coinfected with HBV and HIV-1.

Severe acute exacerbations of hepatitis B have been reported in patients who are coinfected with HBV and HIV-1 and have discontinued emtricitabine or tenofovir DF, two of the components of ATRIPLA.

In some patients infected with HBV and treated with emtricitabine, the exacerbations of hepatitis B were associated with liver decompensation and liver failure.

Patients who are coinfected with HIV-1 and HBV should be closely monitored with both clinical and laboratory follow up for at least several months after stopping treatment with ATRIPLA.

If appropriate, initiation of anti-hepatitis B therapy may be warranted.

ATRIPLA should not be administered with HEPSERA ® (adefovir dipivoxil) [See Drug Interactions (7.2) ] .

5.3 Drug Interactions Efavirenz plasma concentrations may be altered by substrates, inhibitors, or inducers of CYP3A.

Likewise, efavirenz may alter plasma concentrations of drugs metabolized by CYP3A [See Contraindications (4.2) , Drug Interactions (7.1) ] .

5.4 Coadministration with Related Products Related drugs not for coadministration with ATRIPLA include EMTRIVA (emtricitabine), VIREAD (tenofovir DF), TRUVADA (emtricitabine/tenofovir DF), and SUSTIVA (efavirenz), which contain the same active components as ATRIPLA.

Due to similarities between emtricitabine and lamivudine, ATRIPLA should not be coadministered with drugs containing lamivudine, including Combivir (lamivudine/zidovudine), Epivir, or Epivir-HBV (lamivudine), Epzicom (abacavir sulfate/lamivudine), or Trizivir (abacavir sulfate/lamivudine/zidovudine).

5.5 Psychiatric Symptoms Serious psychiatric adverse experiences have been reported in patients treated with efavirenz.

In controlled trials of 1008 subjects treated with regimens containing efavirenz for a mean of 2.1 years and 635 subjects treated with control regimens for a mean of 1.5 years, the frequency (regardless of causality) of specific serious psychiatric events among subjects who received efavirenz or control regimens, respectively, were: severe depression (2.4%, 0.9%), suicidal ideation (0.7%, 0.3%), nonfatal suicide attempts (0.5%, 0%), aggressive behavior (0.4%, 0.5%), paranoid reactions (0.4%, 0.3%), and manic reactions (0.2%, 0.3%).

When psychiatric symptoms similar to those noted above were combined and evaluated as a group in a multifactorial analysis of data from Study AI266006 (006), treatment with efavirenz was associated with an increase in the occurrence of these selected psychiatric symptoms.

Other factors associated with an increase in the occurrence of these psychiatric symptoms were history of injection drug use, psychiatric history, and receipt of psychiatric medication at study entry; similar associations were observed in both the efavirenz and control treatment groups.

In Study 006, onset of new serious psychiatric symptoms occurred throughout the study for both efavirenz-treated and control-treated subjects.

One percent of efavirenz-treated subjects discontinued or interrupted treatment because of one or more of these selected psychiatric symptoms.

There have also been occasional postmarketing reports of death by suicide, delusions, and psychosis-like behavior, although a causal relationship to the use of efavirenz cannot be determined from these reports.

Patients with serious psychiatric adverse experiences should seek immediate medical evaluation to assess the possibility that the symptoms may be related to the use of efavirenz, and if so, to determine whether the risks of continued therapy outweigh the benefits [See Adverse Reactions (6) ].

5.6 Nervous System Symptoms Fifty-three percent (531/1008) of subjects receiving efavirenz in controlled trials reported central nervous system symptoms (any grade, regardless of causality) compared to 25% (156/635) of subjects receiving control regimens.

These symptoms included dizziness (28.1% of the 1008 subjects), insomnia (16.3%), impaired concentration (8.3%), somnolence (7.0%), abnormal dreams (6.2%), and hallucinations (1.2%).

Other reported symptoms were euphoria, confusion, agitation, amnesia, stupor, abnormal thinking, and depersonalization.

The majority of these symptoms were mild-moderate (50.7%); symptoms were severe in 2.0% of subjects.

Overall, 2.1% of subjects discontinued therapy as a result.

These symptoms usually begin during the first or second day of therapy and generally resolve after the first 2–4 weeks of therapy.

After 4 weeks of therapy, the prevalence of nervous system symptoms of at least moderate severity ranged from 5% to 9% in subjects treated with regimens containing efavirenz and from 3% to 5% in subjects treated with a control regimen.

Patients should be informed that these common symptoms were likely to improve with continued therapy and were not predictive of subsequent onset of the less frequent psychiatric symptoms [See Warnings and Precautions (5.5) ] .

Dosing at bedtime may improve the tolerability of these nervous system symptoms [See Dosage and Administration (2) ] .

Analysis of long-term data from Study 006, (median follow-up 180 weeks, 102 weeks, and 76 weeks for subjects treated with efavirenz + zidovudine + lamivudine, efavirenz + indinavir, and indinavir + zidovudine + lamivudine, respectively) showed that, beyond 24 weeks of therapy, the incidences of new-onset nervous system symptoms among efavirenz-treated subjects were generally similar to those in the indinavir-containing control arm.

Patients receiving ATRIPLA should be alerted to the potential for additive central nervous system effects when ATRIPLA is used concomitantly with alcohol or psychoactive drugs.

Patients who experience central nervous system symptoms such as dizziness, impaired concentration, and/or drowsiness should avoid potentially hazardous tasks such as driving or operating machinery.

5.7 New Onset or Worsening Renal Impairment Emtricitabine and tenofovir are principally eliminated by the kidney; however, efavirenz is not.

Since ATRIPLA is a combination product and the dose of the individual components cannot be altered, patients with creatinine clearance <50 mL/min should not receive ATRIPLA.

Renal impairment, including cases of acute renal failure and Fanconi syndrome (renal tubular injury with severe hypophosphatemia), has been reported with the use of tenofovir DF [See Adverse Reactions (6.3) ].

It is recommended that creatinine clearance be calculated in all patients prior to initiating therapy and as clinically appropriate during therapy with ATRIPLA.

Routine monitoring of calculated creatinine clearance and serum phosphorus should be performed in patients at risk for renal impairment, including patients who have previously experienced renal events while receiving HEPSERA.

ATRIPLA should be avoided with concurrent or recent use of a nephrotoxic agent.

5.8 Reproductive Risk Potential Pregnancy Category D: Efavirenz may cause fetal harm when administered during the first trimester to a pregnant woman.

Pregnancy should be avoided in women receiving ATRIPLA.

Barrier contraception must always be used in combination with other methods of contraception (e.g., oral or other hormonal contraceptives).

Because of the long half-life of efavirenz, use of adequate contraceptive measures for 12 weeks after discontinuation of ATRIPLA is recommended.

Women of childbearing potential should undergo pregnancy testing before initiation of ATRIPLA.

If this drug is used during the first trimester of pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential harm to the fetus.

There are no adequate and well-controlled studies of ATRIPLA in pregnant women.

ATRIPLA should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus, such as in pregnant women without other therapeutic options.

Antiretroviral Pregnancy Registry: To monitor fetal outcomes of pregnant women, an Antiretroviral Pregnancy Registry has been established.

Physicians are encouraged to register patients who become pregnant by calling (800) 258-4263.

Efavirenz: As of July 2008, the Antiretroviral Pregnancy Registry has received prospective reports of 526 pregnancies exposed to efavirenz-containing regimens, nearly all of which were first-trimester exposures (507 pregnancies).

Birth defects occurred in 13 of 407 live births (first-trimester exposure) and 2 of 37 live births (second/third-trimester exposure).

One of these prospectively reported defects with first-trimester exposure was a neural tube defect.

A single case of anophthalmia with first-trimester exposure to efavirenz has also been prospectively reported; however, this case included severe oblique facial clefts and amniotic banding, a known association with anophthalmia.

There have been five retrospective reports of findings consistent with neural tube defects, including meningomyelocele.

All mothers were exposed to efavirenz-containing regimens in the first trimester.

Although a causal relationship of these events to the use of efavirenz has not been established, similar defects have been observed in preclinical studies of efavirenz.

Malformations have been observed in 3 of 20 fetuses/infants from efavirenz-treated cynomolgus monkeys (versus 0 of 20 concomitant controls) in a developmental toxicity study.

The pregnant monkeys were dosed throughout pregnancy (postcoital days 20–150) with efavirenz 60 mg/kg daily, a dose which resulted in plasma drug concentrations similar to those in humans given 600 mg/day of efavirenz.

Anencephaly and unilateral anophthalmia were observed in one fetus, microophthalmia was observed in another fetus, and cleft palate was observed in a third fetus.

Efavirenz crosses the placenta in cynomolgus monkeys and produces fetal blood concentrations similar to maternal blood concentrations.

Efavirenz has been shown to cross the placenta in rats and rabbits and produces fetal blood concentrations of efavirenz similar to maternal concentrations.

An increase in fetal resorptions was observed in rats at efavirenz doses that produced peak plasma concentrations and AUC values in female rats equivalent to or lower than those achieved in humans given 600 mg once daily of efavirenz.

Efavirenz produced no reproductive toxicities when given to pregnant rabbits at doses that produced peak plasma concentrations similar to and AUC values approximately half of those achieved in humans given 600 mg once daily of efavirenz.

5.9 Rash In controlled clinical trials, 26% (266/1008) of subjects treated with 600 mg efavirenz experienced new-onset skin rash compared with 17% (111/635) of subjects treated in control groups.

Rash associated with blistering, moist desquamation, or ulceration occurred in 0.9% (9/1008) of subjects treated with efavirenz.

The incidence of Grade 4 rash (e.g., erythema multiforme, Stevens-Johnson syndrome) in subjects treated with efavirenz in all studies and expanded access was 0.1%.

Rashes are usually mild-to-moderate maculopapular skin eruptions that occur within the first 2 weeks of initiating therapy with efavirenz (median time to onset of rash in adults was 11 days) and, in most subjects continuing therapy with efavirenz, rash resolves within 1 month (median duration, 16 days).

The discontinuation rate for rash in clinical trials was 1.7% (17/1008).

ATRIPLA can be reinitiated in patients interrupting therapy because of rash.

ATRIPLA should be discontinued in patients developing severe rash associated with blistering, desquamation, mucosal involvement, or fever.

Appropriate antihistamines and/or corticosteroids may improve the tolerability and hasten the resolution of rash.

Experience with efavirenz in subjects who discontinued other antiretroviral agents of the NNRTI class is limited.

Nineteen subjects who discontinued nevirapine because of rash have been treated with efavirenz.

Nine of these subjects developed mild-to-moderate rash while receiving therapy with efavirenz, and two of these subjects discontinued because of rash.

5.10 Liver Enzymes In patients with known or suspected history of hepatitis B or C infection and in patients treated with other medications associated with liver toxicity, monitoring of liver enzymes is recommended [See also Warnings and Precautions (5.2) ].

In patients with persistent elevations of serum transaminases to greater than five times the upper limit of the normal range, the benefit of continued therapy with ATRIPLA needs to be weighed against the unknown risks of significant liver toxicity [See Adverse Reactions (6.2) ] .

5.11 Decreases in Bone Mineral Density Bone mineral density (BMD) monitoring should be considered for HIV-1 infected subjects who have a history of pathologic bone fracture or are at risk for osteopenia.

Although the effect of supplementation with calcium and vitamin D was not studied, such supplementation may be beneficial for all patients.

If bone abnormalities are suspected then appropriate consultation should be obtained.

In a 144-week study of treatment-naive subjects receiving tenofovir DF, decreases in BMD were seen at the lumbar spine and hip in both arms of the study.

At Week 144, there was a significantly greater mean percentage decrease from baseline in BMD at the lumbar spine in subjects receiving tenofovir DF + lamivudine + efavirenz compared with subjects receiving stavudine + lamivudine + efavirenz.

Changes in BMD at the hip were similar between the two treatment groups.

In both groups, the majority of the reduction in BMD occurred in the first 24–48 weeks of the study and this reduction was sustained through 144 weeks.

Twenty-eight percent of tenofovir DF-treated subjects vs.

21% of the comparator subjects lost at least 5% of BMD at the spine or 7% of BMD at the hip.

Clinically relevant fractures (excluding fingers and toes) were reported in 4 subjects in the tenofovir DF group and 6 subjects in the comparator group.

Tenofovir DF was associated with significant increases in biochemical markers of bone metabolism (serum bone-specific alkaline phosphatase, serum osteocalcin, serum C-telopeptide, and urinary N-telopeptide), suggesting increased bone turnover.

Serum parathyroid hormone levels and 1,25 Vitamin D levels were also higher in subjects receiving tenofovir DF.

The effects of tenofovir DF-associated changes in BMD and biochemical markers on long-term bone health and future fracture risk are unknown.

For additional information, consult the tenofovir DF prescribing information.

Cases of osteomalacia (associated with proximal renal tubulopathy and which may contribute to fractures) have been reported in association with the use of tenofovir DF [See Adverse Reactions (6.3) ] .

5.12 Convulsions Convulsions have been observed in patients receiving efavirenz, generally in the presence of known medical history of seizures.

Caution must be taken in any patient with a history of seizures.

Patients who are receiving concomitant anticonvulsant medications primarily metabolized by the liver, such as phenytoin and phenobarbital, may require periodic monitoring of plasma levels [See Drug Interactions (7.3) ].

5.13 Immune Reconstitution Syndrome Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including the components of ATRIPLA.

During the initial phase of combination antiretroviral treatment, patients whose immune system responds may develop an inflammatory response to indolent or residual opportunistic infections [such as Mycobacterium avium infection, cytomegalovirus, Pneumocystis jirovecii pneumonia (PCP), or tuberculosis], which may necessitate further evaluation and treatment.

5.14 Fat Redistribution Redistribution/accumulation of body fat including central obesity, dorsocervical fat enlargement (buffalo hump), peripheral wasting, facial wasting, breast enlargement, and “cushingoid appearance” have been observed in patients receiving antiretroviral therapy.

The mechanism and long-term consequences of these events are currently unknown.

A causal relationship has not been established.

WARNING AND CAUTIONS

5 WARNINGS AND PRECAUTIONS Suicidal Behavior and Ideation (5.1) Patients should be advised that VIMPAT may cause dizziness and ataxia.

(5.2) Caution is advised for patients with known cardiac conduction problems [e.g., second-degree atrioventricular (AV) block], who are taking drugs known to induce PR interval prolongation, or with severe cardiac disease such as myocardial ischemia or heart failure.

(5.3) Patients should be advised that VIMPAT may cause syncope.

(5.4) In patients with seizure disorders, VIMPAT should be gradually withdrawn to minimize the potential of increased seizure frequency.

(5.5) Multiorgan Hypersensitivity Reactions (5.6) Phenylketonurics (5.7) 5.1 Suicidal Behavior and Ideation Antiepileptic drugs (AEDs), including VIMPAT, 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 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 of events 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 one week after starting 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 Risk by indication for antiepileptic drugs in the pooled analysis 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.

Anyone considering prescribing VIMPAT or any other AED must balance this risk with the risk of untreated illness.

Epilepsy and many other illnesses for which antiepileptics 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, the prescriber needs to consider whether the emergence of these symptoms in any given patient may be related to the illness being treated.

Patients, their caregivers, and families should be informed that AEDs increase the risk of suicidal thoughts and behavior and should be advised of the need to be alert for the emergence or worsening of the signs and symptoms of depression, any unusual changes in mood or behavior, or the emergence of suicidal thoughts, behavior, or thoughts about self-harm.

Behaviors of concern should be reported immediately to healthcare providers.

5.2 Dizziness and Ataxia Patients should be advised that VIMPAT may cause dizziness and ataxia.

Accordingly, they should be advised not to drive a car or to operate other complex machinery until they are familiar with the effects of VIMPAT on their ability to perform such activities.

In patients with partial-onset seizures taking 1 to 3 concomitant AEDs, dizziness was experienced by 25% of patients randomized to the recommended doses (200 to 400 mg/day) of VIMPAT (compared with 8% of placebo patients) and was the adverse event most frequently leading to discontinuation (3%).

Ataxia was experienced by 6% of patients randomized to the recommended doses (200 to 400 mg/day) of VIMPAT (compared to 2% of placebo patients).

The onset of dizziness and ataxia was most commonly observed during titration.

There was a substantial increase in these adverse events at doses higher than 400 mg/day.

[see Adverse Reactions/ Table 2 (6.1) ] 5.3 Cardiac Rhythm and Conduction Abnormalities PR interval prolongation Dose-dependent prolongations in PR interval with VIMPAT have been observed in clinical studies in patients and in healthy volunteers.

[see Clinical Pharmacology (12.2) ] In clinical trials in patients with partial-onset epilepsy, asymptomatic first-degree atrioventricular (AV) block was observed as an adverse reaction in 0.4% (4/944) of patients randomized to receive VIMPAT and 0% (0/364) of patients randomized to receive placebo.

In clinical trials in patients with diabetic neuropathy, asymptomatic first-degree AV block was observed as an adverse reaction in 0.5% (5/1023) of patients receiving VIMPAT and 0% (0/291) of patients receiving placebo.

Second degree or higher AV block has been reported in postmarketing experience in epilepsy patients.

When VIMPAT is given with other drugs that prolong the PR interval, further PR prolongation is possible.

Patients should be made aware of the symptoms of second-degree or higher AV block (e.g.

slow or irregular pulse, feeling of lightheadedness and fainting) and told to contact their physician should any of these occur.

VIMPAT should be used with caution in patients with known conduction problems (e.g.

marked first-degree AV block, second-degree or higher AV block and sick sinus syndrome without pacemaker), or with severe cardiac disease such as myocardial ischemia or heart failure.

In such patients, obtaining an ECG before beginning VIMPAT, and after VIMPAT is titrated to steady-state, is recommended.

Atrial fibrillation and Atrial flutter In the short-term investigational trials of VIMPAT in epilepsy patients, there were no cases of atrial fibrillation or flutter, however, both have been reported in open label epilepsy trials and in postmarketing experience.

In patients with diabetic neuropathy, 0.5% of patients treated with VIMPAT experienced an adverse reaction of atrial fibrillation or atrial flutter, compared to 0% of placebo-treated patients.

VIMPAT administration may predispose to atrial arrhythmias (atrial fibrillation or flutter), especially in patients with diabetic neuropathy and/or cardiovascular disease.

Patients should be made aware of the symptoms of atrial fibrillation and flutter (e.g., palpitations, rapid pulse, shortness of breath) and told to contact their physician should any of these symptoms occur.

5.4 Syncope In the short-term controlled trials of VIMPAT in epilepsy patients with no significant system illnesses, there was no increase in syncope compared to placebo.

In the short-term controlled trials of VIMPAT in patients with diabetic neuropathy, 1.2% of patients who were treated with VIMPAT reported an adverse reaction of syncope or loss of consciousness, compared to 0% of placebo-treated patients with diabetic neuropathy.

Most of the cases of syncope were observed in patients receiving doses above 400 mg/day.

The cause of syncope was not determined in most cases.

However, several were associated with either changes in orthostatic blood pressure, atrial flutter/fibrillation (and associated tachycardia), or bradycardia.

5.5 Withdrawal of Antiepileptic Drugs (AEDs) As with all AEDs, VIMPAT should be withdrawn gradually (over a minimum of 1 week) to minimize the potential of increased seizure frequency in patients with seizure disorders.

5.6 Multiorgan Hypersensitivity Reactions One case of symptomatic hepatitis and nephritis was observed among 4011 subjects exposed to VIMPAT during clinical development.

The event occurred in a healthy volunteer, 10 days after stopping VIMPAT treatment.

The subject was not taking any concomitant medication and potential known viral etiologies for hepatitis were ruled out.

The subject fully recovered within a month, without specific treatment.

The case is consistent with a delayed multiorgan hypersensitivity reaction.

Additional potential cases included 2 with rash and elevated liver enzymes and 1 with myocarditis and hepatitis of uncertain etiology.

Multiorgan hypersensitivity reactions (also known as D rug R eaction with E osinophilia and S ystemic S ymptoms, or DRESS) have been reported with other anticonvulsants and typically, although not exclusively, present with fever and rash associated with other organ system involvement, that may or may not include eosinophilia, hepatitis, nephritis, lymphadenopathy, and/or myocarditis.

Because this disorder is variable in its expression, other organ system signs and symptoms not noted here may occur.

If this reaction is suspected, VIMPAT should be discontinued and alternative treatment started.

5.7 Phenylketonurics VIMPAT oral solution contains aspartame, a source of phenylalanine.

A 200 mg dose of VIMPAT oral solution (equivalent to 20 mL) contains 0.32 mg of phenylalanine.