Author: druginteractionchecker_lgaiz4

WARNING AND CAUTIONS

5 WARNINGS AND PRECAUTIONS Life-threatening serious rash and/or rash-related death may result.

(Boxed Warning, 5.1) Fatal or life-threatening hypersensitivity reaction: Multiorgan hypersensitivity reactions, also known as Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), may be fatal or life threatening.

Early signs may include rash, fever, and lymphadenopathy.

These reactions may be associated with other organ involvement, such as hepatitis, hepatic failure, blood dyscrasias, or acute multiorgan failure.

LAMICTAL should be discontinued if alternate etiology for this reaction is not found.

(5.2) Blood dyscrasias (e.g., neutropenia, thrombocytopenia, pancytopenia): May occur, either with or without an associated hypersensitivity syndrome.

(5.3) Suicidal behavior and ideation.

(5.4) Clinical worsening, emergence of new symptoms, and suicidal ideation/behaviors may be associated with treatment of bipolar disorder.

Patients should be closely monitored, particularly early in treatment or during dosage changes.

(5.5) Aseptic meningitis reported in pediatric and adult patients.

(5.6) Medication errors involving LAMICTAL have occurred.

In particular the names LAMICTAL or lamotrigine can be confused with names of other commonly used medications.

Medication errors may also occur between the different formulations of LAMICTAL.

(3.4, 5.7, 16, 17.10) 5.1 Serious Skin Rashes [see Boxed Warning] Pediatric Population: The incidence of serious rash associated with hospitalization and discontinuation of LAMICTAL in a prospectively followed cohort of pediatric patients (2 to 16 years of age) with epilepsy receiving adjunctive therapy was approximately 0.8% (16 of 1,983).

When 14 of these cases were reviewed by 3 expert dermatologists, there was considerable disagreement as to their proper classification.

To illustrate, one dermatologist considered none of the cases to be Stevens-Johnson syndrome; another assigned 7 of the 14 to this diagnosis.

There was 1 rash-related death in this 1,983-patient cohort.

Additionally, there have been rare cases of toxic epidermal necrolysis with and without permanent sequelae and/or death in US and foreign postmarketing experience.

There is evidence that the inclusion of valproate in a multidrug regimen increases the risk of serious, potentially life-threatening rash in pediatric patients.

In pediatric patients who used valproate concomitantly, 1.2% (6 of 482) experienced a serious rash compared with 0.6% (6 of 952) patients not taking valproate.

Adult Population: Serious rash associated with hospitalization and discontinuation of LAMICTAL occurred in 0.3% (11 of 3,348) of adult patients who received LAMICTAL in premarketing clinical trials of epilepsy.

In the bipolar and other mood disorders clinical trials, the rate of serious rash was 0.08% (1 of 1,233) of adult patients who received LAMICTAL as initial monotherapy and 0.13% (2 of 1,538) of adult patients who received LAMICTAL as adjunctive therapy.

No fatalities occurred among these individuals.

However, in worldwide postmarketing experience, rare cases of rash-related death have been reported, but their numbers are too few to permit a precise estimate of the rate.

Among the rashes leading to hospitalization were Stevens-Johnson syndrome, toxic epidermal necrolysis, angioedema, and those associated with multiorgan hypersensitivity [see Warnings and Precautions (5.2)] .

There is evidence that the inclusion of valproate in a multidrug regimen increases the risk of serious, potentially life-threatening rash in adults.

Specifically, of 584 patients administered LAMICTAL with valproate in epilepsy clinical trials, 6 (1%) were hospitalized in association with rash; in contrast, 4 (0.16%) of 2,398 clinical trial patients and volunteers administered LAMICTAL in the absence of valproate were hospitalized.

Patients With History of Allergy or Rash to Other Antiepileptic Drugs: The risk of nonserious rash may be increased when the recommended initial dose and/or the rate of dose escalation of LAMICTAL is exceeded and in patients with a history of allergy or rash to other AEDs.

5.2 Multiorgan Hypersensitivity Reactions and Organ Failure Multiorgan hypersensitivity reactions, also known as Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), have occurred with LAMICTAL.

Some have been fatal or life threatening.

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

Eosinophilia is often present.

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

Fatalities associated with acute multiorgan failure and various degrees of hepatic failure have been reported in 2 of 3,796 adult patients and 4 of 2,435 pediatric patients who received LAMICTAL in epilepsy clinical trials.

Rare fatalities from multiorgan failure have also been reported in postmarketing use.

Isolated liver failure without rash or involvement of other organs has also been reported with LAMICTAL.

It is important to note that early manifestations of hypersensitivity (e.g., fever, lymphadenopathy) may be present even though a rash is not evident.

If such signs or symptoms are present, the patient should be evaluated immediately.

LAMICTAL should be discontinued if an alternative etiology for the signs or symptoms cannot be established.

Prior to initiation of treatment with LAMICTAL, the patient should be instructed that a rash or other signs or symptoms of hypersensitivity (e.g., fever, lymphadenopathy) may herald a serious medical event and that the patient should report any such occurrence to a physician immediately.

5.3 Blood Dyscrasias There have been reports of blood dyscrasias that may or may not be associated with multiorgan hypersensitivity (also known as DRESS) [see Warnings and Precautions (5.2)] .

These have included neutropenia, leukopenia, anemia, thrombocytopenia, pancytopenia, and, rarely, aplastic anemia and pure red cell aplasia.

5.4 Suicidal Behavior and Ideation Antiepileptic drugs (AEDs), including LAMICTAL, 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 1 case of suicidal thinking or behavior for every 530 patients treated.

There were 4 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 1 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 mechanism 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 to 100 years) in the clinical trials analyzed.

Table 7 shows absolute and relative risk by indication for all evaluated AEDs.

Table 7.

Risk by Indication for Antiepileptic Drugs in the Pooled Analysis Indication Placebo Patients With Events Per 1,000 Patients Drug Patients With Events Per 1,000 Patients Relative Risk: Incidence of Events in Drug Patients/Incidence in Placebo Patients Risk Difference: Additional Drug Patients With Events Per 1,000 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 LAMICTAL 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, 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.

5.5 Use in Patients With Bipolar Disorder Acute Treatment of Mood Episodes: Safety and effectiveness of LAMICTAL in the acute treatment of mood episodes have not been established.

Children and Adolescents (less than 18 years of age): Safety and effectiveness of LAMICTAL in patients below the age of 18 years with mood disorders have not been established [see Suicidal Behavior and Ideation (5.4)] .

Clinical Worsening and Suicide Risk Associated With Bipolar Disorder: Patients with bipolar disorder may experience worsening of their depressive symptoms and/or the emergence of suicidal ideation and behaviors (suicidality) whether or not they are taking medications for bipolar disorder.

Patients should be closely monitored for clinical worsening (including development of new symptoms) and suicidality, especially at the beginning of a course of treatment or at the time of dose changes.

In addition, patients with a history of suicidal behavior or thoughts, those patients exhibiting a significant degree of suicidal ideation prior to commencement of treatment, and young adults are at an increased risk of suicidal thoughts or suicide attempts, and should receive careful monitoring during treatment [see Suicidal Behavior and Ideation (5.5)] .

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

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

Overdoses have been reported for LAMICTAL, some of which have been fatal [see Overdosage (10.1)] .

5.6 Aseptic Meningitis Therapy with LAMICTAL increases the risk of developing aseptic meningitis.

Because of the potential for serious outcomes of untreated meningitis due to other causes, patients should also be evaluated for other causes of meningitis and treated as appropriate.

Postmarketing cases of aseptic meningitis have been reported in pediatric and adult patients taking LAMICTAL for various indications.

Symptoms upon presentation have included headache, fever, nausea, vomiting, and nuchal rigidity.

Rash, photophobia, myalgia, chills, altered consciousness, and somnolence were also noted in some cases.

Symptoms have been reported to occur within 1 day to one and a half months following the initiation of treatment.

In most cases, symptoms were reported to resolve after discontinuation of LAMICTAL.

Re-exposure resulted in a rapid return of symptoms (from within 30 minutes to 1 day following re-initiation of treatment) that were frequently more severe.

Some of the patients treated with LAMICTAL who developed aseptic meningitis had underlying diagnoses of systemic lupus erythematosus or other autoimmune diseases.

Cerebrospinal fluid (CSF) analyzed at the time of clinical presentation in reported cases was characterized by a mild-to-moderate pleocytosis, normal glucose levels, and mild-to-moderate increase in protein.

CSF white blood cell count differentials showed a predominance of neutrophils in a majority of the cases, although a predominance of lymphocytes was reported in approximately one third of the cases.

Some patients also had new onset of signs and symptoms of involvement of other organs (predominantly hepatic and renal involvement), which may suggest that in these cases the aseptic meningitis observed was part of a hypersensitivity reaction [see Warnings and Precautions (5.2)] .

5.7 Potential Medication Errors Medication errors involving LAMICTAL have occurred.

In particular, the names LAMICTAL or lamotrigine can be confused with the names of other commonly used medications.

Medication errors may also occur between the different formulations of LAMICTAL.

To reduce the potential of medication errors, write and say LAMICTAL clearly.

Depictions of the LAMICTAL Tablets, Chewable Dispersible Tablets, and Orally Disintegrating Tablets can be found in the Medication Guide that accompanies the product to highlight the distinctive markings, colors, and shapes that serve to identify the different presentations of the drug and thus may help reduce the risk of medication errors.

To avoid the medication error of using the wrong drug or formulation, patients should be strongly advised to visually inspect their tablets to verify that they are LAMICTAL, as well as the correct formulation of LAMICTAL, each time they fill their prescription.

5.8 Concomitant Use With Oral Contraceptives Some estrogen-containing oral contraceptives have been shown to decrease serum concentrations of lamotrigine [see Clinical Pharmacology (12.3)] .

Dosage adjustments will be necessary in most patients who start or stop estrogen-containing oral contraceptives while taking LAMICTAL [see Dosage and Administration (2.1)] .

During the week of inactive hormone preparation (“pill-free” week) of oral contraceptive therapy, plasma lamotrigine levels are expected to rise, as much as doubling at the end of the week.

Adverse reactions consistent with elevated levels of lamotrigine, such as dizziness, ataxia, and diplopia, could occur.

5.9 Withdrawal Seizures As with other AEDs, LAMICTAL should not be abruptly discontinued.

In patients with epilepsy there is a possibility of increasing seizure frequency.

In clinical trials in patients with Bipolar Disorder, 2 patients experienced seizures shortly after abrupt withdrawal of LAMICTAL; however, there were confounding factors that may have contributed to the occurrence of seizures in these bipolar patients.

Unless safety concerns require a more rapid withdrawal, the dose of LAMICTAL should be tapered over a period of at least 2 weeks (approximately 50% reduction per week) [see Dosage and Administration (2.1)] .

5.10 Status Epilepticus Valid estimates of the incidence of treatment-emergent status epilepticus among patients treated with LAMICTAL are difficult to obtain because reporters participating in clinical trials did not all employ identical rules for identifying cases.

At a minimum, 7 of 2,343 adult patients had episodes that could unequivocally be described as status epilepticus.

In addition, a number of reports of variably defined episodes of seizure exacerbation (e.g., seizure clusters, seizure flurries) were made.

5.11 Sudden Unexplained Death in Epilepsy (SUDEP) During the premarketing development of LAMICTAL, 20 sudden and unexplained deaths were recorded among a cohort of 4,700 patients with epilepsy (5,747 patient-years of exposure).

Some of these could represent seizure-related deaths in which the seizure was not observed, e.g., at night.

This represents an incidence of 0.0035 deaths per patient-year.

Although this rate exceeds that expected in a healthy population matched for age and sex, it is within the range of estimates for the incidence of sudden unexplained deaths in patients with epilepsy not receiving LAMICTAL (ranging from 0.0005 for the general population of patients with epilepsy, to 0.004 for a recently studied clinical trial population similar to that in the clinical development program for LAMICTAL, to 0.005 for patients with refractory epilepsy).

Consequently, whether these figures are reassuring or suggest concern depends on the comparability of the populations reported upon to the cohort receiving LAMICTAL and the accuracy of the estimates provided.

Probably most reassuring is the similarity of estimated SUDEP rates in patients receiving LAMICTAL and those receiving other AEDs, chemically unrelated to each other, that underwent clinical testing in similar populations.

Importantly, that drug is chemically unrelated to LAMICTAL.

This evidence suggests, although it certainly does not prove, that the high SUDEP rates reflect population rates, not a drug effect.

5.12 Addition of LAMICTAL to a Multidrug Regimen That Includes Valproate Because valproate reduces the clearance of lamotrigine, the dosage of lamotrigine in the presence of valproate is less than half of that required in its absence.

5.13 Binding in the Eye and Other Melanin-Containing Tissues Because lamotrigine binds to melanin, it could accumulate in melanin-rich tissues over time.

This raises the possibility that lamotrigine may cause toxicity in these tissues after extended use.

Although ophthalmological testing was performed in one controlled clinical trial, the testing was inadequate to exclude subtle effects or injury occurring after long-term exposure.

Moreover, the capacity of available tests to detect potentially adverse consequences, if any, of lamotrigine’s binding to melanin is unknown [see Clinical Pharmacology (12.2)] .

Accordingly, although there are no specific recommendations for periodic ophthalmological monitoring, prescribers should be aware of the possibility of long-term ophthalmologic effects.

5.14 Laboratory Tests The value of monitoring plasma concentrations of lamotrigine in patients treated with LAMICTAL has not been established.

Because of the possible pharmacokinetic interactions between lamotrigine and other drugs including AEDs (see Table 15), monitoring of the plasma levels of lamotrigine and concomitant drugs may be indicated, particularly during dosage adjustments.

In general, clinical judgment should be exercised regarding monitoring of plasma levels of lamotrigine and other drugs and whether or not dosage adjustments are necessary.

WARNING AND CAUTIONS

5 WARNINGS AND PRECAUTIONS Hypotension/bradycardia/syncope: Titrate slowly and monitor vital signs frequently in patients at risk for hypotension, heart block, bradycardia, syncope, cardiovascular disease, vascular disease, cerebrovascular disease or chronic renal failure.

Measure heart rate and blood pressure prior to initiation of therapy, following dose increases, and periodically while on therapy.

Avoid concomitant use of drugs with additive effects unless clinically indicated.

Advise patients to avoid becoming dehydrated or overheated.

( 5.1 ) Somnolence/Sedation: Has been observed with clonidine hydrochloride extended-release tablets.

Consider the potential for additive sedative effects with CNS depressant drugs.

Caution patients against operating heavy equipment or driving until they know how they respond to clonidine hydrochloride extended-release tablets.

( 5.2 ) Cardiac Conduction Abnormalities: May worsen sinus node dysfunction and atrioventricular (AV) block, especially in patients taking other sympatholytic drugs.

Titrate slowly and monitor vital signs frequently.

( 5.5 ) 5.1 Hypotension/Bradycardia Treatment with clonidine hydrochloride extended-release tablets can cause dose-related decreases in blood pressure and heart rate [see Adverse Reactions (6.1) ] .

Measure heart rate and blood pressure prior to initiation of therapy, following dose increases, and periodically while on therapy.

Titrate clonidine hydrochloride extended-release tablets slowly in patients with a history of hypotension, and those with underlying conditions that may be worsened by hypotension and bradycardia; e.g., heart block, bradycardia, cardiovascular disease, vascular disease, cerebrovascular disease, or chronic renal failure.

In patients who have a history of syncope or may have a condition that predisposes them to syncope, such as hypotension, orthostatic hypotension, bradycardia, or dehydration, advise patients to avoid becoming dehydrated or overheated.

Monitor blood pressure and heart rate, and adjust dosages accordingly in patients treated concomitantly with antihypertensives or other drugs that can reduce blood pressure or heart rate or increase the risk of syncope.

5.2 Sedation and Somnolence Somnolence and sedation were commonly reported adverse reactions in clinical studies.

In patients that completed 5 weeks of therapy in a controlled, fixed dose pediatric monotherapy study, 31% of patients treated with 0.4 mg/day and 38% treated with 0.2 mg/day versus 4% of placebo treated patients reported somnolence as an adverse event.

In patients that completed 5 weeks of therapy in a controlled flexible dose pediatric adjunctive to stimulants study, 19% of patients treated with clonidine hydrochloride extended-release tablets+stimulant versus 7% treated with placebo+stimulant reported somnolence.

Before using clonidine hydrochloride extended-release tablets with other centrally active depressants (such as phenothiazines, barbiturates, or benzodiazepines), consider the potential for additive sedative effects.

Caution patients against operating heavy equipment or driving until they know how they respond to treatment with clonidine hydrochloride extended-release tablets.

Advise patients to avoid use with alcohol.

5.3 Rebound Hypertension Abrupt discontinuation of clonidine hydrochloride extended-release tablets can cause rebound hypertension.

In adults with hypertension, sudden cessation of clonidine hydrochloride extended-release formulation treatment in the 0.2 to 0.6 mg/day range resulted in reports of headache, tachycardia, nausea, flushing, warm feeling, brief lightheadedness, tightness in chest, and anxiety.

In adults with hypertension, sudden cessation of treatment with immediate-release clonidine has, in some cases, resulted in symptoms such as nervousness, agitation, headache, and tremor accompanied or followed by a rapid rise in blood pressure and elevated catecholamine concentrations in the plasma.

No studies evaluating abrupt discontinuation of clonidine hydrochloride extended-release tablets in children with ADHD have been conducted; however, to minimize the risk of rebound hypertension, gradually reduce the dose of clonidine hydrochloride extended-release tablets in decrements of no more than 0.1 mg every 3 to 7 days.

Patients should be instructed not to discontinue clonidine hydrochloride extended-release tablet therapy without consulting their physician due to the potential risk of withdrawal effects.

5.4 Allergic Reactions In patients who have developed localized contact sensitization to clonidine transdermal system, continuation of clonidine transdermal system or substitution of oral clonidine hydrochloride extended-release tablet therapy may be associated with the development of a generalized skin rash.

In patients who develop an allergic reaction from clonidine transdermal system, substitution of oral clonidine hydrochloride extended-release tablets may also elicit an allergic reaction (including generalized rash, urticaria, or angioedema).

5.5 Cardiac Conduction Abnormalities The sympatholytic action of clonidine may worsen sinus node dysfunction and atrioventricular (AV) block, especially in patients taking other sympatholytic drugs.

There have been post-marketing reports of patients with conduction abnormalities and/or taking other sympatholytic drugs who developed severe bradycardia requiring IV atropine, IV isoproterenol, and temporary cardiac pacing while taking clonidine.

Titrate clonidine hydrochloride extended-release tablets slowly and monitor vital signs frequently in patients with cardiac conduction abnormalities or patients concomitantly treated with other sympatholytic drugs.

WARNING AND CAUTIONS

5 WARNINGS AND PRECAUTIONS • LABA increase the risk of asthma-related death and asthma-related hospitalizations.

Prescribe only for recommended patient populations.

( 5.1 ) • Do not initiate in acutely deteriorating COPD or asthma.

Do not use to treat acute symptoms.

( 5.2 ) • Do not use in combination with an additional medicine containing a LABA because of risk of overdose.

( 5.3 ) • Candida albicans infection of the mouth and pharynx may occur.

Monitor patients periodically.

Advise the patient to rinse his/her mouth with water without swallowing after inhalation to help reduce the risk.

( 5.4 ) • Increased risk of pneumonia in patients with COPD.

Monitor patients for signs and symptoms of pneumonia.

( 5.5 ) • Potential worsening of infections (e.g., existing tuberculosis; fungal, bacterial, viral, or parasitic infections; ocular herpes simplex).

Use with caution in patients with these infections.

More serious or even fatal course of chickenpox or measles can occur in susceptible patients.

( 5.6 ) • Risk of impaired adrenal function when transferring from systemic corticosteroids.

Taper patients slowly from systemic corticosteroids if transferring to BREO ELLIPTA.

( 5.7 ) • Hypercorticism and adrenal suppression may occur with very high dosages or at the regular dosage in susceptible individuals.

If such changes occur, discontinue BREO ELLIPTA slowly.

( 5.8 ) • If paradoxical bronchospasm occurs, discontinue BREO ELLIPTA and institute alternative therapy.

( 5.10 ) • Use with caution in patients with cardiovascular disorders because of beta-adrenergic stimulation.

( 5.12 ) • Assess for decrease in bone mineral density initially and periodically thereafter.

( 5.13 ) • Close monitoring for glaucoma and cataracts is warranted.

( 5.14 ) • Use with caution in patients with convulsive disorders, thyrotoxicosis, diabetes mellitus, and ketoacidosis.

( 5.15 ) • Be alert to hypokalemia and hyperglycemia.

( 5.16 ) 5.1 Asthma-Related Death LABA, such as vilanterol, one of the active ingredients in BREO ELLIPTA, increase the risk of asthma-related death.

Currently available data are inadequate to determine whether concurrent use of inhaled corticosteroids or other long-term asthma control drugs mitigates the increased risk of asthma-related death from LABA.

Available data from controlled clinical trials suggest that LABA increase the risk of asthma-related hospitalization in pediatric and adolescent patients.

Therefore, when treating patients with asthma, physicians should only prescribe BREO ELLIPTA for patients not adequately controlled on a long-term asthma control medication, such as an inhaled corticosteroid, or whose disease severity clearly warrants initiation of treatment with both an inhaled corticosteroid and a LABA.

Once asthma control is achieved and maintained, assess the patient at regular intervals and step down therapy (e.g., discontinue BREO ELLIPTA) if possible without loss of asthma control and maintain the patient on a long-term asthma control medication, such as an inhaled corticosteroid.

Do not use BREO ELLIPTA for patients whose asthma is adequately controlled on low- or medium-dose inhaled corticosteroids.

A 28-week, placebo-controlled, US trial that compared the safety of another LABA (salmeterol) with placebo, each added to usual asthma therapy, showed an increase in asthma-related deaths in subjects receiving salmeterol (13/13,176 in subjects treated with salmeterol vs.

3/13,179 in subjects treated with placebo; relative risk: 4.37 [95% CI: 1.25, 15.34]).

The increased risk of asthma-related death is considered a class effect of LABA, including vilanterol, one of the active ingredients in BREO ELLIPTA.

No trial adequate to determine whether the rate of asthma-related death is increased in subjects treated with BREO ELLIPTA has been conducted.

Data are not available to determine whether the rate of death in patients with COPD is increased by LABA.

5.2 Deterioration of Disease and Acute Episodes BREO ELLIPTA should not be initiated in patients during rapidly deteriorating or potentially life-threatening episodes of COPD or asthma.

BREO ELLIPTA has not been studied in subjects with acutely deteriorating COPD or asthma.

The initiation of BREO ELLIPTA in this setting is not appropriate.

COPD may deteriorate acutely over a period of hours or chronically over several days or longer.

If BREO ELLIPTA 100/25 no longer controls symptoms of bronchoconstriction; the patient’s inhaled, short-acting, beta 2 -agonist becomes less effective; or the patient needs more short-acting beta 2 -agonist than usual, these may be markers of deterioration of disease.

In this setting a reevaluation of the patient and the COPD treatment regimen should be undertaken at once.

For COPD, increasing the daily dose of BREO ELLIPTA 100/25 is not appropriate in this situation.

Increasing use of inhaled, short-acting beta 2 -agonists is a marker of deteriorating asthma.

In this situation, the patient requires immediate reevaluation with reassessment of the treatment regimen, giving special consideration to the possible need for replacing the current strength of BREO ELLIPTA with a higher strength, adding additional inhaled corticosteroid, or initiating systemic corticosteroids.

Patients should not use more than 1 inhalation once daily of BREO ELLIPTA.

BREO ELLIPTA should not be used for the relief of acute symptoms, i.e., as rescue therapy for the treatment of acute episodes of bronchospasm.

BREO ELLIPTA has not been studied in the relief of acute symptoms and extra doses should not be used for that purpose.

Acute symptoms should be treated with an inhaled, short-acting beta 2 -agonist.

When beginning treatment with BREO ELLIPTA, patients who have been taking oral or inhaled, short-acting beta 2 -agonists on a regular basis (e.g., 4 times a day) should be instructed to discontinue the regular use of these drugs and to use them only for symptomatic relief of acute respiratory symptoms.

When prescribing BREO ELLIPTA, the healthcare provider should also prescribe an inhaled, short-acting beta 2 -agonist and instruct the patient on how it should be used.

5.3 Excessive Use of BREO ELLIPTA and Use with Other Long-acting Beta 2 -agonists BREO ELLIPTA should not be used more often than recommended, at higher doses than recommended, or in conjunction with other medicines containing LABA, as an overdose may result.

Clinically significant cardiovascular effects and fatalities have been reported in association with excessive use of inhaled sympathomimetic drugs.

Patients using BREO ELLIPTA should not use another medicine containing a LABA (e.g., salmeterol, formoterol fumarate, arformoterol tartrate, indacaterol) for any reason.

5.4 Local Effects of Inhaled Corticosteroids In clinical trials, the development of localized infections of the mouth and pharynx with Candida albicans has occurred in subjects treated with BREO ELLIPTA.

When such an infection develops, it should be treated with appropriate local or systemic (i.e., oral) antifungal therapy while treatment with BREO ELLIPTA continues, but at times therapy with BREO ELLIPTA may need to be interrupted.

Advise the patient to rinse his/her mouth with water without swallowing following inhalation to help reduce the risk of oropharyngeal candidiasis.

5.5 Pneumonia An increase in the incidence of pneumonia has been observed in subjects with COPD receiving BREO ELLIPTA 100/25 in clinical trials.

There was also an increased incidence of pneumonias resulting in hospitalization.

In some incidences these pneumonia events were fatal.

Physicians should remain vigilant for the possible development of pneumonia in patients with COPD as the clinical features of such infections overlap with the symptoms of COPD exacerbations.

In replicate 12-month trials in 3,255 subjects with COPD who had experienced a COPD exacerbation in the previous year, there was a higher incidence of pneumonia reported in subjects receiving fluticasone furoate/vilanterol 50 mcg/25 mcg: 6% (48 of 820 subjects); BREO ELLIPTA 100/25: 6% (51 of 806 subjects); or BREO ELLIPTA 200/25: 7% (55 of 811 subjects) than in subjects receiving vilanterol 25 mcg: 3% (27 of 818 subjects).

There was no fatal pneumonia in subjects receiving vilanterol or fluticasone furoate/vilanterol 50 mcg/25 mcg.

There was fatal pneumonia in 1 subject receiving BREO ELLIPTA 100/25 and in 7 subjects receiving BREO ELLIPTA 200/25 (less than 1% for each treatment group).

5.6 Immunosuppression Persons who are using drugs that suppress the immune system are more susceptible to infections than healthy individuals.

Chickenpox and measles, for example, can have a more serious or even fatal course in susceptible children or adults using corticosteroids.

In such children or adults who have not had these diseases or been properly immunized, particular care should be taken to avoid exposure.

How the dose, route, and duration of corticosteroid administration affect the risk of developing a disseminated infection is not known.

The contribution of the underlying disease and/or prior corticosteroid treatment to the risk is also not known.

If a patient is exposed to chickenpox, prophylaxis with varicella zoster immune globulin (VZIG) may be indicated.

If a patient is exposed to measles, prophylaxis with pooled intramuscular immunoglobulin (IG) may be indicated.

(See the respective package inserts for complete VZIG and IG prescribing information.) If chickenpox develops, treatment with antiviral agents may be considered.

Inhaled corticosteroids should be used with caution, if at all, in patients with active or quiescent tuberculosis infections of the respiratory tract; systemic fungal, bacterial, viral, or parasitic infections; or ocular herpes simplex.

5.7 Transferring Patients from Systemic Corticosteroid Therapy Particular care is needed for patients who have been transferred from systemically active corticosteroids to inhaled corticosteroids because deaths due to adrenal insufficiency have occurred in patients with asthma during and after transfer from systemic corticosteroids to less systemically available inhaled corticosteroids.

After withdrawal from systemic corticosteroids, a number of months are required for recovery of hypothalamic-pituitary-adrenal (HPA) function.

Patients who have been previously maintained on 20 mg or more of prednisone (or its equivalent) may be most susceptible, particularly when their systemic corticosteroids have been almost completely withdrawn.

During this period of HPA suppression, patients may exhibit signs and symptoms of adrenal insufficiency when exposed to trauma, surgery, or infection (particularly gastroenteritis) or other conditions associated with severe electrolyte loss.

Although BREO ELLIPTA may control COPD or asthma symptoms during these episodes, in recommended doses it supplies less than normal physiological amounts of glucocorticoid systemically and does NOT provide the mineralocorticoid activity that is necessary for coping with these emergencies.

During periods of stress, a severe COPD exacerbation, or a severe asthma attack, patients who have been withdrawn from systemic corticosteroids should be instructed to resume oral corticosteroids (in large doses) immediately and to contact their physicians for further instruction.

These patients should also be instructed to carry a warning card indicating that they may need supplementary systemic corticosteroids during periods of stress, a severe COPD exacerbation, or a severe asthma attack.

Patients requiring oral corticosteroids should be weaned slowly from systemic corticosteroid use after transferring to BREO ELLIPTA.

Prednisone reduction can be accomplished by reducing the daily prednisone dose by 2.5 mg on a weekly basis during therapy with BREO ELLIPTA.

Lung function (FEV 1 or peak expiratory flow), beta-agonist use, and COPD or asthma symptoms should be carefully monitored during withdrawal of oral corticosteroids.

In addition, patients should be observed for signs and symptoms of adrenal insufficiency, such as fatigue, lassitude, weakness, nausea and vomiting, and hypotension.

Transfer of patients from systemic corticosteroid therapy to BREO ELLIPTA may unmask allergic conditions previously suppressed by the systemic corticosteroid therapy (e.g., rhinitis, conjunctivitis, eczema, arthritis, eosinophilic conditions).

During withdrawal from oral corticosteroids, some patients may experience symptoms of systemically active corticosteroid withdrawal (e.g., joint and/or muscular pain, lassitude, depression) despite maintenance or even improvement of respiratory function.

5.8 Hypercorticism and Adrenal Suppression Inhaled fluticasone furoate is absorbed into the circulation and can be systemically active.

Effects of fluticasone furoate on the HPA axis are not observed with the therapeutic doses of BREO ELLIPTA.

However, exceeding the recommended dosage or coadministration with a strong cytochrome P450 3A4 (CYP3A4) inhibitor may result in HPA dysfunction [see Warnings and Precautions (5.9), Drug Interactions (7.1)] .

Because of the possibility of significant systemic absorption of inhaled corticosteroids in sensitive patients, patients treated with BREO ELLIPTA should be observed carefully for any evidence of systemic corticosteroid effects.

Particular care should be taken in observing patients postoperatively or during periods of stress for evidence of inadequate adrenal response.

It is possible that systemic corticosteroid effects such as hypercorticism and adrenal suppression (including adrenal crisis) may appear in a small number of patients who are sensitive to these effects.

If such effects occur, BREO ELLIPTA should be reduced slowly, consistent with accepted procedures for reducing systemic corticosteroids, and other treatments for management of COPD or asthma symptoms should be considered.

5.9 Drug Interactions with Strong Cytochrome P450 3A4 Inhibitors Caution should be exercised when considering the coadministration of BREO ELLIPTA with long-term ketoconazole and other known strong CYP3A4 inhibitors (e.g., ritonavir, clarithromycin, conivaptan, indinavir, itraconazole, lopinavir, nefazodone, nelfinavir, saquinavir, telithromycin, troleandomycin, voriconazole) because increased systemic corticosteroid and increased cardiovascular adverse effects may occur [see Drug Interactions (7.1), Clinical Pharmacology (12.3)].

5.10 Paradoxical Bronchospasm As with other inhaled medicines, BREO ELLIPTA can produce paradoxical bronchospasm, which may be life threatening.

If paradoxical bronchospasm occurs following dosing with BREO ELLIPTA, it should be treated immediately with an inhaled, short-acting bronchodilator; BREO ELLIPTA should be discontinued immediately; and alternative therapy should be instituted.

5.11 Hypersensitivity Reactions, Including Anaphylaxis Hypersensitivity reactions such as anaphylaxis, angioedema, rash, and urticaria may occur after administration of BREO ELLIPTA.

Discontinue BREO ELLIPTA if such reactions occur.

There have been reports of anaphylactic reactions in patients with severe milk protein allergy after inhalation of other powder medications containing lactose; therefore, patients with severe milk protein allergy should not use BREO ELLIPTA [see Contraindications (4)] .

5.12 Cardiovascular Effects Vilanterol, like other beta 2 -agonists, can produce a clinically significant cardiovascular effect in some patients as measured by increases in pulse rate, systolic or diastolic blood pressure, and also cardiac arrhythmias, such as supraventricular tachycardia and extrasystoles.

If such effects occur, BREO ELLIPTA may need to be discontinued.

In addition, beta-agonists have been reported to produce electrocardiographic changes, such as flattening of the T wave, prolongation of the QTc interval, and ST segment depression, although the clinical significance of these findings is unknown.

Fatalities have been reported in association with excessive use of inhaled sympathomimetic drugs.

In healthy subjects, large doses of inhaled fluticasone furoate/vilanterol (4 times the recommended dose of vilanterol, representing a 12- or 10-fold higher systemic exposure than seen in subjects with COPD or asthma, respectively) have been associated with clinically significant prolongation of the QTc interval, which has the potential for producing ventricular arrhythmias.

Therefore, BREO ELLIPTA, like other sympathomimetic amines, should be used with caution in patients with cardiovascular disorders, especially coronary insufficiency, cardiac arrhythmias, and hypertension.

5.13 Reduction in Bone Mineral Density Decreases in bone mineral density (BMD) have been observed with long-term administration of products containing inhaled corticosteroids.

The clinical significance of small changes in BMD with regard to long-term consequences such as fracture is unknown.

Patients with major risk factors for decreased bone mineral content, such as prolonged immobilization, family history of osteoporosis, postmenopausal status, tobacco use, advanced age, poor nutrition, or chronic use of drugs that can reduce bone mass (e.g., anticonvulsants, oral corticosteroids) should be monitored and treated with established standards of care.

Since patients with COPD often have multiple risk factors for reduced BMD, assessment of BMD is recommended prior to initiating BREO ELLIPTA and periodically thereafter.

If significant reductions in BMD are seen and BREO ELLIPTA is still considered medically important for that patient’s COPD therapy, use of medicine to treat or prevent osteoporosis should be strongly considered.

5.14 Glaucoma and Cataracts Glaucoma, increased intraocular pressure, and cataracts have been reported in patients with COPD or asthma following the long-term administration of inhaled corticosteroids.

Therefore, close monitoring is warranted in patients with a change in vision or with a history of increased intraocular pressure, glaucoma, and/or cataracts.

5.15 Coexisting Conditions BREO ELLIPTA, like all medicines containing sympathomimetic amines, should be used with caution in patients with convulsive disorders or thyrotoxicosis and in those who are unusually responsive to sympathomimetic amines.

Doses of the related beta 2 -adrenoceptor agonist albuterol, when administered intravenously, have been reported to aggravate preexisting diabetes mellitus and ketoacidosis.

5.16 Hypokalemia and Hyperglycemia Beta-adrenergic agonist medicines may produce significant hypokalemia in some patients, possibly through intracellular shunting, which has the potential to produce adverse cardiovascular effects.

The decrease in serum potassium is usually transient, not requiring supplementation.

Beta-agonist medications may produce transient hyperglycemia in some patients.

In clinical trials evaluating BREO ELLIPTA in subjects with COPD or asthma, there was no evidence of a treatment effect on serum glucose or potassium.

5.17 Effect on Growth Orally inhaled corticosteroids may cause a reduction in growth velocity when administered to children and adolescents.

[See Use in Specific Populations (8.4).]

WARNING AND CAUTIONS

5 WARNINGS AND PRECAUTIONS The most serious adverse reactions associated with nevirapine are hepatitis/hepatic failure, Stevens-Johnson syndrome, toxic epidermal necrolysis, and hypersensitivity reactions.

Hepatitis/hepatic failure may be associated with signs of hypersensitivity which can include severe rash or rash accompanied by fever, general malaise, fatigue, muscle or joint aches, blisters, oral lesions, conjunctivitis, facial edema, eosinophilia, granulocytopenia, lymphadenopathy, or renal dysfunction.

The first 18 weeks of therapy with nevirapine are a critical period during which intensive clinical and laboratory monitoring of patients is required to detect potentially life-threatening hepatic events and skin reactions.

The optimal frequency of monitoring during this time period has not been established.

Some experts recommend clinical and laboratory monitoring more often than once per month, and in particular, include monitoring of liver enzyme tests prior to beginning the 14-day lead-in period with immediate-release VIRAMUNE, prior to initiation of VIRAMUNE XR (during the lead-in period), and at two weeks after initiation of VIRAMUNE XR therapy.

After the initial 18-week period, frequent clinical and laboratory monitoring should continue throughout VIRAMUNE XR treatment.

In addition, the 14-day lead-in period with immediate-release VIRAMUNE has been demonstrated to reduce the frequency of rash [ see Dosage and Administration (2.2 , 2.5) ].

Patients already on a regimen of immediate-release VIRAMUNE twice daily who switch to VIRAMUNE XR therapy should continue with their ongoing clinical and laboratory monitoring.

Hepatotoxicity: Fatal and non-fatal hepatotoxicity has been reported.

Monitor liver function tests before and during therapy.

Permanently discontinue nevirapine if clinical hepatitis or transaminase elevations combined with rash or other systemic symptoms occur.

Do not restart nevirapine after recovery.

(5.1) Rash: Fatal and non-fatal skin reactions, including Stevens-Johnson syndrome, toxic epidermal necrolysis, and hypersensitivity reactions, have been reported.

Permanently discontinue nevirapine if severe skin reactions or hypersensitivity reactions occur.

Check transaminase levels immediately for all patients who develop a rash in the first 18 weeks of treatment.

(5.2) Monitor patients for immune reconstitution syndrome and fat redistribution.

(5.5 , 5.6) 5.1 Hepatotoxicity and Hepatic Impairment Severe, life-threatening, and in some cases fatal hepatotoxicity, including fulminant and cholestatic hepatitis, hepatic necrosis and hepatic failure, have been reported in patients treated with nevirapine.

The risk of symptomatic hepatic events regardless of severity is greatest in the first 6 weeks of therapy.

The risk continued to be greater in the nevirapine groups in controlled clinical trials through 18 weeks of treatment.

However, hepatic events may occur at any time during treatment.

In some cases, patients presented with non-specific, prodromal signs or symptoms of fatigue, malaise, anorexia, nausea, jaundice, liver tenderness or hepatomegaly, with or without initially abnormal serum transaminase levels.

Rash was observed in approximately half of the patients with symptomatic hepatic adverse events.

Fever and flu-like symptoms accompanied some of these hepatic events.

Some events, particularly those with rash and other symptoms, have progressed to hepatic failure with transaminase elevation, with or without hyperbilirubinemia, hepatic encephalopathy, prolonged partial thromboplastin time, or eosinophilia.

Rhabdomyolysis has been observed in some patients experiencing skin and/or liver reactions associated with nevirapine use.

Patients with signs or symptoms of hepatitis must be advised to discontinue nevirapine and immediately seek medical evaluation, which should include liver enzyme tests.

Transaminases should be checked immediately if a patient experiences signs or symptoms suggestive of hepatitis and/or hypersensitivity reaction.

Transaminases should also be checked immediately for all patients who develop a rash in the first 18 weeks of treatment.

Physicians and patients should be vigilant for the appearance of signs or symptoms of hepatitis, such as fatigue, malaise, anorexia, nausea, jaundice, bilirubinuria, acholic stools, liver tenderness, or hepatomegaly.

The diagnosis of hepatotoxicity should be considered in this setting, even if transaminases are initially normal or alternative diagnoses are possible [ see Boxed Warning , Dosage and Administration (2.4) , and Patient Counseling Information (17.1) ].

If clinical hepatitis or transaminase elevations combined with rash or other systemic symptoms occur, permanently discontinue nevirapine.

Do not restart nevirapine after recovery.

In some cases, hepatic injury progresses despite discontinuation of treatment.

The patients at greatest risk of hepatic events, including potentially fatal events, are women with high CD4 + cell counts.

In a retrospective analysis of pooled clinical trials with immediate-release VIRAMUNE, during the first 6 weeks of treatment women had a 3-fold higher risk than men for symptomatic, often rash-associated, hepatic events (6% versus 2%).

Patients with higher CD4 + cell counts at initiation of nevirapine therapy are at higher risk for symptomatic hepatic events.

Women with CD4 + cell counts greater than 250 cells/mm 3 had a 12-fold higher risk of symptomatic hepatic adverse events compared to women with CD4 + cell counts less than 250 cells/mm 3 (11% versus 1%).

An increased risk was observed in men with CD4 + cell counts greater than 400 cells/mm 3 (6% versus 1% for men with CD4 + cell counts less than 400 cells/mm 3 ).

However, all patients, regardless of gender, CD4 + cell count, or antiretroviral treatment history, should be monitored for hepatotoxicity since symptomatic hepatic adverse events have been reported at all CD4 + cell counts.

Co-infection with hepatitis B or C and/or increased transaminase elevations at the start of therapy with nevirapine are associated with a greater risk of later symptomatic events (6 weeks or more after starting nevirapine) and asymptomatic increases in AST or ALT.

In addition, serious hepatotoxicity (including liver failure requiring transplantation in one instance) has been reported in HIV-1 uninfected individuals receiving multiple doses of immediate-release VIRAMUNE in the setting of post-exposure prophylaxis (PEP), an unapproved use.

Use of VIRAMUNE XR for occupational and non-occupational PEP is contraindicated [ see Contraindications (4.2) ].

Increased nevirapine trough concentrations have been observed in some patients with hepatic fibrosis or cirrhosis.

Therefore, carefully monitor patients with either hepatic fibrosis or cirrhosis for evidence of drug-induced toxicity.

Do not administer nevirapine to patients with moderate or severe (Child-Pugh Class B or C, respectively) hepatic impairment [ see Contraindications (4.1) , Use in Specific Populations (8.7) , and Clinical Pharmacology (12.3) ].

VIRAMUNE XR has not been evaluated in subjects with hepatic impairment.

5.2 Skin Reactions Severe and life-threatening skin reactions, including fatal cases, have been reported in patients taking nevirapine.

These have occurred most frequently during the first 6 weeks of therapy.

These have included cases of Stevens-Johnson syndrome, toxic epidermal necrolysis, and hypersensitivity reactions characterized by rash, constitutional findings, and organ dysfunction including hepatic failure.

Rhabdomyolysis has been observed in some patients experiencing skin and/or liver reactions associated with nevirapine use.

Patients developing signs or symptoms of severe skin reactions or hypersensitivity reactions (including, but not limited to, severe rash or rash accompanied by fever, general malaise, fatigue, muscle or joint aches, blisters, oral lesions, conjunctivitis, facial edema, and/or hepatitis, eosinophilia, granulocytopenia, lymphadenopathy, and renal dysfunction) must permanently discontinue nevirapine and seek medical evaluation immediately [ see Boxed Warning and Patient Counseling Information (17.1) ].

Do not restart nevirapine following severe skin rash, skin rash combined with increased transaminases or other symptoms, or hypersensitivity reaction.

If patients present with a suspected nevirapine-associated rash, measure transaminases immediately.

Permanently discontinue nevirapine in patients with rash-associated transaminase elevations [ see Warnings and Precautions (5.1) ].

Patients must initiate therapy with immediate-release VIRAMUNE daily for the first 14 days.

This lead-in period has been shown to reduce the frequency of rash.

Discontinue nevirapine if a patient experiences severe rash or any rash accompanied by constitutional findings.

Do not initiate VIRAMUNE XR if a patient experiencing a mild to moderate rash without constitutional symptoms during the 14-day immediate-release VIRAMUNE lead-in period of 200 mg/day (150 mg/m 2 /day in pediatric patients) until the rash has resolved.

The total duration of the immediate-release VIRAMUNE lead-in dosing period must not exceed 28 days at which point an alternative regimen should be sought [ see Dosage and Administration (2.5) ].

Patients must be monitored closely if isolated rash of any severity occurs.

Delay in stopping nevirapine treatment after the onset of rash may result in a more serious reaction.

Women appear to be at higher risk than men of developing rash with nevirapine.

In a clinical trial of immediate-release VIRAMUNE, concomitant prednisone use (40 mg per day for the first 14 days of nevirapine administration) was associated with an increase in incidence and severity of rash during the first 6 weeks of nevirapine therapy.

Therefore, use of prednisone to prevent nevirapine-associated rash is not recommended.

5.3 Resistance VIRAMUNE XR must not be used as a single agent to treat HIV-1 or added on as a sole agent to a failing regimen.

Resistant virus emerges rapidly when nevirapine is administered as monotherapy.

The choice of new antiretroviral agents to be used in combination with nevirapine should take into consideration the potential for cross resistance.

When discontinuing an antiretroviral regimen containing VIRAMUNE XR, the long half-life of nevirapine should be taken into account; if antiretrovirals with shorter half-lives than nevirapine are stopped concurrently, low plasma concentrations of nevirapine alone may persist for a week or longer and virus resistance may subsequently develop [ see Microbiology (12.4) ].

5.4 Drug Interactions See Table 4 for listings of established and potential drug interactions [ see Drug Interactions (7) ].

Concomitant use of St.

John’s wort ( Hypericum perforatum ) or St.

John’s wort-containing products and nevirapine is not recommended.

Co-administration of St.

John’s wort with non-nucleoside reverse transcriptase inhibitors (NNRTIs), including nevirapine, is expected to substantially decrease NNRTI concentrations and may result in sub-optimal levels of nevirapine and lead to loss of virologic response and possible resistance to nevirapine or to the class of NNRTIs.

Co-administration of nevirapine and efavirenz is not recommended as this combination has been associated with an increase in adverse reactions and no improvement in efficacy.

5.5 Immune Reconstitution Syndrome Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including nevirapine.

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 jiroveci pneumonia, or tuberculosis), which may necessitate further evaluation and treatment.

Autoimmune disorders (such as Graves’ disease, polymyositis, and Guillain-Barré syndrome) have also been reported to occur in the setting of immune reconstitution, however, the time to onset is more variable, and can occur many months after initiation of treatment.

5.6 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.