Author: druginteractionchecker_lgaiz4

WARNING AND CAUTIONS

5 WARNINGS AND PRECAUTIONS Drug Reaction with Eosinophilia and Systemic Symptoms (Multiorgan hypersensitivity): Discontinue if alternative etiology is not established (5.1) Anaphylaxis and Angioedema: Discontinue and evaluate patient immediately (5.2) Driving Impairment; Somnolence/Sedation and Dizziness: Warn patients not to drive until they have gained sufficient experience to assess whether their ability to drive or operate heavy machinery will be impaired (5.3, 5.4) Increased seizure frequency may occur in patients with seizure disorders if gabapentin is abruptly discontinued (5.5) Suicidal Behavior and Ideation: Monitor for suicidal thoughts/behavior (5.6) Respiratory depression: May occur with gabapentin when used with concomitant central nervous system (CNS) depressants or in the setting of underlying respiratory impairment.

Monitor patients and adjust dosage as appropriate (5.7) Neuropsychiatric Adverse Reactions in Children 3 to 12 Years of Age: Monitor for such events (5.8) 5.1 Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)/Multiorgan Hypersensitivity Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), also known as multiorgan hypersensitivity, has occurred with gabapentin.

Some of these reactions 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, hematological 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.

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

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

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

5.2 Anaphylaxis and Angioedema Gabapentin can cause anaphylaxis and angioedema after the first dose or at any time during treatment.

Signs and symptoms in reported cases have included difficulty breathing, swelling of the lips, throat, and tongue, and hypotension requiring emergency treatment.

Patients should be instructed to discontinue gabapentin and seek immediate medical care should they experience signs or symptoms of anaphylaxis or angioedema.

5.3 Effects on Driving and Operating Heavy Machinery Patients taking gabapentin should not drive until they have gained sufficient experience to assess whether gabapentin impairs their ability to drive.

Driving performance studies conducted with a prodrug of gabapentin (gabapentin enacarbil tablet, extended-release) indicate that gabapentin may cause significant driving impairment.

Prescribers and patients should be aware that patients’ ability to assess their own driving competence, as well as their ability to assess the degree of somnolence caused by gabapentin, can be imperfect.

The duration of driving impairment after starting therapy with gabapentin is unknown.

Whether the impairment is related to somnolence [see Warnings and Precautions (5.4) ] or other effects of gabapentin is unknown.

Moreover, because gabapentin causes somnolence and dizziness [see Warnings and Precautions (5.4) ] , patients should be advised not to operate complex machinery until they have gained sufficient experience on gabapentin to assess whether gabapentin impairs their ability to perform such tasks.

5.4 Somnolence/Sedation and Dizziness During the controlled epilepsy trials in patients older than 12 years of age receiving doses of gabapentin up to 1,800 mg daily, somnolence, dizziness, and ataxia were reported at a greater rate in patients receiving gabapentin compared to placebo: i.e., 19% in drug versus 9% in placebo for somnolence, 17% in drug versus 7% in placebo for dizziness, and 13% in drug versus 6% in placebo for ataxia.

In these trials somnolence, ataxia and fatigue were common adverse reactions leading to discontinuation of gabapentin in patients older than 12 years of age, with 1.2%, 0.8% and 0.6% discontinuing for these events, respectively.

During the controlled trials in patients with post-herpetic neuralgia, somnolence, and dizziness were reported at a greater rate compared to placebo in patients receiving gabapentin, in dosages up to 3,600 mg per day: i.e., 21% in gabapentin-treated patients versus 5% in placebo-treated patients for somnolence and 28% in gabapentin-treated patients versus 8% in placebo-treated patients for dizziness.

Dizziness and somnolence were among the most common adverse reactions leading to discontinuation of gabapentin.

Patients should be carefully observed for signs of central nervous system (CNS) depression, such as somnolence and sedation, when gabapentin is used with other drugs with sedative properties because of potential synergy.

In addition, patients who require concomitant treatment with morphine may experience increases in gabapentin concentrations and may require dose adjustment [ see Drug Interactions (7.2) ].

5.5 Withdrawal Precipitated Seizure, Status Epilepticus Antiepileptic drugs should not be abruptly discontinued because of the possibility of increasing seizure frequency.

In the placebo-controlled epilepsy studies in patients > 12 years of age, the incidence of status epilepticus in patients receiving gabapentin was 0.6% (3 of 543) vs.

0.5% in patients receiving placebo (2 of 378).

Among the 2,074 patients > 12 years of age treated with gabapentin across all epilepsy studies (controlled and uncontrolled), 31 (1.5%) had status epilepticus.

Of these, 14 patients had no prior history of status epilepticus either before treatment or while on other medications.

Because adequate historical data are not available, it is impossible to say whether or not treatment with gabapentin is associated with a higher or lower rate of status epilepticus than would be expected to occur in a similar population not treated with gabapentin.

5.6 Suicidal Behavior and Ideation Antiepileptic drugs (AEDs), including gabapentin, increase the risk of suicidal thoughts or behavior in patients taking these drugs for any indication.

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

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

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

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

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

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

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

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

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

Table 2 shows absolute and relative risk by indication for all evaluated AEDs.

TABLE 2.

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 3.4 3.5 2.4 Psychiatric 5.7 8.5 1.5 2.9 Other 1 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 gabapentin 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.

5.7 Respiratory Depression There is evidence from case reports, human studies, and animal studies associating gabapentin with serious, life-threatening, or fatal respiratory depression when co-administered with CNS depressants, including opioids, or in the setting of underlying respiratory impairment.

When the decision is made to co-prescribe gabapentin with another CNS depressant, particularly an opioid, or to prescribe gabapentin to patients with underlying respiratory impairment, monitor patients for symptoms of respiratory depression and sedation, and consider initiating gabapentin at a low dose.

The management of respiratory depression may include close observation, supportive measures, and reduction or withdrawal of CNS depressants (including gabapentin).

5.8 Neuropsychiatric Adverse Reactions (Pediatric Patients 3 to 12 Years of Age) Gabapentin use in pediatric patients with epilepsy 3 to 12 years of age is associated with the occurrence of CNS related adverse reactions.

The most significant of these can be classified into the following categories: 1) emotional lability (primarily behavioral problems), 2) hostility, including aggressive behaviors, 3) thought disorder, including concentration problems and change in school performance, and 4) hyperkinesia (primarily restlessness and hyperactivity).

Among the gabapentin-treated patients, most of the reactions were mild to moderate in intensity.

In controlled clinical epilepsy trials in pediatric patients 3 to 12 years of age, the incidence of these adverse reactions was: emotional lability 6% (gabapentin-treated patients) vs.

1.3% (placebo-treated patients); hostility 5.2% vs.

1.3%; hyperkinesia 4.7% vs.

2.9%; and thought disorder 1.7% vs.

0%.

One of these reactions, a report of hostility, was considered serious.

Discontinuation of gabapentin treatment occurred in 1.3% of patients reporting emotional lability and hyperkinesia and 0.9% of gabapentin-treated patients reporting hostility and thought disorder.

One placebo-treated patient (0.4%) withdrew due to emotional lability.

5.9 Tumorigenic Potential In an oral carcinogenicity study, gabapentin increased the incidence of pancreatic acinar cell tumors in rats [see Nonclinical Toxicology (13.1)] .

The clinical significance of this finding is unknown.

Clinical experience during gabapentin’s premarketing development provides no direct means to assess its potential for inducing tumors in humans.

In clinical studies in adjunctive therapy in epilepsy comprising 2,085 patient-years of exposure in patients > 12 years of age, new tumors were reported in 10 patients (2 breast, 3 brain, 2 lung, 1 adrenal, 1 non-Hodgkin’s lymphoma, 1 endometrial carcinoma in situ ), and preexisting tumors worsened in 11 patients (9 brain, 1 breast, 1 prostate) during or up to 2 years following discontinuation of gabapentin.

Without knowledge of the background incidence and recurrence in a similar population not treated with gabapentin, it is impossible to know whether the incidence seen in this cohort is or is not affected by treatment.

5.10 Sudden and Unexplained Death in Patients with Epilepsy During the course of premarketing development of gabapentin, 8 sudden and unexplained deaths were recorded among a cohort of 2,203 epilepsy patients treated (2,103 patient-years of exposure) with gabapentin.

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

This represents an incidence of 0.0038 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 gabapentin (ranging from 0.0005 for the general population of epileptics to 0.003 for a clinical trial population similar to that in the gabapentin program, to 0.005 for patients with refractory epilepsy).

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

WARNING AND CAUTIONS

5 WARNINGS AND PRECAUTIONS • Clinical Worsening/Suicide Risk: Monitor for clinical worsening and suicidal thinking and behavior ( 5.1 ).

• Serotonin Syndrome or Neuroleptic Malignant Syndrome-Like Reactions: Have been reported with antidepressants.

Discontinue trazodone hydrochloride tablets and initiate supportive treatment ( 5.2 , 7 ).

• Activation of Mania/Hypomania: Screen for bipolar disorder and monitor for mania/hypomania ( 5.3 ).

• QT Prolongation: Increases the QT interval.

Avoid use with drugs that also increase the QT interval and in patients with risk factors for prolonged QT interval ( 5.4 ).

• Use in Patients With Heart Disease: Use with caution in patients with cardiac disease ( 5.5 ).

• Orthostatic Hypotension and Syncope: Have occurred.

Warn patients of risk and symptoms of hypotension ( 5.6 ).

• Abnormal Bleeding: May increase the risk of bleeding.

Use with NSAIDs, aspirin, or other drugs that affect coagulation may compound this risk ( 5.7 , 7 ).

• Interaction With MAOIs: Do not use concomitantly or within 14 days of monoamine oxidase inhibitors ( 5.8 , 7 ).

• Priapism: Has occurred.

Warn male patients of this risk and how/when to seek medical attention ( 5.9 ).

• Hyponatremia: Can occur in association with SIADH ( 5.10 ).

• Potential for Cognitive and Motor Impairment: Has potential to impair judgment, thinking, and motor skills.

Advise patients to use caution when operating machinery ( 5.11 ).

• Angle-Closure Glaucoma: Angle closure glaucoma has occurred in patients with untreated anatomically narrow angles treated with antidepressants.

( 5.12 ) • Discontinuation Symptoms: May occur with abrupt discontinuation and include anxiety and sleep disturbance.

Upon discontinuation, taper trazodone hydrochloride tablets and monitor for symptoms ( 5.13 ).

5.1 Clinical Worsening and Suicide Risk Patients with major depressive disorder (MDD), both adult and pediatric, may experience worsening of their depression and/or the emergence of suicidal ideation and behavior (suicidality) or unusual changes in behavior, whether or not they are taking antidepressant medications, and this risk may persist until significant remission occurs.

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

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

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

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

The pooled analyses of placebo-controlled trials in children and adolescents with MDD, obsessive compulsive disorder (OCD), or other psychiatric disorders included a total of 24 short-term trials of 9 antidepressant drugs in over 4,400 patients.

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

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

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

The risk differences (drug vs.

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

These risk differences (drug-placebo difference in the number of cases of suicidality per 1,000 patients treated) are provided in Table 1 .

Table 1 Age Range Drug-Placebo Difference in Number of Cases of Suicidality per 1,000 Patients Treated Increases Compared to Placebo < 18 14 additional cases 18 to 24 5 additional cases Decreases Compared to Placebo 25 to 64 1 fewer case ≥ 65 6 fewer cases No suicides occurred in any of the pediatric trials.

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

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

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

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

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

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

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

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

Such monitoring should include daily observation by families and caregivers .

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

5.2 Serotonin Syndrome or Neuroleptic Malignant Syndrome (NMS)-Like Reactions The development of a potentially life-threatening serotonin syndrome or neuroleptic malignant syndrome (NMS)-like reactions have been reported with antidepressants alone and may occur with trazodone treatment, but particularly with concomitant use of other serotoninergic drugs (including SSRIs, SNRIs and triptans) and with drugs that impair metabolism of serotonin (including monoamine oxidase inhibitors [MAOIs]), or with antipsychotics or other dopamine antagonists.

Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, and coma), autonomic instability (e.g., tachycardia, labile blood pressure, and hyperthermia), neuromuscular aberrations (e.g., hyperreflexia, incoordination) and/or gastrointestinal symptoms (e.g., nausea, vomiting, and diarrhea).

Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome, which includes hyperthermia, muscle rigidity, autonomic instability with possible rapid fluctuation of vital signs, and mental status changes.

Treatment with trazodone hydrochloride tablets and any concomitant serotonergic or antidopaminergic agents, including antipsychotics, should be discontinued immediately if the above reactions occur and supportive symptomatic treatment should be initiated.

Trazodone hydrochloride tablets should not be used within 14 days of an MAOI [see Warnings and Precautions ( 5.8 ) and Drug Interactions ( 7 )].

If concomitant treatment with trazodone hydrochloride tablets and an SSRI, SNRI or a 5-hydroxytryptamine receptor agonist (triptan) is clinically warranted, careful observation of the patient is advised, particularly during treatment initiation and dose increases.

The concomitant use of trazodone hydrochloride tablets with serotonin precursors (such as tryptophan) is not recommended.

5.3 Screening Patients for Bipolar Disorder and Monitoring for Mania/Hypomania A major depressive episode may be the initial presentation of bipolar disorder.

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

Whether any of the symptoms described for clinical worsening and suicide risk represent such a conversion is unknown.

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

It should be noted that trazodone hydrochloride tablets are not approved for use in treating bipolar depression.

5.4 QT Prolongation and Risk of Sudden Death Trazodone is known to prolong the QT/QT c interval.

Some drugs that prolong the QT/QT c interval can cause torsade de pointes with sudden, unexplained death.

The relationship of QT prolongation is clearest for larger increases (20 msec and greater), but it is possible that smaller QT/QT c prolongations may also increase risk, especially in susceptible individuals, such as those with hypokalemia, hypomagnesemia, or a genetic predisposition to prolonged QT/QT c .

Although torsade de pointes has not been observed with the use of trazodone hydrochloride tablets at recommended doses in premarketing trials, experience is too limited to rule out an increased risk.

However, there have been postmarketing reports of torsade de pointes with the immediate-release form of trazodone (in the presence of multiple confounding factors), even at doses of 100 mg per day or less.

5.5 Use in Patients With Heart Disease Trazodone hydrochloride is not recommended for use during the initial recovery phase of myocardial infarction.

Caution should be used when administering trazodone hydrochloride tablets to patients with cardiac disease and such patients should be closely monitored, since antidepressant drugs (including trazodone hydrochloride) may cause cardiac arrhythmias.

QT prolongation has been reported with trazodone therapy [see Warnings and Precautions (5.4)] .

Clinical studies in patients with preexisting cardiac disease indicate that trazodone hydrochloride may be arrhythmogenic in some patients in that population.

Arrhythmias identified include isolated PVCs, ventricular couplets, tachycardia with syncope, and torsade de pointes.

Postmarketing events have been reported at doses of 100 mg or less with the immediate-release form of trazodone.

Concomitant administration of drugs that prolong the QT interval or that are inhibitors of CYP3A4 may increase the risk of cardiac arrhythmia.

5.6 Orthostatic Hypotension and Syncope Hypotension, including orthostatic hypotension and syncope has been reported in patients receiving trazodone hydrochloride.

Concomitant use with an antihypertensive may require a reduction in the dose of the antihypertensive drug.

5.7 Abnormal Bleeding Postmarketing data have shown an association between use of drugs that interfere with serotonin reuptake and the occurrence of gastrointestinal (GI) bleeding.

While no association between trazodone and bleeding events, in particular GI bleeding, was shown, patients should be cautioned about potential risk of bleeding associated with the concomitant use of trazodone and NSAIDs, aspirin, or other drugs that affect coagulation or bleeding.

Other bleeding events related to SSRIs and SNRIs have ranged from ecchymosis, hematoma, epistaxis, and petechiae to life-threatening hemorrhages.

5.8 Interaction With MAOIs In patients receiving serotonergic drugs in combination with a monoamine oxidase inhibitor (MAOI), there have been reports of serious, sometimes fatal reactions including hyperthermia, rigidity, myoclonus, autonomic instability with rapid fluctuation in vital signs, and mental status changes that include extreme agitation progressing to delirium and coma.

These reactions have also been reported in patients who have recently discontinued antidepressant treatment and have been started on an MAOI.

Some cases presented with features resembling neuroleptic malignant syndrome.

Furthermore, limited animal data on the effects of combined use of serotonergic antidepressants and MAOIs suggest that these drugs may act synergistically to elevate blood pressure and evoke behavioral excitation.

Therefore, it is recommended that trazodone hydrochloride tablets should not be used in combination with an MAOI or within 14 days of discontinuing treatment with an MAOI.

Similarly, at least 14 days should be allowed after stopping trazodone hydrochloride tablets before starting an MAOI.

5.9 Priapism Rare cases of priapism (painful erections greater than 6 hours in duration) were reported in men receiving trazodone.

Priapism, if not treated promptly, can result in irreversible damage to the erectile tissue.

Men who have an erection lasting greater than 6 hours, whether painful or not, should immediately discontinue the drug and seek emergency medical attention [see Adverse Reactions ( 6.2 ) and Overdosage ( 10 )].

Trazodone should be used with caution in men who have conditions that might predispose them to priapism (e.g., sickle cell anemia, multiple myeloma, or leukemia), or in men with anatomical deformation of the penis (e.g., angulation, cavernosal fibrosis, or Peyronie’s disease).

5.10 Hyponatremia Hyponatremia may occur as a result of treatment with antidepressants.

In many cases, this hyponatremia appears to be the result of the syndrome of inappropriate antidiuretic hormone secretion (SIADH).

Cases with serum sodium lower than 110 mmol/L have been reported.

Elderly patients may be at greater risk of developing hyponatremia with antidepressants.

Also, patients taking diuretics or who are otherwise volume-depleted can be at greater risk.

Discontinuation of trazodone hydrochloride tablets should be considered in patients with symptomatic hyponatremia and appropriate medical intervention should be instituted.

Signs and symptoms of hyponatremia include headache, difficulty concentrating, memory impairment, confusion, weakness, and unsteadiness, which can lead to falls.

Signs and symptoms associated with more severe and/or acute cases have included hallucination, syncope, seizure, coma, respiratory arrest, and death.

5.11 Potential for Cognitive and Motor Impairment Trazodone hydrochloride tablets may cause somnolence or sedation and may impair the mental and/or physical ability required for the performance of potentially hazardous tasks.

Patients should be cautioned about operating hazardous machinery, including automobiles, until they are reasonably certain that the drug treatment does not affect them adversely 5.12 Angle-Closure Glaucoma Angle-Closure Glaucoma: The pupillary dilation that occurs following use of many antidepressant drugs including trazodone hydrochloride tablets may trigger an angle closure attack in a patient with anatomically narrow angles who does not have a patent iridectomy 5.13 Discontinuation Symptoms Withdrawal symptoms including anxiety, agitation and sleep disturbances, have been reported with trazodone.

Clinical experience suggests that the dose should be gradually reduced before complete discontinuation of the treatment.

WARNING AND CAUTIONS

5 WARNINGS AND PRECAUTIONS Drug Reaction with Eosinophilia and Systemic Symptoms (Multiorgan hypersensitivity): Discontinue if alternative etiology is not established (5.1) Anaphylaxis and Angioedema: Discontinue and evaluate patient immediately (5.2) Driving Impairment; Somnolence/Sedation and Dizziness: Warn patients not to drive until they have gained sufficient experience to assess whether their ability to drive or operate heavy machinery will be impaired (5.3, 5.4) Increased seizure frequency may occur in patients with seizure disorders if gabapentin is abruptly discontinued (5.5) Suicidal Behavior and Ideation: Monitor for suicidal thoughts/behavior (5.6) Respiratory depression: May occur with gabapentin when used with concomitant central nervous system (CNS) depressants or in the setting of underlying respiratory impairment.

Monitor patients and adjust dosage as appropriate (5.7) Neuropsychiatric Adverse Reactions in Children 3 to 12 Years of Age: Monitor for such events (5.8) 5.1 Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)/Multiorgan Hypersensitivity Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), also known as multiorgan hypersensitivity, has occurred with gabapentin.

Some of these reactions 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, hematological 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.

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

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

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

5.2 Anaphylaxis and Angioedema Gabapentin can cause anaphylaxis and angioedema after the first dose or at any time during treatment.

Signs and symptoms in reported cases have included difficulty breathing, swelling of the lips, throat, and tongue, and hypotension requiring emergency treatment.

Patients should be instructed to discontinue gabapentin and seek immediate medical care should they experience signs or symptoms of anaphylaxis or angioedema.

5.3 Effects on Driving and Operating Heavy Machinery Patients taking gabapentin should not drive until they have gained sufficient experience to assess whether gabapentin impairs their ability to drive.

Driving performance studies conducted with a prodrug of gabapentin (gabapentin enacarbil tablet, extended-release) indicate that gabapentin may cause significant driving impairment.

Prescribers and patients should be aware that patients’ ability to assess their own driving competence, as well as their ability to assess the degree of somnolence caused by gabapentin, can be imperfect.

The duration of driving impairment after starting therapy with gabapentin is unknown.

Whether the impairment is related to somnolence [see Warnings and Precautions (5.4) ] or other effects of gabapentin is unknown.

Moreover, because gabapentin causes somnolence and dizziness [see Warnings and Precautions (5.4) ] , patients should be advised not to operate complex machinery until they have gained sufficient experience on gabapentin to assess whether gabapentin impairs their ability to perform such tasks.

5.4 Somnolence/Sedation and Dizziness During the controlled epilepsy trials in patients older than 12 years of age receiving doses of gabapentin up to 1,800 mg daily, somnolence, dizziness, and ataxia were reported at a greater rate in patients receiving gabapentin compared to placebo: i.e., 19% in drug versus 9% in placebo for somnolence, 17% in drug versus 7% in placebo for dizziness, and 13% in drug versus 6% in placebo for ataxia.

In these trials somnolence, ataxia and fatigue were common adverse reactions leading to discontinuation of gabapentin in patients older than 12 years of age, with 1.2%, 0.8% and 0.6% discontinuing for these events, respectively.

During the controlled trials in patients with post-herpetic neuralgia, somnolence, and dizziness were reported at a greater rate compared to placebo in patients receiving gabapentin, in dosages up to 3,600 mg per day: i.e., 21% in gabapentin-treated patients versus 5% in placebo-treated patients for somnolence and 28% in gabapentin-treated patients versus 8% in placebo-treated patients for dizziness.

Dizziness and somnolence were among the most common adverse reactions leading to discontinuation of gabapentin.

Patients should be carefully observed for signs of central nervous system (CNS) depression, such as somnolence and sedation, when gabapentin is used with other drugs with sedative properties because of potential synergy.

In addition, patients who require concomitant treatment with morphine may experience increases in gabapentin concentrations and may require dose adjustment [ see Drug Interactions (7.2) ].

5.5 Withdrawal Precipitated Seizure, Status Epilepticus Antiepileptic drugs should not be abruptly discontinued because of the possibility of increasing seizure frequency.

In the placebo-controlled epilepsy studies in patients > 12 years of age, the incidence of status epilepticus in patients receiving gabapentin was 0.6% (3 of 543) vs.

0.5% in patients receiving placebo (2 of 378).

Among the 2,074 patients > 12 years of age treated with gabapentin across all epilepsy studies (controlled and uncontrolled), 31 (1.5%) had status epilepticus.

Of these, 14 patients had no prior history of status epilepticus either before treatment or while on other medications.

Because adequate historical data are not available, it is impossible to say whether or not treatment with gabapentin is associated with a higher or lower rate of status epilepticus than would be expected to occur in a similar population not treated with gabapentin.

5.6 Suicidal Behavior and Ideation Antiepileptic drugs (AEDs), including gabapentin, increase the risk of suicidal thoughts or behavior in patients taking these drugs for any indication.

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

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

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

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

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

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

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

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

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

Table 2 shows absolute and relative risk by indication for all evaluated AEDs.

TABLE 2.

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 3.4 3.5 2.4 Psychiatric 5.7 8.5 1.5 2.9 Other 1 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 gabapentin 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.

5.7 Respiratory Depression There is evidence from case reports, human studies, and animal studies associating gabapentin with serious, life-threatening, or fatal respiratory depression when co-administered with CNS depressants, including opioids, or in the setting of underlying respiratory impairment.

When the decision is made to co-prescribe gabapentin with another CNS depressant, particularly an opioid, or to prescribe gabapentin to patients with underlying respiratory impairment, monitor patients for symptoms of respiratory depression and sedation, and consider initiating gabapentin at a low dose.

The management of respiratory depression may include close observation, supportive measures, and reduction or withdrawal of CNS depressants (including gabapentin).

5.8 Neuropsychiatric Adverse Reactions (Pediatric Patients 3 to 12 Years of Age) Gabapentin use in pediatric patients with epilepsy 3 to 12 years of age is associated with the occurrence of CNS related adverse reactions.

The most significant of these can be classified into the following categories: 1) emotional lability (primarily behavioral problems), 2) hostility, including aggressive behaviors, 3) thought disorder, including concentration problems and change in school performance, and 4) hyperkinesia (primarily restlessness and hyperactivity).

Among the gabapentin-treated patients, most of the reactions were mild to moderate in intensity.

In controlled clinical epilepsy trials in pediatric patients 3 to 12 years of age, the incidence of these adverse reactions was: emotional lability 6% (gabapentin-treated patients) vs.

1.3% (placebo-treated patients); hostility 5.2% vs.

1.3%; hyperkinesia 4.7% vs.

2.9%; and thought disorder 1.7% vs.

0%.

One of these reactions, a report of hostility, was considered serious.

Discontinuation of gabapentin treatment occurred in 1.3% of patients reporting emotional lability and hyperkinesia and 0.9% of gabapentin-treated patients reporting hostility and thought disorder.

One placebo-treated patient (0.4%) withdrew due to emotional lability.

5.9 Tumorigenic Potential In an oral carcinogenicity study, gabapentin increased the incidence of pancreatic acinar cell tumors in rats [see Nonclinical Toxicology (13.1)] .

The clinical significance of this finding is unknown.

Clinical experience during gabapentin’s premarketing development provides no direct means to assess its potential for inducing tumors in humans.

In clinical studies in adjunctive therapy in epilepsy comprising 2,085 patient-years of exposure in patients > 12 years of age, new tumors were reported in 10 patients (2 breast, 3 brain, 2 lung, 1 adrenal, 1 non-Hodgkin’s lymphoma, 1 endometrial carcinoma in situ ), and preexisting tumors worsened in 11 patients (9 brain, 1 breast, 1 prostate) during or up to 2 years following discontinuation of gabapentin.

Without knowledge of the background incidence and recurrence in a similar population not treated with gabapentin, it is impossible to know whether the incidence seen in this cohort is or is not affected by treatment.

5.10 Sudden and Unexplained Death in Patients with Epilepsy During the course of premarketing development of gabapentin, 8 sudden and unexplained deaths were recorded among a cohort of 2,203 epilepsy patients treated (2,103 patient-years of exposure) with gabapentin.

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

This represents an incidence of 0.0038 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 gabapentin (ranging from 0.0005 for the general population of epileptics to 0.003 for a clinical trial population similar to that in the gabapentin program, to 0.005 for patients with refractory epilepsy).

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

WARNING AND CAUTIONS

5 WARNINGS AND PRECAUTIONS • Clinical Worsening/Suicide Risk: Monitor for clinical worsening and suicidal thinking and behavior ( 5.1 ).

• Serotonin Syndrome or Neuroleptic Malignant Syndrome-Like Reactions: Have been reported with antidepressants.

Discontinue trazodone hydrochloride tablets and initiate supportive treatment ( 5.2 , 7 ).

• Activation of Mania/Hypomania: Screen for bipolar disorder and monitor for mania/hypomania ( 5.3 ).

• QT Prolongation: Increases the QT interval.

Avoid use with drugs that also increase the QT interval and in patients with risk factors for prolonged QT interval ( 5.4 ).

• Use in Patients With Heart Disease: Use with caution in patients with cardiac disease ( 5.5 ).

• Orthostatic Hypotension and Syncope: Have occurred.

Warn patients of risk and symptoms of hypotension ( 5.6 ).

• Abnormal Bleeding: May increase the risk of bleeding.

Use with NSAIDs, aspirin, or other drugs that affect coagulation may compound this risk ( 5.7 , 7 ).

• Interaction With MAOIs: Do not use concomitantly or within 14 days of monoamine oxidase inhibitors ( 5.8 , 7 ).

• Priapism: Has occurred.

Warn male patients of this risk and how/when to seek medical attention ( 5.9 ).

• Hyponatremia: Can occur in association with SIADH ( 5.10 ).

• Potential for Cognitive and Motor Impairment: Has potential to impair judgment, thinking, and motor skills.

Advise patients to use caution when operating machinery ( 5.11 ).

• Angle-Closure Glaucoma: Angle closure glaucoma has occurred in patients with untreated anatomically narrow angles treated with antidepressants.

( 5.12 ) • Discontinuation Symptoms: May occur with abrupt discontinuation and include anxiety and sleep disturbance.

Upon discontinuation, taper trazodone hydrochloride tablets and monitor for symptoms ( 5.13 ).

5.1 Clinical Worsening and Suicide Risk Patients with major depressive disorder (MDD), both adult and pediatric, may experience worsening of their depression and/or the emergence of suicidal ideation and behavior (suicidality) or unusual changes in behavior, whether or not they are taking antidepressant medications, and this risk may persist until significant remission occurs.

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

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

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

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

The pooled analyses of placebo-controlled trials in children and adolescents with MDD, obsessive compulsive disorder (OCD), or other psychiatric disorders included a total of 24 short-term trials of 9 antidepressant drugs in over 4,400 patients.

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

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

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

The risk differences (drug vs.

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

These risk differences (drug-placebo difference in the number of cases of suicidality per 1,000 patients treated) are provided in Table 1 .

Table 1 Age Range Drug-Placebo Difference in Number of Cases of Suicidality per 1,000 Patients Treated Increases Compared to Placebo < 18 14 additional cases 18 to 24 5 additional cases Decreases Compared to Placebo 25 to 64 1 fewer case ≥ 65 6 fewer cases No suicides occurred in any of the pediatric trials.

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

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

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

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

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

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

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

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

Such monitoring should include daily observation by families and caregivers .

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

5.2 Serotonin Syndrome or Neuroleptic Malignant Syndrome (NMS)-Like Reactions The development of a potentially life-threatening serotonin syndrome or neuroleptic malignant syndrome (NMS)-like reactions have been reported with antidepressants alone and may occur with trazodone treatment, but particularly with concomitant use of other serotoninergic drugs (including SSRIs, SNRIs and triptans) and with drugs that impair metabolism of serotonin (including monoamine oxidase inhibitors [MAOIs]), or with antipsychotics or other dopamine antagonists.

Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, and coma), autonomic instability (e.g., tachycardia, labile blood pressure, and hyperthermia), neuromuscular aberrations (e.g., hyperreflexia, incoordination) and/or gastrointestinal symptoms (e.g., nausea, vomiting, and diarrhea).

Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome, which includes hyperthermia, muscle rigidity, autonomic instability with possible rapid fluctuation of vital signs, and mental status changes.

Treatment with trazodone hydrochloride tablets and any concomitant serotonergic or antidopaminergic agents, including antipsychotics, should be discontinued immediately if the above reactions occur and supportive symptomatic treatment should be initiated.

Trazodone hydrochloride tablets should not be used within 14 days of an MAOI [see Warnings and Precautions ( 5.8 ) and Drug Interactions ( 7 )].

If concomitant treatment with trazodone hydrochloride tablets and an SSRI, SNRI or a 5-hydroxytryptamine receptor agonist (triptan) is clinically warranted, careful observation of the patient is advised, particularly during treatment initiation and dose increases.

The concomitant use of trazodone hydrochloride tablets with serotonin precursors (such as tryptophan) is not recommended.

5.3 Screening Patients for Bipolar Disorder and Monitoring for Mania/Hypomania A major depressive episode may be the initial presentation of bipolar disorder.

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

Whether any of the symptoms described for clinical worsening and suicide risk represent such a conversion is unknown.

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

It should be noted that trazodone hydrochloride tablets are not approved for use in treating bipolar depression.

5.4 QT Prolongation and Risk of Sudden Death Trazodone is known to prolong the QT/QT c interval.

Some drugs that prolong the QT/QT c interval can cause torsade de pointes with sudden, unexplained death.

The relationship of QT prolongation is clearest for larger increases (20 msec and greater), but it is possible that smaller QT/QT c prolongations may also increase risk, especially in susceptible individuals, such as those with hypokalemia, hypomagnesemia, or a genetic predisposition to prolonged QT/QT c .

Although torsade de pointes has not been observed with the use of trazodone hydrochloride tablets at recommended doses in premarketing trials, experience is too limited to rule out an increased risk.

However, there have been postmarketing reports of torsade de pointes with the immediate-release form of trazodone (in the presence of multiple confounding factors), even at doses of 100 mg per day or less.

5.5 Use in Patients With Heart Disease Trazodone hydrochloride is not recommended for use during the initial recovery phase of myocardial infarction.

Caution should be used when administering trazodone hydrochloride tablets to patients with cardiac disease and such patients should be closely monitored, since antidepressant drugs (including trazodone hydrochloride) may cause cardiac arrhythmias.

QT prolongation has been reported with trazodone therapy [see Warnings and Precautions (5.4)] .

Clinical studies in patients with preexisting cardiac disease indicate that trazodone hydrochloride may be arrhythmogenic in some patients in that population.

Arrhythmias identified include isolated PVCs, ventricular couplets, tachycardia with syncope, and torsade de pointes.

Postmarketing events have been reported at doses of 100 mg or less with the immediate-release form of trazodone.

Concomitant administration of drugs that prolong the QT interval or that are inhibitors of CYP3A4 may increase the risk of cardiac arrhythmia.

5.6 Orthostatic Hypotension and Syncope Hypotension, including orthostatic hypotension and syncope has been reported in patients receiving trazodone hydrochloride.

Concomitant use with an antihypertensive may require a reduction in the dose of the antihypertensive drug.

5.7 Abnormal Bleeding Postmarketing data have shown an association between use of drugs that interfere with serotonin reuptake and the occurrence of gastrointestinal (GI) bleeding.

While no association between trazodone and bleeding events, in particular GI bleeding, was shown, patients should be cautioned about potential risk of bleeding associated with the concomitant use of trazodone and NSAIDs, aspirin, or other drugs that affect coagulation or bleeding.

Other bleeding events related to SSRIs and SNRIs have ranged from ecchymosis, hematoma, epistaxis, and petechiae to life-threatening hemorrhages.

5.8 Interaction With MAOIs In patients receiving serotonergic drugs in combination with a monoamine oxidase inhibitor (MAOI), there have been reports of serious, sometimes fatal reactions including hyperthermia, rigidity, myoclonus, autonomic instability with rapid fluctuation in vital signs, and mental status changes that include extreme agitation progressing to delirium and coma.

These reactions have also been reported in patients who have recently discontinued antidepressant treatment and have been started on an MAOI.

Some cases presented with features resembling neuroleptic malignant syndrome.

Furthermore, limited animal data on the effects of combined use of serotonergic antidepressants and MAOIs suggest that these drugs may act synergistically to elevate blood pressure and evoke behavioral excitation.

Therefore, it is recommended that trazodone hydrochloride tablets should not be used in combination with an MAOI or within 14 days of discontinuing treatment with an MAOI.

Similarly, at least 14 days should be allowed after stopping trazodone hydrochloride tablets before starting an MAOI.

5.9 Priapism Rare cases of priapism (painful erections greater than 6 hours in duration) were reported in men receiving trazodone.

Priapism, if not treated promptly, can result in irreversible damage to the erectile tissue.

Men who have an erection lasting greater than 6 hours, whether painful or not, should immediately discontinue the drug and seek emergency medical attention [see Adverse Reactions ( 6.2 ) and Overdosage ( 10 )].

Trazodone should be used with caution in men who have conditions that might predispose them to priapism (e.g., sickle cell anemia, multiple myeloma, or leukemia), or in men with anatomical deformation of the penis (e.g., angulation, cavernosal fibrosis, or Peyronie’s disease).

5.10 Hyponatremia Hyponatremia may occur as a result of treatment with antidepressants.

In many cases, this hyponatremia appears to be the result of the syndrome of inappropriate antidiuretic hormone secretion (SIADH).

Cases with serum sodium lower than 110 mmol/L have been reported.

Elderly patients may be at greater risk of developing hyponatremia with antidepressants.

Also, patients taking diuretics or who are otherwise volume-depleted can be at greater risk.

Discontinuation of trazodone hydrochloride tablets should be considered in patients with symptomatic hyponatremia and appropriate medical intervention should be instituted.

Signs and symptoms of hyponatremia include headache, difficulty concentrating, memory impairment, confusion, weakness, and unsteadiness, which can lead to falls.

Signs and symptoms associated with more severe and/or acute cases have included hallucination, syncope, seizure, coma, respiratory arrest, and death.

5.11 Potential for Cognitive and Motor Impairment Trazodone hydrochloride tablets may cause somnolence or sedation and may impair the mental and/or physical ability required for the performance of potentially hazardous tasks.

Patients should be cautioned about operating hazardous machinery, including automobiles, until they are reasonably certain that the drug treatment does not affect them adversely 5.12 Angle-Closure Glaucoma Angle-Closure Glaucoma: The pupillary dilation that occurs following use of many antidepressant drugs including trazodone hydrochloride tablets may trigger an angle closure attack in a patient with anatomically narrow angles who does not have a patent iridectomy 5.13 Discontinuation Symptoms Withdrawal symptoms including anxiety, agitation and sleep disturbances, have been reported with trazodone.

Clinical experience suggests that the dose should be gradually reduced before complete discontinuation of the treatment.

WARNING AND CAUTIONS

5 WARNINGS AND PRECAUTIONS Drug Reaction with Eosinophilia and Systemic Symptoms (Multiorgan hypersensitivity): Discontinue if alternative etiology is not established (5.1) Anaphylaxis and Angioedema: Discontinue and evaluate patient immediately (5.2) Driving Impairment; Somnolence/Sedation and Dizziness: Warn patients not to drive until they have gained sufficient experience to assess whether their ability to drive or operate heavy machinery will be impaired (5.3, 5.4) Increased seizure frequency may occur in patients with seizure disorders if gabapentin is abruptly discontinued (5.5) Suicidal Behavior and Ideation: Monitor for suicidal thoughts/behavior (5.6) Respiratory depression: May occur with gabapentin when used with concomitant central nervous system (CNS) depressants or in the setting of underlying respiratory impairment.

Monitor patients and adjust dosage as appropriate (5.7) Neuropsychiatric Adverse Reactions in Children 3 to 12 Years of Age: Monitor for such events (5.8) 5.1 Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)/Multiorgan Hypersensitivity Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), also known as multiorgan hypersensitivity, has occurred with gabapentin.

Some of these reactions 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, hematological 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.

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

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

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

5.2 Anaphylaxis and Angioedema Gabapentin can cause anaphylaxis and angioedema after the first dose or at any time during treatment.

Signs and symptoms in reported cases have included difficulty breathing, swelling of the lips, throat, and tongue, and hypotension requiring emergency treatment.

Patients should be instructed to discontinue gabapentin and seek immediate medical care should they experience signs or symptoms of anaphylaxis or angioedema.

5.3 Effects on Driving and Operating Heavy Machinery Patients taking gabapentin should not drive until they have gained sufficient experience to assess whether gabapentin impairs their ability to drive.

Driving performance studies conducted with a prodrug of gabapentin (gabapentin enacarbil tablet, extended-release) indicate that gabapentin may cause significant driving impairment.

Prescribers and patients should be aware that patients’ ability to assess their own driving competence, as well as their ability to assess the degree of somnolence caused by gabapentin, can be imperfect.

The duration of driving impairment after starting therapy with gabapentin is unknown.

Whether the impairment is related to somnolence [see Warnings and Precautions (5.4) ] or other effects of gabapentin is unknown.

Moreover, because gabapentin causes somnolence and dizziness [see Warnings and Precautions (5.4) ] , patients should be advised not to operate complex machinery until they have gained sufficient experience on gabapentin to assess whether gabapentin impairs their ability to perform such tasks.

5.4 Somnolence/Sedation and Dizziness During the controlled epilepsy trials in patients older than 12 years of age receiving doses of gabapentin up to 1,800 mg daily, somnolence, dizziness, and ataxia were reported at a greater rate in patients receiving gabapentin compared to placebo: i.e., 19% in drug versus 9% in placebo for somnolence, 17% in drug versus 7% in placebo for dizziness, and 13% in drug versus 6% in placebo for ataxia.

In these trials somnolence, ataxia and fatigue were common adverse reactions leading to discontinuation of gabapentin in patients older than 12 years of age, with 1.2%, 0.8% and 0.6% discontinuing for these events, respectively.

During the controlled trials in patients with post-herpetic neuralgia, somnolence, and dizziness were reported at a greater rate compared to placebo in patients receiving gabapentin, in dosages up to 3,600 mg per day: i.e., 21% in gabapentin-treated patients versus 5% in placebo-treated patients for somnolence and 28% in gabapentin-treated patients versus 8% in placebo-treated patients for dizziness.

Dizziness and somnolence were among the most common adverse reactions leading to discontinuation of gabapentin.

Patients should be carefully observed for signs of central nervous system (CNS) depression, such as somnolence and sedation, when gabapentin is used with other drugs with sedative properties because of potential synergy.

In addition, patients who require concomitant treatment with morphine may experience increases in gabapentin concentrations and may require dose adjustment [ see Drug Interactions (7.2) ].

5.5 Withdrawal Precipitated Seizure, Status Epilepticus Antiepileptic drugs should not be abruptly discontinued because of the possibility of increasing seizure frequency.

In the placebo-controlled epilepsy studies in patients > 12 years of age, the incidence of status epilepticus in patients receiving gabapentin was 0.6% (3 of 543) vs.

0.5% in patients receiving placebo (2 of 378).

Among the 2,074 patients > 12 years of age treated with gabapentin across all epilepsy studies (controlled and uncontrolled), 31 (1.5%) had status epilepticus.

Of these, 14 patients had no prior history of status epilepticus either before treatment or while on other medications.

Because adequate historical data are not available, it is impossible to say whether or not treatment with gabapentin is associated with a higher or lower rate of status epilepticus than would be expected to occur in a similar population not treated with gabapentin.

5.6 Suicidal Behavior and Ideation Antiepileptic drugs (AEDs), including gabapentin, increase the risk of suicidal thoughts or behavior in patients taking these drugs for any indication.

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

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

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

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

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

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

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

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

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

Table 2 shows absolute and relative risk by indication for all evaluated AEDs.

TABLE 2.

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 3.4 3.5 2.4 Psychiatric 5.7 8.5 1.5 2.9 Other 1 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 gabapentin 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.

5.7 Respiratory Depression There is evidence from case reports, human studies, and animal studies associating gabapentin with serious, life-threatening, or fatal respiratory depression when co-administered with CNS depressants, including opioids, or in the setting of underlying respiratory impairment.

When the decision is made to co-prescribe gabapentin with another CNS depressant, particularly an opioid, or to prescribe gabapentin to patients with underlying respiratory impairment, monitor patients for symptoms of respiratory depression and sedation, and consider initiating gabapentin at a low dose.

The management of respiratory depression may include close observation, supportive measures, and reduction or withdrawal of CNS depressants (including gabapentin).

5.8 Neuropsychiatric Adverse Reactions (Pediatric Patients 3 to 12 Years of Age) Gabapentin use in pediatric patients with epilepsy 3 to 12 years of age is associated with the occurrence of CNS related adverse reactions.

The most significant of these can be classified into the following categories: 1) emotional lability (primarily behavioral problems), 2) hostility, including aggressive behaviors, 3) thought disorder, including concentration problems and change in school performance, and 4) hyperkinesia (primarily restlessness and hyperactivity).

Among the gabapentin-treated patients, most of the reactions were mild to moderate in intensity.

In controlled clinical epilepsy trials in pediatric patients 3 to 12 years of age, the incidence of these adverse reactions was: emotional lability 6% (gabapentin-treated patients) vs.

1.3% (placebo-treated patients); hostility 5.2% vs.

1.3%; hyperkinesia 4.7% vs.

2.9%; and thought disorder 1.7% vs.

0%.

One of these reactions, a report of hostility, was considered serious.

Discontinuation of gabapentin treatment occurred in 1.3% of patients reporting emotional lability and hyperkinesia and 0.9% of gabapentin-treated patients reporting hostility and thought disorder.

One placebo-treated patient (0.4%) withdrew due to emotional lability.

5.9 Tumorigenic Potential In an oral carcinogenicity study, gabapentin increased the incidence of pancreatic acinar cell tumors in rats [see Nonclinical Toxicology (13.1)] .

The clinical significance of this finding is unknown.

Clinical experience during gabapentin’s premarketing development provides no direct means to assess its potential for inducing tumors in humans.

In clinical studies in adjunctive therapy in epilepsy comprising 2,085 patient-years of exposure in patients > 12 years of age, new tumors were reported in 10 patients (2 breast, 3 brain, 2 lung, 1 adrenal, 1 non-Hodgkin’s lymphoma, 1 endometrial carcinoma in situ ), and preexisting tumors worsened in 11 patients (9 brain, 1 breast, 1 prostate) during or up to 2 years following discontinuation of gabapentin.

Without knowledge of the background incidence and recurrence in a similar population not treated with gabapentin, it is impossible to know whether the incidence seen in this cohort is or is not affected by treatment.

5.10 Sudden and Unexplained Death in Patients with Epilepsy During the course of premarketing development of gabapentin, 8 sudden and unexplained deaths were recorded among a cohort of 2,203 epilepsy patients treated (2,103 patient-years of exposure) with gabapentin.

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

This represents an incidence of 0.0038 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 gabapentin (ranging from 0.0005 for the general population of epileptics to 0.003 for a clinical trial population similar to that in the gabapentin program, to 0.005 for patients with refractory epilepsy).

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

WARNING AND CAUTIONS

5 WARNINGS AND PRECAUTIONS • Coagulopathy : May result in bleeding, death.

Monitor anticoagulant response (e.g., INR) and adjust anticoagulant dose accordingly.

( 5.1 ) • Diarrhea : May be severe.

Interrupt capecitabine tablets treatment immediately until diarrhea resolves or decreases to grade 1.

Recommend standard antidiarrheal treatments.

( 5.2 ) • Cardiotoxicity : Common in patients with a prior history of coronary artery disease.

( 5.3 ) • Increased Risk of Severe or Fatal Adverse Reactions in Patients with Low or Absent Dihydropyrimidine Dehydrogenase (DPD) Activity: Withhold or permanently discontinue capecitabine tablets in patients with evidence of acute early-onset or unusually severe toxicity, which may indicate near complete or total absence of DPD activity.

No capecitabine tablets dose has been proven safe in patients with absent DPD activity.

( 5.4 ) • Dehydration and Renal Failure : Interrupt capecitabine tablets treatment until dehydration is corrected.

Potential risk of acute renal failure secondary to dehydration.

Monitor and correct dehydration.

( 5.5 ) • Embryo-Fetal Toxicity: Can cause fetal harm.

Advise females of reproductive potential of the potential risk to a fetus and to use effective contraception.

( 5.6 , 8.1 , 8.3 ) • Mucocutaneous and Dermatologic Toxicity : Severe mucocutaneous reactions, Steven-Johnson Syndrome (SJS) and Toxic Epidermal Necrolysis (TEN), have been reported.

Capecitabine tablets should be permanently discontinued in patients who experience a severe mucocutaneous reaction during treatment.

Capecitabine tablets may induce hand-and-foot syndrome.

Persistent or severe hand-and-foot syndrome can lead to loss of fingerprints which could impact patient identification.

Interrupt capecitabine tablets treatment until the hand-and-foot syndrome event resolves or decreases in intensity.

( 5.7 ) • Hyperbilirubinemia : Interrupt capecitabine tablets treatment immediately until the hyperbilirubinemia resolves or decreases in intensity.

( 5.8 ) • Hematologic : Do not treat patients with neutrophil counts < 1.5 x 10 9 /L or thrombocyte counts < 100 x 10 9 /L.

If grade 3-4 neutropenia or thrombocytopenia occurs, stop therapy until condition resolves.

( 5.9 ) 5.1 Coagulopathy Patients receiving concomitant capecitabine and oral coumarin-derivative anticoagulant therapy should have their anticoagulant response (INR or prothrombin time) monitored closely with great frequency and the anticoagulant dose should be adjusted accordingly [see Boxed Warning and Drug Interactions (7.1) ].

5.2 Diarrhea Capecitabine tablets can induce diarrhea, sometimes severe.

Patients with severe diarrhea should be carefully monitored and given fluid and electrolyte replacement if they become dehydrated.

In 875 patients with either metastatic breast or colorectal cancer who received capecitabine tablets monotherapy, the median time to first occurrence of grade 2 to 4 diarrhea was 34 days (range from 1 to 369 days).

The median duration of grade 3 to 4 diarrhea was 5 days.

National Cancer Institute of Canada (NCIC) grade 2 diarrhea is defined as an increase of 4 to 6 stools/day or nocturnal stools, grade 3 diarrhea as an increase of 7 to 9 stools/day or incontinence and malabsorption, and grade 4 diarrhea as an increase of ≥ 10 stools/day or grossly bloody diarrhea or the need for parenteral support.

If grade 2, 3 or 4 diarrhea occurs, administration of capecitabine tablets should be immediately interrupted until the diarrhea resolves or decreases in intensity to grade 1 [see Dosage and Administration (2.3) ] .

Standard antidiarrheal treatments (e.g., loperamide) are recommended.

Necrotizing enterocolitis (typhlitis) has been reported.

5.3 Cardiotoxicity The cardiotoxicity observed with capecitabine tablets includes myocardial infarction/ischemia, angina, dysrhythmias, cardiac arrest, cardiac failure, sudden death, electrocardiographic changes, and cardiomyopathy.

These adverse reactions may be more common in patients with a prior history of coronary artery disease.

5.4 Dihydropyrimidine Dehydrogenase Deficiency Based on postmarketing reports, patients with certain homozygous or certain compound heterozygous mutations in the DPD gene that result in complete or near complete absence of DPD activity are at increased risk for acute early-onset of toxicity and severe, life-threatening, or fatal adverse reactions caused by capecitabine tablets (e.g., mucositis, diarrhea, neutropenia, and neurotoxicity).

Patients with partial DPD activity may also have increased risk of severe, life-threatening, or fatal adverse reactions caused by capecitabine tablets.

Withhold or permanently discontinue capecitabine tablets based on clinical assessment of the onset, duration and severity of the observed toxicities in patients with evidence of acute early-onset or unusually severe toxicity, which may indicate near complete or total absence of DPD activity.

No capecitabine tablets dose has been proven safe for patients with complete absence of DPD activity.

There is insufficient data to recommend a specific dose in patients with partial DPD activity as measured by any specific test.

5.5 Dehydration and Renal Failure Dehydration has been observed and may cause acute renal failure which can be fatal.

Patients with pre-existing compromised renal function or who are receiving concomitant capecitabine tablets with known nephrotoxic agents are at higher risk.

Patients with anorexia, asthenia, nausea, vomiting or diarrhea may rapidly become dehydrated.

Monitor patients when capecitabine tablets are administered to prevent and correct dehydration at the onset.

If grade 2 (or higher) dehydration occurs, capecitabine tablets treatment should be immediately interrupted and the dehydration corrected.

Treatment should not be restarted until the patient is rehydrated and any precipitating causes have been corrected or controlled.

Dose modifications should be applied for the precipitating adverse event as necessary [see Dosage and Administration (2.3) ] .

Patients with moderate renal impairment at baseline require dose reduction [see Dosage and Administration (2.4) ] .

Patients with mild and moderate renal impairment at baseline should be carefully monitored for adverse reactions.

Prompt interruption of therapy with subsequent dose adjustments is recommended if a patient develops a grade 2 to 4 adverse event as outlined in Table 2 [see Dosage and Administration (2.3) , Use in Specific Populations (8.7) , and Clinical Pharmacology (12.3) ] .

5.6 Embryo-Fetal Toxicity Based on findings from animal reproduction studies and its mechanism of action, capecitabine tablets may cause fetal harm when given to a pregnant woman [see Clinical Pharmacology (12.1) ] .

Limited available data are not sufficient to inform use of capecitabine tablets in pregnant women.

In animal reproduction studies, administration of capecitabine to pregnant animals during the period of organogenesis caused embryolethality and teratogenicity in mice and embryolethality in monkeys at 0.2 and 0.6 times the exposure (AUC) in patients receiving the recommended dose respectively [see Use in Specific Populations (8.1) ] .

Apprise pregnant women of the potential risk to a fetus.

Advise females of reproductive potential to use effective contraception during treatment and for 6 months following the last dose of capecitabine tablets [see Use in Specific Populations (8.3) ] .

5.7 Mucocutaneous and Dermatologic Toxicity Severe mucocutaneous reactions, some with fatal outcome, such as Stevens-Johnson syndrome and Toxic Epidermal Necrolysis (TEN) can occur in patients treated with capecitabine tablets [see Adverse Reactions (6.4) ] .

Capecitabine tablets should be permanently discontinued in patients who experience a severe mucocutaneous reaction possibly attributable to capecitabine tablets treatment.

Hand-and-foot syndrome (palmar-plantar erythrodysesthesia or chemotherapy-induced acral erythema) is a cutaneous toxicity.

Median time to onset was 79 days (range from 11 to 360 days) with a severity range of grades 1 to 3 for patients receiving capecitabine tablets monotherapy in the metastatic setting.

Grade 1 is characterized by any of the following: numbness, dysesthesia/paresthesia, tingling, painless swelling or erythema of the hands and/or feet and/or discomfort which does not disrupt normal activities.

Grade 2 hand-and-foot syndrome is defined as painful erythema and swelling of the hands and/or feet and/or discomfort affecting the patient’s activities of daily living.

Grade 3 hand-and-foot syndrome is defined as moist desquamation, ulceration, blistering or severe pain of the hands and/or feet and/or severe discomfort that causes the patient to be unable to work or perform activities of daily living.

Persistent or severe hand-and-foot syndrome (grade 2 and above) can eventually lead to loss of fingerprints which could impact patient identification.

If grade 2 or 3 hand-and-foot syndrome occurs, administration of capecitabine tablets should be interrupted until the event resolves or decreases in intensity to grade 1.

Following grade 3 hand-and-foot syndrome, subsequent doses of capecitabine tablets should be decreased [see Dosage and Administration (2.3) ] .

5.8 Hyperbilirubinemia In 875 patients with either metastatic breast or colorectal cancer who received at least one dose of capecitabine tablets 1250 mg/m 2 twice daily as monotherapy for 2 weeks followed by a 1-week rest period, grade 3 (1.5-3 x ULN) hyperbilirubinemia occurred in 15.2% (n = 133) of patients and grade 4 (> 3 x ULN) hyperbilirubinemia occurred in 3.9% (n = 34) of patients.

Of 566 patients who had hepatic metastases at baseline and 309 patients without hepatic metastases at baseline, grade 3 or 4 hyperbilirubinemia occurred in 22.8% and 12.3%, respectively.

Of the 167 patients with grade 3 or 4 hyperbilirubinemia, 18.6% (n = 31) also had postbaseline elevations (grades 1 to 4, without elevations at baseline) in alkaline phosphatase and 27.5% (n = 46) had postbaseline elevations in transaminases at any time (not necessarily concurrent).

The majority of these patients, 64.5% (n = 20) and 71.7% (n = 33), had liver metastases at baseline.

In addition, 57.5% (n = 96) and 35.3% (n = 59) of the 167 patients had elevations (grades 1 to 4) at both prebaseline and postbaseline in alkaline phosphatase or transaminases, respectively.

Only 7.8% (n = 13) and 3.0% (n = 5) had grade 3 or 4 elevations in alkaline phosphatase or transaminases.

In the 596 patients treated with capecitabine tablets as first-line therapy for metastatic colorectal cancer, the incidence of grade 3 or 4 hyperbilirubinemia was similar to the overall clinical trial safety database of capecitabine tablets monotherapy.

The median time to onset for grade 3 or 4 hyperbilirubinemia in the colorectal cancer population was 64 days and median total bilirubin increased from 8 μm/L at baseline to 13 μm/L during treatment with capecitabine tablets.

Of the 136 colorectal cancer patients with grade 3 or 4 hyperbilirubinemia, 49 patients had grade 3 or 4 hyperbilirubinemia as their last measured value, of which 46 had liver metastases at baseline.

In 251 patients with metastatic breast cancer who received a combination of capecitabine tablets and docetaxel, grade 3 (1.5 to 3 x ULN) hyperbilirubinemia occurred in 7% (n = 17) and grade 4 (> 3 x ULN) hyperbilirubinemia occurred in 2% (n = 5).

If drug-related grade 3 to 4 elevations in bilirubin occur, administration of capecitabine tablets should be immediately interrupted until the hyperbilirubinemia decreases to ≤ 3.0 x ULN [ see recommended dose modifications under Dosage and Administration (2.3) ] .

5.9 Hematologic In 875 patients with either metastatic breast or colorectal cancer who received a dose of 1250 mg/m 2 administered twice daily as monotherapy for 2 weeks followed by a 1-week rest period, 3.2%, 1.7%, and 2.4% of patients had grade 3 or 4 neutropenia, thrombocytopenia or decreases in hemoglobin, respectively.

In 251 patients with metastatic breast cancer who received a dose of capecitabine tablets in combination with docetaxel, 68% had grade 3 or 4 neutropenia, 2.8% had grade 3 or 4 thrombocytopenia, and 9.6% had grade 3 or 4 anemia.

Patients with baseline neutrophil counts of < 1.5 x 10 9 /L and/or thrombocyte counts of < 100 x 10 9 /L should not be treated with capecitabine tablets.

If unscheduled laboratory assessments during a treatment cycle show grade 3 or 4 hematologic toxicity, treatment with capecitabine tablets should be interrupted.

5.10 Geriatric Patients Patients ≥ 80 years old may experience a greater incidence of grade 3 or 4 adverse reactions.

In 875 patients with either metastatic breast or colorectal cancer who received capecitabine tablets monotherapy, 62% of the 21 patients ≥ 80 years of age treated with capecitabine tablets experienced a treatment-related grade 3 or 4 adverse event: diarrhea in 6 (28.6%), nausea in 3 (14.3%), hand-and-foot syndrome in 3 (14.3%), and vomiting in 2 (9.5%) patients.

Among the 10 patients 70 years of age and greater (no patients were > 80 years of age) treated with capecitabine tablets in combination with docetaxel, 30% (3 out of 10) of patients experienced grade 3 or 4 diarrhea and stomatitis, and 40% (4 out of 10) experienced grade 3 hand-and-foot syndrome.

Among the 67 patients ≥ 60 years of age receiving capecitabine tablets in combination with docetaxel, the incidence of grade 3 or 4 treatment-related adverse reactions, treatment-related serious adverse reactions, withdrawals due to adverse reactions, treatment discontinuations due to adverse reactions and treatment discontinuations within the first two treatment cycles was higher than in the < 60 years of age patient group.

In 995 patients receiving capecitabine tablets as adjuvant therapy for Dukes’ C colon cancer after resection of the primary tumor, 41% of the 398 patients ≥ 65 years of age treated with capecitabine tablets experienced a treatment-related grade 3 or 4 adverse event: hand-and-foot syndrome in 75 (18.8%), diarrhea in 52 (13.1%), stomatitis in 12 (3.0%), neutropenia/granulocytopenia in 11 (2.8%), vomiting in 6 (1.5%), and nausea in 5 (1.3%) patients.

In patients ≥ 65 years of age (all randomized population; capecitabine 188 patients, 5-FU/LV 208 patients) treated for Dukes’ C colon cancer after resection of the primary tumor, the hazard ratios for disease-free survival and overall survival for capecitabine tablets compared to 5-FU/LV were 1.01 (95% C.I.

0.80 – 1.27) and 1.04 (95% C.I.

0.79 – 1.37), respectively.

5.11 Hepatic Insufficiency Patients with mild to moderate hepatic dysfunction due to liver metastases should be carefully monitored when capecitabine tablets are administered.

The effect of severe hepatic dysfunction on the disposition of capecitabine tablets is not known [see Use in Specific Populations (8.6) and Clinical Pharmacology (12.3) ] .

5.12 Combination With Other Drugs Use of capecitabine tablets in combination with irinotecan has not been adequately studied.