Cymbalta Delayed Release Capsules

Cymbalta side effects can include night sweats, nocturnal hydrosis, and hot flash like symptoms sweating and hyperhidrosis.  This medication has many warnings associated with it regardless of purchasing online discount or   generic. There is some information on Fibromyalgia located on the symptom page. References to weight gain may be found here. You may find information for Anxiety here. This information is always subject to change please consult you doctor before taking this drug. 

DESCRIPTION

Cymbalta® (duloxetine hydrochloride) is a selective serotonin and norepinephrine reuptake inhibitor (SSNRI) for oral administration. Its chemical designation is (+)-( S )- N -methyl-(gamma)-(1-naphthyloxy)-2-thiophenepropylamine hydrochloride. The empirical formula is C ₁₈ H ₁₉ NOS·HCl, which corresponds to a molecular weight of 333.88. The structural formula is:

WARNINGS

Clinical Worsening and Suicide Risk --Patients with major depressive disorder, both adult and pediatric, may experience worsening of their depression and/or the emergence of suicidal ideation and behavior (suicidality), whether or not they are taking antidepressant medications, and this risk may persist until significant remission occurs. Although there has been a long-standing concern that antidepressants may have a role in inducing worsening of depression and the emergence of suicidality in certain patients, a causal role for antidepressants in inducing such behaviors has not been established. Nevertheless, patients being treated with antidepressants should be observed closely for clinical worsening and suicidality, especially at the beginning of a course of drug therapy, or at the time of dose changes, either increases or decreases. Consideration should be given to changing the therapeutic regimen, including possibly discontinuing the medication, in patients whose depression is persistently worse or whose emergent suicidality is severe, abrupt in onset, or was not part of the patient's presenting symptoms.

Because of the possibility of co-morbidity between major depressive disorder and other psychiatric and nonpsychiatric disorders, the same precautions observed when treating patients with major depressive disorder should be observed when treating patients with other psychiatric and nonpsychiatric disorders.

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, consideration should be given to changing the therapeutic regimen, including possibly discontinuing the medication, in patients for whom such 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, and the other symptoms described above, as well as the emergence of suicidality, and to report such symptoms immediately to health care providers. Prescriptions for Cymbalta should be written for the smallest quantity of capsules consistent with good patient management, in order to reduce the risk of overdose.

If the decision has been made to discontinue treatment, medication should be tapered, as rapidly as is feasible, but with recognition that abrupt discontinuation can be associated with certain symptoms ( see PRECAUTIONS and DOSAGE AND ADMINISTRATION , Discontinuing Cymbalta, for a description of the risks of discontinuation of this drug).

A major depressive episode may be the initial presentation of bipolar disorder. It is generally believed (though not established in controlled trials) that treating such an episode with an antidepressant alone may increase the likelihood of precipitation of a mixed/manic episode in patients at risk for bipolar disorder. Whether any of the symptoms described above represent such a conversion is unknown. However, prior to initiating treatment with an antidepressant, patients 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 this drug is not approved for use in treating bipolar depression.

Monoamine Oxidase Inhibitors (MAOI) --In patients receiving a serotonin reuptake inhibitor in combination with a monoamine oxidase inhibitor, there have been reports of serious, sometimes fatal, reactions including hyperthermia, rigidity, myoclonus, autonomic instability with possible rapid fluctuations of 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 serotonin reuptake inhibitors and are then started on an MAOI. Some cases presented with features resembling neuroleptic malignant syndrome. The effects of combined use of this drug and MAOIs have not been evaluated in humans or animals. Therefore, because this drug is an inhibitor of both serotonin and norepinephrine reuptake, it is recommended that this drug not be used in combination with an MAOI, or within at least 14 days of discontinuing treatment with an MAOI. Based on the half-life of Cymbalta, at least 5 days should be allowed after stopping this drug before starting an MAOI.

PRECAUTIONS

General

Hepatotoxicity --this drug increases the risk of elevation of serum transaminase levels. Liver transaminase elevations resulted in the discontinuation of 0.4% (31/8454) of Cymbalta-treated patients. In these patients, the median time to detection of the transaminase elevation was about two months. In controlled trials in MDD, elevations of alanine transaminase (ALT) to >3 times the upper limit of normal occurred in 0.9% (8/930) of Cymbalta-treated patients and in 0.3% (2/652) of placebo-treated patients. In controlled trials in DPN, elevations of ALT to >3 times the upper limit of normal occurred in 1.68% (8/477) of Cymbalta-treated patients and 0% (0/187) of placebo-treated patients. In the full cohort of placebo-controlled trials in any indication, 1% (39/3732) of Cymbalta-treated patients had a >3 times the upper limit of normal elevation of ALT compared to 0.2% (6/2568) of placebo-treated patients. In placebo-controlled studies using a fixed-dose design, there was evidence of a dose-response relationship for ALT and AST elevation of >3 times the upper limit of normal and >5 times the upper limit of normal, respectively.

The combination of transaminase elevations and elevated bilirubin, without evidence of obstruction, is generally recognized as an important predictor of severe liver injury. Three Cymbalta patients had elevations of transaminases and bilirubin, but also had elevation of alkaline phosphatase, suggesting an obstructive process; in these patients, there was evidence of heavy alcohol use and this may have contributed to the abnormalities seen. Two placebo-treated patients also had transaminase elevations with elevated bilirubin. Because it is possible that duloxetine and alcohol may interact to cause liver injury, this drug should ordinarily not be prescribed to patients with substantial alcohol use.

Effect on Blood Pressure --In MDD clinical trials, Cymbalta treatment was associated with mean increases in blood pressure, averaging 2 mm Hg systolic and 0.5 mm Hg diastolic and an increase in the incidence of at least one measurement of systolic blood pressure over 140 mm Hg compared to placebo.

Blood pressure should be measured prior to initiating treatment and periodically measured throughout treatment ( see ADVERSE REACTIONS , Vital Sign Changes ).

Activation of Mania/Hypomania --In placebo-controlled trials in patients with major depressive disorder, activation of mania or hypomania was reported in 0.1% (1/1139) of Cymbalta-treated patients and 0.1% (1/777) of placebo-treated patients. Activation of mania/hypomania has been reported in a small proportion of patients with mood disorders who were treated with other marketed drugs effective in the treatment of major depressive disorder. As with these other agents, this drug should be used cautiously in patients with a history of mania.

Seizures --Cymbalta has not been systematically evaluated in patients with a seizure disorder, and such patients were excluded from clinical studies. In placebo-controlled clinical trials in patients with major depressive disorder, seizures occurred in 0.1% (1/1139) of patients treated with this drug and 0% (0/777) of patients treated with placebo. In placebo-controlled clinical trials in patients with diabetic peripheral neuropathy, seizures did not occur in any patients treated with either this drug or placebo. Cymbalta should be prescribed with care in patients with a history of a seizure disorder.

Controlled Narrow-Angle Glaucoma --In clinical trials, Cymbalta was associated with an increased risk of mydriasis; therefore, it should be used cautiously in patients with controlled narrow-angle glaucoma ( see CONTRAINDICATIONS , Uncontrolled Narrow-Angle Glaucoma ).

Discontinuation of Treatment with Cymbalta --Discontinuation symptoms have been systematically evaluated in patients taking Cymbalta. Following abrupt discontinuation in MDD placebo-controlled clinical trials of up to 9-weeks duration, the following symptoms occurred at a rate greater than or equal to 2% and at a significantly higher rate in Cymbalta-treated patients compared to those discontinuing from placebo: dizziness; nausea; headache; paresthesia; vomiting; irritability; and nightmare.

During marketing of other SSRIs and SNRIs (serotonin and norepinephrine reuptake inhibitors), there have been spontaneous reports of adverse events occurring upon discontinuation of these drugs, particularly when abrupt, including the following: dysphoric mood, irritability, agitation, dizziness, sensory disturbances (e.g., paresthesias such as electric shock sensations), anxiety, confusion, headache, lethargy, emotional lability, insomnia, hypomania, tinnitus, and seizures. Although these events are generally self-limiting, some have been reported to be severe.

Patients should be monitored for these symptoms when discontinuing treatment with Cymbalta. A gradual reduction in the dose rather than abrupt cessation is recommended whenever possible. If intolerable symptoms occur following a decrease in the dose or upon discontinuation of treatment, then resuming the previously prescribed dose may be considered. Subsequently, the physician may continue decreasing the dose but at a more gradual rate ( see DOSAGE AND ADMINISTRATION ).

Use in Patients with Concomitant Illness --Clinical experience with Cymbalta in patients with concomitant systemic illnesses is limited. There is no information on the effect that alterations in gastric motility may have on the stability of Cymbalta's enteric coating. As duloxetine is rapidly hydrolyzed in acidic media to naphthol, caution is advised in using Cymbalta in patients with conditions that may slow gastric emptying (e.g., some diabetics).

Cymbalta has not been systematically evaluated in patients with a recent history of myocardial infarction or unstable coronary artery disease. Patients with these diagnoses were generally excluded from clinical studies during the product's premarketing testing. However, the electrocardiograms of 321 patients who received Cymbalta in MDD placebo-controlled clinical trials and had qualitatively normal ECGs at baseline were evaluated; Cymbalta was not associated with the development of clinically significant ECG abnormalities ( see ADVERSE REACTIONS , Electrocardiogram Changes ).

In DPN placebo-controlled clinical trials, Cymbalta-treated patients did not develop abnormal ECGs at a rate different from that in placebo-treated patients ( see ADVERSE REACTIONS , Electrocardiogram Changes ).

In clinical trials of Cymbalta for the management of neuropathic pain associated with diabetic peripheral neuropathy, the mean duration of diabetes was approximately 11 years, the mean baseline fasting blood glucose was 163 mg/dL, and the mean baseline hemoglobin A1 _c (HbA _1c ) was 7.8%. In these studies, small increases in fasting blood glucose were observed in Cymbalta-treated patients compared to placebo at 12 weeks and routine care at 52 weeks. The increase was similar at both time points. Overall diabetic control did not worsen as evidenced by stable HbA _1c values and by no differences in incidence of serious and non-serious diabetes-related adverse events relative to placebo or routine care.

Increased plasma concentrations of duloxetine, and especially of its metabolites, occur in patients with end-stage renal disease (requiring dialysis). For this reason, Cymbalta is not recommended for patients with end-stage renal disease or severe renal impairment (creatinine clearance <30 mL/min) ( see CLINICAL PHARMACOLOGY and DOSAGE AND ADMINISTRATION ).

Markedly increased exposure to duloxetine occurs in patients with hepatic insufficiency and Cymbalta should not be administered to these patients ( see CLINICAL PHARMACOLOGY and DOSAGE AND ADMINISTRATION ).

Information for Patients

Physicians are advised to discuss the following issues with patients for whom they prescribe Cymbalta.

Patients and their families should be encouraged to be alert to the emergence of anxiety, agitation, panic attacks, insomnia, irritability, hostility, impulsivity, akathisia, hypomania, mania, worsening of depression, and suicidal ideation, especially early during antidepressant treatment. Such symptoms should be reported to the patient's physician, especially if they are severe, abrupt in onset, or were not part of the patient's presenting symptoms.

Cymbalta should be swallowed whole and should not be chewed or crushed, nor should the contents be sprinkled on food or mixed with liquids. All of these might affect the enteric coating.

Any psychoactive drug may impair judgment, thinking, or motor skills. Although in controlled studies Cymbalta has not been shown to impair psychomotor performance, cognitive function, or memory, it may be associated with sedation. Therefore, patients should be cautioned about operating hazardous machinery including automobiles, until they are reasonably certain that Cymbalta therapy does not affect their ability to engage in such activities.

Patients should be advised to inform their physicians if they are taking, or plan to take, any prescription or over-the-counter medications, since there is a potential for interactions.

Although Cymbalta does not increase the impairment of mental and motor skills caused by alcohol, use of Cymbalta concomitantly with heavy alcohol intake may be associated with severe liver injury. For this reason, Cymbalta should ordinarily not be prescribed for patients with substantial alcohol use.

Patients should be advised to notify their physician if they become pregnant or intend to become pregnant during therapy.

Patients should be advised to notify their physician if they are breast-feeding.

While patients with MDD may notice improvement with Cymbalta therapy in 1 to 4 weeks, they should be advised to continue therapy as directed.

Laboratory Tests

No specific laboratory tests are recommended.

ADVERSE REACTIONS

Cymbalta has been evaluated for safety in 2418 patients diagnosed with major depressive disorder who participated in multiple-dose premarketing trials, representing 1099 patient-years of exposure. Among these 2418 Cymbalta-treated patients, 1139 patients participated in eight 8- or 9-week, placebo-controlled trials at doses ranging from 40 to 120 mg/day, while the remaining 1279 patients were followed for up to 1 year in an open-label safety study using flexible doses from 80 to 120 mg/day. Two placebo-controlled studies with doses of 80 and 120 mg/day had 6-month maintenance extensions. Of these 2418 patients, 993 Cymbalta-treated patients were exposed for at least 180 days and 445 Cymbalta-treated patients were exposed for at least 1 year.

Cymbalta has also been evaluated for safety in 1074 patients with diabetic peripheral neuropathy representing 472 patient-years of exposure. Among these 1074 Cymbalta-treated patients, 568 patients participated in two 12- to 13-week, placebo-controlled trials at doses ranging from 20 to 120 mg/day. An additional 449 patients were enrolled in an open-label safety study using 120 mg/day for a duration of 6 months. Another 57 patients, originally treated with placebo, were exposed to Cymbalta for up to 12 months at 60 mg twice daily in an extension phase. Among these 1074 patients, 484 had 6 months of exposure to Cymbalta, and 220 had 12 months of exposure.

For both MDD and DPN clinical trials, adverse reactions were assessed by collecting adverse events, results of physical examinations, vital signs, weights, laboratory analyses, and ECGs.

Clinical investigators recorded adverse events using descriptive terminology of their own choosing. To provide a meaningful estimate of the proportion of individuals experiencing adverse events, grouping similar types of events into a smaller number of standardized event categories is necessary. In the tables and tabulations that follow, MedDRA terminology has been used to classify reported adverse events.

The stated frequencies of adverse events represent the proportion of individuals who experienced, at least once, a treatment-emergent adverse event of the type listed. An event was considered treatment-emergent if it occurred for the first time or worsened while receiving therapy following baseline evaluation. Events reported during the studies were not necessarily caused by the therapy, and the frequencies do not reflect investigator impression (assessment) of causality.

The cited figures provide the prescriber with some basis for estimating the relative contribution of drug and non-drug factors to the adverse event incidence rate in the population studied. The prescriber should be aware that the figures in the tables and tabulations cannot be used to predict the incidence of adverse events in the course of usual medical practice where patient characteristics and other factors differ from those that prevailed in the clinical trials. Similarly, the cited frequencies cannot be compared with figures obtained from other clinical investigations involving different treatments, uses, and investigators.

Adverse Events Reported as Reasons for Discontinuation of Treatment in Placebo-Controlled Trials

Major Depressive Disorder

Approximately 10% of the 1139 patients who received in the MDD placebo-controlled trials discontinued treatment due to an adverse event, compared with 4% of the 777 patients receiving placebo. Nausea (Cymbalta 1.4%, placebo 0.1%) was the only common adverse event reported as reason for discontinuation and considered to be drug-related (i.e., discontinuation occurring in at least 1% of the Cymbalta-treated patients and at a rate of at least twice that of placebo).

Diabetic Peripheral Neuropathic Pain

Approximately 14% of the 568 patients who received Cymbalta in the DPN placebo-controlled trials discontinued treatment due to an adverse event, compared with 7% of the 223 patients receiving placebo. Nausea (Cymbalta 3.5%, placebo 0.4%), dizziness (Cymbalta 1.6%, placebo 0.4%), somnolence (Cymbalta 1.6%, placebo 0%) and fatigue (Cymbalta 1.1%, placebo 0%) were the common adverse events reported as reasons for discontinuation and considered to be drug-related (i.e., discontinuation occurring in at least 1% of the Cymbalta-treated patients and at a rate of at least twice that of placebo).

Adverse Events Occurring at an Incidence of 2% or More Among Cymbalta-Treated Patients in Placebo-Controlled Trials

Major Depressive Disorder

Table 1 gives the incidence of treatment-emergent adverse events that occurred in 2% or more of patients treated with Cymbalta in the acute phase of MDD placebo-controlled trials and with an incidence greater than placebo. The most commonly observed adverse events in Cymbalta-treated MDD patients (incidence of 5% or greater and at least twice the incidence in placebo patients) were: nausea; dry mouth; constipation; decreased appetite; fatigue; somnolence; and increased sweating ( see Table 1).

Diabetic Peripheral Neuropathic Pain

Table 2 gives the incidence of treatment-emergent adverse events that occurred in 2% or more of patients treated with Cymbalta in the acute phase of DPN placebo-controlled trials (doses of 20 to 120 mg/day) and with an incidence greater than placebo. The most commonly observed adverse events in Cymbalta-treated DPN patients (incidence of 5% or greater and at least twice the incidence in placebo patients) were: nausea; somnolence; dizziness; constipation; dry mouth; hyperhidrosis; decreased appetite; and asthenia ( see Table 2).

 

Adverse events seen in men and women were generally similar except for effects on sexual function (described below). Clinical studies of Cymbalta did not suggest a difference in adverse event rates in people over or under 65 years of age. There were too few non-Caucasian patients studied to determine if these patients responded differently from Caucasian patients.

Effects on Male and Female Sexual Function

Although changes in sexual desire, sexual performance and sexual satisfaction often occur as manifestations of a psychiatric disorder, they may also be a consequence of pharmacologic treatment. Reliable estimates of the incidence and severity of untoward experiences involving sexual desire, performance and satisfaction are difficult to obtain, however, in part because patients and physicians may be reluctant to discuss them. Accordingly, estimates of the incidence of untoward sexual experience and performance cited in product labeling are likely to underestimate their actual incidence. Table 3 displays the incidence of sexual side effects spontaneously reported by at least 2% of either male or female patients taking Cymbalta in MDD placebo-controlled trials.

 

Because adverse sexual events are presumed to be voluntarily underreported, the Arizona Sexual Experience Scale (ASEX), a validated measure designed to identify sexual side effects, was used prospectively in 4 MDD placebo-controlled trials. In these trials, as shown in Table 4 below, patients treated with Cymbalta experienced significantly more sexual dysfunction, as measured by the total score on the ASEX, than did patients treated with placebo. Gender analysis showed that this difference occurred only in males. Males treated with Cymbalta experienced more difficulty with ability to reach orgasm (ASEX Item 4) than males treated with placebo. Females did not experience more sexual dysfunction on Cymbalta than on placebo as measured by ASEX total score. These studies did not, however, include an active control drug with known effects on female sexual dysfunction, so that there is no evidence that its effects differ from other antidepressants. Negative numbers signify an improvement from a baseline level of dysfunction, which is commonly seen in depressed patients. Physicians should routinely inquire about possible sexual side effects.

Urinary Hesitation

Cymbalta is in a class of drugs known to affect urethral resistance. If symptoms of urinary hesitation develop during treatment with Cymbalta, consideration should be given to the possibility that they might be drug-related.

Laboratory Changes

Cymbalta treatment, for up to 9-weeks in MDD or 13-weeks in DPN placebo-controlled clinical trials, was associated with small mean increases from baseline to endpoint in ALT, AST, CPK, and alkaline phosphatase; infrequent, modest, transient, abnormal values were observed for these analytes in Cymbalta-treated patients when compared with placebo-treated patients ( see PRECAUTIONS ).

Vital Sign Changes

Cymbalta treatment, for up to 9-weeks in MDD placebo-controlled clinical trials of 40 to 120 mg daily doses caused increases in blood pressure, averaging 2 mm Hg systolic and 0.5 mm Hg diastolic compared to placebo and an increase in the incidence of at least one measurement of systolic blood pressure over 140 mm Hg ( see PRECAUTIONS ).

Cymbalta treatment, for up to 9-weeks in MDD placebo-controlled clinical trials and for up to 13-weeks in DPN placebo-controlled trials caused a small increase in heart rate compared to placebo of about 2 beats per minute.

Weight Changes

In MDD placebo-controlled clinical trials, patients treated with Cymbalta for up to 9-weeks experienced a mean weight loss of approximately 0.5 kg, compared with a mean weight gain of approximately 0.2 kg in placebo-treated patients.

In DPN placebo-controlled clinical trials, patients treated with Cymbalta for up to 13-weeks experienced a mean weight loss of approximately 1.1 kg, compared with a mean weight gain approximately 0.2 kg in placebo-treated patients.

Electrocardiogram Changes

Electrocardiograms were obtained from 321 Cymbalta-treated patients with major depressive disorder and 169 placebo-treated patients in clinical trials lasting up to 8-weeks. The rate-corrected QT (QTc) interval in Cymbalta-treated patients did not differ from that seen in placebo-treated patients. No clinically significant differences were observed for QT, PR, and QRS intervals between Cymbalta-treated and placebo-treated patients.

Electrocardiograms were obtained from 528 Cymbalta-treated patients with DPN and 205 placebo-treated patients in clinical trials lasting up to 13-weeks. The rate-corrected QT (QTc) interval in Cymbalta-treated patients did not differ from that seen in placebo-treated patients. No clinically significant differences were observed for QT, PR, QRS, or QTc measurements between Cymbalta-treated and placebo-treated patients.

Other Adverse Events Observed During the Premarketing Evaluation of Cymbalta for MDD and the Pain of DPN

Following is a list of modified MedDRA terms that reflect treatment-emergent adverse events as defined in the introduction to the ADVERSE REACTIONS section reported by patients treated with Cymbalta at multiple doses throughout the dose range studied during any phase of a trial within the premarketing database. The events included are those not already listed elsewhere in ADVERSE REACTIONS and not considered in the WARNINGS and PRECAUTIONS sections, that were reported with an incidence of greater than or equal to 0.05% and by more than patient, are not common as background events and were considered possibly drug related (e.g., because of the drug's pharmacology) or potentially important.

It is important to emphasize that, although the events reported occurred during treatment with Cymbalta, they were not necessarily caused by it. Events are further categorized by body system and listed in order of decreasing frequency according to the following definitions: frequent adverse events are those occurring in at least 1/100 patients (only those not already listed in the tabulated results from placebo-controlled trials appear in this listing); infrequent adverse events are those occurring in 1/100 to 1/1000 pa-tients; rare events are those occurring in fewer than 1/1000 patients.

Blood and Lymphatic System Disorders -- Infrequent: anemia, leukopenia, increased white blood cell count, lymphadenopathy, and thrombocytopenia.

Cardiac Disorders -- Infrequent: atrial fibrillation, bundle branch block right, cardiac failure, cardiac failure congestive, coronary artery disease, and myocardial infarction.

Eye Disorders -- Infrequent: diplopia, glaucoma, keroconjunctivitis sicca, macular degeneration, maculopathy, photopsia, and retinal detachment.

Gastrointestinal Disorders -- Frequent: gastritis; Infrequent: apthous stomatitis, blood in stool, colitis, diverticulitis, dysphagia, esophageal stenosis acquired, gastric irritation, gastric ulcer, gingivitis, impaired gastric emptying, irritable bowel syndrome, lower abdominal pain, and melena.

General Disorders and Administration Site Conditions -- Frequent: rigors; Infrequent: edema, feeling jittery, influenza-like illness, and thirst.

Hepato-biliary Disorders -- Infrequent: hepatic steatosis.

Investigations -- Frequent: weight increased; Infrequent: blood cholesterol increased, blood creatinine increased, and urine output decreased.

Metabolism and Nutrition Disorders -- Frequent: hypoglycemia and increased appetite; Infrequent: dehydration, dyslipidemia, hypercholesterolemia, hyperlipidemia, and hypertriglyceridemia.

Musculoskeletal and Connective Tissue Disorders -- Infrequent: muscular weakness.

Nervous System Disorders -- Frequent: hypoesthesia; Infrequent: ataxia and dysarthria.

Psychiatric Disorders -- Frequent: initial insomnia, irritability, lethargy, nervousness, nightmare, restlessness, and sleep disorder; Infrequent: completed suicide, mania, mood swings, pressure of speech, sluggishness, and suicide attempt.

Renal and Urinary Disorders -- Frequent: dysuria; Infrequent: micturition urgency, nephropathy, urinary hesitation, urinary incontinence, urinary retention, and urine flow decreased.

Respiratory, Thoracic and Mediastinal Disorders -- Infrequent: oropharyngeal swelling.

Skin and Subcutaneous Tissue Disorders -- Frequent:
night
sweats, pruritus, rash, and skin ulcer; Infrequent: acne, alopecia, cold sweat, ecchymosis, eczema, erythema, erythe-matous rash, exfoliative dermatitis, face edema, hyperkeratosis, increased tendency to bruise, photosensitivity reaction, and pruritic rash.

Vascular Disorders -- Infrequent: hypertensive crisis, peripheral edema, and phlebitis.