Belexa

Belexa, the S-enantiomer of citalopram, belongs to a class of antidepressant agents known as selective serotonin-reuptake inhibitors (SSRIs). Despite distinct structural differences between compounds in this class, SSRIs possess similar pharmacological activity. As with other antidepressant agents, several weeks of therapy may be required before a clinical effect is seen. SSRIs are potent inhibitors of neuronal serotonin reuptake. They have little to no effect on norepinephrine or dopamine reuptake and do not antagonize α- or β-adrenergic, dopamine D2 or histamine H1 receptors. During acute use, SSRIs block serotonin reuptake and increase serotonin stimulation of somatodendritic 5-HT1A and terminal autoreceptors. Chronic use leads to desensitization of somatodendritic 5-HT1A and terminal autoreceptors. The overall clinical effect of increased mood and decreased anxiety is thought to be due to adaptive changes in neuronal function that leads to enhanced serotonergic neurotransmission. Side effects include dry mouth, nausea, dizziness, drowsiness, sexual dysfunction and headache. Side effects generally occur within the first two weeks of therapy and are usually less severe and frequent than those observed with tricyclic antidepressants. Belexa may be used to treat major depressive disorder (MDD) and generalized anxiety disorder (GAD).

Major Depressive Disorder

Belexa (Belexa) is indicated for the acute and maintenance treatment of major depressive disorder in adults and in adolescents 12 to 17 years of age.

A major depressive episode (DSM-IV) implies a prominent and relatively persistent (nearly every day for at least 2 weeks) depressed or dysphoric mood that usually interferes with daily functioning, and includes at least five of the following nine symptoms: depressed mood, loss of interest in usual activities, significant change in weight and/or appetite, insomnia or hypersomnia, psychomotor agitation or retardation, increased fatigue, feelings of guilt or worthlessness, slowed thinking or impaired concentration, a suicide attempt or suicidal ideation.

Generalized Anxiety Disorder

Belexa is indicated for the acute treatment of Generalized Anxiety Disorder (GAD) in adults.

Generalized Anxiety Disorder (DSM-IV) is characterized by excessive anxiety and worry (apprehensive expectation) that is persistent for at least 6 months and which the person finds difficult to control. It must be associated with at least 3 of the following symptoms: restlessness or feeling keyed up or on edge, being easily fatigued, difficulty concentrating or mind going blank, irritability, muscle tension, and sleep disturbance.

Belexa (Belexa) is an antidepressant belonging to a group of drugs called selective serotonin reuptake inhibitors (SSRIs). The way Belexa works is still not fully understood. It is thought to positively affect communication between nerve cells in the central nervous system and/or restore chemical balance in the brain.

Belexa is used to treat anxiety in adults. Belexa is also used to treat major depressive disorder in adults and adolescents who are at least 12 years old.

Belexa may also be used for purposes not listed in this medication guide.

Belexa should be administered once daily, in the morning or evening, with or without food.

Major Depressive Disorder

Initial Treatment

Adolescents

The recommended dose of Belexa is 10 mg once daily. A flexible-dose trial of Belexa (10 to 20 mg/day) demonstrated the effectiveness of Belexa. If the dose is increased to 20 mg, this should occur after a minimum of three weeks.

Adults

The recommended dose of Belexa is 10 mg once daily. A fixed-dose trial of Belexa demonstrated the effectiveness of both 10 mg and 20 mg of Belexa, but failed to demonstrate a greater benefit of 20 mg over 10 mg. If the dose is increased to 20 mg, this should occur after a minimum of one week.

Maintenance Treatment

It is generally agreed that acute episodes of major depressive disorder require several months or longer of sustained pharmacological therapy beyond response to the acute episode. Systematic evaluation of continuing Belexa 10 or 20 mg/day in adults patients with major depressive disorder who responded while taking Belexa during an 8-week, acute-treatment phase demonstrated a benefit of such maintenance treatment. Nevertheless, the physician who elects to use Belexa for extended periods should periodically re-evaluate the long-term usefulness of the drug for the individual patient. Patients should be periodically reassessed to determine the need for maintenance treatment.

Generalized Anxiety Disorder

Initial Treatment

Adults

The recommended starting dose of Belexa is 10 mg once daily. If the dose is increased to 20 mg, this should occur after a minimum of one week.

Maintenance Treatment

Generalized anxiety disorder is recognized as a chronic condition. The efficacy of Belexa in the treatment of GAD beyond 8 weeks has not been systematically studied. The physician who elects to use Belexa for extended periods should periodically re-evaluate the long-term usefulness of the drug for the individual patient.

Special Populations

10 mg/day is the recommended dose for most elderly patients and patients with hepatic impairment.

No dosage adjustment is necessary for patients with mild or moderate renal impairment. Belexa should be used with caution in patients with severe renal impairment.

Discontinuation of Treatment with Belexa

Symptoms associated with discontinuation of Belexa and other SSRIs and SNRIs have been reported. Patients should be monitored for these symptoms when discontinuing treatment. 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.

Switching a Patient To or From a Monoamine Oxidase Inhibitor (MAOI) Intended to Treat Psychiatric Disorders

At least 14 days should elapse between discontinuation of an MAOI intended to treat psychiatric disorders and initiation of therapy with Belexa. Conversely, at least 14 days should be allowed after stopping Belexa before starting an MAOI intended to treat psychiatric disorders.

Use of Belexa with Other MAOIs such as Linezolid or Methylene Blue

Do not start Belexa in a patient who is being treated with linezolid or intravenous methylene blue because there is an increased risk of serotonin syndrome. In a patient who requires more urgent treatment of a psychiatric condition, other interventions, including hospitalization, should be considered.

In some cases, a patient already receiving Belexa therapy may require urgent treatment with linezolid or intravenous methylene blue. If acceptable alternatives to linezolid or intravenous methylene blue treatment are not available and the potential benefits of linezolid or intravenous methylene blue treatment are judged to outweigh the risks of serotonin syndrome in a particular patient, Belexa should be stopped promptly, and linezolid or intravenous methylene blue can be administered. The patient should be monitored for symptoms of serotonin syndrome for 2 weeks or until 24 hours after the last dose of linezolid or intravenous methylene blue, whichever comes first. Therapy with Belexa may be resumed 24 hours after the last dose of linezolid or intravenous methylene blue.

The risk of administering methylene blue by non-intravenous routes (such as oral tablets or by local injection) or in intravenous doses much lower than 1 mg/kg with Belexa is unclear. The clinician should, nevertheless, be aware of the possibility of emergent symptoms of serotonin syndrome with such use.

See also:
What is the most important information I should know about Belexa?

Do not take Belexa together with a monoamine oxidase inhibitor (MAOI) such as furazolidone (Furoxone), isocarboxazid (Marplan), phenelzine (Nardil), rasagiline (Azilect), selegiline (Eldepryl, Emsam, Zelapar), or tranylcypromine (Parnate). You must wait at least 14 days after stopping an MAOI before you can take Belexa. After you stop taking Belexa, you must wait at least 14 days before you start taking an MAOI.

You may have thoughts about suicide when you first start taking an antidepressant, especially if you are younger than 24 years old. Your doctor will need to check you at regular visits for at least the first 12 weeks of treatment.

Report any new or worsening symptoms to your doctor, such as: mood or behavior changes, anxiety, panic attacks, trouble sleeping, or if you feel impulsive, irritable, agitated, hostile, aggressive, restless, hyperactive (mentally or physically), more depressed, or have thoughts about suicide or hurting yourself.

Tell your doctor right away if you become pregnant while taking this medication. Belexa may cause heart defects or serious lung problems in a newborn if you take the medication during pregnancy. However, you may have a relapse of depression if you stop taking your antidepressant. Do not start or stop taking Belexa during pregnancy without your doctor's advice.

It is dangerous to try and purchase Belexa on the Internet or from vendors outside of the United States. Medications distributed from Internet sales may contain dangerous ingredients, or may not be distributed by a licensed pharmacy. Samples of Belexa purchased on the Internet have been found to contain haloperidol (Haldol), a potent antipsychotic drug with dangerous side effects. For more information, contact the U.S. Food and Drug Administration (FDA) or visit www.fda.gov/buyonlineguide.

Use Belexa solution as directed by your doctor. Check the label on the medicine for exact dosing instructions.

• Belexa solution comes with an extra patient information sheet called a Medication Guide. Read it carefully. Read it again each time you get Belexa solution refilled.
• Take Belexa solution by mouth with or without food.
• Use a measuring device marked for medicine dosing. Ask your pharmacist for help if you are unsure of how to measure your dose.
• Taking Belexa solution at the same time each day will help you remember to take it.
• Continue to take Belexa solution even if you feel well. Do not miss any doses.
• Do not suddenly stop taking Belexa solution without checking with your doctor. Side effects may occur. They may include mental or mood changes, numbness or tingling of the skin, dizziness, confusion, headache, trouble sleeping, or unusual tiredness. You will be closely monitored when you start Belexa solution and whenever a change in dose is made.
• If you miss a dose of Belexa solution, take it as soon as possible. If it is almost time for your next dose, skip the missed dose and go back to your regular dosing schedule. Do not take 2 doses at once.

Ask your health care provider any questions you may have about how to use Belexa solution.

Use: Labeled Indications

Major depressive disorder (unipolar): Acute and maintenance treatment of unipolar major depressive disorder (MDD)

Generalized anxiety disorder: Acute treatment of generalized anxiety disorder (GAD)

Off Label Uses

Binge eating disorder

Data from a limited number of patients studied suggest that Belexa may be beneficial to improve weight loss, severity of illness, binge frequency, and binge days in patients with binge eating disorder.

Based on the American Association of Clinical Endocrinologists and American College of Endocrinology (AACE/ACE) position statement on menopause, the Endocrine Society guideline on the treatment of menopause symptoms, and the North American Menopause Society (NAMS) position statement on nonhormonal management of menopause-associated vasomotor symptoms, SSRIs (including Belexa) are effective and recommended alternatives for the management of vasomotor symptoms associated with menopause in patients with contraindications to hormonal therapy or who prefer not to use hormonal therapy. Based on the American Cancer Society/American Society of Clinical Oncology (ACS/ASCO) breast cancer survivorship care guideline, SSRIs may be used to help mitigate vasomotor symptoms of premature menopause in women previously treated for breast cancer.

See also:
What other drugs will affect Belexa?

Pharmacodynamic Interactions: Contraindicated Combinations: Nonselective MAOIs: Cases of serious reactions have been reported in patients receiving an SSRI in combination with a nonselective monoamine oxidase inhibitor (MAOI), and in patients who have recently discontinued SSRI treatment and have been started on MAOI treatment. In some cases, the patient developed serotonin syndrome.

Belexa is contraindicated in combination with nonselective MAOIs. Belexa may be started 14 days after discontinuing treatment with an irreversible MAOI and at least 1 day after discontinuing treatment with the reversible MAOI (RIMA), moclobemide. At least 7 days should elapse after discontinuing Belexa treatment, before starting a nonselective MAOI.

Inadvisable Combinations: Reversible, Selective MAO-A Inhibitor (Moclobemide): Due to the risk of serotonin syndrome, the combination of Belexa with a MAO-A inhibitor is not recommended. If the combination proves necessary, it should be started at the minimum recommended dosage and clinical monitoring is strongly recommended.

Combinations Requiring Precautions for Use: Selegiline: In combination with selegiline (irreversible MAO-B inhibitor), caution is required due to the risk of developing serotonin syndrome. Selegiline doses up to 10 mg/day have been safely co-administered with racemic citalopram.

Serotonergic Medicinal Products: Co-administration with serotonergic medicinal products (eg, tramadol, sumatriptan and other triptans) may lead to serotonin syndrome.

Medicinal Products Lowering the Seizure Threshold: SSRIs can lower the seizure threshold. Caution is advised when concomitantly using other medicinal products capable of lowering the seizure threshold.

Lithium, Tryptophan: There have been reports of enhanced effects when SSRIs have been given together with lithium or tryptophan, therefore concomitant use of SSRIs with these medicinal products should be undertaken with caution.

St. John's Wort: Concomitant use of SSRIs and herbal remedies containing St. John's wort (Hypericum perforatum) may result in an increased incidence of adverse reactions.

Hemorrhage: Altered anticoagulant effects may occur when Belexa is combined with oral anticoagulants. Patients receiving oral anticoagulant therapy should receive careful coagulation monitoring when Belexa is started or stopped.

Alcohol: No pharmacodynamic or pharmacokinetic interactions are expected between Belexa and alcohol. However, as with other psychotropic medicinal products, the combination with alcohol is not advisable.

Pharmacokinetic Interactions: Influence of Other Medicinal Products on the Pharmacokinetics of Belexa: The metabolism of Belexa is mainly mediated by CYP2C19. CYP3A4 and CYP2D6 may also contribute to the metabolism although to a smaller extent. The metabolism of the major metabolite S-DCT (demethylated Belexa) seems to be partly catalyzed by CYP2D6.

Co-administration of Belexa with omeprazole (a CYP2C19 inhibitor) resulted in moderate (approximately 50%) increase in the plasma concentrations of Belexa.

Co-administration of Belexa with cimetidine (moderately potent general enzyme inhibitor) resulted in moderate (approximately 70%) increase in the plasma concentrations of Belexa.

Caution should thus be exercised at the upper end of the dose range of Belexa when used concomitantly with CYP2C19 inhibitors (eg, fluoxetine, fluvoxamine, lansoprazole, ticlopidine) or cimetidine. A reduction in the dose of Belexa may be necessary based on clinical judgment.

Effect of Belexa on the Pharmacokinetics of Other Medicinal Products: Belexa is an inhibitor of the enzyme CYP2D6. Caution is recommended when Belexa is co-administered with medicinal products that are mainly metabolized by this enzyme, and that have a narrow therapeutic index eg, flecainide, propafenone and metoprolol (when used in cardiac failure), or some CNS-acting medicinal products that are mainly metabolized by CYP2D6 eg, antidepressants eg, desipramine, clomipramine and nortryptyline or antipsychotics eg, risperidone, thioridazine and haloperidol. Dosage adjustment may be warranted.

Co-administration with desipramine or metoprolol resulted in both cases in a 2-fold increase in the plasma levels of these two CYP2D6 substrates.

In vitro studies have demonstrated that Belexa may also cause weak inhibition of CYP2C19. Caution is recommended with concomitant use of medicinal products that are metabolized by CYP2C19.

See also:
What are the possible side effects of Belexa?

Clinical Trials Experience

Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice.

Clinical Trial Data Sources

Pediatrics (6 -17 years)

Adverse events were collected in 576 pediatric patients (286 Belexa, 290 placebo) with major depressive disorder in double-blind placebo-controlled studies. Safety and effectiveness of Belexa in pediatric patients less than 12 years of age has not been established.

Adults

Adverse events information for Belexa was collected from 715 patients with major depressive disorder who were exposed to Belexa and from 592 patients who were exposed to placebo in double-blind, placebo-controlled trials. An additional 284 patients with major depressive disorder were newly exposed to Belexa in open-label trials. The adverse event information for Belexa in patients with GAD was collected from 429 patients exposed to Belexa and from 427 patients exposed to placebo in double-blind, placebo-controlled trials.

Adverse events during exposure were obtained primarily by general inquiry and recorded by clinical investigators using terminology of their own choosing. Consequently, it is not possible to provide a meaningful estimate of the proportion of individuals experiencing adverse events without first grouping similar types of events into a smaller number of standardized event categories. In the tables and tabulations that follow, standard World Health Organization (WHO) terminology has been used to classify reported adverse events.

The stated frequencies of adverse reactions 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.

Adverse Events Associated with Discontinuation of Treatment

Major Depressive Disorder

Pediatrics (6 -17 years)

Adverse events were associated with discontinuation of 3.5% of 286 patients receiving Belexa and 1% of 290 patients receiving placebo. The most common adverse event (incidence at least 1% for Belexa and greater than placebo) associated with discontinuation was insomnia (1% Belexa, 0% placebo).

Adults

Among the 715 depressed patients who received Belexa in placebo-controlled trials, 6% discontinued treatment due to an adverse event, as compared to 2% of 592 patients receiving placebo. In two fixed-dose studies, the rate of discontinuation for adverse events in patients receiving 10 mg/day Belexa was not significantly different from the rate of discontinuation for adverse events in patients receiving placebo. The rate of discontinuation for adverse events in patients assigned to a fixed dose of 20 mg/day Belexa was 10%, which was significantly different from the rate of discontinuation for adverse events in patients receiving 10 mg/day Belexa (4%) and placebo (3%). Adverse events that were associated with the discontinuation of at least 1% of patients treated with Belexa, and for which the rate was at least twice that of placebo, were nausea (2%) and ejaculation disorder (2% of male patients).

Generalized Anxiety Disorder

Adults

Among the 429 GAD patients who received Belexa 10-20 mg/day in placebo-controlled trials, 8% discontinued treatment due to an adverse event, as compared to 4% of 427 patients receiving placebo. Adverse events that were associated with the discontinuation of at least 1% of patients treated with Belexa, and for which the rate was at least twice the placebo rate, were nausea (2%), insomnia (1%), and fatigue (1%).

Incidence of Adverse Reactions in Placebo-Controlled Clinical Trials

Major Depressive Disorder

Pediatrics (6 -17 years)

The overall profile of adverse reactions in pediatric patients was generally similar to that seen in adult studies, as shown in Table 2. However, the following adverse reactions (excluding those which appear in Table 2 and those for which the coded terms were uninformative or misleading) were reported at an incidence of at least 2% for Belexa and greater than placebo: back pain, urinary tract infection, vomiting, and nasal congestion.

Adults

The most commonly observed adverse reactions in Belexa patients (incidence of approximately 5% or greater and approximately twice the incidence in placebo patients) were insomnia, ejaculation disorder (primarily ejaculatory delay), nausea, sweating increased, fatigue, and somnolence.

Table 2 enumerates the incidence, rounded to the nearest percent, of treatment-emergent adverse events that occurred among 715 depressed patients who received Belexa at doses ranging from 10 to 20 mg/day in placebo-controlled trials. Events included are those occurring in 2% or more of patients treated with Belexa and for which the incidence in patients treated with Belexa was greater than the incidence in placebo-treated patients.

TABLE 2 : Treatment-Emergent Adverse Reactions observed with a frequency of ≥ 2% and greater than placebo for Major Depressive Disorder

Dose Dependency of Adverse Reactions

The potential dose dependency of common adverse reactions (defined as an incidence rate of ≥ 5% in either the 10 mg or 20 mg Belexa groups) was examined on the basis of the combined incidence of adverse reactions in two fixed-dose trials. The overall incidence rates of adverse events in 10 mg Belexa-treated patients (66%) was similar to that of the placebo-treated patients (61%), while the incidence rate in 20 mg/day Belexa-treated patients was greater (86%). Table 4 shows common adverse reactions that occurred in the 20 mg/day Belexa group with an incidence that was approximately twice that of the 10 mg/day Belexa group and approximately twice that of the placebo group.

TABLE 4 : Incidence of Common Adverse Reactions in Patients with Major Depressive Disorder

Male and Female Sexual Dysfunction with SSRIs

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. In particular, some evidence suggests that SSRIs can cause such untoward sexual experiences.

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 5 : Incidence of Sexual Side Effects in Placebo-Controlled Clinical Trials

There are no adequately designed studies examining sexual dysfunction with Belexa treatment.

Priapism has been reported with all SSRIs.

While it is difficult to know the precise risk of sexual dysfunction associated with the use of SSRIs, physicians should routinely inquire about such possible side effects.

Vital Sign Changes

Belexa and placebo groups were compared with respect to (1) mean change from baseline in vital signs (pulse, systolic blood pressure, and diastolic blood pressure) and (2) the incidence of patients meeting criteria for potentially clinically significant changes from baseline in these variables. These analyses did not reveal any clinically important changes in vital signs associated with Belexa treatment. In addition, a comparison of supine and standing vital sign measures in subjects receiving Belexa indicated that Belexa treatment is not associated with orthostatic changes.

Weight Changes

Patients treated with Belexa in controlled trials did not differ from placebo-treated patients with regard to clinically important change in body weight.

Laboratory Changes

Belexa and placebo groups were compared with respect to (1) mean change from baseline in various serum chemistry, hematology, and urinalysis variables, and (2) the incidence of patients meeting criteria for potentially clinically significant changes from baseline in these variables. These analyses revealed no clinically important changes in laboratory test parameters associated with Belexa treatment.

ECG Changes

Electrocardiograms from Belexa (N=625) and placebo (N=527) groups were compared with respect to outliers defined as subjects with QTc changes over 60 msec from baseline or absolute values over 500 msec post-dose, and subjects with heart rate increases to over 100 bpm or decreases to less than 50 bpm with a 25% change from baseline (tachycardic or bradycardic outliers, respectively). None of the patients in the Belexa group had a QTcF interval > 500 msec or a prolongation > 60 msec compared to 0.2% of patients in the placebo group. The incidence of tachycardic outliers was 0.2% in the Belexa and the placebo group. The incidence of bradycardic outliers was 0.5% in the Belexa group and 0.2% in the placebo group.

QTcF interval was evaluated in a randomized, placebo and active (moxifloxacin 400 mg) controlled cross-over, escalating multiple-dose study in 113 healthy subjects. The maximum mean (95% upper confidence bound) difference from placebo arm were 4.5 (6.4) and 10.7 (12.7) msec for 10 mg and supratherapeutic 30 mg Belexa given once daily, respectively. Based on the established exposure-response relationship, the predicted QTcF change from placebo arm (95% confidence interval) under the Cmax for the dose of 20 mg is 6.6 (7.9) msec. Belexa 30 mg given once daily resulted in mean Cmax of 1.7-fold higher than the mean Cmax for the maximum recommended therapeutic dose at steady state (20 mg). The exposure under supratherapeutic 30 mg dose is similar to the steady state concentrations expected in CYP2C19 poor metabolizers following a therapeutic dose of 20 mg.

Other Reactions Observed During the Premarketing Evaluation of Belexa

Following is a list of treatment-emergent adverse events, as defined in the introduction to the ADVERSE REACTIONS section, reported by the 1428 patients treated with Belexa for periods of up to one year in double-blind or open-label clinical trials during its premarketing evaluation. The listing does not include those events already listed in Tables 2 & 3, those events for which a drug cause was remote and at a rate less than 1% or lower than placebo, those events which were so general as to be uninformative, and those events reported only once which did not have a substantial probability of being acutely life threatening. Events are categorized by body system. Events of major clinical importance are described in the WARNINGS AND PRECAUTIONS section.

Cardiovascular - hypertension, palpitation.

Central and Peripheral Nervous System Disorders - light-headed feeling, migraine.

Gastrointestinal Disorders - abdominal cramp, heartburn, gastroenteritis.

General - allergy, chest pain, fever, hot flushes, pain in limb.

Metabolic and Nutritional Disorders - increased weight.

Musculoskeletal System Disorders - arthralgia, myalgia jaw stiffness.

Psychiatric Disorders - appetite increased, concentration impaired, irritability.

Reproductive Disorders/Female - menstrual cramps, menstrual disorder.

Respiratory System Disorders - bronchitis, coughing, nasal congestion, sinus congestion, sinus headache.

Skin and Appendages Disorders - rash.

Special Senses - vision blurred, tinnitus.

Urinary System Disorders - urinary frequency, urinary tract infection.

Post-Marketing Experience

Adverse Reactions Reported Subsequent to the Marketing of Belexa

The following additional adverse reactions have been identified from spontaneous reports of Belexa received worldwide. These adverse reactions have been chosen for inclusion because of a combination of seriousness, frequency of reporting, or potential causal connection to Belexa and have not been listed elsewhere in labeling. However, because these adverse reactions were reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. These events include:

Blood and Lymphatic System Disorders: anemia, agranulocytis, aplastic anemia, hemolytic anemia, idiopathic thrombocytopenia purpura, leukopenia, thrombocytopenia.

Cardiac Disorders: atrial fibrillation, bradycardia, cardiac failure, myocardial infarction, tachycardia, torsade de pointes, ventricular arrhythmia, ventricular tachycardia.

Ear and labyrinth disorders: vertigo

Endocrine Disorders: diabetes mellitus, hyperprolactinemia, SIADH.

Eye Disorders: angle closure glaucoma, diplopia, mydriasis, visual disturbance.

Gastrointestinal Disorder: dysphagia, gastrointestinal hemorrhage, gastroesophageal reflux, pancreatitis, rectal hemorrhage.

General Disorders and Administration Site Conditions: abnormal gait, asthenia, edema, fall, feeling abnormal, malaise.

Hepatobiliary Disorders: fulminant hepatitis, hepatic failure, hepatic necrosis, hepatitis.

Immune System Disorders: allergic reaction, anaphylaxis.

Investigations: bilirubin increased, decreased weight, electrocardiogram QT prolongation, hepatic enzymes increased, hypercholesterolemia, INR increased, prothrombin decreased.

Metabolism and Nutrition Disorders: hyperglycemia, hypoglycemia, hypokalemia, hyponatremia.

Musculoskeletal and Connective Tissue Disorders: muscle cramp, muscle stiffness, muscle weakness, rhabdomyolysis.

Nervous System Disorders: akathisia, amnesia, ataxia, choreoathetosis, cerebrovascular accident, dysarthria, dyskinesia, dystonia, extrapyramidal disorders, grand mal seizures (or convulsions), hypoaesthesia, myoclonus, nystagmus, Parkinsonism, restless legs, seizures, syncope, tardive dyskinesia, tremor.

Pregnancy, Puerperium and Perinatal Conditions: spontaneous abortion.

Psychiatric Disorders: acute psychosis, aggression, agitation, anger, anxiety, apathy, completed suicide, confusion, depersonalization, depression aggravated, delirium, delusion, disorientation, feeling unreal, hallucinations (visual and auditory), mood swings, nervousness, nightmare, panic reaction, paranoia, restlessness, self-harm or thoughts of self-harm, suicide attempt, suicidal ideation, suicidal tendency.

Renal and Urinary Disorders: acute renal failure, dysuria, urinary retention.

Reproductive System and Breast Disorders: menorrhagia, priapism.

Respiratory, Thoracic and Mediastinal Disorders: dyspnea, epistaxis, pulmonary embolism, pulmonary hypertension of the newborn.

Skin and Subcutaneous Tissue Disorders: alopecia, angioedema, dermatitis, ecchymosis, erythema multiforme, photosensitivity reaction, Stevens Johnson Syndrome, toxic epidermal necrolysis, urticaria.

Vascular Disorders: deep vein thrombosis, flushing, hypertensive crisis, hypotension, orthostatic hypotension, phlebitis, thrombosis.