Celesta

Celesta hydrobromide belongs to a class of antidepressant agents known as selective serotonin-reuptake inhibitors (SSRIs). Celesta and its N-demethylated metabolites exist as a racemic mixture but its effects are largely due to the S-enantiomer, S-Celesta and S-demthylcitalopram. 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. Celesta is approved for treatment of depression. Unlabeled indications include mild dementia-associated agitation in nonpsychotic patients, smoking cessation, ethanol abuse, obsessive-compulsive disorder (OCD) in children, and diabetic neuropathy. Celesta has the fewest drug-drug interactions of the SSRIs.

Celesta (Celesta HBr) is indicated for the treatment of depression.

The efficacy of Celesta in the treatment of depression was established in 4-6 week, controlled trials of outpatients whose diagnosis corresponded most closely to the DSM-III and DSM-III-R category of major depressive disorder.

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.

The antidepressant action of Celesta in hospitalized depressed patients has not been adequately studied.

The efficacy of Celesta in maintaining an antidepressant response for up to 24 weeks following 6 to 8 weeks of acute treatment was demonstrated in two placebo-controlled trials. Nevertheless, the physician who elects to use Celesta for extended periods should periodically re-evaluate the long-term usefulness of the drug for the individual patient.

Celesta (Celesta) is an antidepressant in a group of drugs called selective serotonin reuptake inhibitors (SSRIs).

Celesta is used to treat depression.

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

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

Initial Treatment

Celesta (Celesta HBr) should be administered at an initial dose of 20 mg once daily, with an increase to a maximum dose of 40 mg/day at an interval of no less than one week. Doses above 40 mg/day are not recommended due to the risk of QT prolongation. Additionally, the only study pertinent to dose response for effectiveness did not demonstrate an advantage for the 60 mg/day dose over the 40 mg/day dose.

Special Populations

20 mg/day is the maximum recommended dose for patients who are greater than 60 years of age, patients with hepatic impairment, and for CYP2C19 poor metabolizers or those patients taking cimetidine or another CYP2C19 inhibitor.

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

Treatment of Pregnant Women During the Third Trimester

Neonates exposed to Celesta and other SSRIs or SNRIs, late in the third trimester, have developed complications requiring prolonged hospitalization, respiratory support, and tube feeding. When treating pregnant women with Celesta during the third trimester, the physician should carefully consider the potential risks and benefits of treatment.

Maintenance Treatment

It is generally agreed that acute episodes of depression require several months or longer of sustained pharmacologic therapy. Systematic evaluation of Celesta in two studies has shown that its antidepressant efficacy is maintained for periods of up to 24 weeks following 6 or 8 weeks of initial treatment (32 weeks total). In one study, patients were assigned randomly to placebo or to the same dose of Celesta (20-60 mg/day) during maintenance treatment as they had received during the acute stabilization phase, while in the other study, patients were assigned randomly to continuation of Celesta 20 or 40 mg/day, or placebo, for maintenance treatment. In the latter study, the rates of relapse to depression were similar for the two dose groups. Based on these limited data, it is not known whether the dose of Celesta needed to maintain euthymia is identical to the dose needed to induce remission. If adverse reactions are bothersome, a decrease in dose to 20 mg/day can be considered.

Discontinuation of Treatment with Celesta

Symptoms associated with discontinuation of Celesta 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 Celesta. Conversely, at least 14 days should be allowed after stopping Celesta before starting an MAOI intended to treat psychiatric disorders.

Use of Celesta with Other MAOIs, Such as Linezolid or Methylene Blue

Do not start Celesta 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 Celesta 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, Celesta 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 Celesta 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 Celesta 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 Celesta?

You should not use Celesta if you are allergic to it, or if you also take pimozide.

Do not use Celesta if you have taken an MAO inhibitor in the past 14 days. A dangerous drug interaction could occur. MAO inhibitors include furazolidone, isocarboxazid, linezolid, phenelzine, rasagiline, selegiline, and tranylcypromine.

Before taking Celesta, tell your doctor if you have a heart rhythm disorder, a personal or family history of Long QT syndrome, or an electrolyte imbalance (such as low levels of potassium or magnesium in your blood).

Tell your doctor about all other medicines you use. There are many other medicines that can increase your risk of heart rhythm problems if you use them together with Celesta.

Some young people have thoughts about suicide when first taking an antidepressant. Your doctor will need to check your progress at regular visits while you are using Celesta. Your family or other caregivers should also be alert to changes in your mood or symptoms.

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. Do not start or stop taking Celesta during pregnancy without your doctor's advice.

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

• Celesta solution comes with an extra patient information sheet called a Medication Guide. Read it carefully. Read it again each time you get Celesta solution refilled.
• Take Celesta 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 Celesta solution at the same time each day will help you remember to take it.
• Do not suddenly stop taking Celesta solution without checking with your doctor. You may have an increased risk of side effects (eg, mental or mood changes, numbness or tingling of the skin, dizziness, confusion, headache, trouble sleeping, unusual tiredness). If you need to stop Celesta solution, your doctor may need to gradually lower your dose.
• Continue to take Celesta solution even if you feel well. Do not miss any doses.
• If you miss a dose of Celesta 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 Celesta solution.

Use: Labeled Indications

Major depressive disorder (unipolar): Treatment of unipolar major depressive disorder

Off Label Uses

Aggressive or agitated behavior associated with dementia

Data from a randomized, double-blind, placebo-controlled study support the use of Celesta in the treatment of agitation associated with dementia.

Based on the American Association of Clinical Endocrinologists and American College of Endocrinology position statement on menopause, the Endocrine Society guideline on the treatment of symptoms of menopause, and the North American Menopause Society position statement on nonhormonal management of menopause-associated vasomotor symptoms, SSRIs (including Celesta) are an effective and recommended alternative 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 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 Celesta?

Serotonergic Drugs

Triptans

There have been rare postmarketing reports of serotonin syndrome with use of an SSRI and a triptan. If concomitant treatment of Celesta with a triptan is clinically warranted, careful observation of the patient is advised, particularly during treatment initiation and dose increases.

CNS Drugs - Given the primary CNS effects of Celesta, caution should be used when it is taken in combination with other centrally acting drugs.

Alcohol - Although Celesta did not potentiate the cognitive and motor effects of alcohol in a clinical trial, as with other psychotropic medications, the use of alcohol by depressed patients taking Celesta is not recommended.

Monoamine Oxidase Inhibitors (MAOIs) - See CONTRAINDICATIONS, WARNINGS and DOSAGE AND ADMINISTRATION.

Drugs That Interfere With Hemostasis (NSAIDs, Aspirin, Warfarin, etc.) - Serotonin release by platelets plays an important role in hemostasis. Epidemiological studies of the case-control and cohort design that have demonstrated an association between use of psychotropic drugs that interfere with serotonin reuptake and the occurrence of upper gastrointestinal bleeding have also shown that concurrent use of an NSAID or aspirin may potentiate the risk of bleeding. Altered anticoagulant effects, including increased bleeding, have been reported when SSRIs and SNRIs are coadministered with warfarin. Patients receiving warfarin therapy should be carefully monitored when Celesta is initiated or discontinued.

Cimetidine - In subjects who had received 21 days of 40 mg/day Celesta, combined administration of 400 mg twice a day cimetidine for 8 days resulted in an increase in Celesta AUC and Cmax of 43% and 39%, respectively.

Celesta 20 mg/day is the maximum recommended dose for patients taking concomitant cimetidine because of the risk of QT prolongation.

Digoxin - In subjects who had received 21 days of 40 mg/day Celesta, combined administration of Celesta and digoxin (single dose of 1 mg) did not significantly affect the pharmacokinetics of either Celesta or digoxin.

Lithium - Coadministration of Celesta (40 mg/day for 10 days) and lithium (30 mmol/day for 5 days) had no significant effect on the pharmacokinetics of Celesta or lithium. Nevertheless, plasma lithium levels should be monitored with appropriate adjustment to the lithium dose in accordance with standard clinical practice. Because lithium may enhance the serotonergic effects of Celesta, caution should be exercised when Celesta and lithium are coadministered.

Pimozide - In a controlled study, a single dose of pimozide 2 mg co-administered with Celesta 40 mg given once daily for 11 days was associated with a mean increase in QTc values of approximately 10 msec compared to pimozide given alone. Celesta did not alter the mean AUC or Cmax of pimozide. The mechanism of this pharmacodynamic interaction is not known.

Theophylline - Combined administration of Celesta (40 mg/day for 21 days) and the CYP1A2 substrate theophylline (single dose of 300 mg) did not affect the pharmacokinetics of theophylline. The effect of theophylline on the pharmacokinetics of Celesta was not evaluated.

Sumatriptan - There have been rare postmarketing reports describing patients with weakness, hyperreflexia, and incoordination following the use of a SSRI and sumatriptan. If concomitant treatment with sumatriptan and an SSRI (e.g., fluoxetine, fluvoxamine, paroxetine, sertraline, Celesta) is clinically warranted, appropriate observation of the patient is advised.

Warfarin - Administration of 40 mg/day Celesta for 21 days did not affect the pharmacokinetics of warfarin, a CYP3A4 substrate. Prothrombin time was increased by 5%, the clinical significance of which is unknown.

Carbamazepine - Combined administration of Celesta (40 mg/day for 14 days) and carbamazepine (titrated to 400 mg/day for 35 days) did not significantly affect the pharmacokinetics of carbamazepine, a CYP3A4 substrate. Although trough Celesta plasma levels were unaffected, given the enzyme-inducing properties of carbamazepine, the possibility that carbamazepine might increase the clearance of Celesta should be considered if the two drugs are coadministered.

Triazolam - Combined administration of Celesta (titrated to 40 mg/day for 28 days) and the CYP3A4 substrate triazolam (single dose of 0.25 mg) did not significantly affect the pharmacokinetics of either Celesta or triazolam.

Ketoconazole - Combined administration of Celesta (40 mg) and ketoconazole (200 mg) decreased the Cmax and AUC of ketoconazole by 21% and 10%, respectively, and did not significantly affect the pharmacokinetics of Celesta.

CYP2C19 Inhibitors - Celesta 20 mg/day is the maximum recommended dose for patients taking concomitant CYP2C19 inhibitors because of the risk of QT prolongation.

Metoprolol - Administration of 40 mg/day Celesta for 22 days resulted in a two-fold increase in the plasma levels of the beta-adrenergic blocker metoprolol. Increased metoprolol plasma levels have been associated with decreased cardioselectivity. Coadministration of Celesta and metoprolol had no clinically significant effects on blood pressure or heart rate.

Imipramine and Other Tricyclic Antidepressants (TCAs) - In vitro studies suggest that Celesta is a relatively weak inhibitor of CYP2D6. Coadministration of Celesta (40 mg/day for 10 days) with the TCA imipramine (single dose of 100 mg), a substrate for CYP2D6, did not significantly affect the plasma concentrations of imipramine or Celesta. However, the concentration of the imipramine metabolite desipramine was increased by approximately 50%. The clinical significance of the desipramine change is unknown. Nevertheless, caution is indicated in the coadministration of TCAs with Celesta.

Electroconvulsive Therapy (ECT) - There are no clinical studies of the combined use of electroconvulsive therapy (ECT) and Celesta.

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

The premarketing development program for Celesta included Celesta exposures in patients and/or normal subjects from 3 different groups of studies: 429 normal subjects in clinical pharmacology/pharmacokinetic studies; 4422 exposures from patients in controlled and uncontrolled clinical trials, corresponding to approximately 1370 patient-exposure years. There were, in addition, over 19,000 exposures from mostly open-label, European postmarketing studies. The conditions and duration of treatment with Celesta varied greatly and included (in overlapping categories) open-label and double-blind studies, inpatient and outpatient studies, fixed-dose and dose-titration studies, and short-term and long-term exposure. Adverse reactions were assessed by collecting adverse events, results of physical examinations, vital signs, weights, laboratory analyses, ECGs, and results of ophthalmologic examinations.

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 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.

Adverse Findings Observed In Short-Term, Placebo-Controlled Trials

Adverse Events Associated with Discontinuation of Treatment

Among 1063 depressed patients who received Celesta at doses ranging from 10 to 80 mg/day in placebo-controlled trials of up to 6 weeks in duration, 16% discontinued treatment due to an adverse event, as compared to 8% of 446 patients receiving placebo. The adverse events associated with discontinuation and considered drug-related (i.e., associated with discontinuation in at least 1% of Celesta-treated patients at a rate at least twice that of placebo) are shown in TABLE 2. It should be noted that one patient can report more than one reason for discontinuation and be counted more than once in this table.

TABLE 2: Adverse Events Associated with Discontinuation of Treatment in Short-Term, Placebo-Controlled, Depression Trials

Adverse Events Occurring at an Incidence of 2% or More Among Celesta-Treated Patients

Table 3 enumerates the incidence, rounded to the nearest percent, of treatment-emergent adverse events that occurred among 1063 depressed patients who received Celesta at doses ranging from 10 to 80 mg/day in placebo-controlled trials of up to 6 weeks in duration. Events included are those occurring in 2% or more of patients treated with Celesta and for which the incidence in patients treated with Celesta was greater than the incidence in placebo-treated patients.

The prescriber should be aware that these figures 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 which 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. The cited figures, however, do provide the prescribing physician 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 only commonly observed adverse event that occurred in Celesta patients with an incidence of 5% or greater and at least twice the incidence in placebo patients was ejaculation disorder (primarily ejaculatory delay) in male patients.

TABLE 3: Treatment-Emergent Adverse Events: Incidence in Placebo-Controlled Clinical Trials*

Dose Dependency of Adverse Events

The potential relationship between the dose of Celesta administered and the incidence of adverse events was examined in a fixed-dose study in depressed patients receiving placebo or Celesta 10, 20, 40, and 60 mg. Jonckheere's trend test revealed a positive dose response (p < 0.05) for the following adverse events: fatigue, impotence, insomnia, sweating increased, somnolence, and yawning.

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.

The table below displays the incidence of sexual side effects reported by at least 2% of patients taking Celesta in a pool of placebo-controlled clinical trials in patients with depression.

In female depressed patients receiving Celesta, the reported incidence of decreased libido and anorgasmia was 1.3% (n=638 females) and 1.1% (n=252 females), respectively.

There are no adequately designed studies examining sexual dysfunction with Celesta 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

Celesta 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 Celesta treatment. In addition, a comparison of supine and standing vital sign measures for Celesta and placebo treatments indicated that Celesta treatment is not associated with orthostatic changes.

Weight Changes

Patients treated with Celesta in controlled trials experienced a weight loss of about 0.5 kg compared to no change for placebo patients.

Laboratory Changes

Celesta 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 Celesta treatment.

ECG Changes

In a thorough QT study, Celesta was found to be associated with a dose-dependent increase in the QTc interval.

Electrocardiograms from Celesta (N=802) and placebo (N=241) 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). In the Celesta group 1.9% of the patients had a change from baseline in QTcF > 60 msec compared to 1.2% of the patients in the placebo group. None of the patients in the placebo group had a post-dose QTcF > 500 msec compared to 0.5% of the patients in the Celesta group. The incidence of tachycardic outliers was 0.5% in the Celesta group and 0.4% in the placebo group. The incidence of bradycardic outliers was 0.9% in the Celesta group and 0.4% in the placebo group.

Other Events Observed During The Premarketing Evaluation Of Celesta (Celesta HBr)

Following is a list of WHO terms that reflect treatment-emergent adverse events, as defined in the introduction to the ADVERSE REACTIONS section, reported by patients treated with Celesta at multiple doses in a range of 10 to 80 mg/day during any phase of a trial within the premarketing database of 4422 patients. All reported events are included except those already listed in Table 3 or elsewhere in labeling, those events for which a drug cause was remote, those event terms which were so general as to be uninformative, and those occurring in only one patient. It is important to emphasize that, although the events reported occurred during treatment with Celesta, 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 on one or more occasions in at least 1/100 patients; infrequent adverse events are those occurring in less than 1/100 patients but at least 1/1000 patients; rare events are those occurring in fewer than 1/1000 patients.

Cardiovascular - Frequent: tachycardia, postural hypotension, hypotension. Infrequent: hypertension, bradycardia, edema (extremities), angina pec toris, extrasystoles, cardiac failure, flushing, myocardial infarction, cerebrovascular accident, myocardial ischemia. Rare: transient ischemic attack, phlebitis, atrial fibrillation, cardiac arrest, bundle branch block.

Central and Peripheral Nervous System Disorders - Frequent: paresthesia, migraine. Infrequent: hyperkinesia, vertigo, hypertonia, extrapyramidal disorder, leg cramps, involuntary muscle contractions, hypokinesia, neuralgia, dystonia, abnormal gait, hypesthesia, ataxia. Rare: abnormal coordination, hyperesthesia, ptosis, stupor.

Endocrine Disorders - Rare: hypothyroidism, goiter, gynecomastia.

Gastrointestinal Disorders - Frequent: saliva increased, flatulence. Infrequent: gastritis, gastroenteritis, stomatitis, eructation, hemorrhoids, dysphagia, teeth grinding, gingivitis, esophagitis. Rare: colitis, gastric ulcer, cholecystitis, cholelithiasis, duodenal ulcer, gastroesophageal reflux, glossitis, jaundice, diverticulitis, rectal hemorrhage, hiccups.

General - Infrequent: hot flushes, rigors, alcohol intolerance, syncope, influenza-like symptoms. Rare: hayfever.

Hemic and Lymphatic Disorders - Infrequent: purpura, anemia, epistaxis, leukocytosis, leucopenia, lymphadenopathy. Rare: pulmonary embolism, granulocytopenia, lymphocytosis, lymphopenia, hypochromic anemia, coagulation disorder, gingival bleeding.

Metabolic and Nutritional Disorders - Frequent: decreased weight, increased weight. Infrequent: increased hepatic enzymes, thirst, dry eyes, increased alkaline phosphatase, abnormal glucose tolerance. Rare: bilirubinemia, hypokalemia, obesity, hypoglycemia, hepatitis, dehydration.

Musculoskeletal System Disorders - Infrequent: arthritis, muscle weakness, skeletal pain. Rare: bursitis, osteoporosis.

Psychiatric Disorders - Frequent: impaired concentration, amnesia, apathy, depression, increased appetite, aggravated depression, suicide attempt, confusion. Infrequent: increased libido, aggressive reaction, paroniria, drug dependence, depersonalization, hallucination, euphoria, psychotic depression, delusion, paranoid reaction, emotional lability, panic reaction, psychosis. Rare: catatonic reaction, melancholia.

Reproductive Disorders/Female* - Frequent: amenorrhea. Infrequent: galactorrhea, breast pain, breast enlargement, vaginal hemorrhage.

*% based on female subjects only: 2955

Respiratory System Disorders - Frequent: coughing. Infrequent: bronchitis, dyspnea, pneumonia. Rare: asthma, laryngitis, bronchospasm, pneumonitis, sputum increased.

Skin and Appendages Disorders - Frequent: rash, pruritus. Infrequent: photosensitivity reaction, urticaria, acne, skin discoloration, eczema, alopecia, dermatitis, skin dry, psoriasis. Rare: hypertrichosis, decreased sweating, melanosis, keratitis, cellulitis, pruritus ani.

Special Senses - Frequent: accommodation abnormal, taste perversion. Infrequent: tinnitus, conjunctivitis, eye pain. Rare: mydriasis, photophobia, diplopia, abnormal lacrimation, cataract, taste loss.

Urinary System Disorders - Frequent: polyuria. Infrequent: micturition frequency, urinary incontinence, urinary retention, dysuria. Rare: facial edema, hematuria, oliguria, pyelonephritis, renal calculus, renal pain.

Other Events Observed During The Postmarketing Evaluation Of Celesta (Celesta HBr)

It is estimated that over 30 million patients have been treated with Celesta since market introduction. Although no causal relationship to Celesta treatment has been found, the following adverse events have been reported to be temporally associated with Celesta treatment, and have not been described elsewhere in labeling: acute renal failure, akathisia, allergic reaction, anaphylaxis, angioedema, choreoathetosis, chest pain, delirium, dyskinesia, ecchymosis, epidermal necrolysis, erythema multiforme, gastrointestinal hemorrhage, angle closure glaucoma, grand mal convulsions, hemolytic anemia, hepatic necrosis, myoclonus, nystagmus, pancreatitis, priapism, prolactinemia, prothrombin decreased, QT prolonged, rhabdomyolysis, spontaneous abortion, thrombocytopenia, thrombosis, ventricular arrhythmia, torsade de pointes, and withdrawal syndrome.

Drug Abuse And Dependence

Controlled Substance Class

Celesta (Celesta HBr) is not a controlled substance.

Physical And Psychological Dependence

Animal studies suggest that the abuse liability of Celesta is low. Celesta has not been systematically studied in humans for its potential for abuse, tolerance, or physical dependence. The premarketing clinical experience with Celesta did not reveal any drug-seeking behavior. However, these observations were not systematic and it is not possible to predict, on the basis of this limited experience, the extent to which a CNS-active drug will be misused, diverted, and/or abused once marketed. Consequently, physicians should carefully evaluate Celesta patients for history of drug abuse and follow such patients closely, observing them for signs of misuse or abuse (e.g., development of tolerance, incrementations of dose, drug-seeking behavior).