Celexa® (citalopram hydrobromide)

Celexa® (citalopram hydrobromide)

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Celexa® (citalopram hydrobromide)

Celexa® (citalopram HBr) is an orally administered selective serotonin reuptake inhibitor (SSRI) with a chemical structure unrelated to that of other SSRIs or of tricyclic, tetracyclic, or other available antidepressant agents. Citalopram HBr is a racemic bicyclic phthalane derivative designated (±)-1-(3-dimethylaminopropyl)-1-(4-fluorophenyl)-1,3-dihydroisobenzofuran-5-carbonitrile

The molecular formula is C20H22BrFN2O and its molecular weight is 405.35.

Citalopram HBr occurs as a fine, white to off-white powder. Citalopram HBr is sparingly soluble in water and soluble in ethanol.

Celexa 10 mg are film-coated, oval tablets containing citalopram HBr in strengths equivalent to 10 mg citalopram base. Celexa 20 mg and 40 mg are film-coated, oval, scored tablets containing citalopram HBr in strengths equivalent to 20 mg or 40 mg citalopram base. The tablets also contain the following inactive ingredients: copolyvidone, corn starch, crosscarmellose sodium, glycerin, lactose monohydrate, magnesium stearate, hypromellose, microcrystalline cellulose, polyethylene glycol, and titanium dioxide. Iron oxides are used as coloring agents in the beige (10 mg) and pink (20 mg) tablets.

Pharmacodynamics

The mechanism of action of citalopram HBr as an antidepressant is presumed to be linked to potentiation of serotonergic activity in the central nervous system (CNS) resulting from its inhibition of CNS neuronal reuptake of serotonin (5-HT). In vitro and in vivo studies in animals suggest that citalopram is a highly selective serotonin reuptake inhibitor (SSRI) with minimal effects on norepinephrine (NE) and dopamine (DA) neuronal reuptake. Tolerance to the inhibition of 5-HT uptake is not induced by long-term (14-day) treatment of rats with citalopram. Citalopram is a racemic mixture (50/50), and the inhibition of 5-HT reuptake by citalopram is primarily due to the (S)-enantiomer.

Citalopram has no or very low affinity for 5-HT1A, 5-HT2A, dopamine D1 and D2, α1-, α2-, and β-adrenergic, histamine H1, gamma aminobutyric acid (GABA), muscarinic cholinergic, and benzodiazepine receptors. Antagonism of muscarinic, histaminergic, and adrenergic receptors has been hypothesized to be associated with various anticholinergic, sedative, and cardiovascular effects of other psychotropic drugs.

Indications

Celexa (citalopram HBr) is indicated for the treatment of depression.

Dosage and administraion

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

Celexa (citalopram 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.

Contraindications

The use of MAOIs intended to treat psychiatric disorders with Celexa or within 14 days of stopping treatment with Celexa is contraindicated because of an increased risk of serotonin syndrome. The use of Celexa within 14 days of stopping an MAOI intended to treat psychiatric disorders is also contraindicated.

Starting Celexa in a patient who is being treated with MAOIs such as linezolid or intravenous methylene blue is also contraindicated because of an increased risk of serotonin syndrome

Concomitant use in patients taking pimozide is contraindicated

Celexa is contraindicated in patients with a hypersensitivity to citalopram or any of the inactive ingredients in Celexa.

Warnings

Clinical Worsening and Suicide Risk: Patients with major depressive disorder (MDD), both adult and pediatric, may experience worsening of their depression and/or the emergence of suicidal ideation and behavior (suicidality) or unusual changes in behavior, whether or not they are taking antidepressant medications, and this risk may persist until significant remission occurs. Suicide is a known risk of depression and certain other psychiatric disorders, and these disorders themselves are the strongest predictors of suicide.

QT-Prolongation and Torsade de Pointes: Citalopram causes dose-dependent QTc prolongation, an ECG abnormality that has been associated with Torsade de Pointes (TdP), ventricular tachycardia, and sudden death, all of which have been observed in postmarketing reports for citalopram

Screening Patients for Bipolar Disorder: 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

Serotonin Syndrome: The development of a potentially life-threatening serotonin syndrome has been reported with SNRIs and SSRIs, including Celexa, alone but particularly with concomitant use of other serotonergic drugs (including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, trytophan, buspirone, amphetamines, and St. John’s Wort) and with drugs that impair metabolism of serotonin (in particular, MAOIs, both those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue).

Angle Closure Glaucoma: The pupillary dilation that occurs following use of many antidepressant drugs including Celexa may trigger an angle closure attack in a patient with anatomically narrow angles who does not have a patent iridectomy.

Precautions

Abnormal Bleeding: SSRIs and SNRIs, including Celexa, may increase the risk of bleeding events. Concomitant use of aspirin, nonsteroidal anti-inflammatory drugs, warfarin, and other anticoagulants may add to the risk. Case reports and epidemiological studies (case-control and cohort design) have demonstrated an association between use of drugs that interfere with serotonin reuptake and the occurrence of gastrointestinal bleeding. Bleeding events related to SSRIs and SNRIs use have ranged from ecchymoses, hematomas, epistaxis, and petechiae to life-threatening hemorrhages.

Hyponatremia: Hyponatremia may occur as a result of treatment with SSRIs and SNRIs, including Celexa. In many cases, this hyponatremia appears to be the result of the syndrome of inappropriate antidiuretic hormone secretion (SIADH), and was reversible when Celexa was discontinued. Cases with serum sodium lower than 110 mmol/L have been reported. Elderly patients may be at greater risk of developing hyponatremia with SSRIs and SNRIs.

Activation of Mania/Hypomania: In placebo-controlled trials of Celexa, some of which included patients with bipolar disorder, activation of mania/hypomania was reported in 0.2% of 1063 patients treated with Celexa and in none of the 446 patients treated with placebo. Activation of mania/hypomania has also been reported in a small proportion of patients with major affective disorders treated with other marketed antidepressants.

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Interference with Cognitive and Motor Performance: In studies in normal volunteers, Celexa in doses of 40 mg/day did not produce impairment of intellectual function or psychomotor performance. Because any psychoactive drug may impair judgment, thinking, or motor skills, however, patients should be cautioned about operating hazardous machinery, including automobiles, until they are reasonably certain that Celexa therapy does not affect their ability to engage in such activities.

Drug interactions

Triptans: There have been rare postmarketing reports of serotonin syndrome with use of an SSRI and a triptan. If concomitant treatment of Celexa 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 citalopram, caution should be used when it is taken in combination with other centrally acting drugs.

Alcohol – Although citalopram 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 Celexa is not recommended.

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 Celexa is initiated or discontinued.

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

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

Lithium – Coadministration of Celexa (40 mg/day for 10 days) and lithium (30 mmol/day for 5 days) had no significant effect on the pharmacokinetics of citalopram 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 citalopram, caution should be exercised when Celexa and lithium are coadministered.

Pimozide – In a controlled study, a single dose of pimozide 2 mg co-administered with citalopram 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.

Theophylline – Combined administration of Celexa (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 citalopram 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, citalopram) is clinically warranted, appropriate observation of the patient is advised.

Use in specific populations

Pregnancy: Pregnancy Category C. In animal reproduction studies, citalopram has been shown to have adverse effects on embryo/fetal and postnatal development, including teratogenic effects, when administered at doses greater than human therapeutic doses.

Pregnancy-Nonteratogenic Effects: Neonates exposed to Celexa and other SSRIs or serotonin and norepinephrine reuptake inhibitors (SNRIs), late in the third trimester, have developed complications requiring prolonged hospitalization, respiratory support, and tube feeding. Such complications can arise immediately upon delivery. Reported clinical findings have included respiratory distress, cyanosis, apnea, seizures, temperature instability, feeding difficulty, vomiting, hypoglycemia, hypotonia, hypertonia, hyperreflexia, tremor, jitteriness, irritability, and constant crying.

Labor and Delivery: The effect of Celexa on labor and delivery in humans is unknown.

Nursing Mothers: As has been found to occur with many other drugs, citalopram is excreted in human breast milk. There have been two reports of infants experiencing excessive somnolence, decreased feeding, and weight loss in association with breastfeeding from a citalopram-treated mother; in one case, the infant was reported to recover completely upon discontinuation of citalopram by its mother and in the second case, no follow-up information was available.

Pediatric Use: Safety and effectiveness in the pediatric population have not been established

Adverse reactions

  • Cardiovascular: tachycardia, postural hypotension, hypotension
  • Central and Peripheral Nervous System Disorders: paresthesia, migraine
  • Gastrointestinal Disorders: saliva increased, flatulence
  • Metabolic and Nutritional Disorders: decreased weight, increased weight.
  • Psychiatric Disorders: impaired concentration, amnesia, apathy, depression, increased appetite, aggravated depression, suicide attempt, confusion.
  • Skin and Appendages Disorders: rash, pruritus
Overdosage

Symptoms most often accompanying citalopram overdose, alone or in combination with other drugs and/or alcohol, included dizziness, sweating, nausea, vomiting, tremor, somnolence, and sinus tachycardia. In more rare cases, observed symptoms included amnesia, confusion, coma, convulsions, hyperventilation, cyanosis, rhabdomyolysis, and ECG changes (including QTc prolongation, nodal rhythm, ventricular arrhythmia, and very rare cases of torsade de pointes). Acute renal failure has been very rarely reported accompanying overdose.

Management of Overdose

Establish and maintain an airway to ensure adequate ventilation and oxygenation. Gastric evacuation by lavage and use of activated charcoal should be considered. Careful observation and cardiac and vital sign monitoring are recommended, along with general symptomatic and supportive care. Due to the large volume of distribution of citalopram, forced diuresis, dialysis, hemoperfusion, and exchange transfusion are unlikely to be of benefit. There are no specific antidotes for Celexa.

Storage

Store at 25°C (77°F); excursions permitted to 15 – 30°C (59-86°F).

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