Citalopram Hydrobromide - Uses, Dosage, Side Effects, Drug Warnings, and Precautions

Overview

Citalopram hydrobromide is a selective serotonin reuptake inhibitor. The primary FDA (Food and Drugs Administration) approved use is to treat depression in adults. Non-FDA-approved clinical uses include the treatment of obsessive-compulsive disorder, premenstrual dysphoric disorder, postmenopausal flushing, panic disorder, alcohol use disorder, and coronary arteriosclerosis.

Citalopram hydrobromide is a prescription drug that is available as an oral tablet. It is also available as an oral solution. It got its FDA approval for use in the year 1998. Citalopram works by restoring the balance of a natural substance called serotonin in the brain.

How Does Citalopram Hydrobromide Work?

Citalopram hydrobromide belongs to the antidepressant class of drugs called selective serotonin reuptake inhibitors (SSRIs). The drug acts by increasing the level of serotonin in the brain, elevating mood, and reducing depression. It increases the serotonin concentration and enhances serotonin's effects at nerve junctions. This, in turn, provides anxiety relief, eases depression symptoms, and promotes feelings of well-being and contentment. Several studies have confirmed that Citalopram hydrobromide is primarily a selective serotonin reuptake inhibitor and has minimal dopamine and norepinephrine neuronal reuptake effects.

Indications and Uses of Citalopram Hydrobromide:

Citalopram hydrobromide is listed by the WHO (World Health Organization) as an essential medicine for treating major depressive disorders.

FDA-Approved Indication:

Use of Citalopram hydrobromide in adults older than 18 years of age to treat depression.

Off-Label Uses:

• Generalized anxiety disorder (GAD).

• Obsessive-compulsive disorder (OCD).

• Social anxiety disorder (SAD).

• Separation anxiety disorder.

• Post-traumatic stress disorder (PTSD).

• Premenstrual dysphoric disorder (PMDD).

• Binge eating disorder.

• Panic disorder.

The uses and disadvantages of off-label uses of Citalopram hydrobromide depend upon the patient's condition and the clinician's judgment. Placebo-controlled trials had shown that an antidepressant effect was maintained for up to 24 weeks when the drug was used for four to six weeks for acute treatment. However, the clinician who plans to use Citalopram hydrobromide for extended periods must periodically re-evaluate the patient's status. In addition, the drug's effectiveness in hospitalized depressed patients is yet to be studied.

Contraindications:

Citalopram hydrobromide is contraindicated to be used concomitantly with monoamine oxidase inhibitors (MAOIs) as it can result in serotonin syndrome or serotonergic hyperactivity and in patients with a known history of allergy to the active drug or the inactive components of the medications.

Symptoms of serotonin syndrome include:

• Rigidity.

• Hyperthermia.

• Autonomic instability.

• Changes in mental status.

• Coma.

Citalopram hydrobromide is also contraindicated in the following situations:

• Patients with a history of hypersensitivity to active or inactive ingredients of the drug.

• Patients with known QT interval prolongation.

• Patients with congenital long QT syndrome.

• Patients on Urokinase, Linezolid, Pimozide, Dapoxetine, or Methylene Blue.

Citalopram hydrobromide poses a danger of causing dangerous arrhythmias as it can increase thioridazine concentrations due to inhibitory effects on the CYP2D6 enzyme. Therefore, waiting for a minimum of 14 days before starting MAOI after discontinuing Citalopram hydrobromide is recommended.

Dosage and Administration

Citalopram hydrobromide is available in dosages of 10 mg, 20 mg, 40 mg oral tablets, and 10 mg/5 mL oral solution. The drug is administered orally in adults younger than 60 years of age. The doctor will determine the dose of the drug based on the medical condition, age, and severity of the disease. Based on the response, the dose may be increased or decreased. It is important to follow the instructions carefully and also to report to the doctor if any side effects are experienced.

The general dosing information of Citalopram is as follows:

Dosage Modifications:

The drug is started in low doses, and gradually the doses are increased based on the patient's response.

The following are the dosages that are administered:

• The initial dose is 20 mg once daily with or without food.

• The dose can be increased to a maximum of 40 mg daily. The maximum recommended dose is 40 mg.

• Maximum daily dosage of 20 mg in patients above 60 or those with poor CYP2C19 enzyme metabolizers.

Patients at significant risk of developing side effects should be started with low doses, and a dose of only 10 mg must be gradually increased in increments. Also, higher doses helped treat OCD (obsessive-compulsive disorder) patients. Doses above 40 mg daily are not recommended due to an increased risk of QT prolongation.

How to Use Citalopram Hydrobromide?

Capsules and Tablet:

Take with or without food as directed by the doctor with a glass of water.

Liquid Solution:

• Accurately measure the medication using a measuring device or spoon.

• Use as instructed by the pharmacist.

Follow the instructions on the drug leaflet or, in case of doubts, talk to the pharmacist.

What Are Warnings and Precautions?

Warnings:

Adult and pediatric patients with major depressive disorder (MDD) can experience worsening symptoms or develop a suicidal tendency, whether on treatment or not. This risk persists until significant remission occurs. Also, the major risk of depressive disorders and other psychiatric disorders is suicide. There is a significant concern that starting treatment for depression can aggravate or worsen symptoms or increase suicidal tendencies during the early phases of treatment.

Studies have shown an increased suicidal behavior in patients younger than 24 years of age compared to older adults. However, whether the suicidal risk rises with the long-term use of antidepressant drugs is unknown. There is evidence that there was a reduced recurrence of depressive episodes in older patients on antidepressants. It is recommended to monitor patients on antidepressant drugs for symptoms like worsening symptoms, suicidality, unusual behavioral changes during the initial months of treatment, or change in the type of drug or its dosages.

The alarming symptoms that have to be monitored that are considered precursors for suicidality include:

• Anxiety.

• Agitation.

• Irritability.

• Insomnia.

• Panic attacks.

• Hostility.

• Impulsivity.

• Aggressiveness.

• Psychomotor restlessness.

• Hypomania.

• Mania.

The therapy must be discontinued in case of persisting or severe symptoms. Also, the drug must be discontinued in a tapered and fast way. Abrupt discontinuation must be avoided as it can cause severe side effects. Caregivers of the patients must be advised to regularly monitor for new symptoms and report to the doctor immediately. Also, Citalopram hydrobromide must be prescribed in smaller quantities to reduce the overdose risk.

1. QT Prolongation:

Citalopram hydrobromide causes dose-dependent prolongation of QTc that is associated with Torsade de Pointes (TdP), ventricular tachycardia, and sudden death. Therefore, doses of the drug above 40 mg/day are not recommended.

Citalopram is not indicated for use in patients with congenital long QT syndrome, hypokalemia, hypomagnesemia, recent myocardial infarction, or uncompensated heart failure. Citalopram hydrobromide should also be avoided in patients who take other drugs that prolong the QTc interval.

The list includes:

• Class IA (Quinidine, Procainamide).

• Class III (Amiodarone, Sotalol).

• Antipsychotic medications (Chlorpromazine, Thioridazine).

• Antibiotics (Gatifloxacin, Moxifloxacin).

• Antiarrhythmic medications.

• Medications like Pentamidine, Levomethadyl acetate, and Methadone.

The dosage of Citalopram Hydrobromide must be limited in patients who are poor metabolizers of CYP2C19 and those taking concomitant CYP2C19 inhibitors, patients with hepatic impairment, and patients older than 60 years of age. The maximum daily dose for these patients is 20 mg. Regular monitoring of electrolytes and ECG is recommended. Citalopram use must be discontinued in patients with persistent QTc measurements >500 ms. Also, patients experiencing symptoms of arrhythmias require evaluation and monitoring.

2. Screening Patients for Bipolar Disorder:

Patients must be thoroughly screened for the risk of bipolar disorder before starting the antidepressant drug, as antidepressants tend to precipitate manic or mixed symptoms in patients with bipolar disorder. Citalopram hydrobromide is not approved to treat bipolar depression.

3. Serotonin Syndrome:

There is a risk of developing a severe life-threatening condition called serotonin syndrome when Citalopram is used concomitantly with other serotonergic drugs or drugs that impair serotonin metabolism. The emergence of the symptoms like mental status changes, autonomic instability, neuromuscular signs, or gastrointestinal symptoms has to be monitored.

Concomitant use of Citalopram and MAOIs (monoamine oxidase inhibitors) like Linezolid or Methylene Blue is contraindicated. Citalopram must be discontinued before the start of treatment with MAOIs.

4. Angle-Closure Glaucoma:

Pupillary dilatation that occurs as a side effect of many antidepressants, including Citalopram, can trigger an angle closure attack in patients with anatomically narrow angles and without a patent iridectomy.

Precautions:

1. Discontinuation of Citalopram Treatment:

Severe adverse effects have been reported upon the abrupt discontinuation of Citalopram and other antidepressants. Therefore, the physician must choose tapered discontinuation rather than an abrupt one. The following symptoms are noted due to the discontinuation of Citalopram, that includes:

1. Irritability.

2. Agitation.

3. Dizziness.

4. Dysphoric mood.

5. Sensory disturbances.

6. Anxiety.

7. Confusion.

8. Lethargy.

9. Insomnia.

10. Emotional lability.

11. Hypomania.

2. Abnormal Bleeding:

Abnormal bleeding episodes ranging from epistaxis, ecchymoses, hematomas, and petechiae to life-threatening hemorrhages have been reported with the concomitant use of Citalopram or other SSRIs or SNRIs (serotonin or norepinephrine reuptake inhibitors) with Aspirin, NSAIDs, Warfarin, or other anticoagulants.

3. Hyponatremia:

Hyponatremia with the use of Citalopram has been reported predominantly in elderly patients, those on diuretics, volume-depleted patients, or due to the syndrome of inappropriate antidiuretic hormone secretion (SIADH). Cases with serum sodium of less than 110 mmol/L have been reported. Hyponatremia presents symptoms like headache, memory impairment, difficulty concentrating, weakness, instability, and falls. Citalopram use must be discontinued in patients with symptomatic hyponatremia, and necessary treatment must be started.

4. Activation of Mania:

Citalopram must be used cautiously in patients with bipolar disorder due to the risk of activation of mania.

5. Seizures:

Citalopram must be used with caution in patients with a history of seizure disorder, as it was studied that around 0.3% of patients treated with Citalopram had seizures.

6. Interference With Cognitive and Motor Performance:

Patients on Citalopram must be cautioned about using machinery and automobiles until they are certain that the drug use does not impact their cognitive or motor skills.

7. Use in Patients With Concomitant Illness:

There is limited data available on the effects of Citalopram in patients with systemic illnesses. However, Citalopram should be avoided in patients with cardiac conditions due to the risk of prolongation of QT interval. Electrolyte levels should be monitored in patients with hypokalemia or hypomagnesemia. Lower doses of Citalopram are recommended in hepatic impairment patients as the drug clearance has decreased, and plasma concentrations increased. The drug must be cautiously administered in renal-impaired patients.

Onset of Action:

Over 80% of the orally administered Citalopram is absorbed from the stomach and reaches the blood circulation. It reaches its maximum concentration in the blood within three and a half hours for capsules and within four hours for tablets. It is primarily excreted through feces and the rest in urine. Improvement in the condition may be observed within one to four weeks after the therapy is initiated, and a complete response may be expected within eight to 12 weeks.

What Are the Adverse Effects?

Adverse effects occur in about ten percent of patients treated with Citalopram:

More common side effects include:

• CNS (central nervous system) symptoms like headache, dizziness, insomnia, or drowsiness.

• Dermatologic symptoms like diaphoresis.

• Gastrointestinal symptoms like nausea, vomiting, diarrhea, constipation, or xerostomia.

• Sexual symptoms like ejaculation disorder.

Less common adverse effects include:

• Hematologic symptoms like hemorrhage.

• Cardiovascular symptoms like prolonged QT interval, myocardial infarction, and Torsades de pointes.

• Neurological symptoms like cerebrovascular accidents.

• Psychiatric symptoms like mania and suicide.

• Other symptoms like serotonin syndrome.

A rare side effect of Citalopram is hyponatremia, which is more common in elderly patients, women, people with low body weight or concurrent diuretic use, or recent pneumonia.

Laboratory Tests:

There are no specific laboratory tests recommended.

For Patients:

What Is Depression?

Depression is a mental health condition in which a person experiences low moods and loss of interest in activities nearly every day for at least two weeks. The other symptoms include difficulty concentrating, feeling of excessive guilt, low self-worth, disrupted sleep, changes in appetite, feeling tired all the time, hopelessness about the future, and thoughts about death or suicide. During a depressive episode, a person has difficulty handling personal, family, educational, social, occupational, or other important functions.

How Is Depression Managed?

There are effective treatment modalities for depression. Treatment varies based on the severity and pattern of depressive episodes, including behavioral activation, cognitive behavioral therapy, interpersonal psychotherapy, and medications like SSRIs (selective serotonin reuptake inhibitors) and TCAs (tricyclic antidepressants). Medicines must not be started for mild depression. Continuous monitoring of the patients during the initiation of treatment and during therapy is necessary. Depression affects about five percent of the population worldwide, and the severity of symptoms can be reduced with proper care and management.

For Doctors:

What Are the Drug Interaction?

Serotonergic Drugs:

Citalopram hydrobromide is contraindicated to be used concomitantly with monoamine oxidase inhibitors (MAOIs) as it can result in serotonin syndrome or serotonergic hyperactivity. Symptoms of serotonin syndrome include:

• Rigidity.

• Hyperthermia.

• Autonomic instability.

• Changes in mental status.

• Coma.

Triptans:

Close monitoring is advised for cases where Citalopram and triptans have to be used concomitantly during treatment initiation and increasing doses.

CNS Drugs:

Citalopram should be used cautiously when used in combination with centrally-acting drugs.

Alcohol:

Consumption of alcohol by depressed patients on Citalopram is contraindicated.

Drugs That Interfere With Hemostasis:

Drugs like NSAIDs, Aspirin, and Warfarin, when used concomitantly with Citalopram, induced gastrointestinal bleeding in a few patients. Therefore, patients should be monitored cautiously during Citalopram use.

Cimetidine:

Patients on Citalopram 40 mg/day showed increased AUC (area under the curve) and Cmax (peak serum concentration). The maximum recommended dose of Citalopram is 20 mg daily in patients on Cimetidine, as there is a risk of QT prolongation.

Digoxin:

The pharmacokinetics of both Citalopram and Digoxin remained unchanged when used together.

Lithium:

Studies revealed no change in the pharmacokinetics of both Citalopram and Lithium when co-administered. However, as high plasma levels of Lithium can increase the serotonergic effects of Citalopram; the lithium levels must be adjusted accordingly.

Pimozide:

Pimozide 2 mg and Citalopram 40 mg, when administered together, did not alter the AUC or Cmax levels of Pimozide; however, there was an increase in QTc values.

Theophylline:

Citalopram and CYP1A2 substrate theophylline, when co-administered, did not affect the pharmacokinetics of Theophylline.

Sumatriptan:

Although using Citalopram and Sumatriptan is clinically warranted, an appropriate observation for symptoms like weakness, incoordination, and hyperreflexia is necessary.

Warfarin:

The use of Citalopram and Warfarin did not affect the pharmacokinetics of Warfarin; however, there was a 5 % increase in prothrombin time.

Carbamazepine:

Concurrent use of Citalopram and Carbamazepine did not affect the pharmacokinetics of Carbamazepine. However, as Carbamezapine has enzyme-inducing properties, it can increase the clearance of Citalopram.

Triazolam:

Combined administration of Citalopram 200 mg and Triazolam 0.25 mg single dose did not affect the pharmacokinetics of both drugs.

Ketoconazole:

Combined administration of Citalopram 40 mg and Ketoconazole 200 mg did not affect the pharmacokinetics of Citalopram. However, there was a decrease in the AUC and Cmax of Ketoconazole.

CYP2C19 Inhibitors:

20 mg/day of Citalopram is the maximum recommended dose in patients taking CYP2C19 inhibitors due to the risk of QT prolongation.

Metoprolol:

Concurrent administration of Citalopram and beta-adrenergic blockers like Metoprolol caused a two-fold increase in plasma levels of Metoprolol. However, no significant effects on blood pressure or heart rate were noted.

What Is the Use in Specific Populations?

Pregnancy Non-Teratogenic Effects:

Neonates exposed to Citalopram during the third trimester developed respiratory complications immediately after birth. Clinical findings included cyanosis, apnea, seizures, respiratory distress, feeding difficulties, vomiting, hypoglycemia, hypotonia, hypertonia, jitteriness, temperature instability, and constant crying. These findings occurred due to the direct effects of the drug or discontinuation syndrome.

SSRIs like Citalopram during pregnancy cause persistent pulmonary hypertension of the newborn (PPHN), leading to morbidity and mortality in a few cases. Based on the case, the use of Citalopram in pregnant patients should be decided by the physician. Studies have shown that discontinuing antidepressants during pregnancy causes a relapse of depression.

Labor and Delivery:

There are no significant studies on the effects of Citalopram on labor and delivery.

Breastfeeding:

The drug is excreted in human breast milk, causing symptoms like drowsiness, decreased feeding, and weight loss in infants. Therefore, a decision on whether to discontinue Citalopram or breastfeeding should be made after considering the risks and benefits for both the mother and the baby.

Pediatric Use:

There are no established reports on the safety and effectiveness of pediatric usage of the drug. However, the height and weight of pediatric patients must be monitored.

Geriatric Use:

There were no significant changes in clinical response in younger patients and patients above 60 years. However, there was a considerable risk of hyponatremia in elderly patients. The dosage of Citalopram in elderly patients is 20 mg/day.

Description:

Active Ingredient:

Citalopram Hydrobromide.

Inactive Ingredients:

Copolyvidone, corn starch, croscarmellose sodium, glycerin, lactose monohydrate, magnesium stearate, hypromellose, microcrystalline cellulose, polyethylene glycol, titanium dioxide, and iron dioxide for coloring.

Clinical Pharmacology:

Pharmacodynamics:

The mechanism of action of Citalopram is by potentiation of serotonergic activity in the central nervous system leading to inhibition of CNS neuronal reuptake of serotonin.

Pharmacokinetics:

The biotransformation of Citalopram is mainly hepatic. The drug has a terminal half-life of 35 hours. With a once-daily dose, steady plasma concentrations are achieved within one week.

Absorption and Distribution:

Peak blood levels occur four hours after oral administration of 40 mg of Citalopram. The bioavailability of the drug was 80% relative to an intravenous dose. Absorption is not affected by food. The binding of Citalopram (CT), dimethyl citalopram (DCT), and didemethylcitalopram (DDCT) to human plasma proteins was about 80%. The half-life is 35 hours on average, and it was found to significantly increase in patients with hepatic impairment, mild to moderate renal impairment, poor CYP2C19 inhibitors, and elderly patients.

Metabolism and Elimination:

Citalopram is metabolized to desmethylcitalopram (DCT), desmethylcitalopram (DDCT), citalopram-N-oxide, and a deaminated propionic acid derivative. Following intravenous administration, the fraction of drugs recovered as Citalopram and DCT in urine, was 10% and 5%, respectively. Unchanged Citalopram hydrobromide is a prominent component in human plasma. Citalopram is eight times more potent than its metabolites in inhibiting serotonin reuptake.

Drug Abuse and Dependence

Controlled Substance Class:

Citalopram hydrobromide is not a controlled substance.

Physical and Psychological Dependence:

There is limited information on whether Citalopram has the potential for abuse, tolerance, or physical dependence. Therefore, physicians must carefully monitor patients on Citalopram with a history of drug abuse. They must be observed for signs of misuse or overdosages like the development of tolerance, drug-seeking behavior, or incrementations of dose.

Overdosage:

Cases of Citalopram overdose from 2000 mg to up to 6000 mg have been reported. However, there were no fatalities when compared to other SSRIs. Symptoms of Citalopram overdose included:

• Nausea.

• Vomiting.

• Dizziness.

• Sweating.

• Drowsiness.

• Tremor.

• Sinus tachycardia.

• Amnesia.

• Coma.

• Confusion.

• Hyperventilation.

• Cyanosis.

• ECG changes.

• Acute renal failure (rare symptom).

Management of Overdose:

An airway has to be established and maintained to provide adequate ventilation and oxygenation to the patient. Gastric evacuation is done by lavage and the use of activated charcoal. Monitoring the vital and cardiac signs is pivotal. Symptomatic and supportive care must also be provided to the patient. Unfortunately, there are no antidotes for Citalopram. The doctor must consider contacting a poison control center for information on the treatment of any overdose, as overdosages can involve more than one drug or alcohol.

Discontinuation Syndrome (Abrupt Discontinuation of Antidepressant):

Discontinuation syndrome commonly occurs in patients who stop the therapy abruptly.

More common symptoms of the condition include:

• Nausea.

• Vomiting.

• Diarrhea.

• Headaches.

• Light-headedness.

• Dizziness.

• Loss of appetite.

• Chills.

• Tremors.

• Sweating.

• Fatigue.

• Drowsiness.

• Sleep disturbances.

Less common symptoms include:

• Cardiac arrhythmias.

• Myalgia.

• Arthralgia.

• Electric shock-like sensations.

• Balance difficulties.

Due to various discontinuation symptoms, it is recommended to taper the dosage gradually over several weeks to months.

Black Box Warning:

Citalopram hydrobromide is associated with worsening depression symptoms and suicidal tendencies, especially in children, adolescents, and adults younger than 24 years. Therefore, patients of any age who start therapy with Citalopram must be closely monitored for unusual changes in behavior, clinical worsening, or suicidal tendency. Treatment-emergent suicidal ideation (TESI) is of more concern in younger patients. However, compared to patients on tricyclic antidepressants, or SSRIs, the suicidal tendency was less in patients on Citalopram.

Monitoring:

Before Treatment:

• Patients must be evaluated for electrolyte levels, especially sodium and potassium. Also, periodic reevaluation during treatment is necessary for patients at risk for electrolyte imbalance.

• Patients should be regularly monitored for QT prolongation. ECG is required for patients with congenital long QT syndrome, bradycardia, recent acute myocardial infarction, hypomagnesemia, hypokalemia, uncompensated heart failure, or concurrent use of other QT-prolonging drugs.

During Treatment:

• During the initial months of therapy or when there is a change in dosage, patients must be regularly monitored for unusual changes in behavior, worsening of depression, or suicidal tendencies. Weekly appointments are recommended during the first month, followed by alternate weeks the next month and every three months after that.

• Weight, height, and growth must be monitored regularly in children and adolescents.

• According to Beer's criteria, sodium levels must be monitored closely in elderly patients above 65 years during the initiation of treatment and when adjusting the dosage.

Toxicity:

Studies have shown no toxicity, even up to doses of 100 mg. However, there was a risk of developing serotonin hyperactivity even at therapeutic doses when used concomitantly with another serotonergic medication.

In cases of intentional overdose, where up to 600 mg of Citalopram has been ingested, cardiac monitoring for up to eight hours is mandatory. In the post-observation period, the patient can be discharged if the patient has QTc less than 450 milliseconds and is asymptomatic. However, if the QTc is more than 450 milliseconds, continued monitoring in an inpatient setting is necessary.

Storage and Handling:

Citalopram is available in dosages of 10 mg, 20 mg, and 40 mg.

1. 10 mg tablets are available in a bottle of 100 tablets. They are beige in color, oval, and film-coated, with an imprint "FP" on one side and "10 mg" on the other.

2. 20 mg (10 x 10 unit dose) tablets are available in a bottle of 100 tablets. They are pink in color, oval, scored, and film-coated. The imprint on the scored side has "F" on the left side and "P" on the right side. The imprint on the non-scored side has "20 mg".

3. 40 mg (10 x 10 unit dose) tablets are available in a bottle of 100 tablets. They are white, oval, scored, and film-coated. The imprint on the scored side has "F" on the left side and "P" on the right side. Imprint on the non-scored side with "40 mg".