citalopram

Citalopram is indicated for the treatment of major depressive disorder (MDD) in adults [see Clinical Studies ] . Citalopram is a selective serotonin reuptake inhibitor (SSRI) indicated for the treatment of major depressive disorder (MDD) in adults .

Administer once daily with or without food . Initial dosage is 20 mg once daily; after one week may increase to maximum dosage of 40 mg once daily . Patients greater than 60 years of age, patients with hepatic impairment, and CYP2C19 poor metabolizers: maximum recommended dosage is 20 mg once daily . When discontinuing Citalopram, reduce dosage gradually . 2.1 Recommended Dosage Administer Citalopram once daily, with or without food, at an initial dosage of 20 mg once daily, with an increase to a maximum dosage of 40 mg once daily at an interval of no less than one week. Dosages above 40 mg once daily are not recommended due to the risk of QT prolongation [see Warnings and Precautions ] . 2.2 Screen for Bipolar Disorder Prior to Starting Citalopram Prior to initiating treatment with Citalopram or another antidepressant, screen patients for a personal or family history of bipolar disorder, mania, or hypomania [See Warnings and Precautions ] . 2.3 Recommended Dosage for Specific Populations The maximum recommended dosage of Citalopram for patients who are greater than 60 years of age, patients with hepatic impairment, and for CYP2C19 poor metabolizers is 20 mg once daily [see Warnings and Precautions , Clinical Pharmacology ] . 2.4 Dosage Modifications with Concomitant Use of CYP2C19 Inhibitors The maximum recommended dosage of Citalopram when used concomitantly with a CYP2C19 inhibitor is 20 mg once daily [see Warnings and Precautions , Drug Interactions ]. 2.5 Switching Patients to or from a Monoamine Oxidase Inhibitor Antidepressant At least 14 days must elapse between discontinuation of a monoamine oxidase inhibitor (MAOI) antidepressant and initiation of therapy with Citalopram. Conversely, at least 14 days must elapse after stopping Citalopram before starting an MAOI antidepressant [see Contraindications and Warnings and Precautions ]. 2.6 Discontinuing Treatment with Citalopram Adverse reactions may occur upon discontinuation of Citalopram [see Warnings and Precautions ]. Gradually reduce the dosage rather than stopping Citalopram abruptly whenever possible.

12.1 Mechanism of Action The mechanism of action of citalopram is unclear, but is presumed to be related to potentiation of serotonergic activity in the central nervous system (CNS) resulting from its inhibition of CNS neuronal reuptake of serotonin (5-HT).

The following adverse reactions are discussed in greater detail in other sections of the labeling: Hypersensitivity reactions [see Contraindications ] Suicidal thoughts and behaviors in adolescents and young adults [see Warnings and Precautions ] QT-prolongation and torsade de pointes [see Warnings and Precautions ] Serotonin syndrome [see Warnings and Precautions ] Increased risk of bleeding [see Warnings and Precautions ] Activation of mania or hypomania [see Warnings and Precautions ] Discontinuation syndrome [see Warnings and Precautions ] Seizures [see Warnings and Precautions ] Angle-closure glaucoma [see Warnings and Precautions ] Hyponatremia [see Warnings and Precautions ] Sexual Dysfunction [see Warnings and Precautions ] Most common adverse reaction (incidence ≥ 5% and twice placebo) is ejaculation disorder (primarily ejaculation delay) . To report SUSPECTED ADVERSE REACTIONS, contact Cipla Ltd. at 1-866-604-3268 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in clinical practice. The safety for Citalopram included citalopram exposures in patients and/or healthy subjects from 3 different groups of studies: 429 healthy subjects in clinical pharmacology/pharmacokinetic studies; 4,422 exposures from patients in controlled and uncontrolled clinical trials, corresponding to approximately 1,370 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 Citalopram 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 Associated with Discontinuation of Treatment Among 1,063 patients with MDD who received Citalopram at doses ranging from 10 mg to 80 mg once daily in placebo- controlled trials of up to 6 weeks duration, 16% discontinued treatment due to an adverse reaction, as compared to 8% of 446 patients receiving placebo. The adverse reactions associated with discontinuation (i.e., associated with discontinuation in at least 1% of Citalopram-treated patients at a rate at least twice that of placebo) are shown in Table 2 . Table 2: Adverse Reactions Associated with Discontinuation of Citalopram Treatment in Short-Term, Placebo-Controlled MDD Trials * A patient can report more than one reason for discontinuation and be counted more than once in this table. Body System/Adverse Reaction Citalopram Placebo (N=1,063) % (N=446) % General Asthenia 1 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 Citalopram group. The incidence of tachycardic outliers was 0.5% in the Citalopram group and 0.4% in the placebo group. The incidence of bradycardic outliers was 0.9% in the Citalopram group and 0.4% in the placebo group. Other Adverse Reactions Observed During the Premarketing Evaluation of Citalopram The following list of adverse reactions does not include reactions that are: 1) included in Table 3 or elsewhere in labeling, 2) for which a drug cause was remote, 3) which were so general as to be uninformative, and those occurring in only one patient. Adverse reactions are categorized by body system and listed in order of decreasing frequency according to the following definitions: frequent adverse reactions are those occurring on one or more occasions in at least 1/100 patients; infrequent adverse reactions are those occurring in less than 1/100 patients to 1/1000 patients; rare adverse reactions are those occurring in fewer than 1/1000 patients. Cardiovascular - Frequent: tachycardia, postural hypotension, hypotension. Infrequent: hypertension, bradycardia, edema (extremities), angina pectoris, 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, hypoesthesia, 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: hay fever. 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: abnormal accommodation, 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. 6.2 Post marketing Experience The following adverse reactions have been identified during postapproval use of citalopram, the racemate, or escitalopram, the S-enantiomer of citalopram. Because these reactions are 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. Blood and Lymphatic System Disorders : hemolytic anemia, thrombocytopenia, prothrombin decreased. Cardiac Disorders : torsade de pointes, ventricular arrhythmia, QT prolonged Endocrine Disorders : hyperprolactinemia Eye Disorders : angle-closure glaucoma Gastrointestinal Disorders : gastrointestinal hemorrhage, pancreatitis General Disorders and Administrative Site Conditions : withdrawal syndrome Hepatobiliary Disorders : hepatic necrosis Immune System Disorders : anaphylaxis, allergic reaction Musculoskeletal and Connective Tissue Disorders : rhabdomyolysis Nervous System Disorders : grand mal convulsion(s), myoclonus, choreoathetosis, dyskinesia, akathisia, nystagmus Pregnancy, Puerperium and Perinatal Conditions : spontaneous abortion Psychiatric Disorders : delirium Renal and Urinary Disorders : acute renal failure Reproductive System and Breast Disorders : priapism Respiratory, Thoracic and Mediastinal Disorders: anosmia, hyposmia Skin and Subcutaneous Tissue Disorders: Stevens Johnson Syndrome, epidermal necrolysis, angioedema, erythema multiforme, ecchymosis Vascular Disorders: thrombosis

Table 5 presents clinically important drug interactions with Citalopram. Table 5: Clinically Important Drug Interactions with Citalopram Monoamine Oxidase Inhibitors (MAOIs) Clinical Impact Concomitant use of SSRIs, including Citalopram, and MAOIs increases the risk of serotonin syndrome. Intervention Citalopram is contraindicated in patients taking MAOIs, including MAOIs such as linezolid or intravenous methylene blue [see Dosage and Administration , Contraindications , Warnings and Precautions ]. Pimozide Clinical Impact: Concomitant use of Citalopram with pimozide increases plasma concentrations of pimozide, a drug with a narrow therapeutic index, and may increase the risk of QT prolongation and/or ventricular arrhythmias compared to use of Citalopram alone [see Clinical Pharmacology ]. Intervention: Citalopram is contraindicated in patients taking pimozide [see Contraindications, Warnings and Precautions ]. Drugs that Prolong the QTc Interval Clinical Impact: Concomitant use of Citalopram with drugs that prolong QT can cause additional QT prolongation compared to the use of Citalopram alone [see Clinical Pharmacology ]. Intervention: Avoid concomitant use of Citalopram with drugs that prolong the QT interval (Citalopram is contraindicated in patients taking pimozide) [see Contraindications , Warnings and Precautions ]. CYP2C19 Inhibitors Clinical Impact: Concomitant use of Citalopram with CYP2C19 inhibitors increases the risk of QT prolongation and/or ventricular arrhythmias compared to the use of Citalopram alone [see Clinical Pharmacology ]. Intervention: The maximum recommended dosage of Citalopram is 20 mg daily when used concomitantly with a CYP2C19 inhibitor [see Dosage and Administration , Warnings and Precautions ]. Other Serotonergic Drugs Clinical Impact: Concomitant use of Citalopram and other serotonergic drugs (including other SSRIs, SNRIs, triptans, tricyclic antidepressants, opioids, lithium, buspirone, amphetamines, tryptophan, and St. John's Wort) increases the risk of serotonin syndrome. Intervention: Monitor patients for signs and symptoms of serotonin syndrome, particularly during Citalopram initiation and dosage increases. If serotonin syndrome occurs, consider discontinuation of Citalopram and/or concomitant serotonergic drugs [see Warning and Precautions ]. Drugs That Interfere With Hemostasis (antiplatelet agents and anticoagulants) Clinical Impact: Concomitant use of Citalopram and an antiplatelet or anticoagulant may potentiate the risk of bleeding. Intervention: Inform patients of the increased risk of bleeding associated with the concomitant use of Citalopram and antiplatelet agents and anticoagulants. For patients taking warfarin, carefully monitor the international normalized ratio [see Warning and Precautions ]. CYP2C19 Inhibitors : Citalopram 20 mg daily is the maximum recommended dosage for patients taking concomitant CYP2C19 inhibitors .

Pregnancy: SSRI use, particularly late in pregnancy, may increase the risk for persistent pulmonary hypertension and symptoms of poor adaptation (respiratory distress, temperature instability, feeding difficulties, hypotonia, tremor, irritability) in the neonate . 8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to antidepressants during pregnancy. Healthcare providers are encouraged to register patients by calling the National Pregnancy Registry for Antidepressants at 1-844-405-6185 or visiting online at https://womensmentalhealth.org/research/pregnancyregistry/antidepressants. Risk Summary Based on data from published observational studies, exposure to SSRIs, particularly in the month before delivery, has been associated with a less than 2-fold increase in the risk of postpartum hemorrhage [see Warnings and Precautions and Clinical Considerations]. Available data from published epidemiologic studies and postmarketing reports with citalopram use in pregnancy have not established an increased risk of major birth defects or miscarriage. Published studies demonstrated that citalopram levels in both cord blood and amniotic fluid are similar to those observed in maternal serum. There are risks of persistent pulmonary hypertension of the newborn (PPHN) (see Data) and/or poor neonatal adaptation with exposure to selective serotonin reuptake inhibitors (SSRIs), including Citalopram, during pregnancy . There also are risks associated with untreated depression in pregnancy (see Clinical Considerations) . In animal reproduction studies, citalopram caused adverse embryo/fetal effects at doses that caused maternal toxicity (see Data) . The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in the clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Clinical Considerations Disease-Associated Maternal and/or Embryo/Fetal Risk Women who discontinue antidepressants during pregnancy are more likely to experience a relapse of major depression than women who continue antidepressants. This finding is from a prospective longitudinal study of 201 pregnant women with a history of major depressive disorder who were euthymic and taking antidepressants at the beginning of pregnancy. Consider the risk of untreated depression when discontinuing or changing treatment with antidepressant medication during pregnancy and postpartum. Maternal Adverse Reactions Use of Citalopram in the month before delivery may be associated with an increased risk of postpartum hemorrhage [see Warnings and Precautions ]. Fetal/Neonatal Adverse Reactions Neonates exposed to Citalopram and other SSRIs late in 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. These findings are consistent with either a direct toxic effect of SSRIs or possibly, a drug discontinuation syndrome. It should be noted that, in some cases, the clinical picture is consistent with serotonin syndrome [see Warnings and Precautions ] . Data Human Data Exposure during late pregnancy to SSRIs may have an increased risk for persistent pulmonary hypertension of the newborn (PPHN). PPHN occurs in 1- 2 per 1,000 live births in the general population and is associated with substantial neonatal morbidity and mortality. Animal Data Citalopram was administered orally to pregnant rats during the period of organogenesis at doses of 32, 56, and 112 mg/kg/day, which are approximately 8, 14, and 27 times the Maximum Recommended Human Dose (MRHD) of 40 mg, based on mg/m2 body surface area. Citalopram caused maternal toxicity of CNS clinical signs and decreased weight gain at 112 mg/kg/day, which is 27 times the MRHD. At this maternally toxic dose, citalopram decreased embryo/fetal growth and survival and increased fetal abnormalities (including cardiovascular and skeletal defects). The no observed adverse effect level (NOAEL) for maternal and embryofetal toxicity is 56 mg/kg/day, which is approximately 14 times the MRHD. Citalopram was administered orally to pregnant rabbits during the period of organogenesis at doses up to 16 mg/kg/day, which is approximately 8 times the MRHD of 40 mg, based on mg/m2 body surface area. No maternal or embryofetal toxicity was observed. The NOAEL for maternal and embryofetal toxicity is 16 mg/kg/day, which is approximately 8 times the MRHD. Citalopram was administered orally to pregnant rats during late gestation and lactation periods at doses of 4.8, 12.8, and 32 mg/kg/day, which are approximately 1, 3, and 8 times the MRHD of 40 mg, based on mg/m2 body surface area. Citalopram increased offspring mortality during the first 4 days of birth and decreased offspring growth at 32 mg/kg/day, which is approximately 8 times the MRHD. The NOAEL for developmental toxicity is 12.8 mg/kg/day, which is approximately 3 times the MRHD. In a separate study, similar effects on offspring mortality and growth were seen when dams were treated throughout gestation and early lactation at doses ≥ 24 mg/kg/day, which is approximately 6 times the MRHD. A NOAEL was not determined in that study. 8.2 Lactation Risk Summary Data from the published literature report the presence of citalopram in human milk at relative infant doses ranging between 0.7 to 9.4% of the maternal weight-adjusted dosage and a milk/plasma ratio ranging between 0.78 to 4.3. There are reports of breastfed infants exposed to citalopram experiencing irritability, restlessness, excessive somnolence, decreased feeding, and weight loss (see Clinical Considerations). There is no information about effects of citalopram on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for Citalopram and any potential adverse effects on the breastfed child from Citalopram or from the underlying maternal condition. Clinical Considerations Monitor breastfeeding infants for adverse reactions, such as irritability, restlessness, excessive somnolence, decreased feeding, and weightloss. 8.4 Pediatric Use The safety and effectiveness of Citalopram have not been established in pediatric patients. Two placebo-controlled trials in 407 pediatric patients with MDD have been conducted with Citalopram, and the data were not sufficient to support use in pediatric patients. Antidepressants increase the risk of suicidal thoughts and behaviors in pediatric patients [see Boxed Warning, Warnings and Precautions ] . Decreased appetite and weight loss have been observed in association with the use of SSRIs in pediatric patients. 8.5 Geriatric Use Of 4422 patients in clinical studies of Citalopram, 1357 were 60 and over, 1034 were 65 and over, and 457 were 75 and over. In two pharmacokinetic studies, citalopram AUC was increased by 23% and 30%, respectively, in subjects ≥ 60 years of age as compared to younger subjects, and its half-life was increased by 30% and 50%, respectively [see Clinical Pharmacology ]. Therefore, the maximum recommended dosage in patients 60 years of age and older is lower than younger patients [see Dosage and Administration ,Warnings and Precautions ] . SSRIs, including Citalopram, have been associated with cases of clinically significant hyponatremia in elderly patients, who may be at greater risk for this adverse reaction [see Warnings and Precautions ] . 8.6 Hepatic Impairment Increased citalopram exposure occurs in patients with hepatic impairment. The maximum recommended dosage of Citalopram is lower in patients with hepatic impairment [see Dosage and Administration , Clinical Pharmacology ].