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Celexa (Citalopram)

Action and Clinical Pharmacology   Adverse Reactions

Antidepressant

Citalopram hydrobromide is a highly selective and potent serotonin 
(5-hydroxytryptamine 5-HT) reuptake inhibitor with minimal effects on the 
neuronal reuptake of norepinephrine (NE) and dopamine (DA). The ability 
of citalopram to potentiate serotonergic activity in the central nervous 
system via inhibition of the neuronal reuptake of serotonin is thought to be 
responsible for its antidepressant action. Tolerance to the inhibition of serotonin reuptake is not induced by long term (14 days) treatment of rats with citalopram.

Citalopram has no or very low affinity for a series of receptors including serotonin 5-HT_1A, 5-HT₂, dopamine D₁, and D₂, a₁-, a₂-, b-adrenergic, histamine H₁, muscarinic cholinergic, benzodiazepine, gamma aminobutyric acid (GABA) and opioid receptors.

Pharmacokinetics

Absorption
Following the administration of a single oral dose of citalopram (40 mg) to healthy male volunteers, peak blood levels occurred at about 4 hours (range 1 to 6 hours). The absolute bioavailability of citalopram was about 80% (range 52 to 93%) relative to an intravenous dose. Absorption was not affected by food.

Distribution
After intravenous infusion in healthy male volunteers the apparent volume of distribution (V_d)b was about 12 L/kg (range 9-17 L/kg), indicating a pronounced tissue distribution: (V_d)b oral was about 17 L/kg (range 14-17 L/kg). The binding of citalopram and its demethylated metabolites to human plasma proteins is about 80%.

Steady-state
The single- and multiple dose pharmacokinetics of citalopram are linear and dose proportional in a dose range of 10 to 60 mg/day. Steady-state plasma levels are achieved in patients in 1-2 weeks. At a daily dose of 40 mg, the average plasma concentration is about 83 ng/mL (n=114) with a range from 30 to 200 ng/mL. Citalopram does not accumulate during long term treatment. A clear relationship between citalopram plasma levels and therapeutic response or side effects has not been established.

Metabolism
Citalopram is metabolized in the liver to demethylcitalopram (DCT), didemethylcitalopram (DDCT), citalopram N-oxide and a deaninated propionic acid derivative. In vitro studies show that DCT, DDCT and citalopram-N-oxide also inhibit the neuronal reuptake of serotonin but are less selective and less potent than the parent compound and are of minor clinical importance. Unchanged citalopram is the predominant compound in plasma. In vitro studies indicated that the biotransformation of citalopram to its demethyl metabolites depends on both CYP2C19 and CYP3A4, with a small contribution from CYP2D6.

Elimination
The elimination half life of citalopram (t_1/2b) is approximately 37 hours (range 30-42 hours) which allows recommendation of once-daily dosing. The systemic citalopram plasma clearance (Cl₅) is 0.33 L/min. Citalopram is eliminated primarily via the liver (85%) and the remainder via the kidneys; approximately 12% (range 6-21%) of the daily dose is excreted in urine as unchanged citalopram.

Special Populations:   Back to top of page

Elderly Patients
Elderly patients (4 males and 7 females aged 73-90 years), received a 20 mg/day dose of citalopram for 3-4 weeks. In the elderly, steady state plasma levels were elevated (106 ng/mL), half-life prolonged (1.5-3.75 days) and clearance decreased (0.08-0.3 L/min). Elevation of citalopram plasma levels occurred at an earlier age in females than in males, In this population, lower doses and a lower maximum dose of citalopram are recommended.

Reduced Hepatic Function
The pharmacokinetics of citalopram were compared in patients with reduced hepatic function (3 female and 6 male patients aged 41-60 years) to those seen in 12 healthy male volunteers (aged 21-43 years), In patients with reduced hepatic function the half-life of citalopram was approximately doubled (83 hours versus 37 hours), steady state citalopram concentrations increased by 61% and oral clearance decreased by 37%. Consequently the use of citalopram in patients with reduced hepatic function should be approached with caution and lower maximal doses should be prescribed (see PRECAUTIONS and DOSAGE AND ADMINISTRATION).

Reduced Renal Function
In patients with mild to moderate reduction of the renal function (4 females and 3 males, aged 30-55 years), citalopram was being eliminated more slowly than in 12 healthy male volunteers (aged 21-43 years), half-lives being 49 hours versus 37 hours. However, mild to moderate renal impairment had no major influence on the kinetics of citalopram. At present, no information is available for chronic treatment of patients with severely reduced renal function (creatinine clearance <20 mL/min). 

Indications and Clinical Use   Back to top of page

Citalopram hydrobromide is indicated for the symptomatic relief of depressive illness.

The relapse rate was significantly lower in citalopram-treated patients than in placebo-treated patients in two placebo-controlled studies, that were conducted over a 24-week period in patients who responded to 6 or 8 weeks of acute treatment with citalopram (see CLINICAL TRIALS under ACTION AND CLINICAL PHARMACOLOGY.) Nevertheless, the physician who elects to use citalopram for extended periods should periodically reevaluate the long-term usefulness of the drug for the individual patient.

Contraindications   Back to top of page

Monoamine Oxidase Inhibitors
In patients, receiving selective serotonin reuptake inhibitors (SSRIs) in combination with a monoamine oxidase inhibitor (MAOI), there have been reports of serious, sometimes fatal, reactions including hyperthermia, rigidity, myoclonus, autonomic instability with possible rapid fluctuations of vital signs, and mental status changes, including extreme agitation progressing to delirium and coma. These reactions have also been reported in patients who have recently discontinued SSRI treatment and have been started on a MAOI. Some cases presented with features resembling serotonin syndrome. Therefore, it is recommended that citalopram should not be used in combination with a MAOI or within 14 days of discontinuing treatment with a MAOI. Similarly, at least 14 days should elapse after discontinuing citalopram treatment before starting a MAOI.

Precautions   Back to top of page

Suicide
The possibility of a suicide attempt is inherent in depression and may persist until remission occurs. Therefore, high risk patients should be closely supervised throughout therapy with Citalopram hydrobromide and consideration should be given to the possible need for hospitalization. In order to minimize the opportunity for overdosage, prescription for citalopram should be written for the smallest quantity of drug consistent with good patient management.

Activation of Mania/Hypomania
In placebo-controlled trials with citalopram, some of which included patients with bipolar disorder, mania/hypomania was reported in 0.1% of 1027 patents treated with citalopram versus none of the 426 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. If a patient enters a manic phase, citalopram should be discontinued.

Seizures
Citalopram has not been systematically evaluated in patients with a seizure disorder. These patients were excluded from clinical studies during the premarketing testing of citalopram. In clinical trials, seizures occurred in 0.25% of patients treated with citalopram and in 0.23% patients treated with placebo. Like other antidepressants, citalopram should be used with caution in patients with a history of seizure disorder.

Serotonin Syndrome
Rarely, the occurrence of serotonin syndrome has been reported in patients receiving SSRIs. A combination of symptoms, possibly including agitation, confusion, tremor, myoclonus and hyperthermia, may indicate the development of this condition.

5-HT₁ Agonists
There have been rare postmarketing reports describing patients with weakness, hyperreflexia and incoordination, following the concomitant use of a SSRI and the antimigraine drug sumatriptan, a 5-HT₁ agonist. Such interaction should be considered if citalopram is to be used in combination with a 5-HT₁ agonist.

Hyponatremia
Hyponatremia and SIADH (syndrome of inappropriate antidiuretic hormone secretion) have been reported with citalopram use as a rare adverse event.

Pregnancy and Nursing Mothers
The safety of citalopram during pregnancy and lactation has not been established. Therefore, citalopram should not be used during pregnancy, unless, in the opinion of the physician, the expected benefits to the patient markedly outweigh the possible hazards to the fetus. Citalopram is excreted in human milk. Citalopram should not be administered to nursing mothers unless, in the opinion of the treating physician, the expected benefits to the patient markedly outweigh the possible hazards to the child.

Pediatric Use
Safety and effectiveness in patients below the age of 18 have not been established.

Geriatric Use
In premarketing clinical trials, 800 elderly patients (>=65 years of age) have been treated with citalopram. Of these patients 298 were >=75 years old. In a pharmacokinetic study (n=11, age 73 to 90 years), clearance was substantially decreased and half-life prolonged (see PHARMACOKINETICS). In a 6-week placebo-controlled study, approximately equal numbers of patients received citalopram at 20 or 30 mg per day, as the final dose. In about 5% of patients, the final dose was 10 mg per day (see CLINICAL TRIALS). Consequently, elderly patients should be administered lower doses and a lower maximum dose.

Hepatic Impairment
Citalopram clearance was significantly decreased and plasma concentrations, as well as elimination half-life significantly increased (see PHARMACOKINETICS). Consequently, the use of citalopram in hepatically impaired patients should be approached with caution and a lower maximum dosage is recommended.

Renal Impairment
No dosage adjustment is needed in patients with mild to moderate renal impairment. To date, no information is available on the pharmacokinetic or pharmacodynamic effects of citalopram in patients with severely reduced renal function (creatinine clearance <20 mL/min).

Use in Patients with Cardiac Disease
Citalopram has not been systematically evaluated in patients with a recent history of myocardial infarction or unstable heart disease. Patients with these diagnoses were generally excluded from clinical trials during the drugs premarketing assessment. However, the electrocardiograms of patients, who received citalopram in clinical trials, indicate that citalopram was not associated with the development of clinically significant ECG abnormalities.

In clinical trials, citalopram caused small but statistically significant decreases in heart rate (see ECG under ADVERSE REACTIONS) Consequently, caution should be observed when citalopram is initiated in patients with pre-existing slow heart rate.

Use in Diabetic Patients
Citalopram has not been systematically evaluated in diabetic patients since diabetes constituted an exclusion criterion. Although 13 patients did receive insulin during the studies, this number is too small to determine whether citalopram affects the response to insulin. Rare events of hypoglycemia were reported. Citalopram should be used with caution in diabetic patients on insulin or other antidiabetic drugs.

Interference with Cognitive and Motor Performance
In studies in normal volunteers, citalopram in doses of 40 mg/day did not impair cognitive function or psychomotor performance. However, psychotropic medications may impair judgement, thinking or motor skills. Consequently, patients should be cautioned against driving a car or operating hazardous machinery until they are reasonably certain that citalopram does not affect them adversely.

Electroconvulsive Therapy (ECT)
The safety and efficacy of the concurrent use of citalopram and ECT have not been studied.

Abrupt Discontinuation   Back to top of page

After 8 weeks of treatment with citalopram, abrupt discontinuation of treatment caused a higher incidence of anxiety, emotional indifference, impaired concentration, headache, migraine, paresthesia, and tremor than was seen in patients who continued on citalopram. These symptoms are not indicative of addiction.

Although it is not known whether gradual discontinuation will prevent the discontinuation symptoms, it is recommended that the dosage of citalopram should be tapered off over 1 to 2 weeks.

Additional Adverse Events Observed During the Premarketing Evaluation of Citalopram   Back to top of page

The events listed below include all adverse events that were reported in the overall development program of citalopram (n=3652). All reported events are included except those already listed in Table 1 and those events which occurred in only one patient. It is important to emphasize that, although the events reported occurred during treatment with citalopram, they were not necessarily caused by it. The events are enumerated using the following criteria: frequent: adverse events that occurred on one or more occasions in at least 1/100 patients; infrequent: adverse events that occurred in less than 1/100 patients but at least in 1/1000 patients; rare: adverse events that occurred in fewer than 1/1000 patients.

Body as a Whole - General Disorders
Frequent: Influenza-like symptoms, nonpathological trauma, pain. Infrequent: Alcohol intolerance, allergic reaction, allergy, chest pain, edema, hot flushes, leg pain, malaise. rigors, syncope. Rare: Peripheral edema, sudden death, traumatic injury.

Cardiovascular Disorders
Frequent: Postural hypotension, tachycardia. Infrequent: Angina pectoris, arrhythmia. bradycardia, cardiac failure, cerebrovascular disorders, edema dependent, extrasystoles, flushing, hypertension, hypotension, myocardial infarction, myocardial ischemia, peripheral ischemia. Rare: Aggravated hypertension, bundle branch block, cardiac arrest, coronary artery disorder, ECG abnormal, heart disorder, phlebitis, supraventricular extrasystoles.

Central and Peripheral Nervous System Disorders
Frequent: Migraine, paraesthesia. Infrequent: Abnormal gait, ataxia, convulsions, dysphonia, dystonia, extrapyramidal disorder, hyperkinesia, hypertonia, hypoesthesia, hypokinesia, involuntary muscle contractions, leg cramps, neuralgia, speech disorder, vertigo Rare: Abnormal coordination, convulsions grand mal, hyperesthesia, ptosis, sensory disturbance, stupor.

Collagen Disorders
Rare: Rheumatoid arthritis.

Endocrine Disorders
Rare: Goiter, gynecomastia, hypothyroidism.

Gastrointestinal System Disorders
Frequent: Flatulence. Infrequent: Colitis, dental abscess, dysphagia, eructation, gastritis, gastroenteritis, gastrointestinal disorder (not specified), hemorrhoids, increased saliva, teeth-grinding, toothache. Rare: Appendicitis, esophagitis, gastric ulcer, gastroesophageal reflux, gingivitis, stomatitis, tooth disorder, ulcerative stomatitis.

Hematopoietic and Lymphatic Disorders
Infrequent: Anemia, epistaxis, leukocytosis, purpura. Rare: Coagulation disorder, gingival bleeding, granuloytopenia, hematoma, leukopenia, lymphadenopathy, lymphocytosis, pulmonary embolism.

Liver and Biliary System Disorders.
Infrequent: Cholecystitis, cholelithiasis, increased gamma-GT, increased SGPT. Rare: Bilirubinemia, increased SGOT, jaundice.

Metabolic and Nutritional Disorders
Frequent: Weight decrease, weight increase. Infrequent: Leg edema, xerophthalmia. Rare: Dehydration, edema, hypoglycemia, hypokalemia, increased alkaline phosphatase, obesity, thirst.

Musculo-Skeletal System Disorders
Infrequent: Arthralgia, arthritis, arthrosis, dystonia, muscle weakness, myalgia. Rare: Bone disorder, bursitis, osteoporosis, tendon disorder.

Neoplasm
Rare: Breast neoplasm malignant female.

Psychiatric Disorders
Frequent: Abnormal dreaming, aggravated depression, amnesia, apathy, confusion, depression, impaired concentration, increased appetite, sleep disorder, suicide attempt. Infrequent: Abnormal thinking, aggressive reaction, delusion, depersonalization, drug abuse, drug dependence, emotional lability, euphoria, hallucination, increased libido, manic reaction, neurosis, paranoid reaction, paroniria, psychosis, psychotic depression. Rare: Catatonic reaction, hysteria, personality disorder.

Reproductive Disorders, Female
Infrequent: Amenorrhea, breast pain, lactation nonpuerperal, menorrhagia, menstrual disorder, premenstrual syndrome, salpingitis, unintended pregnancy, vaginal dryness, vaginitis. Rare: Breast enlargement, vaginal hemorrhage.

Reproductive Disorders, Male
Infrequent: Penis disorder, prostatic disorder, testis disorder.

Resistance Mechanism Disorders
Infrequent: Abscess, fungal infection, herpes simplex infection, otitis media, viral infection. Rare: Bacterial infection, moniliasis, sepsis.

Respiratory System Disorders
Infrequent: Bronchitis, coughing, dyspnea, pneumonia. Rare: Asthma, bronchospasm, increased sputum, laryngitis, pneumonitis, respiratory disorder.

Skin and Appendage Disorders
Frequent: Pruritus, rash. Infrequent: Acne, alopecia, dermatitis, dry skin, eczema, photosensitivity reaction, psoriasis, rash erythematous, rash maculo-papular, skin discoloration, urticaria. Rare: Cellulitis, decreased sweating, hypertrichosis, melanosis, pruritus ani.

Special Senses, Vision, Hearing and Vestibular Disorders
Frequent: Abnormal accommodation. Infrequent: Conjunctivitis, earache, eye pain, mydriasis, taste perversion, tinnitus. Rare: Eye abnormality, keratitis, photophobia.

Urinary System Disorders
Frequent: Polyuria. Infrequent: Abnormal urine, cystitis, hematuria, micturition frequency, urinary incontinence, urinary retention, urinary tract infection. Rare: Dysuria, facial edema, oliguria, renal calculus, renal pain.

Events Observed During the Post-Marketing Evaluation of Citalopram   Back to top of page

It is estimated that approximately 8 million patients have been treated with citalopram since market introduction. The following adverse events have been reported to be temporarily associated with citalopram treatment in at least 3 patients and are not described elsewhere in labeling.

Abnormal hepatic function, aggravated condition, aggravated migraine, angioedema, asthma, choreoathetosis, decreased drug level, decreased prothrombin time, dyskinesia, eosinophilia, erythema multiforms, gynecological problems, hepatitis, hyperprolactinemia, hyponatremia, increased drug level, increased prothrombin time, mydriasis, neuroleptic malignant syndrome, neuropathy, pancreatitis, pancytopenia, postural hypotension, serotonin syndrome, SIADH, spontaneous abortion/fetal death, thrombocytopenia, ventricular arrhythmia, Torsade de pointes, withdrawal syndrome.

Adverse Reactions   

During the premarketing clinical development, 3652 patients received Citalopram hydrobromide for the treatment of depression. Of these patients, 66% were females and 34% were males. The mean age of the patients was 50 years, with 70% being <60 years old (30% <40 years old, 40% 40 to 59 years old) and 30% being >=60 years old.

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

Adverse Reactions Associated with Discontinuation of Treatment
From the short-term (4 to 6 weeks) placebo-controlled, Phase III clinical trials, 15.9% (163/1027) of the citalopram-treated patients discontinued treatment due to an adverse event. The discontinuation rate in the placebo-treated patients was 7.7% (33/426).

The events associated with discontinuation of citalopram in 1% or more of patients at a rate of at least twice that of placebo, were as follows: Nausea (4.1% versus 0.0%), insomnia (2.4% versus 12%), somnolence (2.4% versus 1.2%), dizziness (2.3% versus 0.7%), vomiting (1.3% versus 0.0%), agitation (1.2% versus 0.0%), asthenia (11% versus 0.5%), and dry mouth (1.1% versus 0.2%).

Incidence of Adverse Events in Placebo-controlled Studies
Table 1 enumerates the incidence of treatment-emergent adverse events that occurred in 1027 depressed patients who received citalopram 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 citalopram, and for which the incidence in patients treated with citalopram was greater than the incidence in placebo-treated patients. Reported adverse events were classified using the standard World Health Organization (WHO)-based dictionary terminology.

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 favors to the adverse event incidence rate in the population studied.

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TABLE 1 - TREATMENT-EMERGENT ADVERSE EVENTS*
INCIDENCE IN PLACEBO-CONTROLLED CLINICALTRIALS

 

Body System/Adverse Event	Percentage of Patients Reporting
	Citalopram (n=1027)	Placebo (n=426)
Body as a Whole
Fatigue	5.2	3.1
Fevers1	2.4	0.2
Autonomic Nervous System
Dry mouth1	19.4	12.2
Sweating increased	10.5	8.0
Central and Peripheral Nervous System
Tremor	8.4	6.3
Gastrointestinal System
Nausea1	20.6	13.4
Diarrhea	8.1	5.4
Dyspepsia	4.3	3.5
Vomiting	3.9	2.6
Abdominal pain	3.1	2.1
Psychiatric
Somnolence1	17.3	9.9
Anorexia1	4.2	1.6
Nervousness	3.6	3.5
Anxiety	3.3	2.1
Agitation1	2.4	0.7
Libido decreased1	2.2	0.2
Yawning1	2.1	0
Reproductive Female2
Dysmenorrhea (<50 years)	2.7	1.6
Reproductive, Male3
Ejaculation disorder1	6.2	1.1
Impotence3	3.2	0.6
Respiratory System
Upper respir. tract infection	5.1	4.7
Rhinitis	4.9	3.3
Pharyngitis	3.4	2.8
Sinusitis1	2.4	0.2
Urinary System
Micturition disorder	2.3	2.1

*Events included are those occurring in 2% or more of patients treated with citalopram, and for which the incidence in patients treated with citalopram was greater than the incidence in placebo-treated patients.
¹Statistically significantly higher incidence in the citalopram group (p<0.05).
²Denominator used was for females only (n=623 for citalopram; n=245 for Placebo).
³Denominator used was for males only (n=404 for citalopram; n=181 for Placebo).

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The following events had an incidence on placebo >= citalopram: asthenia, back pain, headache, dizziness, constipation, palpitation, insomnia, abnormal vision.

Most Frequent Adverse Events
Adverse events that occurred in citalopram-treated patients in the course of the short-term, placebo-controlled trials with an incidence greater than or equal to, 10% were: nausea, dry mouth, somnolence, and increased sweating (Table 1).

Dose Dependency of Adverse Events
The potential relationship between the dose of citalopram and the incidence of an adverse event was examined in a fixed dose short-term, placebo-controlled study in which patients received citalopram at doses of 10, 20, 40 or 60 mg per day. The incidence of insomnia, increased sweating, and fatigue was dose-related.

Male and Female Sexual Dysfunction with SSRIs
While sexual dysfunction is often part of depression and other psychiatric disorders, there is increasing evidence that treatment with selective serotonin reuptake inhibitors (SSRIs) may induce sexual side effects. This is a difficult area to study because patients may not spontaneously report symptoms of this nature, and therefore, it is thought that sexual side effects with SSRIs may be underestimated.

In placebo-controlled, short-term clinical trials, the reported incidence of decreased libido, ejaculation disorders (primarily ejaculation delay and ejaculation failure), and impotence in male depressed patients receiving citalopram (n=404) was 3.7%, 6.2%, and 3.2%, respectively. In female depressed patients receiving citalopram (n=623), the reported incidence of decreased libido and anorgasmia was 1.3% and 1.1%, respectively. The reported incidence of each of these adverse events was <=1% among male and female depressed patients receiving placebo.

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

ECG
Retrospective analyses of electrocardiograms in citalopram-treated (n=779 <60 years and n=313 >=60 years) and placebo-treated (n=74 <60 years and n=43 >=60 years) patients indicated that citalopram decreases heart rate. In patients <60 years old, the mean decrease was approximately 5 bpm, while in patients >=60 years old, mean decreases ranged between 5 to 10 bpm. Following the initial drop, heart rate remained decreased but stable over prolonged periods of time (up to one year in over 100 younger and over 50 elderly patients). The effect was reversible within approximately a week after stopping treatment.

In the 6-week, fixed dose, dose-response study, the mean decreases in heart rate ranged between 2-6 bpm in the 20-60 mg/day dose range, but the effect did not seem to be dose-related and was independent of gender. In placebo-treated patients heart rates remained unaffected. The differences in heart rates between citalopram and placebo-treated patients were statistically significant. ECG parameters, including QT interval, remained unaffected.

Clinical Trials, Drug Interactions, 

Over dosage, Dosage, Pharmaceutical Information

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Clinical Trials   

In a 6-week fixed dose, dose-response study, patients received citalopram at doses of 10, 20, 40, or 60 mg/day or placebo (n=129 to 131 per group). The 40 and 60 mg day doses were titrated, with patients reaching these designated doses within 4 and 8 days, respectively. The study showed that the 40 and 60 mg/day doses were significantly more effective than placebo, although the 60 mg/day dose was not more effective than the 40 mg/day dose. The lower doses did not show statistically significant superiority over placebo, except on the MADRS: on this scale the percent of responders was significantly higher in all the citalopram-treated groups than in the placebo-treated group.

The second study was a 4-week flexible dose study in which 85% of the depressed patients met the criteria for melancholia. At entry, 89 and 91 patients were randomized to the citalopram and placebo groups, respectively. This was the only study in which more male than female patients participated (64% versus 36%). The initial dose of citalopram, 20 mg/day, could be titrated to the maximal tolerated dose or a maximum dose of 80 mg/day. Patients treated with citalopram showed significantly greater improvement than patients treated with placebo. At week 4, the average daily dose was 63 mg, with 52% of patients receiving the 80 mg/day dose.

In a 6-week fixed-dose study, patients received citalopram, 20 or 40 mg/day, or placebo (n=64 to 70 per group). Patients treated with citalopram 40 mg/day, showed significantly greater improvement than placebo-treated patients. The difference between the lower dose of citalopram and placebo was not significant. In another 6-week fixed-dose study, patients received citalopram 20 or 40 mg/day or placebo (n=88 to 97 per group). Although citalopram-treated patients improved to a somewhat greater degree than the placebo-treated patients, the differences between drug and control groups did not reach statistical significance due to a high placebo response, i.e. substantial improvement in the placebo group.

A 6-week, flexible dose study was conducted in elderly, depressed patients (the mean age of male and female patients was 75 and 77 years, respectively) to determine the antidepressant effect and safety of citalopram in this subpopulation. The number of patients who received citalopram and placebo was 98 and 51, respectively. The study allowed patients to enter with lower baseline HAMD scores than are usually acceptable (>=18 in clinical trials). However, only a small percentage of patients had HAMD scores of less than 18 at entry. The dose of citalopram was titrated from a starting dose of 10 mg day to a maximum dose of 30 mg day. Patients treated with citalopram showed significantly greater improvement than patients treated with placebo. The final dose of citalopram was 10, 20 and 30 mg/day in 5%, 51% and 44% of patients, respectively.

The effectiveness of citalopram in preventing relapse was assessed in two long-term studies. Depressed patients who responded to citalopram during an initial 6 or 8 weeks of acute treatment (fixed doses of 20 or 40 mg/day in one study and flexible doses of 20-60 mg/day in the second study) were randomized to continue on citalopram or receive placebo. The number of patients who received citalopram and placebo was 257 and 116, respectively. In both studies, patients who continued on citalopram experienced significantly lower relapse rates over the subsequent 6 months compared to those receiving placebo. In the fixed-dose study, the relapse rates were similar at the 20 and 40 mg/day doses, namely 10% and 12%, respectively. Of the placebo-treated patients, 31% experienced relapse. In the flexible-dose study, the relapse rates were 14% and 24% in the citalopram- and placebo-treated patients, respectively. While the majority of patients (76%) were maintained on 20 or 40 mg/day of citalopram during most of the study, some patients received 60 mg/day, while a few patients were maintained on less than 20 mg/day.

Drug Interactions:   Back to top of page

Monoamine Oxidase Inhibitors (MAOI)
For interactions between citalopram and MAOI, see CONTRAINDICATIONS.

General
The studies described in this section were carried out in young, healthy, mostly male volunteers. In addition, some of the studies, namely interactions with metoprolol, warfarin, digoxin, imipramine, and levomepromazine, utilized only single doses of these drugs, although citalopram was given repeatedly to attain steady state. Thus, data are not available in patients who would be receiving these drugs on an ongoing basis at therapeutic doses.

Metoprolol
Coadministration of citalopram (40 mg/day for 22 days) and the b-adrenergic backing agent metoprolol (single dose of 150 mg), resulted in a two-fold increase in the plasma levels of metoprolol. However, the effect of metoprolol on blood pressure and heart rate was not affected.

Warfarin
Administration of citalopram (40 mg day for 21 days), did not affect either the pharmacokinetics or the pharmacodynamics (prothrombin time) of a single, 1 mg dose of warfarin.

Digoxin
Administration of citalopram (40 mg/day for 21 days) did not affect the pharmacokinetics of digoxin (single dose of 1 mg), although the serum levels of citalopram were slightly lower in the presence of digoxin.

Imipramine
Coadministnation of citalopram (40 mg/day for 10 days) and the tricyclic antidepressant, imipramine (single dose of 100 mg), did not affect the pharmacokinetics of either drug. However, in the presence of citalopram, the concentration of desipramine, the metabolite of imipramine, increased by approximately 50% and its half-life was prolonged. The results indicate that citalopram does not interfere with the demethylation of imipramine to desipramine but does inhibit the metabolism of desipramine to its 2-hydroxy metabolite. Consequently, concomitant treatment with citalopram and imipramine/ desipramine should be undertaken with caution.

Levomepromazme
Coadministration of citalopram (40 mg/day for 10 days) and levomepromazine (single dose of 50 mg), did not affect the pharmacokinetics of either drug.

Lithium
Coadministration of citalopram (40 mg/day for 10 days) and lithium (30 mmol/day for 5 days), did not affect the pharmacokinetics of either drug. However, since lithium may increase serotonergic neurotransmission, concomitant treatment with these two drugs should be undertaken with caution.

Cimetidine
Citalopram 40 mg/day was administered for 29 days. During the last 8 days of treatment, cimetidine (400 mg bid) was added to the treatment regimen. In the presence of cimetidine, a potent inhibitor of hepatic cytochrome P450 enzymes, the C_max and AUC of citalopram was increased by 39% and 41%, respectively. Thus, caution should be exercised at the upper end of the dose range of citalopram when it is used concomitantly with high doses of cimetidine.

Carbamazepine
Carbamazepine, titrated to 400 mg day, was given for 21 days alone and then in combination with citalopram (40 mg day) for an additional 14 days, citalopram did not affect the plasma levels of either carbamazepine, a CYP3A4 substrate, or its metabolite, carbamazepine-epoxide, However, since carbamazepine is a microsomal enzyme inducer, the possibility that carbamazepine may increase the clearance of citalopram should be considered if the two drugs are given concomitantly.

Cytochrome P450 Isozymes
Using in vitro models of human liver microsomes, the biotransformation of citalopram to its demethyl metabolites was shown to depend on both CYP2C19 and CYP3A4, with a small contribution from CYP2D6. Studies have also indicated that citalopram is a weak inhibitor of CYP2D6 and CYP2C19 and a weak or negligible inhibitor of CYP3A4 and CYP1A2. As data are not available from clinical pharmacokinetic studies, the possibility that the clearance of citalopram will be decreased when citalopram is administered with a potent inhibitor of CYP3A4 (e.g., ketoconazole, itraconazole, fluconazole or erythromycin), or a potent inhibitor of CYP2C19 (e.g., omeprazole), should be considered.

Alcohol
Although citalopram did not potentiate the cognitive and psychomotor effects of alcohol in volunteers, the concomitant use of alcohol and citalopram should be avoided.

Other Drugs
In clinical trials, citalopram has been given concomitantly with benzodiazepines (anxiolytics/hypnotics), analgesics (NSAIDs, nonNSAIDs), lithium, antihistamines, antihyperensives or other cardiovascular drugs.

Symptoms and Treatment of Overdosage Back to top of page

Citalopram hydrobromide has a wide margin of safety in overdose. Cases of overdoses involved the ingestion of citalopram either alone or in combination with other drugs and/or alcohol. In clinical trials, with overdoses of citalopram ranging from 180 mg to 2000 mg, all patients recovered. One patient, ingesting over 1500 mg citalopram, had reversible ECG abnormalities, the most important of which was prolongation of QTc.

Of the cases reported postmarketing, six were fatal. The doses of citalopram in these patients ranged from 840 mg to 1960 mg. All but one of these patients had concomitant drugs and/or alcohol. Serum levels of citalopram in patients who ingested 2000 mg, 4000 mg and 5200 mg of the drug were 2900 ng/mL, 3800 ng/mL and 10,040 ng/mL citalopram, respectively. All these patients recovered. Three fatal cases of serotonin syndrome have been reported in patients who took overdoses of moclobemide (Manerix) and citalopram. The plasma concentrations of moclobemide were between 16 and 90 mg/L (therapeutic range: 1 to 3 mg/L) and those of citalopram between 0.3 and 1.7 mg (therapeutic concentration: 0.3 mg/L). This indicates that a relatively low dose of citalopram, given with an overdose of moclobemide represents a serious risk for the patient.

Symptoms most often accompanying citalopram overdose included dizziness, sweating, nausea, vomiting, tremor, and somnolence. In more rare cases, observed symptoms included confusion, loss of consciousness, convulsions, coma, sinus tachycardia, cyanosis, hyperventilation and rhabdomyolysis.

Management of Overdose  Back to top of page

Establish and maintain an airway to ensure adequate ventilation and oxygenation. Gastric lavage and use of activated charcoal should be considered. Cardiac and vital sign monitoring are recommended, along with general symptomatic and supportive measures. There are no specific antidotes for citalopram.

Due to the large volume of distribution of citalopram, forced diuresis, dialysis, hemoperfusion and exchange transfusion are unlikely to be of benefit. In managing overdosage, the possibility of multiple drug involvement must be considered.

Dosage and Administration   Back to top of page

General
Citalopram hydrobromide should be administered once daily, in the morning or evening, with or without food.

Adults
Citalopram should be administered as a single oral dose of 20 mg/day. In patients who do not respond adequately, an increase of dosage to 40 mg/day should be considered. Certain patients may require 60 mg/day. However, in a dose response study, the 60 mg/day dose did not demonstrate an advantage regarding effectiveness over the 40 mg/day dose. Dose increases should usually occur in increments of 20 mg, at intervals of no less than one week.

Elderly Patients
A single oral dose of 20 mg/day is the recommended dose for most elderly patients. Some patients may respond to a 10 mg/day dose (see CLINICAL TRIALS under ACTION AND CLINICAL PHARMACOLOGY). The dose may be titrated to a maximum of 40 mg/day if needed and tolerated.

Hepatic Impairment
Patients with reduced hepatic function should receive dosages of no more than 30 mg/day.

Renal Impairment
No dosage adjustment is necessary for patients with mild to moderate renal impairment. Since there is no information available on the pharmacokinetic or pharmacodynamic effects of citalopram in patients with severe renal impairment, citalopram should be used with caution in these patients.

Maintenance Treatment
Evaluation of citalopram in two placebo-controlled studies has shown that its antidepressant efficacy was maintained for periods of up to 24 weeks, following 6 or 8 weeks of initial treatment (total of 32 weeks) (See CLINICAL TRIALS under ACTION AND CLINICAL PHARMACOLOGY). In the flexible dose study, the great majority of patients were receiving 20 or 40 mg/day doses both at 12 and 24 weeks. During maintenance therapy the dosage should be kept at the lowest effective level and patients should be periodically reassessed to determine the need for continued treatment.

Back to top of page

Switching Patients to or from a Monoamine Oxidase Inhibitor (MAOI) 

At least 14 days should elapse between discontinuation of a MAOI and initiation of therapy with citalopram. Similarly, at least 14 days should be allowed after stopping citalopram before starting a MAOI (see CONTRAINDICATIONS).

Discontinuation of Citalopram Treatment   Back to top of page

Since some patients may experience discontinuation symptoms when citalopram is stopped abruptly, the dose of citalopram should be tapered off over 1 to 2 weeks.

Pharmaceutical Information

 

DRUG SUBSTANCE
Common Name:	Citalopram hydrobromide
Code Name:	Lu 10-171-B
Chemical Name:	(RS)-1-[3-(dimethylamino)propyl]-1-(p-flurophenyl)-5-phthalancarbonitrile, hydrobromide
Structural Formula:
Molecular Formulas:	C20H22BrFN2O
Molecular Weight:	405.35
Description:	White to off-white, crystalline having no more than a slight odour.
Melting Point:	185°-188°C
pH:	5.5-6.5 (0.5% w/v in water)
pKa:	9.5 (microtitration)
Solubility:	Water (sparingly soluble) Ethanol (soluble) Chloroform (freely soluble) Diethylether (very slightly soluble)
Partition Coefficient:	Log P (octanol/phosphate buffer pH 7.4) - 1.57

Composition:
Citalopram tablets contain citalopram hydrobromide corresponding to 20 mg or 40 mg citalopram, and the following non- medicinal ingredients: corn starch,lactose monohydrate, microcrystalline cellulose, copolyvidone, glycerin, croscarmellose sodium, magnesium stearate, methylhydroxypropyl cellulose, polyethylene glycol 400, and titanium dioxide.

Stability and Storage:
Citalopram tablets should be stored in a dry place at room temperature between 15° and 30°C.

What is Cymbalta?

Cymbalta is a new antidepressant manufactured by Eli Lilly and Company, the approval of which Has finally been granted by the U.S. Food and Drug Administration.  This happens on the heals of one suicide of a 19 year-old, in perfect health, no mental disorder, hanging herself at the Eli Lilly complex, after taking Cymbalta. This is approved when pressure is being put on all of the pharmaceutical firs to fully disclose their clinical trials.

Did the FDA feel a little pressure from the current Administration? If you have an adverse event or commit suicide while taking Cymbalta, odds are the current Administration will pay for and support Eli Lilly to beat you in court. The current administration admits this.

August 11, 2004 - The FDA states Cymbalta had nothing to do with the hanging death at the Eli Lilly facility. Let's look at the known data here:

1. You have a healthy 19 year old female as part of the Cymbalta clinical trials.

2. She is given a much higher dosage then recommended.

3. Part of her trial was to quit the Cymbalta quickly

4. She hangs herself

5. She has no mental illness

6. She was in perfect physical health per Eli Lilly

7. She was in the trial to earn money for college

8. The current administration will supply Eli Lilly with their attorneys to help fight consumer lawsuits because "the FDA is never wrong"

9. The FDA uses their own lead attorney to help Eli Lilly and others fight consumer lawsuits because the FDA is never wrong.

10. The current administration is full of Eli Lilly past executives.

11. You would think if the FDA clears Cymbalta as the cause of death, they would disclose why or what the reason was.

12. Amazing, the FDA statement of Cymbalta having nothing to do with this suicide, would come within 1 week of Cymbalta being approved by the FDA and within 3 weeks of the massive launch of Cymbalta by Eli Lilly. Eli Lilly will have more drug reps hit the streets to visit physicians then with any other drug of theirs in the past.

13. If Cymbalta fails, Eli Lilly will suffer on Wall Street.

Eli Lilly is being sued again after a SWAT captain commits suicide after only 3 days of Prozac use. Eli Lilly has already settled 2 suits out of court for the same issue. Know what can happen before you take these medications. There is a way to know. Click here for story. (Opens new browser)

August 4, 2004 - Now that Cymbalta is approved by the FDA will Eli Lilly disclose all of their clinical trials? With a high profile suicide occurring during the clinical trial, will the pressure be enough on Eli Lilly? When a healthy volunteer, with no known mental illness or physical problem commits suicide on Cymbalta, will Eli Lilly disclose all of the facts?

Eli Lilly, I know you are on this Web Site daily, especially when it comes up first on most search engines for your new antidepressant Cymbalta, what are you going to do? Disclose all of the facts or not? If you work with Eli Lilly and feel it is time for you to come clean and disclose all you know about Cymbalta hidden information, Click here and send an e-mail.

Click here for Cymbalta Adverse Reactions and more

What is Cymbalta?

Cymbalta is a brand-name for a drug called duloxetine.  It is in a class of drugs known as dual uptake inhibitors.   So what is a dual uptake inhibitor -- or an uptake inhibitor, for that matter?

The way a neurotransmitter works is, it is passed along from one nerve to another.  A bit of it is sent out at a time from one nerve to the next.  After a bit is sent out and received by the next nerve, any of the neurotransmitter remaining between the nerves is taken back by the first nerve, a process called reuptake. 

A reuptake inhibitor prevents this reuptake process from occurring, which means that, when Cymbalta is active, certain neurotransmitters are transmitted in steady streams from one nerve ending to the next, instead of being sent in bits periodically, which they normally are.  The neurotransmitters affected by Cymbalta are known as serotonin and norepinephrine.  And now we can explain what "dual uptake inhibitor" means -- it simply means a drug that affects the reuptake of two neurotransmitters instead of one. 
Back to top of page

Does Cymbalta cure depression?

Good question.  If depression has never been proven to be caused by neurotransmitters (or the lack of them), that question cannot obviously be answered conclusively. 

Apparently, Eli Lilly and Company knows this.  According to a recent news release from Eli Lilly regarding Cymbalta:   "Many experts believe treating the complete spectrum of depression symptoms is intrinsic to a lasting recovery. As well, combined action through two key neurotransmitters - serotonin and norepinephrine - may provide a more rapid and sustained clinical effect."

Note the subtle uncertainties in these statements, for there is absolutely no scientific proof behind them.  "Many experts believe treating the complete spectrum of depression symptoms..."   "...combined action through two key neurotransmitters - serotonin and norepinephrine - may provide..."

Translation:  They don't know how, why, or if their drug works.  This is evident in the numerous -- and serious -- side effects provided by other antidepressants.  Lilly's press release did not even address side effects, but another of their releases regarding Cymbalta's clinical trials revealed three of the exact same side effects as other antidepressants:  Dizziness, anxiety, and nausea. 

In that Cymbalta has the exact same action as Wyeth's drug Effexor, one could assume the same side effects.  (See "Precautions" section on Effexor page). (Opens new browser)
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What is Depression?

Depression is defined by the Diagnostic and Statistical Manual of Mental Disorders (DSM), published by the American Psychiatric Association, this way: 

The essential feature of a Major Depressive Episode is a period of at least 2 weeks during which there is either depressed mood or the loss of interest or pleasure in nearly all activities.  In children and adolescents, the mood may be irritable rather than sad.  The individual must also experience at least four additional symptoms drawn from a list that includes major changes in appetite or weight, sleep, and psychomotor [of or relating to movement or muscular activity associated with mental processes] activity; decreased energy; feelings of worthlessness or guilt; difficulty thinking, concentrating, or making decisions; or recurrent thoughts of death or suicidal ideation, plans, or attempts."

While these elements can certainly be seen to exist and have been experienced by many, labeling "depression" as an illness has been criticized by many as simply labeling part of life itself as a physical "disease" which must be "cured". 

This could be debated endlessly, however, and whole long texts have been written on the subject.  Depression as a state of mind certainly does exist, and can be painful.  The question to be addressed here, though, is, does depression truly have a physical cause that can be addressed with medication?

For the answer, let's go back to the DSM.  The only information given there as to physical causes of depression is: 

Neurotransmitters implicated in the pathophysiology [study of the physical effects of a disease] of a Major Depressive Episode include norepinephrine, serotonin, acetylcholine
, dopamine, and gamma-aminobutryric acid.  Back to top of page

All right, what does all that mean?  Here's a simple explanation.  A neurotransmitter is a chemical that helps transmit nerve impulses through the nervous system.  There are many different neurotransmitters used by the body.  What the DSM definition is saying is that, by some method, the neurotransmitter chemicals known as  norepinephrine, serotonin, acetylcholine
, dopamine, and gamma-aminobutryric acid seemed to be lower in some depressed people, or higher in non-depressed people. 

Note carefully the use of the word implicated in the DSM definition, however.  And therein is the first clue, for it has never been clinically proven that depression is based in neurotransmitters.  We repeat:  Never.  And believe it or not, there is not a doctor on Earth that will disagree with that statement.

Which leads to the conclusion that a physical cause for depression has never been isolated.  Why, then, is Eli Lilly and Company, Cymbalta's manufacturer, so insistent that Cymbalta is a great treatment for depression?

For the answer to this, let's turn to Eli Lilly and find out exactly what Cymbalta is, and how it works.

Should You Take Cymbalta? Back to top of page

The answer is, of course, up to you.  Before you do, however, become fully informed of the dangers from the manufacturer.  As yet the full list of side effects have not been published. 

You should also be aware of a dangerous metabolism issue that may affect you, and for which you should be tested before you take such a drug. 

CYMBALTA

(duloxetine hydrochloride)

Pharmacokinetics

  CYMBALTA has an elimination half-life of about 12 hours (range 8 to 17 hours) and its pharmacokinetics are dose proportional over the therapeutic range. Steady-state plasma concentrations are typically achieved after 3 days of dosing. Elimination of CYMBALTA is mainly through hepatic metabolism involving two P450 isozymes, CYP2D6 and CYP1A2.

  Absorption and Distribution – Orally administered CYMBALTA is well absorbed. There is a median 2-hour lag until absorption begins (T lag), with maximal plasma concentrations C max) of CYMBALTA occurring 6 hours post dose. Food does not affect the Cmax of CYMBALTA, but delays the time to reach peak concentration from 6 to 10 hours and it marginally decreases the extent of absorption (AUC) by about 10%. There is a 3-hour delay in absorption and a one-third increase in apparent clearance of CYMBALTA after an evening dose as compared to a morning dose.

  The apparent volume of distribution averages about 1640 L. CYMBALTA is highly bound (>90%) to proteins in human plasma, binding primarily to albumin and ą1-acid glycoptrotein. Plasma protein binding of CYMBALTA is not affected by renal or hepatic impairment.

  Metabolism and Elimination – Biotransformation and disposition of CYMBALTA in humans have been determined following oral administration of 14C-labeled CYMBALTA. CYMBALTA comprises about 3% of the total radiolabeled material in the plasma, indication that it undergoes extensive metabolism to numerous metabolites. The major biotransformation pathways for CYMBALTA involve oxidation of the naphthyl ring followed by conjugation and further oxidation. Both CYP2D6 and CYP1A2 catalyze the oxidation of the naphthyl ring in vitro.   Metabolites found in plasma include 4 –hydroxy duloxetine glucuronide and 5-hydroxy, 6-methoxy duloxetine sulfate. Many additional metabolites have been identified in urine, some representing only minor pathways of elimination. Only trace (1% of the dose) amounts of unchanged CYMBALTA are present in the urine. Most (about 70%) of the CYMBALTA dose appears I the urine as metabolites of CYMBALTA; about 20% is excreted in the feces.

  Smoking Status – CYMBALTA bioavailability (AUC) appears to be reduced by about one-third in smokers. Dosage modifications are not recommended for smokers. Back to top of page

  Race – No specific pharmacokinetic study was conducted to investigate the effects of race.

  Renal Insufficiency – Limited data are available on the effects of CYMBALTA in patients with end stage renal disease (ESRD). After a single 60-mg dose of CYMBALTA, Cmax and AUC values were approximately 100% greater inpatients with end stage renal disease receiving chronic intermittent hemodialysis than in subjects with normal renal fuction. The elimination half-life, however, was similar in both groups. The AUC’s of the major circulation metabolites, 4-hydroxy duloxetine glucuronide and 5-hydroxy, 6-methoxy duloxetine sulfate, largely excreted in urine, were approximately 7 – to 9 – fold higher and would be expected to increase further with multiple dosing. For this reason, CYMBALTA is not recommended for patients with ESRD (see DOSAGE AND ADMINISTATION). Studies have not been conducted in patients with a moderate degree of renal dysfunction, but population PK analyses suggest that mild renal dysfunction has no significant effect on CYMBALTA apparent clearance.

Hepatic Insufficiency – Patients with clinically evident hepatic insufficiency have decreased CYMBALTA metabolism and elimination. After a single 20-mg dose of CYMBALTA 6 cirrhotic patients with moderate liver impairment (Child-Pugh Class B) had a mean plasma CYMBALTA clearance about 15% that of age- and gender-matched healthy subjects, with a 5-fold increase in mean exposure (AUC). Although Cmax was similar to normals in the cirrhotic patients, the half-life was about 3 times longer (see PRECAUTIONS). It is recommended that CYMBALTA no be administered to patients with any hepatic insufficiency (see DOSAGE AND ADMINISTRATION).   Back to top of page

Drug-Drug Interactions (also see PRECAUTIONS, Drug Interactions)

Potential for Other Drugs to Affect CYMBALTA.

  Both CYP1A2 and CYP2D6 are responsible for CYMBALTA metabolism.

INDICATIONS AND USAGE

CYMBALTA is indicated for the treatment of major depressive disorder (MDD).

CONTRAINDICATIONS

Hypersensitivity

CYMBALTA is contraindicated in patients with a known hypersensitivity to the product.

WARNINGS Back to top of page

  Clinical Worsening and Suicide Risk – Patients with major depressive disorder, both adult and pediatric, may experience worsening of their depression and/or the emergence of suicidal ideation and behavior (suicidality), whether or not they are taking antidepressant medications, and this risk may persist until significant remission occurs. Although there was been a long-standing concern that antidepressants may have a role in inducing worsening of depression and the emergence of suicidality in certain patients, a causal role for antidepressants in inducing such behaviors has not been established. Nevertheless, patients being treated with antidepressants should be observed closely for clinical worsening and suicidality, especially at the beginning of a course of drug therapy, or at the time of dose changes, either increases of decreases.  Consideration should be given to changing the therapeutic regimen, including possibly discontinuing the medication, in patients whose depression is persistently worse or whose emergent suicidality is severe, abrupt in onset, or was not part of the patient’s presenting symptoms.

  Because of the possibility of co-morbidity between major depressive disorder and other psychiatric and nonpsychiatric disorders, the same precautions observed when treating patients with major depressive disorder should be observed when treating patients with other psychiatric and nonpsychiatric disorders.

  The following symptoms – anxiety, agitation, panic attacks, insomnia, irritability, hostility (aggressiveness), impulsivity, akathisia (psychomotor restlessness), hypomania, and mania – have been reported in adult and pediatric patients being treated with antidepressants for major depressive disorder as well as for other indications, both psychiatric and nonpsychiatric. Although a causal link between the emergence of such symptoms and either the worsening of depression and/or the emergence of suicidal impulses has not been established, consideration should be given to changing the therapeutic regimen, including possibly discontinuing the medications, in patients for whom such symptoms are severe, abrupt in onset, or were not part of the patient’s presenting symptoms.

  Families and caregivers of patients being treated with antidepressants for major depressive disorder or other indications, both psychiatric and nonpsychiatric, should be alerted about the need to monitor patients for the emergence of suicidality, and to report such symptoms immediately to health care providers. Prescriptions for CYMBALTA should be written for the smallest quantity of capsules consistent with good patient management, in order to reduce the risk of overdose.

  If the decision has been made to discontinue treatment, medication should be tapered, as rapidly as is feasible, but with recognition that abrupt discontinuation can be associated with certain symptoms (see PRECAUTIONS and DOSAGE AND ADMINISTRATION, Discontinuing CYMBALTA (duloxetine hydrochloride), for a description  of the risks of discontinuation of CYMBALTA).

Information of Patients Back to top of page

  Physicians are advised to discuss the following issues with patients for whom they prescribe CYMBALTA.

  Patients and their families should be encouraged to be alert to the emergence of anxiety, agitation, panic attacks, insomnia, irritability, hostility, impulsivity, akathisia, hypomania, mania, worsening of depression, and suicidal ideation, especially early during antidepressant treatment. Such symptoms should be reported to the patient’s physician, especially if they are severe, abrupt in onset, or were not part of the patient’s presenting symptoms.

  Any psychoactive drug may impair judgment, thinking, or motor skills.

Drug Interactions (also see CLINICAL PHARMACOLOGY, Drug – Drug

Interactions)

  Inhibitors of CYP2D6 – Because CYP2D6 is involved in CYMBALTA metabolism, concomitant use of CYMBALTA with potent inhibitors of CYP2D6 may result in higher concentrations of CYMBALTA. Paroxetine (20 mg QD) increased the concentration of CYMBALTA (40 mg QD) by about 60%, and greater degrees of inhibition are expected with higher doses of Paroxetine. Similar effect would be expected with other potent CYP2D6 inhibitors (e.g., fluoxetine, quinidine).

 ADVERSE REACTIONS Back to top of page

  CYMBALTA has been evaluated for safety in 2418 patients diagnosed with major depressive disorder who participated in multiple-dose premarketing trials, representing 1099 patient-years of exposure. Among these 2418 CYMBALTA treated patients, 1139 patients participated in eight 8- or 9- week, placebo-controlled trials at doses ranging from 40 to 120 mg/day, while the remaining 1279 patients were followed for up to 1 year in an open-label safety study using flexible doses from 80 to 120 mg/day. Two placebo-controlled studies with doses of 80 to 120 mg/day had 6- month maintenance extensions. Of these 2418 patients, 993 CYMBALTA-treated patients were exposed for at least 180 days and 445 CYMBALTA-treated patients were exposed for at least 1 year. Adverse reactions were assessed by collecting adverse events, results of physical examinations, vital signs, weights, laboratory analyses, and ECGs.

  Clinical investigators recorded adverse events using descriptive terminology of their own choosing. To provide a meaningful estimate of the proportion of individuals experiencing adverse events, grouping similar types of events into a smaller number of standardized event categories is necessary. In the tables and tabulations that follow, MedDRA 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. Events reported during the studies were not necessarily caused by the therapy, and the frequencies do not reflect investigator impression (assessment) of causality.

  The cited figures provide the prescriber 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 prescriber should be aware that the figures in the tables and tabulations 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 that 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.

Adverse Events Reported as Reasons for Discontinuation of Treatment in Placebo-Controlled Trials

  Approximately 10% of the 1139 patients who received CYMBALTA in the placebo-controlled trials discontinued treatment due to an adverse event, compared with 4% of the 777 patients receiving placebo. Nausea (CYMBALTA 1.4%, placebo 0.1%) was the only common adverse event reported as reason for discontinuation and considered to be drug-related (i.e., discontinuation occurring in at least 1% of the CYMBALTA-treated patients and at a rate of at least twice that of placebo).

Adverse Events Occurring at an Incidence of 2% or More Among CYMBALTA-Treated Patients in Placebo-Controlled Trials Back to top of page

  Table 1 gives the incidence of treatment-emergent adverse events that occurred in 2% or more of patients treated with CYMBALTA in the acute phase of MDD placebo-controlled trials and with an incidence greater than placebo. The most commonly observed adverse events in CYMBALTA-treated MDD patients (incidence of 5% or greater and at least twice the incidence in placebo patients) were nausea; dry mouth; constipation; decreased appetite; fatigue; somnolence; and increased sweating.

Effects on Male and Female Sexual Function

  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. 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.

Other Adverse Events Observed During the Premarketing Evaluation of CYMBALTA

  Following is a list of modified MedDRA terms that reflect treatment-emergent adverse events as defined in the introduction to the ADVERSE REACTIONS section reported by patients treated with CYMBALTA at multiple doses throughout the dose range studied during any phase of a trial within the premarketing database. The events included are those not already listed elsewhere in ADVERSE REACTIONS and not considered in the WARNINGS and PRECAUTIONS sections, that were reported with an incidence of greater than or equal to 0.05%, are not common as background events and were considered possibly drug related (e.g., because of the drug’s pharmacology) or potentially important. Back to top of page

  It is important to emphasize that, although the events reported occurred during treatment with CYMBALTA, 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 in at least 1/100 patients (only those not already listed in the tabulated results from placebo-controlled trials appear in this listing); infrequent adverse events are those occurring in 1/100 to 1/1000 patients; rare events are those occurring in fewer than 1/1000 patients.

  Blood and Lymphatic System Disorders – Infrequent: anemia, leukopenia, increased whit blood cell count, lymphadenopathy, and thrombocytopenia.

  Gastrointestinal Disorders – Frequent: gastritis: Infrequent: blood in stool, colitis, dysphagia, esophageal stenosis acquired, gastric ulcer, gingivitis, irritable bowel syndrome, and lower abdominal pain.

  Psychiatric Disorders – Frequent: initial insomnia, irritability, lethargy, nervousness, nightmare, restlessness, and sleep disorder; Infrequent: completed suicide, mania, mood swings, pressure of speech, sluggishness, and suicide attempt.

  Renal and Urinary Disorders – Frequent: dysuria; infrequent: micturition urgency, urinary hesitation, urinary incontinence, urinary retention, and urine flow decreased.

  Skin and Subcutaneous Tissue Disorders – Frequent: night swats, pruritus, and rash; Infrequent: acne, alopecia, cold sweat, ecchymosis, eczema, erythema, face edema, increased tendency to bruise, and photosensitivity reaction.

  Vascular Disorders – Infrequent: peripheral edema and phlebitis.

Discontinuing CYMBALTA (duloxetine hydrochloride) Back to top of page

  Symptoms associated with discontinuation of CYMBALTA and other SSRIs and SNRIs have been reported (see PRECAUTIONS). 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.

Back to top of page

Cymbalta - Side Effects Defined

1. Anorexia – No longer having a desire to eat.
    

2. Apothous Stomatitis – Painful red and swollen open sores on a mucus membrane of the mouth commonly called a canker sore.
    

3. Ataxia – Loss of the ability to move the body with coordination.
    

4. Arterial Fibrillation – A condition of abnormal twitching of the muscles in the blood vessels that moves the oxygenated blood from the heart to the rest of the body.  The unusual twitching is rapid and irregular and replaces the normal rhythm of contraction of the muscle, which sometimes causes a lack of circulation and pulse.
    

5. Blood Cholesterol Increased – An abnormal condition where there is a greater amount in the blood of the oily/fatty substances known as cholesterol.   Cholesterol is a necessary part of living cells (along with proteins and carbohydrates).  Because cholesterol only slightly dissolves in water, it can build up on the walls of the blood vessels, therefore blocking/decreasing the amount of blood flow, which causes blood pressure to go up.  If not corrected, this condition is associated with coronary artery disease.
    

6. Blood Creatinine Increased – A greater than normal number of creatinine or muscular chemical waste molecules in the blood.  Creatinine plays a major role in energy production in muscles.  Since creatinine levels are normally maintained by the kidneys, Blood Creatinine Increased is an indicator of kidney malfunction or failure.
    

7. Blood in Stool – The blood that is in your bowel movement usually comes from any place along your digestive tract (from your mouth to y