Thefollowingadversereactionsarediscussedingreaterdetailinothersectionsofthelabeling:
6.1 ClinicalTrialsExperience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trialsof a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observedinclinicalpractice.
The safety for citalopram included citalopram exposures in patients and/or healthy subjects from 3 different groups ofstudies: 429 healthy subjects in clinical pharmacology/ pharmaco*kinetic studies; 4,422 exposures from patients incontrolled and uncontrolled clinical trials, corresponding to approximately 1,370 patient-exposure years. There were, inaddition, 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,inpatientandoutpatientstudies,fixed-dose anddose-titration studies,and short-termand long-termexposure.
AdverseReactionsAssociatedwithDiscontinuationofTreatment
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% of446 patients receiving placebo. The adverse reactions associated with discontinuation (i.e., associated with discontinuationinat least1% ofcitalopram-treatedpatients ata rateat leasttwicethatofplacebo)areshown inTable 2.
Table 2:Adverse Reactions Associated with Discontinuation of Citalopram Treatment inShort-Term,Placebo-ControlledMDDTrials
| BodySystem/AdverseReaction | Citalopram | Placebo |
| (N=1,063)% | (N=446)% | |
| General | ||
| Asthenia | 1 | <1 |
| GastrointestinalDisorders | ||
| Nausea | 4 | 0 |
| DryMouth | 1 | <1 |
| Vomiting | 1 | 0 |
| CentralandPeripheralNervous SystemDisorders | ||
| Dizziness | 2 | <1 |
| PsychiatricDisorders | ||
| Insomnia | 3 | 1 |
| Somnolence | 2 | 1 |
| Agitation | 1 | <1 |
*Apatient canreportmorethanonereason for discontinuationandbe countedmorethanonceinthistable.
Table 3 enumerates the incidence of adverse reactions that occurred among 1,063 patients with MDD who received citalopramatdosesrangingfrom10mgto 80mgoncedailyinplacebo-controlledtrialsofup to6 weeks duration.
The most common adverse reaction that occurred in citalopram-treated patients with an incidence of 5% or greater and atleast twice the incidence in placebo patients was ejacul*tion disorder (primarily ejacul*tory delay) in male patients (seeTable 3).
Table3:AdverseReactions(≥2%andGreaterthanPlacebo)AmongCitalopram-TreatedPatients*
| BodySystem/AdverseReaction | Citalopram | Placebo |
| (N=1,063)% | (N=446)% | |
| GastrointestinalDisorders | ||
| Nausea | 21 | 14 |
| Diarrhea | 8 | 5 |
| Dyspepsia | 5 | 4 |
| Vomiting | 4 | 3 |
| AbdominalPain | 3 | 2 |
| AutonomicNervous SystemDisorders | ||
| DryMouth | 20 | 14 |
| SweatingIncreased | 11 | 9 |
| PsychiatricDisorders | ||
| Somnolence | 18 | 10 |
| Insomnia | 15 | 14 |
| Anxiety | 4 | 3 |
| Anorexia | 4 | 2 |
| Agitation | 3 | 1 |
| Dysmenorrhea1 | 3 | 2 |
| LibidoDecreased | 2 | <1 |
| Yawning | 2 | <1 |
| Central&PeripheralNervousSystem Disorders | ||
| Tremor | 8 | 6 |
| Urogenital | ||
| ejacul*tionDisorder2,3 | 6 | 1 |
| Impotence3 | 3 | <1 |
| RespiratorySystem Disorders | ||
| UpperRespiratoryTractInfection | 5 | 4 |
| Rhinitis | 5 | 3 |
| Sinusitis | 3 | <1 |
| General | ||
| Fatigue | 5 | 3 |
| Fever | 2 | <1 |
| MusculoskeletalSystem Disorders | ||
| Arthralgia | 2 | 1 |
| Myalgia | 2 | 1 |
*Adverse reactions reported by at least 2% of patients treated with citalopram are reported, except for the followingadverse reactions which had an incidence on placebo ≥ citalopram: headache, asthenia, dizziness, constipation, palpitation,vision abnormal, sleep disorder, nervousness,pharyngitis, micturition disorder, backpain.
1Denominatorusedwasforfemalesonly(N=638citalopram;N=252placebo).
2Primarilyejacul*torydelay.
3Denominatorusedwasformalesonly(N=425citalopram;N=194placebo).
DoseDependentAdverseReactions
The potential relationship between the dosage of citalopram and the incidence of adverse reactions was examined in afixed-dose study in patients with MDD receiving placebo or citalopram 10 mg, 20 mg, 40 mg, or 60 mg (1.5 times themaximum recommended dosage). A positive dose response (p<0.05) was revealed for the following adverse reactions:fatigue,impotence,insomnia, increasedsweating,somnolence, and yawning.
MaleandFemaleSexualDysfunctionwithSSRIs
Although changes in sexual desire, sexual performance, and sexual satisfaction often occur as manifestations of apsychiatric disorder, they may also be a consequence of SSRI treatment. However, reliable estimates of the incidence andseverity of untoward experiences involving sexual desire, performance, and satisfaction are difficult to obtain, in partbecause patients and healthcare providers may be reluctant to discuss them. Accordingly, estimates of the incidence ofuntowardsexualexperienceand performancecited inlabelingmayunderestimatetheiractualincidence.
Table 4 displays the incidence of sexual adverse reactions reported by at least 2% of male patients taking citalopram in apool ofplacebo-controlledclinicaltrialsin patientswith depression.
Table 4: Adverse Reactions (≥2%) Related to Sexual Dysfunction in Citalopram-TreatedMalePatients inPooledPlacebo-ControlledClinicalTrialsofMDD
| Citalopram | Placebo | |
| n(males) | 425(%) | 194(%) |
| Abnormal ejacul*tion(mostly ejacul*torydelay) | 6.1 | 1 |
| Decreasedlibido | 3.8 | <1 |
| Impotence | 2.8 | <1 |
Infemaledepressedpatientsreceivingcitalopram,thereportedincidenceofdecreasedlibidoandan org*smiawas1.3%(n=638females)and 1.1%(n=252females),respectively.
WeightChanges
Patients treated with citalopram in controlled trials experienced a weight loss of about 0.5 kg compared to no change forplacebopatients.
ECGChanges
InathoroughQTstudy,citalopramwasfoundtobeassociatedwitha dose-dependentincreasein theQTcinterval.
Electrocardiograms from citalopram (N=802) and placebo (N=241) groups were compared with respect to outliers definedas subjects with QTc changes over 60 msec from baseline or absolute values over 500 msec post-dose, and subjects withheart rate increases to over 100 bpm or decreases to less than 50 bpm with a 25% change from baseline (tachycardic orbradycardic outliers, respectively). In the citalopram group 1.9% of the patients had a change from baseline in QTcF >60msec compared to 1.2% of the patients in the placebo group. None of the patients in the placebo group had a post-doseQTcF >500 msec compared to 0.5% of the patients in the citalopram group. The incidence of tachycardic outliers was0.5% in the citalopram group and 0.4% in the placebo group. The incidence of bradycardic outliers was 0.9% in thecitalopramgroup and0.4%in the placebogroup.
OtherAdverseReactionsObservedDuringthePremarketingEvaluationofCitalopram
Thefollowinglist of adversereactionsdoesnotincludereactionsthat are: 1)includedinTable3or elsewhereinlabeling, 2) for which a drug cause was remote, 3) which were so general as to be uninformative, and those occurring in only onepatient.
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; infrequentadverse reactions are those occurring in less than 1/100 patients to 1/1000 patients; rare adverse reactions are thoseoccurringin fewerthan 1/1000 patients.
Cardiovascular - Frequent: tachycardia, postural hypotension, hypotension. Infrequent: hypertension, bradycardia, edema(extremities), angina pectoris, extrasystoles, cardiac failure, flushing, myocardial infarction, cerebrovascular accident,myocardialischemia.Rare:transientischemicattack,phlebitis,atrialfibrillation,cardiacarrest,bundlebranchblock.
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: abnormalcoordination,hyperesthesia,ptosis,stupor.
EndocrineDisorders-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,duodenalulcer,gastroesophagealreflux,glossitis,jaundice,diverticulitis,rectalhemorrhage,hiccups.
General-Infrequent:hotflushes,rigors,alcoholintolerance,syncope,influenza-likesymptoms.Rare:hayfever.
Hemic and Lymphatic Disorders - Infrequent: purpura, anemia, epistaxis, leukocytosis, leucopenia, lymphadenopathy.Rare: pulmonary embolism, granulocytopenia, lymphocytosis, lymphopenia, hypochromic anemia, coagulation disorder,gingival bleeding.
Metabolic and Nutritional Disorders - Frequent: decreased weight, increased weight. Infrequent: increased hepaticenzymes, thirst, dry eyes, increased alkaline phosphatase, abnormal glucose tolerance. Rare: bilirubinemia, hypokalemia,obesity,hypoglycemia, hepatitis, dehydration.
MusculoskeletalSystemDisorders-Infrequent:arthritis,muscleweakness,skeletalpain.Rare:bursitis,osteoporosis.
Psychiatric Disorders - Frequent: impaired concentration, amnesia, apathy, depression, increased appetite, aggravateddepression, 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,vagin*l hemorrhage. (*%based on femalesubjects only:2,955)
Respiratory System Disorders - Frequent: coughing. Infrequent: bronchitis, dyspnea, pneumonia. Rare: asthma,laryngitis,bronchospasm,pneumonitis, sputumincreased.
Skin and Appendages Disorders - Frequent: rash, pruritus. Infrequent: photosensitivity reaction, urticaria, acne, skindiscoloration, eczema, alopecia, dermatitis, skin dry, psoriasis. Rare: hypertrichosis, decreased sweating, melanosis,keratitis,cellulitis, pruritusani.
SpecialSenses-Frequent:abnormalaccommodation,tasteperversion.Infrequent:tinnitus,conjunctivitis,eyepain.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,renalcalculus, renal pain.
6.2 PostmarketingExperience
The following adverse reactions have been identified during postapproval use of citalopram, the racemate, orescitalopram,theS-enantiomerofcitalopram.Becausethesereactionsarereportedvoluntarilyfrom apopulationofuncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drugexposure.
BloodandLymphaticSystemDisorders:hemolyticanemia,thrombocytopenia,prothrombindecreased
CardiacDisorders:torsadedepointes,ventriculararrhythmia,QTprolonged
EndocrineDisorders:hyperprolactinemia
EyeDisorders:angle-closureglaucoma
GastrointestinalDisorders:gastrointestinalhemorrhage,pancreatitis
General Disorders and Administrative Site Conditions: withdrawal syndrome
HepatobiliaryDisorders:hepatic necrosis
ImmuneSystemDisorders:anaphylaxis,allergicreaction
MusculoskeletalandConnectiveTissueDisorders:rhabdomyolysis
NervousSystemDisorders:grandmalconvulsion(s),myoclonus,choreoathetosis,dyskinesia,akathisia,nystagmus
Pregnancy,PuerperiumandPerinatalConditions:spontaneousabortion
PsychiatricDisorders:delirium
RenalandUrinaryDisorders:acuterenal failure
ReproductiveSystemandBreast Disorders: priapism
SkinandSubcutaneousTissueDisorders:StevensJohnsonSyndrome,epidermalnecrolysis,angioedema,erythemamultiforme,ecchymosis
VascularDisorders:thrombosis
