Citalopram Hydrobromide: Package Insert and Label Information (Page 2 of 5)

5.8 Angle-closure Glaucoma

The pupillary dilation that occurs following use of many antidepressant drugs, including citalopram tablets, may trigger an angle closure attack in a patient with anatomically narrow angles who does not have a patent iridectomy. Avoid use of antidepressants, including citalopram tablets, in patients with untreated anatomically narrow angles.

5.9 Hyponatremia

Hyponatremia may occur as a result of treatment with SSRIs, including citalopram tablets. Cases of serum sodium lower than 110 mmol/L have been reported. Signs and symptoms of hyponatremia include headache, difficulty concentrating, memory impairment, confusion, weakness, and unsteadiness, which may lead to falls. Signs and symptoms associated with more severe and/or acute cases have included hallucination, syncope, seizure, coma, respiratory arrest, and death. In many cases, this hyponatremia appears to be the result of the syndrome of inappropriate antidiuretic hormone secretion (SIADH).

In patients with symptomatic hyponatremia, discontinue citalopram tablets and institute appropriate medical intervention. Elderly patients, patients taking diuretics, and those who are volume-depleted may be at greater risk of developing hyponatremia with SSRIs [see Use in Specific Populations ( 8.5)] .

5.10 Sexual Dysfunction

Use of SSRIs, including citalopram tablets, may cause symptoms of sexual dysfunction [see Adverse Reactions ( 6.1)] . In male patients, SSRI use may result in ejaculatory delay or failure, decreased libido, and erectile dysfunction. In female patients, SSRI use may result in decreased libido and delayed or absent orgasm.
It is important for prescribers to inquire about sexual function prior to initiation of citalopram tablets and to inquire specifically about changes in sexual function during treatment, because sexual function may not be spontaneously reported. When evaluating changes in sexual function, obtaining a detailed history (including timing of symptom onset) is important because sexual symptoms may have other causes, including the underlying psychiatric disorder. Discuss potential management strategies to support patients in making informed decisions about treatment.

6 ADVERSE REACTIONS

The following adverse reactions are discussed in greater detail in other sections of the labeling:
• Hypersensitivity reactions [see Contraindications ( 4)]
• Suicidal thoughts and behaviors in adolescents and young adults [see Warnings and Precautions ( 5.1)]
• QT-prolongation and torsade de pointes [see Warnings and Precautions ( 5.2)]
• Serotonin syndrome [see Warnings and Precautions ( 5.3)]
• Increased risk of bleeding [see Warnings and Precautions ( 5.4)]
• Activation of mania or hypomania [see Warnings and Precautions ( 5.5)]
• Discontinuation syndrome [see Warnings and Precautions ( 5.6)]
• Seizures [see Warnings and Precautions ( 5.7)]
• Angle-closure glaucoma [see Warnings and Precautions ( 5.8)]
• Hyponatremia [see Warnings and Precautions ( 5.9)] • Sexual Dysfunction [see Warnings and Precautions ( 5.10)]

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 tablets 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 tablets 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 tablets 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

Body System/Adverse Reaction

Citalopram

Placebo

(N=1,063)

%

(N=446)

%

General

Asthenia

1

<1

Gastrointestinal Disorders

Nausea

4

0

Dry Mouth

1

<1

Vomiting

1

0

Central and Peripheral Nervous System Disorders

Dizziness

2

<1

Psychiatric Disorders

Insomnia

3

1

Somnolence

2

1

Agitation

1

<1

* A patient can report more than one reason for discontinuation and be counted more than once in this table.

Table 3 enumerates the incidence of adverse reactions that occurred among 1,063 patients with MDD who received citalopram tablets at doses ranging from 10 mg to 80 mg once daily in placebo-controlled trials of up to 6 weeks duration.

The most common adverse reaction that occurred in citalopram-treated patients with an incidence of 5% or greater and at least twice the incidence in placebo patients was ejaculation disorder (primarily ejaculatory delay) in male patients (see Table 3).

Table 3: Adverse Reactions (≥2% and Greater than Placebo) Among Citalopram-Treated Patients*

Body System/Adverse Reaction

Citalopram

Placebo

(N=1,063)

%

(N=446)

%

Gastrointestinal Disorders

Nausea

21

14

Diarrhea

8

5

Dyspepsia

5

4

Vomiting

4

3

Abdominal Pain

3

2

Autonomic Nervous System Disorders

Dry Mouth

20

14

Sweating Increased

11

9

Psychiatric Disorders

Somnolence

18

10

Insomnia

15

14

Anxiety

4

3

Anorexia

4

2

Agitation

3

1

Dysmenorrhea 1

3

2

Libido Decreased

2

<1

Yawning

2

<1

Central & Peripheral Nervous System Disorders

Tremor

8

6

Urogenital

Ejaculation Disorder 2,3

6

1

Impotence 3

3

<1

Respiratory System Disorders

Upper Respiratory Tract Infection

5

4

Rhinitis

5

3

Sinusitis

3

<1

General

Fatigue

5

3

Fever

2

<1

Musculoskeletal System Disorders

Arthralgia

2

1

Myalgia

2

1

* Adverse reactions reported by at least 2% of patients treated with citalopram are reported, except for the following adverse reactions which had an incidence on placebo ≥ citalopram: headache, asthenia, dizziness, constipation, palpitation, vision abnormal, sleep disorder, nervousness, pharyngitis, micturition disorder, back pain.

1 Denominator used was for females only (N=638 citalopram; N=252 placebo).

2 Primarily ejaculatory delay.

3 Denominator used was for males only (N=425 citalopram; N=194 placebo).

Dose Dependent Adverse Reactions

The potential relationship between the dosage of citalopram and the incidence of adverse reactions was examined in a fixed-dose study in patients with MDD receiving placebo or citalopram tablets 10 mg, 20 mg 40 mg, or 60 mg (1.5 times the maximum recommended dosage). A positive dose response (p<0.05) was revealed for the following adverse reactions: fatigue, impotence, insomnia, increased sweating, somnolence, and yawning.

Male and Female Sexual Dysfunction with SSRIs

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 SSRI treatment. However, reliable estimates of the incidence and severity of untoward experiences involving sexual desire, performance, and satisfaction are difficult to obtain, in part because patients and healthcare providers may be reluctant to discuss them. Accordingly, estimates of the incidence of untoward sexual experience and performance cited in labeling may underestimate their actual incidence.

Table 4 displays the incidence of sexual adverse reactions reported by at least 2% of male patients taking citalopram tablets in a pool of placebo-controlled clinical trials in patients with depression.

Table 4: Adverse Reactions (≥2%) Related to Sexual Dysfunction in citalopram-Treated Male Patients in Pooled Placebo-Controlled Clinical Trials of MDD

Citalopram

Placebo

n (males)

425 (%)

194 (%)

Abnormal ejaculation (mostly ejaculatory delay)

6.1

1

Decreased libido

3.8

<1

Impotence

2.8

<1

In female depressed patients receiving citalopram tablets, the reported incidence of decreased libido and anorgasmia was 1.3% (n=638 females) and 1.1% (n=252 females), respectively.

Weight Changes

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

ECG Changes

In a thorough QT study, citalopram tablets were found to be associated with a dose-dependent increase in the QTc interval.

Electrocardiograms from citalopram (N=802) and placebo (N=241) groups were compared with respect to outliers defined as subjects with QTc changes over 60 msec from baseline or absolute values over 500 msec post-dose, and subjects with heart rate increases to over 100 bpm or decreases to less than 50 bpm with a 25% change from baseline (tachycardic or bradycardic outliers, respectively). In the citalopram group 1.9% of the patients had a change from baseline in QTcF >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 Tablets

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 1/1,000 patients; rare adverse reactions are those occurring in fewer than 1/1,000 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.

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