PAROXETINE: Package Insert and Label Information (Page 2 of 6)
5.10 Hyponatremia
Hyponatremia may occur as a result of treatment with SNRIs and SSRIs, including paroxetine extended-release tablets. Cases with 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 paroxetine extended-release 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 SNRIs and SSRIs. [see Use in Specific Populations (8.5)].
5.11 Reduction Of Efficacy Of Tamoxifen
Some studies have shown that the efficacy of tamoxifen, as measured by the risk of breast cancer relapse/mortality, may be reduced with concomitant use of paroxetine as a result of paroxetine’s irreversible inhibition of CYP2D6 and lower blood levels of tamoxifen [see Drug Interactions (7.3)]. One study suggests that the risk may increase with longer duration of coadministration.
However, other studies have failed to demonstrate such a risk. When tamoxifen is used for the treatment or prevention of breast cancer, prescribers should consider using an alternative antidepressant with little or no CYP2D6 inhibition.
5.12 Bone Fracture
Epidemiological studies on bone fracture risk during exposure to some antidepressants, including SSRIs, have reported an association between antidepressant treatment and fractures. There are multiple possible causes for this observation and it is unknown to what extent fracture risk is directly attributable to SSRI treatment.
5.13 Risk of Allergic Reactions due to Tartrazine
Paroxetine extended-release tablets, 12.5 mg contain FD&C Yellow No. 5 (tartrazine) which may cause allergic-type reactions (including bronchial asthma) in certain susceptible persons. Although the overall incidence of FD&C Yellow No. 5 (tartrazine) sensitivity in the general population is low, it is frequently seen in patients who also have aspirin hypersensitivity.
6 ADVERSE REACTIONS
The following adverse reactions are included in more detail in other sections of the prescribing information:
- Hypersensitivity reactions to paroxetine [see Contraindications (4)]
- Suicidal Thoughts and Behaviors [see Warnings and Precautions (5.1)]
- Serotonin Syndrome [see Warnings and Precautions (5.2)]
- Embryofetal and Neonatal Toxicity [see Warnings and Precautions (5.4)]
- Increased Risk of Bleeding [see Warnings and Precautions ( 5.5)]
- Activation of Mania/Hypomania [see Warnings and Precautions (5.6)]
- Discontinuation Syndrome [see Warnings and Precautions (5.7)]
- Seizures [see Warnings and Precautions (5.8)]
- Angle-closure Glaucoma [see Warnings and Precautions (5.9)]
- Hyponatremia [see Warnings and Precautions (5.10)]
- Bone Fracture [see Warnings and Precautions (5.12)]
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 trials of another drug and may not reflect the rates observed in practice.
Safety data for paroxetine extended-release tablet is from 11 short-term, placebo-controlled clinical trials including 3 studies in patients with major depressive disorder (MDD) (Studies 1, 2, and 3), 3 studies in patients with panic disorder (PD) (Studies 4, 5, and 6), 1 study in patients with social anxiety disorder (SAD) (Study 7), and 4 studies in female patients with premenstrual dysphoric disorder (PMDD) (Studies 8, 9, 10, and 11) [see Clinical Studies (14)]. These 11 trials included 1627 patients treated with paroxetine extended-release tablets.
- Studies 1 and 2 were 12-week studies that enrolled patients 18 to 65 years old who received paroxetine extended-release tablets at doses ranging from 25 mg to 62.5 mg once daily. Study 3 was a 12-week study in patients 60 to 88 years old who received paroxetine extended-release tablets at doses ranging from 12.5 mg to 50 mg once daily.
- Studies 4, 5, and 6 were 10-week studies in patients 19 to 72 years old who received paroxetine extended-release tablets at doses ranging from 12.5 mg to 75 mg once daily.
- Study 7 was a 12-week study that enrolled adult patients who received paroxetine extended-release tablets at doses ranging from 12.5 mg to 37.5 mg once daily.
- Studies 8, 9, and 10 were 12-week, placebo-controlled trials in female patients 18 to 46 years old who received paroxetine extended-release tablets at doses of 12.5 mg or 25 mg once daily. Study 11 was a 12-week placebo-controlled trial in patients 18 to 46 years old who received paroxetine extended-release tablets 2 weeks prior to the onset of menses (luteal phase dosing) at doses of 12.5 mg or 25 mg once daily.
Adverse Reactions Leading to Discontinuation in Patients with MDD, PD, SAD, and PMDD
In pooled studies in patients with MDD, PD and SAD, the most common adverse reactions leading to study withdrawal were: nausea (up to 4% of patients), asthenia, headache, depression, insomnia, and abnormal liver function tests (each occurring in up to 2% of patients), and dizziness, somnolence, and diarrhea (each occurring in up to 1% of patients).
In pooled studies for PMDD, the most common adverse reactions leading to study withdrawal were: nausea (occurring in up to 6% of patients), asthenia (occurring in up to 5% of patients), somnolence (occurring in up to 4% of patients), insomnia (occurring in approximately 2% of patients); and impaired concentration, dry mouth, dizziness, decreased appetite, sweating, tremor, yawn and diarrhea (occurring in less than or equal to 2% of patients).
Adverse Reactions in MDD, PD, and SAD
Table 3 presents the most common adverse reactions in paroxetine extended-release tablets -treated patients (incidence ≥5% and greater than placebo within at least 1 of the indications) in controlled trials in patients with MDD, PD, and SAD.
| MDD 18 to 65 year olds | MDD ≥60 years old | Panic Disorder | Social Anxiety Disorder | |||||
| Body System/ Adverse Reaction | Paroxetine extended-release tablets (N=212) % | Placebo (N=211) % | Paroxetine extended-release tablets (N=104) % | Placebo (N=109 % | Paroxetine extended-release tablets (N=444) % | Placebo (N=445) % | Paroxetine extended-release tablets (N=186) % | Placebo (N=184) % |
| Body as a Whole | ||||||||
| Headache | 27 | 20 | 17 | 13 | NA | NA | 23 | 17 |
| Asthenia | 14 | 9 | 15 | 14 | 15 | 10 | 18 | 7 |
| Abdominal Pain | 7 | 4 | – | – | 6 | 4 | 5 | 4 |
| Back Pain | 5 | 3 | – | – | NA | NA | 4 | 1 |
| Digestive System | ||||||||
| Nausea | 22 | 10 | – | – | 23 | 17 | 22 | 6 |
| Diarrhea | 18 | 7 | 15 | 9 | 12 | 9 | 9 | 8 |
| Dry Mouth | 15 | 8 | 18 | 7 | 13 | 9 | 3 | 2 |
| Constipation | 10 | 4 | 13 | 5 | 9 | 6 | 5 | 2 |
| Flatulence | 6 | 4 | – | – | NA | NA | NA | NA |
| Decreased Appetite | 2 | 12 | 5 | 8 | 6 | 1 | <1 | |
| Dyspepsia | NA | NA | 13 | 10 | NA | NA | 2 | <1 |
| Musculoskel etal System | ||||||||
| Myalgia | NA | NA | – | – | 5 | 3 | NA | NA |
| Nervous System | ||||||||
| Somnolence | 22 | 8 | 21 | 12 | 20 | 9 | 9 | 4 |
| Insomnia | 17 | 9 | 10 | 8 | 20 | 11 | 9 | 4 |
| Dizziness | 14 | 4 | 9 | 5 | NA | NA | 7 | 4 |
| Libido Decreased | 7 | 3 | 8 | <1 | 9 | 4 | 1 | |
| Nervousness | NA | NA | – | – | 8 | 7 | NA | NA |
| Tremor | 7 | 1 | 7 | 0 | 8 | 2 | 4 | 2 |
| Anxiety | NA | NA | – | – | 5 | 4 | 2 | 1 |
| Respiratory System | ||||||||
| Sinusitis | NA | NA | – | – | 8 | 5 | NA | NA |
| Yawn | 0 | – | – | 3 | 0 | 2 | 0 | |
| Skin and Appendages | ||||||||
| Sweating | 6 | 2 | 10 | <1 | 7 | 2 | 14 | 3 |
| Special Senses | ||||||||
| Abnormal Visiona | 5 | 1 | – | – | 3 | <1 | 2 | 0 |
| Urogenital System | ||||||||
| Abnormal Ejaculationb,c | 26 | 1 | 17 | 3 | 27 | 3 | 15 | 1 |
| Female Genital Disorderb,d | 10 | <1 | – | – | 7 | 1 | 3 | 0 |
| Impotenceb | 5 | 3 | 9 | 3 | 10 | 1 | 9 | 0 |
Hyphen = the reaction listed occurred in <5% of patients treated with paroxetine extended-release tablets NA = the adverse reaction listed did not occur in this group of patients
a Mostly blurred vision
b Based on the number of males or females
c Mostly anorgasmia or delayed ejaculation
d Mostly anorgasmia or delayed orgasm
Other Adverse Reactions Observed During the Premarketing Evaluation of Paroxetine Extended-Release Tablets
Adverse reactions from studies in MDD (not including Study 3 in elderly patients), PD, and SAD that occurred between 1% and 5% of patients treated with paroxetine extended-release tablets and at a rate greater than in placebo-treated patients include:, allergic reaction, tachycardia, vasodilatation, hypertension, migraine, vomiting, weight loss, weight gain, hypertonia, paresthesia, agitation, confusion, myoclonus, concentration impaired, depression, rhinitis, cough increased, bronchitis, photosensitivity, eczema, taste perversion, UTI, menstrual disorder, urinary frequency, urination impaired, and vaginitis.
Adverse Reactions in Patients with PMDD
Table 4 displays adverse reactions that occurred (incidence of 5% or more and greater than placebo within at least 1 of the studies) in patients treated with paroxetine extended-release tablets in Studies 8, 9, 10, and 11.
| Body System/Adverse Reaction | % Reporting Adverse Reaction | |||
| Continuous Dosing Studies 8, 9, and 10 | Luteal Phase Dosing Study 11 | |||
| Paroxetine extended-release tablets (n = 681) % | Placebo (n = 349) % | Paroxetine extended-release tablets (n = 246) % | Placebo (n = 120) % | |
| Body as a Whole Asthenia Headache Infection | 17 15 6 | 6 12 4 | 15 NA NA | 4 NA NA |
| Digestive System Nausea Diarrhea Constipation | 17 6 5 | 7 2 1 | 18 6 2 | 2 0 <1 |
| Nervous System Libido Decreased Somnolence Insomnia Dizziness Tremor | 12 9 8 7 4 | 5 2 2 3 <1 | 9 3 7 6 5 | 6 <1 3 3 0 |
| Skin and Appendages Sweating | 7 | <1 | 6 | <1 |
| Urogenital System Female Genital Disordersc | 8 | 1 | 2 | 0 |
NA= the adverse reaction information is not available in this population.
a <1% means greater than zero and less than 1%.
b The luteal phase and continuous dosing PMDD trials were not designed for making direct comparisons between the 2 dosing regimens.
c Mostly anorgasmia or difficulty achieving orgasm.
Dose Dependent Adverse Reactions
Comparison of the incidence of adverse reactions (placebo vs. 12.5 mg paroxetine extended-release tablets vs. 25 mg paroxetine extended-release tablets) from studies 8, 9, 10 showed the following adverse reactions to be dose-related: Nausea, somnolence, sweating, dry mouth, dizziness, decreased appetite, tremor, impaired concentration, yawn, paresthesia, hyperkinesia, and vaginitis.
Male and Female Sexual Dysfunction
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.
The percentage of patients reporting symptoms of sexual dysfunction in the Studies 1 and 2 (nonelderly patients with MDD), 4, 5, 6, 7, 8, 9, 10, and 11 are presented in Table 5:
| Studies 1 and 2 % | Studies 4, 5, and 6 % | Study 7 % | Studies 8, 9, and 11 (Continuous Dosing) % | Study 10 (Luteal Phase Dosing) % | ||||||
| Paroxetine Extended-Release Tablets | Placebo | Paroxetine Extended-Release Tablets | Placebo | Paroxetine Extended-Release Tablets | Placebo | Paroxetine Extended-Release Tablets | Placebo | Paroxetine Extended-Release Tablets | Placebo | |
| n (males) | 78 | 78 | 162 | 194 | 88 | 97 | NA | NA | NA | NA |
| Decreased Libido | 10 | 5 | 9 | 6 | 13 | 1 | NA | NA | NA | NA |
| Abnormal ejaculation | 26 | 1 | 27 | 3 | 15 | 1 | NA | NA | NA | NA |
| Impotence | 5 | 3 | 10 | 1% | 9 | 0 | NA | NA | NA | NA |
| n (females) | 134 | 133 | 282 | 251 | 98 | 87 | 681 | 349 | 246 | 120 |
| Decreased Libido | 4 | 2 | 8 | 2 | 4 | 1 | 12 | 5 | 9 | 6 |
| Orgasmic Disturbance | 10 | <1 | 7 | 1 | 3 | 0 | 8 | 1 | 2 | 0 |
NA = the adverse reaction listed did not occur in this group of patients.
Paroxetine treatment has been associated with several cases of priapism. In those cases with a known outcome, patients recovered without sequelae.
Less Common Adverse Reactions
The following adverse reactions occurred during the clinical studies of paroxetine extended-release tablets and are not included elsewhere in the labeling.
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 1 or more occasions in at least 1/100 patients; infrequent adverse reactions are those occurring in 1/100 to 1/1,000 patients; rare reactions are those occurring in fewer than 1/1,000 patients.
Cardiovascular System: Infrequent was postural hypotension.
Hemic and Lymphatic System: Rare was thrombocytopenia.
Metabolic and Nutritional Disorders: Infrequent were generalized edema and hypercholesteremia.
Nervous System: Infrequent were convulsion, akathisia, and manic reaction.
Psychiatric: Infrequent were hallucinations.
Skin and Appendages: Frequent was rash; infrequent was urticaria; rare was angioedema and erythema multiforme.
Urogenital System: Infrequent was urinary retention; rare was urinary incontinence.
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