Paroxetine Hydrochloride (Page 3 of 9)

5.7 Discontinuation Syndrome

Adverse reactions after discontinuation of serotonergic antidepressants, particularly after abrupt discontinuation, include: nausea, sweating, dysphoric mood, irritability, agitation, dizziness, sensory disturbances (e.g., paresthesia, such as electric shock sensations), tremor, anxiety, confusion, headache, lethargy, emotional lability, insomnia, hypomania, tinnitus, and seizures. A gradual reduction in dosage rather than abrupt cessation is recommended whenever possible [see Dosage and Administration (2.7)].

Adverse reactions have been reported upon discontinuation of treatment with paroxetine in pediatric patients. The safety and effectiveness of Paroxetine in pediatric patients have not been established [see Boxed Warning, Warnings and Precautions (5.1), Use in Specific Populations (8.4)].

5.8 Seizures

Paroxetine has not been systematically evaluated in patients with seizure disorders. Patients with history of seizures were excluded from clinical studies. Paroxetine should be prescribed with caution in patients with a seizure disorder and should be discontinued in any patient who develops seizures.

5.9 Angle-Closure Glaucoma

The pupillary dilation that occurs following use of many antidepressant drugs including Paroxetine may trigger an angle closure attack in a patient with anatomically narrow angles who does not have a patent iridectomy. Cases of angle-closure glaucoma associated with use of paroxetine hydrochloride tablets have been reported. Avoid use of antidepressants, including Paroxetine, in patients with untreated anatomically narrow angles.

5.10 Hyponatremia

Hyponatremia may occur as a result of treatment with SNRIs and SSRIs, including Paroxetine. 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 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 ( 7.1)]. 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 Sexual Dysfunction

​ Use of SSRIs, including Paroxetine, 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 Paroxetine 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 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)]

• Sexual Dysfunction [see Warnings and Precautions (5.13)]

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 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.

• Studies 1 and 2 were 12-week studies that enrolled patients 18 to 65 years old who received Paroxetine 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 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 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 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 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 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-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.

Table 3. Adverse Reactions (≥5% of Patients Treated with Paroxetine and Greater than Placebo) in 10 to 12 Week Studies of MDD, PD, and SAD

	MDD 18 to 65 year olds	MDD ≥60 years old		Panic Disorder	Social Anxiety Disorder
Body System/ Adverse Reaction	Paroxetine (N=212) %	Placebo (N=211) %	Paroxetine (N=104) %	Placebo (N=109) %		Paroxetine (N=444) %	Placebo (N=445) %	Paroxetine (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
Musculoskeletal 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

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

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 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 in Studies 8, 9, 10, and 11.

Table 4. Adverse Reactions ( ≥5% of Patients Treated with Paroxetine and Greater than Placebo) in Pooled Studies PMDD (Studies 8, 9, 11), and in Study 10^a,b,c

Body System/ Adverse Reaction	% Reporting Adverse Reaction
	Continuous Dosing Studies 8 ,9, and 10		Luteal Phase Dosing Study 11
	Paroxetine (n=681) %	Placebo (n=349) %	Paroxetine (n=246) %	Placebo (n=120) %
Body as a Whole
Asthenia	17	6	15	4
Headache	15	12	NA	NA
Infection	6	4	NA	NA
Digestive System
Nausea	17	7	18	2
Diarrhea	6	2	6	0
Constipation	5	1	2	<1
Nervous System
Libido Decreased	12	5	9	6
Somnolence	9	2	3	<1
Insomnia	8	2	7	3
Dizziness	7	3	6	3
Tremor	4	<1	5	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 vs. 25 mg Paroxetine) 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:

Table 5. Adverse Reactions Related To Sexual Dysfunction In Patients Treated With Paroxetine in Pooled 10-12 Week Studies of MDD, PD, SAD, and PMDD

	Studies 1 and 2 %	Studies 4, 5, and 6 %		Study 7 %		Studies 8, 9, and 11 (Continuous Dosing) %		Study 10 (Luteal Phase Dosing) %
	Paroxetine	Placebo	Paroxetine	Placebo	Paroxetine	Placebo	Paroxetine	Placebo	Paroxetine	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 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.