PAROXETINE (Page 4 of 8)

7.3 Other Potentially Significant Drug Interactions

Monoamine Oxidase Inhibitors (MAOIs)

Serious adverse reactions such as serotonin syndrome have been reported in patients receiving a concomitant SSRI and MAOI, in patients started on an SSRI who recently received an MAOI and in patients started on an MAOI who recently received an SSRI. Therefore, concomitant use of MAOIs with Paroxetine Capsules or use of Paroxetine Capsules and an MAOI within 14 days of each other is contraindicated [see Dosage and Administration ( 2.2), Contraindications ( 4.1) and Warnings and Precautions ( 5.2)].

Serotonergic Drugs

If concomitant use of Paroxetine Capsules with other serotonergic drugs (e.g., triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone, amphetamines, and St. John’s Wort) is clinically warranted, consider the increased risk of serotonin syndrome and carefully observe the patient, particularly during treatment initiation [see Warnings and Precautions ( 5.2)].

An interaction between paroxetine and tryptophan may occur when they are co-administered. Adverse experiences, consisting primarily of headache, nausea, sweating, and dizziness, have been reported when tryptophan was administered to patients taking paroxetine. Consequently, concomitant use of Paroxetine Capsules with tryptophan is not recommended.

If concomitant use of Paroxetine Capsules with a serotonergic drug is warranted, carefully observe the patient, particularly during treatment initiation. There have been postmarketing reports of serotonin syndrome with the use of an SSRI and a triptan.

Paroxetine Capsules contain paroxetine, which is also the active ingredient in other drugs. The concomitant use of Paroxetine Capsules with other paroxetine products is not recommended [see Indications and Usage ( 1)].

Drugs that Interfere with Hemostasis (e.g., NSAIDs, Aspirin, and Warfarin)

Altered anticoagulant effects, including increased bleeding, have been reported when SSRIs are co-administered with NSAIDs, aspirin, and warfarin or other drugs that affect coagulation. There may be a pharmacodynamic interaction between paroxetine and warfarin that causes an increased bleeding diathesis despite unaltered prothrombin time. Carefully monitor patients receiving warfarin therapy when Paroxetine Capsules are initiated or discontinued [see Warnings and Precautions ( 5.4)].

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Pregnancy Category X

Risk Summary

Paroxetine Capsules are contraindicated in pregnant women because menopausal VMS does not occur during pregnancy and paroxetine can cause fetal harm. Epidemiological studies have shown that infants exposed to paroxetine in the first trimester of pregnancy may have an increased risk of cardiovascular malformations. Cardiac malformations are a common congenital abnormality. These data would suggest that the risk of a cardiac abnormality following paroxetine exposure in the first trimester may increase the risk from 1% to 2%. Exposure to SSRIs in late pregnancy may lead to an increased risk for neonatal complications requiring prolonged hospitalization, respiratory support, and tube feeding, and/or persistent pulmonary hypertension of the newborn (PPHN). No teratogenicity was seen in reproductive development studies conducted in rats and rabbits. However, an increase in rat pup deaths was seen during the first 4 days of lactation when dosing occurred during the last trimester of gestation and continued throughout lactation, at a dose approximately equal to the maximum recommended human dose (MRHD) for VMS (7.5 mg) on an mg/m2 basis. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus.

Human Data

First-Trimester Pregnancy Exposure

Epidemiologic studies which include data from the Swedish National Registry, a retrospective cohort study using United Healthcare data and a meta-analysis of studies (1992-2008) have shown a less than 2-fold increased risk of cardiac malformations, primarily ventricular septal and atrial septal defects, with first-trimester paroxetine exposure. Two case-control studies using separate databases with > 9000 birth defect cases and > 4000 controls showed 7 and 6 paroxetine-exposed infants respectively, with right ventricular outflow tract obstructions, a 2-to 3-fold increased risk. An increase in overall congenital malformations with first-trimester paroxetine use was not observed in all studies.

Third-Trimester Pregnancy Exposure

Neonates exposed to SSRIs late in the third trimester have developed complications requiring prolonged hospitalization, respiratory support, and tube feeding. Such complications can arise immediately upon delivery. Reported clinical findings have included respiratory distress, cyanosis, apnea, seizures, temperature instability, feeding difficulty, vomiting, hypoglycemia, hypotonia, hypertonia, hyperreflexia, tremor, jitteriness, irritability, and constant crying. These features are consistent with either a direct toxic effect of SSRIs or, possibly, a drug discontinuation syndrome. It should be noted that in some cases, the clinical picture is consistent with serotonin syndrome [see Warnings and Precautions ( 5.2)].
Infants exposed to SSRIs in late pregnancy may have an increased risk for persistent pulmonary hypertension of the newborn (PPHN). PPHN occurs in 1 — 2 per 1000 live births in the general population and is associated with substantial neonatal morbidity and mortality. In a retrospective case-control study of 377 women whose infants were born with PPHN and 836 women whose infants were born healthy, the risk for developing PPHN was approximately 6-fold higher for infants exposed to SSRIs after the 20th week of gestation compared to infants who had not been exposed to antidepressants during pregnancy. There is currently no corroborative evidence regarding the risk for PPHN following exposure to SSRIs in pregnancy; this is the first study that has investigated the potential risk. The study did not include enough cases with exposure to individual SSRIs to determine if all SSRIs posed similar levels of PPHN risk.

Animal Data

Reproduction studies were performed at doses up to 50 mg/kg/day in rats and 6 mg/kg/day in rabbits administered during organogenesis. These doses are approximately 65 (rat) and 16 (rabbit) times the maximum recommended human dose (MRHD) for VMS on an mg/m2 basis. There were no teratogenic effects. However, in rats, there was an increase in pup deaths during the first 4 days of lactation when dosing occurred during the last trimester of gestation and continued throughout lactation. This effect occurred at a dose of 1 mg/kg/day or approximately equal to the MRHD for VMS on an mg/m2 basis. The no-effect dose for rat pup mortality was not determined. The cause of these deaths is unknown.

8.3 Nursing Mothers

Paroxetine is excreted in human milk. Because of the potential for serious adverse reactions in nursing infants from Paroxetine Capsules, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

8.4 Pediatric Use

Safety and effectiveness in pediatric patients have not been established; Paroxetine Capsules are not indicated in the pediatric population.

8.5 Geriatric Use

Clinical studies of Paroxetine Capsules did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Elderly patients may have elevated paroxetine plasma concentrations compared to younger patients. However, no Paroxetine Capsules dose adjustment is considered necessary in elderly patients [see Clinical Pharmacology ( 12.3)].

SSRIs have been associated with cases of clinically significant hyponatremia in elderly patients, who may be at greater risk for this adverse event [see Warnings and Precautions ( 5.6)].

8.6 Renal Impairment

No Paroxetine Capsules dose adjustment is considered necessary in patients with renal impairment [see Clinical Pharmacology ( 12.3)].

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