Risperidone (Page 5 of 10)

6.2 Postmarketing Experience

The following adverse reactions have been identified during postapproval use of risperidone. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. These adverse reactions include: alopecia, anaphylactic reaction, angioedema, atrial fibrillation, cardiopulmonary arrest, catatonia, diabetic ketoacidosis in patients with impaired glucose metabolism, dysgeusia, hypoglycemia, hypothermia, ileus, inappropriate antidiuretic hormone secretion, intestinal obstruction, jaundice, mania, pancreatitis, pituitary adenoma, precocious puberty, pulmonary embolism, QT prolongation, sleep apnea syndrome, somnambulism, Stevens-Johnson syndrome and toxic epidermal necrolysis (SJS/TEN), sudden death, thrombocytopenia, thrombotic thrombocytopenic purpura, urinary retention, and water intoxication.

Postmarketing cases of extrapyramidal symptoms (dystonia and dyskinesia) have been reported in patients concomitantly taking methylphenidate and risperidone when there was an increase or decrease in dosage, initiation, or discontinuation of either or both medications.

7. DRUG INTERACTIONS

7.1 Pharmacokinetic-related Interactions

The dose of risperidone should be adjusted when used in combination with CYP2D6 enzyme inhibitors (e.g., fluoxetine, and paroxetine) and enzyme inducers (e.g., carbamazepine) [see Table 18 and Dosage and Administration (2.5)] . Dose adjustment is not recommended for risperidone when co-administered with ranitidine, cimetidine, amitriptyline, or erythromycin [see Table 18].

Table 18. Summary of Effect of Coadministered Drugs on Exposure to Active Moiety (Risperidone + 9-Hydroxy-Risperidone) in Healthy Subjects or Patients with Schizophrenia

Coadministered Drug

Dosing Schedule

Effect on Active Moiety (Risperidone + 9-Hydroxy-Risperidone (Ratio*)

Risperidone Dose Recommendation

Coadministered Drug

Risperidone

AUC

C max

Enzyme (CYP2D6) Inhibitors

Fluoxetine

20 mg/day

2 or 3 mg twice daily

1.4

1.5

Re-evaluate dosing. Do not exceed 8 mg/day

Paroxetine

10 mg/day

4 mg/day

1.3

Re-evaluate dosing. Do not exceed 8 mg/day

20 mg/day

4 mg/day

1.6

40 mg/day

4 mg/day

1.8

Enzyme (CYP3A/ PgP inducers) Inducers

Carbamazepine

573 ± 168 mg/day

3 mg twice daily

0.51

0.55

Titrate dose upwards. Do not exceed twice the patient’s usual dose

Enzyme (CYP3A) Inhibitors

Ranitidine

150 mg twice daily

1 mg single dose

1.2

1.4

Dose adjustment not needed

Cimetidine

400 mg twice daily

1 mg single dose

1.1

1.3

Dose adjustment not needed

Erythromycin

500 mg four times daily

1 mg single dose

1.1

0.94

Dose adjustment not needed

Other Drugs

Amitriptyline

50 mg twice daily

3 mg twice daily

1.2

1.1

Dose adjustment not needed

*Change relative to reference

Effect of Risperidone on Other Drugs

Lithium

Repeated oral doses of risperidone (3 mg twice daily) did not affect the exposure (AUC) or peak plasma concentrations (C max ) of lithium (n=13). Dose adjustment for lithium is not recommended.

Valproate

Repeated oral doses of risperidone (4 mg once daily) did not affect the pre-dose or average plasma concentrations and exposure (AUC) of valproate (1,000 mg/day in three divided doses) compared to placebo (n=21). However, there was a 20% increase in valproate peak plasma concentration (C max ) after concomitant administration of risperidone. Dose adjustment for valproate is not recommended.

Digoxin

Risperidone (0.25 mg twice daily) did not show a clinically relevant effect on the pharmacokinetics of digoxin. Dose adjustment for digoxin is not recommended.

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