| | Date | Text |
| | June 1997 | Section: Drug Interactions
Pharmacokinetic-Related Interactions
General: “The risks of using of CLOZARIL® (clozapine) in combination with other drugs have not been systematically evaluated.”
“Because CLOZARIL® (clozapine) is highly bound to serum protein, the administration of CLOZARIL® (clozapine) to a patient taking another drug which is highly bound to protein (e.g., warfarin, digoxin) may cause an increase in plasma concentrations of these drugs, potentially resulting in adverse effects. Conversely, adverse effects may result from displacement of protein-bound CLOZARIL® (clozapine) by other highly bound drugs.”
Specific: “Cimetidine and erythromycin may both increase plasma levels of CLOZARIL® (clozapine) potentially resulting in adverse effects.”
“Concomitant use of clozapine with other drug metabolized by cytochrome P450 2D6 may require lower doses than usually prescribed for either clozapine or the other drug.” |
| | August 2001 | Section: Drug Interactions
Pharmacokinetic-Related Interactions
General: “Clozapine is a substrate for many CYP450 isozymes, in particular 1A2, 2D6, and 3A4. The risk of metabolic interactions caused by an effect on an individual isoform is therefore minimized. Nevertheless, caution should be used in patients receiving concomitant treatment with other drugs that are either inhibitors or inducers of these enzymes.”
Specific: “Concomitant administration of drugs known to inhibit the activity of cytochrome P450 isozymes may increase the plasma levels of clozapine. Cimetidine, caffeine and erythromycin may increase plasma levels of CLOZARIL® (clozapine), potentially resulting in adverse effects.” |
| | January 2002–June 2005 | No change |
| | December 2005 | FDA Letter (12/05/2005): “This ‘Changes Being Effected’ supplemental new drug application provides for changes in the product labeling under PRECAUTIONS, Drug Interactions, Pharmacokinetic-Related Interactions to add ciprofloxacin to the list of drugs that may increase plasma levels of CLOZARIL, potentially resulting in adverse effects.”
Section: Drug Interactions
Pharmacokinetic-Related Interactions
Specific: “Concomitant administration of drugs known to inhibit the activity of cytochrome P450 isozymes may increase the plasma levels of clozapine. Cimetidine, caffeine, citalopram, ciprofloxacin, and erythromycin may increase plasma levels of CLOZARIL, potentially resulting in adverse effects.” |
| | June 2008–March 2013 | No change |
| | July 2013 | Dosage and Administration: Section 2.6 Dosage Adjustments with Concomitant use of CYP1A2, CYP2D6, CYP3A4 Inhibitors or CYP1A2, CYP3A4 Inducers
“Dose adjustments may be necessary in patients with concomitant use of: strong CYP1A2 inhibitors (e.g., fluvoxamine, ciprofloxacin, or enoxacin); moderate or weak CYP1A2 inhibitors (e.g., oral contraceptives, or caffeine); CYP2D6 or CYP3A4 inhibitors (e.g., cimetidine, escitalopram, erythromycin, paroxetine, bupropion, fluoxetine, quinidine, duloxetine, terbinafine, or sertraline); CYP3A4 inducers (e.g., phenytoin, carbamazepine, St. John’s wort, and rifampin); or CYP1A2 inducers (e.g., tobacco smoking) (Table 2).”
Drug Interactions: Section 7.1 Potential for Other Drugs to Affect CLOZARIL
CYP1A2 Inhibitors: “Concomitant use of CLOZARIL and CYP1A2 inhibitors can increase plasma levels of clozapine, potentially resulting in adverse reactions. Reduce the CLOZARIL dose to one third of the original dose when CLOZARIL is coadministered with strong CYP1A2 inhibitors (e.g., fluvoxamine, ciprofloxacin, or enoxacin). The CLOZARIL dose should be increased to the original dose when coadministration of strong CYP1A2 inhibitors is discontinued [see Dosage and Administration (2.6), Clinical Pharmacology (12.3)].” |
|
|
