Apalutamide with Clozapine Interaction Details

Brand Names Associated with Apalutamide

Brand Names Associated with Clozapine

Medical Content Editor Dr. Brian Staiger, PharmD
Last updated Mar 04, 2024

Interaction Effect

Reduced clozapine exposure and decreased efficacy

Interaction Summary

Concurrent use of clozapine (CYP3A4 substrate) and a strong CYP3A4 inducer may decrease the plasma concentration of clozapine leading to decreased effectiveness and is not recommended. If concomitant therapy is clinically necessary, monitor for decreased clozapine effectiveness and consider increasing the clozapine dose. When coadministration of a potent CYP3A4 inducer is discontinued, reduce the clozapine dose based on clinical response[1].

Severity

Major

Onset

Unspecified

Evidence

Theoretical

How To Manage Interaction

Concurrent use of clozapine (CYP3A4 substrate) and a strong CYP3A4 inducer may decrease the plasma concentration of clozapine leading to decreased effectiveness and is not recommended. If concomitant therapy is clinically necessary, monitor for decreased clozapine effectiveness and consider increasing the clozapine dose. When coadministration of a potent CYP3A4 inducer is discontinued, reduce the clozapine dose based on clinical response[1].

Mechanism Of Interaction

Induced CYP3A4-mediated metabolism of clozapine

Literature Reports

A) A 41-year-old female patient with disorganized schizophrenia treated with clozapine for 6 months developed subtherapeutic clozapine levels and signs of worsening psychiatric status after St John's wort was self-initiated by the patient. The patient developed signs of increasing disorganization and tension, and the clozapine trough level, which had previously been therapeutic at 0.46 to 0.57 mg/L, was found to be 0.19 mg/L. St John's wort 900 mg daily was started prior to the subtherapeutic measurement. The clozapine trough level increased to 0.32 mg/L 1 month after St John's wort was discontinued and further increased to 0.41 mg/L 2 months after discontinuation; improvement in the patient's psychiatric condition was seen as well [2].

B) A case report described loss of clozapine efficacy following concomitant rifampin administration in a 30-year-old male patient with schizophrenia. The patient had been initiated on clozapine for paranoid schizophrenia. Following problems with clozapine's adverse events (i.e., sedation, hypersalivation) at therapeutically successful doses, he had been controlled on clozapine therapy for 3 months at 300 mg daily when pulmonary tuberculosis was diagnosed. The patient was started on rifampin monotherapy at 600 mg daily. Two weeks later, the patient no longer complained of sedation and hypersalivation, but his psychotic symptoms worsened. At the end of the month, his psychopathology was as severe as when clozapine was first initiated. The dose of clozapine was increased to 550 mg daily with only mild improvement. However, the patient reported no adverse events and was compliant with therapy. Following discontinuation of rifampin after 6 months of therapy, sedation and hypersalivation reappeared within 1 week. The dose of clozapine was not decreased to below 500 mg daily due to the marked improvement in the patient's psychotic symptoms. Induction of the CYP450-mediated clozapine metabolism was postulated as a probable mechanism. However, clozapine plasma levels were not available for confirmation due to laboratory difficulties [3].

C) A 33-year-old male patient with schizophrenia was controlled on clozapine therapy for a few years when a chest X-ray revealed an opacity in the right lower quadrant. Rifampin, isoniazid, and pyrazinamide therapy was instituted for suspected tuberculosis. Within 3.5 weeks, the patient became restless and sleepless, and clozapine serum concentrations were found to have significantly decreased to a subtherapeutic range. The dose of clozapine was increased from 400 mg daily to 600 mg daily without clinical improvement of the patient's psychosis. Rifampin therapy was substituted with ciprofloxacin when the opportunistic infection was found to be mycobacterium xenopi, and within 3 days the clozapine serum concentration increased back to a therapeutic level [4].

D) Over a 3-year period, some drug combinations caused a greater risk of asterixis (flapping tremor) in patients on a regimen of multiple psychopharmacologic agents. With regard to the agents carbamazepine, clozapine, and lithium, incidence of asterixis was greatest in those patients who were on at least 2 of these 3 agents. Out of 10 patients developing asterixis, 5 patients received carbamazepine and clozapine as part of multidrug therapy, and in 2 cases, carbamazepine and clozapine were the sole psychopharmacologic agents. In all cases, serum levels of all the drugs were within normal therapeutic ranges, suggesting an additive effect of combination therapy rather than the effect of a single agent [5].

E) Therapeutic drug monitoring data showed a 50% lower clozapine concentration/dose (C/D) ratio when concurrent carbamazepine was taken compared with clozapine alone. The clozapine C/D ratio was inversely correlated with the dose of carbamazepine. An additional analysis of 8 patients confirmed that upon addition of carbamazepine to the drug regimen, clozapine concentrations decreased significantly. The mean C/D ratio during monotherapy was 1.21 and during cotherapy with carbamazepine fell to 0.30. The change in clozapine metabolism was due to carbamazepine induction of CYP3A4 [6].

F) Two 29-year-old patients with schizophrenia were stabilized on clozapine therapy. Their clozapine plasma concentrations decreased and psychotic symptoms markedly worsened after the addition of phenytoin for seizure activity. Phenytoin reduced clozapine plasma concentrations by 65% to 85% and necessitated an increase in clozapine dosage. The author's possible explanations for the decrease in clozapine plasma concentrations were induction of cytochrome P-450 enzymes by phenytoin, causing increased clozapine metabolism; decreased clozapine absorption due to phenytoin; and/or decreased protein binding of clozapine, making more free drug available for metabolism. If the deterioration in clinical status was not related to the decrease in clozapine plasma levels, the author's possible explanations were rebound psychosis after abruptly decreasing clozapine at the time of seizure activity, spontaneous fluctuation in illness, postictal exacerbation of preexisting psychosis, or postictal psychosis. Clinicians closely monitor clozapine patients for worsening of psychotic symptoms when phenytoin is added to therapy [7].

References

1 ) Product Information: CLOZARIL(R) oral tablets, clozapine oral tablets. HLS Therapeutics USA Inc (per FDA), Rosemont, PA, 2020.

2 ) Van Strater AC & Bogers JP: Interaction of St John's wort (Hypericum perforatum) with clozapine. Int Clin Psychopharmacol 2012; 27(2):121-124.PubMed Abstract: http://www.ncbi.nlm.nih.gov/...

3 ) Peritogiannis V, Pappas D, Antoniou K, et al: Clozapine-rifampicin interaction in a patient with pulmonary tuberculosis. Gen Hosp Psychiatry 2007; 29(3):281-282.PubMed Abstract: http://www.ncbi.nlm.nih.gov/...

4 ) Joos AAB, Frank UG, & Kaschka WP: Pharmacokinetic interaction of clozapine and rifampicin in a forensic patient with an atypical mycobacterial infection (letter). J Clin Psychopharmacol 1998; 18:83-85.

5 ) Rittmannsberger H: Asterixis induced by psychotropic drug treatment. Clin Neuropharmacol 1996; 19:349-355.

6 ) Jerling M, Lindstrom L, Bondesson U, et al: Fluvoxamine inhibition and carbamazepine induction of the metabolism of clozapine: evidence from a therapeutic drug monitoring service. Ther Drug Monit 1994; 16:368-374.

7 ) Miller DD: Effect of phenytoin on plasma clozapine concentrations in two patients. J Clin Psychiatry 1991; 52:23-25.

Apalutamide Overview

• Apalutamide is used to treat certain types of prostate cancer (cancer in men that begins in the prostate [a male reproductive gland]) and has spread to other parts of the body or that has not spread to other parts of the body but has not been helped by other medical treatments. Apalutamide is in a class of medications called androgen receptor inhibitors. It works by blocking the effects of androgen (a male reproductive hormone) to stop the growth and spread of cancer cells.

Clozapine Overview

• Clozapine is used to treat the symptoms of schizophrenia (a mental illness that causes disturbed or unusual thinking, loss of interest in life, and strong or inappropriate emotions) in people who have not been helped by other medications or who have tried to kill themselves and are likely to try to kill or harm themselves again. Clozapine is in a class of medications called atypical antipsychotics. It works by changing the activity of certain natural substances in the brain.

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Definitions

Severity Categories

Contraindicated

These drugs, generally, should not be used together simultaneously due to the high risk of severe adverse effects. Combining these medications can lead to dangerous health outcomes and should be strictly avoided unless otherwise instructed by your provider.

Major

This interaction could result in very serious and potentially life-threatening consequences. If you are taking this drug combination, it is very important to be under close medical supervision to minimize severe side effects and ensure your safety. It may be necessary to change a medication or dosage to prevent harm.

Moderate

This interaction has the potential to worsen your medical condition or alter the effectiveness of your treatment. It's important that you are monitored closely and you potentially may need to make adjustments in your treatment plan or drug dosage to maintain optimal health.

Minor

While this interaction is unlikely to cause significant problems, it could intensify side effects or reduce the effectiveness of one or both medications. Monitoring for changes in symptoms and your condition is recommended, and adjustments may be made if needed to manage any increased or more pronounced side effects.

Onset

Rapid: Onset of drug interaction typically occurs within 24 hours of co-administration.

Delayed: Onset of drug interaction typically occurs more than 24 hours after co-administration.

Evidence

Level of documentation of the interaction.

Established: The interaction is documented and substantiated in peer-reviewed medical literature.

Theoretical: This interaction is not fully supported by current medical evidence or well-documented sources, but it is based on known drug mechanisms, drug effects, and other relevant information.

How To Manage The Interaction

Provides a detailed discussion on how patients and clinicians can approach the identified drug interaction as well as offers guidance on what to expect and strategies to potentially mitigate the effects of the interaction. This may include recommendations on adjusting medication dosages, altering the timing of drug administration, or closely monitoring for specific symptoms.

It's important to note that all medical situations are unique, and management approaches should be tailored to individual circumstances. Patients should always consult their healthcare provider for personalized advice and guidance on managing drug interactions effectively.

Mechanism Of Interaction

The theorized or clinically determined reason (i.e., mechanism) why the drug-drug interaction occurs.

Disclaimer: The information provided on this page is for informational purposes only and should not be considered medical advice. Always consult with a qualified healthcare professional regarding your specific circumstances and medical conditions.

Where Does Our Information Come From?

Information for our drug interactions is compiled from several drug compendia, including:

• Gold Standard Drug Database
• Micromedex
• Lexicomp
• DrugBank

The prescribing information for each drug, as published on DailyMED, is also used. 

Individual drug-drug interaction detail pages contain references specific to that interaction. You can click on the reference number within brackets '[]' to see what reference was utilized.

The information posted is fact-checked by HelloPharmacist clinicians and reviewed quarterly.