Rasagiline, indicated for Parkinson disease (PD), is metabolized in the liver via the cytochrome P450 (CYP) system. Countless other medications including ciprofloxacin are also metabolized in this pathway. Without proper dose adjustment, this concurrent metabolism leads to increased rasagiline blood concentrations and dopamine levels, causing adverse reactions.
Rasagiline, a monoamine oxidase-B inhibitor, is indicated as monotherapy or adjunct therapy for the treatment of PD. It is eliminated from the body through hepatic metabolism via the cytochrome P4501A2 (CYP1A2) pathway and requires a dose adjustment for patients with hepatic impairment or for those taking concomitant medications that inhibit CYP1A2.1,2 Numerous medications inhibit the CYP1A2 enzyme, including ciprofloxacin, fluvoxamine, amiodarone, and cimetidine.3
Ciprofloxacin, as well as fluoroquinolones as a class, should not be used as first-line antibiotics due to numerous adverse reactions and drug interactions. The FDA released a statement in 2016 that the toxicities of fluoroquinolones generally outweigh the benefits in patients with uncomplicated infections. In addition, the FDA expanded on the statement that fluoroquinolones should not be used if there are other first-line therapies available for certain infections, such as uncomplicated urinary tract infections (UTIs), acute bacterial sinusitis, and acute bacterial exacerbation of chronic bronchitis.4
In the event that rasagiline is used concomitantly with ciprofloxacin or other CYP1A2 inhibitors, it is recommended that the rasagiline dose be halved. This recommendation is due to an increased serum concentration of rasagiline, as this boost in concentration could lead to increased dopaminergic effects, such as dyskinesia, ataxia, and paresthesias.1,5,6 A pharmacokinetic study in healthy volunteers (n = 12) found that when rasagiline at 2 mg/day was administered with ciprofloxacin at 500 mg every 12 hours, the area under the curve of rasagiline increased by 83%. While the concentration was increased greatly, there was no change in the elimination half-life of rasagiline.1,5,6
Although the risk of the interaction is stated in the package insert of rasagiline, minimal reports in the literature have identified the consequences of the drug interaction between ciprofloxacin and rasagiline. The following case report reviews the clinical implications of the drug-drug interaction between rasagiline and ciprofloxacin.
Case study
Mr. C, a 69-year-old Black male, presented to the ED with a chief complaint of weakness, fatigue, and back pain. Upon arrival, Mr. C was febrile up to 100.4[degrees] F (38[degrees] C), heart rate of 69 beats/minute, respirations 18 breaths/min, BP 127/68 mm Hg, white blood cell (WBC) count of 12.6 x 109/L, and oxygen saturation of 97% on room air. The computerized tomography abdomen and pelvis from the ED showed emphysematous pyelonephritis, hydronephrosis, and nephrolithiasis.
Mr. C's medical history includes nephrectomy of the left kidney due to renal cell carcinoma in 2008, a right kidney transplant due to end-stage renal disease in August 2017, transplant nephrolithiasis status post lithotripsy with stone removal in July 2018, PD, hypertension, transient ischemic attack, and recurrent UTIs. Due to his history of recurrent UTIs, Mr. C was recently started on prophylactic ciprofloxacin 500 mg three times weekly on Mondays, Wednesdays, and Fridays. Prior to starting ciprofloxacin for recurrent UTIs, the patient had good control of his PD with his current regimen. Mr. C's home medications included rasagiline 1 mg daily, allopurinol 100 mg daily, carbidopa-levodopa 25 mg to 100 mg BID, carvedilol 6.25 mg BID, furosemide 80 mg BID, insulin glargine 10 units nightly, magnesium oxide 400 mg daily, megestrol 40 mg TID, pantoprazole 40 mg daily, prednisone 5 mg daily, sertraline 50 mg daily, spironolactone 25 mg daily, tacrolimus 2 mg BID, and tamsulosin 0.4 mg nightly.
Initial lab studies revealed sodium 136 mEq/L, potassium 4.1 mEq/L, chloride 104 mEq/L, bicarbonate 24 mEq/L, blood urea nitrogen 55 mg/dL, and a serum creatinine (SCr) 2.92 mg/dL. Based on lab studies from a year prior, Mr. C's baseline SCr ranged from 2 to 2.3 mg/dL. A complete blood cell count showed a hemoglobin 12.2 g/dL, hematocrit 37.5%, platelet count 242 x 109/L, and previously stated WBC count.
Mr. C was admitted and diagnosed with pyelonephritis and acute kidney injury (AKI). He was initially treated with cefepime and vancomycin. His urine culture grew an extended spectrum beta lactamase producing Klebsiella pneumoniae, and the patient was switched to ertapenem to finish his antibiotic course. During Mr. C's physical exam, it was noticed that he had increased resting tremor, cogwheel rigidity, and dystonia. Based on his physical exam findings, further investigation revealed that the drug interaction between ciprofloxacin and rasagiline was contributing to his tremor and rigidity. Ciprofloxacin was discontinued from his home medications for UTI prophylaxis. Mr. C's cogwheel rigidity, tremor, and dystonia improved throughout the admission once ciprofloxacin was discontinued. Mr. C's AKI also resolved, and he was discharged on ertapenem to complete a minimum of 3 weeks of antibiotic therapy. Mr. C was discharged on all prior home medications with the exception of ciprofloxacin.
Discussion
Fluoroquinolones are often not recommended as first-line antibiotics due to the numerous associated adverse reactions and growing antimicrobial resistance and should only be used when no other options are available. The FDA has warned about their use with patients older than 65 years as well as with children.4 A few significant fluoroquinolone toxicities include tendon rupture, neurotoxicity, QT prolongation, hepatotoxicity, and Clostridium difficile.7 The potential for drug interactions with CYP enzymes is yet another reason to use these medications with caution. Numerous medications are affected by the CYP enzymes. In the case of a prodrug, CYP can lead to the medication's activation. In other situations, the enzyme system will often metabolize and eliminate the medication. Altering CYP enzymes can lead to minimal drug exposure, an inadequate regimen, or excessive exposure, causing drug toxicities.8
In the case for Mr. C, ciprofloxacin inhibited the metabolism of rasagiline. This inhibition caused an increase in rasagiline blood concentrations, which in turn led to increased circulating dopamine levels. The elevated dopamine then produced the cogwheel rigidity, tremor, and dystonia. Coadministration of these two mediations and other CYP1A2 inhibitors with rasagiline could cause numerous adverse reactions associated with rasagiline, such as symptoms described in the case, and additionally, orthostatic hypotension, dyskinesias, ataxia, and nausea.1
Conclusion
NPs treating patients with PD and considering rasagiline as part of the therapy should be cognizant of the CYP1A2 drug interaction. Per package labeling, the rasagiline dose should be decreased to 0.5 mg once daily when combined with a strong CYP1A2 inhibitor. Lack of adjustment for this interaction will likely lead to increased dopaminergic adverse reactions experienced from increased rasagiline blood levels, which may be associated with a decreased quality of life.
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