Understand the Differences in Carbidopa/Levodopa Formulations for Parkinson Disease

Parkinson disease (PD) is the second most common neurodegenerative disease after Alzheimer disease.¹ Approximately 1 million people in the US are diagnosed with PD and this number is expected to rise to 1.2 million by 2030, per the Parkinson’s Foundation Parkinson’s Prevalence Project.¹

Carbidopa/levodopa is considered the gold standard for the management of PD motor symptoms. A retrospective cohort study spanning 5 years in 11,280 patients revealed that carbidopa/levodopa was the most prescribed first-line treatment in 70% of the population.² Since its approval in 1970, multiple formulations have become available. This has expanded options for patients, but also complicated pharmacologic management for patients, caregivers, and their providers. Understanding differences in the various levodopa formulations and assisting with medication therapy management is a crucial role for pharmacists.

Image credit: LIGHTFIELD STUDIOS | stock.adobe.com

Carbidopa/Levodopa Immediate Release and Orally Disintegrating Tablets

Carbidopa/levodopa immediate release (IR) tablets are commonly the first levodopa formulation prescribed to patients with PD. The IR formulation has a peak onset of 30 minutes to 1 hour with a half-life of 1.5 to 2 hours.³ There is also an orally disintegrating tablet (ODT) formulation for patients with difficulty swallowing pills.⁴ The ODT has a peak onset of 30 minutes and does not require water for administration. However, as PD progresses, the window of levodopa’s effectiveness is significantly reduced, resulting in more “off” time and subsequent requirement of increased doses and/or frequency.⁵ Dyskinesia and motor “on/off” fluctuations develop in about 50% of PD patients within 5 years of treatment.

For those new to therapy, pharmacists should counsel patients to space doses evenly throughout waking hours. Spacing doses throughout the awake hours helps to optimize observed benefits during activities of daily living. Additionally, patients should be advised to avoid taking doses with high fat, high caloric meals because this can delay gastrointestinal absorption up to 2 hours.^3,4

Carbidopa/Levodopa Controlled Release Tablets

Carbidopa/levodopa controlled release (CR) tablets provide a sustained release formulation. It has a bioavailability of 70% to 75% relative to that of IR formulations, with a time to peak of 1.5 to 2 hours.^5,7 Because the time to reach maximal concentration is delayed, some patients may concomitantly take an IR formulation with the first morning dose. The CR tablets utilize a polymeric based drug delivery system that is designed to release carbidopa/levodopa over 4 to 6 hours allowing for 3 times-per-day dosing. However, CR is less systemically bioavailable than IR formulations and may require higher daily doses in some patients to achieve the same level of symptomatic relief. As such, levodopa doses > 800 mg may be divided every 4 to 8 hours during the waking hours. In clinical trials, the CR formulation provided the same therapeutic benefit as the IR formulation; however, with less frequent dosing when compared to IR. Pharmacists should advise patients not to crush, chew, or cut the CR formulation as this may result in carbidopa/levodopa being released too fast.

Carbidopa/Levodopa Extended-Release Capsules

Carbidopa/levodopa extended release (ER) formulations have a bioavailability of 70% relative to that of IR formulations with an initial peak at 1 hour.⁸ The ER formulation allows for an extended duration of action due to its unique formulation of time release beads. Each capsule consists of one-third of IR carbidopa/levodopa beads, which allows it to start working immediately, while the other two-thirds consists of ER carbidopa/levodopa beads, which, when coupled with the IR beads, allows it to maintain serum levels for up to 5 hours. In addition to IR/ER beads, each capsule also contains an excipient containing tartaric acid. This is intended to provide an acidic environment to enhance levodopa absorption.6Because of its duration of action, ER formulations can be initiated at 3 times a day and titrated to a maximum of 5 times a day.⁸

ER formulations are not interchangeable with other carbidopa/levodopa formulations due to variations in dosages and pharmacokinetics. The prescribing information should be consulted when converting to the ER product. For patients who have difficulty swallowing, the capsule may be opened, and the contents of both halves sprinkled into applesauce and consumed immediately.

Carbidopa/Levodopa Continuous Enteral Solution

Enteral carbidopa/levodopa bypasses the stomach to allow for continuous administration over 16 hours directly into the small intestine.⁹ It is administered via a specialty pump into the jejunum through a percutaneous endoscopic gastrostomy (PEG-J). For temporary administration prior to PEG-J tube placement, treatment may be initiated via a naso-jejunal tube. Continuous infusion provides steady pharmacokinetics, increased efficacy, and fewer oral doses throughout the day. Prior to initiating enteral therapy, all carbidopa/levodopa forms should be converted to the IR formulation to facilitate conversion. Conversely, if a patient receiving enteral carbidopa/levodopa is admitted to the hospital and does not have access to it for inpatient use, a neurologist should be consulted to temporarily switch to an IR formulation. Communication with the outpatient neurologist prior to discharge is also warranted to facilitate transition of care.

Levodopa Inhalation Powder

Levodopa inhalation powder provides on-demand inhaled levodopa that starts to work as early as 10 minutes after taking.¹⁰ It is intended to reduce the duration of “off” periods in advanced disease. Because it is a rescue therapy, it should not be used as primary therapy. Levodopa powder for inhalation is supplied in capsules that are inhaled with a product-specific inhaler. Each dose is comprised of 2 capsules, with each capsule loaded into the device and inhaled individually. However, since the inhalation route is intended for “off” periods, patients with severe symptoms may have trouble setting up the inhaler. As such, caregivers should also be instructed on proper use of the inhaler device.

Pharmacist’s Role

Errors related to incorrect levodopa formulations are amongst the top errors observed in patients with PD admitted to the hospital.¹¹ With the variety of formulations, each with their own unique pharmacokinetic properties, appropriate selection is vital. Other safety concerns include delays in medication reconciliation and administration. Pharmacists should ensure timely reconciliation along with documentation of the patient’s dosing schedule to avoid standardized administration times and omission errors. ISMP recommends setting a goal of obtaining a medication history within 2 hours of admission.

In patients that are alert and oriented, discussion with the medical team regarding self-administration may be an option to minimize delays. Although this is not routinely suggested, it may be a solution when frequent (every <4 hours) doses are needed.

Additionally, delays in obtaining nonformulary medications should be minimized. Consultation with the patient’s neurologist may be of benefit if a specific formulation cannot be provided while hospitalized. Ensuring abrupt discontinuation of PD medications is essential to avoid significant adverse events.

References

1. Statistics. Parkinson’s Foundation. Accessed January 29, 2024. https://www.parkinson.org/understanding-parkinsons/statistics#:~:text=Nearly%20one%20million%20people%20in

2. Kalilani L, Friesen D, Boudiaf N, Asgharnejad M. The characteristics and treatment patterns of patients with Parkinson's disease in the United States and United Kingdom: A retrospective cohort study. PLoS One. 2019;14(11):e0225723. doi:10.1371/journal.pone.0225723

3. Sinemet (carbidopa-levodopa immediate release tablets) [package insert]. Jersey City, NJ: Organon; June 2021.

4. Carbidopa-levodopa orally disintegrating tablets [package insert]. Cranbury, NJ: Sun Pharmaceutical; October 2018.

5. Hsu A, Yao HM, Gupta S, Modi NB. Comparison of the pharmacokinetics of an oral extended-release capsule formulation of carbidopa-levodopa (IPX066) with immediate-release carbidopa-levodopa (Sinemet, sustained-release carbidopa-levodopa (Sinemet® CR), and carbidopa-levodopa-entacapone (Stalevo®). J Clin Pharmacol. 2015;55(9):995-1003. doi:10.1002/jcph.514

6. Livingston C, Monroe-Duprey L. A Review of Levodopa Formulations for the Treatment of Parkinson's Disease Available in the United States. J Pharm Pract. 2023:8971900221151194. doi:10.1177/08971900221151194

7. Carbidopa and levodopa controlled-release tablet [package insert], Morgantown, WV: Mylan Pharmaceuticals Inc.; February 2020.

8. Rytary (carbidopa-levodopa extended-release capsules) [package insert].Hayward, CA: Impax Specialty Pharma; December 2019.

9. Duopa (carbidopa-levodopa enteral suspension) [package insert].North Chicago, IL: AbbVie Inc.; March 2022.

10. Inbrija (levodopa inhalation powder) [package insert].Ardsley, NY: Acorda Therapeutics, Inc.; December 2022.

11. Delayed Administration and Contraindicated Drugs Place Hospitalized Parkinson’s Disease Patients at Risk. Institute For Safe Medication Practices. Accessed December 20, 2023. https://www.ismp.org/resources/delayed-administration-and-contraindicated-drugs-place-hospitalized-parkinsons-disease