In January, movement disorder specialist Eleni Okeanis Vaou, MD, was the guest speaker for an episode of Dr. Gilbert Hosts on the different formulations of carbidopa/levodopa available. Carbidopa/levodopa continues to be the gold standard of treatment for the motor symptoms of Parkinson’s disease (PD) and can be very effective in controlling the stiffness and slowness that are characteristic of PD. Knowing the differences between the different formulations and understanding why you are prescribed a specific formulation over another can be confusing. With new and more formulations of carbidopa/levodopa available, physicians can offer more personalized treatment approaches.

Editor’s Note: If you are like me, Dr. Vaou’s talk itself was really in the nitty gritty details of the various carbidopa/levodopa formulations. You might prefer to skip her presentation and proceed to the Question-and-Answer portion of the webinar, which was interesting.

Here are some key points from Dr. Vaou’s talk.

Different formulations of carbidopa/levodopa and levodopa include:

• Oral immediate release carbidopa/levodopa (IR): Fast-acting but short duration (2.5-4 hours).
• Oral controlled release carbidopa/levodopa (CR): Longer action than IR.
• Oral extended release carbidopa/levodopa – Rytary®: Introduced in 2016, had a longer duration (5-6 hours) than IR and CR, with a faster peak than CR.
• Oral extended release carbidopa/levodopa – Crexont®: A new extended release formulation that lasts longer than Rytary® in clinical trials.
• Inhaled levodopa (Inbrija®): This is a powder form of levodopa that is inhaled. This can provide fast relief for “off” episodes, working within 10 minutes and lasting 30 minutes to an hour.
• Subcutaneous continuous foscarbidopa/foslevodopa (Vyalev®): Recently FDA approved, delivered via a pump, bypassing the GI tract for continuous drug delivery.
• Intestinal gel carbidopa/levodopa (Duopa™): Continuous infusion via a surgically placed tube, bypassing the GI tract.

Dr. Vaou disclosed she was a principal investigator for the subcutaneous levodopa pump.

With all the options, the main takeaway is there’s no one-size-fits-all. Doctors consider disease stage, individual needs, lifestyle, side effects, and other factors to determine the best treatment plan. It’s essential to work closely with your doctor to determine the most appropriate treatment strategy for your individual needs.

A recording of the webinar is available on the ADPA YouTube channel.

You can find relevant resources related to the treatment of PD on the Stanford Parkinson’s Website.

• Treating PD
• Medications

Now onto my notes,

Elizabeth

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The Many Forms of Carbidopa/Levodopa

Speaker: Eleni Okeanis Vaou, MD, UT Health San Antonio

Webinar Host: American Parkinson Disease Association

Webinar Date: January 8, 2025

Summary by: Elizabeth Wong, Stanford Parkinson’s Community Outreach


Dr. Vaou disclosed she was a principal investigator for the subcutaneous levodopa pump.

FDA-approved formulations:

• Oral Levodopa includes immediate release (IR), controlled release (CR), extended release (ER).
• Inhaled Levodopa
• Subcutaneous Continuous Levodopa
• Intestinal Gel Levodopa

Immediate release carbidopa/levodopa (IR) has been used since 1975, and remains the most effective for motor symptoms. Comes in various forms, including disintegrating tablets (faster acting but stays in the system as long as tablets).

Controlled release carbidopa/levodopa (CR) provides longer action than IR.

Extended Release (ER)/Rytary® was introduced in 2016 and offers a longer duration of action compared to IR and CR.

When comparing oral formulations, graph was used to illustrate the comparison of concentration of levodopa in immediate release (IR) vs. controlled release (CR) vs extended release (ER) vs carbidopa/levodopa/entacapone (brand name Stalevo®) in the bloodstream over time.

• IR has a rapid peak in the bloodstream but wears off quickly (2.5-3 hours). Early on the disease, it can last maybe 4 hours.
• ER/Rytary® has a faster peak and a longer duration of action (5-6 hours), it does not wear off as fast as IR. Rytary® clinical trial results showed a 1.17-hour greater reduction in daily “off” time compared to IR.
• CR and C/L/E (Stalevo®) don’t last as long as the Rytary®

Inhaled Levodopa (Inbrija®) is a fast-acting formulation (absorbed within 30 minutes), indicated for “off” times (medication wearing off) to bridge to the next dose. Works within 10 minutes and lasts for 30 minutes to an hour.

Recently FDA approved, Crexont® is an extended release formulation of carbidopa/levodopa. Crexont® combines immediate-release granules and extended-release pellets. The immediate release granules consist of carbidopa and levodopa with a disintegrant polymer to allow for rapid dissolution. The extended-release pellets has a central core (the levodopa core) that is surrounded by sustained release polymer that allows for slow release of drug, it is wrapped around by mucoadhesive polymer to keep the pellets sticking to the area of absorption longer, and an enteric polymer to prevent the pellet from disintegrating too early in the stomach. Clinical trials of Crexont® showed:

• 0.53 hours more “on” time compared to IR.
• Reduced dosing frequency (3 times a day vs. 5 times for IR).
• 0.48 hours less “off” time compared to IR.
• Each dose lasts nearly 4 hours compared to 2.21 hours for IR.
• Sustained concentrations above 50% of the peak for approximately 0.8 hours longer than Rytary® and 2.5 hours longer than IR, Crexont® stays longer than any other forms than we have.

Currently available and upcoming infusion systems:

Levodopa-carbidopa intestinal gel (Duopa®): Long-established, continuous infusion via a surgically placed PEG tube. Bypasses the GI tract. Clinical trials showed 2 hours more “on” time without troublesome dyskinesia and a 2-hour reduction in “off” time compared to IR. Drawbacks include surgical placement and maintenance of the PEG tube.

Levodopa/entacapone/carbidopa intestinal gel (LECIG): This is being used in some European countries.

Subcutaneous foscarbidopa and foslevodopa continuous infusion (Vyalev®): Recently FDA approved. Delivered via a pump similar to an insulin pump. Bypasses the GI. Clinical trials showed significant improvements in “on” time (2.72 hours better than IR) and “off” time (nearly 3 hours better than 0.96 hours with IR). Also showed some improvement in sleep due to continuous 24 hour delivery. Some people report waking up without being off.

Subcutaneous Levodopa Carbidopa Pump (Neuroderm/Mitsubishi Tanabe BeyoND study): Not yet FDA approved but showed promising results in phase three trials: 1.72 hours improvement in “on” time and 1.4 hours less “off” time compared to IR.

Continuous subcutaneous apomorphine infusion: This is a different form of dopaminergic medication, it is in the family of dopamine agonists, the results are out from clinical trials, it is not yet FDA approved.

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Question and Answer

Question: Can you review what is “on” and “off” time?

Answer: It’s important for patients to understand and communicate their “on” and “off” times to their neurologists to better manage their symptoms. “On time” is when the medication is working effectively. Typically, about 30 minutes to an hour after taking the medication, patients experience relief from their symptoms. Tremors may lessen or disappear, muscles feel looser, and movement becomes easier and faster. They simply “feel good”. “Off time” is when the medication’s effects wear off. Symptoms return, and patients revert to their previous state as if they hadn’t taken the medication. Tremors may reappear or worsen, walking may become slower, and muscle cramps or tightness may occur. Some may feel “stuck” or unable to move as easily as they did during “on” time.

When your doctor asks how your medication is working, don’t just say “the tremor is always there.” Consider these points on how to communicate “on”and “off” time to your doctor:

• Does the tremor ever go away?
• Does it lessen or improve after taking medication (even if it doesn’t disappear completely)? This improvement indicates the medication is working, and you are “on.”
• How long does this improvement last before symptoms return, indicating you are “off”?

By describing the duration and quality of both “on” and “off” times, you provide valuable information to your physician. This helps providers determine if you are on the correct dose of medication; if the medication is adequately controlling your symptoms; if you need adjustments to your current treatment or if additional therapies should be considered.


Question: What is your algorithm to decide what to prescribe for your patient?

Answer: Having many treatment options is beneficial because it allows for personalized care. No two patients are alike; each case is unique. When deciding on a treatment plan, providers consider:

• Disease Stage: Is the patient in the early or advanced stages of Parkinson’s?
• Individual Needs: What are the patient’s specific symptoms and concerns?
• Activity Level: How active is the patient’s lifestyle?
• Medication Side Effects: Has the patient experienced any side effects from previous medications?
• Blood Pressure: Are there any blood pressure concerns that might influence medication choices?
• Sleep Patterns: What is the patient’s sleep quality like?
• Dosing Preferences: How often is the patient willing or able to take medication?
• Caregiver Support: What level of support is available to the patient?

In the early stages, immediate-release carbidopa/levodopa is often recommended as it provides effective symptom control for a reasonable duration. In later stages, if the medication’s effects start to wear off too quickly or motor symptoms are not adequately controlled (resulting in poor “on” time), adjustments are necessary. This might involve switching to longer-acting formulations to extend the medication’s duration. In more advanced stages, the gastrointestinal (GI) system can slow down, reducing medication absorption. In these cases, therapies that bypass the GI tract, such as infusion therapy or inhaled levodopa, may be considered. Treatment is not “one-size-fits-all.” Doctors carefully consider individual patient factors to make the best possible treatment decisions.


Question: Dietary protein can interfere with absorption of carbidopa/levodopa so could you elaborate on what protein is doing and whether there’s a difference in the proteins effect based on those various options?

Answer: It’s important to clarify that protein is not the enemy for people with Parkinson’s, people need protein, do not shy away from eating protein. There are people who have no protein effect. The issue is that protein can interfere with the absorption of oral carbidopa/levodopa. Regarding protein intake, timing is key. Do not take oral carbidopa/levodopa at the same time as consuming protein. General guidelines are to take your medication either half an hour to one hour before a meal, or one hour after a meal. If you have more advanced Parkinson’s, your gastrointestinal (GI) system may function more slowly. In this case, it’s best to wait one to two hours after a protein-rich meal before taking your medication, to ensure proper absorption.

Any treatment that bypasses the GI tract is not affected by protein intake. This includes infusion therapies (like the subcutaneous pump, Vyalev®), inhaled levodopa (Inbrija®), dopamine agonist patches.

With infusion pumps, particularly Vyalev®, patients can often stop taking oral medication altogether. This eliminates the need to carefully plan meals around medication doses, which many patients find to be a significant improvement in their quality of life. This level of freedom was not possible before these therapies were available.


Question: What are common side effects of carbidopa/levodopa?

Answer: Nausea is a very common side effect. It can usually be managed by starting with a low dose and gradually increasing the dose. I have some extreme examples of patients that can’t even tolerate any dopaminergic medications, it can happen, so in these cases one may consider other treatment options like infusion treatments or DBS. For nausea, carbidopa can also be increased.

Other side effects of carbidopa/levodopa can include:

• Orthostatic hypotension (feeling lightheaded when standing up)
• Sleepiness and tiredness
• Dyskinesia (involuntary movements)
• Motor fluctuations (wearing off) – As the effects of the medication wear off, symptoms can return.

Question: Some people find that their Tremor doesn’t seem to be treated well with carbidopa/levodopa, can you talk about the effect of carbidopa levodopa on tremor?

Answer: Some patients have “tremor-resistant” Parkinson’s disease, meaning their tremors don’t respond well to typical medication therapy. The effectiveness of medication can depend on dose or delivery method. Treatment options for tremor-resistant cases can be to try higher doses of carbidopa/levodopa. Issues with gastrointestinal (GI) absorption can affect how well the medication works. If absorption is a problem, alternative delivery methods may be beneficial, such as infusion pumps.

If higher doses are insufficient or cause unacceptable side effects, other treatment options should be considered, such as deep brain stimulation (DBS) or focused ultrasound. Patients with tremor-resistant Parkinson’s often have a very good response to DBS and other advanced therapies.


Question: When should carbidopa/levodopa be started for those in early-stage Parkinson’s?

Answer: There’s no single “right” time to begin medication. The decision is highly personal and depends on the individual’s experience. There’s no harm in delaying the start of medication. Carbidopa/levodopa treats the symptoms of Parkinson’s; it does not slow or stop the disease’s progression. For people in the early stages of Parkinson’s, exercise is crucial. It has neuroprotective properties and is considered one of the best things you can do.

Whether to start medication depends on how much your symptoms are affecting your life. If tremors, slowness, or stiffness are interfering with social activities, work, or daily tasks (like brushing your teeth or buttoning your shirt), then it might be time to consider medication. Some people may have noticeable tremors but find they don’t significantly impact their daily lives and thus choose to delay medication.

My general advice is you should start medication when you feel ready and when your motor symptoms (slowness, tremor, stiffness) are significantly impacting your life.


Question: Are muscle cramps a side effect of medications, what is the best way to handle cramping especially at night which can be very impactful on quality of life?

Answer: Muscle cramps in Parkinson’s are often a sign of “wearing off,” meaning the medication’s effects are declining. This is why cramps frequently occur at night: many patients don’t take medication that covers the period between bedtime and waking up.

When medication levels are low during sleep, muscles can become stiffer. This stiffness, combined with getting up during the night (e.g., to use the bathroom), can trigger muscle cramps. Therefore, nighttime cramps are a strong indicator that the medication is wearing off.

It’s important to distinguish between muscle cramps and dyskinesia. Muscle cramps are painful muscle spasms. Dyskinesia is involuntary, continuous, dance-like movements. While dyskinesia can become painful over time (due to constant muscle activity), the initial sensation is different from the sharp pain of a muscle cramp.

Cramps are not a direct medication side effect, instead, they are a signal that the medication dosage or timing needs to be adjusted. They indicate that the medication level is too low and therapy needs optimization. Nighttime muscle cramps significantly disrupt sleep and therefore quality of life. It’s crucial to address and treat these cramps to improve sleep quality. Don’t underestimate the importance of managing this symptom.


Question: What is your opinion on adding mucuna to a regime? (Moderator: Mucuna is a product that is derived from a bean that has high concentration, about 6% concentration of dopamine in it, and it can be found in natural food stores and some people use this to help with their Parkinson’s.)

Answer: Mucuna is a natural product derived from a bean that contains levodopa. Some people with Parkinson’s use it as a supplement. A significant drawback is that Mucuna is less potent than standard oral carbidopa/levodopa medications. Therefore, you need to consume much larger quantities to achieve a similar effect. Mucuna may be more suitable for people in the earlier stages of Parkinson’s, perhaps within the first one to three years after diagnosis. If Mucuna provides symptom relief and works for you, it’s generally considered safe to continue using it. It’s simply a natural form of levodopa.


Question: I am new with this diagnosis, carbidopa/levodopa is the first medication I have tried, I have no pain, no cramps, but I have very bad balance, spastic walking. Is carbidopa/levodopa the right medication?

Answer: Those symptoms generally respond less effectively to carbidopa/levodopa and dopaminergic therapies compared to the classic motor symptoms of stiffness, slowness, and tremor. Physical therapy and exercise are the most beneficial treatments for gait problems. Balance and walking (gait) issues in Parkinson’s can be a result of a number of different causes and there is no one treatment for it. There can be different reasons why gait is affected, it could be because patients may be wearing off, or may have cognitive decline. In the early stage, you don’t see a lot of gait problems but when you do and it doesn’t respond to medication, the best treatment is physical therapy and exercise. Sometimes, if carbidopa/levodopa isn’t improving gait, increasing the dose is unlikely to help.


Question: My Parkinson’s affects my speech. When I’m “off” medication, I can barely speak. What’s the best medication in that situation?

Answer: Speech is partly a motor function, so carbidopa/levodopa can improve it to some degree. However, speech is a complex process involving thought, word formation, and articulation. Therefore, medication alone often doesn’t fully resolve speech difficulties. Speech therapy is crucial. Consistent exercises, even outside of formal therapy sessions, are extremely important.


Question: Can you talk about the relationship between carbidopa/levodopa and dyskinesia?

Answer: Dyskinesia (involuntary movements) usually appears after several years of carbidopa/levodopa use (typically 3-10 years, but it varies). Women may be more susceptible to developing it earlier. Dyskinesia can occur at peak dose (when the medication is at its highest concentration) or even as the medication wears off, or sometimes both. Good news is that for the most part, dyskinesia can be treated with other medications and deep brain stimulation (DBS). It’s often an indication to consider DBS, especially if motor fluctuations are also problematic. Infusion pumps have shown promise in decreasing dyskinesia and providing more “on” time without these involuntary movements. Do not avoid starting carbidopa/levodopa out of fear of developing dyskinesia. It remains the most effective treatment for Parkinson’s symptoms, and there are good treatment options available if dyskinesia becomes troublesome. “Troublesome” means it affects your quality of life; mild, unnoticed dyskinesia may not require intervention.


Question: I’ve been on Sinemet for 10 years. Should I ask my neurologist if there is something that might work better?

Answer: The “if it ain’t broke, don’t fix it” principle applies. If your symptoms are well-controlled, there’s no need to change. However, if you feel your symptoms are no longer adequately managed, you should definitely discuss it with your doctor. Don’t hesitate to voice your concerns, even if you’ve become accustomed to certain symptoms. Many new treatments and therapies are available. Seeing a movement disorder specialist can be beneficial, as they have specialized knowledge and experience in managing Parkinson’s and can provide more individualized treatment plans.


Question: Is there a point where you stop carbidopa/levodopa because it’s no longer effective?

Answer: You generally don’t stop carbidopa/levodopa entirely unless severe side effects occur. Stopping abruptly will make symptoms significantly worse. Instead, you can reach a point where increasing the dose is no longer helpful due to side effects, and decreasing it worsens symptoms. This is a “crossroads” where alternative approaches are needed. Symptoms get worse because disease gets worse. Deep brain stimulation (DBS) is often recommended at this stage as an add-on therapy, not a replacement for medication. I do not recommend stopping carbidopa/levodopa.


Question: When should I consider decreasing my carbidopa-levodopa medication?

Answer: You might need to decrease medication if you experience signs of being overmedicated, such as constant sleepiness, worsening dyskinesia, low blood pressure, (lightheadedness or fainting), or hallucinations. Taking medication too frequently (e.g., every two hours) can also be a sign that adjustments are needed. Longer-acting formulations might reduce the need for such frequent dosing. If something “doesn’t look or feel right,” discuss it with your doctor. There is a maximum dosage of carbidopa/levodopa but generally determined by the emergence of side effects. High doses can also lead to impulse control disorders (e.g., gambling, overeating, obsessive behaviors) or even medication overuse where the patient craves more and more of the drug. In these cases, intervention from the provider and family members is often necessary.