Rytary vs Sinemet: Which is Better?

Last updated: May 1, 2017

Which should you (or your doctor) choose, Rytary or Sinemet?

The answer is unsatisfying: it depends on your situation.

The active agents in both Sinemet and Rytary are the same: carbidopa plus levodopa. Given that the ingredients are identical in both drugs, what could be the difference? I'll speak to this question a little later.

Historical Context

Levodopa has been the mainstay for Parkinson’s disease treatment for many years.

Carbidopa was added to the mix because it inhibits the breakdown of levodopa. So as you can imagine, the cocktail increases the duration and effectiveness of levodopa.

Given that the active ingredients in both drugs are identical, what’s the difference between Rytary vs Sinemet?

Enter Rytary

Rytary is a newer extended-release formulation of Sinemet. The therapeutic effects of Rytary last about 4-6 hours verses 1-2 hours for Sinemet.

Rytary lasts longer than Sinemet because it contains both instant-release carbidopa/levodopa and sustained released beads that deliver the drug more gradually. Here’s a good synopsis (or read the full article):

Each capsule of Rytary contains immediate and extended-release beads of levodopa in a 4:1 ratio with carbidopa. Four different dosage strengths, ranging from 23.75/95 mg to 61.25/245 mg carbidopa/ levodopa, are offered. The immediate-release beads take action in approximately 30 minutes and the sustained-release ones last four to six hours. The latter facilitate less frequent dosing (typically three, but up to five, times per day) and a steadier plasma levodopa concentration. Because higher total daily dosages of levodopa are recommended when switching from Sinemet IR or CR, three to four capsules of Rytary are often prescribed at each dosing administration.

Let’s step back. How do these drugs treat Parkinson’s disease?

Dopamine and Parkinson’s Disease

Parkinson’s disease (PD) is one of the most common neurodegenerative diseases, worldwide.

The progressive loss of dopamine-releasing neurons results in PD. Loss of dopaminergic neurons in dorsal striatum impairs motor control [1].

These motor impairments include:

  • bradykinesia (slowness of movement)
  • rigidity
  • resting tremors

Parkinson’s also affects other dimensions. People with PD often develope cognitive and emotional symptoms like dementia and depression [2]. This makes intuitive sense, because dopamine regulates psychological reward. It’s hard to be happy if experiences aren’t rewarding and life isn’t pleasurable!

Levodopa and Carbidopa

Currently, the most effective treatment for motor symptoms of PD is co-administration of levodopa and carbidopa3. Levodopa (L-3,4-dihydroxyphenylalanine or L-DOPA) is a precursor molecule for dopamine. Treatment with L-DOPA significantly improves several PD symptoms including akinesia (voluntary movement impairment), tremor and rigidity.

The mechanism by which L-DOPA improves motor function is not well-understood. It is thought that once L-DOPA is in the bloodstream, it crosses the blood-brain-barrier to enter the brain. There it is taken up by dopaminergic neurons, converted into dopamine, stored and eventually released over time4.

Unfortunately, administration of L-DOPA does have severe side effects, including nausea and vomiting. Treatment can also lead to the development of motor fluctuations and involuntary muscle movements (dyskinesia) in advanced stages of PD5.

One solution is to reduce the amount of L-DOPA required to obtain the clinical effects of L-DOPA. When administered alone, only 1% of L-DOPA enters the brain. This is because L-DOPA is quickly metabolized into dopamine and cleared from the plasma by the decarboxylation process6.

While L-DOPA can be transferred across the blood-brain-barrier by an amino acid transporter, there are no transporters for dopamine. So once L-DOPA is converted into dopamine, it cannot enter the brain. To increase the level of L-DOPA available to enter the brain, a Dopa Decarboxylase (DDC) inhibitor is typically administered in combination with L-DOPA7. Because they cannot enter the brain, DDC inhibitors only block the conversion of L-DOPA into dopamine in the bloodstream. The combined treatment slows the removal of L-DOPA in circulation, resulting in a 10-fold increase in L-DOPA concentrations in the nervous system. DDC inhibitor carbidopa increases the half-life of L-DOPA from 50min to 90min and reduces the amount that is needed to be effective by about 25%. Co-administration also decreases nausea and vomiting side effects of L-DOPA. Thus, treatment with carbidopa and L-DOPA has become a standard treatment for PD10.

In 1991, the Merck & Co PD drug Sinemet received Federal Drug Administration (FDA) approval for the treatment of PD. Sinemet is a combination of carbidopa and levodopa in tablet form11.

Unfortunately, the combination still resulted in the development of dyskinesia and fluctuation in motor control. This fluctuation is known as the on-off phenomenon in treated patients. During “off” times, the patients are not responsive to their medication. Control over their PD symptoms worsens or is lost temporarily. This can happen gradually or suddenly. During “on” times, the patients are responsive to their treatment and their symptoms are less cumbersome.

The phenomenon is due in part to the progression of the disease. Although L-DOPA can be converted, stored and slowly released by dopaminergic neurons, because these neurons are increasingly lost as the disease progresses, this process is eventually compromised by PD.

The controlled release of dopamine is no longer possible in the advanced stages of the disease and so the patient becomes more sensitive to fluctuations in L-DOPA concentration12. Thus, minimizing the instability in L-DOPA is essential to reducing motor fluctuations in treated PD patients.

One of the largest unmet needs of patients with PD is the need to reduce daily “off” time. To combat unresponsiveness to PD medication, a controlled release formulation of Sinemet, Sinemet CR, was developed. Sinemet CR is presented in a tablet that allows for slow release of carbidopa and L-DOPA as the tablet erodes. Sinemet CR provides a sustained release of the drug over a 4-6 hour period which may increase the half-life of L-DOPA13.

The controlled release mechanism also means that it takes longer for the patients to experience the benefits of the treatment. It takes about 2 hours to reach peak L-DOPA concentrations compared to 30min with the conventional form.

Therefore, the immediate release form is typically used along with Sinemet CR for the best results. Sinemet CR does indeed reduce the variation in plasma L-DOPA levels compared to conventional Sinemet14. However, it is less systemically bioavailable and so may require a higher dose to achieve the same symptomatic relief provided by the original form.

Despite improvements in L-DOPA plasma stability achieved by Sinemet CR, patients still experience “off” times, daily. In January 2015, the FDA approved Rytary, a new extended-release drug, for the treatment of PD and related conditions. Similar to Sinemet, Rytary capsules consist of carbidopa and L-DOPA in a 1:4 ratio 15.

Like Sinemet CR, L-DOPA concentrations peak approximately 2hours after consuming Rytary. However, the plasma concentration can be maintained for 4-5 hours before declining. What makes Rytary unique is that carbidopa and L-DOPA are stored in both immediate release and extended release beads within a capsule to provide both immediate and delayed relief of symptoms.

Unlike Sinemet, it can be swallowed whole or opened and sprinkled on food. It can also be used for early, moderate and advanced PD. Most importantly, Rytary reduces the amount of time during the day when patients cannot control their PD symptoms. Patients in the Rytary clinical trial experienced 1.5 fewer hours of “off” time per day compared to other controlled release drugs designed to lengthen L-DOPA efficacy16.

However, there are some drawbacks to the new extended-release PD therapeutic. Rytary is more likely to cause nausea and headaches compared to immediate release forms like conventional Sinemet. Carbidopa and L-DOPA are also less bioavailable (50% and 70% respectively) compared to immediate-release forms17. L-DOPA peak concentrations are also nearly 35% of the peak concentration of Sinemet-like treatments.

The bottom line is co-treatment with carbidopa and L-DOPA is the most effective treatment for PD18. Sinemet and similar generic forms were the standard treatment for PD for several years. While a controlled release form was developed to help reduce motor fluctuations that develop in response to L-DOPA, reducing “off” time remained a significant unmet need for patients with PD. Extended-release Rytary could potentially provide a solution, or at least a step in the right direction, to reducing “off” time and giving patients with PD more control over their symptoms and their lives.


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Xavier Kent

I'm interested in nutrition, nootropics, and javascript. I'm a firm believer in getting really good at one thing.


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