Rytary (carbidopa and levodopa) for Parkinson’s disease
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What is Rytary for Parkinson’s?
Rytary is an approved extended-release formulation of carbidopa and levodopa that can help ease disease symptoms in people with Parkinson’s.
The capsules are designed to immediately release a given amount of the medications upon administration and to continue releasing them slowly over time for several more hours. This method of administration has been shown in clinical trials to reduce off episodes — periods when a medication wears off and disease symptoms are not well controlled — during waking hours by nearly twofold.
Formerly known as IPX066, the therapy was developed by Impax Laboratories, which was combined with Amneal Pharmaceuticals in 2018.
Rytary also had been approved in the European Union, under the name Numient, since 2015. However, Amneal Pharma Europe, the company responsible for its development across the EU, later decided for commercial reasons not to market the product. Accordingly, the European Commission in 2019 withdrew the therapy’s marketing authorization.
Therapy snapshot
| Brand Name: | Rytary |
| Chemical Name: | carbidopa and levodopa |
| Usage: | used to treat Parkinson’s disease; can reduce off episodes |
| Administration: | extended-release oral capsules |
How does Rytary work?
Parkinson’s disease is characterized by the death of dopaminergic neurons, which are nerve cells that communicate with other neurons by releasing a signaling molecule (neurotransmitter) called dopamine.
With the loss of dopaminergic neurons, dopamine levels in the brain decrease dramatically and Parkinson’s patients gradually experience a lack of motor control, among other symptoms.
Because it cannot cross the blood-brain barrier, a semipermeable membrane that protects the brain and spinal cord from circulating toxins or pathogens, dopamine cannot be directly administered into the brain.
Rytary is an oral medication containing levodopa and carbidopa that’s designed to increase dopamine levels in the brain.
Levodopa can directly increase those levels by getting into the brain, where it is broken down into dopamine by nerve cells to replenish the brain’s supply. Carbidopa, on the other hand, decreases the conversion of levodopa outside the nervous system so that more levodopa can reach the brain.
Rytary capsules contain beads that release carbidopa and levodopa at different speeds as they are dissolved in the gastrointestinal tract. One-third of the beads are immediate release, allowing the medication to start working quickly. The other two-thirds are extended release and slowly release the medication over a few hours.
Together, the immediate and extended-release beads ensure absorption occurs over a prolonged period of time, providing a longer and more stable mode of action compared with immediate release only combinations.
Who with Parkinson’s can take Rytary?
Rytary was approved by the U.S. Food and Drug Administration in 2015 to treat people with Parkinson’s disease, including those with early, moderate, and advanced disease.
That approval also included other indications, including post-encephalitic parkinsonism (or Parkinson’s-like symptoms that occur after a brain infection), and parkinsonism that may follow carbon monoxide or manganese intoxication.
Who should not take Rytary?
Rytary is not recommended for people who are being treated with a nonselective monoamine oxidase (MAO) inhibitor — an antidepressant medication — or who have taken a MAO inhibitor within two weeks, as joining the two medications can lead to high blood pressure.
Patients with a major psychotic disorder also should not be given this therapy, due to a higher risk of psychosis exacerbation.
How is Rytary administered in Parkinson’s?
Rytary is available in capsules that come in four strengths:
- The lowest dose are 23.75 mg carbidopa and 95 mg levodopa capsules, which are blue and white and are imprinted with IPX066 on the cap and 95 on the body.
- Another dose are 36.25 mg carbidopa and 145 mg levodopa capsules, which are blue and light blue and imprinted with IPX066 on the cap and 145 on the body.
- Another dose are 48.75 mg carbidopa and 195 mg levodopa capsules, which come in blue and yellow colors and are imprinted with IPX066 on the cap and 195 on the body.
- The highest dose are 61.25 mg carbidopa and 245 mg levodopa capsules, which are all blue and imprinted with IPX066 on the capsule and 245 on the body.
For patients who have not previously taken levodopa, the starting dose is 23.75 mg/95 mg, taken orally three times daily for the first three days.
The dosage may increase to 36.25 mg/145 mg three times daily on the fourth day of treatment. Depending on individual clinical responses and tolerability, it may be increased up to a maximum recommended dose of 97.5 mg/390 mg, taken three times a day.
Patients also can increase the dosing frequency of Rytary capsules from three times a day to five times daily, if more frequent dosing is necessary. However, the maximum recommended daily dose of the medication is 612.5 mg/2,450 mg.
For patients who are transitioning from immediate-release formulations of carbidopa and levodopa, the Rytary starting dose will depend on the daily amount of levodopa they were receiving while on their previous treatment. After conversion to Rytary, any combination of the four Rytary dose strengths can be used to achieve optimal dosing, as long as the maximum recommended dose is not exceeded.
Rytary capsules should not be chewed, divided, or crushed. They should be swallowed whole or their contents may be sprinkled on 1-2 tablespoons of applesause. Capsules also can be taken with or without food, though patients should avoid eating high-protein and high-fat foods that can decrease the absorption of Rytary.
Rytary in clinical trials
Approvals of Rytary were mainly supported by positive data from two Phase 3 studies: APEX-PD (NCT00880620) and ADVANCE-PD (NCT00974974).
APEX-PD
The APEX-PD study, completed in 2010, enrolled 381 people with early Parkinson’s who received one of three fixed doses of the therapy (capsules containing 145 mg, 245 mg, or 390 mg of levodopa) or a placebo, given three times a day for 30 weeks, or about seven months.
Results showed Rotary was well tolerated and provided significant clinical benefits at the three dosages tested. Compared with the placebo, patients treated with Rytary experienced a significantly greater improvement in their motor skills and their ability to perform activities of daily living. Both participants and physicians also reported improvements in the patients’ condition after 30 weeks compared with scores from before initiating treatment.
ADVANCE-PD
The ADVANCE-PD study, completed in 2011, enrolled 393 patients with advanced Parkinson’s disease who were experiencing at least 2.5 daily hours of motor fluctuations, or off periods — periods of time when the medication wears off and is no longer effective.
Participants first underwent a dose-adjustment period in which they received an immediate-release formulation of carbidopa and levodopa for three weeks, followed by a dose-conversion period in which they switched to Rytary for six weeks. Then, all participants were randomized to receive either Rytary or the immediate-release formulation for 13 weeks (totaling 22 weeks, or about five months, in the trial).
At the time of study entry, patients were experiencing off periods for about six hours daily. After the 22 weeks, those assigned to Rytary were experiencing 3.87 hours of off periods per day, compared with 4.88 hours among those given immediate-release carbidopa/levodopa — a significant 1.17 hour difference between groups.
These reductions happened despite patients on Rytary having a significantly lower dosing frequency compared with the other treatment (3.6 vs. 5 doses per day).
Participants on Rytary also experienced significantly greater improvements in their behavior and mood, motor skills, and ability to perform daily activities. Moreover, both patients and doctors reported significant disease improvements among participants.
ASCEND-PD
More recently, the ASCEND-PD trial (NCT01130493) compared Rytary with a combination treatment of carbidopa and levodopa and entacapone, an enzyme inhibitor of levodopa breakdown.
A total of 91 participants with advanced Parkinson’s disease who were taking the combination therapy were switched to Rytary over a six-week period, then randomized to one of the two treatments for two weeks. After a one-week washout with Rytary, to eliminate the medications from patients’ bodies, all were then crossed over to the other treatment for an additional two weeks.
These results showed a significant reduction in off periods with Rytary compared with the combination treatment. Both groups started with an average of 5.9 hours per day of off periods before the start of treatment. That dropped to 3.8 hours per day after two weeks on Rytary, and 5.2 hours per day after the same period on the combination therapy.
On periods, or times when the medication is effectively controlling the disease’s motor symptoms, without dyskinesia, or involuntary movements, also increased significantly with Rytary. The medication also was associated with a reduced dosing frequency and with significant improvements in motor symptoms.
Common side effects of Rytary
The most common side effects of Rytary in people with early Parkinson’s disease include:
- nausea
- dizziness
- headache
- insomnia
- abnormal dreams
- dry mouth
- dyskinesia, or uncontrolled, involuntary movements
- anxiety
- constipation
- vomiting
- orthostatic hypotension, or a drop in blood pressure upon standing.
The most common side effects related to Rytary in advanced Parkinson’s disease include nausea and headache.
Falling asleep during daily activities
There have been reports of people falling asleep during daily activities while on levodopa-based therapies. Before initiating treatment with Rytary, factors for increased sleepiness, such as sleep disorders and other coprescribed sedating medications, should be assessed by and discussed with prescribing healthcare providers.
Discontinuing treatment should be considered in severe cases of daytime sleepiness or episodes of falling asleep during daily activities. Patients in whom the therapy is not stopped should avoid driving and other activities where falling asleep unexpectedly can be dangerous.
High fever and confusion associated with rapid dose reductions
High fever, stiff muscles, changes in breathing and heartbeat, and confusion following rapid dose reductions or discontinuation of dopaminergic therapy have been reported. As such, patients should avoid sudden discontinuation or rapid dose reduction of Rytary. Those who decide to discontinue treatment should do so gradually to avoid these withdrawal symptoms.
Cardiovascular events
Cardiovascular events have occurred in individuals taking Rytary. Patients with irregular heartbeat, called residual arrhythmias, due to a history of heart attack should have their cardiac function monitored in an intensive cardiac care facility during the period of initial Rytary dosage adjustment.
Hallucinations, psychosis, and impulse control
Rytary may cause symptoms such as hallucinations (seeing or hearing things that are not real), psychotic behavior, and impulse control problems, such as urges to gamble and eat, or increased sexual urges.
Due to a risk of worsening psychosis, patients with a major psychotic disorder should not be treated with Rytary. Also, treatment reduction or discontinuation should be considered for patients experiencing impulse control disorders.
Dyskinesia
Treatment with Rytary can cause dyskinesia — uncontrolled, involuntary movements — which can require a dosage reduction of either Rytary or other Parkinson’s medications.
Eye and stomach issues
Rytary may cause increased pressure inside the eye of patients with glaucoma, a disease that can cause vision loss and blindness. Individuals with glaucoma and Parkinson’s should be monitored after initiating treatment with Rytary.
The therapy also may increase the risk of gastrointestinal bleeding in patients who have a history of stomach or intestinal ulcers.
Use in pregnancy and breastfeeding
Rytary has not been well studied in patients who are pregnant or breastfeeding. Based on animal studies, the therapy may cause harm to a developing fetus. Rytary should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Traces of levodopa have also been found in human breast milk. As such, caution should be used when administering Rytary to nursing patients.
Patients who are or plan to become pregnant, or are nursing or plan to breastfeed should discuss this issue with their healthcare providers.
Parkinson’s News Today is strictly a news and information website about the disease. It does not provide medical advice, diagnosis or treatment. This content is not intended to be a substitute for professional medical advice, diagnosis, or treatment. Always seek the advice of your physician or another qualified health provider with any questions you may have regarding a medical condition. Never disregard professional medical advice or delay in seeking it because of something you have read on this website.
FAQs about Rytary
The U.S. Food and Drug Administration approved Rytary in 2015 for the treatment of people with Parkinson’s disease, which may include patients with early, moderate, and advanced disease. The regulatory agency also approved the medication for certain kinds of parkinsonism, or conditions with Parkinson’s-like symptoms.
Based on animal studies, Rytary may cause harm to a developing fetus. However, the therapy has not been well studied in pregnant women so it should be used during pregnancy only if the potential benefits justify the potential risks to the fetus. Patients should always talk to their healthcare providers if they become or intend to become pregnant while on a medication.
Due to reports of people falling asleep during daily activities while on levodopa-based therapies, Rytary’s U.S. label recommends that people initiating therapy should not drive and should avoid other potentially dangerous activities that might result in harm if the patient becomes somnolent.
Based on data from clinical trials, Rytary reaches a peak concentration in the blood about one hour after administration, at which point an easing in Parkinson’s symptoms should already be evident. That effect is then maintained for about 4-5 hours before declining. However, because the initial recommended dose of Rytary may not work for everyone, some patients may require dose adjustments before experiencing the full benefits of the therapy.
Neither hair loss nor weight gain have been reported as side effects of Rytary in clinical trials, but there have been some isolated reports of hair loss in people receiving levodopa-based medications. Weight gain also can occur due to compulsive eating, a potential side effect of the medication. Patients who experience such effects after starting on the Rytary should discuss these issues with their healthcare providers.
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