Rytary (Carbidopa And Levodopa)
Dosage & administration
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Rytary prescribing information
RYTARY is indicated for the treatment of Parkinson's disease, post-encephalitic parkinsonism, and parkinsonism that may follow carbon monoxide intoxication or manganese intoxication.
- Levodopa-naïve patients: Starting dose is 23.75 mg/95 mg three times daily; may increase to 36.25 mg/145 mg three times daily on the fourth day of treatment. ()
2.1 Dosage in Patients Naïve to Levodopa TherapyThe recommended starting dosage of RYTARY in levodopa-naïve patients is 23.75 mg/95 mg taken orally three times a day for the first 3 days. On the fourth day of treatment, the dosage of RYTARY may be increased to 36.25 mg/145 mg taken three times a day.
Based upon individual patient clinical response and tolerability, the RYTARY dose may be increased up to a maximum recommended dose of 97.5 mg/390 mg taken three times a day. The dosing frequency may be changed from three times a day to a maximum of five times a day if more frequent dosing is needed and if tolerated.
Maintain patients on the lowest dosage required to achieve symptomatic control and to minimize adverse reactions such as dyskinesia and nausea. The maximum recommended daily dose of RYTARY is 612.5 mg/2,450 mg.
- See Table 1 for instructions for converting patients taking immediate-release carbidopa-levodopa to an initial dose of RYTARY. Dosages of RYTARY are not interchangeable with other carbidopa-levodopa products. ()
2.2 Converting from Immediate-Release Carbidopa-Levodopa to RYTARYThe dosages of other carbidopa and levodopa products are not interchangeable on a 1:1 basis with the dosages of RYTARY.
To convert patients from immediate-release carbidopa-levodopa to RYTARY, first calculate the patient’s current total daily dose of levodopa. The starting total daily dose of RYTARY is as recommended in Table 1.
After conversion, any combination of the four RYTARY dosage strengths can be used to achieve an optimal dosing. Adjust the dose and dosing frequency as necessary to maintain patient tolerance and sufficient symptomatic control. Administration of concomitant Parkinson’s disease medications should remain stable while adjusting the RYTARY dose. In clinical trials, RYTARY was administered in divided doses of three to five times a day. The maximum recommended total daily dose of RYTARY is 612.5 mg/2,450 mg.
For patients currently treated with carbidopa and levodopa plus a catechol-O-methyl transferase (COMT) inhibitor (such as entacapone), the initial total daily dose of levodopa in RYTARY described in Table 1 may need to be increased.
Use of RYTARY in combination with other levodopa products has not been studied.
Table 1: Conversion from Immediate-Release Carbidopa-Levodopa to RYTARYTotal Daily Dose of Levodopa inImmediate-Release Carbidopa-LevodopaRecommended Starting Dosage of RYTARYTotal Daily Dose of Levodopa in RYTARYRYTARY Dosing Regimen400 mg to 549 mg
855 mg
3 capsules RYTARY 23.75 mg/95 mg taken TIDa
550 mg to 749 mg
1,140 mg
4 capsules RYTARY 23.75 mg/95 mg taken TID
750 mg to 949 mg
1,305 mg
3 capsules RYTARY 36.25 mg/145 mg taken TID
950 mg to 1,249 mg
1,755 mg
3 capsules RYTARY 48.75 mg/195 mg taken TID
Equal to or greater than 1,250 mg
2,340 mg or
4 capsules RYTARY 48.75 mg/195 mg taken TID or
2,205 mg
3 capsules RYTARY 61.25 mg/245 mg taken TID
aTID: three times a day - The maximum recommended daily dose of RYTARY is 612.5 mg/2,450 mg. (,
2.1 Dosage in Patients Naïve to Levodopa TherapyThe recommended starting dosage of RYTARY in levodopa-naïve patients is 23.75 mg/95 mg taken orally three times a day for the first 3 days. On the fourth day of treatment, the dosage of RYTARY may be increased to 36.25 mg/145 mg taken three times a day.
Based upon individual patient clinical response and tolerability, the RYTARY dose may be increased up to a maximum recommended dose of 97.5 mg/390 mg taken three times a day. The dosing frequency may be changed from three times a day to a maximum of five times a day if more frequent dosing is needed and if tolerated.
Maintain patients on the lowest dosage required to achieve symptomatic control and to minimize adverse reactions such as dyskinesia and nausea. The maximum recommended daily dose of RYTARY is 612.5 mg/2,450 mg.
)2.2 Converting from Immediate-Release Carbidopa-Levodopa to RYTARYThe dosages of other carbidopa and levodopa products are not interchangeable on a 1:1 basis with the dosages of RYTARY.
To convert patients from immediate-release carbidopa-levodopa to RYTARY, first calculate the patient’s current total daily dose of levodopa. The starting total daily dose of RYTARY is as recommended in Table 1.
After conversion, any combination of the four RYTARY dosage strengths can be used to achieve an optimal dosing. Adjust the dose and dosing frequency as necessary to maintain patient tolerance and sufficient symptomatic control. Administration of concomitant Parkinson’s disease medications should remain stable while adjusting the RYTARY dose. In clinical trials, RYTARY was administered in divided doses of three to five times a day. The maximum recommended total daily dose of RYTARY is 612.5 mg/2,450 mg.
For patients currently treated with carbidopa and levodopa plus a catechol-O-methyl transferase (COMT) inhibitor (such as entacapone), the initial total daily dose of levodopa in RYTARY described in Table 1 may need to be increased.
Use of RYTARY in combination with other levodopa products has not been studied.
Table 1: Conversion from Immediate-Release Carbidopa-Levodopa to RYTARYTotal Daily Dose of Levodopa inImmediate-Release Carbidopa-LevodopaRecommended Starting Dosage of RYTARYTotal Daily Dose of Levodopa in RYTARYRYTARY Dosing Regimen400 mg to 549 mg
855 mg
3 capsules RYTARY 23.75 mg/95 mg taken TIDa
550 mg to 749 mg
1,140 mg
4 capsules RYTARY 23.75 mg/95 mg taken TID
750 mg to 949 mg
1,305 mg
3 capsules RYTARY 36.25 mg/145 mg taken TID
950 mg to 1,249 mg
1,755 mg
3 capsules RYTARY 48.75 mg/195 mg taken TID
Equal to or greater than 1,250 mg
2,340 mg or
4 capsules RYTARY 48.75 mg/195 mg taken TID or
2,205 mg
3 capsules RYTARY 61.25 mg/245 mg taken TID
aTID: three times a day - RYTARY may be taken with or without food; do not chew, divide or crush. (,
2.4 Administration InformationSwallow RYTARY whole with or without food. A high-fat, high-calorie meal may delay the absorption of levodopa by about 2 hours
[see Clinical Pharmacology (12.3)].Do not chew, divide or crush RYTARY capsules. For patients who have difficulty swallowing intact capsules, administer RYTARY by carefully twisting apart both halves of the capsule. Sprinkle the entire contents of both halves of the capsule on a small amount of applesauce (1 to 2 tablespoons) and consume the mixture immediately. Do not store the drug/food mixture for future use.
)12.3 PharmacokineticsAbsorptionCarbidopaFollowing oral dosing of RYTARY the maximum concentration occurred at approximately 3 hours. The bioavailability of carbidopa from RYTARY relative to immediate-release carbidopa-levodopa tablets was approximately 50%.
LevodopaThe pharmacokinetics of RYTARY were evaluated following single-doses in healthy subjects and following single- and multiple-doses in patients with Parkinson’s disease. The bioavailability of levodopa from RYTARY in patients was approximately 70% relative to immediate-release carbidopa-levodopa. For comparable doses, RYTARY results in a levodopa peak concentration (Cmax) that is 30% that of immediate-release carbidopa-levodopa. Following an initial peak at about one hour, plasma concentrations are maintained for about 4 to 5 hours before declining.
In patients with Parkinson’s disease, multiple-dose pharmacokinetics was comparable to single-dose pharmacokinetics, i.e., there was minimal accumulation of levodopa. Variation in levodopa peak to trough plasma concentrations at steady-state defined as (Cmax-Cmin)/Cavgwas approximately 1.5 for RYTARY compared to approximately 3.2 for immediate-release levodopa.
DistributionCarbidopa is approximately 36% bound to plasma proteins. Approximately 10% to 30% of levodopa is bound to plasma protein.
Metabolism and EliminationCarbidopaThe terminal phase elimination half-life of carbidopa is approximately 2 hours.
Carbidopa is metabolized to two main metabolites: α-methyl-3-methoxy-4-hydroxyphenylpropionic acid and α-methyl-3,4-dihydroxy-phenylpropionic acid. These two metabolites are primarily eliminated in the urine unchanged or as a glucuronide. Unchanged carbidopa accounts for 30% of the total urinary excretion.
Peripheral dopa-decarboxylase may be saturated by carbidopa in other carbidopa-levodopa products at 70 mg per day to 100 mg per day, which produces equivalent exposure to 140 mg to 200 mg of carbidopa provided by RYTARY.
LevodopaThe terminal phase elimination half-life of levodopa, the active moiety of antiparkinsonian activity, is approximately 2 hours in the presence of carbidopa.
Levodopa is extensively metabolized to various metabolites. The two major metabolic pathways are decarboxylation by dopa decarboxylase (DDC) and O-methylation by catechol-O-methyltransferase (COMT).
Dose ProportionalityRYTARY shows approximately dose proportional pharmacokinetics for both carbidopa and levodopa over the levodopa dosage strength range of 95 mg to 245 mg.
Effect of FoodIn healthy adults, oral administration of RYTARY after a high-fat, high-calorie meal reduced Cmaxapproximately 21% and increased AUCinfapproximately 13% for levodopa compared to administration in the fasted state. There may be a delay by 2 hours in the absorption of levodopa when RYTARY is taken with a high-fat, high-calorie meal. In addition, absorption of levodopa may be decreased by a high protein meal.
Specific PopulationsElderlyIn pharmacokinetics studies following a single-dose of RYTARY, the peak concentrations of carbidopa and levodopa are generally similar between younger (45 to 60 years) and older (60 to 75 years) subjects.
GenderIn pharmacokinetics studies following a single-dose of RYTARY:
- Carbidopa
At comparable doses females are reported to have higher carbidopa peak concentrations and systemic exposure (approximately 33%) compared to males. Median time to peak concentration and terminal half-life are comparable between males and females.
- Levodopa
At comparable doses females are reported to have higher levodopa peak concentrations (approximately 23% to 33%) and systemic exposure (approximately 33% to 37%) compared to males. Median time to peak concentration and terminal half-life are comparable between males and females.
Extended-release capsules:
- 23.75 mg carbidopa and 95 mg levodopa: blue and white capsule imprinted with IPX066 on the capsule cap and 95 on the capsule body.
- 36.25 mg carbidopa and 145 mg levodopa: blue and light blue capsule imprinted with IPX066 on the capsule cap and 145 on the capsule body.
- 48.75 mg carbidopa and 195 mg levodopa: blue and yellow capsule imprinted with IPX066 on the capsule cap and 195 on the capsule body.
- 61.25 mg carbidopa and 245 mg levodopa: blue capsule imprinted with IPX066 on the capsule cap and 245 on the capsule body.
Pregnancy: Based on animal data, may cause fetal harm. (
There are no adequate data on the developmental risk associated with the use of RYTARY in pregnant women. In animal studies, carbidopa-levodopa has been shown to be developmentally toxic (including teratogenic effects) at clinically relevant doses
The estimated background risk of major birth defects and miscarriage in the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.
When administered to pregnant rabbits throughout organogenesis, carbidopa-levodopa caused both visceral and skeletal malformation in fetuses at all doses and ratios of carbidopa-levodopa tested. No teratogenic effects were observed when carbidopa-levodopa was administered to pregnant mice throughout organogenesis.
There was a decrease in the number of live pups delivered by rats receiving carbidopa-levodopa during organogenesis.
RYTARY is contraindicated in patients:
- Currently taking a nonselective monoamine oxidase (MAO) inhibitor (e.g., phenelzine and tranylcypromine) or have recently (within 2 weeks) taken a nonselective MAO inhibitor. Hypertension can occur if these drugs are used concurrently [see.]
7.1 Monoamine Oxidase (MAO) InhibitorsThe use of nonselective MAO inhibitors with RYTARY is contraindicated
[see Contraindications (4)]. Discontinue use of any nonselective MAO inhibitors at least two weeks prior to initiating RYTARY.The use of selective MAO-B inhibitors (e.g., rasagiline and selegiline) with RYTARY may be associated with orthostatic hypotension. Monitor patients who are taking these drugs concurrently.
- May cause falling asleep during activities of daily living. ()
5.1 Falling Asleep During Activities of Daily Living and SomnolencePatients treated with levodopa, a component of RYTARY, have reported falling asleep while engaged in activities of daily living, including the operation of motor vehicles, which sometimes resulted in accidents. Although many of these patients reported somnolence while on levodopa, some perceived that they had no warning signs (sleep attack), such as excessive drowsiness, and believed that they were alert immediately prior to the event. Some of these events have been reported more than 1 year after initiation of treatment.
It has been reported that falling asleep while engaged in activities of daily living usually occurs in a setting of pre-existing somnolence, although patients may not give such a history. For this reason, prescribers should reassess patients for drowsiness or sleepiness in RYTARY-treated patients, especially since some of the events occur well after the start of treatment. Prescribers should also be aware that patients may not acknowledge drowsiness or sleepiness until directly questioned about drowsiness or sleepiness during specific activities.
Before initiating treatment with RYTARY, advise patients of the potential to develop drowsiness and specifically ask about factors that may increase the risk for somnolence with RYTARY such as concomitant sedating medications or the presence of a sleep disorder. Consider discontinuing RYTARY in patients who report significant daytime sleepiness or episodes of falling asleep during activities that require active participation (e.g., conversations, eating, etc.).
If a decision is made to continue RYTARY, patients should be advised not to drive and to avoid other potentially dangerous activities that might result in harm if the patients become somnolent. There is insufficient information to establish that dose reduction will eliminate episodes of falling asleep while engaged in activities of daily living.
- Avoid sudden discontinuation or rapid dose reduction to reduce the risk of withdrawal-emergent hyperpyrexia and confusion. ()
5.2 Withdrawal-Emergent Hyperpyrexia and ConfusionA symptom complex that resembles neuroleptic malignant syndrome (characterized by elevated temperature, muscular rigidity, altered consciousness, and autonomic instability), with no other obvious etiology, has been reported in association with rapid dose reduction, withdrawal of, or changes in dopaminergic therapy. Avoid sudden discontinuation or rapid dose reduction in patients taking RYTARY. If the decision is made to discontinue RYTARY, the dose should be tapered to reduce the risk of hyperpyrexia and confusion
[see Dosage and Administration (2.4)]. - Cardiovascular Events: Monitor patients with a history of cardiovascular disease. ()
5.3 Cardiovascular Ischemic EventsCardiovascular ischemic events have occurred in patients taking RYTARY. In a placebo controlled clinical study in patients with early Parkinson's disease, 7/289 (2.4%) of RYTARY-treated patients experienced cardiovascular ischemic adverse reactions compared to 1/92 (1.1%) of placebo-treated patients. In an active-controlled clinical study in patients with advanced Parkinson's disease, 3/450 (0.7%) of RYTARY-treated patients experienced cardiovascular ischemic adverse reactions compared to 0/471 oral immediate-release carbidopa-levodopa-treated patients. These patients all had a previous history of ischemic heart disease or risk factors for ischemic heart disease.
In patients with a history of myocardial infarction who have residual atrial, nodal, or ventricular arrhythmias, cardiac function should be monitored in an intensive cardiac care facility during the period of initial dosage adjustment.
- Hallucinations/Psychosis may occur. ()
5.4 Hallucinations/PsychosisThere is an increased risk for hallucinations and psychosis in patients taking RYTARY. In a controlled clinical trial in patients with advanced Parkinson's disease, 9/201 (4%) of RYTARY-treated patients reported hallucinations or psychosis compared to 2/192 (1%) of oral immediate-release carbidopa-levodopa-treated patients.
Hallucinations present shortly after the initiation of therapy and may be responsive to dose reduction in levodopa. Hallucinations may be accompanied by confusion, insomnia, and excessive dreaming. Abnormal thinking and behavior may present with one or more symptoms, including paranoid ideation, delusions, hallucinations, confusion, psychotic-like behavior, disorientation, aggressive behavior, agitation, and delirium.
Because of the risk of exacerbating psychosis, patients with a major psychotic disorder should not be treated with RYTARY. In addition, medications that antagonize the effects of dopamine used to treat psychosis may exacerbate the symptoms of Parkinson's disease and may decrease the effectiveness of RYTARY
[see Drug Interactions (7.2)]. - Impulse Control Disorders: Consider dose reduction or stopping RYTARY if occurs. ()
5.5 Impulse Control/Compulsive BehaviorsCase reports suggest that patients can experience intense urges to gamble, increased sexual urges, intense urges to spend money, binge eating, and/or other intense urges, and the inability to control these urges while taking one or more of the medications, including RYTARY, that increase central dopaminergic tone and that are generally used for the treatment of Parkinson's disease. In some cases, although not all, these urges were reported to have stopped when the dose was reduced or the medication was discontinued.
Because patients may not recognize these behaviors as abnormal, it is important for prescribers to specifically ask patients or their caregivers about the development of new or increased gambling urges, sexual urges, uncontrolled spending or other urges while being treated with RYTARY. Consider a dose reduction or stopping the medication if a patient develops such urges while taking RYTARY.
- May cause or exacerbate dyskinesia: Consider dose reduction. ()
5.6 DyskinesiaRYTARY can cause dyskinesias that may require a dosage reduction of RYTARY or other medications used for the treatment of Parkinson's disease.