2.1 Dosage in Patients Naïve to Levodopa Therapy

The 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. The maximum recommended daily dose of RYTARY is 612.5 mg / 2450 mg.

Maintain patients on the lowest dosage required to achieve symptomatic control and to minimize adverse reactions such as dyskinesia and nausea.

2.2 Converting from Immediate-Release Carbidopa-Levodopa to RYTARY

To convert patients from immediate-release carbidopa-levodopa to RYTARY, determine the recommended starting dosage of RYTARY using Table 1.

The dosages of other carbidopa and levodopa products are not interchangeable with the dosages of RYTARY.

Adjust the dose to maintain patient tolerance and sufficient symptomatic control. 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. The maximum recommended daily dose of RYTARY is 612.5 mg / 2450 mg.

For patients currently treated with carbidopa and levodopa plus catechol-O-methyl transferase (COMT) inhibitors (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.

2.3 Discontinuation of RYTARY

Avoid sudden discontinuation or rapid dose reduction of RYTARY. The daily dose of RYTARY should be tapered at the time of treatment discontinuation [see Warnings and Precautions (5.2)].

2.4 Administration Information

Swallow 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 opening the capsule, sprinkling the entire contents on a small amount of applesauce (1 to 2 tablespoons), and consuming immediately. Do not store the drug/food mixture for future use.

5.1 Falling Asleep During Activities of Daily Living and Somnolence

Patients 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.

5.2 Withdrawal-Emergent Hyperpyrexia and Confusion

A 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 (2.3)].

5.3 Cardiovascular Ischemic Events

Cardiovascular 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.

5.4 Hallucinations/Psychosis

There 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)].

5.5 Impulse Control/Compulsive Behaviors

Case 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.

5.6 Dyskinesia

RYTARY can cause dyskinesias that may require a dosage reduction of RYTARY or other medications used for the treatment of Parkinson's disease.

5.7 Peptic Ulcer Disease

Treatment with RYTARY may increase the possibility of upper gastrointestinal hemorrhage in patients with a history of peptic ulcer.

5.8 Glaucoma

RYTARY may cause increased intraocular pressure in patients with glaucoma. Monitor intraocular pressure in patients with glaucoma after starting RYTARY.

5.9 Melanoma

Epidemiological studies have shown that patients with Parkinson's disease have a higher risk (2- to approximately 6-fold higher) of developing melanoma than the general population. Whether the increased risk observed was due to Parkinson's disease or other factors, such as drugs used to treat Parkinson's disease, is unclear.

Perform periodic skin examinations to monitor for melanoma in patients receiving RYTARY.

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

The safety population consisted of a total of 978 Parkinson's disease patients who received at least one dose of RYTARY, and had an average duration of exposure of 40 weeks.

7.1 Monoamine Oxidase (MAO) Inhibitors

The 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.

7.2 Dopamine D2 Receptor Antagonists and Isoniazid

Dopamine D2 receptor antagonists (e.g., phenothiazines, butyrophenones, risperidone, metoclopramide) and isoniazid may reduce the effectiveness of levodopa. Monitor patients for worsening Parkinson's symptoms.

7.3 Iron Salts

Iron salts or multi-vitamins containing iron salts can form chelates with levodopa and carbidopa and can cause a reduction in the bioavailability of RYTARY. If iron salts or multi-vitamins containing iron salts are coadministered with RYTARY, monitor patients for worsening Parkinson's symptoms.

8.1 Pregnancy

8.3 Nursing Mothers

Carbidopa is excreted in rat milk. In a study of one nursing mother with Parkinson's disease, excretion of levodopa in human milk was reported. Caution should be exercised when RYTARY is administered to a nursing woman.

8.4 Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

8.5 Geriatric Use

In controlled clinical trials of RYTARY, 418 patients were 65 years or older and no overall differences in safety and efficacy were observed between these patients and those under 65 years of age.

12.1. Mechanism of Action

12.2. Pharmacodynamics

Because its decarboxylase inhibiting activity is limited to extracerebral tissues, administration of carbidopa with levodopa makes more levodopa available to the brain. The addition of carbidopa to levodopa reduces the peripheral effects (nausea, vomiting) due to decarboxylation of levodopa; however, carbidopa does not decrease the adverse reactions due to the central effects of levodopa.

Patients treated with levodopa therapy for Parkinson's disease may develop motor fluctuations characterized by end-of-dose failure, peak dose dyskinesia, 'on-off' phenomenon, and akinesia.

12.3. Pharmacokinetics

13.1. Carcinogenesis, Mutagenesis, Impairment of Fertility

14.1. Patients with Early Parkinson's Disease

The effectiveness of RYTARY in patients with early Parkinson's disease was established in a randomized, double-blind, placebo-controlled, fixed-dose, parallel-group, 30-week clinical trial (Study 1). Patients enrolled in Study 1 (n=381) were Hoehn and Yahr Stage I–III with a median disease duration of 1 year, and had limited or no prior exposure to levodopa and dopamine agonists. Patients continued taking concomitant selective monoamine oxidase B (MAO-B) inhibitors, amantadine, and anticholinergics provided the doses were stable for at least 4 weeks before screening. Eligible patients were randomized (1:1:1:1) to placebo or one of three fixed doses of RYTARY (carbidopa/levodopa doses of 36.25 mg / 145 mg, 61.25 mg / 245 mg, or 97.5 mg / 390 mg, three times a day). Patients were not allowed to receive supplemental levodopa or catechol-O-methyl transferase (COMT) inhibitors. Patients receiving RYTARY initiated treatment at 23.75 mg / 95 mg three times daily (TID). The dose was increased on Day 4 and the maximum study dose (97.5 mg / 390 mg TID) was achieved by Day 22.

The clinical outcome measure in Study 1 was the mean change from baseline in the sum of the Unified Parkinson's Disease Rating Scale (UPDRS) Part II (activities of daily living) score, and UPDRS Part III (motor score) for RYTARY, compared to placebo at Week 30 (or early termination). The mean score decrease (i.e., improvement) from baseline to Week 30 for each of the three RYTARY dosage groups was significantly greater than for placebo. The results of Study 1 are shown in Table 4.

14.2. Patients with Advanced Parkinson's Disease

Study 2 was a 22-week trial consisting of a 3-week dose adjustment of current levodopa treatment prior to a 6-week conversion to RYTARY, which was followed by a 13-week, randomized, multicenter, double-blind, levodopa-containing active control, double-dummy, parallel group trial. The study enrolled 471 (393 randomized) patients (Hoehn & Yahr Stages I-IV) who had been maintained on a stable regimen of at least 400 mg per day of levodopa prior to entry into the trial. Patients were continued on concomitant dopamine agonists, selective monoamine oxidase B (MAO-B) inhibitors, amantadine, and anticholinergics provided the doses were stable for at least 4 weeks prior to screening. Patients were randomized to receive either RYTARY or immediate-release carbidopa-levodopa at the dose determined during the adjustment or conversion phases. Patients were not allowed to receive supplemental carbidopa-levodopa or catechol-O-methyl transferase (COMT) inhibitor products during the trial.

In Study 2, approximately 60% of patients required further up titration and approximately 16% of patients required down titration compared to the recommended starting dose of RYTARY. The final total daily dose of levodopa from RYTARY was approximately double that of the final total daily dose of levodopa from immediate-release tablets. The majority (88%) of patients in Study 2 received less than 2400 mg; the median dose was 1365 mg.

The clinical outcome measure in Study 2 was the percentage of "off" time during waking hours at Week 22 (or at early termination), as assessed by the patient's Parkinson's Disease Diary. The "off" time was significantly improved in RYTARY-treated patients compared to immediate-release carbidopa-levodopa-treated patients (Table 5). The decrease in "off" time observed with RYTARY occurred with a concomitant increase in "on time" without troublesome dyskinesia.

16.1. How Supplied

RYTARY (carbidopa and levodopa) extended-release capsules are available in the following strengths:

• 23.75 mg carbidopa and 95 mg of levodopa: blue and white capsule imprinted with IPX066 on the capsule cap and 95 on the capsule body in bottles of 100 (NDC#64896-661-01) and 240 (NDC#64896-661-43)
• 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 in bottles of 100 (NDC#64896-662-01) and 240 (NDC#64896-662-43)
• 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 in bottles of 100 (NDC#64896-663-01) and 240 (NDC#64896-663-43)
• 61.25 mg carbidopa and 245 mg levodopa: blue capsule imprinted with IPX066 on the capsule cap and 245 on the capsule body in bottles 100 (NDC#64896-664-01) and 240 (NDC#64896-664-43)

16.2 Storage and Handling

Store at 25°C (77°F), excursions permitted to 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature]. Store in a tightly closed container, protected from light and moisture.

Dispense in a tightly closed, light-resistant container.

Dosing Instructions

• Advise patients to not take other carbidopa-levodopa preparations with RYTARY without consulting their healthcare provider [see Dosage and Administration (2.2)].
• Advise patients to call their healthcare provider before stopping RYTARY. Discontinue RYTARY slowly. Tell patients to call their healthcare provider if they develop withdrawal symptoms such as fever, confusion or severe muscle stiffness [see Dosage and Administration (2.3) and Warnings and Precautions (5.2)].
• Advise patients to swallow RYTARY capsules whole, without chewing, dividing, or crushing [see Dosage and Administration (2.4)].
• For patients with difficulty swallowing, the entire contents of the RYTARY capsule may be sprinkled on 1 to 2 tablespoons of applesauce and should be taken immediately [see Dosage and Administration (2.4)].
• Inform patients that a high fat, high calorie meal may delay the absorption of levodopa and the onset of action by 2 to 3 hours. For this reason, consideration should be given to taking the first dose of the day about 1 to 2 hours before eating [see Dosage and Administration (2.4) and Clinical Pharmacology (12.3)].

Falling Asleep

Advise patients that certain side effects such as sleepiness and dizziness that have been reported with RYTARY may affect some patients' ability to drive and operate machinery safely [see Warnings and Precautions (5.1) and Adverse Reactions (6.1)].

Hallucinations and Psychosis

Inform patients that hallucinations can occur with levodopa products [see Warnings and Precautions (5.4)].

Impulse Control Disorder

Inform patients of the potential for experiencing intense urges to gamble, increased sexual urges, and other intense urges and the inability to control these urges while taking one or more of the medications that increase central dopaminergic tone, that are generally used for the treatment of Parkinson's disease [see Warnings and Precautions (5.5)].

Dyskinesia

Instruct patients to notify their healthcare provider if abnormal involuntary movements appear or get worse during treatment with RYTARY [see Warnings and Precautions (5.6 )].

Hypotension and Syncope

Advise patients that they may develop orthostatic hypotension with or without symptoms such as dizziness, nausea, syncope, and sweating [see Adverse Reactions (6.1)]. Advise patients to rise slowly after sitting or lying down, especially if they have been doing so for a prolonged period.

Advise patients of the possible additive sedative effects when taking other CNS depressants in combination with RYTARY.

Pregnancy and Breast-feeding

Instruct patients to notify their physicians if they become pregnant or intend to become pregnant during therapy [see Use in Specific Populations (8.1)].

Instruct patients to notify their physicians if they intend to breast-feed or are breast-feeding an infant [see Use in Specific Populations (8.3)].