Rytary

Overdose

In the active-controlled clinical study, a patient accidentally ingested 4.68 grams of carbidopa/18.7 grams of levodopa contained in RYTARY over a 2-day period. The patient experienced acute psychosis and dyskinesias. The patient recovered and completed the study on a reduced dose of RYTARY.

Based on the limited available information, the acute symptoms of levodopa/dopa decarboxylase inhibitor overdosage can be expected to arise from dopaminergic overstimulation. Doses of a few grams may result in CNS disturbances, with an increasing likelihood of cardiovascular disturbance (e.g., hypotension, tachycardia) and more severe psychiatric problems at higher doses. An isolated report of rhabdomyolysis and another of transient renal insufficiency suggest that levodopa overdosage may give rise to systemic complications, secondary to dopaminergic overstimulation.

Monitor patients and provide supportive care. Patients should receive electrocardiographic monitoring for the development of arrhythmias; if needed, appropriate antiarrhythmic therapy should be given. The possibility that the patient may have taken other drugs, increasing the risk of drug interactions (especially catechol-structured drugs) should be taken into consideration.

Contraindications

RYTARY is contraindicated in patients who are 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.

Undesirable effects

The following serious adverse reactions are discussed below and elsewhere in the labeling:

• Falling asleep during activities of daily living and somnolence
• Withdrawal-emergent hyperpyrexia and confusion
• Cardiovascular ischemic events
• Hallucinations/psychosis
• Impulse control/compulsive behaviors
• Dyskinesia
• Peptic Ulcer Disease
• Glaucoma
• Melanoma

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.

In a placebo-controlled clinical study in patients with early Parkinson's disease (Study 1), the most common adverse reactions with RYTARY (in at least 5% of patients and more frequently than in placebo) were nausea, dizziness, headache, insomnia, abnormal dreams, dry mouth, dyskinesia, anxiety, constipation, vomiting, and orthostatic hypotension.

Table 2 lists adverse reactions occurring in at least 5% of RYTARY-treated patients and at a higher rate than placebo in Study 1.

Table 2: Adverse Reactions in Study 1 in Patients with Early Stage Parkinson's Disease

In Study 1, 12% of patients discontinued RYTARY early due to adverse reactions; a higher proportion of patients in the 61.25 mg / 245 mg RYTARY-treated group (14%) and in the 97.5 mg / 390 mg RYTARY-treated group (15%) experienced adverse reactions leading to early discontinuation compared to (4%) in the placebo group. The most common adverse reactions resulting in early discontinuation were nausea, dizziness, and vomiting.

In an active-controlled clinical study in patients with advanced Parkinson's disease (Study 2), the most common adverse reactions with RYTARY that occurred during dose conversion or maintenance (in at least 5% of patients and more frequently than on oral immediate-release carbidopa-levodopa) were nausea and headache.

Table 3 lists adverse reactions occurring in at least 5% of RYTARY-treated patients and at a higher rate than oral immediate-release carbidopa-levodopa in Study 2.

Table 3: Adverse Reactions in Study 2 in Patients with Advanced Parkinson's Disease

In Study 2, 5% of patients discontinued treatment due to adverse reactions during conversion to RYTARY. The common adverse reactions leading to discontinuation during dose conversion were dyskinesia, anxiety, dizziness, and on and off phenomenon.

Pharmacodynamic properties

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.

Pharmacokinetic properties

Carbidopa

Following 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%.

Levodopa

The 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 carbidopalevodopa. Following an initial peak at about one hour, plasma concentrations are maintained for about 4 to 5 hours before declining.

Carbidopa is approximately 36% bound to plasma proteins. Approximately 10-30% of levodopa is bound to plasma protein.

Carbidopa

The 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 to 100 mg per day, which produces equivalent exposure to 140 to 200 mg of carbidopa provided by RYTARY.

Levodopa

The 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).

RYTARY shows approximately dose proportional pharmacokinetics for both carbidopa and levodopa over the levodopa dosage strength range of 95 mg to 245 mg.

In healthy adults, oral administration of RYTARY after a high-fat, high-calorie meal reduced Cmax approximately 21% and increased AUCinf approximately 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.

Date of revision of the text

Fertility, pregnancy and lactation

There are no adequate and well-controlled studies in pregnant women. It has been reported from individual cases that levodopa crosses the human placental barrier, enters the fetus, and is metabolized. In animal studies, carbidopa-levodopa has been shown to be developmentally toxic (including teratogenic effects) at clinically relevant doses. RYTARY should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

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.

Special warnings and precautions for use

Included as part of the "PRECAUTIONS" Section

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.

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.

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.

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 carbidopalevodopa- 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.

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.

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

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

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

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.

In rats, oral administration of carbidopa-levodopa for two years resulted in no evidence of carcinogenicity.

Carbidopa was mutagenic in the in vitro Ames test and in the in vitro mouse lymphoma tk assay but was negative in the in vivo mouse micronucleus assay.

In reproduction studies, no effects on fertility were observed in rats receiving carbidopa-levodopa.

There are no adequate and well-controlled studies in pregnant women. It has been reported from individual cases that levodopa crosses the human placental barrier, enters the fetus, and is metabolized. In animal studies, carbidopa-levodopa has been shown to be developmentally toxic (including teratogenic effects) at clinically relevant doses. RYTARY should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

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.

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.

Safety and effectiveness in pediatric patients have not been established.

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.

Dosage (Posology) and method of administration

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.

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.

Table 1: Conversion from Immediate-Release Carbidopa-Levodopa to RYTARY

Avoid sudden discontinuation or rapid dose reduction of RYTARY. The daily dose of RYTARY should be tapered at the time of treatment discontinuation.

Swallow RYTARY whole with or without food. A high-fat, high-calorie meal may delay the absorption of levodopa by about 2 hours.

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.

Interaction with other medicinal products and other forms of interaction

The following serious adverse reactions are discussed below and elsewhere in the labeling:

• Falling asleep during activities of daily living and somnolence
• Withdrawal-emergent hyperpyrexia and confusion
• Cardiovascular ischemic events
• Hallucinations/psychosis
• Impulse control/compulsive behaviors
• Dyskinesia
• Peptic Ulcer Disease
• Glaucoma
• Melanoma

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.

In a placebo-controlled clinical study in patients with early Parkinson's disease (Study 1), the most common adverse reactions with RYTARY (in at least 5% of patients and more frequently than in placebo) were nausea, dizziness, headache, insomnia, abnormal dreams, dry mouth, dyskinesia, anxiety, constipation, vomiting, and orthostatic hypotension.

Table 2 lists adverse reactions occurring in at least 5% of RYTARY-treated patients and at a higher rate than placebo in Study 1.

Table 2: Adverse Reactions in Study 1 in Patients with Early Stage Parkinson's Disease

In Study 1, 12% of patients discontinued RYTARY early due to adverse reactions; a higher proportion of patients in the 61.25 mg / 245 mg RYTARY-treated group (14%) and in the 97.5 mg / 390 mg RYTARY-treated group (15%) experienced adverse reactions leading to early discontinuation compared to (4%) in the placebo group. The most common adverse reactions resulting in early discontinuation were nausea, dizziness, and vomiting.

In an active-controlled clinical study in patients with advanced Parkinson's disease (Study 2), the most common adverse reactions with RYTARY that occurred during dose conversion or maintenance (in at least 5% of patients and more frequently than on oral immediate-release carbidopa-levodopa) were nausea and headache.

Table 3 lists adverse reactions occurring in at least 5% of RYTARY-treated patients and at a higher rate than oral immediate-release carbidopa-levodopa in Study 2.

Table 3: Adverse Reactions in Study 2 in Patients with Advanced Parkinson's Disease

In Study 2, 5% of patients discontinued treatment due to adverse reactions during conversion to RYTARY. The common adverse reactions leading to discontinuation during dose conversion were dyskinesia, anxiety, dizziness, and on and off phenomenon.

The use of nonselective MAO inhibitors with RYTARY is contraindicated. 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.

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.

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.