Included as part of the PRECAUTIONS section.
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.
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].
Cardiovascular Ischemic Events
Cardiovascular ischemic events have occurred in patients taking RYTARY. In a placebo controlled clinical study in patients with early Parkinsonâ€™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 Parkinsonâ€™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 Parkinsonâ€™s disease, 9/201 (4%) of RYTARYtreated patients reported hallucinations or psychosis compared to 2/192 (1%) of oral immediaterelease 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 Parkinsonâ€™s disease and may decrease the effectiveness of RYTARY [see DRUG INTERACTIONS].
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 Parkinsonâ€™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 Parkinsonâ€™s disease.
Peptic Ulcer Disease
Treatment with RYTARY may increase the possibility of upper gastrointestinal hemorrhage in patients with a history of peptic ulcer.
RYTARYmay cause increased intraocular pressure in patients with glaucoma. Monitor intraocular pressure in patients with glaucoma after starting RYTARY.
Carcinogenesis, Mutagenesis, Impairment Of Fertility
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.
Impairment Of Fertility
In reproduction studies, no effects on fertility were observed in rats receiving carbidopa-levodopa.
Use In Specific Populations
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 (see Data).
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.
Levodopa has been detected in human milk after administration of carbidopa-levodopa. There are no data on the presence of carbidopa in human milk, the effects of levodopa or carbidopa on the breastfed infant, or the effects on milk production. However, inhibition of lactation may occur because levodopa decreases secretion of prolactin in humans. Carbidopa is excreted in rat milk.
The developmental and health benefits of breastfeeding should be considered along with the motherâ€™s clinical need for RYTARY and any potential adverse effects on the breastfed infant from RYTARY or from the underlying maternal condition.
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.