Carbidopa and Levodopa 25 mg; 100 mg Tablet, Extended Release, 100-count — NDC 60219-2033-1 (Billing 60219-2033-01)

WARNINGS When patients are receiving levodopa without a decarboxylase inhibitor, levodopa must be discontinued at least twelve hours before carbidopa and levodopa extended-release tablets are started. In order to reduce adverse reactions, it is necessary to individualize therapy. See DOSAGE AND ADMINISTRATION section before initiating therapy.

Carbidopa and levodopa extended-release tablets should be substituted at a dosage that will provide approximately 25% of the previous levodopa dosage (see DOSAGE AND ADMINISTRATION ). Carbidopa does not decrease adverse reactions due to central effects of levodopa. By permitting more levodopa to reach the brain, particularly when nausea and vomiting is not a dose-limiting factor, certain adverse central nervous system (CNS) effects, e.g., dyskinesias, will occur at lower dosages and sooner during therapy with carbidopa and levodopa extended-release than with levodopa alone.

Patients receiving carbidopa and levodopa extended-release tablets may develop increased dyskinesias compared to carbidopa and levodopa tablets. Dyskinesias are a common side effect of carbidopa and levodopa treatment. The occurrence of dyskinesias may require dosage reduction.

All patients should be observed carefully for the development of depression with concomitant suicidal tendencies. Carbidopa and levodopa extended-release tablets should be administered cautiously to patients with severe cardiovascular or pulmonary disease, bronchial asthma, renal, hepatic or endocrine disease. As with levodopa, care should be exercised in administering carbidopa and levodopa extended-release tablets to patients with a history of myocardial infarction who have residual atrial, nodal, or ventricular arrhythmias.

In such patients, cardiac function should be monitored with particular care during the period of initial dosage adjustment, in a facility with provisions for intensive cardiac care. As with levodopa, treatment with carbidopa and levodopa extended-release tablets may increase the possibility of upper gastrointestinal hemorrhage in patients with a history of peptic ulcer. Vitamin B6 Deficiency and Seizures Treatment with carbidopa and levodopa extended-release tablets may contribute to reduced vitamin B6 levels.

Higher doses of carbidopa/levodopa may increase the risk of vitamin B6 deficiency. Seizures associated with vitamin B6 deficiency have been reported in the postmarketing setting in patients taking carbidopa and levodopa extended-release tablets. In these reported cases, seizures were refractory to traditional anti-seizure medications and only resolved after vitamin B6 administration.

Other symptoms of vitamin B6 deficiency may occur, including depression, confusion, cheilosis, glossitis, dermatitis, anemia, and/or neuropathy. Evaluate vitamin B6 levels prior to initiation of carbidopa and levodopa extended-release tablets and periodically while on treatment or if symptoms associated with vitamin B6 deficiency are identified. Supplement with vitamin B6 as necessary.

Falling Asleep During Activities of Daily Living and Somnolence Patients taking carbidopa and levodopa extended-release tablets alone or with other dopaminergic drugs have reported suddenly falling asleep without prior warning of sleepiness while engaged in activities of daily living (includes operation of motor vehicles). Road traffic accidents attributed to sudden sleep onset have been reported. Although many patients reported somnolence while on dopaminergic medications, there have been reports of road traffic accidents attributed to sudden onset of sleep in which the patient did not perceive any warning signs, such as excessive drowsiness, and believed that they were alert immediately prior to the event.

Sudden onset of sleep has been reported to occur as long as one year after the initiation of treatment. Falling asleep while engaged in activities of daily living usually occurs in patients experiencing pre-existing somnolence, although some patients… [Excerpted — this section continues on DailyMed.]

ADVERSE REACTIONS In controlled clinical trials, patients predominantly with moderate to severe motor fluctuations while on carbidopa and levodopa tablets were randomized to therapy with either carbidopa and levodopa or carbidopa and levodopa extended-release tablets. The adverse experience frequency profile of carbidopa and levodopa extended-release tablets did not differ substantially from that of carbidopa and levodopa tablets, as shown in Table 1. Table 1: Clinical Adverse Experiences Occurring in 1% or Greater of Patients Adverse Experience Carbidopa and LevodopaExtended-releaseTablets Carbidopa and LevodopaTablets n = 491 n = 524 % % Dyskinesia 16.5

12.2Nausea 5.5

5.7Hallucinations 3.9

3.2Confusion 3.7

2.3Dizziness 2.9

2.3Depression 2.2

1.3Urinary tract infection 2.2

2.3Headache 2.0

1.9Dream abnormalities 1.8

0.8Dystonia 1.8

0.8Vomiting 1.8

1.9Upper respiratory infection 1.8

1.0Dyspnea 1.6 0.4 ‘On-Off’ phenomena 1.6

1.1Back pain 1.6

0.6Dry mouth 1.4

1.1Anorexia 1.2

1.1Diarrhea 1.2

0.6Insomnia 1.2

1.0Orthostatic hypotension 1.0

1.1Shoulder pain 1.0

0.6Chest pain 1.0

0.8Muscle cramps 0.8

1.0Paresthesia 0.8

1.1Urinary frequency 0.8

1.1Dyspepsia 0.6

1.1Constipation 0.2

1.5Abnormal laboratory findings occurring at a frequency of 1% or greater in approximately 443 patients who received carbidopa and levodopa extended-release tablets and 475 who received carbidopa and levodopa tablets during controlled clinical trials included: decreased hemoglobin and hematocrit; elevated serum glucose; white blood cells, bacteria and blood in the urine. The adverse experiences observed in patients in uncontrolled studies were similar to those seen in controlled clinical studies. Other adverse experiences reported overall in clinical trials in 748 patients treated with carbidopa and levodopa extended-release tablets, listed by body system in order of decreasing frequency, include: Body as a Whole: Asthenia, fatigue, abdominal pain, orthostatic effects.

Cardiovascular: Palpitation, hypertension, hypotension, myocardial infarction. Gastrointestinal: Gastrointestinal pain, dysphagia, heartburn. Metabolic: Weight loss.

Musculoskeletal: Leg pain. Nervous System/Psychiatric: Chorea, somnolence, falling, anxiety, disorientation, decreased mental acuity, gait abnormalities, extrapyramidal disorder, agitation, nervousness, sleep disorders, memory impairment. Respiratory: Cough, pharyngeal pain, common cold.

Skin: Rash. Special Senses: Blurred vision. Urogenital: Urinary incontinence.

Laboratory Tests: Decreased white blood cell count and serum potassium; increased BUN, serum creatinine and serum LDH; protein and glucose in the urine. The following adverse experiences have been reported in post-marketing experience with carbidopa and levodopa extended-release tablets: Cardiovascular: Cardiac irregularities, syncope. Gastrointestinal: Taste alterations, dark saliva.

Hypersensitivity: Angioedema, urticaria, pruritus, bullous lesions (including pemphigus-like reactions). Nervous System/Psychiatric: Increased tremor, peripheral neuropathy, psychotic episodes including delusions and paranoid ideation, pathological gambling, increased libido including hypersexuality, impulse control symptoms, seizures (including convulsions). Skin: Alopecia, flushing, dark sweat.

Urogenital: Dark urine. Other adverse reactions that have been reported with levodopa alone and with various carbidopa and levodopa formulations and may occur with carbidopa and levodopa extended-release tablets are: Cardiovascular: Phlebitis. Gastrointestinal: Gastrointestinal bleeding, development of duodenal ulcer, sialorrhea, bruxism, hiccups, flatulence, burning sensation of tongue.

Hematologic: Hemolytic and non-hemolytic anemia, thrombocytopenia, leukopenia, agranulocytosis. Hypersensitivity: Henoch-Schönlein purpura. Metabolic: Weight gain, edema.

Nervous System/Psychiatric: Ataxia, depression with suicidal tendencies, dementia, euphoria, bradykinetic episodes, numbn… [Excerpted — this section continues on DailyMed.]

Drug Interactions Caution should be exercised when the following drugs are administered concomitantly with carbidopa and levodopa extended-release tablets. Symptomatic postural hypotension has occurred when carbidopa and levodopa preparations were added to the treatment of patients receiving some antihypertensive drugs. Therefore, when therapy with carbidopa and levodopa extended-release tablets is started, dosage adjustment of the antihypertensive drug may be required.

For patients receiving MAO inhibitors (Type A or B), see CONTRAINDICATIONS . Concomitant therapy with selegiline and carbidopa and levodopa may be associated with severe orthostatic hypotension not attributable to carbidopa and levodopa alone (see CONTRAINDICATIONS ). There have been rare reports of adverse reactions, including hypertension and dyskinesia, resulting from the concomitant use of tricyclic antidepressants and carbidopa and levodopa preparations.

Dopamine D 2 receptor antagonists (e.g., phenothiazines, butyrophenones, risperidone) and isoniazid may reduce the therapeutic effects of levodopa. In addition, the beneficial effects of levodopa in Parkinson’s disease have been reported to be reversed by phenytoin and papaverine. Patients taking these drugs with carbidopa and levodopa extended-release tablets should be carefully observed for loss of therapeutic response.

Use of carbidopa and levodopa extended-release tablets with dopamine-depleting agents (e.g., reserpine and tetrabenazine) or other drugs known to deplete monoamine stores is not recommended. Carbidopa and levodopa extended-release tablets and iron salts or multivitamins containing iron salts should be coadministered with caution. Iron salts can form chelates with levodopa and carbidopa and consequently reduce the bioavailability of carbidopa and levodopa.

Although metoclopramide may increase the bioavailability of levodopa by increasing gastric emptying, metoclopramide may also adversely affect disease control by its dopamine receptor antagonistic properties.

PRECAUTIONS General As with levodopa, periodic evaluations of hepatic, hematopoietic, cardiovascular, and renal function are recommended during extended therapy. Patients with chronic wide-angle glaucoma may be treated cautiously with carbidopa and levodopa extended-release tablets provided the intraocular pressure is well-controlled and the patient is monitored carefully for changes in intraocular pressure during therapy. Dyskinesia Levodopa alone, as well as carbidopa and levodopa extended-release tablets are associated with dyskinesias.

The occurrence of dyskinesias may require dosage reduction. Hallucinations / Psychotic-Like Behavior Hallucinations and psychotic-like behavior have been reported with dopaminergic medications. In general, hallucinations present shortly after the initiation of therapy and may be responsive to dose reduction in levodopa.

Hallucinations may be accompanied by confusion and to a lesser extent sleep disorder (insomnia) and excessive dreaming. Carbidopa and levodopa extended-release tablets may have similar effects on thinking and behavior. This 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.

Ordinarily, patients with a major psychotic disorder should not be treated with carbidopa and levodopa extended-release tablets, because of the risk of exacerbating psychosis. In addition, certain medications used to treat psychosis may exacerbate the symptoms of Parkinson’s disease and may decrease the effectiveness of carbidopa and levodopa extended-release tablets. Impulse Control / Compulsive Behaviors Reports of patients taking dopaminergic medications (medications that increase central dopaminergic tone), suggest that patients may experience an intense urge to gamble, increased sexual urges, intense urges to spend money, binge eating, and/or other intense urges, and the inability to control these urges.

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 the caregivers about the development of new or increased gambling urges, sexual urges, uncontrolled spending or other urges while being treated with carbidopa and levodopa extended-release tablets. Physicians should consider dose reduction or stopping the medication if a patient develops such urges while taking carbidopa and levodopa extended-release tablets (see Information for Patients ) .

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. For the reasons stated above, patients and providers are advised to monitor for melanomas frequently and on a regular basis when using carbidopa and levodopa extended-release tablets for any indication.

Ideally, periodic skin examinations should be performed by appropriately qualified individuals (e.g., dermatologists). Information for Patients The patient should be informed that carbidopa and levodopa extended-release tablet is an extended-release formulation of carbidopa and levodopa which releases these ingredients over a 4- to 6-hour period. It is important that carbidopa and levodopa extended-release tablets be taken at regular intervals according to the schedule outlined by the physician.

The patient should be cautioned not to change the prescribed dosage regimen and not to add any additional antiparkinson medications, including other carbidopa and levodopa preparations, without first consulting the physician. If abnormal involuntary movements appea… [Excerpted — this section continues on DailyMed.]