Carbidopa and levodopa

INDICATIONS AND USAGE Carbidopa and levodopa extended-release tablets are indicated in the treatment of Parkinson's disease, post-encephalitic parkinsonism, and symptomatic parkinsonism that may follow carbon monoxide intoxication or manganese intoxication.

DOSAGE AND ADMINISTRATION Carbidopa and levodopa extended-release tablet contains carbidopa and levodopa in a 1:4 ratio as either the 50 mg/200 mg tablet or the 25 mg/100 mg tablet. The daily dosage of carbidopa and levodopa extended-release tablets must be determined by careful titration. Patients should be monitored closely during the dose adjustment period, particularly with regard to appearance or worsening of involuntary movements, dyskinesias or nausea. Carbidopa and levodopa extended-release tablets should not be chewed or crushed. Standard drugs for Parkinson's disease, other than levodopa without a decarboxylase inhibitor, may be used concomitantly while carbidopa and levodopa extended-release tablet is being administered, although their dosage may have to be adjusted. Since carbidopa prevents the reversal of levodopa effects caused by pyridoxine, carbidopa and levodopa extended-release tablets can be given to patients receiving supplemental pyridoxine (vitamin B 6 ). Management of Vitamin B 6 Levels Evaluate vitamin B 6 levels prior to initiating carbidopa/levodopa therapies including carbidopa and levodopa extended-release tablets, periodically during treatment, and as clinically indicated (see WARNINGS, Vitamin B6 Deficiency and Seizures ). If vitamin B 6 levels are low, supplement to sufficient levels per standard of care. Patients may initiate and continue treatment with carbidopa and levodopa extended-release tablets while supplementing vitamin B 6 . Initial Dosage Patients currently treated with conventional carbidopa levodopa preparations: Studies show that peripheral dopa-decarboxylase is saturated by the bioavailable carbidopa at doses of 70 mg a day and greater. Because the bioavailabilities of carbidopa and levodopa in carbidopa and levodopa tablets and carbidopa and levodopa extended-release tablets are different, appropriate adjustments should be made, as shown in Table 2. Table 2: Approximate Bioavailabilities at Steady State* Tablet Amount of Levodopa (mg) in Each Tablet Approximate Bioavailability Approximate Amount of Bioavailable Levodopa (mg) in Each Tablet Carbidopa and levodopa extended-release tablets 50 mg/ 200 mg 200 0.70-0.75 † 140-150 Carbidopa and levodopa tablets 25 mg/ 100 mg 100 0.99 ‡ 99 * This table is only a guide to bioavailabilities since other factors such as food, drugs, and inter-patient variabilities may affect the bioavailability of carbidopa and levodopa. † The extent of availability of levodopa from carbidopa and levodopa extended-release tablets was about 70-75% relative to intravenous levodopa or standard carbidopa and levodopa tablets in the elderly. ‡ The extent of availability of levodopa from carbidopa and levodopa tablets was 99% relative to intravenous levodopa in the healthy elderly. Dosage with carbidopa and levodopa extended-release tablets should be substituted at an amount that provides approximately 10% more levodopa per day, although this may need to be increased to a dosage that provides up to 30% more levodopa per day depending on clinical response (see DOSAGE AND ADMINISTRATION, Titration with carbidopa and levodopa extended-release tablets ). The interval between doses of carbidopa and levodopa extended-release tablets should be 4-8 hours during the waking day. (See CLINICAL PHARMACOLOGY, Pharmacodynamics. ) A guideline for initiation of carbidopa and levodopa extended-release tablets is shown in Table 3. Table 3: Guidelines for Initial Conversion from Carbidopa and Levodopa Tablets to Carbidopa and Levodopa Extended-Release Tablets Carbidopa and levodopa tablets Carbidopa and levodopa extended-release tablets Total Daily Dose* Suggested Levodopa (mg) Dosage Regimen 300-400 200 mg b.i.d. 500-600 300 mg b.i.d. or 200 mg t.i.d. 700-800 A total of 800 mg in 3 or more divided doses (e.g., 300 mg a.m., 300 mg early p.m., and 200 mg later p.m.) 900-1000 A total of 1000 mg in 3 or more divided doses (e.g., 400 mg a.m., 400 mg early p.m., and 200 mg later p.m.) *Fo…

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 tablets 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 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 B 6 Deficiency and Seizures Treatment with carbidopa and levodopa extended-release tablets may contribute to reduced vitamin B 6 levels. Higher doses of carbidopa/levodopa may increase the risk of vitamin B 6 deficiency. Seizures associated with vitamin B 6 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 B 6 administration. Other symptoms of vitamin B 6 deficiency may occur, including depression, confusion, cheilosis, glossitis, dermatitis, anemia, and/or neuropathy. Evaluate vitamin B 6 levels prior to initiation of carbidopa and levodopa extended-release tablets and periodically while on treatment or if symptoms associated with vitamin B 6 deficiency are identified. Supplement with vitamin B 6 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 …

CONTRAINDICATIONS Nonselective monoamine oxidase (MAO) inhibitors are contraindicated for use with carbidopa and levodopa extended-release tablets. These inhibitors must be discontinued at least two weeks prior to initiating therapy with carbidopa and levodopa extended-release tablets. Carbidopa and levodopa extended-release tablets may be administered concomitantly with the manufacturer's recommended dose of an MAO inhibitor with selectivity for MAO type B (e.g., selegiline HCl) (see PRECAUTIONS, Drug Interactions ). carbidopa and levodopa extended-release tablets are contraindicated in patients with known hypersensitivity to any component of this drug, and in patients with narrow-angle glaucoma.

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 tablets 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 extended-release tablets, as shown in Table 1. Table 1: Clinical Adverse Experiences Occurring in 1% or Greater of Patients Carbidopa and levodopa extended-release tablets Carbidopa and levodopa tablets n=491 n=524 Adverse Experience % % Dyskinesia 16.5 12.2 Nausea 5.5 5.7 Hallucinations 3.9 3.2 Confusion 3.7 2.3 Dizziness 2.9 2.3 Depression 2.2 1.3 Urinary tract infection 2.2 2.3 Headache 2.0 1.9 Dream abnormalities 1.8 0.8 Dystonia 1.8 0.8 Vomiting 1.8 1.9 Upper respiratory infection 1.8 1.0 Dyspnea 1.6 0.4 ‘On-Off’ phenomena 1.6 1.1 Back pain 1.6 0.6 Dry mouth 1.4 1.1 Anorexia 1.2 1.1 Diarrhea 1.2 0.6 Insomnia 1.2 1.0 Orthostatic hypotension 1.0 1.1 Shoulder pain 1.0 0.6 Chest pain 1.0 0.8 Muscle cramps 0.8 1.0 Paresthesia 0.8 1.1 Urinary frequency 0.8 1.1 Dyspepsia 0.6 1.1 Constipation 0.2 1.5 Abnormal 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 postmarketing 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. Skin Alopecia, flushing, dark sweat. Urogenital Dark urine. Other adverse reactions that have been reported with levodopa alone and with various carbidopa 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, numbness, muscle twitching, blepharospasm (…