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.

Mechanism of Action Parkinson’s disease is a progressive, neurodegenerative disorder of the extrapyramidal nervous system affecting the mobility and control of the skeletal muscular system. Its characteristic features include resting tremor, rigidity, and bradykinetic movements. Symptomatic treatments, such as levodopa therapies, may permit the patient better mobility. Current evidence indicates that symptoms of Parkinson’s disease are related to depletion of dopamine in the corpus striatum. Administration of dopamine is ineffective in the treatment of Parkinson’s disease apparently because it does not cross the blood-brain barrier. However, levodopa, the metabolic precursor of dopamine, does cross the blood-brain barrier, and presumably is converted to dopamine in the brain. This is thought to be the mechanism whereby levodopa relieves symptoms of Parkinson’s disease.

DOSAGE AND ADMINISTRATION Carbidopa and levodopa extended-release tablets contain carbidopa and levodopa in a 1:4 ratio as either the 50-200 tablet or the 25-100 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 tablets are 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 ). 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 immediate-release 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 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. 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 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 immediate-release tablets in the elderly. 140-150 Carbidopa and Levodopa Immediate-Release Tablets 25 mg/100 mg 100 0.99 The extent of availability of levodopa from carbidopa and levodopa immediate-release tablets was 99% relative to intravenous levodopa in the healthy elderly. 99 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 Immediate-Release Tablets to Carbidopa and Levodopa Extended-Release Tablets Carbidopa and Levodopa Immediate-Release Tablets Total Daily Dose For dosing ranges not shown in the table see DOSAGE AND ADMINISTRATION: Initial Dosage: Patients Currently Treated with Conventional Carbidopa and Levodopa Preparations. Levodopa (mg) Carbidopa and Levodopa Extended-Release Tablets Suggested 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.) Patients Currently Treated with Levodopa Without a Decarboxylase Inhibitor Levodopa must be discontinued at least twelve hours before therapy with carbidopa and levodopa extended-release tablets is started. Carbidopa and levodopa extended-release ta

ADVERSE REACTIONS In controlled clinical trials, patients predominantly with moderate to severe motor fluctuations while on carbidopa and levodopa immediate-release were randomized to therapy with either carbidopa and levodopa immediate-release or carbidopa and levodopa extended-release. The adverse experience frequency profile of carbidopa and levodopa extended-release did not differ substantially from that of carbidopa and levodopa immediate-release, as shown in Table 1. Table 1: Clinical Adverse Experiences Occurring in 1% or Greater of Patients Adverse Experience Carbidopa and Levodopa Extended-Release n = 491 % Carbidopa and Levodopa Immediate-Release n = 524 % 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 and 475 who received carbidopa and levodopa immediate-release 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, 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: 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 are: Cardiovascular: Phlebitis. Gastrointestinal: Gastrointestinal bleeding, development of duodenal ulcer, sialorrhea, bruxism, hiccups, flatulence, burning sensation of tongue. Hematologic: Hemolytic and nonhemolytic anemia, thrombocytopenia, leukopenia, agranulocytosis. Hypersensitivity: Henoch-Schonlein purpura. Metabolic: Weight gain, edema. Nervous System/Psychiatric: Ataxia, depression with suicidal tendencies, dementia, euphoria, convulsions (however, a causal relationship has not been establ

WARNINGS When patients are receiving levodopa without a decarboxylase inhibitor, levodopa must be discontinued at least twelve hours before carbidopa and levodopa extended-release is 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 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 may develop increased dyskinesias compared to carbidopa and levodopa immediate-release. 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 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 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 may increase the possibility of upper gastrointestinal hemorrhage in patients with a history of peptic ulcer. Falling Asleep During Activities of Daily Living and Somnolence Patients taking carbidopa and levodopa extended-release 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 preexisting somnolence, although some patients may not give such a history. For this reason, prescribers should reassess patients for drowsiness or sleepiness especially since some of the events occur well after the start of treatment. Prescribers should be aware that patients may not acknowledge drowsiness or sleepiness until directly questioned about drowsiness or sleepiness during specific activities. Patients should be advised to exercise caution while driving or operating machines during treatment with carbidopa and levodopa extended-release. Patients who have already experienced somnolence or an episode of sudden sleep onset should not participate in these activities during treatment with carbidopa and levodopa extended-release. Before initiating treatment with carbidopa and levodopa extended-release, advise patients about the potential to develop drowsiness and ask specifically about factors that may increase the risk for somnolence with carbidopa and levodopa extended-release such as the use of

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. Carbidopa and levodopa extended-release 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 is contraindicated in patients with known hypersensitivity to any component of this drug and in patients with narrow-angle glaucoma.

OVERDOSAGE Management of acute overdosage with carbidopa and levodopa extended-release is the same as with levodopa. Pyridoxine is not effective in reversing the actions of carbidopa and levodopa extended-release. General supportive measures should be employed, along with immediate gastric lavage. Intravenous fluids should be administered judiciously and an adequate airway maintained. Electrocardiographic monitoring should be instituted and the patient carefully observed for the development of arrhythmias; if required, appropriate antiarrhythmic therapy should be given. The possibility that the patient may have taken other drugs as well as carbidopa and levodopa extended-release should be taken into consideration. To date, no experience has been reported with dialysis; hence, its value in overdosage is not known. Based on studies in which high doses of levodopa and/or carbidopa were administered, a significant proportion of rats and mice given single oral doses of levodopa of approximately 1500-2000 mg/kg are expected to die. A significant proportion of infant rats of both sexes are expected to die at a dose of 800 mg/kg. A significant proportion of rats are expected to die after treatment with similar doses of carbidopa. The addition of carbidopa in a 1:10 ratio with levodopa increases the dose at which a significant proportion of mice are expected to die to 3360 mg/kg.