CARBIDOPA AND LEVODOPA

Carbidopa and levodopa extended-release capsule is a combination of carbidopa, an inhibitor of aromatic amino acid decarboxylation, and levodopa, an aromatic amino acid, in extended-release capsules for oral use. Carbidopa is a white to creamy white powder, slightly soluble in water, with a molecular weight of 244.2. It is designated chemically as (-)-L-α-hydrazino-3, 4-dihydroxy-α-methylhydrocinnamic acid monohydrate. Its molecular formula is C 10 H 14 N 2 O 4 • H 2 O and its structural formula is: Capsule content is expressed in terms of anhydrous carbidopa, which has a molecular weight of 226.2. Levodopa is a white to off-white, crystalline powder, slightly soluble in water, with a molecular weight of 197.2. It is designated chemically as (−)-3-(3, 4-Dihydroxyphenyl)-L-alanine. Its molecular formula is C 9 H 11 NO 4 and its structural formula is: Each extended-release capsule contains 23.75 mg carbidopa, USP and 95 mg levodopa USP, 36.25 mg carbidopa, USP and 145 mg levodopa USP, 48.75 mg carbidopa, USP and 195 mg levodopa USP, or 61.25 mg carbidopa, USP and 245 mg levodopa USP. The inactive ingredients are microcrystalline cellulose, mannitol, tartaric acid, ethyl cellulose, hypromellose, sodium starch glycolate, sodium lauryl sulfate, povidone, talc, methacrylic acid copolymers, triethyl citrate, croscarmellose sodium, and magnesium stearate. All capsule shells contain gelatin and titanium dioxide. In addition, all blue capsule shells contain FD&C Blue #2 and yellow iron oxide. All yellow capsule shells contain yellow iron oxide. All capsules imprinted with blue pharmaceutical ink contain FD&C Blue #2, butyl alcohol, dehydrated alcohol, isopropyl alcohol, propylene glycol, shellac and strong ammonia solution. Image Image

Carbidopa and levodopa extended-release capsules are indicated for the treatment of Parkinson's disease, post-encephalitic parkinsonism, and parkinsonism that may follow carbon monoxide intoxication or manganese intoxication. Carbidopa and levodopa extended-release capsule is a combination of carbidopa (an aromatic amino acid decarboxylation inhibitor) and levodopa (an aromatic amino acid) indicated for the treatment of Parkinson's disease, post-encephalitic parkinsonism, and parkinsonism that may follow carbon monoxide intoxication or manganese intoxication ( 1 )

Levodopa-naïve patients: Starting dose is 23.75 mg / 95 mg three times daily; may increase to 36.25 mg / 145 mg three times daily on the fourth day of treatment ( 2.1 ) See Table 1 for instructions for converting patients taking immediate-release carbidopa-levodopa to an initial dose of carbidopa and levodopa extended-release capsules. Dosages of carbidopa and levodopa extended-release capsules are not interchangeable with other carbidopa-levodopa products ( 2.2 ) The maximum recommended daily dose of carbidopa and levodopa extended-release capsules is 612.5 mg/2,450 mg ( 2.1 , 2.2 ) Carbidopa and levodopa extended-release capsules may be taken with or without food; do not chew, divide or crush ( 2.4 , 12.3 ) 2.1 Dosage in Patients Naïve to Levodopa Therapy The recommended starting dosage of carbidopa and levodopa extended-release capsules 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 carbidopa and levodopa extended-release capsules may be increased to 36.25 mg/145 mg taken three times a day. Based upon individual patient clinical response and tolerability, the carbidopa and levodopa extended-release capsules 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. Maintain patients on the lowest dosage required to achieve symptomatic control and to minimize adverse reactions such as dyskinesia and nausea. The maximum recommended daily dose of carbidopa and levodopa extended-release capsules is 612.5 mg/2,450 mg. 2.2 Converting from Immediate-Release Carbidopa-Levodopa to Carbidopa and Levodopa Extended-Release Capsules The dosages of other carbidopa and levodopa products are not interchangeable on a 1:1 basis with the dosages of carbidopa and levodopa extended-release capsules. To convert patients from immediate-release carbidopa-levodopa to carbidopa and levodopa extended-release capsules, first calculate the patient's current total daily dose of levodopa. The starting total daily dose of carbidopa and levodopa extended-release capsules is as recommended in Table 1. After conversion, any combination of the four carbidopa and levodopa extended-release capsules dosage strengths can be used to achieve an optimal dosing. Adjust the dose and dosing frequency as necessary to maintain patient tolerance and sufficient symptomatic control. Administration of concomitant Parkinson's disease medications should remain stable while adjusting the carbidopa and levodopa extended-release capsules dose. In clinical trials, carbidopa and levodopa extended-release capsules were administered in divided doses of three to five times a day. The maximum recommended total daily dose of carbidopa and levodopa extended-release capsule is 612.5 mg/2,450 mg. For patients currently treated with carbidopa and levodopa plus a catechol-O-methyl transferase (COMT) inhibitor (such as entacapone), the initial total daily dose of levodopa in carbidopa and levodopa extended-release capsules described in Table 1 may need to be increased. Use of carbidopa and levodopa extended-release capsules in combination with other levodopa products has not been studied. Table 1 Conversion from Immediate-Release Carbidopa-Levodopa to Carbidopa and Levodopa Extended-Release Capsules Total Daily Dose of Levodopa in Immediate-Release Carbidopa- Levodopa Recommended Starting Dosage of Carbidopa and Levodopa Extended-Release Capsules Total Daily Dose of Levodopa in Carbidopa and Levodopa Extended-Release Capsules Carbidopa and Levodopa Extended-Release Capsules Dosing Regimen 400 mg to 549 mg 855 mg 3 capsules carbidopa and levodopa extended-release capsules 23.75 mg/95 mg taken TID a 550 mg to 749 mg 1,140 mg 4 capsules carbidopa and levodopa extended-release capsules 23.75 mg/95 mg taken TID 750 mg to 949 mg 1,305 mg 3 capsules carbidopa and levodopa extended-release capsules 36.25 mg/145 mg taken TID 950 mg to 1,249 mg 1,755 mg 3 capsules carbidopa and levodopa extended-release capsules 48.75 mg/195 mg taken TID Equal to or greater than 1,250 mg 2,340 mg or 4 capsules carbidopa and levodopa extended-release capsules 48.75 mg/195 mg taken TID or 2,205 mg 3 capsules carbidopa and levodopa extended-release capsules 61.25 mg/245 mg taken TID a TID: three times a day 2.3 Discontinuation of Carbidopa And Levodopa Extended-Release Capsules Avoid sudden discontinuation or rapid dose reduction of carbidopa and levodopa extended-release capsules. The daily dose of carbidopa and levodopa extended-release capsules should be tapered at the time of treatment discontinuation [see Warnings and Precautions ( 5.2 )] . 2.4 Administration Information Swallow carbidopa and levodopa extended-release capsules whole with or without food. A high-fat, high-calorie meal may delay the absorption of levodopa by about 2 hours [see Clinical Pharmacology ( 12.3 )]. Do not chew, divide or crush carbidopa and levodopa extended-release capsules. For patients who have difficulty swallowing intact capsules, administer carbidopa and levodopa extended-release capsules by carefully twisting apart both halves of the capsule. Sprinkle the entire contents of both halves of the capsule on a small amount of applesauce (1 to 2 tablespoons) and consume the mixture immediately. Do not store the drug/food mixture for future use.

Carbidopa and levodopa extended-release capsules are contraindicated in patients: 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 [see Drug Interactions ( 7.1 )] . Nonselective MAO inhibitors ( 4 )

The following serious adverse reactions are discussed below and elsewhere in the labeling: Falling Asleep During Activities of Daily Living and Somnolence [see Warnings and Precautions ( 5.1 )] Withdrawal-Emergent Hyperpyrexia and Confusion [see Warnings and Precautions ( 5.2 )] Cardiovascular Ischemic Events [see Warnings and Precautions ( 5.3 )] Hallucinations/Psychosis [see Warnings and Precautions ( 5.4 )] Impulse Control/Compulsive Behaviors [see Warnings and Precautions ( 5.5 )] Dyskinesia [see Warnings and Precautions ( 5.6 )] Peptic Ulcer Disease [see Warnings and Precautions ( 5.7 )] Glaucoma [see Warnings and Precautions ( 5.8 )] Early Parkinson's disease: Most common adverse reactions (incidence ≥ 5% and greater than placebo) are nausea, dizziness, headache, insomnia, abnormal dreams, dry mouth, dyskinesia, anxiety, constipation, vomiting, and orthostatic hypotension ( 6.1 ) Advanced Parkinson's disease: Most common adverse reactions (incidence ≥ 5% and greater than oral immediate-release carbidopa-levodopa) are nausea and headache ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Zydus Pharmaceuticals (USA) Inc. at 1-877-993-8779 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience 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 carbidopa and levodopa extended-release capsules, and had an average duration of exposure of 40 weeks. Adverse Reactions in Early Parkinson's Disease In a placebo-controlled clinical study in patients with early Parkinson's disease (Study 1), the most common adverse reactions with carbidopa and levodopa extended-release capsules (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 carbidopa and levodopa extended-release capsules-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 Placebo Carbidopa and Levodopa Extended-release Capsules 36.25 mg Carbidopa Carbidopa and Levodopa Extended-release Capsules 61.25 mg Carbidopa Carbidopa and Levodopa Extended-release Capsules 97.5 mg Carbidopa 145 mg Levodopa TID 245 mg Levodopa TID 390 mg Levodopa TID (N=92) (N=87) (N=104) (N=98) % % % % Nausea 9 14 19 20 Dizziness 5 9 19 12 Headache 11 7 13 17 Insomnia 3 2 9 6 Abnormal Dreams 0 2 6 5 Dry Mouth 1 3 2 7 Dyskinesia 0 2 4 5 Anxiety 0 2 3 5 Constipation 1 2 6 2 Vomiting 3 2 2 5 Orthostatic Hypotension 1 1 1 5 Adverse Reactions Leading to Discontinuation in Study 1 In Study 1, 12% of patients discontinued carbidopa and levodopa extended-release capsules early due to adverse reactions; a higher proportion of patients in the 61.25 mg/ 245 mg carbidopa and levodopa extended-release capsules-treated group (14%) and in the 97.5 mg/390 mg carbidopa and levodopa extended-release capsules-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. Adverse Reactions in Advanced Parkinson's Disease In an active-controlled clinical study in patients with advanced Parkinson's disease (Study 2), the most common adverse reactions with carbidopa and levodopa extended-release capsules 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 carbidopa and levodopa extended-release capsules-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 Carbidopa and Levodopa Extended-release Capsules Immediate-Release Carbidopa-Levodopa (N=201) (N=192) Period Dose Conversion a Maintenance Dose Conversion a Maintenance % % % % Nausea 4 3 6 2 Headache 5 1 3 2 a All patients were converted to carbidopa and levodopa extended-release capsules in the open-label Dose Conversion period and then received randomized treatment during maintenance. Adverse Reactions Leading to Discontinuation in Study 2 In Study 2, 5% of patients discontinued treatment due to adverse reactions during conversion to carbidopa and levodopa extended-release capsules. The common adverse reactions leading to discontinuation during dose conversion were dyskinesia, anxiety, dizziness, and on and off phenomenon. 6.2 Postmarketing Experience The following adverse reactions have been identified during post approval use of carbidopa and levodopa extended-release capsules. Because these reactions are reported voluntarily from a population of unknown size, it is not always possible to reliably estimate their frequency or establish causal relationship to carbidopa and levodopa extended-release capsules exposure. Psychiatric : Suicide attempt, suicidal ideation.

Iron salts and dopamine D2 antagonists including metoclopramide: May reduce the effectiveness of carbidopa and levodopa extended-release capsules ( 7.2 , 7.3 ) 7.1 Monoamine Oxidase (MAO) Inhibitors The use of nonselective MAO inhibitors with carbidopa and levodopa extended-release capsules is contraindicated [see Contraindications ( 4 )] . Discontinue use of any nonselective MAO inhibitors at least two weeks prior to initiating carbidopa and levodopa extended-release capsules. The use of selective MAO-B inhibitors (e.g., rasagiline and selegiline) with carbidopa and levodopa extended-release capsules may be associated with orthostatic hypotension. Monitor patients who are taking these drugs concurrently. 7.2 Dopamine D2 Receptor Antagonists and Isoniazid 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. 7.3 Iron Salts Iron salts or multivitamins containing iron salts can form chelates with levodopa and carbidopa and can cause a reduction in the bioavailability of carbidopa and levodopa extended-release capsules. If iron salts or multivitamins containing iron salts are co-administered with carbidopa and levodopa extended-release capsules, monitor patients for worsening Parkinson's symptoms.

16.2 Storage and Handling Store at 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature]. Store in a tightly closed container, protected from light and moisture. Dispense in a tight, light-resistant container as defined in the USP.