CARBIDOPA AND LEVODOPA

INDICATIONS AND USAGE Carbidopa and levodopa orally disintegrating 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. Carbidopa allows patients treated for Parkinson’s disease to use much lower doses of levodopa. Some patients who responded poorly to levodopa have improved on carbidopa and levodopa orally disintegrating tablets. This is most likely due to decreased peripheral decarboxylation of levodopa caused by administration of carbidopa rather than by a primary effect of carbidopa on the nervous system. Carbidopa has not been shown to enhance the intrinsic efficacy of levodopa. Carbidopa may also reduce nausea and vomiting and permit more rapid titration of levodopa.

DOSAGE AND ADMINISTRATION Instructions for Use/Handling Carbidopa and Levodopa Orally Disintegrating Tablets, USP Just prior to administration, GENTLY remove the tablet from the bottle with dry hands. IMMEDIATELY place the carbidopa and levodopa orally disintegrating tablet on top of the tongue where it will dissolve in seconds, then swallow with saliva. Administration with liquid is not necessary. The optimum daily dosage of carbidopa and levodopa orally disintegrating tablets must be determined by careful titration in each patient. Carbidopa and levodopa orally disintegrating tablets are available in a 1:4 ratio of carbidopa to levodopa (carbidopa and levodopa orally disintegrating tablets 25 mg/100 mg) as well as 1:10 ratio (carbidopa and levodopa orally disintegrating tablets 25 mg/250 mg and carbidopa and levodopa orally disintegrating tablets 10 mg/100 mg). Tablets of the two ratios may be given separately or combined as needed to provide the optimum dosage. Studies show that peripheral dopa decarboxylase is saturated by carbidopa at approximately 70 to 100 mg a day. Patients receiving less than this amount of carbidopa are more likely to experience nausea and vomiting. Management of Vitamin B 6 Levels Evaluate vitamin B 6 levels prior to initiating carbidopa/levodopa therapies, including carbidopa and levodopa orally disintegrating tablets, periodically during treatment, and as clinically indicated (See WARNINGS, Vitamin B 6 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 orally disintegrating tablets while supplementing vitamin B 6 . Usual Initial Dosage Dosage is best initiated with one tablet of carbidopa and levodopa orally disintegrating tablets 25 mg/100 mg three times a day. This dosage schedule provides 75 mg of carbidopa per day. Dosage may be increased by one tablet every day or every other day, as necessary, until a dosage of eight tablets of carbidopa and levodopa orally disintegrating tablets 25 mg/100 mg a day is reached. If carbidopa and levodopa orally disintegrating tablet 10 mg/100 mg is used, dosage may be initiated with one tablet three or four times a day. However, this will not provide an adequate amount of carbidopa for many patients. Dosage may be increased by one tablet every day or every other day until a total of eight tablets (2 tablets q.i.d.) is reached. How to Transfer Patients from Levodopa Levodopa must be discontinued at least twelve hours before starting carbidopa and levodopa orally disintegrating tablets . A daily dosage of carbidopa and levodopa orally disintegrating tablets should be chosen that will provide approximately 25% of the previous levodopa dosage. Patients who are taking less than 1500 mg of levodopa a day should be started on one tablet of carbidopa and levodopa orally disintegrating tablets 25 mg/100 mg three or four times a day. The suggested starting dosage for most patients taking more than 1500 mg of levodopa is one tablet of carbidopa and levodopa orally disintegrating tablets 25 mg/250 mg three or four times a day. Maintenance Therapy should be individualized and adjusted according to the desired therapeutic response. At least 70 to 100 mg of carbidopa per day should be provided. When a greater proportion of carbidopa is required, one tablet of carbidopa and levodopa orally disintegrating tablets 25 mg/100 mg may be substituted for each tablet of carbidopa and levodopa orally disintegrating tablets 10 mg/100 mg. When more levodopa is required, carbidopa and levodopa orally disintegrating tablets 25 mg/250 mg should be substituted for carbidopa and levodopa orally disintegrating tablets 25 mg/100 mg or carbidopa and levodopa orally disintegrating tablets 10 mg/100 mg. If necessary, the dosage of carbidopa and levodopa orally disintegrating tablets 25 mg/250 mg may be increased by one-half or one tablet every day or every other da …

CONTRAINDICATIONS Nonselective monoamine oxidase (MAO) inhibitors are contraindicated for use with carbidopa and levodopa orally disintegrating tablets. These inhibitors must be discontinued at least two weeks prior to initiating therapy with carbidopa and levodopa orally disintegrating tablets. Carbidopa and levodopa orally disintegrating 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 orally disintegrating tablets are contraindicated in patients with known hypersensitivity to any component of this drug, and in patients with narrow-angle glaucoma.

ADVERSE REACTIONS The most common adverse reactions reported with carbidopa and levodopa orally disintegrating tablets have included dyskinesias, such as choreiform, dystonic, and other involuntary movements, and nausea. The following other adverse reactions have been reported with carbidopa and levodopa: Body as a Whole Chest pain, asthenia. Cardiovascular Cardiac irregularities, hypotension, orthostatic effects including orthostatic hypotension, hypertension, syncope, phlebitis, palpitation. Gastrointestinal Dark saliva, gastrointestinal bleeding, development of duodenal ulcer, anorexia, vomiting, diarrhea, constipation, dyspepsia, dry mouth, taste alterations. Hematologic Agranulocytosis, hemolytic and non-hemolytic anemia, thrombocytopenia, leukopenia. Hypersensitivity Angioedema, urticaria, pruritus, Henoch-Schönlein purpura, bullous lesions (including pemphigus-like reactions). Musculoskeletal Back pain, shoulder pain, muscle cramps. Nervous System/Psychiatric Psychotic episodes including delusions, hallucinations, and paranoid ideation, bradykinetic episodes (“on-off” phenomenon), confusion, agitation, dizziness, somnolence, dream abnormalities including nightmares, insomnia, paresthesia, headache, depression with or without development of suicidal tendencies, dementia, pathological gambling, increased libido including hypersexuality, impulse control symptoms. Convulsions also have occurred; however, a causal relationship with carbidopa and levodopa has not been established. Respiratory Dyspnea, upper respiratory infection. Skin Rash, increased sweating, alopecia, dark sweat. Urogenital Urinary tract infection, urinary frequency, dark urine. Laboratory Tests Decreased hemoglobin and hematocrit; abnormalities in alkaline phosphatase, SGOT (AST), SGPT (ALT), LDH, bilirubin, BUN, Coombs test; elevated serum glucose; white blood cells, bacteria, and blood in the 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 orally disintegrating tablets are: Body as a Whole Abdominal pain and distress, fatigue. Cardiovascular Myocardial infarction. Gastrointestinal Gastrointestinal pain, dysphagia, sialorrhea, flatulence, bruxism, burning sensation of the tongue, heartburn, hiccups. Metabolic Edema, weight gain, weight loss. Musculoskeletal Leg pain. Nervous System/Psychiatric Ataxia, extrapyramidal disorder, falling, anxiety, gait abnormalities, nervousness, decreased mental acuity, memory impairment, disorientation, euphoria, blepharospasm (which may be taken as an early sign of excess dosage; consideration of dosage reduction may be made at this time), trismus, increased tremor, numbness, muscle twitching, activation of latent Horner’s syndrome, peripheral neuropathy. Respiratory Pharyngeal pain, cough. Skin Malignant melanoma, flushing. Special Senses Oculogyric crises, diplopia, blurred vision, dilated pupils. Urogenital Urinary retention, urinary incontinence, priapism. Miscellaneous Bizarre breathing patterns, faintness, hoarseness, malaise, hot flashes, sense of stimulation. Laboratory Tests Decreased white blood cell count and serum potassium; increased serum creatinine and uric acid; protein and glucose in urine. To report SUSPECTED ADVERSE REACTIONS, contact Rising Pharma Holdings, Inc. at 1-844-874-7464 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

Drug Interactions Caution should be exercised when the following drugs are administered concomitantly with carbidopa and levodopa orally disintegrating tablets. Symptomatic postural hypotension occurred when carbidopa and levodopa orally disintegrating tablets was added to the treatment of a patient receiving antihypertensive drugs. Therefore, when therapy with carbidopa and levodopa orally disintegrating 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 orally disintegrating tablets. 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 orally disintegrating tablets should be carefully observed for loss of therapeutic response. Use of carbidopa and levodopa orally disintegrating tablets with dopamine-depleting agents (e.g., reserpine and tetrabenazine) or other drugs known to deplete monoamine stores is not recommended. Carbidopa and levodopa orally disintegrating 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.

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.

DESCRIPTION Carbidopa and levodopa orally disintegrating tablet, USP is a combination of carbidopa and levodopa for the treatment of Parkinson’s disease and syndrome. Carbidopa and levodopa orally disintegrating tablet is an orally administered formulation of carbidopa and levodopa which rapidly disintegrates on the tongue and does not require water to aid dissolution or swallowing. Carbidopa USP, an inhibitor of aromatic amino acid decarboxylation, is a white, crystalline compound, slightly soluble in water, with a molecular weight of 244.24. It is designated chemically as (-)-L-α-hydrazino-α-methyl-β-(3,4-dihydroxybenzene) propanoic acid monohydrate. Its molecular formula is C 10 H 14 N 2 O 4 . H 2 O, and its structural formula is: Tablet content is expressed in terms of anhydrous carbidopa which has a molecular weight of 226.23. Levodopa USP, an aromatic amino acid, is a white, crystalline compound, slightly soluble in water, with a molecular weight of 197.2. It is designated chemically as (-)-L-α-amino-β-(3,4-dihydroxybenzene) propanoic acid. Its molecular formula is C 9 H 11 NO 4 , and its structural formula is: Carbidopa and levodopa orally disintegrating tablets, USP are supplied as tablets in three strengths: Carbidopa and levodopa orally disintegrating tablets 25 mg/100 mg, containing 25 mg of carbidopa and 100 mg of levodopa. Carbidopa and levodopa orally disintegrating tablets 10 mg/100 mg, containing 10 mg of carbidopa and 100 mg of levodopa. Carbidopa and levodopa orally disintegrating tablets 25 mg/250 mg, containing 25 mg of carbidopa and 250 mg of levodopa. Inactive ingredients are povidone, mannitol, calcium silicate, crospovidone, talc, magnesium stearate, aspartame, tutti-frutti flavor, colloidal silicon dioxide, microcrystalline cellulose. Carbidopa and levodopa orally disintegrating tablets 10 mg/100 mg and 25 mg/250 mg also contain FD&C blue #2 (aluminum lake). Carbidopa and levodopa orally disintegrating tablets 25 mg/100 mg also contain D&C Yellow #10 Aluminum Lake and FD & C Yellow 6 Lake. Meets USP dissolution test 2. Carbidopa structure Levodopa structure

OVERDOSAGE Management of acute overdosage with carbidopa and levodopa orally disintegrating tablets is the same as management of acute overdosage with levodopa. Pyridoxine is not effective in reversing the actions of carbidopa and levodopa orally disintegrating tablets. 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 orally disintegrating tablets 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 1,500 to 2,000 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 3,360 mg/kg.

HOW SUPPLIED Carbidopa and levodopa orally disintegrating tablets, USP 10 mg/100 mg are light blue colored, circular, biconvex, uncoated tablets debossed with “186” on one side and scored on the other side. They are supplied as follows: Bottles of 30 with Child Resistant Cap........NDC 47335-186-83 Bottles of 100 with Child Resistant Cap......NDC 47335-186-88 Bottles of 100.........................................NDC 47335-186-08 Bottles of 1000 .....................................NDC 47335-186-18 Carbidopa and levodopa orally disintegrating tablets, USP 25 mg/100 mg are light yellow colored, circular, biconvex, uncoated tablets debossed with “187” on one side and scored on the other side. They are supplied as follows: Bottles of 30 with Child Resistant Cap........NDC 47335-187-83 Bottles of 100 with Child Resistant Cap......NDC 47335-187-88 Bottles of 100.........................................NDC 47335-187-08 Bottles of 1000......................................NDC 47335-187-18 Carbidopa and levodopa orally disintegrating tablets, USP 25 mg/250 mg are light blue colored, circular, biconvex, uncoated tablets debossed with “188” on one side and scored on the other side. They are supplied as follows: Bottles of 30 with Child Resistant Cap........NDC 47335-188-83 Bottles of 100 with Child Resistant Cap......NDC 47335-188-88 Bottles of 100.........................................NDC 47335-188-08 Bottles of 1000 .....................................NDC 47335-188-18 Storage and Handling Store at 20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C (59° 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/NF. Distributed by: Sun Pharmaceutical Industries, Inc. Cranbury, NJ 08512 Manufactured by: ALKALOIDA Chemical Company Zrt. 4440 Tiszavasvári, Kabay János u. 29., Hungary Revised: 06/2026