| Active Ingredient | CARBIDOPA ; LEVODOPA (DHIVY) |
|---|
| Drug Name | FDA Application No. | Company | Dosage Form;Route | Strength | RLD Strength | Original Approval or Tentative Approval Date |
Exclusivity Expiration (NCE) |
Exclusivity Expiration (ODE) |
Chemical Type |
Review Classification |
Marketing Status |
TE Code |
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| DHIVY | 214869 | RIVERSIDE PHARMA CORP | TABLET;ORAL | 25MG;100MG | _ | November 12, 2021 | _ | _ | Type 5 - New Formulation or New Manufacturer | STANDARD | Prescription | None |
| Parameters | Details |
|---|---|
| Structural Formula |
/Structural_Formula.jpg) |
| Chemical Name | Carbidoba : (–)-L-α-hydrazino-α-methyl-β-(3,4-dihydroxy-benzene) propanoic acid monohydrate Levodopa : (–)-L-α-amino-β-(3,4-dihydroxybenzene) propanoic acid |
| CAS No | Carbidopa : 28860-95-9 Levodopa : 59-92-7 |
| Molecular Formula | Carbidoba : C10H14N2O4•H2O Levodopa : C9H11NO4 |
| Molecular Weight | Carbidoba : 244.3 (Anhydrous carbidopa- 226.3) Levodopa : 197.2 |
| Appearance | Carbidopa is a white, crystalline compound Levodopa is a white, crystalline compound |
| Solubility | Carbidopa slightly soluble in water Levodopa slightly soluble in water |
| Water Solubility | Carbidoba 3.73 mg/mL Levodopa : 3.3 mg/mL |
| Polymorphism | - |
| pKa (Strongest Acidic) | Carbidoba : 2.3 Levodopa : 2.32 |
| pKa (Strongest Basic) | Carbidoba : 1.65 Levodopa : 9.06 |
| Log P | Carbidoba : -0.16, -1.2 Levodopa : -2.3, -1.8 |
| Identification | - |
| Degradation | - |
| Hygroscopic | - |
| Photostability study | - |
| Melting Point | Carbidoba : 203-208°C Levodopa : 295 °C |
| BCS Class | Carbidoba : BCS Class III/ I Levodopa : BCS Class I |
| Manufacture of API | - |
| Parameters | Details |
|---|---|
| Indications and Usage | DHIVY 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 symptomatic parkinsonism that may follow carbon monoxide intoxication or manganese intoxication. |
| Dosage and Administration |
The recommended starting dosage of DHIVY is one 25 mg /100 mg tablet taken orally three times a day. Dosage may be increased by up to one whole tablet every day or every other day, as needed, until a maximum dosage of eight whole tablets of DHIVY a day is reached. Swallow DHIVY with or without food. |
| Mechanism of action |
Carbidopa : When levodopa is administered orally, it is rapidly decarboxylated to dopamine in extracerebral tissues so that only a small portion of a given dose is transported unchanged to the central nervous system. Carbidopa inhibits the decarboxylation of peripheral levodopa, making more levodopa available for delivery to the brain. Levodopa : Levodopa is 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 treats symptoms of Parkinson’s disease. |
| Absorption | Following oral dosing of DHIVY under fasted conditions, the maximum concentration occurred at 3 hours for carbidopa and 1 hour for levodopa. The exposure of DHIVY after dose fractionation is proportional. |
| Food Effect | In healthy adults, oral administration of DHIVY after a high-fat, high-calorie meal reduced levodopa Cmax by approximately 25% while the AUC remained unchanged. The peak concentration of both carbidopa/levodopa were observed approximately 30 minutes later when DHIVY is taken with a high-fat, high-calorie meal. Since levodopa competes with certain amino acids for transport across the gut wall, the absorption of levodopa may be impaired in some patients on a high protein diet. |
| Distribution | Carbidopa is approximately 36% bound to plasma proteins. Levodopa is approximately 10% to 30% bound to plasma proteins. |
| Metabolism | - |
| Elimination |
Following oral dosing of DHIVY under fasted conditions, the half-life was reported at approximately 3.5 hours for carbidopa and 2 hours for levodopa. In clinical pharmacologic studies, simultaneous administration of carbidopa and levodopa produced greater urinary excretion of levodopa in proportion to the excretion of dopamine than administration of the two drugs at separate times. |
| Peak plasma time (Tmax) | Carbidopa : 3 hours Levodopa : 1 hour |
| Half life | Carbidopa : 3.5 hours Levodopa : 2 hours |
| Bioavailability | - |
| Age, gender |
Geriatric Patients A study in eight young healthy subjects (21-22 years) and eight elderly healthy subjects (69-76 years) showed that the absolute bioavailability of levodopa was similar between young and elderly subjects following oral administration of levodopa and carbidopa. However, the systemic exposure (AUC) of levodopa was increased by 55% in elderly subjects compared to young subjects. Based on another study in forty patients with Parkinson’s disease, there was a correlation between age of patients and the increase of AUC of levodopa following administration of levodopa and an inhibitor of peripheral dopa decarboxylase. AUC of levodopa was increased by 28% in elderly patients (≥ 65 years) compared to young patients (< 65 years). Additionally, mean value of Cmax for levodopa was increased by 24% in elderly patients (≥ 65 years) compared to young patients (< 65 years). The AUC of carbidopa was increased in elderly subjects (n=10, 65-76 years) by 29% compared to young subjects (n=24, 23-64 years) following IV administration of 50 mg levodopa with carbidopa (50 mg). This increase is not considered to have a clinically significant impact. |
| DMF | Status | Type | Submit Date | Holder |
|---|---|---|---|---|
| 11246 | I | II | December 8, 1994 | KNOLL AG CARBIDOPA |
| 12379 | A | II | February 19, 1997 | AJINOMOTO CO INC LEVODOPA |
| 12505 | I | II | May 15, 1997 | EGIS PHARMACEUTICALS PRIVATE LTD LEVODOPA USP BULK |
| 1367 | I | II | May 7, 1969 | LILLY RESEARCH LABORATORIES DIV ELI LILLY AND CO LEVODOPA (COMPOUND 7550) |
| 1649 | I | II | February 1, 1971 | GD SEARLE AND CO L-DOPA (OR LEVODOPA) IN BULK ONLY |
| 17846 | A | II | November 20, 2004 | DIVIS LABORATORIES LTD CARBIDOPA USP |
| 17874 | A | II | December 3, 2004 | DIVIS LABORATORIES LTD LEVODOPA USP |
| 18245 | I | II | April 5, 2005 | SMRUTHI ORGANICS LTD CARBIDOPA USP |
| 19899 | A | II | October 16, 2006 | ZHEJIANG CHIRAL MEDICINE CHEMICALS CO LTD CARBIDOPA |
| 20522 | I | II | May 8, 2007 | DELMAR CHEMICALS INC LEVODOPA METHYL ESTER HYDROCHLORIDE |
| 22424 | A | II | December 10, 2008 | ZHEJIANG WILD WIND PHARMACEUTICAL CO LTD CARBIDOPA (NON-STERILE, BULK FORM) |
| 22598 | A | II | March 5, 2009 | SHANDONG XINHUA PHARMACEUTICAL CO LTD LEVODOPA |
| 2344 | I | II | October 17, 1974 | KV PHARMACEUTICAL CO LEVODOPA S.R.C. 300MG |
| 25498 | I | II | November 11, 2011 | TORRENT PHARMACEUTICALS LTD LEVODOPA |
| 25563 | A | II | December 7, 2011 | GLOCHEM INDUSTRIES PRIVATE LTD CARBIDOPA |
| 26416 | A | II | September 14, 2012 | FERMION OY CARBIDOPA |
| 2664 | I | II | April 28, 1976 | HOFFMANN LA ROCHE INC LEVODOPA INJECTABLE |
| 26734 | A | II | January 7, 2013 | ZHEJIANG CHIRAL MEDICINE CHEMICALS CO LTD CRUDE CARBIDOPA |
| 27430 | A | II | July 23, 2013 | SHANDONG XINHUA PHARMACEUTICAL CO LTD CARBIDOPA |
| 27938 | A | II | January 24, 2014 | ZHEJIANG WILD WIND PHARMACEUTICAL CO LTD LEVODOPA |
| 28077 | I | II | April 10, 2014 | HOUSTON CYCLOTRON PARTNERS LP FLUOROLEVODOPA F 18 INJECTION |
| 31612 | A | II | May 11, 2017 | ZHEJIANG HUAHAI PHARMACEUTICAL CO LTD LEVODOPA USP |
| 31654 | A | II | April 20, 2017 | AJINOMOTO CO INC LEVODOPA |
| 32057 | A | II | June 29, 2020 | TEVA PHARMACEUTICAL INDUSTRIES LTD LEVODOPA |
| 35312 | A | II | October 17, 2020 | MAITHRI DRUGS PRIVATE LTD LEVODOPA USP |
| 35521 | A | II | December 31, 2020 | MAITHRI DRUGS PRIVATE LTD CARBIDOPA USP |
| 5044 | I | II | August 9, 1983 | DAIICHI SANKYO CHEMICAL PHARMA CO LTD LEVODOPA AS PRODUCED IN THE HIRATSUKA PLANT |
| 7063 | I | II | June 22, 1987 | NIPPON KAYAKU CO LTD CARBIDOPA |
| 7361 | I | II | February 29, 1988 | AMERICAN CHEMICAL INDUSTRIAL CORP CARBIDOPA |
| 8127 | I | II | July 5, 1989 | DAITO CORP CARBIDOPA |
| 8189 | I | II | August 28, 1989 | EGIS PHARMACEUTICALS PRIVATE LTD CARBIDOPA |
| 8296 | A | II | November 14, 1989 | TEVA PHARMACEUTICAL INDUSTRIES LTD CARBIDOPA USP (DRUG SUBSTANCE) |
| 8444 | I | II | October 20, 1989 | PFC ITALIANA SRL DIV ALFA CHEMICALS ITALIANA LEVODOPA |
| 8656 | A | II | July 11, 1990 | TEVA PHARMACEUTICAL INDUSTRIES LTD CARBIDOPA |
| 8689 | I | II | August 8, 1990 | PVP SOCIEDADE ANONIMA L-DOPA OR LEVODOPA |
| 9061 | I | II | April 15, 1991 | ESTEVE QUIMICA SA CARBIDOPA |
| 9231 | A | II | July 11, 1991 | BACHEM SA CARBIDOPA |
| 9433 | I | II | November 27, 1991 | JUZEN CHEMICAL CORP CARBIDOPA |
| Parameters | Details |
|---|---|
| Strength | 25mg, 100mg |
| Excipients used | Magnesium stearate, microcrystalline cellulose, and pregelatinized starch. |
| Composition of coating material | - |
| Composition of caspule shell | NA |
| Pharmaceutical Development | To be updated soon |
| Manufacture of the product | To be updated soon |
| Tablet / Capsule Image | |
| Appearance | White to off-white tablets, One side of each DHIVY tablet has 3 scores, with each segment containing 6.25 mg of carbidopa and 25 mg of levodopa (1:4 ratio). The unscored side of the tablet is debossed with logo “AV70l”. |
| Imprint code / Engraving / Debossment | One side of each DHIVY tablet has 3 scores, with each segment containing 6.25 mg of carbidopa and 25 mg of levodopa (1:4 ratio). The unscored side of the tablet is debossed with logo “AV70l”. |
| Score | 3 scores |
| Color | White to off-white |
| Shape | - |
| Dimension | - |
| Mfg by | - |
| Mfg for | - |
| Marketed by | - |
| Distributed by |
Riverside Pharmaceuticals Corporation Washington, DC 20006, USA |
| Application No. | Prod No | Patent No | Patent Expiration | Drug Substance Claim | Drug Product Claim | Patent Use Code | Delist Requested | Link |
|---|---|---|---|---|---|---|---|---|
| There are no unexpired patents for this product in the Orange Book Database. | ||||||||
| USP Apparatus | Speed (RPMs) | Medium | Volume (mL) | Recommended Sampling Times (minutes) | Date Updated |
|---|---|---|---|---|---|
| Not Available | |||||
| Label | Link |
|---|---|
| FDA label | Download |
| FDA chemistry review | |
| FDA Pharmacology Review(s) | |
| FDA Clinical Pharmacology Biopharmaceutics Review(s) | |
| FDA BE Recommendation | |
| European Public Assessment Report |
| Territory | Brand name / Generic company name | Link |
|---|---|---|
| EU | - | |
| UK | - | |
| US | - |
| - |
| www.accessdata.fda.gov, www.drugbank.ca, www.ema.europa.eu, www.medicines.org.uk, dailymed.nlm.nih.gov |
