Drug Facts
Composition & Profile
Identifiers & Packaging
16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied DHIVY (carbidopa and levodopa) tablets are white to off-white tablets with functional scoring containing 25 mg of carbidopa and 100 mg of levodopa. 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”. DHIVY is supplied as follows: NDC 75854-701-01 bottles of 100. Four copies of the Instructions for Use are included with the bottle, and additional copies, as needed, can be printed. 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 light-resistant container.; PACKAGE LABEL.PRINCIPAL DISPLAY PANEL C:\Users\admin\Desktop\Dhivy\Dhivy-label-2022.jpg
- 16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied DHIVY (carbidopa and levodopa) tablets are white to off-white tablets with functional scoring containing 25 mg of carbidopa and 100 mg of levodopa. 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”. DHIVY is supplied as follows: NDC 75854-701-01 bottles of 100. Four copies of the Instructions for Use are included with the bottle, and additional copies, as needed, can be printed. 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 light-resistant container.
- PACKAGE LABEL.PRINCIPAL DISPLAY PANEL C:\Users\admin\Desktop\Dhivy\Dhivy-label-2022.jpg
Overview
DHIVY ® (carbidopa levodopa) is a combination of carbidopa, an inhibitor of aromatic amino acid decarboxylation, and levodopa, an aromatic amino acid, in tablets for oral use. Carbidopa is a white, crystalline compound, slightly soluble in water, with a molecular weight of 244.3. It is designated chemically as (–)-L-α-hydrazino-α-methyl-β-(3,4-dihydroxy-benzene) propanoic acid monohydrate. It has a pKa of 2.3. 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 226.3. Levodopa 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. It has a pKa of 2.32. Its molecular formula is C 9 H 11 NO 4 and its structural formula is: DHIVY is supplied as tablets for oral administration containing 25 mg of carbidopa and 100 mg of levodopa. The inactive ingredients are magnesium stearate, microcrystalline cellulose, and pregelatinized starch. 4e672b0d-figure-01 4e672b0d-figure-02
Indications & Usage
DHIVY is indicated for the treatment of Parkinson’s disease, post-encephalitic parkinsonism, and symptomatic parkinsonism that may follow carbon monoxide intoxication or manganese intoxication. 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 ( 1 )
Dosage & Administration
The recommended starting dosage of DHIVY is one 25 mg /100 mg tablet taken orally three times a day. ( 2.1 ) 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. ( 2.1 ) Swallow DHIVY with or without food. ( 2.3 ) 2.1 Initial Dosage and Maintenance of Therapy The recommended starting dosage of DHIVY is one 25 mg / 100 mg tablet taken orally three times a day. This dosage schedule provides 75 mg of carbidopa per day. Dosage may be increased by up to one whole tablet every day or every other day, as needed to a maximum daily dosage of eight whole tablets. Dosing with DHIVY should be individualized and adjusted according to clinical response and tolerability. The tablet is functionally scored to facilitate dose adjustment. At least 70 mg to 100 mg of carbidopa per day should be provided. Experience with total daily dosages of carbidopa greater than 200 mg is limited. Monitor patients closely during the dose adjustment period. Specifically, involuntary movements may occur with DHIVY, which may require dosage reduction. Blepharospasm may be a useful early sign of excess dosage in some patients. Maintain patients on the lowest dosage required to achieve symptomatic control and to minimize adverse reactions, such as dyskinesia and nausea. 2.2 Discontinuation of DHIVY Avoid sudden discontinuation or rapid dose reduction of DHIVY. The daily dosage of DHIVY should be tapered at the time of treatment discontinuation [see Warnings and Precautions (5.2) ] . If general anesthesia is required, DHIVY may be continued as long as the patient is permitted to take fluids and medication by mouth. If therapy is interrupted temporarily, the patient should be observed for symptoms resembling neuroleptic malignant syndrome, and the usual daily dosage may be administered as soon as the patient is able to take oral medication. 2.3 Administration Information Swallow DHIVY with or without food. The patient should be advised that a change in diet to foods that are high in protein may delay the absorption of levodopa and may reduce the amount taken up in the circulation. Excessive acidity also delays stomach emptying, thus delaying the absorption of levodopa. If the patient has difficulty swallowing the tablet due to its size, the tablet can be broken at the score lines.
Warnings & Precautions
May cause falling asleep during activities of daily living ( 5.1 ) Avoid sudden discontinuation or rapid dose reduction to reduce the risk of withdrawal-emergent hyperpyrexia and confusion ( 5.2 ) Cardiovascular Ischemic Events: Monitor patients with a history of cardiovascular disease ( 5.3 ) Hallucinations/Psychosis may occur ( 5.4 ) Impulse Control/Compulsive Behaviors: Consider dose reduction or stopping DHIVY if impulse control disorders occur ( 5.5 ) May cause or exacerbate dyskinesia: Consider dose reduction ( 5.6 ) 5.1 Falling Asleep During Activities of Daily Living and Somnolence Patients taking carbidopa/levodopa alone or with other dopaminergic drugs have reported suddenly falling asleep without prior warning of sleepiness while engaged in activities of daily living, including the operation of motor vehicles which have resulted in accidents. Although many patients reported somnolence while on dopaminergic medications, some perceived that they had no warning signs (sleep attack), such as excessive drowsiness, and believed that they were alert immediately prior to the event. Sudden onset of sleep has been reported to occur more than one year after the initiation of treatment. It has been reported that falling asleep while engaged in activities of daily living usually occurs in a setting of pre-existing somnolence, although some patients may not give such a history. For this reason, prescribers should reassess patients for drowsiness or sleepiness in DHIVY-treated patients, 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. Before initiating treatment with DHIVY, advise patients about the potential to develop drowsiness and ask specifically about factors that may increase the risk for somnolence with DHIVY such as the use of concomitant sedating medications and the presence of sleep disorders. Consider discontinuing DHIVY in patients who report significant daytime sleepiness or episodes of falling asleep during activities that require active participation (e.g., conversations, eating, etc.). If treatment with DHIVY continues, advise patients not to drive and to avoid other potentially dangerous activities that might result in harm if the patients become somnolent. There is insufficient information to establish that dose reduction will eliminate episodes of falling asleep while engaged in activities of daily living. 5.2 Withdrawal-Emergent Hyperpyrexia and Confusion A symptom complex that resembles neuroleptic malignant syndrome (characterized by elevated temperature, muscular rigidity, altered consciousness, and autonomic instability), with no other obvious etiology, has been reported in association with rapid dose reduction, withdrawal of, or changes in dopaminergic therapy. Avoid sudden discontinuation or rapid dose reduction in patients taking DHIVY. If the decision is made to discontinue DHIVY, the dose should be tapered to reduce the risk of hyperpyrexia and confusion [see Dosage and Administration (2.2) ] . 5.3 Cardiovascular Ischemic Events In patients with a history of myocardial infarction who have residual atrial, nodal, or ventricular arrhythmias, cardiac function should be monitored in an intensive cardiac care facility during the period of initial dosage adjustment. 5.4 Hallucinations/Psychotic-Like Behavior Hallucinations and psychotic-like behavior have been reported with dopaminergic medications. In general, hallucinations present shortly after the initiation of therapy and may be responsive to dose reduction in levodopa. Hallucinations may be accompanied by confusion, sleep disorder (insomnia), and excessive dreaming. Abnormal thinking and behavior may present with one or more symptoms, including paranoid ideation, delusions, hallucinations, confusion, psychotic-like behavior, disorientation, aggressive behavior, agitation, and delirium. Patients with a major psychotic disorder should not be treated with DHIVY, because of the risk of exacerbating psychosis. In addition, medications that antagonize the effects of dopamine used to treat psychosis may exacerbate the symptoms of Parkinson’s disease and may decrease the effectiveness of DHIVY [see Drug Interactions (7.2) ] . 5.5 Impulse Control/Compulsive Behaviors Case reports suggest that patients can experience an intense urge to gamble, increased sexual urges, intense urges to spend money, binge eating, and/or other intense urges, and the inability to control these urges while taking one or more of the medications, including DHIVY, that increase central dopaminergic tone and that are generally used for the treatment of Parkinson’s disease. In some cases, although not all, these urges were reported to have stopped when the dosage was reduced or the medication was discontinued. Because patients may not recognize these behaviors as abnormal, it is important for prescribers to specifically ask patients or the caregivers about the development of new or increased gambling urges, sexual urges, uncontrolled spending, or other urges while being treated with DHIVY. Consider dosage reduction or stopping the medication if a patient develops such urges while taking DHIVY. 5.6 Dyskinesia DHIVY can cause dyskinesias that may require a dosage reduction of DHIVY or other medications used for the treatment of Parkinson’s disease. 5.7 Peptic Ulcer Disease Treatment with DHIVY may increase the possibility of upper gastrointestinal hemorrhage in patients with a history of peptic ulcer. 5.8 Glaucoma DHIVY may cause increased intraocular pressure in patients with glaucoma. Monitor intraocular pressure in patients with glaucoma after starting DHIVY. 5.9 Laboratory Tests DHIVY may cause a positive Coombs test or false-positive reaction for urinary ketone bodies when a test tape is used for determination of ketonuria. This reaction will not be altered by boiling the urine specimen. False-negative tests may result with the use of glucose-oxidase methods of testing for glucosuria. Cases of falsely diagnosed pheochromocytoma in patients on carbidopa-levodopa therapy have been reported. Caution should be exercised when interpreting the plasma and urine levels of catecholamines and their metabolites in patients on carbidopa levodopa therapy. 5.10 Depression/Suicidality All patients taking DHIVY should be observed carefully for the development of depression with concomitant suicidal tendencies.
Contraindications
DHIVY is contraindicated in patients Currently taking a nonselective monoamine oxidase (MAO) inhibitor (e.g., phenelzine, linezolid, 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) ] . With known hypersensitivity to any component of DHIVY [see Adverse Reactions (6) ] . Nonselective MAO inhibitors ( 4 ) With known hypersensitivity to any component of DHIVY ( 4 )
Adverse Reactions
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/Psychotic-Like Behavior [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) ] Depression//Suicidality [see Warnings and Precautions (5.10) ] The most common adverse reactions reported with carbidopa/levodopa tablets have included dyskinesias, such as choreiform, dystonic, and other involuntary movements, and nausea. The following other adverse reactions have been reported with carbidopa/levodopa tablets: 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 DHIVY 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 levodopa formulations, and may occur with DHIVY 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. The most common adverse reactions reported with carbidopa/levodopa tablets have included dyskinesias, such as choreiform, dystonic, and other involuntary movements, and nausea To report SUSPECTED ADVERSE REACTIONS, contact Avion Pharmaceuticals at 1-888-612-8466 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
Drug Interactions
Iron salts and dopamine D2 antagonists including metoclopramide: May reduce the effectiveness of DHIVY ( 7.2 , 7.3 ) 7.1 Monoamine Oxidase (MAO) Inhibitors The use of nonselective MAO inhibitors with DHIVY is contraindicated [see Contraindications (4) ] . Discontinue use of any nonselective MAO inhibitors at least two weeks prior to initiating DHIVY. DHIVY may be administered concomitantly with the manufacturer's recommended dose of selective MAO-B inhibitors (e.g., rasagiline or selegiline HCl). Concomitant therapy with selegiline and carbidopa/levodopa may be associated with severe orthostatic hypotension not attributable to carbidopa/levodopa alone. 7.2 Dopamine D 2 Receptor Antagonists and Isoniazid Dopamine D 2 receptor antagonists (e.g., phenothiazines, butyrophenones, risperidone) and isoniazid may reduce the effectiveness of levodopa. Monitor patients taking these drugs with DHIVY 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 DHIVY. If iron salts or multivitamins containing iron salts are co-administered with DHIVY, monitor patients for worsening Parkinson’s symptoms. 7.4 Antihypertensive Drugs Symptomatic postural hypotension occurred when carbidopa/levodopa was added to the treatment of a patient receiving antihypertensive drugs. Therefore, when therapy with DHIVY is started, dosage adjustment of the antihypertensive drug may be required. 7.5 Dopamine-Depleting Agents Use of DHIVY with dopamine-depleting agents (e.g., reserpine and tetrabenazine) or other drugs known to deplete monoamine stores is not recommended. 7.6 Metoclopramide Although metoclopramide may increase the bioavailability of levodopa by increasing gastric emptying, metoclopramide may also reduce effectiveness of levodopa by its dopamine receptor antagonistic properties.
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