Dhivy Drug Information

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

Management of Vitamin B6 Levels Evaluate vitamin B6 levels prior to initiating

treatment with carbidopa-levodopa therapies including DHIVY, periodically during treatment, and as clinically indicated . If vitamin B6 levels are low, supplement to sufficient levels per standard of care. Patients may initiate and continue treatment with DHIVY while supplementing vitamin B6.

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.

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 . 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.

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.

The following serious adverse reactions are discussed below and elsewhere in the labeling: Falling Asleep During Activities of Daily Living and Somnolence Withdrawal-Emergent Hyperpyrexia and Confusion Cardiovascular Ischemic Events Hallucinations/Psychotic-Like Behavior Impulse Control/Compulsive Behaviors Dyskinesia Vitamin B6 Deficiency and Seizures Peptic Ulcer Disease Glaucoma Depression/Suicidality 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, seizures (including convulsions). 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.

Monoamine Oxidase (MAO) Inhibitors

The use of nonselective MAO inhibitors with DHIVY is contraindicated . 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.

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.

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.

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.

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.

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.

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 . With known hypersensitivity to any component of DHIVY. Nonselective MAO inhibitors With known hypersensitivity to any component of DHIVY

Based on the limited available information, the acute symptoms of levodopa/dopa decarboxylase inhibitor overdosage can be expected to arise from dopaminergic overstimulation. Doses of a few grams may result in CNS disturbances, with an increasing likelihood of cardiovascular disturbance (e.g., hypotension, tachycardia) and more severe psychiatric problems at higher doses. An isolated report of rhabdomyolysis and another of transient renal insufficiency suggest that levodopa overdosage may give rise to systemic complications, secondary to dopaminergic overstimulation.

Monitor patients and provide supportive care. Patients should receive electrocardiographic monitoring for the development of arrhythmias; if needed, appropriate antiarrhythmic therapy should be given. The possibility that the patient may have taken other drugs, increasing the risk of drug interactions (especially catechol-structured drugs) should be taken into consideration.