Carbidopa Levodopa

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 )

DHIVY tablets are white to off-white tablets containing 25 mg of carbidopa and 100 mg of levodopa. Each DHIVY tablet has 3 functional scores with each segment containing 6.25 mg of carbidopa and 25 mg of levodopa. Tablets: Carbidopa and levodopa 25 mg/100 mg, functionally scored. Each DHIVY tablet has 3 functional scores with each segment containing 6.25 mg of carbidopa and 25 mg of levodopa.( 3 )

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 )

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 ( 2.3 ) ] .

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 Vitamin B6 Deficiency and Seizures Treatment with carbidopa-levodopa, including DHIVY, contribute to reduced Vitamin B6 levels. Higher doses of carbidopa/levodopa may increase the risk of vitamin B6 deficiency. Seizures associated with vitamin B6 deficiency have been reported in the postmarketing setting in patients taking carbidopa-levodopa. In these reported cases, seizures were refractory to traditional antiseizure medications and only resolved after vitamin B6 administration. Other symptoms of vitamin B6 deficiency may occur, including depression, confusion, cheilosis, glossitis, dermatitis, anemia, and/or neuropathy. Evaluate vitamin B6 levels prior to initiation of DHIVY and periodically while on treatment or if symptoms associated with vitamin B6 deficiency are identified. Supplement with vitamin B6 as necessary.

5.8 Peptic Ulcer Disease Treatment with DHIVY may increase the possibility of upper gastrointestinal hemorrhage in patients with a history of peptic ulcer.

5.9 Glaucoma DHIVY may cause increased intraocular pressure in patients with glaucoma. Monitor intraocular pressure in patients with glaucoma after starting DHIVY.

5.10 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.

5.11 Depression/Suicidality All patients taking DHIVY should be observed carefully for the development of depression with concomitant suicidal tendencies.

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 )] Vitamin B6 Deficiency and Seizures [see Warnings and Precautions ( 5.7 )] Peptic Ulcer Disease [see Warnings and Precautions ( 5.8 )] Glaucoma [see Warnings and Precautions ( 5.9 )] Depression/Suicidality [see Warnings and Precautions ( 5.11 )] 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 ( 6 ). 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.

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.

Pregnancy: Based on animal data, may cause fetal harm ( 8.1 )

8.1 Pregnancy Risk Summary There are no adequate data on the developmental risk associated with the use of DHIVY in pregnant women. In animal studies, carbidopa/levodopa has been shown to be developmentally toxic (including teratogenic effects) at clinically relevant doses ( see Data ). The estimated background risk of major birth defects and miscarriage in the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Data Animal Data When administered to pregnant rabbits throughout organogenesis, carbidopa-levodopa caused both visceral and skeletal malformations in fetuses at all doses and ratios of carbidopa-levodopa tested. No teratogenic effects were observed when carbidopa-levodopa was administered to pregnant mice throughout organogenesis.

8.2 Lactation Risk Summary Levodopa has been detected in human milk after administration of carbidopa-levodopa. There are no data on the presence of carbidopa in human milk, the effects of levodopa or carbidopa on the breastfed infant, or the effects on milk production. However, inhibition of lactation may occur because levodopa decreases secretion of prolactin in humans. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for DHIVY and any potential adverse effects on the breastfed infant from DHIVY or from the underlying maternal condition.

8.4 Pediatric Use Safety and effectiveness in pediatric patients have not been established.

8.5 Geriatric Use Of the total number of subjects in clinical studies of immediate-release carbidopa-levodopa tablets (i.e., Sinemet ® ), almost half of the patients were older than age 65 years, and few were age 75 years and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, but greater sensitivity of some older individuals to adverse drug reactions such as hallucinations cannot be ruled out. The systemic exposure of levodopa was increased in elderly subjects compared to young subjects [see Clinical Pharmacology ( 12.3 ) ] . There is no specific dosing recommendation based upon clinical pharmacology data as carbidopa/levodopa is titrated as tolerated for clinical effect.