What are the side effects of Co-Careldopa (Carbidopa-Levodopa)?

From the Guidelines

Co-careldopa can cause a range of side effects, including nausea, vomiting, abdominal pain, dyspepsia, constipation, weight decrease, dry mouth, diarrhea, anorexia, and GI disorders, as well as metabolic effects and hyperhomocysteinemia, which can impact nutritional status and increase the risk of malnutrition and cardiovascular diseases 1.

Common Side Effects

• Nausea and vomiting
• Abdominal pain and dyspepsia
• Constipation and diarrhea
• Weight decrease and anorexia
• Dry mouth and changes in taste

Metabolic Effects

• Levodopa can induce metabolic changes in adipose tissue and skeletal muscles, disturbing lipid and carbohydrate metabolism 1
• Reduction in muscle glucose uptake, which might induce glucose intolerance
• Long-term treatment with levodopa can induce hypersecretion of insulin and growth hormone

Cardiovascular and Neurological Effects

• Hyperhomocysteinemia, which can increase the risk of cardiovascular diseases, dementia, and depression 1
• Higher relative risk for coronary artery disease with high plasma homocysteine levels
• Dyskinesias, which can be associated with weight loss and other motor symptoms

Management and Prevention

• Starting with a low dose and gradually increasing can help minimize side effects
• Patients should report persistent or severe side effects to their healthcare provider promptly
• Supplementation with vitamin B6, B12, and folate may be warranted to maintain normal homocysteine levels 1

From the FDA Drug Label

ADVERSE REACTIONS The most common adverse reactions reported with carbidopa and levodopa therapy 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 nonhemolytic 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.

The side effects of co-careldopa include:

• Common adverse reactions: dyskinesias, nausea
• Body as a Whole: chest pain, asthenia, abdominal pain and distress, fatigue
• Cardiovascular: cardiac irregularities, hypotension, orthostatic effects, hypertension, syncope, phlebitis, palpitation, myocardial infarction
• Gastrointestinal: dark saliva, gastrointestinal bleeding, development of duodenal ulcer, anorexia, vomiting, diarrhea, constipation, dyspepsia, dry mouth, taste alterations, gastrointestinal pain, dysphagia, sialorrhea, flatulence, bruxism, burning sensation of the tongue, heartburn, hiccups
• Hematologic: agranulocytosis, hemolytic and nonhemolytic anemia, thrombocytopenia, leukopenia
• Hypersensitivity: angioedema, urticaria, pruritus, Henoch-Schönlein purpura, bullous lesions
• Musculoskeletal: back pain, shoulder pain, muscle cramps, leg pain
• Nervous System/Psychiatric: psychotic episodes, bradykinetic episodes, confusion, agitation, dizziness, somnolence, dream abnormalities, insomnia, paresthesia, headache, depression, dementia, pathological gambling, increased libido, impulse control symptoms, ataxia, extrapyramidal disorder, falling, anxiety, gait abnormalities, nervousness, decreased mental acuity, memory impairment, disorientation, euphoria, blepharospasm, trismus, increased tremor, numbness, muscle twitching, activation of latent Horner’s syndrome, peripheral neuropathy
• Respiratory: dyspnea, upper respiratory infection, pharyngeal pain, cough
• Skin: rash, increased sweating, alopecia, dark sweat, malignant melanoma, flushing
• Urogenital: urinary tract infection, urinary frequency, dark urine, urinary retention, urinary incontinence, priapism
• Laboratory Tests: decreased hemoglobin and hematocrit, abnormalities in alkaline phosphatase, SGOT, SGPT, LDH, bilirubin, BUN, Coombs test, elevated serum glucose, white blood cells, bacteria, and blood in the urine, decreased white blood cell count and serum potassium, increased serum creatinine and uric acid, protein and glucose in urine 2

From the Research

Side Effects of Co-Careldopa

• The most common side effects of co-careldopa, a combination of levodopa and carbidopa, include nausea, vomiting, and dyskinesia 3, 4, 5.
• Long-term use of co-careldopa can lead to fluctuations in motor behavior and increase the risk of oxidative stress 6.
• Approximately 80% of patients with Parkinson's disease develop levodopa-induced dyskinesia (LID) in the advanced stages of the disease 3.
• Co-careldopa can cause irreversible dyskinesias, which have been attributed to carbidopa, not levodopa 5.
• The mechanism of action of carbidopa can lead to irreversible binding and inactivation of vitamin B6, interfering with over 300 enzyme and protein functions 5.

Specific Side Effects

• Vomiting during therapy sessions was the most frequent adverse event in patients taking co-careldopa, occurring in 6.2% of patients compared to 3.2% of patients taking placebo 4.
• Dyskinesias measured by the Unified Dyskinesia Rating Scale (UDysRS) were significantly reduced in patients taking levodopa-carbidopa intestinal gel (LCIG) compared to oral optimized medical treatment (OMT) 7.
• Treatment-emergent adverse events were reported in 44.3% of patients taking LCIG, with serious adverse events occurring in 7.1% of patients 7.

Patient Outcomes

• Co-careldopa did not improve walking ability in patients after stroke, with no significant difference in the ability to walk independently between patients taking co-careldopa and those taking placebo 4.
• LCIG significantly reduced dyskinesia and improved quality of life, motor symptoms, and non-motor symptoms in patients with advanced Parkinson's disease compared to OMT 7.