Co-careldopa (carbidopa and levodopa) oral
- Drugs List
- Therapeutic Indications
- Dosage
- Contraindications
- Precautions and Warnings
- Pregnancy and Lactation
- Side Effects
- Monograph
Presentation
Tablets containing co-careldopa
Co-careldopa is a mixture of carbidopa and levodopa, proportions are expressed in the form x+y where x and y are the strengths in milligrams of carbidopa and levodopa respectively.
Drugs List
Therapeutic Indications
Uses
Parkinson's disease (not drug induced)
Unlicensed Uses
Dihydrobiopterin reductase deficiency
Dystonias in children
Tetrahydrobiopterin synthesis defects
Dosage
The optimum daily dose of co-careldopa should be carefully titrated for each patient.
Adults
Parkinson's disease
Patients not receiving levodopa
Initial dose of one 25mg + 100mg tablet three times daily, thus providing 75mg carbidopa daily. Dosage may be increased by one 12.5mg + 50mg tablet or one 25mg + 100mg tablet every day or every other day, as considered necessary, until a daily dose of 200mg carbidopa and 800mg of levodopa is reached.
If the initial dose is started with 10mg + 100mg or 12.5mg + 50mg tablets, the dose should be one tablet 3 or 4 times daily. Upward titration may be required by some patients to achieve optimum carbidopa dosage. The dosage may be increased by one tablet every day or alternate days until a total of 8 tablets is reached.
If the initial dose is started with 25mg + 250mg, the dose should be one half tablet taken once or twice daily. This may not provide the optimum amount of carbidopa required by some patients. If required, one half tablet every day, or every other day may be added to the regimen until optimal response is reached.
Response has been observed in one day, and sometimes after one dose. Fully effective doses are usually reached within seven days as compared to weeks or months with levodopa alone.
Co-careldopa 12.5mg + 50mg or 10mg + 100mg tablets may be used to facilitate dosage titration according to the individual needs of the patient.
Patients receiving levodopa
Standard levodopa formulations should be discontinued at least 12 hours before starting therapy with co-careldopa. The easiest way to transfer patients is to give co-careldopa as the first morning dose after a night without any levodopa. This dose of co-careldopa should be approximately 20% of the previous daily dosage of levodopa.
Patients taking less than 1500mg levodopa daily should be started on one tablet of co-careldopa 25mg + 100mg three or four times daily dependent on patient need. The suggested starting dose for patients taking more than 1500mg levodopa a day is one tablet of co-careldopa 25mg + 250mg three or four times a day.
N.B. At the time that this monograph was reviewed there were no licensed preparations for levodopa monotherapy in routine use.
Maintenance
Therapy with co-careldopa should be individualised and adjusted gradually to achieve maximal patient response. When a greater proportion of carbidopa is required, each tablet of co-careldopa 10mg + 100mg may be replaced with a tablet of co-careldopa 25mg + 100mg or 12.5mg + 50mg.
When more levodopa is required, co-careldopa 25mg + 250mg should be substituted at a dosage of one tablet three or four times a day. If necessary, the dosage of co-careldopa 25mg + 250mg may be increased by half to one tablet every other day to a maximum of 8 tablets a day. Experience with a total daily dose greater than 200mg carbidopa is limited.
Patients receiving levodopa with another decarboxylase inhibitor
When transferring patients, dosage should be discontinued 12 hours before co-careldopa is initiated. The initial dosage should provide the same amount of levodopa as contained in the other levodopa/decarboxylase inhibitor combination.
Patients receiving other antiparkinsonian agents
Current evidence suggest that other antiparkinson agents may be continued when co-careldopa is introduced, although dosage may need to be adjusted in line with manufacturers recommendations.
Children
Dopamine-sensitive dystonias including Segawa syndrome and dystonias related to cerebral palsy (unlicensed)
Children aged 3 months to 18 years
Initial dose of 62.5 micrograms + 250 micrograms/kg two to three times daily. If considered necessary, dose may be increased every 2 to 3 days, to a maximum of 0.25mg + 1mg/kg three times daily, based on individual patient response.
Treatment of defects in tetrahydrobiopterin synthesis and dihydrobiopterin reductase deficiency (unlicensed)
Children 1 month to 18 years
Initial dose of 62.5 micrograms + 250 micrograms/kg to 125 micrograms + 500 micrograms/kg four times daily. If considered necessary, dose may be increased every 4 to 5 days, based on individual patient response, to a maintenance dose of 0.625mg + 2.5mg/kg to 0.75mg + 3mg/kg four times daily.
Regularly review patients receiving higher doses when considering using a preparation containing 1:10 carbidopa:levodopa. It is recommended every 3 to 6 months in early childhood.
Neonates
Treatment of defects in tetrahydrobiopterin synthesis and dihydrobiopterin reductase deficiency (unlicensed)
Initial dose of 62.5 micrograms + 250 micrograms/kg to 125 micrograms + 500 micrograms/kg four times daily. If considered necessary, dose may be increased every 4 to 5 days, based on individual patient response, to a maintenance dose of 0.625mg + 2.5mg/kg to 0.75mg + 3mg/kg four times daily.
Regularly review patients receiving higher doses when considering using a preparation containing 1:10 carbidopa:levodopa. It is recommended every 3 to 6 months in early childhood.
Additional Dosage Information
Studies have shown that the peripheral dopa-decarboxylase is fully inhibited (saturated) by carbidopa at doses between 70mg and 100mg daily. Patients receiving doses lower than this amount of carbidopa are more likely to experience nausea and vomiting.
Standard antiparkinson drugs, other than levodopa alone, may be continued while co-careldopa is being administered, however their dosage may need to be adjusted.
Therapeutic and adverse effects are seen more rapidly with co-careldopa than with levodopa alone, patients should be carefully monitored during the dose titration period. Involuntary movements, in particular blepharospasm, are a useful early sign of excess dosage in some patients.
Contraindications
Suspected malignant melanoma
Within 2 weeks of discontinuing MAOIs
Breastfeeding
History of malignant melanoma
Malignant melanoma
Narrow angle glaucoma
Pregnancy
Severe cardiac failure
Severe psychiatric disorder
Precautions and Warnings
Children under 18 years
Females of childbearing potential
Predisposition to narrow angle glaucoma
Asthma
Cardiac arrhythmias
Cushing's disease
Diabetes mellitus
Endocrine disease
Hepatic impairment
History of myocardial infarction
History of peptic ulcer
History of psychosis
History of seizures
Hyperthyroidism
Ischaemic heart disease
Open angle glaucoma
Osteomalacia
Phaeochromocytoma
Psychiatric disorder
Pulmonary disease
Renal impairment
Severe cardiovascular disorder
Advise patient/carer risk of dopamine dysregulation syndrome (DDS)
Advise patient somnolence may affect ability to drive or operate machinery
Advise patient that sudden onset sleep episodes may affect ability to drive
Administration of a partial dose may result in worsening of symptoms
Take at a different time from iron supplement
Monitor cardiovascular function
Monitor for melanoma regularly
Monitor for mental changes, suicidal depression and antisocial behaviour
Monitor patients at risk of glaucoma for increases in intraocular pressure
Monitor patients for impulse control disorders
Monitor renal, hepatic and haematological parameters
Review treatment if impulse control disorders symptoms occur
Reduce dose if dyskinesia occurs
May affect results of some laboratory tests
May colour urine red
Avoid abrupt withdrawal: May cause signs of neuroleptic malignant syndrome
Reduce dose or discontinue if sudden onset of sleep during daily activities
Female: Ensure adequate contraception during treatment
Advise patient/carer about symptoms of impulse control disorders
Advise patients that hallucinations can occur
Patients with a history of severe involuntary movements or psychotic episodes when treated with levodopa alone, should be carefully observed during substitution with co-careldopa. These reactions are thought to be due to increased levels of dopamine in the brain following administration of levodopa. Dose reduction may be required.
If general anaesthesia is required therapy with co-careldopa should be continued for as long as the patient is permitted to take fluids and medication by mouth. If therapy has to be temporarily stopped, co-careldopa should be re-started as soon as oral medication can be taken, at the same daily dose as before.
Pregnancy and Lactation
Pregnancy
Co-careldopa is contraindicated in pregnancy.
Animal studies have shown teratogenicity. Both levodopa and combinations of levodopa and carbidopa have caused visceral and skeletal malformations in rabbits. No adverse outcomes associated with this drug have been observed in a limited number of human pregnancies though. Data published in 1995 describes the two pregnancies which were terminated at 8 weeks and 10 weeks by a women with juvenile parkinson's disease who had been taking 200 mg+800 mg/day of carbidopa/levodopa. The relatively high concentrations of dopamine in foetal peripheral organs and neural tissue implied that the foetuses had metabolised levodopa. Because neurotransmitters are known to alter early neural development in animals and cultured cells, the investigators cautioned that the increased amounts of dopamine found in this study suggested that chronic use of levodopa during gestation could induce long term damage. Because of this potential risk to the foetus, co-careldopa should not be used during pregnancy.
The use of all medication in pregnancy should be avoided whenever possible; particularly in the first trimester. Non-drug treatments should also be considered. When essential, a medication with the best safety record over time should be chosen, employing the lowest effective dose for the shortest possible time. Polypharmacy should be avoided. Teratogens taken in the pre-embryonic period, often quoted as lasting until 14 to 17 days post-conception, are believed to have an all-or-nothing effect. Where drugs have a short half-life, and when the date of conception is certain, this may allow women to be reassured where drug exposure has occurred within this time frame. Further advice may be available from the UK National Teratology Information Service (NTIS) and through ToxBase, available via password on the internet ( www.toxbase.org ) or if this is unavailable at the backup site ( www.toxbasebackup.org ).
Lactation
Co-careldopa is contraindicated in breastfeeding.
Levodopa is excreted into human breast milk but it is unknown whether carbidopa is excreted. A study in 1974 provided clinical evidence that levodopa inhibits lactation. Doses of 500 to 3500 mg/day of levodopa were given orally to ten female patients with a history of inappropriate galactorrhoea. Partial to complete suppression of lactation was observed but when the treatment was stopped, lactation returned to normal. Briggs (2011) classifies levodopa and carbidopa separately as probably being compatible with breast feeding. However, Hale (2010) puts levodopa in a risk category of possibly hazardous because there is positive evidence of risk to a breastfed infant or to breast milk production. Because of the potential for adverse effects in the newborn and the suppression of lactation, co-careldopa should not be administered to lactating women.
Neonates, infants born prematurely, those with low birth weight, those with an unstable gastrointestinal function or who have serious illnesses may require special consideration. For any infant, if a drug is prescribed to the nursing mother, it should be at the lowest practical dose and for the shortest time. When drug administration is unavoidable and breastfeeding is to continue, minimisation of exposure of the infant to the drug may sometimes be achieved by timing the maternal doses to just after a feeding episode. Infants exposed to drugs via breast milk should be monitored for unusual signs or symptoms. Interactions between the drug received by the infant from the mother's milk and medication prescribed for the infant should also be considered, for example, when the drug given to the infant may prevent metabolism of the drug received via breast milk.
Specialist advice is available from the UK Drugs in Lactation Advisory Service at https://www.midlandsmedicines.nhs.uk/content.asp?section=6&subsection=17&pageIdx=1
Counselling
Advise patients that if the tablet must be subdivided to aid in swallowing, the tablet should be consumed only if the whole dose can be taken. Administration of a partial dose may result in worsening symptoms.
Take at a different time from iron supplement.
Advise patients that hallucinations can occur.
Advise patient/carer risk of dopamine dysregulation syndrome (DDS).
Advise patient/carer about symptoms of impulse control disorders.
May colour urine red.
Advise patients to ensure adequate contraception during treatment.
Advise patient somnolence may affect ability to drive or operate machinery.
Advise patient that sudden onset sleep episodes may affect ability to drive.
Side Effects
Activation of latent Horner's syndrome
Agitation
Agranulocytosis
Alopecia
Alterations in hepatic enzymes
Anaemia
Angioedema
Anorexia
Anxiety
Asthenia
Ataxia
Binge eating
Bitter taste
Blepharospasm
Blurred vision
Bradykinesia
Bruxism
Burning tongue
Cardiac disorders
Chest pain
Chorea
Compulsive behaviour
Confusion
Constipation
Convulsions
Dark saliva
Dark sweat
Darkening of urine
Delusions
Dementia
Depression
Diarrhoea
Diplopia
Disorientation
Dizziness
Dopamine dysregulation syndrome
Dream abnormalities
Dry mouth
Duodenal ulcer
Dyskinesia
Dysphagia
Dyspnoea
Dystonia
Euphoria
Exanthema
Extrapyramidal effects
Flatulence
Flushing
Gait abnormality
Gastro-intestinal pain
Gastrointestinal bleeding
Hallucinations
Headache
Henoch-Schonlein purpura
Hiccups
Hoarseness
Hot flushes
Hypersalivation
Hypersensitivity reactions
Hypersexuality
Hypertension
Increased libido
Insomnia
Leucopenia
Loss of mental acuity
Malaise
Malignant melanoma
Motor disturbances
Muscle spasm
Nausea
Neuroleptic malignant syndrome
Numbness
Oedema
Orthostatic hypotension
Palpitations
Paraesthesia
Paranoia
Pathological gambling
Peripheral neuropathy
Phlebitis
Priapism
Pruritus
Pupillary dilatation
Rash
Somnolence
Sudden sleep onset episodes
Suicidal tendencies
Sweating
Syncope
Thrombocytopenia
Tremor
Trismus
Urinary incontinence
Urinary retention
Urticaria
Vomiting
Weakness
Weight changes
Effects on Laboratory Tests
Co-careldopa has caused abnormalities in numerous laboratory tests. These include elevated levels of blood urea nitrogen, AST (SGOT), ALT (SGPT), LDH, bilirubin, alkaline phosphatase, creatinine and uric acid.
Decreased haemoglobin, haematocrit, elevated serum glucose and white blood cells, bacteria and blood in the urine have been reported.
Positive Coombs' tests have been reported.
Co-careldopa may cause a false positive result when the dipstick test for urinary ketone is performed, and this is not altered by boiling the urine. The use of glucose oxidase methods may give false negative results for glycosuria.
Overdosage
It is strongly recommended that the UK National Poisons Information Service be consulted on cases of suspected or actual overdose where there is doubt over the degree of risk or about appropriate management.
The following number will direct the caller to the relevant local centre (0844) 892 0111
Information may be obtained if you have access to ToxBase the primary clinical toxicology database of the National Poisons Information Service. This is available via password on the internet ( www.toxbase.org ) or if this is unavailable at the backup site ( www.toxbasebackup.org ).
Further Information
Last Full Review: February 2014
Reference Sources
Drugs During Pregnancy and Lactation: Treatment Options and Risk Assessment, 2nd edition (2007) ed. Schaefer, C., Peters, P. and Miller, R. Elsevier, London.
Drugs in Pregnancy and Lactation: A Reference Guide to Fetal and Neonatal Risk, 9th edition (2011) ed. Briggs, G., Freeman, R. and Yaffe, S. Lippincott Williams & Wilkins, Philadelphia.
Martindale: The Complete Drug Reference, 37th edition (2011) ed. Sweetman, S. Pharmaceutical Press, London.
Medications and Mothers' Milk, 14th Edition (2010) Hale, T. Hale Publishing, Amarillo, Texas.
Summary of Product Characteristics: Co-Careldopa 10/100 mg Tablets. Teva Pharma B.V. Revised June 2013.
Summary of Product Characteristics: Co-Careldopa 25/100 mg Tablets. Teva Pharma B.V. Revised June 2013.
Summary of Product Characteristics: Co-Careldopa 25/250 mg Tablets. Teva Pharma B.V. Revised June 2013.
Summary of Product Characteristics: Sinemet 62.5, 110, plus and 275 Tablets. Bristol-Myers Squibb Pharmaceuticals Ltd. Revised March 2013.
NICE Evidence Services Available at: www.nice.org.uk Last accessed: 31 August 2017
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