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CO-CARELDOPA 10MG/100MG TABLETS

Active substance(s): CARBIDOPA MONOHYDRATE / LEVODOPA

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SUMMARY OF PRODUCT CHARACTERISTICS
1

NAME OF THE MEDICINAL PRODUCT
Co-careldopa 10 mg/100 mg tablets

2

QUALITATIVE AND QUANTITATIVE COMPOSITION
Each tablet of Co-careldopa a contains 10.8 mg carbidopa monohydrate
(equivalent to 10mg of anhydrous carbidopa) and 100 mg levodopa.
For the full list of excipients, see section 6.1.
.

3

Pharmaceutical form

Tablet.
Co-careldopa 10 mg/100 mg tablets are light blue coloured, round shaped, scored
tablet with C and break line on one side and 18 on other side of tablet.

4

CLINICAL PARTICULARS

4.1

Therapeutic indications
Antiparkinsonian agent.
For treatment of Parkinson's disease and syndrome.

4.2

Posology and method of administration
Posology
To be taken orally.
The optimum daily dosage of Co-careldopa must be determined by careful titration in
each patient.
Co-careldopa tablets are available in a ratio of 1:4 or 1:10 of carbidopa to levodopa to
provide facility for fine dosage titration for each patient.

General Considerations
Studies show that the peripheral dopa-decarboxylase is fully inhibited (saturated) by
carbidopa at doses between 70 and 100 mg a day. Patients receiving less than this
amount of carbidopa are more likely to experience nausea and vomiting.
Standard antiparkinsonian drugs, other than levodopa alone, may be continued while
Co-careldopa is being administered, although their dosage may have to be adjusted.
Because both therapeutic and adverse effects are seen more rapidly with Cocareldopa than with levodopa, patients should be carefully monitored during the
dosage adjustment period. Involuntary movements, particularly blepharospasm, are a
useful early sign of excess dosage in some patients.
Patients not receiving levodopa
Dosage may be best initiated with one tablet of Co-careldopa 25 mg/100 mg three
times a day. This dosage schedule provides 75 mg of carbidopa per day. Dosage may
be increased by one tablet of Co-careldopa 12.5 mg/50 mg or Co-careldopa 25
mg/100 mg every day or every other day, as necessary, until a dosage equivalent of
eight tablets of Co-careldopa 25 mg/100 mg a day is reached.
If Co-careldopa 10 mg/100 mg Tablets or Co-careldopa 12.5 mg/50 mg Tablets are
used, dosage may be initiated with one tablet three or four times a day. Titration
upward may be required in some patients to achieve optimum dosage of carbidopa.
The dosage may be increased by one tablet every day or every other day until a total
of eight tablets (two tablets q.d.s.) is reached.
Response has been observed in one day, and sometimes after one dose. Fully
effective doses usually are reached within seven days as compared to weeks or
months with levodopa alone.
Co-careldopa 12.5 mg/50 mg Tablets or Co-careldopa 10 mg/100 mg Tablets may be
used to facilitate dosage titration according to the needs of the individual patient.
Patients receiving levodopa
Discontinue levodopa at least 12 hours (24 hours for slow-release preparations)
before starting therapy with Co-careldopa. The easiest way to do this is to give Cocareldopa as the first morning dose after a night without any levodopa. The dose of
Co-careldopa should be approximately 20% of the previous daily dosage of levodopa.
Patients taking less than 1,500 mg levodopa a day should be started on one tablet of
Co-careldopa 25 mg/100 mg three or four times a day dependent on patient need. The
suggested starting dose for most patients taking more than 1,500 mg levodopa a day
is one tablet of Co-careldopa 25 mg/250 mg three or four times a day.
Maintenance

Therapy with Co-careldopa should be individualised and adjusted gradually
according to response. When a greater proportion of carbidopa is required, each tablet
of Co-careldopa 10 mg/100 mg may be replaced with a tablet of Co-careldopa 25
mg/100 mg or Co-careldopa 12.5 mg/50 mg.
When more levodopa is required, Co-careldopa 25 mg/250 mg Tablets should be
substituted at a dosage of one tablet three or four times a day. If necessary, the dosage
of Co-careldopa 25 mg/250 mg Tablets may be increased by one tablet every day or
every other day to a maximum of eight tablets a day. Experience with a total daily
dosage greater than 200 mg carbidopa is limited.
Patients receiving levodopa with another decarboxylase inhibitor
When transferring a patient to Co-careldopa from levodopa combined with another
decarboxylase inhibitor, discontinue dosage at least 12 hours before Co-careldopa is
started. Begin with a dosage of
Co-careldopa that will provide the same amount of levodopa as contained in the other
levodopa/decarboxylase inhibitor combination.
Patients receiving other antiparkinsonian agents
Current evidence indicates that other antiparkinsonian agents may be continued when
Co-careldopa is introduced, although dosage may have to be adjusted in line with
manufacturer’s recommendations.
Use in children
The safety of Co-careldopa in patients under 18 years of age has not been established
and its use in patients below the age of 18 is not recommended.
Use in the elderly
There is wide experience in the use of this product in elderly patients. The
recommendations set out above reflect the clinical data derived from this experience.

4.3

Contraindications
Hypersensitivity to the active substances or to any of the excipients listed in section
6.1.
Non-selective monoamine oxidase (MAO) inhibitors are contraindicated for use with
Co-careldopa. These inhibitors must be discontinued at least two weeks
before starting Co-careldopa. Co-careldopa may be administered concomitantly
with the manufacturer's recommended dose of an MAO inhibitor with selectivity for
MAO type B (e.g. selegiline hydrochloride). (See section 4.5 'Interaction with other
medicinal products and other forms of interaction'.)
Co-careldopa is contraindicated in patients with narrow-angle glaucoma.

Since levodopa may activate a malignant melanoma, it should not be used in patients
with suspicious undiagnosed skin lesions or a history of melanoma.
Use in patients with severe psychoses.
See also section 4.6 'Fertility, pregnancy and lactation'.

4.4

Special warnings and precautions for use
Co-careldopa is not recommended for the treatment of drug-induced extra pyramidal
reactions.
Co-careldopa should be administered cautiously to patients with severe
cardiovascular or pulmonary disease, bronchial asthma, renal, hepatic or endocrine
disease, or history of peptic ulcer disease (because of the possibility of upper gastrointestinal haemorrhage).
Care should be exercised when Co-careldopa is administered to patients with a
history of myocardial infarction who have residual atrial nodal, or ventricular
arrhythmias. Cardiac function should be monitored with particular care in such
patients during the period of initial dosage adjustment.
Levodopa has been associated with somnolence and episodes of sudden sleep onset.
Sudden onset of sleep during daily activities, in some cases without awareness or
warning signs, has been reported very rarely. Patients must be informed of this and
advised to exercise caution while driving or operating machines during treatment with
levodopa. Patients who have experienced somnolence and/or an episode of sudden
sleep onset must refrain from driving or operating machines. Furthermore a reduction
of dosage or termination of therapy may be considered.
All patients should be monitored carefully for the development of mental changes,
depression with suicidal tendencies, and other serious antisocial behaviour. Patients
with current psychoses should be treated with caution.
Dyskinesias may occur in patients previously treated with levodopa alone because
carbidopa permits more levodopa to reach the brain and, thus, more dopamine to be
formed. The occurrence of dyskinesias may require dosage reduction.
As with levodopa, Co-careldopa may cause involuntary movements and mental
disturbances. Patients with a history of severe involuntary movements or psychotic
episodes when treated with levodopa alone should be observed carefully when Cocareldopa is substituted. These reactions are thought to be due to increased brain
dopamine following administration of levodopa, and use of Co-careldopa may cause a
recurrence. A syndrome resembling the neuroleptic malignant syndrome including
muscular rigidity, elevated body temperature, mental changes and increased serum
creatine phosphokinase has been reported with the abrupt withdrawal of

antiparkinsonian agents. Therefore, any abrupt dosage reduction or withdrawal of Cocareldopa should be carefully observed, particularly in patients who are also receiving
neuroleptics.

Impulse control disorders
Patients should be regularly monitored for the development of impulse control
disorders. Patients and carers should be made aware that behavioural symptoms of
impulse control disorders including pathological gambling, increased libido,
hypersexuality, compulsive spending or buying, binge eating and compulsive eating
can occur in patients treated with dopamine agonists and/or other dopaminergic
treatments containing levodopa including Co-careldopa. Review of treatment is
recommended if such symptoms develop.
Concomitant administration of psycho-active drugs such as phenothiazines or
butyrophenones should be carried out with caution, and the patient carefully observed
for loss of antiparkinsonian effect. Patients with a history of convulsions should be
treated with caution.
As with levodopa, periodic evaluation of hepatic, haematopoetic, cardiovascular and
renal function are recommended during extended therapy.
Patients with chronic wide-angle glaucoma may be treated cautiously with Cocareldopa, provided the intra-ocular pressure is well controlled and the patient
monitored carefully for changes in intra-ocular pressure during therapy.
If general anaesthesia is required, therapy with Co-careldopa may be continued for as
long as the patient is permitted to take fluids and medication by mouth. If therapy has
to be stopped temporarily, Co-careldopa may be restarted as soon as oral medication
can be taken at the same daily dosage as before.
Epidemiological studies have shown that patients with Parkinson's disease have a
higher risk of developing melanoma than the general population (approximately 2-6
fold higher). It is unclear whether the increased risk observed was due to Parkinson's
disease, or other factors such as drugs used to treat Parkinson's disease. Therefore
patients and providers are advised to monitor for melanomas on a regular basis when
using Co-careldopa for any indication. Ideally, periodic skin examinations should be
performed by appropriately qualified individuals (e.g., dermatologists).
Laboratory Tests
Commonly, levels of blood urea nitrogen, creatinine, and uric acid are lower during
administration of Co-careldopa than with levodopa. Transient abnormalities include
elevated levels of blood urea, AST (SGOT), ALT (SGPT), LDH, bilirubin, and
alkaline phosphatase.
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, both with Co-careldopa and levodopa
alone. Co-careldopa may cause a false positive result when a dipstick is used to test
for urinary ketone; and this reaction is not altered by boiling the urine. The use of
glucose oxidase methods may give false negative results for glycosuria.

4.5

Interaction with other medicinal products and other forms of interaction
Caution should be exercised when the following drugs are administered
concomitantly with Co-careldopa.
Antihypertensive agents
Postural hypotension can occur when Co-careldopa is added to the treatment of
patients already receiving antihypertensive drugs. Dosage adjustment of the
antihypertensive agent may be required.
Antidepressants
Rarely, reactions including hypertension and dyskinesia have been reported with the
concomitant use of tricyclic antidepressants. (See first paragraph of section 4.3
'Contraindications' for patients receiving MAOIs).
Anticholinergics
Anticholinergics may affect the absorption and thus the patient's response.
Iron
Studies demonstrate a decrease in the bioavailability of carbidopa and/or levodopa
when it is ingested with ferrous sulphate or ferrous gluconate.
Other drugs
To date there has been no indication of interactions that would preclude concurrent
use of standard antiparkinsonian drugs.
Dopamine D2 receptor antagonists (e.g. phenothiazines, butyrophenones, and
risperidone) and isoniazid, may reduce the therapeutic effects of levodopa. The
beneficial effects of levodopa in Parkinson's disease have been reported to be
reversed by phenytoin and papaverine. Patients taking these drugs with Co-careldopa
should be carefully observed for loss of therapeutic response.
Use of Co-careldopa with dopamine-depleting agents (e.g., tetrabenazine) or other
drugs known to deplete monoamine stores is not recommended.
Concomitant therapy with selegiline and carbidopa-levodopa may be associated with
severe orthostatic hypotension not attributable to carbidopa-levodopa alone (see
section 4.3 'Contraindications').

Since levodopa competes with certain amino acids, the absorption of Co-careldopa
may be impaired in some patients on a high protein diet.
The effect of simultaneous administration of antacids with Co-careldopa on the
bioavailability of levodopa has not been studied.
Co-careldopa may be given to patients with Parkinson's disease and syndrome who
are taking vitamin preparations that contain pyridoxine hydrochloride (Vitamin B6).

4.6

Fertility, pregnancy and lactation
Although the effects of Co-careldopa on human pregnancy are unknown, both
levodopa and
combinations of carbidopa and levodopa have caused visceral and skeletal
malformations in rabbits. Therefore, the use of Co-careldopa in women of
childbearing potential requires that the anticipated benefits of the drug be weighed
against possible hazards should pregnancy occur.
Breast-feeding
It is not known whether carbidopa is excreted in human milk. In a study of one
nursing mother with Parkinson's disease, excretion of levodopa in human breast milk
was reported. Because many drugs are excreted in human milk and because of the
potential for serious adverse reactions in infants, a decision should be made whether
to discontinue breast-feeding or discontinue the use of Co-careldopa, taking into
account the importance of the drug to the mother.

4.7

Effects on ability to drive and use machines
Individual responses to medication may vary and certain side effects that have been
reported with Co-careldopa may affect some patients' ability to drive or operate
machinery. Patients treated with levodopa and presenting with somnolence and/or
sudden sleep episodes must be informed to refrain from driving or engaging in
activities where impaired alertness may put themselves or others at risk of serious
injury or death (e.g. operating machines), until such recurrent episodes and
somnolence have resolved (see also section 4.4 'Special warnings and precautions for
use').

4.8

Undesirable effects
Side effects that occur frequently with Co-careldopa are those due to the central
neuropharmacological activity of dopamine. These reactions can usually be
diminished by dosage reduction. The most common are dyskinesias including
choreiform, dystonic and other involuntary movements and nausea. Muscle twitching
and blepharospasm may be taken as early signs to consider dosage reduction.
Other side effects reported in clinical trials or in post-marketing experience include:

Body as a whole: syncope, chest pain, anorexia.
Cardiovascular: cardiac irregularities and/or palpitations, orthostatic effects including
hypotensive episodes, hypertension, phlebitis.
Gastro-intestinal: vomiting, gastro-intestinal bleeding, development of duodenal
ulcer, diarrhoea, dark saliva.
Haemotologic: leucopenia, haemolytic and non-haemolytic anaemia,
thrombocytopenia, agranulocytosis.
Hypersensitivity: angioedema, urticaria, pruritus, Henoch-Schonlein purpura.
Nervous System/Psychiatric: neuroleptic malignant syndrome (see 4.3
'Contraindications'), bradykinetic episodes (the “on-off” phenomenon), dizziness,
paraesthesia, psychotic episodes including delusions, hallucinations and paranoid
ideation, depression with or without development of suicidal tendencies, dementia,
dream abnormalities, agitation, confusion, increased libido. Levodopa is associated
with somnolence and has been associated very rarely with excessive daytime
somnolence and sudden sleep onset episodes.
Respiratory: dyspnoea.
Skin: alopecia, rash, dark sweat.
Urogenital: dark urine.
Rarely convulsions have occurred; however, a causal relationship with Co-careldopa
has not been established.
Other side effects that have been reported with levodopa or levodopa/carbidopa
combinations and may be potential side effects with Co-careldopa include:
Gastro-intestinal: dyspepsia, dry mouth, bitter taste, sialorrhoea, dysphagia, bruxism,
hiccups, abdominal pain and distress, constipation, flatulence, burning sensation of
the tongue.
Metabolic: weight gain or loss, oedema.
Nervous System/Psychiatric: asthenia, decreased mental acuity, disorientation, ataxia,
numbness, increased hand tremor, muscle cramp, trismus, activation of latent
Horner's syndrome, insomnia, anxiety, euphoria, falling and gait abnormalities.
Impulse control disorders

Pathological gambling, increased libido, hypersexuality, compulsive spending or
buying, binge eating and compulsive eating can occur in patients treated with
dopamine agonists and/or other dopaminergic treatments containing levodopa
including Co-careldopa (see section 4.4. 'Special warnings and precautions for use')
Skin: flushing, increased sweating.
Special senses: diplopia, blurred vision, dilated pupils, oculogyric crises.
Urogenital: urinary retention, urinary incontinence, priapism.
Miscellaneous: weakness, faintness, fatigue, headache, hoarseness, malaise, hot
flushes, sense of stimulation, bizarre breathing patterns, malignant melanoma (see
section 4.3 'Contraindications').
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is
important. It allows continued monitoring of the benefit/risk balance of the medicinal
product. Healthcare professionals are asked to report any suspected adverse reactions
via the national reporting system,
United Kingdom,
Yellow Card Scheme,
Website: www.mhra.gov.uk/yellowcard

4.9

Overdose
Management of acute overdosage with Co-careldopa is basically the same as
management of acute
overdosage with levodopa; however pyridoxine is not effective in reversing the
actions of Co-careldopa. ECG monitoring should be instituted, and the patient
carefully observed for the possible development of arrhythmias; if required,
appropriate anti-arrhythmic therapy should be given. The possibility that the patient
may have taken other drugs as well as Co-careldopa should be taken into
consideration. To date, no experience has been reported with dialysis, and hence its
value in the treatment of overdosage is not known. The terminal half-life of levodopa
is about two hours in the presence of carbidopa.

5

PHARMACOLOGICAL PROPERTIES

5.1

Pharmacodynamic properties
Pharmacotherapeutic group: Anti-Parkison drugs, dopaminergic agents, ATC code:
N04BA02 Mechanism of action
Levodopa is a precursor of dopamine, and is given as replacement therapy in
Parkinson's disease.

Carbidopa is a peripheral dopa decarboxylase inhibitor. It prevents metabolism of
levodopa to dopamine in the peripheral circulation, ensuring that a higher proportion
of the dose reaches the brain, where dopamine acts. A lower dose of levodopa can be
used, reducing the incidence and severity of side effects.
Pharmacodynamic effects
Co-careldopa is useful in relieving many of the symptoms of parkinsonism,
particularly rigidity and bradykinesia. It is frequently helpful in the management of
tremor, dysphagia, sialorrhoea, and postural instability associated with Parkinson's
disease and syndrome.
Clinical efficacy and safety
When response to levodopa alone is irregular, and signs and symptoms of Parkinson's
disease are not controlled evenly throughout the day, substitution of Co-careldopa
usually reduces fluctuations in response. By reducing some of the adverse reactions
produced by levodopa alone, Co-careldopa permits more patients to obtain adequate
relief from the symptoms of Parkinson's disease.

5.2

Pharmacokinetic properties
Absorption
Following oral dosing levodopa, in the absence of decarboxylase inhibitor, is rapidly
but variably absorbed from the gastro-intestinal tract. It has a plasma half life of about
1 hour and is mainly converted by decarboxylation to dopamine, a proportion of
which is converted to noradrenaline. Up to 30 % is converted to 3-O-methyldopa
which has a half life of 9 to 22 hours. About 80 % of levodopa is excreted in the urine
within 24 hours mainly as homovanillic acid and dihydroxyphenylactic acid. Less
than 1% is excreted unchanged.
Distribution
Once in the circulation it competes with other neutral amino acids for transport across
the blood brain barrier. Once it has entered the striatal neurones it is decarboxylated
to dopamine, stored and released from presynaptic neurones. Because levodopa is so
rapidly decarboxylated in the gastro-intestinal tract and the liver, very little
unchanged drug is available for transport into the brain. The peripheral
decarboxylation reduces the therapeutic effectiveness of levodopa but is responsible
for many of its side effects. For this reason levodopa is usually administered together
with a peripheral decarboxylase inhibitor such as carbidopa, so that lower doses may
be given to achieve the same therapeutic effect.
Biotransformation
Carbidopa in the absence of levodopa, is rapidly but incompletely absorbed from the
gastrointestinal tract following oral dosing. Following an oral dose approximately
50% is recorded in the urine, with about 3% of this as unchanged drug. It does not
cross the blood brain barrier but crosses the placenta and is excreted in breast milk.

Turnover of the drug is rapid and virtually all unchanged drug appears in the urine
within 7 hours.
Elimination
Carbidopa inhibits the peripheral decarboxylation of levodopa to dopamine but as it
does not cross the blood brain barrier, effective brain levels of dopamine get produced
with lower levels of levodopa therapy reducing the peripheral side effects, noticeably
nausea and vomiting and cardiac arrhythmias.

5.3

Preclinical safety data
Co-careldopa is well established in medical use. Preclinical data is broadly consistent
with clinical experience. (For reproductive toxicity, see section 4.6 'Fertility,
pregnancy and Lactation'.)

6

PHARMACEUTICAL PARTICULARS

6.1

List of excipients
Crospovidone
Quinine yellow lake (E104)
Magnesium stearate
Cellulose microcrystalline
Maize starch

Indigo carmine lake (E132)
6.2

Incompatibilities
Not applicable.

6.3

Shelf life
36 months

6.4

Special precautions for storage
No special storage conditions

6.5

Nature and contents of container
Tablets are packed in Alu-Alu blisters.

The blister packs comprise of blister strip which consists of cold-formable aluminium
based blister foil (Alu-Alu foil) & Plain aluminium foil/HSL.
Packs containing:

100 tablets
Not all pack sizes may be marketed.

6.6

Special precautions for disposal
Any unused medicinal product or waste material should be disposed of in
accordance with local requirements.

7

MARKETING AUTHORISATION HOLDER
Strandhaven Limited t/a Somex Pharma,
Ilford, Essex.
IG3 8BS.UK

8

MARKETING AUTHORISATION NUMBER(S)
PL15764/0106

9

DATE OF FIRST AUTHORISATION/RENEWAL OF THE
AUTHORISATION
09/03/2016

10

DATE OF REVISION OF THE TEXT
05/07/2016

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Source: Medicines and Healthcare Products Regulatory Agency

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