Antiparkinsonian agent.

 

Treatment of Parkinson's disease, Zydolev ® frequently is helpful in the management of  tremor, dysphagia, sialorrhea and postural instability associated with Parkinson's disease.

Posology

 

To be taken orally.
The optimum daily dosage of Zydolev ® must be determined by careful titration in each
patient.
Zydolev ® 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 dopadecarboxylase 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 Zydolev® is being administered, although their dosage may have to be adjusted.
Because both therapeutic and adverse effects are seen more rapidly with Zydolev® 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 'Zydolev® 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 ‘Zydolev® 25 mg/100 mg' every day or every other day, as necessary, until a dosage equivalent of eight tablets of Zydolev® 25 mg/100 mg' a day 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.
Patients receiving levodopa Discontinue levodopa at least 12 hours (24 hours for slow-release preparations) before starting therapy with Zydolev®. The easiest way to do this is to give Zydolev® as the first morning dose after a night without any levodopa. The dose of Zydolev® 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 Zydolev®
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 Zydolev® 25 mg/250 mg' three or four times a day.
 

Maintenance Therapy with Zydolev® should be individualized and adjusted gradually according to response.
When more levodopa is required, Zydolev® 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 Zydolev® 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 Zydolev® from levodopa combined with another decarboxylase inhibitor, discontinue dosage at
least 12 hours before Zydolev® is started.
Begin with a dosage of Zydolev® 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 Zydolev® is introduced, although dosage may have to be adjusted in line with manufacturers recommendations.

Use in children
The safety of Zydolev® 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.

Zydolev® should not be given when administration of a sympathomimetic amine is contraindicated. Non-selective monoamine oxidase (MAO) inhibitors are contraindicated for use with Zydolev®. These inhibitors must be discontinued at least two weeks prior to initiating therapy with Zydolev®. Zydolev® 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 4.5 'Interaction with other medicinal products and other forms of interaction'.) Zydolev® is contraindicated in patients with known hypersensitivity to any component of this medication, and in patients with narrow angle glaucoma. Because levodopa may activate a malignant melanoma, Zydolev® should not be used in patients with suspicious undiagnosed skin lesions or a history of melanoma. Use in patients with severe psychoses. See also 4.6 'Pregnancy and lactation'.

Zydolev® may be given to patients already receiving levodopa alone. However, the levodopa alone must be discontinued at least 12 hours before therapy with Zydolev® is started.
Zydolev® should be substituted at a dosage that will provide approximately 25% of the previous levodopa dosage (see Posology and method of administration).
Zydolev® is not recommended for the treatment of drug-induced extrapyramidal reactions or for the treatment of Huntington's chorea.
Zydolev® should be administered cautiously to patients with severe cardiovascular or pulmonary disease, bronchial asthma, renal, hepatic or endocrine disease, or with a history of peptic ulcer disease (because of the possibility of upper gastrointestinal hemorrhage) or of convulsions.
Care should be exercised in administering Zydolev® or to patients with a history of recent myocardial infarction who have residual atrial, nodal, or ventricular arrhythmia. In such patients, cardiac function should be monitored with particular care during the period of initial dosage administration and titration.
A symptom complex resembling the neuroleptic malignant syndrome including muscular rigidity, elevated body temperature, mental changes, and increased serum creatine phosphokinase has been reported when antiparkinsonian agents were withdrawn abruptly.
Therefore, patients should be observed carefully when the dosage of Carbidopa-levodopa combinations is reduced abruptly or discontinued, especially if the patient is receiving antipsychotics.
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, Zydolev® may cause involuntary movements and mental disturbances. Patients with current or history of severe involuntary movements or psychotic episodes when treated with levodopa alone or levodopa/decarboxylase inhibitor combination should be observed carefully when Zydolev® is substituted. These reactions are thought to be due to increased brain dopamine following administration of levodopa and use of Zydolev® may cause recurrence. Dosage reduction may be required. All patients should be observed carefully for the development of depression with concomitant suicidal tendencies. Patients with past or current psychoses should be treated with caution.
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.
Periodic evaluations of hepatic, hematopoietic, cardiovascular and renal function are recommended during extended therapy.
Patients with chronic wide-angle glaucoma may be treated cautiously with Zydolev®, provided the intraocular pressure is well controlled and the patient monitored carefully for changes in intraocular pressure during therapy.

If general anaesthesia is required, Zydolev® may be continued as long as the patient is permitted to take fluids and medication by mouth. If therapy is interrupted temporarily, the usual dosage should be administered as soon as the patient is able to take oral medicine.
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 factor 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 Zydolev® for any indication. Ideally, periodic skin examinations should be performed by appropriately qualified individuals (e.g., dermatologists). 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 Zydolev®. Review of treatment is recommended if such symptoms develop.

Laboratory Tests
“Commonly, levels of blood urea nitrogen, creatinine, and uric acid are lower during administration of Zydolev® than with levodopa. Transient abnormalities include elevated levels of blood urea, AST (SGOT), ALT (SGPT), LDH, bilirubin, and alkalin phosphatase.
Decreased hemoglobin, hematocrit, elevated serum glucose and white blood cells, bacteria and blood in the urine have been reported. Positive Coombs' tests have been reported, both with Zydolev® and levodopa alone. Zydolev® 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.
 

Dopamine Dysregulation Syndrome (DDS) is an addictive disorder resulting in excessive use of the product seen in some patients treated with carbidopa/ levodopa. Before initiation of treatment, patients and caregivers should be warned of the potential risk of developing DDS (see also section 4.8).

Caution should be exercised when the following drugs are administered concomitantly with Zydolev®

 

Antihypertensive agents
Symptomatic postural hypotension has occurred when levodopa/decarboxylase inhibitor combinations were added to the treatment of patients receiving some antihypertensive drugs.
Therefore, when therapy with Zydolev® is started, dosage adjustment of the antihypertensive drug may be required.

 

Antidepressants
There have been rare reports of adverse reactions, including hypertension and dyskinesia, resulting from the concomitant use of tricyclic antidepressants and carbidopa-levodopa preparations. (For patients receiving monoamine oxidase inhibitors, see 4.3 'Contraindications').
 

Iron Studies demonstrate a decrease in the bioavailability of Carbidopa and/or levodopa when it is ingested with ferrous sulphate or ferrous gluconate.

Anticholinergics
Anticholinergics may affect the absorption and thus the patient's response 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 effectsof 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 Zydolev® should be observed carefully for loss of therapeutic response.
Use of Zydolev® 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 4.3 'Contraindications').
Since levodopa competes with certain amino acids, the absorption of levodopa may be impaired in some patients on a high protein diet.
The effect of simultaneous administration of antacids with Zydolev® on the bioavailability of levodopa has not been studied.
Zydolev® may be given to patients with Parkinson's disease and syndrome who are taking vitamin preparations that contain pyridoxine hydrochloride (Vitamin B6).
Phenytoin which is used to treat fits (convulsions) and papaverine which is used to treat impotence in men have been reported to reverse the beneficial action of levopoda

 

Zydolev® should not be given during pregnancy and to nursing mothers.

 

Pregnancy:

Although the effects of Zydolev® 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 Zydolev® in women of childbearing potential requires that the anticipated benefits of the drug be weighedagainst possible hazards should pregnancy occur.

 

Breastfeeding mothers:

 

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 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 Zydolev®, taking into account the importance of the drug to the mother.

Individual responses to medication may vary. Certain side effects that have been reported with Zydolev® 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 other 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').

Side effects that occur frequently in patients receiving Zydolev® are those due to the central

neuropharmacologic activity of dopamine.

These reactions usually can be diminished by dosage reduction. The most common side

effects reported with Zydolev® are dyskinesias,(a form of abnormal involuntary movements),

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 that also were reported frequently (above 2%) were:

nausea, hallucinations, confusion, dizziness, chorea and dry mouth.

 

Side effects occurring less frequently (1-2%)

were:

dream abnormalities, dystonia,somnolence, insomnia, depression, asthenia,

vomiting and anorexia.

Other side effects reported in clinical trials or in post-marketing experience include:

Body as a whole: chest pain, syncope, anorexia Cardiovascular: palpitation, orthostatic effects

including hypotensive episodes, hypertension, phlebitis.

 

Gastro-intestinal:

vomiting, constipation, diarrhea, dyspepsia, gastro-intestinal pain, dark

saliva, gastro-intestinal bleeding, development

of duodenal ulcer.

 

Hypersensitivity:

angioedema, urticaria, pruritus, Henoch-Schonlein purpura.

 

Haemotologic:

leucopenia, haemolytic and non-haemolytic anaemia, thrombocytopenia, agranulocytosis.

 

Metabolic:

weightloss. Nervous System/Psychiatric:

Neuroleptic malignant syndrome (see 4.3 'Contraindications'), agitation, anxiety,

decreased mental acuity, dizziness, paraesthesia, disorientation, fatigue, headache,

extrapyramidal and movement disorders, falling, gait abnormalities, muscle cramps, bradykinetic episodes (The on-off phenomenon), depression with or without development of suicidal tendencies, dementia, dream abnormalities, confusion increased libido, psychotic episodes including delusions, hallucinations and paranoid ideation. Levodopa is associated with somnolence and has been associated very rarely with excessive daytime somnolence and sudden sleep onset episodes.

 

Respiratory:

dyspnea

 

Skin:

flushing, alopecia, rash, dark sweat. Special Senses: blurred vision.

 

Urogenital: dark urine.

Laboratory Tests Abnormalities in various laboratory tests have occurred with Carbidopa-levodopa preparations and may occur with Zydolev®. These include elevations of liver function tests such as alkaline phosphatase, SGOT (AST), SGPT (ALT), LDH, bilirubin, blood urea nitrogen, creatinine, uric acid and positive Coombs' test.

 

Carbidopa-levodopa preparations may cause a 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 glycosuria.

Decreased haemoglobin and haematocrit, elevated serum glucose and white blood cells,

bacteria and blood in the urine have been reported with standard Zydolev®.

 

Other side effects that have been reported with levodopa or levodopa/carbidopa combinations

and may be potential side-effects with Zydolev® are listed below:

 

Cardiovascular: cardiac irregularities, hypertension, phlebitis.

Gastro-intestinal: dyspepsia, dry mouth, bitter taste, sialorrhoea, dysphagia, bruxism, hiccups,

gastro-intestinal bleeding, flatulence, burning sensation of tongue, development of duodenal

ulcer, abdominal pain distress, constipation.

Haematologic: leucopenia, haemolytic and nonhaemolytic anaemia, thrombocytopenia,

agranulocytosis.

Metabolic: weight gain or loss, oedema.

 

Nervous system/Psychiatric: asthenia, decreased mental acuity, disorientation, ataxia, numbness,

increased hand tremor, muscle cramp, muscle twitching, blepharospasm, trismus, activation of

latent Horner's syndrome, insomnia, anxiety, euphoria, and dementia, falling, gait abnormalities, depression with suicidal tendencies and Dopamine Dysregulation Syndrome.

Description of selected adverse reactions Dopamine Dysregulation Syndrome (DDS) is an

addictive disorder seen in some patients treated with carbidopa/ levodopa. Affected patients

show a compulsive pattern of dopaminergic drug misuse above doses adequate to control

motor symptoms, which may in some cases result in severe dyskinesias (see also section

4.4). 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 Zydolev® (see section 4.4. 'Special warnings and precautions for use').

Patients treated with dopamine agonists for treatment of Parkinson's disease, especially at

high doses, have been reported as exhibiting signs of pathological gambling, increased libido

and hypersexuality, generally reversible upon reduction of the dose or treatment discontinuation.

Skin: increased sweating, flushing.Special senses: diplopia, dilated pupils, oculogyric crises, blurred vision.

Urogenital: urinary retention, urinary incontinence, priapism. Miscellaneous: weight gain, oedema, weakness, faintness, fatigue, headache, hoarseness, malaise, hot flashes, sense of stimulation,

bizarre breathing patterns, malignant melanoma (see 4.3 Contraindications), Henoch-Schonlein

purpura.

Convulsions have occurred; however, a causal relationship with levodopa or levodopa/carbidopa combinations has not been established.

 

To report any side effect(s):

• Saudi Arabia:

 

- The National Pharmacovigilance Centre (NPC) Toll free phone: 19999 E-mail: npc.drug@sfda.gov.sa   Website: https://ade.sfda.gov.sa/

 

• Other GCC States:

 

-       Please contact the relevant competent authority.

 

 

 

Management of acute overdosage with Zydolev® is basically the same as management of acute overdosage with levodopa; however, pyridoxine is not effective in reversing the actions of Zydolev®. General supportive measures should be employed along with immediate gastric lavage. Intravenous fluids should be administered judiciously, and an adequate airway maintained.

Electrocardiographic monitoring should be instituted, and the patient observed carefully for the development of arrhythmias; if required, appropriate antiarrhythmic therapy should be given. The possibility that the patient may have taken other drugs as well as Zydolev® should be taken into consideration. To date, no experience has been reported with dialysis; hence, its value.

in overdosage is not known. The terminal half-life of levodopa is about two hours in the

presence of carbidopa.

Management of acute overdosage with Zydolev® is basically the same as management of acute overdosage with levodopa; however, pyridoxine is not effective in reversing the actions of Zydolev®. General supportive measures should be employed along with immediate gastric lavage. Intravenous fluids should be administered judiciously and an adequate airway maintained.
Electrocardiographic monitoring should be instituted, and the patient observed carefully for the development of arrhythmias; if required, appropriate antiarrhythmic therapy should be given. The possibility that the patient may have taken other drugs as well as Zydolev® should be taken into consideration. To date, no experience has been reported with dialysis; hence, its value in overdosage is not known. The terminal half-life of levodopa is about two hours in the
presence of carbidopa.

 

Zydolev® is a combination of Carbidopa, an aromatic amino acid decarboxylase inhibitor, and levodopa, the metabolic precursor of dopamine, for use in the treatment of Parkinson's disease.

Levodopa relieves the symptoms of Parkinson's disease by being decarboxylated to dopamine in the brain.

 

Carbidopa, which does not cross the blood-brain barrier, inhibits only the extracerebral decarboxylation of levodopa, making more levodopa available for transport to the brain and subsequent conversion to dopamine.While pyridoxine hydrochloride (Vitamin B6) is known to accelerate the peripheral metabolism of levodopa to dopamine, Carbidopa prevents this action.

Zydolev® 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.

When response to levodopa alone is irregular, and signs and symptoms of Parkinson's disease are not controlled evenly throughout the day, substitution of Zydolev® usually reduces fluctuations in response. By reducing some of the adverse reactions produced by levodopa alone, Zydolev® permits more patients to obtain adequate relief from the symptoms of Parkinson's disease.

The medicine has appeared harmful in animal trials (visceral and skeletal malformations in rabbits).

Zydolev® is well established in medical use. Preclinical data is broadly consistent with clinical experience. (For reproductive toxicity, see section 4.6 'Pregnancy and lactation')

Microcrysalline Cellulose

Ferric Ox ide red

Hydroxypropyl Cellulose

Purified water

Crospovi done Type-A

Pregelatin ized starch

Microcrysalline Cellulose 102

Magnesium stearate

Not applicable

24 Months

Store below 30°C.

Protect from light.

Alu-Alu Blister Pack:

The Carbidopa and Levodopa Tablets USP 25mg/250mg Tablets will be packed in a blister formed from 148 mm cold form film, 25μ OPA/45μ Alu Foil/60μ PVC AMCOR sealed by 0.025mm Aluminium foil

Zydus Lifesciences Limited

Zydus Corporate Park Scheme No 63 Survey No 536 Khoraj Gandhinagar

Nr Vaishnodevi Circle Ahmedabad G

Gujarat, India