Flexilev

Treatment of advanced levodopa-responsive Parkinson's disease with severe motor fluctuations and hyperkinesia or dyskinesia when available combinations of Parkinson medicinal products have not given satisfactory results.

Antiparkinson agent.

Idiopathic Parkinson's disease, in particular to reduce off-period in patients who previously have been treated with levodopa/decarboxylase inhibitors, or with levodopa alone and who have experienced motor fluctuations. The experience is limited with 'Flexilev' and 'Half Flexilev' in patients who have not been treated with levodopa before.

Antiparkinsonian agent.

For treatment of Parkinson's disease and syndrome.

Flexilev is a gel for continuous intestinal administration. For long-term administration, the gel should be administered with a portable pump directly into the duodenum or upper jejunum by a permanent tube via percutaneous endoscopic gastrostomy with an outer transabdominal tube and an inner intestinal tube. Alternatively, a radiological gastrojejunostomy may be considered if percutaneous endoscopic gastrostomy is not suitable for any reason. Establishment of the transabdominal port and dose adjustments should be carried out in association with a neurological clinic.

A temporary nasoduodenal/nasojejunal tube should be considered to determine if the patient responds favourably to this method of treatment before a permanent percutaneous endoscopic gastrostomy with jejunal tube (PEG-J) is placed. In cases where the physician considers this assessment is not necessary, the nasojejunal test phase may be waived and treatment initiated directly with placement of the PEG-J. The dose should be adjusted to an optimal clinical response for the individual patient, which means maximizing the functional ON-time during the day by minimizing the number and duration of OFF episodes (bradykinesia) and minimizing ON-time with disabling dyskinesia. See recommendations under Dosage.

Flexilev should be given initially as monotherapy. If required other medicinal products for Parkinson's disease can be taken concurrently. For administration of Flexilev only the CADD-legacy 1400 pump (CE 0473) should be used. A manual with instructions for using the portable pump is delivered together with the pump.

Treatment with Flexilev using a permanent tube can be discontinued at any time by withdrawing the tube and letting the wound heal. Treatment should then continue with oral medicinal products including levodopa/carbidopa.

Dosage:

The total dose/day of Flexilev is composed of three individually adjusted doses: the morning bolus dose, the continuous maintenance dose and extra bolus doses administered over approximately 16 hours. In addition to daytime, if medically justified Flexilev may be administered during the night.

The medicine cassettes are for single use only and should not be used for longer than 16 hours, even if some medicinal product remains. Do not reuse an opened cassette.

By the end of the storage time the gel might become slightly yellow. This does not influence the concentration of the medicine or the treatment.

Morning dose: The morning bolus dose is administered by the pump to rapidly achieve the therapeutic dose level (within 10-30 minutes). The dose should be based on the patient's previous morning intake of levodopa + the volume to fill the tubing. The total morning dose is usually 5-10 ml, corresponding to 100-200 mg levodopa. The total morning dose should not exceed 15 ml (300 mg levodopa).

Continuous maintenance dose: The maintenance dose is adjustable in steps of 2 mg/hour (0.1 ml/hour). The dose should be calculated according to the patient's previous daily intake of levodopa. When supplementary medicines are discontinued the Flexilev dose should be adjusted. The continuous maintenance dose is adjusted individually. It should be kept within a range of 1-10 ml/hour (20-200 mg levodopa/hour) and is usually 2-6 ml/hour (40-120 mg levodopa/hour). The maximum recommended daily dose is 200 ml. In exceptional cases a higher dose may be needed.

Example:

Daily intake of levodopa as Flexilev: 1640 mg/day

Morning bolus dose: 140 mg = 7 ml (excluding the volume to fill the intestinal tube)

Continuous maintenance dose: 1500 mg/day

1500 mg/day: 20 mg/ml = 75 ml Flexilev per day

The intake is calculated over 16 hours: 75 ml/16 hours = 4.7 ml/hour.

Extra bolus doses: To be given as required if the patient becomes hypokinetic during the day. The extra dose should be adjusted individually, normally 0.5-2.0 ml. In rare cases a higher dose may be needed. If the need for extra bolus doses exceeds 5 per day the maintenance dose should be increased.

After the initial dose setting, fine adjustments of the morning bolus dose, the maintenance dose and extra bolus doses should be carried out over a few weeks.

Monitoring of treatment: A sudden deterioration in treatment response with recurring motor fluctuations should lead to the suspicion that the distal part of the tube has become displaced from the duodenum/jejunum into the stomach. The location of the tube should be determined by X-ray and the end of the tube repositioned to the duodenum/jejunum.

Special Populations

Paediatric population

There is no relevant use of Flexilev in the paediatric population in the indication of advanced levodopa-responsive Parkinson's disease with severe motor fluctuations and hyper-/dyskinesia.

Geriatric Population

There is a considerable experience in the use of levodopa/carbidopa in elderly patients. Doses for all patients including geriatric population are individually adjusted by titration.

Renal/hepatic impairment

There are no studies on the pharmacokinetics of carbidopa and levodopa in patients with hepatic or renal impairment. Dosing with Flexilev is individualized by titration to optimal effect (which corresponds to individually optimized levodopa and carbidopa plasma exposures); therefore, potential effects of hepatic or renal impairment on levodopa and carbidopa exposure are indirectly accounted for in dose titration. Dose titration should be conducted with caution in patients with severe renal and hepatic impairment.

Interruption of therapy

In the case of suspected or diagnosed dementia with a decreased confusion threshold, the pump of the patient should be handled only by the nursing staff or a caregiver.

When a cassette is about to be used, it should be attached to the portable pump and the system connected to the nasoduodenal tube or duodenal/jejunal tube for administration, according to the instructions given.

'Flexilev' and 'Half Flexilev' tablets contain a 1:4 ratio of carbidopa to levodopa ('Flexilev': carbidopa 50 mg/levodopa 200 mg, 'Half Flexilev' 25 mg/100 mg per tablet). The daily dosage of 'Flexilev' must be determined by careful titration. Patients should be monitored closely during the dose adjustment period, particularly with regard to appearance or worsening of nausea or abnormal involuntary movements, including dyskinesias, chorea and dystonia.

Route of administration: oral

'Flexilev' and 'Half Flexilev' may only be administered as whole tablets. So that the controlled release properties of the product can be maintained, tablets should not be chewed, crushed, or halved.

Standard antiparkinson drugs, other than levodopa alone, may be continued while 'Flexilev' or 'Half Flexilev' are being administered, although their dosage may have to be adjusted. Since carbidopa prevents the reversal of levodopa effects caused by pyridoxine, 'Flexilev' or 'Half Flexilev' can be given to patients receiving supplemental pyridoxine (vitamin B6).

Initial Dose

Patients currently treated with conventional levodopa/decarboxylase inhibitor combinations

Dosage with 'Flexilev' should be substituted initially at an amount that provides no more than approximately 10% more levodopa per day when higher dosages are given (more than 900 mg per day). The dosing interval between doses should be prolonged by 30 to 50% at intervals ranging from 4 to 12 hours. It is recommended to give the smaller dose, if divided doses are not equal, at the end of the day. The dose needs to be titrated further depending on clinical response, as indicated below under 'Titration'. Dosages that provide up to 30% more levodopa per day may be necessary.

A guide for substitution of 'Flexilev' treatment for conventional levodopa/decarboxylase inhibitor combinations is shown in the table below:

Guideline for Conversion from 'Sinemet' to 'Flexilev'

'Half Flexilev' is available to facilitate titration when 100 mg steps are required.

Patients currently treated with levodopa alone

Levodopa must be discontinued at least eight hours before therapy with 'Flexilev' is started. In patients with mild to moderate disease, the initial recommended dose is one tablet of 'Flexilev' twice daily.

Patients not receiving levodopa

In patients with mild to moderate disease, the initial recommended dose is one tablet of 'Flexilev' twice daily. Initial dosages should not exceed 600 mg per day of levodopa, nor be given at intervals of less than six hours.

Titration

Following initiation of therapy, doses and dosing intervals may be increased or decreased, depending upon therapeutic response. Most patients have been adequately treated with two to eight tablets per day of 'Flexilev' administered as divided doses at intervals ranging from four to twelve hours during the waking day. Higher doses (up to 12 tablets) and shorter intervals (less than four hours) have been used, but are not usually recommended.

When doses of 'Flexilev' are given at intervals of less than four hours, or if the divided doses are not equal, it is recommended that the smaller doses be given at the end of the day. In some patients the onset of effect of the first morning dose may be delayed for up to one hour compared with the response usually obtained from the first morning dose of 'Sinemet'.

An interval of at least three days between dosage adjustments is recommended.

Maintenance

Because Parkinson's disease is progressive, periodic clinical evaluations are recommended and adjustment of the dosage regimen of 'Flexilev' or 'Half Flexilev' may be required.

Addition of other antiparkinson medication

Anticholinergic agents, dopamine agonists and amantadine can be given with 'Flexilev' or 'Half Flexilev'. Dosage adjustment of 'Flexilev' or 'Half Flexilev' may be necessary when these agents are added to an existing treatment regimen for 'Flexilev' or 'Half Flexilev'.

Interruption of therapy

Patients should be observed carefully if abrupt reduction or discontinuation of 'Flexilev' or 'Half Flexilev' is required, especially if the patient is receiving antipsychotics (see 4.4 'Special warnings and precautions for use').

Use in Children

Safety and effectiveness of 'Flexilev' or 'Half Flexilev' in infants and children have not been established, and its use in patients below the age of 18 is not recommended.

To be taken orally.

The optimum daily dosage of 'Flexilev' must be determined by careful titration in each patient.

'Flexilev' 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 'Flexilev' is being administered, although their dosage may have to be adjusted.

Because both therapeutic and adverse effects are seen more rapidly with 'Flexilev' 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 'Flexilev Plus 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 'Flexilev 12.5 mg/50 mg' or 'Flexilev Plus 25 mg/100 mg' every day or every other day, as necessary, until a dosage equivalent of eight tablets of 'Flexilev Plus 25 mg/100 mg' a day is reached.

If 'Flexilev 10 mg/100 mg Tablets' or 'Flexilev 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.

'Flexilev 12.5 mg/50 mg Tablets' or 'Flexilev 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 'Flexilev'. The easiest way to do this is to give 'Flexilev' as the first morning dose after a night without any levodopa. The dose of 'Flexilev' 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 'Flexilev Plus 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 'Flexilev 25 mg/250 mg' three or four times a day.

Maintenance

Therapy with 'Flexilev' should be individualised and adjusted gradually according to response. When a greater proportion of carbidopa is required, each tablet of 'Flexilev 10 mg/100 mg' may be replaced with a tablet of 'Flexilev Plus 25 mg/100 mg' or 'Flexilev 12.5 mg/50 mg'.

When more levodopa is required, 'Flexilev 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 'Flexilev 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 'Flexilev' from levodopa combined with another decarboxylase inhibitor, discontinue dosage at least 12 hours before 'Flexilev' is started. Begin with a dosage of 'Flexilev' 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 'Flexilev' is introduced, although dosage may have to be adjusted in line with manufacturers recommendations.

Use in children

The safety of 'Flexilev' 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.

Flexilev is contraindicated in patients with:

- hypersensitivity to the active substances or to any of the excipients listed in section 6.1.

- narrow-angle glaucoma

- severe heart failure

- severe cardiac arrhythmia

- acute stroke

- non-selective MAO inhibitors and selective MAO type A inhibitors are contraindicated for use with Flexilev. These inhibitors must be discontinued at least two weeks prior to initiating therapy with Flexilev. Flexilev may be administered concomitantly with the manufacturer's recommended dose of an MAO inhibitor with selectivity for MAO type B (e.g., selegiline HCl).

- conditions in which adrenergics are contraindicated, e.g. pheochromocytoma, hyperthyroidism and Cushing's syndrome.

Because levodopa may activate malignant melanoma, Flexilev should not be used in patients with suspicious undiagnosed skin lesions or a history of melanoma.

'Flexilev' or 'Half Flexilev' should not be given when administration of a sympathomimetic amine is contraindicated.

Non-selective monoamine oxidase (MAO) inhibitors are contraindicated for use with 'Flexilev' or 'Half Flexilev'. These inhibitors must be discontinued at least two weeks prior to initiating therapy with 'Flexilev' or 'Half Flexilev'. 'Flexilev' or 'Half Flexilev' 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 'Interactions with other medicinal products and other forms of interaction').

'Flexilev' or 'Half Flexilev' 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, 'Flexilev' or 'Half Flexilev' should not be used in patients with suspicious undiagnosed skin lesions or a history of melanoma.

Use in patients with severe psychoses.

Non-selective monoamine oxidase (MAO) inhibitors are contraindicated for use with 'Flexilev'. These inhibitors must be discontinued at least two weeks before starting 'Flexilev'. 'Flexilev' 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'.)

'Flexilev' is contraindicated in patients with narrow-angle glaucoma and in patients with known hypersensitivity to any component of this medication.

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 4.6 'Pregnancy and lactation'.

Several warnings and precautions below are generic for levodopa and, therefore, also for Flexilev.

- Flexilev is not recommended for the treatment of drug-induced extrapyramidal reactions.

- Flexilev therapy should be administered with caution to patients with severe cardiovascular or pulmonary disease, bronchial asthma, renal, hepatic or endocrine disease, or history of peptic ulcer disease or of convulsions.

- In patients with a history of myocardial infarction who have residual atrial nodal or ventricular arrhythmias, cardiac function should be monitored with particular care during the period of initial dosage adjustments.

- All patients treated with Flexilev should be monitored carefully for the development of mental changes, depression with suicidal tendencies, and other serious mental changes. Patients with past or current psychosis should be treated with caution.

- Concomitant administration of antipsychotics with dopamine receptor blocking properties, particularly D₂ receptor antagonists should be carried out with caution, and the patient carefully observed for loss of antiparkinsonian effect or worsening of parkinsonian symptoms, see section 4.5.

- Patients with chronic wide-angle glaucoma may be treated with Flexilev with caution, provided the intra-ocular pressure is well controlled and the patient is monitored carefully for changes in intra-ocular pressure.

- Flexilev may induce orthostatic hypotension.

- Levodopa has been associated with somnolence and episodes of sudden sleep onset in patients with Parkinson's disease and caution should therefore be exercised when driving and operating machines.

- A symptom complex resembling Neuroleptic Malignant Syndrome (NMS), including muscular rigidity, increased body temperature, mental changes (e.g. agitation, confusion, coma) and increased serum creatine phosphokinase, has been reported when anti-Parkinsonian medicinal products were withdrawn abruptly. Rhabdomyolysis secondary to Neuroleptic Malignant Syndrome or severe dyskinesias have been observed rarely in patients with Parkinson's disease. Therefore, patients should be carefully observed when the dose of levodopa/carbidopa combinations are abruptly reduced or discontinued, especially if the patient is receiving anti-psychotics. Neither NMS nor rhabdomyolysis has been reported in association with Flexilev.

- 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 pathologic gambling, increased libido and 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 Flexilev. Review of treatment is recommended if such symptoms develop.

- Epidemiological studies have shown that patients with Parkinson's disease have a higher risk of developing melanoma than the general population. It is unclear whether the increased risk observed was due to Parkinson's disease or other factors, such as medicines used to treat Parkinson's disease. Therefore patients and providers are advised to monitor for melanomas on a regular basis when using Flexilev for any indication. Ideally, periodic skin examinations should be performed by appropriately qualified individuals (e.g. dermatologists).

- If general anaesthesia is required, treatment with Flexilev may be continued for as long as the patient is permitted to take fluids and medicinal products by mouth. If therapy has to be stopped temporarily, Flexilev at the same dose as before may be restarted as soon as oral intake of fluid is allowed.

- The dose of Flexilev may need to be adjusted downwards in order to avoid levodopa induced dyskinesias.

- Periodic evaluation of hepatic, haematopoietic, cardiovascular and renal function is recommended during extended therapy with Flexilev.

- Flexilev contains hydrazine, a degradation product of carbidopa that can be genotoxic and possibly carcinogenic. The average recommended daily dose of Flexilev is 100 ml, containing 2 g levodopa and 0.5 g carbidopa. The maximum recommended daily dose is 200 ml. This includes hydrazine at up to an average exposure of 4 mg/day, with a maximum of 8 mg/day. The clinical significance of this hydrazine exposure is not known.

- Previous surgery in the upper part of the abdomen may lead to difficulty in performing gastrostomy or jejunostomy.

- Reported complications in the clinical studies, and seen post-marketing, include bezoar, ileus, implant site erosion/ulcer, intestinal haemorrhage, intestinal ischaemia, intestinal obstruction, intestinal perforation, intussusception, pancreatitis, peritonitis, pneumoperitoneum and post-operative wound infection. Bezoars are retained concretions of indigestible material (such as vegetable or fruit non-digestible fibers) in the intestinal tract. Most bezoars reside in the stomach but bezoars may be encountered elsewhere in the intestinal tract. A bezoar around the tip of the jejunal tube may function as a lead point for intestinal obstruction or the formation of intussusception. Abdominal pain may be a symptom of the above listed complications. Some events may result in serious outcomes, such as surgery and/or death. Patients should be advised to notify their physician if they experience any of the symptoms associated with the above events.

- Reduced ability to handle the system (pump, tube connections) can lead to complications. In such patients a caregiver (e.g. nurse, assistant nurse, or close relative) should assist the patient.

- A sudden or gradual worsening of bradykinesia may indicate an obstruction in the device for whatever reason and needs to be explored.

- Dopamine Dysregulation Syndrome (DDS) is an addictive disorder resulting in excessive use of the product seen in some patients treated with levodopa/carbidopa.).

Use in Children

Safety and effectiveness of 'Flexilev' or 'Half Flexilev' in infants and children have not been established, and its use in patients below the age of 18 is not recommended.

'Flexilev' or 'Half Flexilev' should not be given when administration of a sympathomimetic amine is contraindicated.

Non-selective monoamine oxidase (MAO) inhibitors are contraindicated for use with 'Flexilev' or 'Half Flexilev'. These inhibitors must be discontinued at least two weeks prior to initiating therapy with 'Flexilev' or 'Half Flexilev'. 'Flexilev' or 'Half Flexilev' 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 'Interactions with other medicinal products and other forms of interaction').

'Flexilev' or 'Half Flexilev' 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, 'Flexilev' or 'Half Flexilev' should not be used in patients with suspicious undiagnosed skin lesions or a history of melanoma.

Use in patients with severe psychoses.

When patients are receiving levodopa monotherapy, levodopa must be discontinued at least eight hours before therapy with 'Flexilev' or 'Half Flexilev' is started (at least 12 hours if slow-release levodopa has been administered).

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.

'Flexilev' and 'Half Flexilev' are not recommended for the treatment of drug-induced extrapyramidal reactions or for the treatment of Huntingdon's chorea.

Based on the pharmacokinetic profile of 'Flexilev' the onset of effect in patients with early morning dyskinesias may be slower than with conventional 'Sinemet'. The incidence of dyskinesias is slightly higher during treatment with 'Flexilev' than with conventional 'Sinemet' (16.5% vs 12.2%) in advanced patients with motor fluctuations.

'Flexilev' or 'Half Flexilev' 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 or of convulsions.

Care should be exercised in administering 'Flexilev' or 'Half Flexilev' 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.

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.

As with levodopa, 'Flexilev' or 'Half Flexilev' may cause involuntary movements and mental disturbances. Patients with a history of severe involuntary movements or psychotic episodes when treated with levodopa alone or levodopa/decarboxylase inhibitor combination should be observed carefully when 'Flexilev' or 'Half Flexilev' is substituted. These reactions are thought to be due to increased brain dopamine following administration of levodopa and use of 'Flexilev' or 'Half Flexilev' 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.

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.

Patients with chronic wide-angle glaucoma may be treated cautiously with 'Flexilev' or 'Half Flexilev', provided the intraocular pressure is well controlled and the patient monitored carefully for changes in intraocular pressure during therapy.

Periodic evaluations of hepatic, haematopoietic, cardiovascular and renal function are recommended during extended therapy.

If general anaesthesia is required, 'Flexilev' or 'Half Flexilev' may be continued as long as the patient is permitted to take oral medication. 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 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 'Flexilev' for any indication. Ideally, periodic skin examinations should be performed by appropriately qualified individuals (e.g., dermatologists).

Laboratory Tests

Abnormalities in various laboratory tests have occurred with carbidopa-levodopa preparations and may occur with 'Flexilev' or 'Half Flexilev'. 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 'Sinemet'.

Dopamine Dysregulation Syndrome (DDS) is an addictive disorder resulting in excessive use of the product seen in some patients treated with carbidopa/ levodopa.).

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 Sinemet. Review of treatment is recommended if such symptoms develop.

'Flexilev' is not recommended for the treatment of drug-induced extrapyramidal reactions.

'Flexilev' 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 gastro-intestinal haemorrhage).

Care should be exercised when 'Flexilev' 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, 'Flexilev' 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 'Flexilev' is substituted. These reactions are thought to be due to increased brain dopamine following administration of levodopa, and use of 'Flexilev' 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 'Flexilev' should be carefully observed, particularly in patients who are also receiving neuroleptics.

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 'Flexilev', 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 'Flexilev' 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, 'Flexilev' 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 'Flexilev' 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 'Flexilev' 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 'Flexilev' and levodopa alone.

'Flexilev' 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.).

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 Flexilev. Review of treatment is recommended if such symptoms develop.

Flexilev can have a major influence on the ability to drive and use machines.

Individual responses to medication may vary.'Special warnings and precautions for use').

Individual responses to medication may vary and certain side effects that have been reported with 'Flexilev' may affect some patients' ability to drive or operate machinery.'Special warnings and precautions for use').

Drug-related undesirable effects that occur frequently with the Flexilev system include nausea and dyskinesia.

Device- and procedure related undesirable effects that occur frequently with the Flexilev system include abdominal pain, complications of device insertion, excessive granulation tissue, incision site erythema, postoperative wound infection, post procedural discharge, procedural pain, and procedural site reaction.

Most of these adverse reactions were reported early in the studies, subsequent to the percutaneous endoscopic gastrostomy procedure and occurred during the first 28 days.

Undesirable effects reported with Flexilev

The safety of Flexilev was compared to the standard oral formulation of levodopa/carbidopa (100 mg/25 mg) in a total of 71 advanced Parkinson's disease patients who participated in a randomized, double-blind, double-dummy, active controlled study of 12 weeks duration. Additional safety information was collected in an open-label, 12-month study in 354 patients with advanced Parkinson's disease and open-label extension studies.

An analysis was performed for patients who received Flexilev in all studies, regardless of the study design (double-blind or open-label) to allow for a summary of drug-related adverse reactions. Another analysis was performed for patients who received Flexilev or placebo gel through a PEG-J to allow for a summary of procedure-related and device-related adverse reactions in all studies, regardless of the study design (double-blind or open-label).

Drug-, Procedure- and device-related adverse reactions based on treatment emergent frequencies, regardless of causality assigned, in addition to adverse reactions identified during post-approval use of Flexilev are presented in Table 1.

Table 1. Adverse Reaction Data Derived From Clinical Trials and Post-marketing Experience

^a ADRs observed in clinical trials. Frequencies assigned reflect adverse event frequencies and are regardless of causality assigned by the investigator

^b ADRs observed with Flexilev for which estimations of frequencies were not available. Frequencies assigned are based on historical data for oral levodopa/carbidopa.

^c Impulse control disorders: Pathological gambling, increased libido and 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 'Special warnings and precautions for use').

^d Dopamine Dysregulation Syndrome (DDS) is an addictive disorder seen in some patients treated with levodopa/ carbidopa.).

^e Complication of device insertion was a commonly reported adverse reaction for both the nasojejunal tube and the PEG-J. This adverse reaction was co-reported with 1 or more of the following adverse reactions for the nasojejunal tube: oropharyngeal pain, abdominal distention, abdominal pain, abdominal discomfort, pain, throat irritation, gastrointestinal injury, esophageal haemorrhage, anxiety, dysphagia, and vomiting. For the PEG-J, this adverse reaction was co-reported with 1 or more of the following adverse reactions: abdominal pain, abdominal discomfort, abdominal distension, flatulence, or pneumoperitoneum. Other non-serious adverse reactions that were co-reported with complication of device insertion included abdominal discomfort, abdominal pain upper, duodenal ulcer, duodenal ulcer haemorrhage, erosive duodenitis, gastritis erosive, gastrointestinal haemorrhage, peritonitis, pneumoperitoneum, small intestine ulcer.

Dislocation of the intestinal tube backwards into the stomach or an obstruction in the device leads to reappearance of the motor fluctuations.

The following additional adverse reactions (listed in MedDRA preferred terms) have been observed with oral levodopa/carbidopa and could occur with Flexilev:

Table 2. Adverse Reaction Observed with Oral Levodopa/Carbidopa

Laboratory values: The following laboratory abnormalities have been reported with levodopa/carbidopa treatment and should, therefore, be acknowledged when treating patients with Flexilev: elevated urea nitrogen, alkaline phosphatases, S-AST, S-ALT, LDH, bilirubin, blood sugar, creatinine, uric acid and positive Coomb's test, and lowered values of haemoglobin and haematocrit. Leucocytes, bacteria and blood in the urine have been reported. Levodopa/carbidopa, and thus Flexilev, may cause a false positive result when a dipstick is used to test for urinary ketone; this reaction is not altered by boiling the urine sample. The use of glucose oxidase methods may give false negative results for glucosuria.

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 Yellow Card Scheme:

Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store

In controlled clinical trials in patients with moderate to severe motor fluctuations 'Flexilev' did not produce side-effects which were unique to the modified-release formulation.

The side-effect reported most frequently was dyskinesia (a form of abnormal involuntary movements). A greater incidence of dyskinesias was seen with 'Flexilev' than with 'Sinemet'.

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.

Cardiovascular: palpitation, orthostatic effects including hypotensive episodes.

Gastro-intestinal: constipation, diarrhoea, dyspepsia, gastro-intestinal pain, dark saliva.

Hypersensitivity: angioedema, urticaria, pruritus.

Metabolic: weight loss.

Nervous System/Psychiatric: neuroleptic malignant syndrome (see 4.3 'Contraindications'), agitation, anxiety, decreased mental acuity, paraesthesia, disorientation, fatigue, headache, extrapyramidal and movement disorders, falling, gait abnormalities, muscle cramps, on-off phenomenon, increased libido, psychotic episodes including delusions and paranoid ideation. Levodopa is associated with somnolence and has been associated very rarely with excessive daytime somnolence and sudden sleep onset episodes.

Respiratory: dyspnoea

Skin: flushing, alopecia, rash, dark sweat.

Special Senses: blurred vision.

Urogenital: dark urine.

Other side effects that have been reported with levodopa or levodopa/carbidopa combinations and may be potential side-effects with 'Flexilev' are listed below:

Cardiovascular: cardiac irregularities, hypertension, phlebitis.

Gastro-intestinal: bitter taste, sialorrhoea, dysphagia, bruxism, hiccups, gastro-intestinal bleeding, flatulence, burning sensation of tongue, development of duodenal ulcer.

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

Nervous system/Psychiatric: ataxia, numbness, increased hand tremor, muscle twitching, blepharospasm, trismus, activation of latent Horner's syndrome, euphoria, and dementia, 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.).

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 'Special warnings and precautions for use')

Skin: increased sweating.

Special senses: diplopia, dilated pupils, oculogyric crises.

Urogenital: urinary retention, urinary incontinence, priapism.

Miscellaneous: weight gain, oedema, weakness, faintness, 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.

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 Yellow Card Scheme at: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store

Side effects that occur frequently with 'Flexilev' 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 'Flexilev' has not been established.

Other side effects that have been reported with levodopa or levodopa/carbidopa combinations and may be potential side effects with 'Flexilev' 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, gait abnormalities 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.).

Impulse control disorders

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 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 Yellow Card Scheme at website www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store

Most prominent clinical symptoms of an overdose with levodopa/carbidopa are dystonia and dyskinesia. Blepharospasms can be an early sign of overdose.

The treatment of an acute overdose of Flexilev is in general the same as that of an acute overdose of levodopa: However, pyridoxine has no effect on the reversal of the action of Flexilev. Electrocardiographic monitoring should be used and the patient observed carefully for the development of cardiac arrhythmias; if necessary an appropriate antiarrhythmic therapy should be given. The possibility that the patient took other medicinal products together with Flexilev should be taken into consideration. To date experiences with dialysis have not been reported, therefore its value in the treatment of overdose is unknown.

Management of acute overdosage with 'Flexilev' or 'Half Flexilev' is basically the same as management of acute overdosage with levodopa; however, pyridoxine is not effective in reversing the actions of 'Flexilev' or 'Half Flexilev'.

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 'Flexilev' or 'Half Flexilev' should be taken into consideration. To date, no experience has been reported with dialysis; hence, its value in overdosage is not known.

Treatment

Management of acute overdosage with 'Flexilev' is basically the same as management of acute overdosage with levodopa; however pyridoxine is not effective in reversing the actions of 'Flexilev'. 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 'Flexilev' 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.

Pharmacotherapeutic group: Anti-Parkinson drugs, levodopa and decarboxylase inhibitor

ATC code: N04BA02.

Mechanism of Action:

Flexilev is a combination of levodopa and carbidopa (ratio 4:1) in a gel for continuous intestinal infusion in advanced Parkinson's disease with severe motor fluctuations and hyper-/dyskinesia. Levodopa is a metabolic precursor of dopamine that relieves symptoms of Parkinson's disease following decarboxylation to dopamine in the brain. Carbidopa, which does not cross the blood-brain barrier, inhibits the extracerebral decarboxylation of levodopa, which means that a larger amount of levodopa becomes available for transportation to the brain and transformation into dopamine. Without the simultaneous administration of carbidopa much larger amounts of levodopa would be required to achieve the desired effect. Intestinal infusion of individualized doses of Flexilev maintains plasma concentrations of levodopa at steady levels within the individual therapeutic windows.

Pharmacodynamic Effects:

Intestinal therapy with Flexilev reduces the motor fluctuations and decreases the “Off” time for patients with advanced Parkinson's disease who have received tablet treatment with levodopa/decarboxylase inhibitor for many years. The motor fluctuations and hyper-/dyskinesias are reduced due to less variable plasma concentrations than oral carbidopa/levodopa which allows treatment in a narrow therapeutic window. Therapeutic effects on motor fluctuations and hyper-/dyskinesias are often achieved during the first treatment day.

Clinical Efficacy and Safety:

The efficacy of Flexilev was confirmed in two identically-designed Phase 3, 12-week, randomized, double-blind, double-dummy, active-controlled, parallel group, multicenter studies to evaluate the efficacy, safety, and tolerability of Flexilev against levodopa/carbidopa 100/25 mg tablets. The studies were conducted with patients with advanced Parkinson's disease who were levodopa-responsive and had persistent motor fluctuations despite optimized treatment with oral levodopa carbidopa and other available anti-Parkinson's disease medications and enrolled a total of 71 patients. The results of the two studies were combined and a single analysis was conducted.

The primary efficacy endpoint, change in normalized "Off" time (baseline to endpoint) based on Parkinson's Disease Diary^© data using last observation carried forward demonstrated a statistically significant least square (LS) mean difference in favor of the Flexilev treatment group (Table 3).

The primary end point results were supported by a Mixed Model Repeated Measures (MMRM) analysis which examined the change from baseline to each post-baseline study visit. This analysis of “Off” time demonstrated a statistically significant greater improvement of the Flexilev group over the LC-oral group at Week 4, and that improvement was shown to be statistically significant at Weeks 8, 10, and 12.

This change in “Off” time was associated with a statistically significant LS mean difference from baseline in the average daily normalized "On" time without troublesome dyskinesia between the Flexilev treatment group and the active control group based on Parkinson's Disease Diary^© data. The baseline values were collected three days prior to randomization and after 28 days of oral therapy standardization.

Table 3 Change from Baseline to Endpoint in "Off" Time and in "On" Time Without Troublesome Dyskinesia

SD = standard deviation; SE = standard error

^a. Active control, oral levodopa/carbidopa 100/25 mg tablets

Analyses of other secondary efficacy endpoints, in order of the hierarchical testing procedure, demonstrated statistically significant results for Flexilev compared to oral levodopa/-carbidopa for the Parkinson's Disease Questionnaire (PDQ-39) Summary Index (an index Parkinson's disease-related quality of life), Clinical Global Impression (CGI-I) score, and Unified Parkinson's Disease Rating Scale (UPDRS) Part II score (Activities of Daily Living (ADL)). The PDQ-39 Summary Index showed a decrease from baseline of 10.9 points at week 12. Other secondary endpoints, UPDRS Part III score, EQ-5D Summary Index, and ZBI total score, did not meet statistical significance based on the hierarchical testing procedure.

A Phase 3, open-label, single-arm, multicenter study was conducted to assess the long-term safety and tolerability of Flexilev over 12 months in 354 patients. The target population was levodopa-responsive patients with advanced Parkinson's disease and motor fluctuations despite optimized treatment with available Parkinson's disease medications. The average daily normalized "Off" time changed by - 4.44 hours from Baseline to Endpoint (6.77 hours at Baseline and 2.32 hours at Endpoint) with a corresponding 4.8 hour increase in “On” time without dyskinesia.

Pediatric population

The safety of Flexilev in patients under 18 years of age has not been established and its use in patients below the age of 18 is not recommended.

'Flexilev' and 'Half Flexilev' are a combination of carbidopa, an aromatic amino acid decarboxylase inhibitor, and levodopa, the metabolic precursor of dopamine, in a polymer-based controlled-release tablet formulation, for use in the treatment of Parkinson's disease. 'Flexilev' and 'Half Flexilev' are particularly useful to reduce 'off' time in patients treated previously with a conventional levodopa/decarboxylase inhibitor combination who have had dyskinesias and motor fluctuations.

Patients with Parkinson's disease treated with preparations containing levodopa may develop motor fluctuations characterised by end-of-dose failure, peak dose dyskinesia, and akinesia. The advanced form of motor fluctuations ('on-off' phenomenon) is characterised by unpredictable swings from mobility to immobility. Although the causes of the motor fluctuations are not completely understood, it has been demonstrated that they can be attenuated by treatment regimens that produce steady plasma levels of levodopa.

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. This normally obviates the necessity for large doses of levodopa at frequent intervals. The lower dosage reduces or may help eliminate gastro-intestinal and cardiovascular side-effects, especially those which are attributed to dopamine being formed in extracerebral tissues.

'Flexilev' and 'Half Flexilev' are designed to release their active ingredients over a four-six hour period. With this formulation there is less variation in plasma levodopa levels and the peak plasma level is 60% lower than with conventional 'Sinemet', as established in healthy volunteers.

In clinical trials, patients with motor fluctuations experienced reduced 'off'-time with 'Flexilev' when compared with 'Sinemet'. The reduction of the 'off'-time is rather small (about 10%) and the incidence of dyskinesias increases slightly after administration of 'Flexilev' compared to standard 'Sinemet'. Global ratings of improvement and activities of daily living in the 'on' and 'off' state, as assessed by both patient and physician, were better during therapy with 'Flexilev' than with 'Sinemet'. Patients considered 'Flexilev' to be more helpful for their clinical fluctuations, and preferred it over 'Sinemet'. In patients without motor fluctuations, 'Flexilev' under controlled conditions, provided the same therapeutic benefit with less frequent dosing than with 'Sinemet'. Generally, there was no further improvement of other symptoms of Parkinson's disease.

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.

'Flexilev' 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 'Flexilev' usually reduces fluctuations in response. By reducing some of the adverse reactions produced by levodopa alone, 'Flexilev' permits more patients to obtain adequate relief from the symptoms of Parkinson's disease.

Absorption

Flexilev is administered via an inserted tube directly into the duodenum or jejunum. Levodopa is absorbed quickly and effectively from the intestine through a high capacity transport system for amino acids. The absolute bioavailability of levodopa from oral levodopa/carbidopa immediate release tablets is reported to be 84-99%. A cross-study population pharmacokinetic analysis suggested that Flexilev has comparable levodopa bioavailability to the oral levodopa/carbidopa (100/25 mg) tablets.

In a Phase 1 study, intrajejunal administration of Flexilev rapidly achieved therapeutic plasma levels of levodopa and maintained consistent levodopa levels over the course of infusion. Following termination of infusion, levodopa levels declined rapidly (Figure 1). The intra-subject variability in levodopa plasma concentrations starting from hour 2 to hour 16 following initiation of infusion was low (13%).

Figure 1. Plasma Concentrations (mean ± standard deviation) versus Time Profile of Levodopa with Flexilev 16-Hour Infusion

In a Flexilev double-blind, active-controlled, Phase 3 Study, the intra-subject variability in levodopa plasma concentrations was lower for patients treated with Flexilev (21%) than in patients treated with oral levodopa/carbidopa 100/25 mg over-encapsulated tablets (67%).

Distribution

Levodopa is co-administered with carbidopa, a decarboxylase inhibitor, which increases the bioavailability and decreases clearance for levodopa. Clearance and volume of distribution for levodopa is 0.3 l/hour/kg and 0.9-1.6 l/kg, respectively, when given together with a decarboxylase inhibitor. The partitioning ratio for levodopa between erythrocytes and plasma is approximately 1. The protein binding of levodopa in plasma is negligible (about 10%-30%). Levodopa is transported into the brain by the carrier mechanism for large neutral amino acids.

Carbidopa is approximately 36% bound to plasma protein. Carbidopa does not cross the blood-brain barrier.

Biotransformation and elimination

When administered with carbidopa, the elimination half-life for levodopa is approximately 1.5 hours. Levodopa is eliminated completely through metabolism and the metabolites formed are excreted mainly in the urine. Four metabolic pathways are known, but levodopa is mainly eliminated via metabolism by the aromatic amino acid decarboxylase (AAAD) and the catechol-O-methyl-transferase (COMT) enzymes. Other routes of metabolism are transamination and oxidation. The decarboxylation of levodopa to dopamine by AAAD is the major enzymatic pathway when no enzyme inhibitor is co-administered. When levodopa is co-administered with carbidopa, the decarboxylase enzyme is inhibited, so that metabolism via catechol-O-methyl-transferase (COMT) becomes the dominant metabolic pathway. O-methylation of levodopa by COMT forms 3-O-methyldopa.

Carbidopa is metabolized to two main metabolites (α-methyl-3-methoxy-4-hydroxyphenylpropionic acid and α-methyl-3,4-dihydroxyphenylpropionic acid). These 2 metabolites are primarily eliminated in the urine unchanged or as glucuronide conjugates. Unchanged carbidopa accounts for 30% of the total urinary excretion. The elimination half-life of carbidopa is approximately 2 hours.

Pharmacokinetic-pharmacodynamic relationship

The reduced fluctuations in the plasma concentration of levodopa reduce fluctuations in the treatment response. The levodopa dose needed varies considerably in advanced Parkinson's disease and it is important that the dose is individually adjusted based on the clinical response. Development of tolerance over time has not been observed with Flexilev.

The pharmacokinetics of levodopa following administration of 'Flexilev' were studied in young and elderly healthy volunteers. The mean time to peak plasma levodopa level after 'Flexilev' was approximately two hours compared to 0.75 hours with 'Sinemet'. The mean peak plasma levodopa levels were 60% lower with 'Flexilev' than with 'Sinemet'. The in vivo absorption of levodopa following administration of 'Flexilev' was continuous for 4 to 6 hours. In these studies, as with patients, plasma levodopa concentrations fluctuated in a narrower range than with 'Sinemet'. Because the bioavailability of levodopa from 'Flexilev' relative to 'Sinemet' is approximately 70%, the daily dosage of levodopa in the controlled release formulation will usually be higher than with conventional formulations. There was no evidence that 'Flexilev' released its ingredients in a rapid or uncontrolled fashion.

The pharmacokinetics of levodopa following administration of 'Half Flexilev' were studied in patients with Parkinson's disease. Chronic three month, open-label, twice daily dosing with 'Half Flexilev' (range: 50 mg carbidopa, 200 mg levodopa up to 150 mg carbidopa, 600 mg levodopa per day) did not result in accumulation of plasma levodopa. The dose-adjusted bioavailability for one 'Half Flexilev' tablet was equivalent to that for one 'Flexilev' tablet. The mean peak concentration of levodopa following administration of one 'Half Flexilev' tablet was greater than 50% of that following one 'Flexilev' tablet. Mean time-to-peak plasma levels may be slightly less for 'Half Flexilev' than for 'Flexilev'.

It is not known whether or not or to what extent the absorption is influenced by a protein rich diet. The bioavailability may be influenced by drugs which affect the gastro-intestinal propulsion.

Following oral dosing levodopa, in the absence of decarboxylase inhibitor, is rapidly but variably absorbed from the gastro-intestinal tract. t 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.

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.

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.

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.

Non-clinical data reveal no special hazard for humans based on conventional studies of safety, pharmacology, repeated dose toxicity, genotoxicity, and carcinogenic potential. In reproductive toxicity studies both levodopa and the combination of carbidopa/levodopa have caused visceral and skeletal malformations in rabbits.

Hydrazine is a degradation product of Carbidopa.).

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