Flexilev

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SUMMARY OF PRODUCT CHARACTERISTICS

1. NAME OF THE MEDICINAL PRODUCT

Flexilev 5 mg/1.25 mg, dispersible tablet for dose dispenser

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

One dispersible tablet contains: levodopa 5 mg and carbidopa monohydrate corresponding to
carbidopa 1.25 mg.

For the full list of excipients, see section 6.1.

3. PHARMACEUTICAL form

Dispersible tablet for dose dispenser.

White, spherical tablets with a diameter of about 3 mm.

4. Clinical particulars

4.1 Therapeutic indications

Flexilev is indicated for treatment of adult patients with idiopathic Parkinson's disease and syndrome.

4.2 Posology and method of administration

Posology

Treatment with Flexilev primarily focuses on individualized therapy using the dose dispenser, MyFID. The optimum daily dosage of levodopa/carbidopa must be determined by careful titration in each patient.

Flexilev are available as small dose tablets in a ratio of 1:4 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 carbidopa/levodopa is being administered, although their dosage may have to be adjusted.

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.

Dosage may be best initiated with a 100/25 dose three times a day. This dosage schedule provides 75 mg of carbidopa per day. Dosage may be increased by 50/12.5-100/25 mg of Flexilev every day or every other day, as necessary, maximum until a dosage eqvivalent of 800/200 mg of Flexilev 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

Flexilev tablets may be used to facilitate dosage titration according to the needs of the individual patient.

Maintenance

Therapy with Flexilev should be individualized and adjusted gradually according to response. Patients who experience fluctuations in response and end of dose effect (wearing-off) may be helped by dividing the dosage into smaller, more frequent dosing without, however, altering the total daily dose.

If necessary, the dosage of Flexilevmay be increased to a maximum of 2000/500 mg a day. Experience with a total daily dosage greater than 200 mg carbidopa is limited.

Patients receiving levodopa with another decarboxylase inhibitor

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 carbidopa/levodopa is introduced, although dosage may have to be adjusted in line with manufacturer’s recommendations.

Use in the elderly

There is wide experience in the use of levodopa/carbidopa in elderly patients. The recommendations set out above reflect the clinical data derived from this experience.

Patients with renal impairment

Impact of renal function on levodopa/carbidopa clearance is limited. Flexilev should be administered cautiously to patients with renal impairment.. The dose should be titrated individually.

Patients with hepatic impairment

Flexilev should be administered cautiously to patients with mild to moderate hepatic impairment. The dose should be titrated individually.

Paediatric population

The safety of Flexilev in patients under 18 years has not been established.

There is no relevant use of Flexilev in children and adolescents in the indication of patients with idiopathic Parkinson's disease.

Method of administration

Oral use. Flexilev is dispensed with a dose dispenser. Only MyFID dose dispenser is to be used. The dose dispenser is loaded with a cartridge containing 750 dispersible tablets. The dose dispenser delivers the individualized dose based on a number of micro-tablets (small tablets, each with a low dose of levodopa/carbidopa).

The tablets should be dissolved in half a glass of water. When dissolved, a whitish dispersion is formed within few minutes. Intake should be done immediately after dissolution. The dose dispenser has a reminder function to facilitate dosage compliance. The dose dispenser is also equipped with a system for dose recording and symptom rating from which data can be transmitted to the treating physician.

At total daily dosages of 300–400 mg levodopa one cartridge lasts for about a week and a half.

When the cartridge is empty, it can easily be replaced by the patient.

For further information, see the manual of the dose dispenser.

Intake with food and drink: If possible, Flexilev should be taken 30 minutes before or 1 hour after meals. Intake of Flexilev with protein-rich food can reduce the effect.

4.3 Contraindications

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

Non-selective monoamine oxidase (MAO) inhibitors and selective MAO type A inhibitors are contraindicated for use with Flexilev.

These inhibitors must be discontinued at least two weeks before starting 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 hydrochloride). (See section 4.5 'Interaction with other medicinal products and other forms of interaction'.)

Flexilev is contraindicated in patients with narrow-angle glaucoma.

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

Conditions in which adrenergics are contraindicated, e.g. pheochromocytoma, hyperthyroidism, Cushing's syndrome, severe cardiovascular diseases.

4.4 Special warnings and precautions for use

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.

Flexilev may induce orthostatic hypotension. Therefore Flexilev should be given cautiously to patients who are taking other medicinal products which may cause orthostatic hypotension.

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.

As with levodopa, Flexilevmay 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 Flexilevis substituted. These reactions are thought to be due to increased brain dopamine following administration of levodopa, and use of Flexilev may cause a recurrence.

At abrupt withdrawal of anti-Parkinsonian agents (especially during concomitant treatment with neuroleptics), Neuroleptic Malignant Syndrome including muscular rigidity, elevated body temperature, mental changes and elevated serum creatinine phosphokinase values have been reported.

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.

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.

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.

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, carbidopa/levodopa 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 medicinal products 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).

Effect on laboratory tests

Commonly, levels of blood urea nitrogen, creatinine, and uric acid are lower during administration of carbidopa/levodopa 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 carbidopa/levodopa 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.

4.5 Interaction with other medicinal products and other forms of interaction

No interaction studies have been performed with Flexilev. The following interactions are known from generic combination of levodopa/carbidopa.

The following combination is contraindicated:

Non-selective MAO inhibitors and selective MAO-A inhibitors should not be given concomitantly with Flexilev and must be discontinued at least two weeks prior to initiation of the treatment, see Section 4.3.

The following combinations with Flexilev may require dose adjustment:

Butyrophenone derivatives: Butyrophenone derivatives counteract the effect of levodopa by blocking dopamine receptors in the brain.

Phenothiazines substituted with dimethylaminopropyl link/piperazine ring: Phenothiazines counteracts the effects of levodopa by blocking dopamine receptors in the brain. Phenothiazines with piperidine chain (thioridazine and pericyazine) have relatively weak dopamine receptor blocking properties.

Ferrous iron, oral preparations: Concomitant administration of single doses of ferrous sulphate and levodopa to healthy volunteers reduces the bioavailability of levodopa by 50%, probably because of chelating. Also the bioavailability of carbidopa is reduced (by 75%). The agents should be given with the longest possible time intervals.

Pimozide: pimozide counteracts the effect of levodopa by blocking dopamine receptors in the brain.

Risperidone and isoniazid may reduce the therapeutic effects of levodopa.

Concomitant therapy with selegiline and carbidopa/levodopa has been associated with severe orthostatic hypotension not attributed to carbidopa/levodopa only.

Rarely, reactions including hypertension and dyskinesia have been reported with the concomitant use of tricyclic antidepressants.

4.6 Fertility, pregnancy and lactation

Pregnancy
There are no or limited amount of data from the use of carbidopa/levodopa in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3). Flexilevis not recommended during pregnancy or in women of childbearing potential not using contraception unless the benefits for the mother outweigh the possible risk to the fetus.

Breastfeeding

It is not known whether carbidopa or its metabolites are excreted in human milk. Animal studies have shown excretion of carbidopa in breast milk. Levodopa and possibly levodopa metabolites are excreted in human milk. There is insufficient information on the effects of carbidopa/levodopa or their metabolites in newborns/infants. Breastfeeding should be discontinued during treatment with CarbiFlexilev.

Fertility

There are no data on the effects of carbidopa/levodopa on human fertility. No adverse effect on fertility has been observed in animal studies with levodopa alone. Fertility studies in animals have not been conducted with the combination of carbidopa and levodopa.

4.7 Effects on ability to drive and use machines

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

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

Undesirable effects

Summary of the safety profile

Side effects that occur frequently with carbidopa/levodopa 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.

Description of selected adverse reactions

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 Carbidopa/ Levodopa (see section 4.4 “Special warning and precautions for use”).

Tabulated list of adverse reactions

Adverse events classified by MedDRA convention and frequency;

Very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000); no known frequency (cannot be estimated from the available data).

MedDRA System Organ Class	Common (≥ 1/100 to < 1/10)	Uncommon (>1/1,000 to <1/100)	Rare (>1/10,000 to <1/1,000)	Very rare (<1/10,000)	Not known (cannot be estimated from the available data)
Blood and lymphatic system disorders			Leukopenia, haemolytic and non-haemolytic anaemia, thrombocytopenia	Agranulocytosis
Metabolism and nutrition disorders	Anorexia	Weight gain or loss
Psychiatric disorders	Hallucinations, confusion, dizziness, nightmares, sleepiness, fatigue, insomnia, depression with very rare suicide attempts, euphoria, dementia, feeling of stimulation, dream abnormalities		Agitation, fear, reduced thinking capacity, disorientation, headache, increased libido, numbness and convulsions, psychotic episodes including delusions and paranoid ideation
Nervous system disorders	Dyskinesia, chorea, dystonia, extrapyramidal and movement disorders, bradykinetic episodes (the “on-off” phenomenon) may appear some months to years after the beginning of treatment with levodopa and is probably related to the progression of the disease. The adaptation of dose schedule and dose intervals may be required.	Ataxia, increased hand tremor	Malignant neuroleptic syndrome, paraesthesia, falling, walking defects, trismus	Levodopa/carbidopa is associated with somnolence and has been associated very rarely with excessive daytime somnolence and sudden sleep onset episodes.	Muscle twitching
Eye disorders			Blurred vision, blepharospasm, activation of a latent Horner's syndrome, diplopia, dilated pupils, and oculogyric crises. Blepharospasm can be an early sign of overdosage.
Cardiac disorders	Palpitations, irregular heartbeat
Vascular disorders	Orthostatic hypotension, inclination to faint, syncope	Hypertension	Phlebitis
Respiratory, thoracic and mediastinal disorders		Hoarseness, chest pain	Dyspnoea, abnormal breathing pattern
Gastrointestinal disorders	Nausea, vomiting, dry mouth, bitter taste	Constipation, diarrhoea, sialorrhoea, dysphagia, flatulence	Dyspepsia, gastrointestinal pain, dark saliva, bruxism, hiccups, gastrointestinal bleeding, burning sensation of the tongue, duodenal ulceration
Skin and subcutaneous tissue disorders		Oedema	Angioedema, urticaria, pruritus, facial redness, hair loss, rash, increased sweating, dark sweat and Henoch-Schonlein purpura
Musculoskeletal and connective tissue disorders		Muscle spasms
Renal and urinary disorders		Dark urine	Urinary retention, urinary incontinence, priapism
General disorders and administration site conditions		Asthenia, weakness, malaise, hot flushes

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.

4.9 Overdose

Toxicity: 100 mg to a 2-year-old gave after charcoal no symptoms. 5 g to adult resulted in moderate intoxication.

Symptoms: Nausea, vomiting, restlessness, abnormal movements, agitation, dyskinesia, choreiform movements. Possibly hallucinations, seizures, sinus tachycardia, hypertension possibly followed by postural hypotension. Possibly electrolyte imbalances. Rhabdomyolysis and renal failure in rare cases.

ECG monitoring should be instituted and the patient should be carefully monitored for the possible development of arrhythmias. If required, anti-arrhythmic therapy should be given.

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 medicinal products 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.

5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Anti-Parkinson drugs, dopaminergic agents, ATC code: N04BA02

Mechanism of action

Levodopa is a precursor of dopamine, and is given as replacement therapy in Parkinson's disease.

Carbidopa is a peripheral dopa decarboxylase inhibitor. It prevents metabolism of levodopa to dopamine in the peripheral circulation, ensuring that a higher proportion of the dose reaches the brain, where dopamine acts. A lower dose of levodopa can be used, reducing the incidence and severity of side effects.

Pharmacodynamic effects

Carbidopa/levodopa is useful in relieving many of the symptoms of parkinsonism, particularly rigidity and bradykinesia. It is frequently helpful in the management of tremor, dysphagia, sialorrhoea, and postural instability associated with Parkinson's disease and syndrome.

Clinical efficacy and safety

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

5.2 Pharmacokinetic properties

Absorption
Levodopa is rapidly and completely absorbed, but undergoes extensive first pass metabolism. The bioavailability of levodopa is approximately 30% without co-administration of carbidopa. Levodopa is co-administered with carbidopa, a decarboxylase inhibitor, which increases the bioavailability and decreases clearance for levodopa. Following administration of a single dose of Flexilev, the maximum plasma concentration of levodopa occurs approximately after 30 minutes.

A clinical study showed that at a dose of 45 mg given at 2.5-hour intervals (after a bolus dose of 75 mg, 6 doses in total) gave a more consistent plasma concentration of levodopa than tablets with levodopa/ carbidopa/entacapone, 100 mg levodopa, given every six hours (3 doses in total).

Distribution

Volume of distribution for levodopa is 0.9-1.6 l/kg, 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

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. Clearance for levodopa is 0.3 l/hour/kg, when given together with a decarboxylase inhibitor. When administered with carbidopa, the elimination half-life for levodopa is approximately 1.5 hours.

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.

5.3 Preclinical safety data

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

6. PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Cellulose microcrystalline

Silica, colloidal anhydrous

Corn starch

Sodium starch glycolate

Magnesium stearate

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

3 years.

6.4 Special precautions for storage

Store in the original package in order to protect from light and moisture.

Once the foil bag is removed the cartridge should be used within 2 months and be stored below 30°C.

Nature and contents of container

The dose-dispenser cartridge of polypropylene containing 750 dispersible tablets for dose dispenser.

Each cartridge is packaged in an aluminium foil/polyethylene/polyester (virgin, oriented, primed) bag.

Package size: 10x750 tablets.

Flexilev should be use with a dose dispenser. Only MyFID dose dispenser should be used. The dispenser is provided separately from the Flexilev tablet.

6.6 Special precautions for disposal <and other handling>

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

7. MARKETING AUTHORISATION HOLDER

Sensidose AB

Vetenskapsvägen 10

S-191 38 Sollentuna

Sweden

8. MARKETING AUTHORISATION NUMBER(S)

<[To be completed nationally]>

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

<[To be completed nationally]>

10. DATE OF REVISION OF THE TEXT

30 June 2016