Posology : מינונים

4.2    Posology and method of administration

Posology
For intestinal use (see section 6.6). The dose should be titrated to achieve the optimal clinical response in the individual patient, which involves maximising the functional ON-time during the day by minimising the number and duration of OFF episodes (bradykinesia) and minimising ON-time with disabling dyskinesia.

The total dose/day of Lecigon is composed of three individually adjusted doses: the morning bolus dose, the continuous maintenance dose, and extra bolus doses. Treatment is usually limited to the patient's awake period. If medically justified, Lecigon can be administered up to 24 hours/day. The maximum recommended daily dose is 100 ml (which corresponds to 2000 mg levodopa, 500 mg carbidopa monohydrate and 2000 mg entacapone –see also section 4.4).

During the maintenance dose, the plasma concentration/time profile of levodopa has a somewhat different appearance, with a gradually increasing levodopa concentration in plasma over the course of the day, than previously observed from intestinal gel with levodopa/carbidopa alone. An example of a plasma concentration/time profile when using Lecigon can be found in section 5.2. If individual needs exist, the pump can be preprogrammed to provide up to three maintenance doses over the course of the day/24-hour period. In case of dyskinesias in the latter part of the day, reductions of 10–20% during the middle of the day may be relevant. All maintenance doses should be titrated until the desired clinical effect is reached.

The multiple maintenance dose function may also be useful, for example, in patients with persistent dyskinesias or stiffness with recurring need of extra doses in the latter part of the day, or for patients with 24-hour treatment who need a reduction of the maintenance dose during the night.

Morning dose
The morning dose is administered by the pump to rapidly achieve the therapeutic dose level (within 30 minutes). The dose is adjusted in increments of 0.1 ml (2 mg). 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 continuous maintenance dose is administered by the pump to maintain the therapeutic dose level.
The maintenance dose is adjusted in increments of 2 mg/hour (0.1 ml/hour). The maintenance dose is usually 0.7–5.0 ml/hour (15–100 mg levodopa/hour). The maximum recommended daily dose is 100 ml (2000 mg levodopa).

Extra bolus doses
Extra doses are given as required if the patient becomes hypokinetic. The extra dose is normally less than 3 ml but is adjusted individually. An increase in the continuous maintenance dose should be considered if the need for extra doses exceeds 5 doses per day.

Titration during transition from levodopa/carbidopa to Lecigon
Lecigon contains entacapone, which enhances the effect of levodopa. It may therefore be necessary to reduce the total daily intake of Lecigon by, on average, 20–35% compared to the patient's previous dose of levodopa and carbidopa without catechol-O-methyl transferase (COMT) inhibitors. Because the effect of entacapone on levodopa is dose dependent, a larger dose reduction is expected in high- dose patients.

The initial dose setting is based on the patient's daily levodopa intake. The size of the morning dose should be the same as the previous levodopa morning intake, to reach a therapeutic plasma concentration as quickly as possible, plus the volume required to fill the tube. The continuous maintenance dose should be based on the patient's daily levodopa intake (excluding the morning dose) and initially reduced to 65% of the previous daily levodopa intake. The doses are then titrated gradually, based on clinical symptoms, until the desired effect is achieved.

Example of initial dose setting prior to titration:
Previous total daily dose of levodopa: 1360 mg
Previous morning dose of levodopa: 100 mg
Previous daily levodopa intake (excluding the morning dose): 1260 mg/day 
Morning dose: 100 mg
Corresponds to a volume of: 100 mg / 20 mg/ml = 5 ml
Total morning dose: 5 ml + 3 ml (volume to fill the tube) = 8 ml

Continuous maintenance dose: 1260 mg/day
Continuous maintenance dose reduced to 65%: 1260 mg/day x 0.65 = 819 mg/day Intake per hour (calculated based on 16 hours of administration per day): 819 mg / 16 hours= 51 mg/hour
Corresponding to an hourly flow rate of: 51 mg/hour / 20 mg/ml = 2.5–2.6 ml/hour 
Titration during transition from levodopa/benserazide to Lecigon
Entacapone increases the bioavailability of levodopa from standard preparations of levodopa/benserazide slightly more (5–10%) than from standard preparations of levodopa/carbidopa.
The transition from levodopa/benserazide to Lecigon has not been studied.

Titration during transition from levodopa/carbidopa/entacapone to Lecigon The initial dose setting is based on the patient's daily levodopa intake. The initial size of the morning dose should be the same as the previous levodopa morning intake plus the volume required to fill the tube. The continuous maintenance dose is converted 1:1 and is based on the patient's daily levodopa intake (excluding the morning dose). The doses are then titrated gradually, based on clinical symptoms, until the desired effect is achieved.

Transition from combination therapy with levodopa/DDC inhibitor/tolcapone to Lecigon has not been studied.

Transition from concomitant levodopa/carbidopa and dopamine agonist therapy to Lecigon When transitioning from dopamine agonist therapy to Lecigon monotherapy, the risk of dopamine agonist withdrawal symptoms should be taken into consideration and abrupt dopamine agonist discontinuation should be avoided.

Monitoring of treatment
After initial titration, the morning dose and maintenance dose are fine-tuned over the course of a few weeks.
Lecigon is initially given as monotherapy. If needed, other anti-Parkinsonian medicinal products can be taken concurrently (for concomitant treatment of Parkinson's disease, see also sections 4.3 and 4.5).
If treatment with other anti-Parkinsonian medicinal products is discontinued or changed, it may be necessary to adjust the doses of Lecigon.

A sudden deterioration in treatment response with recurring motor fluctuations should lead to the suspicion that the duodenal/jejunal tube has been dislocated to the stomach. The location of the tube should be determined by X-ray. If the position is incorrect, the end of the tube is to be repositioned to the duodenum/upper jejunum.

Treatment in connection with dementia
In case of suspected or diagnosed dementia with a decreased confusion threshold, the pump should only be handled by a healthcare professional or caregiver.

Abuse of the medicinal product
If abuse of the medicinal product is suspected, there is a lock function in the pump used with Lecigon (Crono LECIG). This function prevents the patient from being able to change the pump settings.

Special populations

Paediatric population
There is no relevant use of Lecigon in the paediatric population in the indication of advanced Parkinson's disease with severe motor fluctuations and hyperkinesia/dyskinesia.

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

Hepatic impairment
The dosage of Lecigon is individually adjusted by titration to the dose that provides optimal effect (which corresponds to individually optimised plasma exposure to levodopa, carbidopa and entacapone). Thus, any effects of hepatic impairment on levodopa, carbidopa and entacapone exposure are taken into account in the dose titration. There are no pharmacokinetic studies of carbidopa and levodopa in patients with hepatic impairment. The elimination of entacapone is reduced in patients with mild to moderate hepatic impairment. It is therefore recommended that dose titration be conducted with caution in patients with mild to moderate hepatic impairment. It may be necessary to reduce the dose (see section 5.2). Lecigon should not be used in patients with severe hepatic impairment; see section 4.3.

Renal impairment
The dosage of Lecigon is individually adjusted by titration to the dose that provides optimal effect (which corresponds to individually optimised plasma exposure to levodopa, carbidopa and entacapone). Thus, any effects of renal impairment on levodopa, carbidopa and entacapone exposure are taken into account in the dose titration. Renal impairment does not affect the pharmacokinetics of entacapone. There are no specific pharmacokinetic studies of levodopa and carbidopa in patients with renal impairment. It is therefore recommended that dose titration be conducted with caution in patients with severe renal impairment, including those receiving dialysis treatment (see section 5.2).

Interruption of therapy

Treatment with Lecigon can be interrupted at any time by removing the tube and allowing the wound to heal.
Patients should be carefully observed in case a sudden reduction of the dose is required or if it becomes necessary to discontinue treatment with Lecigon, particularly if the patient is receiving antipsychotics; see section 4.4.
If treatment is discontinued, the patient should receive an alternative treatment.

Method of administration

Lecigon is a gel for continuous intestinal delivery (delivery to the duodenum or upper jejunum). Only pump Crono LECIG (CE 0476) may be used for the administration of Lecigon. A manual with instructions for using the portable pump is supplied with the pump.

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.

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. The surgery and dose adjustment should be carried out in association with a neurological clinic.

Cartridge replacement

In order to use a new cartridge, it should be attached to the portable pump and the system connected to the tube for administration, according to the instructions given.

The cartridge is for single use only and should not be used for more than 24 hours.
The dosing pump with installed cartridge can be worn close to the body for up to 16 hours. During overnight treatment, the pump should not be worn next to the body but can, for example, be kept on the bedside table.
Once opened, a cartridge may be used into the next day, i.e., up to 24 hours after it was first opened.
The cartridge is removed from the pump after 24 hours of use or when used up, whichever occurs first.

The gel may become slightly yellow/reddish by the end of the shelf life. This does not influence the concentration of the medicine or the effect of treatment.