Posology : מינונים

4.2    Posology and method of administration

Posology

Produodopa is administered as a continuous subcutaneous infusion, 24 hours per day.

The recommended starting infusion rate of Produodopa is determined by converting the daytime levodopa intake to levodopa equivalents (LE) and then increasing it to account for a 24-hour administration (see Initiation of treatment). The dose may be adjusted to reach a clinical response that maximises the functional “On” time and minimises the number and duration of “Off” episodes and “On” episodes with troublesome dyskinesia. The maximum recommended daily dose of foslevodopa is 6000 mg (or 25 ml of Produodopa per day equivalent to approximately 4260 mg levodopa per day).

Produodopa replaces levodopa-containing medications and catechol-O-methyl transferase (COMT)- inhibitors. If required, other classes of medicinal products for Parkinson's disease can be taken concurrently.

Initiation of treatment
Patients selected for treatment with Produodopa should be capable of understanding and using the delivery system themselves or with assistance from a caregiver.

Patients should be trained on the proper use of Produodopa and the delivery system (see Method of administration) prior to initiating treatment with Produodopa and, as necessary, thereafter.

Three steps are required to initiate treatment with Produodopa.

•        Step 1: Calculate the LE based on the levodopa-containing medications used during the patient’s awake time.

•        Step 2: Determine the hourly infusion rate of Produodopa.

•        Step 3: Determine the volume of the loading dose.

Step 1: Calculate the LE based on the levodopa-containing medications used during the patient’s awake time.

The levodopa amount from all levodopa-containing formulations used during the awake time of the day (typically 16-hour/day) should be converted to LE using the appropriate dose multiplication factor from Table 1 and then summed. For this calculation, only consider levodopa and COMT inhibitors. Do not include rescue levodopa or any other anti-Parkinsonian medication or therapy, including medications taken outside of awake time (e.g., night-time dosing) in this calculation. If any COMT inhibitors are taken within a 24-hour period, regardless of the COMT inhibitor dose, a correction factor should be applied to the sum of LE as presented in Table 1.

Table 1. Calculating the Levodopa Equivalents (LE)

Levodopa formulation                                             Dose multiplication factor Immediate-release, including enteral suspension                  1 a
Sustained-release, controlled-release or prolonged-release       0.75 If any COMT inhibitor is used, multiply sum of calculated LE from above by 1.33a a
The levodopa contained in combined LD/CD/COMT-inhibitor formulations count as immediate- release and needs to be added to the LE from all other sources of levodopa before the sum is multiplied for the COMT-inhibitors correction factor (i.e., do not apply COMT correction factor to single LE).
CD = carbidopa; LD = levodopa; COMT = catechol-O-methyl transferase; LE = levodopa equivalents.
Step 2: Determine the hourly infusion rate of Produodopa.

Refer to Table 2 for suggested Produodopa starting infusion rates based on the LE calculated in Step 1.

The hourly infusion rate for Produodopa in Table 2 is based on a patient’s LE intake during a typical 16-hour awake time (LE16).

If the LE determined in Step 1 were based on an awake time either longer or shorter than 16 hours, the LE should be adjusted to a 16-hour period. To adjust to a 16-hour period, take the LE calculated in Step 1, divide by the number of hours the patient is typically awake, and then multiply by 16. Then refer to Table 2 for Produodopa suggested starting infusion rates. An alternative is to calculate the starting hourly infusion rate according to the formula given under Table 2, where X is the number of patient’s awake hours/day.

The hourly infusion rate determined in this step should be entered as the Base infusion rate when programming the pump (refer to the pump instructions for use for details).

Table 2. Suggested Produodopa starting hourly infusion rate

LE16 (LE from all oral LD-containing
Suggested Produodopa starting hourly infusion medications taken over 16-hour awake time rate (ml/hr)a administered over 24 hours
(mg))
< 400                                                                      0.15 400-499                                                                 0.15-0.17
500-599                                                                 0.17-0.20 600-699                                                                 0.20-0.24 700-799                                                                 0.24-0.27 800-899                                                                 0.27-0.30 900-999                                                                 0.30-0.34 1000-1099                                                               0.34-0.37 1100-1199                                                               0.37-0.40 1200-1299                                                               0.40-0.44 1300-1399                                                               0.44-0.47 1400-1499                                                               0.47-0.51 1500-1599                                                               0.51-0.54 1600-1699                                                               0.54-0.57 1700-1799                                                               0.57-0.61 1800-1899                                                               0.61-0.64 1900-1999                                                               0.64-0.68 2000-2099                                                               0.68-0.71
2100-2199                                                               0.71-0.74
2200-2299                                                               0.74-0.78
2300-2399                                                               0.78-0.81
2400-2499                                                               0.81-0.84
2500-2599                                                               0.84-0.88
2600-2699                                                               0.88-0.91
2700-2799                                                               0.91-0.94
2800-2899                                                               0.94-0.98
2900-2999                                                               0.98-1.01
3000-3099                                                               1.01-1.04 >3100                                                                      1.04 a
The hourly infusion rate can be calculated using the following formula, where X is the number of patient’s awake hours used to determine the LE (e.g., X=16, in the table above).

Hourly infusion rate (ml/hr) = [(LE ∙ 0.92 ∙ 1.41) ∕ 240] ∕ X 
Assumptions used to generate the “Suggested Produodopa starting hourly infusion rate”: • Total daily LE over 16 hours are increased by 50% to account for 24-hour dosing • Subcutaneous foslevodopa is 8% more bioavailable than enterally absorbed levodopa • The molecular weight ratio between foslevodopa and levodopa is 1.41:1 • One millilitre of Produodopa contains 240 mg of foslevodopa and 12 mg of foscarbidopa • Most patients with PD are treated with oral PD medications during their waking time (typically 16-hour/day treatment period); once the amount of foslevodopa needed over the 16-hour period has been calculated, it is divided by 240 mg to determine the number of millilitres needed over the 16-hour period, and then divided over 16 hours to establish the hourly infusion rate

LE = levodopa equivalents; LD = levodopa.

Step 3: Determine the volume of the loading dose.

A loading dose can be administered immediately prior to commencing the hourly infusion to quickly achieve symptomatic control when starting Produodopa therapy in an "Off" state (or if the pump has been off for more than 3 hours). Loading doses can be administered either via the pump or using oral immediate-release carbidopa-levodopa tablets.

Table 3 provides the recommended loading dose volume (ml) of Produodopa to be programmed into the pump (refer to the pump instructions for use for details) and the corresponding amount of immediate-release levodopa (mg), regardless of the peripheral inhibitor of the DOPA decarboxylase (e.g., carbidopa, benserazide) co-administered.

Table 3. Determination of Produodopa volume recommended for the loading dose 
Recommended loading dose volume (ml) to be            Approximate corresponding levodopa programmed into the pump                                 amount (mg)
0.6                                              100
0.9-1.2                                          150-200
1.5-1.8                                          250-300
2.0                                              350
0.1 ml of Produodopa contains 24 mg foslevodopa (equivalent to approximately 17 mg of levodopa). The pump is capable of delivering a loading dose ranging from 0.1 ml to a maximum of 3.0 ml, in increments of 0.1 ml.

Optimisation and maintenance

The healthcare professional may adjust the starting hourly infusion rate to achieve the optimal clinical response for the patient. The hourly infusion rate should be delivered continuously over the 24-hour daily infusion period. If desired, the healthcare professional can program and enable 2 alternative hourly infusion rates (Low/High). All infusion rates may be adjusted in increments of 0.01 ml/hr (which is equivalent to approximately 1.7 mg of levodopa/hour) and should not exceed 1.04 ml/hr (or approximately 4260 mg levodopa per day [6000 mg of foslevodopa per day]). The pump incorporates 

secure access to dose configuration to prevent patients from making changes to their pre-programmed flow rates or Extra Dose functionality.

Produodopa can be taken alone or, if necessary, with other concurrent medicinal products for Parkinson’s disease, based on the judgement of the healthcare professional. A reduction in other concomitant medications for Parkinson’s disease, followed by an adjustment in Produodopa dosage, may be considered during Produodopa infusion. The concomitant use of Produodopa with other levodopa-containing medications or with medicinal products that significantly regulate synaptic dopamine levels (such as COMT inhibitors) has not been studied.

Alternative flow rate

The pump also allows for 2 alternative infusion rate options to be programmed for patient use (Low/High). The alternative infusion rates must be enabled and pre-programmed by the healthcare professional and may be selected by patients to account for changes in functional demand, e.g., lowering the dosage at night-time or increasing the dose for prolonged intense activity (refer to the pump instructions for use for details).

Extra doses

If enabled by their healthcare professional, patients may self-administer an Extra Dose to manage acute “Off” symptoms experienced during continuous infusion. The Extra Dose volume can be chosen from 5 options (see Table 4). The Extra Dose feature is limited to no more than 1 extra dose per hour.
If 5 or more extra doses are used by the patient during the 24-hour/day treatment period, a revision of the Base Infusion Rate should be considered. The ability to enable this function, as well as the minimum time required between extra doses, is determined by the healthcare professional and cannot be modified by the patient (refer to the pump instructions for use for details on programming the Extra Dose feature).

Table 4. Extra dose option for Produodopa

Produodopa volume                    Levodopa equivalents
(ml)                                  (mg)
0.10                                  17
0.15                                 25.5
0.20                                  34
0.25                                 42.5
0.30                                  51
Method of administration

Produodopa is administered subcutaneously, preferably in the abdomen, avoiding a 5-cm radius area from the navel. Use aseptic technique when preparing and administering this product. The infusion set (cannula) can remain in place for up to 3 days when the medication is infused continuously. Rotate the infusion site and use a new infusion set at least every 3 days. It is recommended that new infusion sites be at least 2.5 cm from sites used within the previous 12 days. Produodopa should not be infused into areas where the site is tender, bruised, red, or hard to the touch. For administration of Produodopa only the Vyafuser pump should be used (refer to the pump instructions for use for details) using sterile, single-use infusion components (syringe, infusion set, and vial adapter) qualified for use. Patients should be trained on the proper use of Produodopa and the delivery system (pump, solution vial, vial adapter, syringe, infusion set, carrying accessory, rechargeable battery, and charger) prior to initiating treatment with Produodopa and, as necessary, thereafter.


In a Pharmacokinetic crossover study, administration of Produodopa via the arm and thigh resulted in nearly equivalent exposure to the abdomen (see section 5.2 Absorption). Long-term safety and efficacy of administration to the arm and thigh have not been evaluated.
The medication should be stored and handled as described in section 6.4, Special precautions for storage. The medication vials are for single use only. Once the content of a vial is transferred into the syringe, the contents of the syringe should be administered within 24 hours. Used medication vials and syringes should be discarded according to local regulations. Syringes must be discarded, even if residual product remains, as instructed by the healthcare professional (see section 6.6 Special precautions for disposal).

Interruption of therapy

Sudden discontinuation or rapid dose reduction of Produodopa, without administration of alternative dopaminergic therapy, should be generally avoided (see section 4.4).

Produodopa can be interrupted without further actions for brief periods of time, such as when the patient is taking a shower. For interruptions longer than 1 hour, a new infusion set (tubing and cannula) should be used and rotated to a different infusion site. If the infusion has been interrupted for longer than 3 hours, the patient may also self-administer a loading dose, if enabled by their healthcare professional, to quickly re-establish symptom control.

If treatment with Produodopa is interrupted for a prolonged time (>24 hours) or permanently discontinued, the healthcare professional should determine appropriate alternative dopaminergic treatment (e.g., oral levodopa/carbidopa). Treatment with Produodopa may be resumed at any time following instructions as for initiation of Produodopa (see section 4.2 Initiation of treatment).

Special populations

The pharmacokinetics of Produodopa has not been evaluated in any special population. Produodopa is intended for use in Parkinson’s disease patients who are already on a stable dose of oral levodopa.
Differences in exposure are not considered clinically significant because Produodopa is optimised once patients begin therapy. Therefore, covariate effects are not expected to impact clinical efficacy or safety. See section 5.2 for more information on the pharmacokinetics of levodopa and carbidopa in special populations.