Numient - summary of medicine characteristics

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

3. PHARMACEUTICAL FORM

4.1 Therapeutic indications

Symptomatic treatment of adult patients with Parkinson’s di­sease.

4.2 Posology and method of administration

Posology

Numient is recommended to be dosed orally, approximately every 6 hours. Dosing this medicinal product more than 5 times per day is not recommended.

Each capsule strength may be used alone, or in combination with other capsule strengths as required. Use of this medicinal product with other levodopa containing medicinal products has not been studied.

Dose recommendations should be followed at initiation of treatment and adapted according to clinical response.

Initial dose and titration in levodopa-naïve patients

The starting dose is one capsule containing 95 mg of levodopa and 23.75 mg carbidopa three times daily (TID) for the first three days; this may be increased to a dose of one modified-release hard capsule containing 145 mg of levodopa and 36.25 mg carbidopa three times daily from Day 4 of treatment.

Further increases should be individualized based on clinical response. The daily dose must be det careful titration. Patients should be maintained on the lowest dose required to achieve sympto and to minimize adverse reactions such as dyskinesia and nausea.

There is limited experience with a total daily dose of more than 1,170 mg of levodopa levodopa-naive patients.

Converting patients from other levodopa/ dopa-decarboxylase (DDC) inhibit immediate release medicinal products to Numient

As a result of Numient’s phar­macokinetic characteristics, the doses and dosing frequency of Numient are not directly interchangeable with those of other levodopa/DDC inhibitor immediate release medicinal products (see section 5.2).

When patients are initially converted from immediate release levodopa/DDC inhibitor medicinal products to Numient, the dosing conversion guidelines provided in Table 1 are recommended for initial dosing.

Table 1: Guidelines for initial conversion from immediate release (IR) levodopa/DDC inhibitor medicinal products to Numient in Parkinson’s disease patients.

When patients are initially converted from immediate release levodopa/DDC inhibitor plus catechol-O-methyl transferase (COMT) inhibitors (such as entacapone) to Numient the dosing conversion guidelines provided in Table 2 are recommended for initial dosing.

Table 2: Guidelines for initial conversion from immediate release levodopa/DDC inhibitor plus catechol-O-methyl transferase (COMT) inhibitors (such as entacapone) to Numient in Parkinson’s disease patients

950 to 1249 _____________­_______2205 _______________3 hard capsules 245 mg/61.25 mg TID

>1250                     ­2940              4 hard capsules 245 mg/61.25 mg TID

When converting patients from levodopa/DDC inhibitor medicinal products to Numient, the dos should be adjusted to maintain sufficient symptomatic control. The dosing frequency may be changed from three times a day to a maximum of five times a day if sufficient symptomatic control is not observed. In studies in advanced Parkinson’s disease patients, there is limited data using doses above 2,450 mg of levodopa and 612.5 mg of carbidopa given as Numient.

The final total daily dose of levodopa from Numient is about double that of the final total daily dose of levodopa from immediate release tablets while the final total daily dose of levodopa from Numient is about three times that of the final total daily dose of levodopa from the combination of levodopa/DDC inhibitor/enta­capone.

Converting patients specifically from other levodopa/DDC inhibitor modified-release medicinal products to Numient

For patients currently treated with other levodopa/DDC inhibitor modified-release medicinal products, limited information regarding conversion to Numient is available. The initial total daily dose of Numient described in Table 1 above may need to be decreased by approximately 30% for patients converting specifically from levodopa/DDC inhibitor modified-release medicinal products to Numient.

Maintenance

Because Parkinson's disease is progressive, periodic clinical evaluations are recommended. Therapy should be individualized and adjusted for each patient according to the desired therapeutic response.

Addition of other medicinal products for the treatment of Parkinson’s di­sease

Modified-release levodopa/carbidopa may be used together with other medicinal products for the treatment of Parkinson’s di­sease. However, dose adjustments may be required (see section 4.5).

Interruption of therapy

Sporadic cases of a symptom complex resembling neuroleptic malignant syndrome (NMS) have been associated with dose reductions and withdrawal of levodopa/carbidopa containing medicinal products. Patients should be observed carefully if abrupt reduction or discontinuation of the modified-release levodopa/carbidopa capsule medicinal product is required, especially if the patient is receiving antipsychotics (see section 4.4).

If general anaesthesia is required, the modified-release levodopa/carbidopa capsule medicinal product may be continued as long as the patient is permitted to take oral medicinal products. If therapy is interrupted temporarily, the usual dose should be administered as soon as the patient is able to take oral medicinal products.

Elderly

No dose adjustment of the modified-release levodopa/carbidopa medicinal product is required for elderly patients.

Renal impairment

Impact of renal function on levodopa/carbidopa clearance is limited (see section 5.2). Numient has not been studied in patients with renal impairment. It is recommended to administer this medicinal product cautiously to patients with severe renal disease (see section 4.4).

Hepatic impairment

Numient has not been studied in patients with hepatic impairment. It is recommended to admini medicinal product cautiously to patients with severe hepatic impairment (see section 4.4).

Paediatric population

The safety and efficacy of Numient in children under 18 years of age have not be available.

Method of administration

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

igle glaucoma.

Co-administration with non-selective monoamine oxidase (MAO) inhibitors. These inhibitors must be discontinued at least two weeks prior to initiating therapy (see section 4.5).

A previous history of neuroleptic malignant syndrome (NMS) and/or non-traumatic rhabdomyolysis.

4.4 Special warnings and precautions for use

CNS effects and mental disturbances

Somnolence and episodes of sudden sleep onset

Levodopa has been associated with somnolence and episodes of sudden sleep onset (see section 4.7). 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 (see section 4.7). Patients who have experienced somnolence and/or an episode of sudden sleep onset must refrain from driving or operating machines. Furthermore a reduction of dose or termination of therapy may be considered.

Neuroleptic malignant syndrome (NMS)

Sporadic cases of a symptom complex resembling NMS have been reported in association wit reductions or withdrawal of levodopa/carbidopa medicinal products. NMS is a life-threateni characterized by fever or hyperthermia and can be associated with rhabdomyolysis. Neur including muscle rigidity, involuntary movements, altered consciousness, mental st disturbances, such as autonomic dysfunction, tachycardia, tachypnoea, sweating, h laboratory findings, such as creatine phosphokinase elevation, leucocytosis, my serum myoglobin have been reported. Therefore, patients must be monitored levodopa/carbidopa is reduced abruptly or discontinued, especially if the pati (see section 4.2).

Mental disturbances

Patients may experience new or worsening mental status and including psychotic-like and suicidal behaviour during levod dose of levodopa. This abnormal thinking and behaviour can consist of one or more of a variety of manifestations including anxiety, depression, paranoid ideation, delusions, hallucinations, confusion, psychotic-like behaviour, disorientation, aggressive behaviour, agitation, and delirium.

Dyskinesias

Medicinal products containing levodopa cause dyskinesias that may require treatment adjustment. Carbidopa permits more levodopa to reach the brain and more dopamine to be formed increasing the risk for certain adverse CNS reactions including dyskinesia. It is recommended to monitor patients for the onset or evolution of dyskinesia and to adjust levodopa/carbidopa doses accordingly.

Orthostatic hypotension

Levodopa/carbidopa can cause orthostatic hypotension. Levodopa/carbidopa should be used with caution in case of concomitant use of medicinal products that may cause orthostatic hypotension, e.g. anti-hypertensive medicinal products.

Non-selective monoamine oxidase inhibitors must be discontinued at least 2 weeks prior to treatment initiation with the modified-release levodopa/carbidopa capsule medicinal product (see section 4.3). Numient can be taken concomitantly with the recommended dose of an MAO inhibitor, which is selective for MAO inhibitor type B such as selegiline and rasagiline. There is a recognized drug-drug interaction of levodopa with type B MAO inhibitors which potentiates the effects of levodopa. The combination may be associated with severe orthostatic hypotension.

The dose of levodopa may need to be reduced when an MAO inhibitor selective for type B is added. Patients should be maintained on the lowest dose required to achieve symptomatic control and to minimize adverse reactions.

Dopamine D2 receptor antagonists, benzodiazepines and isoniazid

Dopamine D2 receptor antagonists (e.g., phenothiazines, butyrophenones, risperidone), benzodiazepines and isoniazid may reduce the therapeutic effects of levodopa. Patients taking these medicinal products together with levodopa/carbidopa should be monitored carefully for loss of therapeutic response.

Tricyclic antidepressants

There have been rare reports of adverse reactions, including hypertension and dyskinesia, resulting from the concomitant use of tricyclic antidepressants and levodopa/carbidopa.

Antihypertensives

Symptomatic postural hypotension has occurred when combinations of levodopa and a decar inhibitor are added to the treatment of patients already receiving certain antihypertensives. D of the antihypertensive medicinal products may be required during the titration phase of treat modified-release levodopa/carbidopa medicinal product.

Anticholinergics

Anticholinergic medicinal products can work synergistically with levodopa, in order to improve tremor. Concurrent use can, however, cause a worsening of involuntary motor disorders. Anticholinergic medicinal products may impair the effect of levodopa, due to a delayed absorption. A dose adjustment of levodopa may be required.

Phenytoin and papaverine

There have been rare reports that the beneficial effects of levodopa in Parkinson's disease are reversed by phenytoin and papaverine. Patients taking these medicinal products with levodopa/carbidopa should be carefully monitored for loss of therapeutic response.

COMT inhibitors

The effect of co-administration of this modified-release levodopa/carbidopa capsule product and COMT inhibitors such as entacapone has net be en studied. The addition of entacapone to levodopa/carbidopa has been demonstrated to increase the levodopa bioavailability by 30%. The dose of the modified-release levodopa/carbidopa capsule medicinal product may need to be decreased with concomitant use of COMT inhibitors.

opa and ferrous salts or multivitamins containing ferrous salts should be co-administered us salts can form chelates with levodopa and carbidopa. Products containing ferrous odopa/carbidopa should be administered separately with the longest possible time interval

nistrations (see section 4.2).

In vivo , co-administration of Numient with up to 40% volume-to-volume (v/v) alcohol did not result in dosedumping of levodopa or carbidopa.

Food interaction

In healthy adults, oral administration of Numient after a high-fat, high-calorie meal reduced levodopa Cmax 21% while the overall extent of absorption of levodopa (AUCinf) was similar (13% increase) to that observed in the fasted state (see section 5.2). Administration with a high-fat, high-calorie meal delays levodopa absorption by up to 2 hours (see section 4.2).

Following administration of the modified-release hard capsule contents sprinkled over a small quantity (e.g., 2 tablespoons) of soft food such as apple sauce, yoghurt, or pudding, the rate and extent of absorption of levodopa was similar to that observed in the fasted state.

Levodopa competes with certain amino acids for transport, therefore high protein meals may impair t absorption of levodopa.

Effect of levodopa and carbidopa on the metabolism of other medicinal products

Inhibition or induction effects of levodopa and carbidopa have not been investigate

4.6 Fertility, pregnancy and lactation

Pregnancy

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

Breast-feeding

Carbidopa is excreted in rat milk, but it is not known whether carbidopa or its metabolites are excreted in human breast milk. In a study of one breastfeeding mother with Parkinson’s di­sease, excretion of levodopa in human milk was reported. There is insufficient information on the effects of levodopa/carbidopa or their metabolites in newborns/infants. Breast-feeding should be discontinued during treatment with Numient.

Fertility levodopa or carbidopa on human fertility. Effects of levodopa on fertility ee section 5.3).

a major influence on the ability to drive and use machines. Certain side effects such as ess that have been reported with this modified-release levodopa/carbidopa capsule uct may affect some patients' ability to drive or operate machinery.

ing treated with this modified-release levodopa/carbidopa capsule medicinal product 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).

4.8 Undesirable effects

Summary of the safety profile

The most frequently reported adverse reactions with Numient were nausea, occurring in approximately 12% of all patients; dizziness, headache, and dyskinesia, each occurring in approximately 8% of all patients; and insomnia, occurring in approximately 6% of all patients. Serious events of gastrointestinal haemorrhage (uncommon) and of allergic oedema (uncommon) were reported in the clinical studies with Numient. A symptom complex resembling neuroleptic malignant syndrome and rhabdomyolysis may occur with levodopa/carbidopa medicinal products, although no cases have been identified in clinical studies with Numient.

Tabulated list of adverse reactions

Adverse reactions are listed below by system organ class (SOC) and frequency (Table 3). defined as: very common (>1/10); common (>1/100 to <1/10); uncommon (>1/1,000 to < 1/10,000 to <1/1,000), very rare (<1/10,000), not known (cannot be estimated from the av Within each frequency category, the adverse reactions are presented in order of decreasin

a) Adverse reactions not observed in the clinical development of Numient but reported for other levodopa/carbidopa medicinal products.

b) Combined term that includes atrial fibrillation, atrial flutter, atrioventricular block, bundle branch block, sick sinus syndrome, bradycardia, and tachycardia

Description of selected adverse react ions

Sudden sleep onset

Numient is associated with somnolence and has been associated very rarely with excessive daytime somnolence and sudden sleep onset episodes.

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 (see section 4.4).

Laboratory values

Cases of falsely diagnosed phaeochromocytoma in patients on levodopa/carbidopa therapy have been reported very rarely. Caution should be exercised when interpreting the plasma and urine levels of catecholamines and their metabolites in patients on levodopa or levodopa/carbidopa therapy.

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

Symptoms and signs

The acute symptoms of levodopa/DDC inhibitor overdose can be expected to arise from dopaminergic overstimulation. Doses of a few grams may result in CNS disturbances, with an increasing likelihood of cardiovascular disturbance (e.g. hypotension, sinus tachycardia) and more severe psychiatric problems at higher doses. Levodopa overdose may give rise to systemic complications, secondary to dopaminergic overstimulation.

Treatment

Management of acute overdose with levodopa/DDC preparations is the same as management of a overdose with levodopa. Pyridoxine is not effective in reversing the actions of this combination m

product. Electrocardio­graphic monitoring should be instituted and the patient should be o for the development of arrhythmias; if required, give appropriate antiarrhythmic therapy. management should be as clinically indicated or as recommended by the national poisons available.

5. PHARMACOLOGICAL PROPERTIES5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Anti-Parkinson drugs, dopaminer

Mechanism of action

Clinical efficacy and safety

Levodopa-naive patients with Parkinson’s di­sease

APEX-PD

The effectiveness of Numient in patients with early Parkinson’s disease was established in a randomized, double-blind, placebo-controlled, fixed-dose, parallel-group, 30-week clinical trial in 381 patients who had a median disease duration of 1 year and limited or no prior exposure to levodopa and dopamine agonists. Patients continued on stable concomitant anti-Parkinson medicinal product. Eligible patients were randomized (1:1:1:1) to placebo or one of three fixed levodopa/carbidopa doses of 145 mg/36.25 mg, 245 mg/61.25 mg, or 390 mg/97.5 mg, three times a day. Patients were not allowed to receive supplemental levodopa or catechol-O-methyl transferase (COMT) inhibitors. Patients receiving the modified-release levodopa/carbidopa medicinal product initiated treatment at 95 mg levodopa/23.75 mg carbidopa three times daily (TID). The dose was increased starting on Day 4 and the highest target dose (390 mg levodopa/97.5 mg carbidopa TID) was achieved by Day 22.

The primary efficacy endpoint was the mean change from baseline of the Unified Parkinson’s Disease Rating Scale (UPDRS) Part II (activities of daily living) score plus Part III motor score at week 30 or early termination. Each of the three modified-release levodopa/carbidopa treatments was statistically significantly superior to placebo on the primary measure (Table 4).

Table 4: Mean change from baseline in UPDRS Part II plus Part III score at week 30 (or at early termination) in levodopa naïve patients with Parkinson’s disease (APEX-PD)

a) For the UPDRS, higher scores indicate greater seve ity < f impairment

b) All values based on 361 patients from the Inter t to Treat population who had valid End of Study values

c) Negative numbers indicate improvement as c ompared with the baseline value

d) Three times per day

e) P-value is less than 0.05 versus placebo

Patients with advanced Parkinson’s di­sease

The efficacy and safety of Numient in patients with advanced stage Parkinson’s disease have been evaluated in 2 double-blind, active-controlled studies: parallel study ADVANCE-PD (study IPX066-B09–02; 22 weeks) and cross-over study ASCEND-PD (study IPX066-B-09–06 Part 1; 11 weeks).

In both studies the primary endpoint was the percentage “off” time during waking hours. The main secondary endpoints included “off” time, “on” time without troublesome dyskinesia, and UPDRS Parts II+III score. In the ADVANCE-PD study, the Clinical Global Impression of Change was also assessed.

ADVANCE-PD

The ADVANCE-PD study was a 22-week study consisting of a 3-week dose adjustment of pre-study immediate release levodopa/carbidopa treatment prior to a 6-week conversion to Numient. Next, patients were randomized to a double-blind, 13-week study treatment period of either optimized immediate release levodopa/carbidopa treatment or Numient. A total of 471 included patients had been maintained on a stable regimen of at least 400 mg per day of levodopa prior to entry into the trial. Dosing of concomitant antiParkinson medicinal products was kept stable. Patients were not allowed to receive supplemental levodopa/carbidopa or catechol-O-methyl transferase (COMT) inhibitor medicinal products during the trial. A total of 393 patients (mean age 63.2 years; 65% male patients) were randomized.

ASCEND-PD

The ASCEND-PD study was a randomized, double-blind, 2-treatment, 2-period crossover study in which 110 patients on a stable regimen of levodopa/carbi­dopa/entacapo­ne (LCE) containing at least 400 mg per day of levodopa were included. Minimum dosing frequency was four times per day for at least 4 weeks upon entry into the trial. Concomitant anti-Parkinson medicinal products were kept stable during the study. LCE treatment was converted into Numient over a 6-week period. Following this dose conversion, 91 study patients (mean age: 64.1 years; 75% male patients) were randomized to receive Numient followed by prestudy LCE or vice versa. All efficacy data is based on 84 patients who completed the study with the exception of patient diary data which is based on 83. Each double-blind study period lasted 2 weeks. In between these periods, all patients received open-label Numient treatment for 1 week.

The most frequently recorded concomitant medicinal products for Parkinson’s disease in randomi patients were dopamine agonists (64%), and MAO inhibitors (37%).

Results

Main study results are summarized in Table 5.

Table 5: Main results of studies in advanced Parkinson’s di­sease

Abbreviations: CGI-C: clinical global impression of change from baseline; CI: confidence interval; IR: immediate release; LCE:

Levodopa/Carbi­dopa/Entacapo­ne; L-dopaf: Levodopa/Carbidopa; LS: least squares; PD: Parkinson’s di­sease; SD: standard deviation; N/A: not available; hrs: hours; yrs: years.

*In the ADVANCE-PD study an Analysis of Covariance (ANCOVA) model for End of Study was used with treatment and centres as main effects and interaction term for treatment by centre and baseline as covariate.

Data in the ASCEND-PD study were analysed using a standard mixed-model analysis of variance. Treatment, sequence and period were included as fixed effects, intra- and inter subject factors were included as random effects. There was no evidence of period, sequence/carry-over effects in the ASCEND-PD study (p-values all > 0.10).

Paediatric population

The European Medicines Agency has waived the obligation to submit the results of studies with Numient in all subsets of the paediatric population in the treatment of idiopathic Parkinson’s disease (see section 4.2 for information on paediatric use).

5.2 Pharmacokinetic properties

Absorption

Levodopa

The pharmacokinetics of Numient were evaluated following single doses in healthy subjects and foll single and multiple doses in patients with Parkinson’s di­sease. The single dose pharmacokinetics i adults following oral administration of 2 Numient 195 mg levodopa/48.75 mg carbidopa capsu presented in Figure 1.

llowing a

Following multiple dosing in patients, modified-release levodopa/carbidopa had reduced fluctuations in levodopa plasma concentrations with peak-to-trough fluctuation index of 1.5 with minimal accumulation of levodopa.

Carbidopa

Following oral dosing of the modified-release levodopa/carbidopa medicinal product the maximum concentration occurred at approximately 3.5 hours. The bioavailability of carbidopa from this medicinal product relative to immediate release levodopa and carbidopa tablets was approximately 50%.

Renal excretion of intact levodopa accounts for only about 10% of clearance. Thus, impaired renal function may potentially have a small effect on the exposure of levodopa. Modified-release levodopa/carbidopa should be administered cautiously to patients with severe renal impairment (see section 4.2).

Hepatic impairment

There are no studies on the pharmacokinetics of levodopa and carbidopa in patients with hepatic impairment (see section 4.2). Modified-release levodopa/carbidopa should be administered cautiously to patients with severe hepatic impairment.

Paediatric population

There are no studies on the pharmacokinetics of levodopa and carbidopa when administered as Numient in children.

Elderly

In the pharmacokinetic studies conducted in patients following a single dose of Numient, systemic exposure to levodopa generally increased with increasing age with AUC values being, on average, approximately 15% higher in elderly (>65 years) than younger subjects (<65 years).

Gender

Levodopa

Following a single dose of Numient in patients with Parkinson’s disease the plasma AUC a levodopa was higher in females than males (on average, 37% for AUC and 35% for Cmax) are primarily explained by the lower body weight in females.

5.3 Preclinical safety data

Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, and carcinogenic potential.

Reproductive toxicology

6.1 List of excipients

Capsule shell

Indigo carmine (E132), lake

Yellow iron oxide (E172)

Titanium dioxide (E171)

Gelatine

Ink

SB-6018 blue ink

Shellac (E904)

Propylene glycol

Indigo carmine (E132), lake

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

30 months

• 90 days after first opening.

  
  

6.4 Special precautions for storage

6.5 Nature and contents of container

Opaque, white, high-density polyethylene (HDPE) bottle with polypropylene screw closure. Desiccant is included in the bottle.

One bottle containing 25, 100 or 240 modified-release hard capsules.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal

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

7. MARKETING AUTHORISATION HOLDER

Amneal Pharma Europe Ltd 70 Sir John Rogerson’s Quay Dublin 2

Ireland

8. MARKETING AUTHORISATION NUMBERS

Numient 95 mg/23.75 mg modified-release hard capsules

EU/1/15/1044/001 (25 modified-release hard capsules)

EU/1/15/1044/002 (100 modified-release hard capsules)

EU/1/15/1044/003 (240 modified-release hard capsules)

Numient 145 mg/36.25 mg modified-release hard capsules

EU/1/15/1044/004 (25 modified-release hard capsules)

EU/1/15/1044/005 (100 modified-release hard capsules)

EU/1/15/1044/006 (240 modified-release hard capsules)

Numient 195 mg/48.75 mg modified-release hard capsules

EU/1/15/1044/007 (25 modified-release hard capsules)

EU/1/15/1044/008 (100 modified-release hard capsules)

EU/1/15/1044/009 (240 modified-release hard capsules)

Numient 245 mg/61.25 mg modified-release hard capsules

EU/1/15/1044/010 (25 modified-release hard capsules)

EU/1/15/1044/011 (100 modified-release hard capsules)

EU/1/15/1044/012 (240 modified-release hard capsules)