Summary of medicine characteristics - Numient
2. QUALITATIVE AND QUANTITATIVE COMPOSITION
95 mg/23.75 mg modified-release hard capsules
Each capsule contains 95 mg levodopa and 23.75 mg carbidopa (as monohydrate)
145 mg/36.25 mg modified-release hard capsules
Each capsule contains 145 mg levodopa and 36.25 mg carbidopa (as monohydrate)
195 mg/48.75 mg modified-release hard capsules
Each capsule contains 195 mg levodopa and 48.75 mg carbidopa (as monohydrate
245 mg/61.25 mg modified-release hard capsules
Each capsule contains 245 mg levodopa and 61.25 mg carbidopa (as monohyd
For the full list of excipients, see section 6.1.
3. PHARMACEUTICAL FORM
Modified-release hard capsule
95 mg/23.75 mg modified-release hard capsule
White body and a blue cap of 18 × 6 mm
145 mg/36.25 mg modified-release har
Light blue body and a blue cap of 1
ith “IPX066” and “95” in blue ink.
le
m imprinted with “IPX066” and “145” in blue ink.
195 mg/48.75 mg modified- Yellow body and a blue c
hard capsule
8 mm imprinted with “IPX066” and “195” in blue ink.
245 mg/61.25 mg modified- release hard capsule
Blue body and a blue cap of 23 × 9 mm imprinted with “IPX066” and “245” in blue ink.
4.
PARTICULARS
4.1 Therapeutic indications
Symptomatic treatment of adult patients with Parkinson’s disease.
4.2 Posology and method of administration
4.2 Posology and method of administrationPosology
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.
by l
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.
dministered in
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.
Total daily dose of levodopa Initial
in immediate release
levodopa/DDC inhibitor (mg)
400 to 549
550 to 749
750 to 949
950 to 1249
>1250
tal daily dose of umient
dopa in mg)
855 __________
1140 _________
1305 _________
1755 _________
2340
Suggested initial dose of Numient
2205
3 hard capsules 95 mg/23.75 mg TID
4 hard capsules 95 mg/23.75 mg TID
3 hard capsules 145 mg/36.25 mg TID
3 hard capsules 195 mg/48.75 mg TID
4 hard capsules 195 mg/48.75 mg TID or
3 hard capsules x 245 mg/61.25 mg TID
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
| Total daily dose of levodopa (mg) in levodopa/DDC inhibitor/entacapone | Initial total daily dose of Numient (levodopa in mg) | Suggested initial dose of Numient |
| 400 to 549 | 1140 | 4 hard capsules 95 mg/23.75 mg TID |
| 550 to 749 | 1470 | 2 hard capsules 245 mg/61.25 mg TID |
| 750 to 949 | 1755 | 3 hard capsules 195 mg/48.75 mg TID |
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
s
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.
ished. No data are
Method of administration
Numient should be administered with a glass of water and can be take
high-calorie meal delays the absorption of levodopa by two hou clinical response by decreasing the absorption of levodopa (see be taken at the same time as high protein meals. The modified-r
ith or without food. A high-fat, r, high protein meals may impair
ction 4.5). Therefore, Numient should not ease hard capsule should be swallowed
whole, and not chewed or crushed, in order to maintain the modified-release effect of the levodopa/carbidopa medicinal product. Alternatively, for patients that have difficulty swallowing a capsule, this medicinal product may be administered by carefully openi e capsule and sprinkling the entire contents on a small
amount (e.g., 2 tablespoons) of soft food suc product/food mixture should be swallowed stored for future use. It cannot be exclu Therefore, the medicinal product sh
le sauce, yoghurt, or pudding. The medicinal
etely and immediately without chewing and should not be heating may change the properties of the medicinal product. be heated or added to hot food.
Products containing ferrous sulphate should be administered separately from levodopa/carbidopa, with the longest possible time inte etween administrations (see section 4.5).
4.3 Contraindicati
Hypersensitivityto the active substances or to any of the excipients listed in section 6.1.
igle glaucoma.
Na
ochromocytoma.
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.
s receiving antipsychotics
Neuroleptic malignant syndrome (NMS)
rome findings, es; other
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).
or hypotension; umria, and increased y when the dose of
Mental disturbances
l changes, which may be severe, nt or after starting or increasing the
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.
Patients with a major psychotic disorder or a
levodopa/carbidopa because of the risk used to treat psychosis may exacerbate effectiveness of levodopa/carbidopa C worsening of Parkinson’s motor sympt 4.5).
of psychotic disorder must be treated cautiously with ng psychosis. In addition, certain medicinal products
.he symptoms of Parkinson's disease and may decrease the 'ncomitant use of antipsychotics should be monitored carefully for ms especially when D2-receptor antagonists are used (see section
Impulse control disor Patients should be reg should be made a
gambling, in eating, and other dop develop.
monitored for the development of impulse control disorders. Patients and carers ehavioural symptoms of impulse control disorders including pathological
ibido, hypersexuality, compulsive spending or buying, binge eating and compulsive ine dysregulation syndrome can occur in patients treated with dopamine agonists and/or gic treatments containing levodopa. Review of treatment is recommended if such symptoms
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.
Glaucoma
Patients with chronic wide-angle glaucoma may be treated cautiously with levodopa/carbidopa provided the intraocular pressure is well-controlled and the patient is monitored carefully for changes in intraocular pressure during therapy.
Melanoma
Epidemiological studies have shown that patients with Parkinson’s disease have a higher risk (2– to approximately 6-fold higher) of developing melanoma than the general population. Whether the increased risk observed was due to Parkinson’s disease or other factors, such as medicinal products used to tre Parkinson’s disease, is unclear.
For the reasons stated above, patients and prescribing physicians are advised to monitor for frequently and on a regular basis when using levodopa/carbidopa, especially in patients wit undiagnosed skin lesions or a history of melanoma. Periodic skin examinations performe qualified individuals (e.g., dermatologists) are recommended.
Laboratory testing
as icious, ppropriately
Decreased haemoglobin and haematocrit have been observed on long-term levodopa/carbidopa treatment. Periodic evaluation of hepatic, haematopoietic, cardiovascular and rena’ function is recommended during extended therapy.
Levodopa/carbidopa preparations may provide a false-positive test for ketone bodies, if a test strip is
used for determining any ketonuria. This reaction does not change upon boiling the urine sample. False negative results might be obtained upon application of glucose-oxidase methods for glucosuria.
Special populations
Levodopa/carbidopa should be administered cardiovascular or pulmonary disease, b peptic ulcer disease (because of the possibi convulsions.
utiously to patients with ischemic heart disease, severe sthma, renal, hepatic or endocrine disease, or history of
of upper gastro-intestinal haemorrhage) and a history of
Care should be exercised in a stering levodopa/carbidopa to patients with a history of myocardial infarction who have residual nodal, or ventricular arrhythmias. In such patients, cardiac function should be monitored with particular care during the period of initial dose adjustment.
Monoamine
e inhibitors
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
ustment t with this
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.
Ferrous salts
with caution sulphate betwee
Levodopa/carbi
Alcohol interaction
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.
There are no data on the e were evaluated in mouse
Fertility levodopa or carbidopa on human fertility. Effects of levodopa on fertility ee section 5.3).
Levodopa m
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.
Pat
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.
ies are
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
ilable data). seriousness.
| Adverse reactions observed in the clinical development of Numient | ||||
| System organ class | Very Common | Common | Uncommon | Unknowna) |
| Neoplasm benign, malignant and unspecified (including cysts and polyps) | Melanoma (see section 4.4) | |||
| Blood and lymphatic system disorders | Anaemia | Agranulocytosis thrombocy topenia, leucopenia | ||
| Metabolism and nutrition disorders | Weight decrease | Decreased appetite, weight increase | ||
| Psychiatric disorders | Cognitive impairment, confusional state, hallucination, depression (see section 4.5), anxiety, abnormal dreams, insomnia | Psychotic episode, impulse control disorder (see section 4.4), agitation xff… | Suicide attempt (see section 4.4), disorientation, dopaminergic dysregulation syndrome, euphoria, increased libido | |
| Nervous system disorders | Dystonia, on and off / phenomenon, dyskinesia, somnolence, gait disturbance, dizziness, worsening of Parkinson’s disease, paraesth esia headache, tremor | c onvulsions, sudden onset of sleep (see section 4.4), trismus, restless legs syndrome | Neuroleptic malignant syndrome (see sections 4.3 and 4.4), ataxia | |
| Eye disorders | J | Blurred vision, diplopia, mydriasis, | Oculogyric crises, activation of latent Horner's syndrome, blepharospasm | |
| Cardiac disorders ♦ | Cardiac rhythm disorders'3) (see section 4.4) | Palpitations | ||
| Vascular disorders | Orthostatic hypotension (see section 4.4 and 4.9), hypertension (see section 4.5) | Syncope, thrombophlebitis | ||
| Respiratory, thoracic and mediastinal disorders | Dyspnoea | Abnormal breathing pattern, hoarseness | ||
| Gastrointestinal disorders | Nausea | Abdominal pain, constipation, diarrhoea, dry mouth, vomiting | Gastrointestinal hemorrhage, peptic ulcer disease (see section 4.4), dysphagia, dyspepsia, dysgeusia, glossodynia, flatulence | Dark saliva, bruxism, hiccups, sialorrhoea |
| Skin and | Hot flushes, | Allergic oedema, | Henoch-Schonlein | |
| Adverse reactions observed in the clinical development of Numient | ||||
| System organ class | Very Common | Common | Uncommon | Unknowna) |
| subcutaneous tissue disorders | hyperhidrosis, rash (see section 4.3) | pruritus (see section 4.3) | purpura, urticaria (see section 4.3), hair loss, exanthema, dark sweat | |
| Musculoskeletal and connective tissue disorders | Muscle spasms | |||
| Renal and urinary disorders | Urinary retention | Dark urine urinoryO incontinence | ||
| Reproductive system and breast disorders | Priapism | |||
| General disorders and administration site conditions | Fall, peripheral oedema, non-cardiac chest pain, asthenia, fatigue | Malaise | ||
| Investigations | Elevated AST, ALT, LDH bilirubin, blood sugar, creatinine, uric acid; lowered values of haemoglobin and haematocrit; blood in urine | Elevated urea nitrogen, alkaline phosphatases; positive Coomb’s test; leucocytes, and bacteria in the urine | ||
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
dicinal refully
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.
ther
tre, where
ATC code: N04BA02
5. PHARMACOLOGICAL PROPERTIES5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Anti-Parkinson drugs, dopaminer
Mechanism of action
Levodopa is a precursor of dopamine, and is given
mine replacement therapy in Parkinson's disease.
Carbidopa is a peripheral aromatic amino aci to dopamine in the peripheral circulation, ens
where dopamine exerts its therapeutic administered with carbidopa, reduci
d decarboxylase inhibitor. It prevents metabolism of levodopa uring that a higher proportion of the dose reaches the brain,. A lower dose of levodopa can be used when it is co-
ncidence and severity of peripheral side effects.
Pharmacodynamic effects
When levodopa is administered orally, it is rapidly decarboxylated to dopamine in extracerebral tissues so that only a small portion of a given dose is transported unchanged to the central nervous system. For this
reason, large doses
extracerebra
of levodopa are required for adequate therapeutic effect and these may often be
usea and other adverse reactions, some of which are attributable to dopamine formed in
s.
not
nhibits decarboxylation of peripheral levodopa. It does not cross the blood-brain barrier and does e metabolism of levodopa within the central nervous system. Since its decarboxylase inhibiting
activity is limited to extracerebral tissues, administration of carbidopa with levodopa makes more levodopa
available for delivery to the brain. The addition of carbidopa to levodopa reduces the peripheral effects (nausea, vomiting) due to decarboxylation of levodopa; however, carbidopa does not decrease the adverse reactions due to the central effects of levodopa.
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)
| Mean UPDRS (Part á i an | d Part III) Scorea) | ||
| Treatment | Baseline b) | Week 30 (or at early termination) | Change from baseline at week 30 (or at early termination)0 |
| Placebo | 36.5 | 35.9 | –0.6 |
| Numient 145 mgd) | 36.1 | Jk 24.4 | –11.7 e) |
| Numient 245 mgd) | 38.2 | _ , 25.3 | –12.9 e) |
| Numient 390 mgd) | 36.3 \A | 21.4 | –14.9 e) |
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
| Study | ADVANCE-PD | ASCEND-PD (cross-over) | ||
| Number of patients | ||||
| N entered | 471 | 110 | ||
| N in conversion | 450 | 110 | ||
| N randomised | 393 | 91 | ||
| N completed | 368 | 84 | ||
| Features of randomized patients | ||||
| Age [yrs (SD)] | 63.2 (9.4) | 64.1 (9.3) | ||
| Duration PD [yrs (SD)] | 7.4 (4.5) | 10.0 (5.3) K | ||
| Outcomes _VP | ||||
| Study arms | Numient | IR L-dopaf | Numient | ( LCE |
| n=201 | n=192 | n= | 84 | |
| Dose (mg), median (range) | 1,330 (570; 5,390) | 800 (400; 2,000) | 1,495 (735; 4,90 0) 1 | 600 k (400; 1,600) |
| Percentage “off” time | ||||
| Baseline, mean | 36.9% | 36.0% | 36.1% | |
| Endpoint, mean | 23.8% | 29.8% | xi 24.0% | 32.5% |
| Difference (95% CI) | –5.8% (-8.8; –2.7) | -C% -8.6% (-12.4; –4.7) | ||
| p-value | < 0.0001 | < 0.0001 | ||
| “Off” time (hrs)* ' | ||||
| Baseline, mean | 6.1 | 5.9 h- | 5.9 | |
| Change at endpoint | –2.2 | ,4–1.0 | –2.1 | –0.7 |
| Difference (95% CI) | –1.0 (-1 5 –0.5) | –1.4 (-2.1; –0.8) | ||
| p-value | < 0.0001 | < 0.0001 | ||
| “On” time without troublesome dyskinesia (hrs)* { | ||||
| Baseline, mean | 10.0' | 10.1 | 9.8 | |
| Change at endpoint | +1.9 * | +0.8 | +1.5 | +0.1 |
| Difference (95% CI) | JV 1.0 (0.5; 1.5) | 1.4 (0.7; 2.0) | ||
| p-value | kV 0.0002 | < 0.0001 | ||
| UPDRSn .In score | I?*’ | |||
| Baseline, mean | 32.3 | 32.4 | 32.0 | |
| Change at endpoint | –5.7 | –2.1 | –2.7 | –0.3 |
| Difference (95% CI) | –4.0 (-5.9; –2.0) | –2.6 (-4.8; –0.4) | ||
| p-value | < 0.0001 | 0.0233 | ||
| Responder analyses _ 'ff | ||||
| >1 hour improvement in “off” time (95% CI) | 63.2% (56.5; 69.9) | 45.3% (38.3; 52.4) | 64.0% (54.1; 74.0) | 50.0% (39.6; 60.5) |
| p-value | < 0.0001 | 0.0094 | ||
| CGI-C much improved (95% CI) | 40.0% (33.2; 46.8) | 13.7% (8.8; 18.6) | N/A | N/A |
| p-value | < 0.0001 | N/A | ||
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
Figure 1: Mean concentration-time profiles of levodopa plasma concentrations in 22 single oral dose of 2 Numient 195 mg levodopa/48.75 mg carbidopa capsules
The bioavailability o release levodopa/car
that is 30% t plasma conc are reach
evodopa from Numient in patients was approximately 70% relative to immediate opa. For comparable doses, Numient results in a levodopa peak concentration (Cmax) ediate-release levodopa/carbidopa. Following an initial peak at about one hour,
co
mo
trations are maintained for about 4 to 5 hours before declining. Peak plasma concentrations about 4.5 hours. In patients with Parkinson’s disease, multiple-dose pharmacokinetics was single-dose pharmacokinetics, i.e. there was a minimal accumulation of levodopa from the
release levodopa/carbidopa medicinal product.
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%.
Food effect
In healthy adults, oral administration of the modified-release levodopa/carbidopa medicinal product after a high-fat, high-calorie meal reduced levodopa Cmax by 21%. The extent of absorption of levodopa (AUCinf) was similar (13% increase) to that observed in the fasted state. Administration with a high-fat, high-calorie meal delays levodopa absorption by up to 2 hours.
Following administration of the modified-release hard capsule contents sprinkled over a small quantity of soft food such as apple sauce, 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.
Distribution
Levodopa
Levodopa is bound to plasma protein only to a small extent (10–30%). Levodopa c barrier by active transporters for large neutral amino acids.
Carbidopa
Carbidopa is approximately 36% bound to plasma proteins. Carbi at clinically relevant doses.
e blood-brain
Biotransformation
not cross the blood-brain barrier
Levodopa
Levodopa is extensively metabolized to various metabolites. The two major metabolic pathways are decarboxylation by dopa decarboxylase (DDC) and O-methylation by catechol-O-methyltransferase (COMT). Unchanged levodopa accounts for less than 10% of the total urinary excretion. The terminal phase elimination half-life of levodopa, the active moiety of antiparkinsonian activity, is approximately 2 hours in the presence of carbidopa.
Carbidopa
Carbidopa is metabolized to two a-methyl-3, 4-dihydroxy-phen unchanged or as glucuronide.
in metabolites: a-methyl-3-methoxy-4-hydroxyphenylpropionic acid and ionic acid. These two metabolites are primarily eliminated in the urine anged carbidopa accounts for 30% of the total urinary excretion. The
terminal phase elimination half-life of carbidopa is approximately 2 hours.
Dose linearity
Numient shows dose proportional pharmacokinetics for both carbidopa and levodopa over the levodopa dose strength range of 95 mg to 245 mg.
Re
irment
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.
of
se differences
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
Both levodopa and combinations of carbidopa and in rabbits.
aused visceral and skeletal malformations
No effects were seen on male or female reproductiv monkeys with levodopa alone, or in combination wi mildly affect mating behaviour in male rats.
s in repeat dose toxicology studies in mice, rats or idopa. However, levodopa has been shown to
Capsule contents
ARS
-
6. PHARMACEUTICAL PA
6.1 List of excipients
Cellulose, microc Mannitol Tartaric acid Ethylcellulose Hypromellose
So
rch glycolate
Sodium laurilsulfate
Povidone
Talc
Methacrylic acid – methyl methacrylate copolymers (1:1)
Methacrylic acid – methyl methacrylate copolymers (1:2)
Triethyl citrate
Croscarmellose sodium
Magnesium stearate
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)