Levodopa/ Carbidopa/ Entacapone

Registered South African indications:

• Parkinson's disease

Contraindications

• Hypersensitivity to the active ingredient or any of its excipients
• Hypersensitivity to soya or peanut
• Severe hepatic impairment
• Narrow angle glaucoma
• Phaeochromocytoma
• Previous history of neuroleptic malignant syndrome and/or non- traumatic rhabdomyolysis
• Coadministration with monoamine oxidase inhibitors

Cautions

• Pregnancy
• Breastfeeding
• Renal impairment
• Mild to moderate hepatic impairment
• Drug-induced extrapyramidal reactions
• Ischaemic heart disease
• Severe cardiovascular disease
• Severe pulmonary disease 
• Asthma
• Endocrine disease
• History of peptic ulcer disease
• History of seizures
• Myocardial infarction
• Atrial, nodular or ventricular arrhythmias
• Past or current psychosis
• Wide angle glaucoma
• Patients at risk of orthostatic hypotension
• Abrupt withdrawal
• High protein diet
• May impair ability to drive and operate machinery

Forms avail. in SA and covered in this monograph: tab

Parkinson's disease
- End-of-dose motor fluctuations not stabilised on levodopa/dopa decarboxylase (DDC) inhibitor treatment

Levodopa/ Carbidopa/ Entacapone
50/12.5/200 (mg)
100/25/200 (mg)
150/37.5/200 (mg)

• Oral (tab): Doses should be individualised based on levodopa dose; Max: 10 tab/24hrs

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See additional prescribing points

Not established for use in children below 18 years

Pregnancy 

• FDA Pregnancy Category C

Breastfeeding

• Caution

Renal Impairment

• Caution; no information available

Hepatic Impairment

• Mild to moderate: Caution; dose adjustment recommended 
• Severe: Contraindicated

Elderly

• No dose adjustment recommended

Porphyria Information

• Probably not porphyrinogenic (PNP)

Drugs in Sport

• Permitted - No warning

Central Nervous System Disorders

• Asthenia
• Depression
• Hallucination
• Confusion
• Abnormal dreams 
• Anxiety
• Insomnia
• Psychosis 
• Agitation
• Suicidal behaviour
• Dyskinesia
• Aggravated Parkinsonism
• Tremor
• On and off phenomenon
• Dystonia
• Mental impairment
• Somnolence
• Dizziness
• Headache
• Neuroleptic malignant syndrome

Cardiovascular Disorders

• Irregular heart rhythm
• Myocardial infarction
• Orthostatic hypotension
• Hypertension

Respiratory Disorders

• Dyspnoea

Gastrointestinal Disorders

• Diarrhoea
• Nausea and vomiting
• Constipation
• Dyspepsia
• Abdominal pain
• Dry mouth
• Colitis
• Dysphagia
• Gastrointestinal haemorrhage

Hepatobiliary Disorders

• Abnormal hepatic function test
• Hepatitis

Genitourinary Disorders

• Chromaturia
• Urinary tract infection
• Urinary retention

Endocrine and Metabolic Disorders

• Decreased weight
• Decreased appetite

Musculoskeletal Disorders

• Pain
• Muscle spasms
• Arthralgia
• Rhabdomyolysis

Skin and Subcutaneous Tissue Disorders

• Rash
• Hyperhidrosis
• Discolouration of skin, nails, hair, sweat
• Angioedema
• Urticaria

Immune, Blood and Lymphatic System Disorders

• Anaemia
• Thrombocytopenia

Sensory Disorders

• Blurred vision

• Antipsychotics
• Selegiline
• Antihypertensives
• Antidepressants
• Dopamine receptor antagonists
• Phenytoin
• Papaverine
• Iron preparations
• Diazepam
• Warfarin
• Ibuprofen

• Hepatic function
• Full blood count
• Renal function
• Vital signs
• Dermatological examination

Specific cases may require

• Weight
• Serum iron
• Chest X-ray
• ECG
• Ophthalmic examination

Directions for switching patient from another therapy to levodopa/carbidopa/entacapone

• Patients currently on entacapone and standard release levodopa/carbidopa in doses equal to the combination tablet can be directly switched to the corresponding combination tablets
• Patients currently on entacapone and levodopa/carbidopa with doses not equal to any combination tablet should be carefully titrated for optimal clinical response. The combination tablet should be adjusted to correspond as closely as possible to the total daily dose of levodopa currently used
• Patients currently on entacapone and levodopa/benserazide should stop their current treatment for one night and start the combination therapy the next morning. Treatment should begin at the same amount of levodopa
• It is not recommended to initiate patients on the combination treatment prior to stabilisation of the patient on entacapone as a separate medication

Levodopa
Levodopa, the precursor of dopamine, crosses the blood brain barrier and relieves the symptoms of the disease. As levodopa is extensively metabolised in the periphery, only a small portion of a given dose reaches the central nervous system when levodopa is administered without metabolic enzyme inhibitors. 

Carbidopa
Carbidopa are peripheral DOPA decarboxylase (DDC) inhibitors which reduce the peripheral metabolism of levodopa to dopamine, and thus, more levodopa is available to the brain. When decarboxylation of levodopa is reduced with the co-administration of a DDC inhibitor, a lower dose of levodopa can be used and the incidence of adverse reactions such as nausea is reduced. With inhibition of the decarboxylase by a DDC inhibitor, catechol-O-methyltransferase (COMT) becomes the major peripheral metabolic pathway catalyzing the conversion of levodopa to 3-O-methyldopa, a potentially harmful metabolite of levodopa. 

Entacapone
Entacapone is a reversible, specific and mainly peripherally acting COMT inhibitor designed for concomitant administration with levodopa. Entacapone slows the clearance of levodopa from the bloodstream resulting in an increased area under the curve in the pharmacokinetic profile of levodopa. Consequently the clinical response to each dose of levodopa is enhanced and prolonged.

COMBINATION PREPARATIONS

Carbidopa/ Entacapone/ Levodopa

Tablet 12.5mg/200mg/50mg

• Stalevo (Equity Pharmaceuticals) originator

Tablet 25mg/200mg/100mg

• Stalevo (Equity Pharmaceuticals) originator

Tablet 37.5mg/200mg/150mg

• Stalevo (Equity Pharmaceuticals) originator