A summary of product monograph of Teva-levocarbidopa. It is manufactured by Teva and used for symptomatic treatment of Parkinson disease.

1. Product MonographTeva-levocarbidopa(levodopaand carbidopatablets, USP)
MunaAli B.Pharm.
Pharmaceutical Quality Control and Quality Assurance (QC/QA) Postgraduate Program
Presented at Academy of Applied Pharmaceutical Science (AAPS), Toronto, ON
2013-2014

2. Pharmaceutical Information
Therapeutic Classification:Anti-Parkinson Agent
A combination of carbidopaand levodopafor
the treatment of Parkinson’s disease and
syndrome.

3. Levodopa
Chemical Name:(-)-3-{3,4-Dihydroxyphenyl)-L- alanine
Structural Formula:
Molecular Formula: C9H11NO4
Molecular Weight: 197.19

4. Carbidopa
Chemical Name: (-)-L-α-Hydrazino-3,4-dihydroxy-α- methylhydrocinnamicacid monohydrate
Structural Formula:
Molecular Formula:C10H14N2O4•H2O
Molecular Weight:244.25

5. Clinical Pharmacology
Mechanism of Action
•Parkinson’s disease is a progressive, neurodegenerative disorder of the extrapyramidalnervous system affecting the mobility and control of the skeletal muscular system
•Symptomatic treatments, such as levodopatherapies, may permit the patient better mobility

6. Clinical Pharmacology
Mechanism of Action
•Current evidence indicates that symptoms of Parkinson's disease are related to depletion of dopamine in the corpus striatum
•Dopamine is ineffective in the treatment of Parkinson's disease apparently because it does not cross the blood-brain barrier
•Levodopa, the metabolic precursor of dopamine, does cross the blood-brain barrier, and presumably is converted to dopamine in the brain

7. Clinical Pharmacology
Pharmacodynamics
•When levodopais administered orally it is rapidly decarboxylatedto dopamine in extracerebraltissues
•Only a small portion of a given dose is transported unchanged to the central nervous system
•Large doses of levodopaare required for adequate therapeutic effect accompanied by nausea and other adverse reactions attributable to dopamine formed in extracerebraltissues
•Levodopacompetes with certain amino acids for transport across the gut wall
•The absorption of levodopamay be impaired in some patients on a high protein diet

8. Clinical Pharmacology
Pharmacodynamics
•Carbidopainhibits decarboxylationof peripheral levodopa. It does not cross the blood-brain barrier and does not affect the metabolism of levodopawithin the central nervous system
•The incidence of levodopa-induced nausea and vomiting is less with the combination product than with levodopa
•Since its decarboxylaseinhibiting activity is limited to extracerebraltissues, administration of carbidopawith levodopamakes more levodopaavailable for transport to the brain

9. Clinical Pharmacology
Pharmacokinetics
•Carbidopareduces the amount of levodoparequired to produce a given response by about 75%
•When carbidopaadministered with levodopa, it increased both plasma levels and the plasma half-life of levodopa
•The plasma half-life of levodopais about 50 minutes, without carbidopa
•The half-life of levodopais increased to about 1.5 hours when administered together with carbidopa
•Pyridoxine hydrochloride (vitamin B6) may reverse the effects of levodopaby increasing the rate of aromatic amino acid decarboxylation
•Carbidopainhibits this action of pyridoxine
•Carbidopaand levodopacan be given to patients receiving supplemental pyridoxine (vitamin B6)

10. Indications and Clinical Use
•Teva-levocarbidopais indicated for the treatment of Parkinson’s disease
•It is not recommended for the treatment of drug- induced extrapyramidalreactions
•Carbidopadoes not decrease adverse reactions due to central effects of levodopa
•By permitting more levodopato reach the brain, particularly, certain adverse CNS effects, e.g., dyskinesias, may occur at lower dosages and sooner during therapy with Teva-levocarbidopathan with levodopa.

11. Contraindications
•Non selective monoamine oxidase(MAO) inhibitors are contraindicated for use with Teva-levocarbidopa
•These inhibitors must be discontinued at least two weeks prior to initiating therapy with Teva-levocarbidopa
•It may be administered concomitantly with a MAO inhibitor with selectivity for MAO type B (e.g. selegilineHCI)

12. Contraindications
•Sympathomimeticamine is contraindicated
•Patients with clinical or laboratory evidence of uncompensated cardiovascular, endocrine, hematologic, hepatic, pulmonary (including bronchial asthma), or renal disease; or to patients with narrow angle glaucoma
•Patients with suspicious, undiagnosed skin lesions or a history of melanoma, Because levodopamay activate a malignant melanoma
•Patients with known hypersensitivity to any component of this medication

13. Warnings
•When patients already receiving levodopaare switched to Teva-levocarbidopa, levodopamust be discontinued for at least 12 hours or more before Teva-levocarbidopais started
•Teva-levocarbidopashould be substituted at a dosage that will provide approximately 20% of the previous levodopadosage
•Patients should be instructed not to take additional levodopaunless it is prescribed by the physician

14. Warnings
•Patients should be monitored carefully for the development of depression with suicidal tendencies
•Cardiac function should be monitored with particular care during the period of initial dosage adjustment in a facility with provisions for intensive cardiac care

15. Warnings
•Patients should be observed carefully when the dosage of Teva-levocarbidopais reduced abruptly or discontinued, especially if the patient is receiving neuroleptics
•Due to sporadic cases of a symptom complex resembling NeurolepticMalignant Syndrome(NMS) have been reported in association with dose reductions or withdrawal of therapy with antiparkinsonianagents

16. NeurolepticMalignant Syndrome (NMS)
•It is a life-threatening neurological disorder most often caused by an adverse reaction to neurolepticor antipsychotic drugs. NMS typically consists of muscle rigidity, fever, autonomic instability

17. Precautions
Laboratory Tests:
•Teva-levocarbidopamay cause a false-positive reaction for urinary ketonebodies when a tape test is used for determination of ketonuria
•Cases of falsely diagnosed pheochromocytomain patients with levodopa-carbidopatherapy have been reported very rarely

18. Precautions
Drug Interactions:
Caution should be exercised when the following drugs are administered concomitantly with Teva- levocarbidopa
1.Antihypertensive Drugs
2.Psychoactive Drugs
3.Isoniazid
4.Anestetics
5.Iron Salts
6.Metoclopramide

19. Adverse Reactions
•The most common serious adverse reactions: dyskinesias, including choreiform, dystonicand other involuntary movements, and nausea.
•Other serious adverse reactions are mental changes including paranoid ideation and psychotic episodes, depression with or without development of suicidal tendencies, and dementia

20. Body as a whole
syncope, chest pain, anorexia, asthenia
Cardiovascular
cardiac irregularities and/or palpitation, hypotension, orthostatic
effects including hypotensive episodes, hypertension, phlebitis
Gastrointestinal
vomiting, gastrointestinal bleeding, development of duodenal ulcer, diarrhea, dark saliva, constipation, dyspepsia, dry mouth,
taste alterations
Hematologic
leukopenia, hemolytic and non-hemolytic anemia,
thrombocytopenia, agranulocytosis
Hypersensitivity
angioedema, urticaria, pruritus, Henoch-Schönleinpurpura,bullouslesions (including pemphigus-like reactions).
Musculoskeletal
back pain, shoulder pain, muscle cramps
Nervous System/Psychiatric
neurolepticmalignant syndrome, bradykineticepisodes (the “on-off” phenomenon), dizziness, somnolence, paresthesia, psychotic episodes including delusions, hallucinations and paranoid ideation, dream abnormalities including nightmares, insomnia, headache, depression with or without development of suicidal tendencies, dementia, agitation, confusion, increased libido
Respiratory
dyspnea, upper respiratory infection
Skin
alopecia, rash, increased sweating, dark sweat
Urogenital
dark urine, urinary frequency, urinary tract infection

21. Treatment of Overdosage
•The same as management of acute overdosagewith levodopaalone
•However, Pyridoxine is not effective in reversing the actions of Teva-levocarbidopa
•Immediate gastric lavage
•Intravenous fluids
•ECG monitoring for the possible development of arrhythmias

22. Dosage and Administration
•The optimum daily dosage must be determined by careful titration in each patient.
•Carbidopaand levodopatablets USP are available in a 1:4 ratio of carbidopato levodopa(25 mg/100 mg) and 1:10 ratio (25 mg/250 mg and 10 mg/100 mg).
•Tablets of the two ratios may be given separately or combined as needed to provide the optimum dosage.
•Patients receiving less than this amount of carbidopaare more likely to experience nausea and vomiting.
•Because peripheral dopa-decarboxylaseis saturated by carbidopaat approximately 70 to 100 mg a day.

23. References
•http://webprod5.hc-sc.gc.ca/dpd- bdpp/info.do?code=68470&lang=eng
•http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=a15f5833-42f0-4890-9596- 992eef0846e5

24. Questions?

25. Thank You