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Summary of Product Monograph - Teva-levocarbidopa

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

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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
Pharmaceutical Information Therapeutic Classification:Anti-Parkinson Agent A combination of carbidopaand levodopafor the treatment of Parkinsons disease and syndrome.
Levodopa Chemical Name:(-)-3-{3,4-Dihydroxyphenyl)-L- alanine Structural Formula: Molecular Formula: C9H11NO4 Molecular Weight: 197.19
Carbidopa Chemical Name: (-)-L-留-Hydrazino-3,4-dihydroxy-留- methylhydrocinnamicacid monohydrate Structural Formula: Molecular Formula:C10H14N2O4H2O Molecular Weight:244.25
Clinical Pharmacology Mechanism of Action Parkinsons 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
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
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
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
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)
Indications and Clinical Use Teva-levocarbidopais indicated for the treatment of Parkinsons 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.
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)
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
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
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
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
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
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
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
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
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-Sch旦nleinpurpura,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
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
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.
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
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Summary of Product Monograph - Teva-levocarbidopa

  • 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 Parkinsons 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-留-Hydrazino-3,4-dihydroxy-留- methylhydrocinnamicacid monohydrate Structural Formula: Molecular Formula:C10H14N2O4H2O Molecular Weight:244.25
  • 5. Clinical Pharmacology Mechanism of Action Parkinsons 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 Parkinsons 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-Sch旦nleinpurpura,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