Carbidopa And Levodopa

Carbidopa and levodopa extended-release tablets, USP are indicated  in  the  treatment  of  Parkinson’s  disease,  post-encephalitic  parkinsonism,  and  symptomatic  parkinsonism  that  may  follow  carbon  monoxide  intoxication  or  manganese  intoxication.

Carbidopa and levodopa extended-release tablet contains carbidopa and levodopa in a 1:4 ratio as either the 25 mg/100 mg  tablet or the 50 mg/200 mg tablet.  The  daily  dosage  of carbidopa and levodopa extended-release tablets must  be  determined  by  careful  titration.  Patients  should  be  monitored closely during the dose adjustment period, particularly with regard to appearance or  worsening  of  involuntary  movements,  dyskinesias  or  nausea.  Carbidopa and levodopa extended-release tablets should  not  be  chewed  or  crushed.

Standard  drugs  for  Parkinson’s  disease,  other  than  levodopa  without  a  decarboxylase  inhibitor,  may  be  used  concomitantly  while  carbidopa and levodopa extended-release tablet is  being  administered,  although  their  dosage  may  have  to  be  adjusted.

Since carbidopa prevents the reversal of levodopa effects caused by pyridoxine, carbidopa and levodopa extended-release tablets can  be  given  to  patients  receiving  supplemental  pyridoxine  (vitamin  B₆).

^*  This  table  is  only  a  guide  to  bioavailabilities  since  other  factors  such  as  food,  drugs,  and  inter-patient  variabilities  may  affect  the  bioavailability of carbidopa and  levodopa. 

^†  The  extent  of  availability  of  levodopa  from  carbidopa and levodopa extended-release tablets was  about  70 to 75%  relative  to  intravenous  levodopa  or  standard carbidopa and levodopa tablets in the  elderly.

^‡ The extent of availability of levodopa from carbidopa and levodopa tablets was 99% relative to intravenous levodopa in the healthy  elderly.

Dosage with carbidopa and levodopa extended-release tablets should be substituted at an amount that provides approximately 10%  more levodopa  per   day,  although  this  may  need  to  be  increased  to  a  dosage  that  provides  up  to  30%  more levodopa per day depending on clinical response (see DOSAGE AND ADMINISTRATION,

A  guideline  for  

* For dosing ranges not shown in the table see DOSAGE AND ADMINISTRATION,

Following initiation of therapy, doses and dosing intervals may be increased or decreased  depending  upon therapeutic response. Most patients have been adequately treated with doses of carbidopa and levodopa extended-release tablets that  provide 400 to 1600 mg of levodopa per day, administered as divided doses at intervals ranging from 4  to 8 hours during the waking day. Higher doses of carbidopa and levodopa extended-release tablets (2400 mg or more of levodopa per day)  and  shorter  intervals  (less  than  4  hours)  have  been  used,  but  are  not  usually  recommended.

When  doses  of  carbidopa and levodopa extended-release tablets  are  given  at  intervals  of  less  than  4  hours,  and/or  if  the  divided  doses  are  not  equal,  it  is  recommended  that  the  smaller  doses  be  given  at  the  end  of  the   day.

An  interval  of  at  least  3   days  between  dosage  adjustments  is  recommended.

Because  Parkinson’s  disease  is  progressive,  periodic  clinical evaluations  are  recommended;  adjustment  of  the  dosage  regimen  of  carbidopa and levodopa extended-release tablets may  be  required.

Anticholinergic agents, dopamine agonists, and amantadine can be given with carbidopa and levodopa extended-release tablets.  Dosage  adjustment  of  carbidopa and levodopa extended-release tablets may  be  necessary  when  these  agents  are  added.

A dose of carbidopa levodopa immediate release 25 mg/100 mg or 10 mg/100 mg (one half or a whole tablet) can  be  added  to  the  dosage  regimen  of  carbidopa and levodopa extended-release tablets  in  selected  patients  with  advanced  disease  who  need  additional  immediate-release  levodopa  for  a  brief  time  during  daytime  hours. 

Sporadic cases of hyperpyrexia and confusion have been associated with dose reductions  and  withdrawal of carbidopa and levodopa tablets or carbidopa and levodopa extended-release tablets. 

Patients should be observed carefully if abrupt reduction or discontinuation of carbidopa and levodopa extended-release tablet is  required,  especially  if  the  patient  is  receiving  neuroleptics.  (See  WARNINGS.) 

If  general  anesthesia  is  required,  carbidopa and levodopa extended-release tablets may  be  continued  as  long  as  the  patient  is  permitted  to take  oral  medication.  If  therapy  is  interrupted  temporarily,  the  patient  should  be  observed  for  symptoms resembling NMS, and the usual dosage should be administered as soon as the patient is able to take  oral  medication.

In controlled clinical trials, patients predominantly with moderate to severe motor fluctuations while  on  carbidopa and levodopa tablets were  randomized  to  therapy  with  either  carbidopa and levodopa tablets or  carbidopa and levodopa extended-release tablets.  The  adverse  experience frequency  profile  of  carbidopa and levodopa extended-release tablets did  not  differ  substantially  from  that  of  carbidopa and levodopa,  as  shown  in  Table  1.

Abnormal laboratory findings occurring at a frequency of 1% or greater in approximately 443  patients who  received  carbidopa and levodopa extended-release tablets  and  475  who  received  carbidopa and levodopa tablets during  controlled  clinical  trials  included:  decreased hemoglobin and hematocrit; elevated serum glucose; white blood cells, bacteria and blood  in the  urine.

The  adverse  experiences  observed  in  patients  in  uncontrolled  studies  were  similar  to  those  seen  in controlled clinical  studies.

Other adverse experiences reported overall in clinical trials in 748 patients treated with carbidopa and levodopa extended-release tablets, listed  by  body  system  in  order  of  decreasing  frequency,  include:

Asthenia,  fatigue,  abdominal  pain,  orthostatic  effects.

Palpitation,  hypertension,  hypotension,  myocardial  infarction.

Gastrointestinal  pain,  dysphagia,  heartburn.

Weight  loss.

Leg  pain.

Chorea, somnolence, falling, anxiety, disorientation, decreased mental acuity, gait  abnormalities, extrapyramidal  disorder,  agitation,  nervousness,  sleep  disorders,  memory  impairment.

Cough, pharyngeal pain, common  cold.

Rash.

Blurred  vision.

Urinary  incontinence.

Decreased white blood cell count and serum potassium; increased BUN, serum creatinine and  serum  LDH; protein and glucose in the  urine.

The  following  adverse  experiences  have  been  reported  in  postmarketing  experience  with  carbidopa and levodopa extended-release tablets:

Cardiac irregularities,  syncope.

Taste alterations, dark  saliva.

Angioedema,  urticaria,  pruritus,  bullous  lesions  (including  pemphigus-like  reactions).

Increased tremor, peripheral neuropathy, psychotic episodes including delusions and  paranoid ideation,  pathological  gambling,  increased  libido  including  hypersexuality,  impulse  control  symptoms.

Alopecia, flushing, dark  sweat.

Dark  urine.

Other  adverse  reactions  that  have  been  reported  with  levodopa  alone  and  with  various  carbidopa  levodopa  formulations  and  may  occur  with  carbidopa and levodopa extended-release tablets are:

Phlebitis.

Gastrointestinal  bleeding,  development  of  duodenal  ulcer,  sialorrhea,  bruxism,  hiccups,  flatulence,  burning sensation of  tongue.

Hemolytic  and  non-hemolytic  anemia,  thrombocytopenia,  leukopenia,  agranulocytosis.

Henoch-Schönlein  purpura.

Weight gain,  edema.

Ataxia, depression with suicidal tendencies, dementia, euphoria, convulsions (however, a  causal  relationship has not been established); bradykinetic  episodes,  numbness,  muscle  twitching,  blepharospasm (which may be taken as an early sign of excess dosage; consideration of  dosage  reduction  may  be  made  at  this  time),  trismus,  activation  of  latent  Horner’s  syndrome,  nightmares.

Malignant  melanoma  (see  also  CONTRAINDICATIONS),  increased  sweating.

Oculogyric crises, mydriasis,  diplopia.

Urinary retention,  priapism.

Faintness,  hoarseness,  malaise,  hot  flashes,  sense  of  stimulation,  bizarre  breathing  patterns.

Abnormalities  in  alkaline  phosphatase,  SGOT  (AST),  SGPT  (ALT),  bilirubin,  Coombs  test,  uric  acid.

Symptomatic  postural  hypotension  has  occurred  when  carbidopa  levodopa  preparations  were  added  to the  treatment  of  patients  receiving  some  antihypertensive  drugs.  Therefore,  when  therapy  with carbidopa and levodopa extended-release tablet is  started,  dosage  adjustment  of  the  antihypertensive  drug  may  be  required.

For  patients  receiving  MAO  inhibitors  (Type  A  or  B),  see  CONTRAINDICATIONS.  Concomitant  therapy  with selegiline and carbidopa levodopa may be associated with severe orthostatic hypotension  not  attributable  to  carbidopa  levodopa  alone  (see  CONTRAINDICATIONS).

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

Dopamine D₂ receptor antagonists (e.g., phenothiazines, butyrophenones, risperidone) and  isoniazid may reduce the therapeutic effects of levodopa. In addition, the beneficial effects of levodopa  in Parkinson’s  disease  have  been  reported  to  be  reversed  by  phenytoin  and  papaverine.  Patients  taking  these  drugs  with  carbidopa and levodopa extended-release tablets should  be  carefully  observed  for  loss  of  therapeutic  response.

Use  of  carbidopa and levodopa extended-release tablets with  dopamine-depleting  agents  (e.g.,  reserpine  and  tetrabenazine)  or  other  drugs  known  to  deplete  monoamine  stores  is  not  recommended.

Carbidopa and levodopa extended-release tablets and  iron  salts  or  multivitamins  containing  iron  salts  should  be  coadministered  with caution. Iron salts can form chelates with levodopa and carbidopa and consequently reduce  the  bioavailability  of  carbidopa  and  levodopa.

Although metoclopramide may increase the bioavailability of levodopa by increasing gastric  emptying,  metoclopramide may also adversely affect disease control by its dopamine receptor  antagonistic properties.

Carbidopa and levodopa extended-release tablets, USP are an extended-release  combination  of  carbidopa  and  levodopa  for  the treatment of Parkinson’s disease and  syndrome. 

Carbidopa, USP , an  inhibitor  of  aromatic  amino  acid  decarboxylation,  is  a  white to creamy white,  odorless or practically odorless powder,  freely soluble in 3N hydrochloric acid, slightly soluble in water and in methanol, practically insoluble in alcohol, in acetone, in chloroform and in ether, with a molecular weight of 244.24. It is designated chemically as  (-)-L-α­hydrazino-α-methyl-β-(3,4-dihydroxybenzene)  propanoic  acid  monohydrate. Its empirical formula  is C₁₀H₁₄N₂O₄•H₂O, and its structural formula  is:

 

Tablet  content  is  expressed  in  terms  of  anhydrous  carbidopa,  which  has  a  molecular  weight  of  226.24.

Levodopa, USP, an  aromatic  amino  acid,  is  a  white to off-white, odorless , crystalline  powder,  slightly  soluble  in  water, freely soluble in 3N hydrochloric acid and insoluble in alcohol  with  a molecular weight of 197.19. It is designated chemically as  (-)-L-α-amino-β-(3,4-dihydroxybenzene)  propanoic  acid.  Its  empirical  formula  is  C₉H₁₁NO₄,  and  its  structural  formula  is:

Carbidopa and levodopa extended-release tablets, USP are supplied as extended-release tablets containing either 25 mg of carbidopa and 100 mg of levodopa, or 50 mg of carbidopa  and  200 mg of levodopa. Inactive ingredients  are hydroxypropyl  cellulose,  magnesium  stearate, and hypromellose. Carbidopa and levodopa extended-release tablets USP, 25 mg/100 mg and carbidopa and levodopa extended-release tablets USP, 50 mg/200 mg also contain FD&C  Blue  #2 Aluminium Lake  and  FD&C  Red  #40 Aluminium Lake. 

The  25 mg/100 mg  tablet  is  supplied  as  an  oval shaped  mottled  tablet  that  is  dappled-purple  in  color  and  is debossed with  “L519”  on  one  side  and  plain  on  the  other.  The  50 mg/200 mg  tablet  is  supplied  as  an  oval shaped  mottled  tablet  that  is  dappled-purple  in  color  and  is debossed with  “L520”  on  one  side  and  plain  on  the  other.  Carbidopa and levodopa extended-release tablets, USP are polymeric-based drug delivery system that controls the release of carbidopa and  levodopa  as  it  slowly  erodes.  Carbidopa and levodopa extended-release tablet 25 mg/100 mg  is  available  to  facilitate  titration  when  100  mg  steps  are  required.

FDA approved dissolution specifications differs from the USP dissolution specifications.