Label: CARBIDOPA AND LEVODOPA tablet, extended release

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.

Mechanism of Action
Parkinson’s disease is a progressive, neurodegenerative disorder of the extrapyramidal nervous system affecting the mobility and control of the skeletal muscular system. Its characteristic features include resting tremor, rigidity, and bradykinetic movements. Symptomatic treatments, such as levodopa therapies, may permit the patient better mobility.

Current evidence indicates that symptoms of Parkinson's disease are related to depletion of dopamine in the corpus striatum. Administration of dopamine is ineffective in the treatment of Parkinson’s disease apparently because it does not cross the blood-brain barrier. However, levodopa, the metabolic precursor of dopamine, does cross the blood-brain barrier, and presumably is converted to dopamine in the brain. This is thought to be the mechanism whereby levodopa relieves symptoms of Parkinson’s disease.

Pharmacodynamics
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 of levodopa are required for adequate therapeutic effect, and these may often be accompanied by nausea and other adverse reactions, some of which are attributable to dopamine formed in extracerebral tissues.

Since levodopa competes with certain amino acids for transport across the gut wall, the absorption of levodopa may be impaired in some patients on a high protein diet.

Carbidopa inhibits decarboxylation of peripheral levodopa. It does not cross the blood-brain barrier and does not affect the 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 transport to the brain.

Patients treated with levodopa therapy for Parkinson’s disease may develop motor fluctuations characterized by end-of-dose failure, peak dose dyskinesia, and akinesia. The advanced form of motor fluctuations (‘on-off’ phenomenon) is characterized by unpredictable swings from mobility to immobility. Although the causes of the motor fluctuations are not completely understood, in some patients they may be attenuated by treatment regimens that produce steady plasma levels of levodopa.

Carbidopa and levodopa extended-release tablets contain either 25 mg of carbidopa and 100 mg of levodopa, or 50 mg of carbidopa and 200 mg of levodopa in a extended-release dosage form designed to release these ingredients over a 4- to 6-hour period. With carbidopa and levodopa extended-release tablets there is less variation in plasma levodopa levels than with carbidopa and levodopa tablets, the conventional formulation. However, carbidopa and levodopa extended-release tablets are less systemically bioavailable than carbidopa and levodopa tablets and may require increased daily doses to achieve the same level of symptomatic relief as provided by carbidopa and levodopa tablets.

In clinical trials, patients with moderate to severe motor fluctuations who received carbidopa and levodopa extended-release tablets did not experience quantitatively significant reductions in ‘off’ time when compared to carbidopa and levodopa tablets. However, global ratings of improvement as assessed by both patient and physician were better during therapy with carbidopa and levodopa extended-release tablets than with carbidopa and levodopa tablets. In patients without motor fluctuations, carbidopa and levodopa extended-release tablets, under controlled conditions, provided the same therapeutic benefit with less frequent dosing when compared to carbidopa and levodopa tablets.

Pharmacokinetics
Carbidopa reduces the amount of levodopa required to produce a given response by about 75% and, when administered with levodopa, increases both plasma levels and the plasma half-life of levodopa, and decreases plasma and urinary dopamine and homovanillic acid.

Elimination half-life of levodopa in the presence of carbidopa is about 1.5 hours. Following carbidopa and levodopa extended-release tablets, the apparent half-life of levodopa may be prolonged because of continuous absorption.

In healthy elderly subjects (56 to 67 years old) the mean time-to-peak concentration of levodopa after a single dose of carbidopa and levodopa extended-release tablets 50 mg/200 mg was about 2 hours as compared to 0.5 hours after standard carbidopa and levodopa tablets. The maximum concentration of levodopa after a single dose of carbidopa and levodopa extended-release tablets was about 35% of the standard carbidopa and levodopa tablets (1151 vs. 3256 ng/mL). 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 absolute bioavailability of levodopa from carbidopa and levodopa extended-release tablets (relative to I.V.) in young subjects was shown to be only about 44%. The extent of availability and the peak concentrations of levodopa were comparable in the elderly after a single dose and at steady state after t.i.d. administration of carbidopa and levodopa extended-release tablets 50 mg/200 mg. In elderly subjects, the average trough levels of levodopa at steady state after the CR tablet were about 2 fold higher than after the standard carbidopa and levodopa tablets (163 vs. 74 ng/mL).

In these studies, using similar total daily doses of levodopa, plasma levodopa concentrations with carbidopa and levodopa extended-release tablets fluctuated in a narrower range than with carbidopa and levodopa tablets. Because the bioavailability of levodopa from carbidopa and levodopa extended-release tablets relative to carbidopa and levodopa tablets is approximately 70 to 75%, the daily dosage of levodopa necessary to produce a given clinical response with the sustained-release formulation will usually be higher.

The extent of availability and peak concentrations of levodopa after a single dose of carbidopa and levodopa extended-release tablets 50 mg/200 mg increased by about 50% and 25%, respectively, when administered with food.

At steady state, the bioavailability of carbidopa from carbidopa and levodopa tablet is approximately 99% relative to the concomitant administration of carbidopa and levodopa. At steady state, carbidopa bioavailability from carbidopa and levodopa extended-release tablets 50 mg/200 mg is approximately 58% relative to that from carbidopa and levodopa tablets.

Pyridoxine hydrochloride (vitamin B6), in oral doses of 10 mg to 25 mg, may reverse the effects of levodopa by increasing the rate of aromatic amino acid decarboxylation. Carbidopa inhibits this action of pyridoxine.

Special Populations
Geriatric: A study in eight young healthy subjects (21 to 22 yr) and eight elderly healthy subjects (69 to 76 yr) showed that the absolute bioavailability of levodopa was similar between young and elderly subjects following oral administration of levodopa and carbidopa. However, the systemic exposure (AUC) of levodopa was increased by 55% in elderly subjects compared to young subjects. Based on another study in forty patients with Parkinson’s disease, there was a correlation between age of patients and the increase of AUC of levodopa following administration of levodopa and an inhibitor of peripheral dopa decarboxylase. AUC of levodopa was increased by 28% in elderly patients (≥ 65 yr) compared to young patients (< 65 yr). Additionally, mean value of Cmax for levodopa was increased by 24% in elderly patients (≥ 65 yr) compared to young patients (< 65 yr) (see PRECAUTIONS, Geriatric Use).

The AUC of carbidopa was increased in elderly subjects (n=10, 65 to 76 yr) by 29% compared to young subjects (n=24, 23 to 64 yr) following IV administration of 50 mg levodopa with carbidopa (50 mg). This increase is not considered a clinically significant impact.

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.

Nonselective monoamine oxidase (MAO) inhibitors are contraindicated for use with carbidopa and levodopa extended-release tablets. These  inhibitors  must  be  discontinued  at  least  two  weeks  prior  to  initiating  therapy  with  carbidopa and levodopa extended-release tablets. Carbidopa and levodopa extended-release tablets may  be  administered  concomitantly  with  the  manufacturer’s  recommended  dose  of  an  MAO  inhibitor  with  selectivity  for  MAO   type  B  (e.g.,  selegiline  HCl)  (see  PRECAUTIONS,  Drug  Interactions).

Carbidopa and levodopa extended-release tablets are contraindicated in patients with known hypersensitivity to any component of this  drug, and  in  patients  with  narrow-angle  glaucoma.

When  patients  are  receiving  levodopa  without  a  decarboxylase  inhibitor,  levodopa  must  be discontinued  at  least  twelve  hours  before  carbidopa and levodopa extended-release tablets are started.  In  order  to  reduce  adverse  reactions,  it  is  necessary  to  individualize  therapy.  See DOSAGE   AND  ADMINISTRATION  section before initiating  therapy. 

Carbidopa and levodopa extended-release tablets should  be  substituted  at  a  dosage  that  will  provide  approximately  25%  of  the  previous  levodopa dosage (see DOSAGE AND  ADMINISTRATION).

Carbidopa does not decrease adverse reactions due to central effects of levodopa. By permitting  more levodopa  to  reach  the  brain,  particularly  when  nausea  and  vomiting  is  not  a  dose-limiting  factor,  certain adverse central nervous system (CNS) effects, e.g., dyskinesias, will occur at lower dosages and  sooner  during  therapy  with  carbidopa and levodopa extended-release tablets than  with  levodopa  alone.

Patients receiving carbidopa and levodopa extended-release tablets may develop increased dyskinesias compared to  carbidopa and levodopa tablets. Dyskinesias  are  a  common  side  effect  of  carbidopa  levodopa  treatment.  The  occurrence  of  dyskinesias  may require dosage  reduction.

All patients should be observed carefully for the development of depression with concomitant  suicidal  tendencies.

Carbidopa and levodopa extended-release tablets should be administered cautiously to patients with severe cardiovascular or  pulmonary disease,  bronchial  asthma,  renal,  hepatic  or  endocrine  disease.

As with levodopa, care should be exercised in administering carbidopa and levodopa extended-release tablets to patients with a history  of  myocardial infarction who have residual atrial, nodal, or ventricular arrhythmias. In such patients,  cardiac  function  should  be  monitored  with  particular  care  during  the  period  of  initial  dosage  adjustment,  in  a  facility with provisions for intensive cardiac  care.

As  with  levodopa,  treatment  with  carbidopa and levodopa extended-release tablets may  increase  the  possibility  of  upper  gastrointestinal  hemorrhage  in  patients  with  a  history  of  peptic  ulcer.
Falling  Asleep  During  Activities  of  Daily  Living  and  Somnolence 

Patients  taking  carbidopa and levodopa extended-release tablets alone  or  with  other  dopaminergic  drugs  have  reported  suddenly  falling  asleep without prior warning of sleepiness while engaged in activities of daily living (includes operation  of  motor  vehicles).  Road  traffic  accidents  attributed  to  sudden  sleep  onset  have  been  reported.  Although  many patients reported somnolence while on dopaminergic medications, there have been reports of  road  traffic  accidents  attributed  to  sudden  onset  of  sleep  in  which  the  patient  did  not  perceive  any  warning  signs,  such  as  excessive  drowsiness,  and  believed  that  they  were  alert  immediately  prior  to  the  event. Sudden  onset  of  sleep  has  been  reported  to  occur  as  long  as  one   year  after  the  initiation  of  treatment.

Falling  asleep  while  engaged  in  activities  of  daily  living  usually  occurs  in  patients  experiencing  pre­ existing  somnolence,  although  some  patients  may  not  give  such  a  history.  For  this  reason,  prescribers should  reassess  patients  for  drowsiness  or  sleepiness  especially  since  some  of  the  events  occur  well  after  the start of treatment. Prescribers should be aware that patients may not acknowledge drowsiness  or  sleepiness  until  directly  questioned  about  drowsiness  or  sleepiness  during  specific  activities.  Patients should  be  advised  to  exercise  caution  while  driving  or  operating  machines  during  treatment  with  carbidopa and levodopa extended-release tablets. Patients who have already experienced somnolence or an episode of sudden sleep onset should  not  participate  in  these  activities  during  treatment  with  carbidopa and levodopa extended-release tablets.

Before initiating treatment with carbidopa and levodopa extended-release tablets, advise patients about the potential to  develop  drowsiness  and  ask  specifically  about  factors  that  may  increase  the  risk  for  somnolence  with  carbidopa and levodopa extended-release tablets such as the use of concomitant sedating medications and the presence of sleep disorders.  Consider  discontinuing  carbidopa and levodopa extended-release tablets  in  patients  who  report  significant  daytime  sleepiness  or  episodes  of  falling  asleep during activities that require active participation (e.g., conversations, eating, etc.). If treatment  with carbidopa and levodopa extended-release tablets continues, patients should be advised not to drive and to avoid other potentially  dangerous  activities  that  might  result  in  harm  if  the  patients  become  somnolent.  There  is  insufficient  information  to establish  that  dose  reduction  will  eliminate  episodes  of  falling  asleep  while  engaged  in  activities  of  daily  living.

Hyperpyrexia and  Confusion

Sporadic cases of a symptom complex resembling neuroleptic malignant syndrome (NMS) have  been  reported  in  association  with  dose  reductions  or  withdrawal  of  certain  antiparkinsonian  agents  such  as  levodopa, carbidopa levodopa and carbidopa levodopa extended release. Therefore, patients should  be  observed  carefully  when  the  dosage  of  levodopa  is  reduced  abruptly  or  discontinued,  especially  if  the  patient is receiving  neuroleptics.

NMS is an uncommon but life-threatening syndrome characterized by fever or  hyperthermia.  Neurological  findings,  including  muscle  rigidity,  involuntary  movements,  altered  consciousness,  mental  status  changes;  other  disturbances,  such  as  autonomic  dysfunction,  tachycardia,  tachypnea,  sweating,  hyper- or hypotension; laboratory findings, such as creatine phosphokinase elevation,  leukocytosis, myoglobinuria,  and  increased  serum  myoglobin  have  been  reported.

The  early  diagnosis  of  this  condition  is  important  for  the  appropriate  management  of  these  patients. Considering NMS as a possible diagnosis and ruling out other acute illnesses (e.g., pneumonia,  systemic infection,  etc.)  is  essential.  This  may  be  especially  complex  if  the  clinical  presentation  includes  both serious medical illness and untreated or inadequately treated extrapyramidal signs and symptoms  (EPS). Other  important  considerations  in  the  differential  diagnosis  include  central  anticholinergic  toxicity,  heat  stroke,  drug  fever,  and  primary  central  nervous  system  (CNS)  pathology.

The management of NMS should include: 1) intensive symptomatic treatment and medical  monitoring  and 2) treatment of any concomitant serious medical problems for which specific treatments are  available.  Dopamine agonists, such as bromocriptine, and muscle relaxants, such as dantrolene, are often used  in the  treatment  of  NMS;  however,  their  effectiveness  has  not  been  demonstrated  in  controlled  studies.

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.

Table 1: Clinical Adverse Experiences Occurring in 1% or Greater of  Patients 

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:

Body as a  Whole 

Asthenia,  fatigue,  abdominal  pain,  orthostatic  effects.

Cardiovascular 

Palpitation,  hypertension,  hypotension,  myocardial  infarction.

Gastrointestinal 

Gastrointestinal  pain,  dysphagia,  heartburn.

Metabolic 

Weight  loss.

Musculoskeletal 

Leg  pain.

Nervous  System/Psychiatric 

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

Respiratory 

Cough, pharyngeal pain, common  cold.

Skin 

Rash.

Special  Senses 

Blurred  vision.

Urogenital 

Urinary  incontinence.

Laboratory  Tests 

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:

Cardiovascular 

Cardiac irregularities,  syncope.

Gastrointestinal 

Taste alterations, dark  saliva.

Hypersensitivity 

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

Nervous  System/Psychiatric 

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

Skin 

Alopecia, flushing, dark  sweat.

Urogenital 

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:

Cardiovascular 

Phlebitis.

Gastrointestinal 

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

Hematologic 

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

Hypersensitivity 

Henoch-Schönlein  purpura.

Metabolic 

Weight gain,  edema.

Nervous  System/Psychiatric 

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.

Skin 

Malignant  melanoma  (see  also  CONTRAINDICATIONS),  increased  sweating.

Special  Senses 

Oculogyric crises, mydriasis,  diplopia.

Urogenital 

Urinary retention,  priapism.

Miscellaneous 

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

Laboratory  Tests 

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

Management of acute overdosage with carbidopa and levodopa extended-release tablet is the same as with levodopa. Pyridoxine is  not  effective in reversing the actions of carbidopa and levodopa extended-release tablets.

General supportive measures should be employed, along with immediate gastric lavage.  Intravenous  fluids should be administered judiciously and an adequate airway maintained.  Electrocardiographic monitoring  should  be  instituted  and  the  patient  carefully  observed  for  the  development  of  arrhythmias;  if required,  appropriate  antiarrhythmic  therapy  should  be  given.  The  possibility  that  the  patient  may  have taken  other  drugs  as  well  as  carbidopa and levodopa extended-release tablets  should  be  taken  into  consideration.  To  date,  no  experience has  been  reported  with  dialysis;  hence,  its  value  in  overdosage  is  not  known.

Based  on  studies  in  which  high  doses  of  levodopa  and/or  carbidopa  were  administered,  a  significant  proportion  of  rats  and  mice  given  single  oral  doses  of  levodopa  of  approximately  1500 to 2000  mg/kg  are expected  to  die.  A  significant  proportion  of  infant  rats  of  both  sexes  are  expected  to  die  at  a  dose  of  800  mg/kg.  A  significant  proportion  of  rats  are  expected  to  die  after  treatment  with  similar  doses  of  carbidopa. The addition of carbidopa in a 1:10 ratio with levodopa increases the dose at which  a significant  proportion  of  mice  are  expected  to  die  to  3360  mg/kg.

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).
 Initial  Dosage 

Patients currently treated with conventional carbidopa levodopa preparations: Studies show  that  peripheral  dopa-decarboxylase  is  saturated  by  the  bioavailable  carbidopa  at  doses  of  70  mg  a  day  and  greater.  Because  the  bioavailabilities  of  carbidopa  and  levodopa  in  carbidopa and levodopa tablets and  carbidopa and levodopa extended-release tablets are different,  appropriate  adjustments  should  be  made,  as  shown  in  Table  2. 

Table 2: Approximate Bioavailabilities at Steady  State*

*  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, Titration  with carbidopa and levodopa extended-release tablets). The interval between doses of carbidopa and levodopa extended-release tablets should be 4 to 8 hours during the waking   day. (See  CLINICAL  PHARMACOLOGY,  Pharmacodynamics.)

A  guideline  for  initiation  of  carbidopa and levodopa extended-release tablet is  shown  in  Table  3.
Table 3: Guidelines for Initial Conversion from Carbidopa and Levodopa Tablets to Carbidopa and Levodopa Extended-Release Tablets 

* For dosing ranges not shown in the table see DOSAGE AND ADMINISTRATION, Initial Dosage — Patients currently treated  with conventional carbidopa levodopa  preparations.

Patients currently treated with levodopa without a decarboxylase inhibitor: Levodopa must  be  discontinued at least twelve hours before therapy with carbidopa and levodopa extended-release tablet is started. Carbidopa and levodopa extended-release tablets should  be  substituted at a dosage that will provide approximately 25% of the previous levodopa dosage. In  patients with  mild  to  moderate  disease,  the  initial  dose  is  usually  1  tablet  of  carbidopa and levodopa extended-release tablet 50 mg/200 mg  b.i.d.

Patients  not  receiving  levodopa:  In  patients  with  mild  to  moderate  disease,  the  initial  recommended  dose is 1 tablet of carbidopa and levodopa extended-release tablet 50 mg/200 mg b.i.d. Initial dosage should not be given at intervals of less than  6 hours.

 Titration with Carbidopa and Levodopa Extended-Release Tablets 

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.

 Maintenance 

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.

 Addition of Other Antiparkinson  Medications 

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. 
Interruption of  Therapy 

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.

Carbidopa and levodopa extended-release tablets USP, 25 mg/100 mg containing 25  mg of  carbidopa  and  100  mg  of  levodopa,  are  dappled-purple  in  color,  oval shaped mottled tablets  debossed with “L519”  on  one  side  and  plain  on  other side.  They  are  supplied  as  follows:

NDC 46708-332-30                Bottle of 30 tablets

NDC 46708-332-31                Bottle of 100 tablets

NDC 46708-332-91                Bottle of  1000 tablets

Carbidopa and levodopa extended-release tablets USP, 50 mg/200 mg containing 50  mg of  carbidopa  and  200  mg  of  levodopa,  are  dappled-purple  in  color,  oval shaped mottled tablets debossed with “L520”  on  one  side  and  plain  on  other side.  They  are  supplied  as  follows:

NDC 46708-333-30                Bottle of 30 tablets

NDC 46708-333-31                Bottle of 100 tablets

NDC 46708-333-91                Bottle of  1000 tablets

 
Storage and  Handling 

Store at 25°C (77°F), excursions permitted to 15° to 30°C (59° to 86°F) [see USP Controlled  Room  Temperature].  Store  in  a  tightly  closed  container,  protected  from  light  and  moisture.

Dispense  in  a  tightly  closed,  light-resistant  container.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

Manufactured by:

Alembic Pharmaceuticals Limited
(Formulation Division),
Village Panelav, P. O. Tajpura,
Near Baska, Taluka-Halol,
Panchmahal, Gujarat, India. 

Revised:  01/2018

NDC 46708-332-30
Carbidopa and Levodopa
Extended-Release
Tablets, USP
25 mg /100 mg
Rx only
30 Tablets
Alembic

NDC 46708-333-30
Carbidopa and Levodopa
Extended-Release
Tablets, USP
50 mg /200 mg
Rx only
30 Tablets
Alembic