NDC 46708-332 Carbidopa And Levodopa

Carbidopa And Levodopa

NDC Product Code 46708-332

NDC Code: 46708-332

Proprietary Name: Carbidopa And Levodopa What is the Proprietary Name?
The proprietary name also known as the trade name is the name of the product chosen by the medication labeler for marketing purposes.

Non-Proprietary Name: Carbidopa And Levodopa What is the Non-Proprietary Name?
The non-proprietary name is sometimes called the generic name. The generic name usually includes the active ingredient(s) of the product.

Product Characteristics

Color(s):
PURPLE (C48327 - DAPPLED-PURPLE)
Shape: OVAL (C48345)
Size(s):
10 MM
Imprint(s):
L519
Score: 1

NDC Code Structure

NDC 46708-332-30

Package Description: 30 TABLET, EXTENDED RELEASE in 1 BOTTLE

NDC 46708-332-31

Package Description: 100 TABLET, EXTENDED RELEASE in 1 BOTTLE

NDC 46708-332-91

Package Description: 1000 TABLET, EXTENDED RELEASE in 1 BOTTLE

NDC Product Information

Carbidopa And Levodopa with NDC 46708-332 is a a human prescription drug product labeled by Alembic Pharmaceuticals Limited. The generic name of Carbidopa And Levodopa is carbidopa and levodopa. The product's dosage form is tablet, extended release and is administered via oral form.

Labeler Name: Alembic Pharmaceuticals Limited

Dosage Form: Tablet, Extended Release - A solid dosage form containing a drug which allows at least a reduction in dosing frequency as compared to that drug presented in conventional dosage form.

Product Type: Human Prescription Drug What kind of product is this?
Indicates the type of product, such as Human Prescription Drug or Human Over the Counter Drug. This data element matches the “Document Type” field of the Structured Product Listing.

Carbidopa And Levodopa Active Ingredient(s)

What is the Active Ingredient(s) List?
This is the active ingredient list. Each ingredient name is the preferred term of the UNII code submitted.

  • CARBIDOPA 25 mg/1
  • LEVODOPA 100 mg/1

Inactive Ingredient(s)

About the Inactive Ingredient(s)
The inactive ingredients are all the component of a medicinal product OTHER than the active ingredient(s). The acronym "UNII" stands for “Unique Ingredient Identifier” and is used to identify each inactive ingredient present in a product.

  • HYDROXYPROPYL CELLULOSE (1600000 WAMW) (UNII: RFW2ET671P)
  • MAGNESIUM STEARATE (UNII: 70097M6I30)
  • HYPROMELLOSE, UNSPECIFIED (UNII: 3NXW29V3WO)
  • FD&C BLUE NO. 2 (UNII: L06K8R7DQK)
  • FD&C RED NO. 40 (UNII: WZB9127XOA)

Administration Route(s)

What are the Administration Route(s)?
The translation of the route code submitted by the firm, indicating route of administration.

  • Oral - Administration to or by way of the mouth.

Pharmacological Class(es)

What is a Pharmacological Class?
These are the reported pharmacological class categories corresponding to the SubstanceNames listed above.

  • Aromatic Amino Acid - [EPC] (Established Pharmacologic Class)
  • Amino Acids -
  • Aromatic - [CS]

Product Labeler Information

What is the Labeler Name?
Name of Company corresponding to the labeler code segment of the Product NDC.

Labeler Name: Alembic Pharmaceuticals Limited
Labeler Code: 46708
FDA Application Number: ANDA210341 What is the FDA Application Number?
This corresponds to the NDA, ANDA, or BLA number reported by the labeler for products which have the corresponding Marketing Category designated. If the designated Marketing Category is OTC Monograph Final or OTC Monograph Not Final, then the Application number will be the CFR citation corresponding to the appropriate Monograph (e.g. “part 341”). For unapproved drugs, this field will be null.

Marketing Category: ANDA - A product marketed under an approved Abbreviated New Drug Application. What is the Marketing Category?
Product types are broken down into several potential Marketing Categories, such as NDA/ANDA/BLA, OTC Monograph, or Unapproved Drug. One and only one Marketing Category may be chosen for a product, not all marketing categories are available to all product types. Currently, only final marketed product categories are included. The complete list of codes and translations can be found at www.fda.gov/edrls under Structured Product Labeling Resources.

Start Marketing Date: 06-06-2019 What is the Start Marketing Date?
This is the date that the labeler indicates was the start of its marketing of the drug product.

Listing Expiration Date: 12-31-2020 What is the Listing Expiration Date?
This is the date when the listing record will expire if not updated or certified by the product labeler.

Exclude Flag: N What is the NDC Exclude Flag?
This field indicates whether the product has been removed/excluded from the NDC Directory for failure to respond to FDA’s requests for correction to deficient or non-compliant submissions. Values = ‘Y’ or ‘N’.

* Please review the disclaimer below.

Carbidopa And Levodopa Product Labeling Information

The product labeling information includes all published material associated to a drug. Product labeling documents include information like generic names, active ingredients, ingredient strength dosage, routes of administration, appearance, usage, warnings, inactive ingredients, etc.

Product Labeling Index

Description

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.

Clinical Pharmacology

Mechanism of ActionParkinson’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.PharmacodynamicsWhen 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.PharmacokineticsCarbidopa 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 PopulationsGeriatric: 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.

Indications  And  Usage

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.

Contraindications

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.

Warnings

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  ConfusionSporadic 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.

General

As  with  levodopa,  periodic  evaluations  of  hepatic,  hematopoietic,  cardiovascular,  and  renal  function  are recommended during extended  therapy.Patients with chronic wide-angle glaucoma may be treated cautiously with carbidopa and levodopa extended-release tablets provided  the  intraocular  pressure  is  well-controlled  and  the  patient  is  monitored  carefully  for  changes  in  intraocular  pressure during  therapy. Dyskinesia Levodopa alone, as well as carbidopa and levodopa extended-release tablets, is associated with dyskinesias. The occurrence  of  dyskinesias  may  require  dosage  reduction. Hallucinations / Psychotic-Like  Behavior Hallucinations  and  psychotic-like  behavior  have  been  reported  with  dopaminergic  medications.  In general, hallucinations present shortly after the initiation of therapy and may be responsive to  dose reduction  in  levodopa.  Hallucinations  may  be  accompanied  by  confusion  and  to  a  lesser  extent  sleep  disorder (insomnia) and excessive  dreaming.Carbidopa and levodopa extended-release tablets may have similar effects on thinking and behavior. This abnormal thinking and  behavior  may  present  with  one  or  more  symptoms,  including  paranoid  ideation,  delusions,  hallucinations,  confusion,  psychotic-like  behavior,  disorientation,  aggressive  behavior,  agitation,  and  delirium.Ordinarily, patients with a major psychotic disorder should not be treated with carbidopa and levodopa extended-release tablets,  because of  the  risk  of  exacerbating  psychosis.  In  addition,  certain  medications  used  to  treat  psychosis  may  exacerbate  the  symptoms  of  Parkinson’s  disease  and  may  decrease  the  effectiveness  of  carbidopa and levodopa extended-release tablets. Impulse Control / Compulsive  Behaviors Reports of patients taking dopaminergic medications (medications that increase central  dopaminergic tone), suggest that patients may experience an intense urge to gamble, increased sexual urges,  intense urges  to  spend  money,  binge  eating,  and/or  other  intense  urges,  and  the  inability  to  control  these  urges.  In some cases, although not all, these urges were reported to have stopped when the dose was reduced  or  the medication was discontinued. Because patients may not recognize these behaviors as abnormal, it is important  for  prescribers  to  specifically  ask  patients  or  the  caregivers  about  the  development  of  new  or  increased  gambling  urges,  sexual  urges,  uncontrolled  spending  or  other  urges  while  being  treated  with carbidopa and levodopa extended-release tablets. Physicians should consider dose reduction or stopping the medication if a patient  develops  such  urges  while  taking  carbidopa and levodopa extended-release tablets [see  Information  for  Patients]. Melanoma Epidemiological  studies  have  shown  that  patients  with  Parkinson’s  disease  have  a  higher  risk  (2-  to approximately 6-fold higher) of developing melanoma than the general population. Whether the  increased  risk  observed  was  due  to  Parkinson’s  disease  or  other  factors,  such  as  drugs  used  to  treat  Parkinson’s disease, is  unclear.For the reasons stated above, patients and providers are advised to monitor for melanomas  frequently and  on  a  regular  basis  when  using  carbidopa and levodopa extended-release tablets for  any  indication.  Ideally,  periodic  skin  examinations  should  be  performed  by  appropriately  qualified  individuals  (e.g.,  dermatologists).

Information For Patients

The  patient  should  be  informed  that  carbidopa and levodopa extended-release tablet is  an  extended-release  formulation  of  carbidopa and levodopa which releases these ingredients over a 4- to 6-hour period. It is important that carbidopa and levodopa extended-release tablets be  taken  at  regular  intervals  according  to  the  schedule  outlined  by  the  physician.  The  patient  should  be  cautioned  not  to  change  the  prescribed  dosage  regimen  and  not  to  add  any  additional  antiparkinson  medications,  including  other  carbidopa and levodopa  preparations,  without  first  consulting  the  physician.If  abnormal  involuntary  movements  appear  or  get  worse  during  treatment  with  carbidopa and levodopa extended-release tablets,  the  physician  should  be  notified,  as  dosage  adjustment  may  be  necessary.Patients  should  be  advised  that  sometimes  the  onset  of  effect  of  the  first  morning  dose  of  carbidopa and levodopa extended-release tablets may be delayed for up to 1 hour compared with the response usually obtained from the first  morning  dose  of  carbidopa and levodopa tablets.  The  physician  should  be  notified  if  such  delayed  responses  pose  a  problem  in treatment.Patients  should  be  advised  that,  occasionally,  dark  color  (red,  brown,  or  black)  may  appear  in  saliva, urine,  or  sweat  after  ingestion  of  carbidopa and levodopa extended-release tablets.  Although  the  color  appears  to  be  clinically  insignificant, garments may become  discolored.The  patient  should  be  informed  that  a  change  in  diet  to  foods  that  are  high  in  protein  may  delay  the  absorption  of  levodopa  and  may  reduce  the  amount  taken  up  in  the  circulation.  Excessive  acidity  also delays  stomach  emptying,  thus  delaying  the  absorption  of  levodopa.  Iron  salts  (such  as  in  multivitamin  tablets) may  also  reduce  the  amount  of  levodopa  available  to  the  body.  The  above  factors  may  reduce  the  clinical  effectiveness  of  the  levodopa  or  carbidopa  levodopa  therapy.Patients  must  be  advised  that  the  whole  or  half  tablet  should  be  swallowed  without  chewing  or  crushing.Patients  should  be  alerted  to  the  possibility  of  sudden  onset  of  sleep  during  daily  activities,  in  some cases without awareness or warning signs, when they are taking dopaminergic agents,  including  levodopa. Patients should be advised to exercise caution while driving or operating machinery and that  if they  have  experienced  somnolence  and/or  sudden  sleep  onset,  they  must  refrain  from  these  activities. (See  WARNINGS,  Falling  Asleep  During  Activities  of  Daily  Living  and  Somnolence.)There  have  been  reports  of  patients  experiencing  intense  urges  to  gamble,  increased  sexual  urges, and other intense urges, and the inability to control these urges while taking one or more of  the  medications that increase central dopaminergic tone and that are generally used for the treatment  of  Parkinson’s disease, including carbidopa and levodopa extended-release tablets. Although it is not proven that the medications caused  these events,  these  urges  were  reported  to  have  stopped  in  some  cases  when  the  dose  was  reduced  or  the  medication  was  stopped.  Prescribers  should  ask  patients  about  the  development  of  new  or  increased  gambling  urges,  sexual  urges  or  other  urges  while  being  treated  with  carbidopa and levodopa extended-release tablets.  Patients  should inform  their  physician  if  they  experience  new  or  increased  gambling  urges,  increased  sexual  urges,  or  other  intense  urges  while  taking  carbidopa and levodopa extended-release tablets.  Physicians  should  consider  dose  reduction  or  stopping  the  medication  if  a  patient  develops  such  urges  while  taking  carbidopa and levodopa extended-release tablets.  (See  PRECAUTIONS,  Impulse Control / Compulsive  Behaviors).

Laboratory Tests

Abnormalities in laboratory tests may include elevations of liver function tests such as  alkaline  phosphatase,  SGOT  (AST),  SGPT  (ALT),  lactic  dehydrogenase  (LDH),  and  bilirubin.  Abnormalities  in blood urea nitrogen (BUN) and positive Coombs test have also been reported. Commonly, levels of  blood  urea  nitrogen,  creatinine,  and  uric  acid  are  lower  during  administration  of  carbidopa  levodopa  preparations  than with  levodopa.Carbidopa and levodopa  preparations,  such  as  carbidopa and levodopa tablets and  carbidopa and levodopa extended-release tablets,  may  cause  a  false-positive reaction  for  urinary  ketone  bodies  when  a  test  tape  is  used  for  determination  of  ketonuria.  This  reaction  will not be altered by boiling the urine specimen. False-negative tests may result with the use of  glucose­ oxidase methods of testing for  glucosuria.Cases of falsely diagnosed pheochromocytoma in patients on carbidopa levodopa therapy have  been  reported  very  rarely.  Caution  should  be  exercised  when  interpreting  the  plasma  and  urine  levels  of  catecholamines  and  their  metabolites  in  patients  on  levodopa  or  carbidopa  levodopa  therapy.

Drug Interactions

Caution should be exercised when the following drugs  are administered concomitantly with carbidopa and levodopa extended-release tablets.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.

Carcinogenesis, Mutagenesis, Impairment Of Fertility

In a two-year bioassay of carbidopa and levodopa tablets, no evidence of carcinogenicity was found in rats receiving  doses  of  approximately  two  times  the  maximum  daily  human  dose  of  carbidopa  and  four  times  the  maximum  daily  human  dose  of  levodopa  (equivalent  to  8  carbidopa and levodopa extended-release tablets).In  reproduction  studies  with  carbidopa and levodopa tablets,  no  effects  on  fertility  were  found  in  rats  receiving  doses  of  approximately two times the maximum daily human dose of carbidopa and four times the maximum  daily human  dose  of  levodopa  (equivalent  to  8  carbidopa and levodopa extended-release tablets).

Pregnancy

Pregnancy Category C. No teratogenic effects were observed in a study in mice receiving up to 20  times  the maximum recommended human dose of carbidopa and levodopa tablets. There was a decrease in the number of live  pups  delivered by rats receiving approximately two times the maximum recommended human dose  of  carbidopa  and  approximately  five  times  the  maximum  recommended  human  dose  of  levodopa  during  organogenesis. Carbidopa and levodopa tablets caused both visceral and skeletal malformations in rabbits at all doses  and  ratios  of  carbidopa/levodopa  tested,  which  ranged  from  10  times/5  times  the  maximum  recommended  human  dose  of  carbidopa/levodopa  to  20  times/10  times  the  maximum  recommended  human  dose  of  carbidopa/levodopa.There  are  no  adequate  or  well-controlled  studies  in  pregnant  women.  It  has  been  reported  from  individual cases that levodopa crosses the human placental barrier, enters the fetus, and is  metabolized.  Carbidopa  concentrations  in  fetal  tissue  appeared  to  be  minimal.  Use  of  carbidopa and levodopa extended-release tablets  in  women  of  childbearing  potential  requires  that  the  anticipated  benefits  of  the  drug  be  weighed  against  possible hazards to mother and  child.

Nursing Mothers

Levodopa  has  been  detected  in  human  milk.  Caution  should  be  exercised  when  carbidopa and levodopa extended-release tablet is administered to a nursing  woman.

Pediatric Use

Safety  and  effectiveness  in  pediatric  patients  have  not  been  established.  Use  of  the  drug  in  patients below the age of 18 is not  recommended.

Geriatric Use

In the clinical efficacy trials for carbidopa and levodopa tablets, almost half of the patients were older than 65, but few  were older than 75. No overall meaningful differences in safety or effectiveness were observed between  these subjects and younger subjects, but greater sensitivity of some older individuals to adverse drug  reactions  such as hallucinations cannot be ruled out. There is no specific dosing recommendation based  upon  clinical  pharmacology  data  as  carbidopa and levodopa tablets and  carbidopa and levodopa extended-release tablets are  titrated  as  tolerated  for  clinical  effect.

Adverse Reactions

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   Carbidopa and Levodopa Extended-Release Tablets n=491 Carbidopa and Levodopa Tablets n=524 Adverse  Experience % % Dyskinesia 16.5 12.2 Nausea 5.5 5.7 Hallucinations 3.9 3.2 Confusion 3.7 2.3 Dizziness 2.9 2.3 Depression 2.2 1.3 Urinary tract infection 2.2 2.3 Headache 2 1.9 Dream  abnormalities 1.8 0.8 Dystonia 1.8 0.8 Vomiting 1.8 1.9 Upper respiratory infection 1.8 1 Dyspnea 1.6 0.4 ‘On-Off’ phenomena1.6 1.1 Back  pain 1.6 0.6 Dry  mouth 1.4 1.1 Anorexia 1.2 1.1 Diarrhea 1.2 0.6 Insomnia 1.2 1 Orthostatic hypotension 1 1.1 Shoulder pain 1 0.6 Chest pain 1 0.8 Muscle  cramps 0.8 1 Paresthesia 0.8 1.1 Urinary  frequency 0.8 1.1 Dyspepsia 0.6 1.1 Constipation 0.2 1.5 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.

Overdosage

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.

Dosage And Administration

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*Tablet Amount  of Levodopa  (mg) in Each Tablet Approximate Bioavailability Approximate  Amount of  Bioavailable Levodopa (mg) in Each Tablet Carbidopa and levodopa extended-release tablets                    50 mg/200 mg 200 0.7 to 0.75†140 to 150 Carbidopa and levodopa tablets                   25 mg/100 mg 100 0.99‡99 *  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 Carbidopa and Levodopa Tablets Carbidopa and Levodopa Extended-Release Tablets Total Daily  Dose*Suggested Levodopa  (mg) Dosage  Regimen 300 to 400200 mg  b.i.d. 500 to 600300 mg b.i.d. or 200 mg  t.i.d. 700 to 800A total of 800 mg in 3 or more divided  doses (e.g., 300 mg a.m., 300 mg early p.m.,  and 200 mg later  p.m.) 900 to 1000A total of 1000 mg in 3 or more divided  doses (e.g., 400 mg a.m., 400 mg early p.m.,  and 200 mg later  p.m.) * 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.

How Supplied

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 tabletsNDC 46708-332-31                Bottle of 100 tabletsNDC 46708-332-91                Bottle of  1000 tabletsCarbidopa 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 tabletsNDC 46708-333-31                Bottle of 100 tabletsNDC 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

* Please review the disclaimer below.