You can find out more about NPF's National Medical Director, Dr. Michael S. Okun, by also visiting the NPF Center of Excellence, University of Florida Center for Movement Disorders & Neurorestoration.

Recently, there has been a shortage of brand formulation of carbidopa/levodopa (Sinemet) for PD patients.  The shortage has left patients asking critical questions as to how switching to a generic formulation will potentially affect their individual PD symptoms and their overall health.  In this months What’s Hot column we intend to address these issues.

There is an ongoing debate about generic drug use for a multitude of conditions, including epilepsy, psychosis, hypertension, post-organ transplantation and several infectious diseases. Most of the concerns involve drugs with narrow therapeutic indices. There is a heightened attention to healthcare costs and macroeconomic policy as well as microeconomic business decisions that may impact the use of generic drugs.  The issues surrounding generic substitution for chronic degenerative conditions such as in PD continue to be controversial subjects for physicians, pharmacists, patients, Medicare/governmental insurance programs, and for private insurance companies. The United States Food and Drug Administration (FDA) requires that generic drugs meet a standard for bioequivalence prior to market approval, but this may not translate to therapeutic efficacy, or to overall patient tolerance. In a complex disease such as PD, Medicare, governmental run health care systems and third party insurance companies should allow physicians and patients the chance to properly document the superiority of brand versus generic approaches.  In the U.S. and many countries around the world, there is currently no obligation for payers to respect these types of patient-specific bedside trials and there has been no standardization of the process.

As PD progresses, the response to medication may become increasingly inconsistent. Inevitably, patients usually later in the course of PD will require higher dosages, more frequent dosing, and the use of complex drug combinations to treat symptoms and to try to maintain as much quality of life as possible. Long term levodopa therapy is associated with motor fluctuations and dyskinesia, and these two issues may pose a challenge for both specialist and non-specialist physicians. Additionally, emergence of non-motor manifestations and comorbidities requiring use of a multitude of other non-dopaminergic drugs (e.g., SSRIs, antipsychotics, anticholinergics) have a largely unknown impact on levodopa absorption and transport in a PD patient. These are all factors that may be influenced by generic versus brand drugs.

Reducing health care related expenses is a compelling force for the use of generics as substitutes for branded products. The cost of medications creates both an economic burden for payers, and for patients, as the direct patient payment is typically a function of the total cost of the medication.

In an effort to reduce health related expenditures, many insurance companies have turned to generic substitution.  Generic drugs are typically available at a fraction of the cost of branded forms.  Currently, there are multiple pharmaceutical companies that manufacture a generic formulation of carbidopa/levodopa (i.e. Actavis US, Sandoz and Teva Pharmaceuticals, among others). Dopamine agonists, monaamine oxidase inhibitors and anticholinergics are also available through various generic brands.

The manufacturers of a generic formulation must show that there is an “essential similarity” between the generic formulation and the commercially available branded originator. The US Food and Drug Administration (FDA) must approve whether a generic drug formulation is bioequivalent with its branded counterpart before it can be marketed in the US. The basic assumption in bioequivalence is that the two (generics and brand) products are pharmaceutically equivalent, and that their bioavailabilities (rate and extent of availability) after being administered in the same molar dose are similar such that their efficacy and safety, can be expected to be the same. Pharmaceutical equivalents mean that the two drugs have the same active ingredients, are of the same dosage form, route of administration and are identical in strength or concentration. The regulatory limits applied in bioequivalence studies require that the areas under the drug concentration versus time curves (AUC ratio of generics versus brand) be within 90% confidence intervals and the maximum plasma concentrations (Cmax ratio between generics versus brand) fall within 80-125%. These integral measures by definition do not consider that different rates of drug delivery may impact efficacy.

The development of a brand name formulation requires the demonstration of pharmacokinetics, efficacy, safety and tolerability.  This must be performed in healthy subjects, and also in the target patient population. The development of a generic equivalent however, requires only the demonstration of bioequivalence with brand name counterparts and testing is done only in healthy subjects. The fact that the generics are not tested on PD patients has the potential to result in a “relative therapeutic inequivalence,” because of the uniqueness of the PD population. For example, PD patients often experience slow absorption of their first orally-administered dose of medication in the morning due to low gastric motility. PD patients often use multiple drugs (i.e. dopamine agonists, anticholinergics, psychotropics) which may amplify differences between generic and branded formulations. Issues regarding drug–drug interactions with the different formulations of carbidopa/levodopa (extended release, immediate release), dopamine agonists, monoamine oxidase inhibitors and anticholinergics have not been addressed by simple bioequivalence studies.

There are very few available reports from either patients or physicians that address the question of the “essential similarity” of generic drugs. There are few anecdotal reports of generic drugs resulting in difficulty in PD. Whether the lack of information has been influenced by reporting biases from physicians and or patients, adverse events, or lack of efficacy due to disease progression remains unknown.

PD has a multitude of motor and non-motor symptoms, which can be complex and require meticulous assessment and comprehensive treatment. It is not uncommon to use combinations of drugs to optimize symptom control. Physicians and patients commonly work together to develop a reasonable, and often empirical combination of treatment approaches tailored to each patient. Blood levels of levodopa are correlated with the emergence of many symptoms including cardinal motor manifestations, on/off fluctuations, anxiety, mood symptoms and these can all impact quality of life. Patients may also experience “freezing” or dyskinesia, and these symptoms may be particularly influenced by even subtle fluctuations in serum levodopa level.

Pahwa et al published a small study on the pharmacokinetic differences between Sinemet (brand) and Atamet (generic carbidopa/levodopa). This study involved a single dose of Sinemet in 30 patients all with idiopathic PD (10 previously untreated patients, 10 with early disease and 10 with motor fluctuations/dyskinesia). This pilot study suggested that the generic formulation of carbidopa/levodopa (Atamet) given in a single dose was bioequivalent.  In another open label conversion study of 86 PD patients on Sinemet who were switched to generic carbidopa/levodopa, the majority of the patients  (69%) either preferred generic carbidopa/levodopa or had no preference. Patients who did not tolerate generic carbidopa/levodopa had more advanced disease and more off time, dose failures and orthostatic hypotension.  This study suggested that a subgroup of patients might not be well controlled with generic medications, and may need either higher doses of a generic preparation or the use of brand medication.

Considering the recent issues surrounding availability of brand Sinemet, we suggest that if a generic must be used to stick with a single brand, and to work with your doctor to adjust drug dosages to adequately control your PD symptoms.  If the generic formulation is weaker, you may for example need higher doses and/or more frequent dosing.  If it is stronger, you may require lower doses or less frequent dosing.  Finally, in some cases it may be a one to one switch and you will notice no changes.  When attempts to tailor drug therapy with a generic have been unsuccessful, we suggest having your doctor appeal to the insurance company for a brand drug.  It is important that in the appeal letter there are meticulous details of the various failed trials with the generic medication.

NPF is committed to keeping you informed of developments on this issue. We will alert you if we get any more information about either a shortage developing or the crisis being averted. If you are informed by your doctor or pharmacist that SINEMET® is not available in your area, please contact us at 1-800-4PD-INFO (473-4636) or If you have any questions, Dr. Okun is prepared to address issues about the shortage and generic substitution on our Ask the Doc online discussion forum.

Selected References:

Pahwa R, Marjama J, McGuire D, Lyons K, Zwiebel F, Silverstein P, et al. Pharmacokinetic comparison of Sinemet and Atamet (generic carbidopa/levodopa): a single-dose study. Mov Disord. 1996 Jul;11(4):427-30.

Pahwa RPR, Lyons K, Majama J, et al. Clinical experience with generic carbidopdlevodopa (G-L) in patients with Parkinson’s disease (PD). Neurology. 1994;44:A244.

Berg MJ, Gross RA, Haskins LS, Zingaro WM, Tomaszewski KJ. Generic substitution in the treatment of epilepsy: patient and physician perceptions. Epilepsy Behav. 2008 Nov;13(4):693-9.

Kesselheim AS, Stedman MR, Bubrick EJ, Gagne JJ, Misono AS, Lee JL, et al. Seizure outcomes following the use of generic versus brand-name antiepileptic drugs: a systematic review and meta-analysis. Drugs. 2010 Mar 26;70(5):605-21.

Borgheini G. The bioequivalence and therapeutic efficacy of generic versus brand-name psychoactive drugs. Clin Ther. 2003 Jun;25(6):1578-92.

Bobo WV, Stovall JA, Knostman M, Koestner J, Shelton RC. Converting from brand-name to generic clozapine: a review of effectiveness and tolerability data. Am J Health Syst Pharm. 2010 Jan 1;67(1):27-37.

*Special thanks to Crisley Go, M.D., and Peter Schmidt, PhD. who provided much of the content and insight for this column based on a NPF Quality Initiative Article (2011)

Posted: 3/1/2011 6:00:00 AM by Cathy Whitlock

Browse current and archived What's Hot in PD? articles, the National Parkinson Foundation's monthly blog for people with Parkinson's written by our National Medical Director, Dr. Michael S. Okun. 

April 2015
What to tell Parkinson’s patients about diet and taking statin drugs

March 2015
Everything a Parkinson’s Disease Patient Needs to Know About the New Dopamine Pump

February 2015
Tips for Parkinson’s Disease Patients Switching from Sinemet or Madopar to Rytary (IPX066)

January 2015
More Evidence Linking Gut Bacteria to Parkinson’s Disease: A Guide for Patients

December 2014
Two New Therapies for Parkinson’s Disease Patients to get Excited About: Vaccines and Monoclonal Antibodies

November 2014
The Importance of a Monitoring Strategy When Prescribing Dopamine Agonists: Lessons from the National Parkinson Foundation Data

October 2014
Is Midlife Migraine Related to Late Life Parkinson’s Disease?

September 2014
Deep Brain Stimulation for Parkinson’s Disease: NPF Congratulates Mahlon DeLong and Alim-Louis Benabid and Looks to a Bright Future in Human Neural-Network Modulation

August 2014
Everything You Need to Know About Medical Marijuana and Parkinson’s Disease

July 2014
The End for Levodopa Phobia: New Study Shows Sinemet is a Safe Initial Therapy for Treatment of Parkinson's Disease

June 2014
Is light therapy a potential treatment modality in Parkinson’s disease?

May 2014
How does the most common genetic cause of Parkinson’s Disease (LRRK2) cause Parkinson’s disease and could it be used to help develop a better therapy?

April 2014
An Update on DAT Scanning for Parkinson’s Disease Diagnosis

March 2014
Could Northera (Droxidopa) Be an Alternative Treatment for Low Blood Pressure and Passing Out Symptoms?

February 2014
The Dream of a Pill Free Existence and the Continuous Dopaminergic Pump for the Treatment of Parkinson's Disease

January 2014
Should I take Inosine to Raise my Uric Acid Levels and Treat my Parkinson’s Disease?

December 2013
Could Fungus and Mold be an Important Contributor to Parkinson’s Disease?

November 2013
Pimavanserin and the Hope for a Better Drug for Hallucinations and Psychosis in Parkinson’s Disease

October 2013
Halting of the Creatine Study

September 2013
The Importance of Identifying and Treating Caregiver Strain

August 2013
Putting Parkinson’s Disease Information into the Palm of Your Hand: Parkinson’s Enters the Smartphon

July 2013
What Parkinson’s Disease Patients Need to Know about H. Pylori Gastrointestinal Infections

June 2013
A2A Receptor Antagonists and Parkinson’s Disease Treatment

May 2013
Another Setback for Trophic Factor Treatment in Parkinson's Disease

April 2013
IPX066 and What Patients Really Want in New Carbidopa/Levodopa (Sinemet) Formulations

March 2013
The Weather Forecast for Parkinson’s Disease Calls for Worldwide Economic Storm

February 2013
Defeating the Barriers to Implementing Exercise Regimens in Parkinson’s Disease Patients

January 2013
When should you start medication therapy for Parkinson’s disease?

December 2012
Neurologist Care Reduces Hospitalizations in Parkinson's Disease

November 2012
A Victory in Court for Parkinson's Disease Patients who Require Ongoing Rehabilitative Therapies

October 2012
Given the recent FDA announcement about Mirapex (pramipexole), should I be worried about dopamine agonists?

September 2012
What about the new Parkinson’s Disease Vaccine? What should I know?

August 2012
Caffeine as a Potential Treatment for Parkinson’s Disease

July 2012
Time to Consider GPi DBS for Parkinson’s Disease: A Shift in the Practice of Patient Selection for DBS

June 2012
A New Treatment for Parkinson’s Disease-Related Constipation

May 2012
Too Many Pills: Improving Delivery Systems for Parkinson’s Disease Drugs

April 2012
Measuring Quality and Assessing Depression in Parkinson's Disease

March 2012
Watch out for Unexpected Obstacles if You Use a Cueing Strategy to Break Freezing of Gait in Parkinson’s Disease

February 2012
Pill Color, Generic Medications and Insurance Issues: Important Medication-Related Tips for the Parkinson’s Disease Patient

January 2012
Are Blood Tests for Parkinson’s Disease on the Horizon?

December 2011
Placing Stem Cells in Animal Models of Parkinson’s Disease: Another Important Step

November 2011
Important News for the Parkinson’s Disease Community: More Evidence that Sinemet and Madopar are Not Toxic and do Not Accelerate Disease Progression

October 2011
The Case for All Parkinson’s Disease Patients to be Co-managed by a Primary Care-Neurologist Team

September 2011
Scientists say Research on Brain Proteins Involved in Parkinson’s Disease is “Shaping” Up

August 2011
Who Actually Takes Care of Most of the Parkinson’s Patients Worldwide: The Need for Education and the Parkinson’s Toolkit

July 2011
If you are Dizzy or Passing Out, it could be Your Parkinson’s Disease or Parkinson’s Disease Medications

June 2011
How Will Group Visits for Parkinson’s Disease Fit into the Future of Parkinson’s Disease Care?

May 2011
Why Patients Should be Wary of Chelation Therapy for Parkinson’s Disease

April 2011
Opening the Door to Gene Therapy in Parkinson’s Disease: The Need for Refinement of the Technology and Approach

March 2011
Does it Matter if I Can’t Get Brand Sinemet?

February 2011
Should I get a DaTscan or PET scan to confirm my diagnosis of Parkinson’s disease?

January 2011
A Critical Reappraisal of the Worst Drugs in Parkinson’s Disease

December 2010
Environmental Risks for PD: Manganese, Welding, Mining, and Parkinsonism

November 2010
Calling for the FDA to Revise the Eight Sinemet a Day Rule

October 2010
Dry Cleaning Solvents and Potential Environmental Risks for Developing Parkinson’s Disease

September 2010
Maintaining the Balance: Why Parkinson’s Disease Patients Need to Understand Drug Recalls, Withdrawals, and Safety Alerts

August 2010
Shining a Light on Parkinson’s Disease: Optogenetics Has a Bright Future in Research

July 2010
Poor Medication Management of Parkinson's Disease During Hospital Admissions: Patients and Families Can Improve Their Hospital-Based Management

June 2010
Why Are Patches and Continuous Release Technology a Big Deal to Parkinson's?

May 2010
Is the PD SURG Trial Another Surge Forward for DBS Therapy?

April 2010
Cycling in PD in Those Who Can’t Walk: Is it Possible?

March 2010
New iPS Stem Cells for PD: What Does it Mean?

February 2010
Time for Comprehensive Care Networks for PD

January 2010
Is Parkinson's Disease a Prion Disease?

December 2009
Parkinson's Disease Linked to Gaucher's Disease

November 2009
Brain Cells Keep Time Stamps: Implications for Parkinson's Disease Therapies

October 2009
Is it Safe to Have an MRI with a DBS in Place?

September 2009
Take Care of Your Bones as They Are Affected in Parkinson's Disease (Even in Men)

August 2009
Is it Time to Start Paying Attention to Pain Symptoms in Parkinson's Disease Patients?

July 2009
Glutathione Fails to Demonstrate Significant Improvement in PD Symptoms

June 2009
Keeping an Eye on Trials Important to the Parkinson's Disease Patient

May 2009
Increased Risk of Melanoma in Parkinson's Disease

April 2009
Finally a DBS Expert Consensus Statement Aimed at Their True Customers: The Patients

March 2009
Pesticides and Environmental Exposure in Parkinson's disease: Should We Stay Away From the Stink Truck?

February 2009
Is Exercise Effective Treatment and Protection Against PD?

January 2009
Why are Transplant Trials Struggling to Succeed in the Treatment of PD?

December 2008
Are Monoamine Oxidase Inhibitors Disease Modifying or Neuroprotective in PD?

November 2008
Update on Gene Therapy for Parkinson's Disease

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Each month, we will feature a new column by NPF's National Medical Director, Dr. Michael Okun, on the latest developments in Parkinson's disease research. Read the latest "What's Hot in PD?" below.

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