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 idiopathicPD (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.
The Parkinson's Foundation 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 firstname.lastname@example.org. 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.
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.
You can find out more about our National Medical Director, Dr. Michael S. Okun, by also visiting the Center of Excellence, University of Florida Health Center for Movement Disorders and Neurorestoration. Dr. Okun is also the author of the Amazon #1 Parkinson's Best Seller 10 Secrets to a Happier Life and 10 Breakthrough Therapies for Parkinson's Disease.
*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)