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FDA Approves Rytary (Extended-Release Carbidopa/Levodopa Capsules)

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Impax Pharmaceuticals Announce FDA Approval of RYTARY™ (Carbidopa and Levodopa) Extended-Release Capsules for the Treatment of Parkinson's disease

PR Newswire

January 08, 2015: 08:01 AM ET

 

HAYWARD, Calif., Jan. 8, 2015 /PRNewswire/ -- Impax Pharmaceuticals, a division of Impax Laboratories, Inc. (NASDAQ: IPXL), today announced that the U.S. Food and Drug Administration (FDA) approved RYTARY, an extended-release oral capsule formulation of carbidopa-levodopa, for the treatment of Parkinson's disease, post-encephalitic parkinsonism, and parkinsonism that may follow carbon monoxide intoxication and / or manganese intoxication. RYTARY is not for use in patients using nonselective monoamine oxidase inhibitors (MAO) inhibitors.

Logo - http://photos.prnewswire.com/prnh/20140402/PH96035LOGO

"The FDA approval of RYTARY (pronounced rye-TAR-ee) is an important new development for the treatment of Parkinson's disease and provides an extended-release carbidopa-levodopa product that treats Parkinson's disease," said Fred Wilkinson, president and CEO, Impax Laboratories. "RYTARY is designed to address one of the most significant unmet needs for patients living with Parkinson's disease, which is to reduce the amount of time during the day when their symptoms are not adequately controlled."

"There are approximately one million Americans living with this chronic disease and we are pleased to offer this new therapy as a treatment option for those patients," added Wilkinson. "Today's approval of RYTARY is also a significant milestone for Impax because it is our first branded drug internally developed and approved for commercialization."

RYTARY contains immediate release and extended-release beads, with a specific amount of carbidopa and levodopa in a 1:4 ratio, and provides both initial and extended levodopa plasma concentrations after a single dose. RYTARY may be swallowed whole or, for patients who have trouble swallowing, the capsule may be opened and the beads sprinkled on applesauce and consumed immediately.

Impax expects the four strengths of RYTARY, 23.75mg/95mg, 36.25mg/145mg, 48.75mg/195mg, and 61.25mg/245mg (carbidopa/levodopa) to be available for commercial distribution in February 2015.

The RYTARY clinical program studied patients with early (levodopa-naive) to advanced Parkinson's disease in the U.S. and in Europe. In APEX-PD (Study 1), a trial that enrolled and randomized 381 levodopa-naive patients, the study met its primary efficacy endpoint of mean change from baseline in the sum of Unified Parkinson's Disease Rating Scale (UPDRS) Part II (activities of daily living) score and UPDRS Part III (motor skills) score for RYTARY versus placebo at Week 30 (or early termination).

In ADVANCE-PD (Study 2), a trial of 393 randomized patients with advanced Parkinson's disease having "off" time, the results showed treatment with RYTARY reduced the percentage of "off" time (36.9% to 23.8%) from baseline versus immediate-release carbidopa-levodopa (36.0% to 29.8%) during waking hours to end of study. RYTARY also increased "on" time without troublesome dyskinesia during waking hours versus baseline to end of study by 1.8 hours. Less "off" time was primary related to more "on" time without troublesome dyskinesia.

The most common adverse reactions with RYTARY in the APEX-PD trial (in at least 5% of patients and more frequently than in placebo) were nausea, dizziness, headache, insomnia, abnormal dreams, dry mouth, dyskinesia, anxiety, constipation, vomiting, and orthostatic hypotension. The most common adverse reactions with RYTARY in the ADVANCE-PD trial (in at least 5% of patients and more frequently than an oral immediate-release carbidopa-levodopa) were nausea and headache.

About Parkinson's disease

Parkinson's disease is a chronic neurodegenerative movement disorder affecting approximately one million people in the U.S., with 50,000-60,000 new cases diagnosed each year in the U.S. alone. There is currently no known cure for Parkinson's.

About RYTARY

IMPORTANT SAFETY INFORMATION

RYTARY is contraindicated in patients who are currently taking or have recently (within 2 weeks) taken a nonselective monoamine oxidase (MAO) inhibitor (e.g., phenelzine and tranylcypromine). Hypertension can occur if these drugs are used concurrently.

Patients treated with levodopa (a component of RYTARY) have reported falling asleep while engaged in activities of daily living, including the operation of motor vehicles, which sometimes resulted in accidents. Although many of these patients reported somnolence while on levodopa, some perceived that they had no warning signs (sleep attack), such as excessive drowsiness, and believed that they were alert immediately prior to the event. Some of these events have been reported more than 1 year after initiation of treatment. Before initiating treatment with RYTARY, advise patients of the potential to develop drowsiness and specifically ask about factors that may increase the risk for somnolence with RYTARY such as concomitant sedating medications or the presence of a sleep disorder. Prescribers should consider discontinuing RYTARY in patients who report significant daytime sleepiness or episodes of falling asleep during activities that require active participation (e.g., conversations, eating, etc.). If a decision is made to continue RYTARY, patients should be advised not to drive and to avoid other potentially dangerous activities that might result in harm if the patients become somnolent.

A symptom complex that resembles neuroleptic malignant syndrome (characterized by elevated temperature, muscular rigidity, altered consciousness, and autonomic instability), with no other obvious etiology, has been reported in association with rapid dose reduction, withdrawal of, or changes in dopaminergic therapy. Avoid sudden discontinuation or rapid dose reduction in patients taking RYTARY. If the decision is made to discontinue RYTARY, the dose should be tapered to reduce the risk of hyperpyrexia and confusion.

Cardiovascular ischemic events have occurred in patients taking RYTARY. In patients with a history of myocardial infarction who have residual atrial, nodal, or ventricular arrhythmias, cardiac function should be monitored in an intensive cardiac care facility during the period of initial dosage adjustment.

There is an increased risk for hallucinations and psychosis in patients taking RYTARY. Hallucinations present shortly after the initiation of therapy and may be responsive to dose reduction in levodopa. Hallucinations may be accompanied by confusion and sleep disorder (insomnia) and excessive dreaming. 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.

Because of the risk of exacerbating psychosis, patients with a major psychotic disorder should not be treated with RYTARY. In addition, medications that antagonize the effects of dopamine used to treat psychosis may exacerbate the symptoms of Parkinson's disease and may decrease the effectiveness of RYTARY.

Case reports suggest that patients can experience intense urges to gamble, increased sexual urges, intense urges to spend money, binge eating, and/or other intense urges, and the inability to control these urges while taking one or more of the medications, including RYTARY, that increase central dopaminergic tone and that are generally used for the treatment of Parkinson's disease. 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 their caregivers about the development of new or increased gambling urges, sexual urges, uncontrolled spending, or other urges while being treated with RYTARY. Consider a dose reduction or stopping the medication if a patient develops such urges while taking RYTARY.

RYTARY can cause dyskinesias that may require a dosage reduction of RYTARY or other medications used for the treatment of Parkinson's disease.

Treatment with RYTARY may increase the possibility of upper gastrointestinal hemorrhage in patients with a history of peptic ulcer and may cause increased intraocular pressure in patients with glaucoma.

RYTARY should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Caution should be exercised when RYTARY is administered to a nursing woman.

Overdosage

The acute symptoms of levodopa/dopa decarboxylase inhibitor overdosage can be expected to arise from dopaminergic overstimulation (cardiovascular and CNS disturbances).

Drug Interactions:

Monitor patients taking selective MAO-B inhibitors and carbidopa-levodopa. The combination may be associated with orthostatic hypotension. RYTARY should be co-administered cautiously with: dopamine D2 antagonists (metoclopramide), isoniazid, and iron salts.

RYTARY should not be chewed, divided, or crushed.

About Impax Pharmaceuticals

Impax Pharmaceuticals is the branded products division of Impax Laboratories, Inc. Impax Pharmaceuticals is focused on targeting significant unmet needs, with a primary focus on developing treatments for neurological disorders. For more information, please visit its web site at www.impaxpharma.com.

About Impax Laboratories, Inc.

Impax Laboratories, Inc. (Impax) is a technology based specialty pharmaceutical company applying its formulation expertise and drug delivery technology to the development of controlled-release and specialty generics in addition to the development of central nervous system disorder branded products. Impax markets its generic products through its Global Pharmaceuticals division and markets its branded through the Impax Pharmaceuticals division. Additionally, where strategically appropriate, Impax develops marketing partnerships to fully leverage its technology platform and pursues partnership opportunities that offer alternative dosage form technologies, such as injectables, nasal sprays, inhalers, patches, creams, and ointments. For more information, please visit the Company's web site at: www.impaxlabs.com.

"Safe Harbor" statement under the Private Securities Litigation Reform Act of 1995:

To the extent any statements made in this news release contain information that is not historical; these statements are forward-looking in nature and express the beliefs and expectations of management. Such statements are based on current expectations and involve a number of known and unknown risks and uncertainties that could cause the Company's future results, performance, or achievements to differ significantly from the results, performance, or achievements expressed or implied by such forward-looking statements. Such risks and uncertainties include, but are not limited to: fluctuations in revenues and operating income; the Company's ability to promptly correct the issues raised in the warning letter and Form 483 observations received from the FDA; the Company's ability to successfully develop and commercialize pharmaceutical products in a timely manner; reductions or loss of business with any significant customer; the impact of consolidation of the Company's customer base; the impact of competition; the substantial portion of our total revenues derived from sales of a limited number of products; the Company's ability to sustain profitability and positive cash flows; any delays or unanticipated expenses in connection with the operation of the Company's manufacturing facilities; the effect of foreign economic, political, legal, and other risks on the Company's operations abroad; the uncertainty of patent litigation and other legal proceedings; the increased government scrutiny on the Company's agreements with brand pharmaceutical companies; product development risks and the difficulty of predicting FDA filings and approvals; consumer acceptance and demand for new pharmaceutical products; the impact of market perceptions of the Company and the safety and quality of the Company's products; the Company's determinations to discontinue the manufacture and distribution of certain products; the Company's ability to achieve returns on its investments in research and development activities; the Company's inexperience in conducting clinical trials and submitting new drug applications; the Company's ability to successfully conduct clinical trials; the Company's reliance on third parties to conduct clinical trials and testing; the Company's lack of a license partner for commercialization of IPX066 outside of the United States; impact of illegal distribution and sale by third parties of counterfeits or stolen products; the availability of raw materials and impact of interruptions in the Company's supply chain; the Company's policies regarding returns, allowances and chargebacks; the use of controlled substances in the Company's products; the effect of current economic conditions on our industry, business, results of operations and financial condition; disruptions or failures in the Company's information technology systems and network infrastructure; the Company's reliance on alliance and collaboration agreements; the Company's reliance on licenses to proprietary technologies; the Company's dependence on certain employees; the Company's ability to comply with legal and regulatory requirements governing the healthcare industry; the regulatory environment; the Company's ability to protect its intellectual property; exposure to product liability claims; risks relating to goodwill and intangibles; changes in tax regulations; the Company's ability to manage growth, including through potential acquisitions; the Company's ability to meet expectations regarding the timing and completion of the proposed transaction with Tower Holdings Inc. and Lineage Therapeutics Inc., the Company's ability to consummate such proposed transaction; the conditions to the completion of such proposed transaction (including the receipt of the regulatory approvals required for the transaction not being obtained on the terms expected or on the anticipated schedule), the integration of the acquired business by the Company being more difficult, time-consuming or costly than expected, operating costs, customer loss and business disruption (including, without limitation, difficulties in maintaining relationships with employees, customers, clients or suppliers) being greater than expected following the proposed transaction, the retention of certain key employees of the acquired business being difficult, the Company's and the acquired business's expected or targeted future financial and operating performance and results, the combined company's capacity to bring new products to market, and the possibility that the Company may be unable to achieve expected synergies and operating efficiencies in connection with the proposed transaction within the expected time-frames or at all and to successfully integrate the acquired business, the restrictions imposed by the Company's credit facility; uncertainties involved in the preparation of the Company's financial statements; the Company's ability to maintain an effective system of internal control over financial reporting; the effect of terrorist attacks on the Company's business; the location of the Company's manufacturing and research and development facilities near earthquake fault lines; expansion of social media platforms and other risks described in the Company's periodic reports filed with the Securities and Exchange Commission. Forward-looking statements speak only as to the date on which they are made, and the Company undertakes no obligation to update publicly or revise any forward-looking statement, regardless of whether new information becomes available, future developments occur or otherwise.

Company Contact:

Mark Donohue

Investor Relations and Corporate Communications

(215) 558-4526

www.impaxlabs.com

To view the original version on PR Newswire, visit:http://www.prnewswire.com/news-releases/impax-pharmaceuticals-announce-fda-approval-of-rytary-carbidopa-and-levodopa-extended-release-capsules-for-the-treatment-of-parkinsons-disease-300017730.html

SOURCE Impax Laboratories, Inc.

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Could you give us your professional opinion adv vs disadvantage as compared to what we gave now? I'd sinemet

Thank you

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It is too soon to tell as we need to use it in practice.  Here is my What's Hot blog addressing this new and exciting therapy. IPX066 is Rytary:

 

We frequently hear from Parkinson’s disease patients that their current carbidopa/levodopa medication preparations fail to adequately address their disease-related symptoms.  The frequently cited medication related problems include:

  1. Medication dosages taking too long to “kick in” and start working
  2. Medication wearing off before the next scheduled medication dose
  3. Severe on-off medication fluctuation periods (e.g. rapid cycling during the day ranging from feeling completely on medication to completely off medication)
  4. Dyskinesia (too much movement, usually resulting from too high of a blood level of dopamine)
  5. Too many pills
  6. Too many medication dosage intervals (e.g. taking medications every 1-2 hours throughout the waking day). 

Patients also have other issues that levodopa does not address, including walking, balance, talking, and thinking issues, but these will likely require a totally different approach than simple levodopa replacement.  Dr. Robert Hauser at the National Parkinson Foundation Center of Excellence at the University of South Florida, along with colleagues from 68 North American and European study sites, recently published a paper on a new extended release formulation of carbidopa/levodopa (IPX066).  In this month’s What’s Hot in PD? Column, I will review the results of the Hauser et. al. study, and also discuss the pressing need for better medication formulations to address the symptoms Parkinson’s disease.

The new formulation that was studied, carbidopa/levodopa extended release (IPX066), is different than its predecessors.  It contains special beads designed to dissolve at different rates within the stomach and the intestines.  The medication capsule was in general designed to provide longer lasting benefit for patients with Parkinson’s disease.  This current randomized study included 393 Parkinson’s disease patients who all reported at least of 2.5 hours of “off time,” defined as periods when they felt the medication was not working.  The authors aimed to improve the number of hours of “off time” each day for patients randomized to the new extended release formulation (IPX066) as compared to the older and standard regular release carbidopa/levodopa.   The results revealed that the group on extended release formulations took less overall medication dosages (3.6 vs. 5 doses per day); however they also took more total pills. The daily “off-time” improved by over an hour each day in the extended release formulation.  Both medications in this trial were safe and well tolerated.

If we return to the six areas where Parkinson’s disease patients have been seeking improved medication formulations, IPX066 was observed to improve issues in two categories: wearing off between dosages, and improvement by increasing the time interval between dosages.  The results of the current study cannot be widely applied to patients with severe dyskinesia, severe on-off fluctuations, and later stage disease.  The new extended release formulation also increased the total blood-stream levodopa exposure by 30-40% as compared to conventional immediate release levodopa.  Increasing levodopa in the bloodstream is thought to decrease the threshold for dyskinesia, as has been observed with other Parkinson’s drugs such as Entacapone and Stalevo. Although dosed less frequently, the extended release formulation actually required more total pills per day. The authors felt that a newer formulation of the same drug, which they anticipate will be used in clinical practice, would allow for a decrease in pill number. 

Patients and families should be excited by the news that a new formulation of carbidopa/levodopa will be released in the next several months.  However, patients and clinicians should be aware that there are limitations in the use of IPX066, and that caution should be exercised, especially in potentially lowering the dyskinesia threshold.  Dosages and dosage intervals of any formulation of carbidopa/levodopa, including IPX066, should be carefully adjusted at each clinic visit to address changes in Parkinson’s symptoms.  The success or failure of dopamine replacement therapy is more dependent on the expert adjusting the therapy than the formulation.  It is good news that drug manufacturers are now listening to Parkinson’s disease patients, and are trying to address their six major concerns, though it would seem obvious there is a lot of room for improvement.

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Dr Okun,

 

For someone like my mom who has been taking Stalevo crushed for the past 2 years and getting the extreme highs associated with too much too soon (will not swallow whole otherwise and Sinemet was no improvement)  This is a better choice for her since the tiny beads can be mixed in apple sauce so it's like swallowing it whole and reaping the benefits of even distribution right?

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Your theory could be reasonable; though I am not sure the FDA has cleared the pill to be broken and put in apple sauce (though many patients find creative solutions that work).  The use of Rytary for her could be brilliant or it could be a disaster.  The only way to find out will be to work with your doctor and create a monitoring plan, and trial period.  Finding the right dose and interval, and also tuning the dose to her symptoms may take time.  I will cross my fingers and hope that you are successful.  You can teach us by writing in and telling us about your experience.

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According to the press release it is forumlated for people who have trouble swallowing.  A dream come true for me at least.  I'm actually surprised that not too many people on the forum are elated about this new medication.

 

RYTARY contains immediate release and extended-release beads, with a specific amount of carbidopa and levodopa in a 1:4 ratio, and provides both initial and extended levodopa plasma concentrations after a single dose. RYTARY may be swallowed whole or, for patients who have trouble swallowing, the capsule may be opened and the beads sprinkled on applesauce and consumed immediately.

 

Will you be prescribing this for your patients? 

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We will definitely try it.  I am excited if the FDA gets behind the idea that it is ok to break the capsule and sprinkle on food.  I have not seen this recommendation supported by them before.  It is exciting and we will have to see who this new medication will work for.

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You can now do this with Namenda XR so I think more and more drug companies are following their lead and making capsules with beads that can be opened and mixed in apple sauce.  Brilliant move which couldn't come sooner.  

 

The next step would be knowing how to convert that to what people are taking now in Sinemet or Stalevo in terms of doses and if insurance will pay for this and if so when.   The doses indicated for Rytary is different so it's hard to match.  Exciting progress indeed.  Thank you.

 

 

 

 

 

 

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A few comments.

 

First, it looks like the FDA is ok with breaking and sprinkling Rytary and also Namenda extended release into food like apple sauce.

 

Second, it will be hard to know if this pill will be better or worse in moderate to severe cases of dyskinesia as it was not tested specifically for this group of patients.  Only time and individual situations will tell.

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I'm still confused about dyskinesia.  I always thought it happens when too much levodopa is in the system that causes the body to go into involuntary movements.  If Rytary is suppose to contain both immediate and long acting release  then wouldn't it cause less dyskinesia since it will give you just enough at the beginning to get you moving and then slowly even out the rest of the dosage before it is leaves your system.  

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Dear Dr Okun,

My husband 's sleep has become fragmented in July with waking up after 3 hours of sleep and had trouble falling back to sleep. He was on Sinement 25/100 one tablet about 90 minutes before bed. However since he increases to 1.5 tablets taken 30 minutes before bed, he has been able to sleep about 6 hours. Do you think the Rytary may even help him to sleep longer ? Thank you for your advice

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I doubt the Rytary itself will help the sleep and awakening.  What we find helps the most is redosing the sinemet once or twice during the night if one awakens and can't get back to sleep.

 

The other question on dyskinesia is complex.  Most of the time it appears at peak dose in the bloodstream (1-1.5 hours after a dose) but not always.  To date by changing to extended release CR sinemet and using other strategies it has not been a panacea for dyskinesia.  The best approach is to adjust dose and frequency of whichever formulation you choose.

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It's here it's here...  Dr. Okun -  Do you know how to change from Stalevo 150mg 3 times a day to Rytary?  What is the = dosage from Stalevo to Rytary?   My mom's doctor is not familiar with this yet so I can ask for the dosage to try and report back to her in a month and I think she will be ok with it. 

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Yes I saw that already.  It did NOT mention Stalevo to Rytary unless I was reading it wrong.   Am I correct in that it is to be taken as 3 capsules per dose which would be 9 a day total?  When I called CVS pharmacy they quoted me the price based on 30 day supply.  How will this work? 

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It is indeed in most cases 3 capsules per dose.  We do not have a Stalevo conversion, but I suspect most docs will start with same amount of sinemet in Stalevo and see how that works and adjust up if needed.

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That is a good question, and one I don't have the insider knowledge to answer.  It may have to do with the delivery system (all the spheres in the capsule are various sizes).

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But if you have to take them all the same time anyways then it will all go in your body at the same rate whether  you open one capsule or 3.  I'm talking in terms of putting them all in apple sauce.  They will all go in the same mixture so why not put them in 1 capsule for easier use.   Unless of course down the road people may take 2 at a time or 4 at a time so then there is no guessing of how much to add.  Too weird. 

 

Dr. Okun - have you given any of your patients to take yet?  

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of course, three capsules of beads into one capsule, could create a capsule that is too big to swallow........

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This is zone theory, but I must admit I do not know exactly the reasoning!

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We are just starting to prescribe this drug and as we get more information we will update you on our experiences.

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OK, I'm on Rytary as of 0600 yesterday morning. I'm taking 12 capsules of the 195MG per day.  I take 3 capsules at 0600, 1000, 1400 & 1800.  My cost/copay through Express Scripts/Tricare (retired military) according to the website is $16 for 90 days mail order/home delivery and $20 for 30 days at retail pharmacy.  My MDS (who was involved in the clinical trials and helped the FDA and Impax with the Rytary dosage schedule) gave me 200 sample capsules, wrote me a 30 day script that I dropped off at Rite Aid this morning and a 90 day with 3 refills that I mailed to Express Scripts today. Too early to tell how Rytary is going to work.  I've only took my 4 doses yesterday and my first dose this morning (3 capsules each).  I'll let every know how it's working in a few days.  According to my MDS it will take.... "2-3 weeks to establish a stable clinical state or clinical picture after the switch to Rytary."

 I was concerned about the 12 hrs between my 6PM dose and my 6AM dose but I made through the first night with no problems  Slumpy

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