Extended Release Carbidopa Levodopa In Parkinson Disease

Why Is This Medication Prescribed

The combination of levodopa and carbidopa is used to treat the symptoms of Parkinson’s disease and Parkinson’s-like symptoms that may develop after encephalitis or injury to the nervous system caused by carbon monoxide poisoning or manganese poisoning. Parkinson’s symptoms, including tremors , stiffness, and slowness of movement, are caused by a lack of dopamine, a natural substance usually found in the brain. Levodopa is in a class of medications called central nervous system agents. It works by being converted to dopamine in the brain. Carbidopa is in a class of medications called decarboxylase inhibitors. It works by preventing levodopa from being broken down before it reaches the brain. This allows for a lower dose of levodopa, which causes less nausea and vomiting.

Ipx066 Regimens In Early Parkinsons Disease

At month 9 of the extension , 83.3 % of the patients with early PD were taking 4351170 mg/day of IPX066, corresponding to approximately 300820 mg/day of IR levodopa after correction for 70 % relative bioavailability. The median total dosage of IPX066 was 720 mg/day, corresponding to approximately 500 mg/day of IR levodopa. The dosages were similar to the IPX066 dosages used in the antecedent early PD study . In addition, 78.3 % of the patients had maintained their three times daily dosing. Another 9.9 % were taking IPX066 twice daily, one patient was taking it once daily, 11.0 % were taking it four times daily, and one patient was taking it five times daily.

Demographics And Baseline Characteristics

Of the 393 patients who entered the double-blind phase of the study, 183 had No Dyskinesia at baseline, 131 had Non-Troublesome Dyskinesia Only, and 79 had Troublesome Dyskinesia. Demographics and baseline characteristics of the three groups are displayed in Table 1. Concomitant PD medications are noted in Supplementary Table 1. Age at randomization was youngest and PD duration was longest for the TD group. In addition, both OFF time and ON time without troublesome dyskinesia were least for the TD group. At the same time, the TD group was receiving the highest daily LD dosage and had the highest number of daily LD administrations. Baseline UPDRS scores were similar across groups.

Table 1

Demographic and Baseline Disease Characteristics

Data are Mean or n . UPDRS, Unified Parkinsons Disease Rating Scale. UPDRS II and III are in the ON-state.

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What Should I Do If I Forget A Dose

Take the missed dose of the regular tablet, orally disintegrating tablet, extended-release tablet, or extended-release capsule as soon as you remember it. However, if it is almost time for the next dose, skip the missed dose and continue your regular dosing schedule. Do not take a double dose to make up for a missed one.

If you are using levodopa and carbidopa enteral infusion and will be disconnecting the infusion pump for a short time , other than the normal nightly disconnection, ask your doctor if you should use an extra dose before you disconnect the pump. If the infusion pump will be disconnected for longer than 2 hours, call your doctor you probably will be advised to take levodopa and carbidopa by mouth while you are not using the suspension.

Carbidopa And Levodopa Extended Release Capsules In Patients With And Without Troublesome And Non

Article type: Research Article

Authors: Hauser, Robert A.a * | Zeitlin, Leonidb | Fisher, Stanleyc | DSouza, Richardc

Affiliations: University of South Florida, Tampa, FL, USA | Quartesian, Princeton, NJ, USA | Amneal Pharmaceuticals, Bridgewater, NJ, USA

Correspondence: Correspondence to: Robert A. Hauser, MD, MBA, Parkinsons Disease and Movement Disorders Center, Parkinson Foundation Center of Excellence, University of South Florida, 4001 E. Fletcher Ave, 6th Floor, Tampa, FL 33613, USA. Tel.: +1 813 396 0768 Fax: +1 813 905 9829 E-mail: .

Keywords: Levodopa, extended release, Parkinsons disease, treatment, dyskinesia, OFF

DOI: 10.3233/JPD-202010

Journal: Journal of Parkinson’s Disease, vol. 10, no. 3, pp. 915-925, 2020

Abstract

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How Is This Medicine Best Taken

Use this medicine as ordered by your doctor. Read all information given to you. Follow all instructions closely.

• Take with or without food.
• Swallow whole. Do not chew or crush.
• Some products may be broken in half. Do not chew or crush. Talk with your pharmacist or doctor.
• If you take an iron product or a multivitamin that has iron, ask your doctor or pharmacist how to take it with this medicine . Iron may lower how well your body is able to absorb this medicine .
• Diets high in protein, fat, or calories may lower how well your body absorbs this medicine tell your doctor if you have a diet like this or if you will be changing your diet. Talk with your doctor.
• Do not stop taking this medicine all of a sudden or lower your dose without talking to your doctor. Side effects may happen.
• Keep taking this medicine even when you are not having symptoms.
• Keep a diary of your signs.
• Keep taking this medicine as you have been told by your doctor or other health care provider, even if you feel well.
• Take this medicine at the same time of day.

What do I do if I miss a dose?

• Take a missed dose as soon as you think about it.
• If it is close to the time for your next dose, skip the missed dose and go back to your normal time.
• Do not take 2 doses at the same time or extra doses.

Carbidopa/levodopa Orally Disintegrating Tablets

This formulation of carbidopa/levodopa dissolves in the mouth. Although it is absorbed in the gut, the fact that it does not have to be broken down in the stomach means that onset of action of the medication is somewhat quicker than regular Sinemet. It is also useful for those who have difficulty swallowing pills.

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Dose Conversion In Clinical Practice

The conversion procedures utilized in the ER CD/LD clinical trials, may be impractical in clinical practice. Roughly 60% of patients required a dosage higher than those that the trials conversion tables had recommended for their initial regimens. In addition, the conversion tables listed only TID regimens . At the end of conversion, the mean dosing frequency was higher than TID . Finally, the tables did not distinguish between patients taking evenly divided levodopa doses and those taking uneven doses , either before or after conversion.

How can the ER CD/LD dosing guidelines based on clinical trials be modified to best suit the individual patient with PD? The advisory meeting considered various clinical scenarios.

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How Do I Store And/or Throw Out Carbidopa And Levodopa Extended

• Store at room temperature.
• Store in a dry place. Do not store in a bathroom.
• Protect from light.
• Keep all drugs in a safe place. Keep all drugs out of the reach of children and pets.
• Throw away unused or expired drugs. Do not flush down a toilet or pour down a drain unless you are told to do so. Check with your pharmacist if you have questions about the best way to throw out drugs. There may be drug take-back programs in your area.

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How Should I Use This Medication

Take this medication by mouth with a glass of water. Follow the directions on the prescription label. Swallow whole. Do not crush, chew, or divide the capsules. If you have trouble swallowing, you may open the capsule by carefully twisting apart both halves of the capsule and sprinkle the entire contents on 1 to 2 tablespoons of applesauce. Take the medication/food mixture immediately, and do not store for future use. Take your doses at regular intervals. Do not take your medication more often than directed. Do not stop taking except on the advice of your care team.

A high fat, high calorie meal may slow the absorption of the medication into your system and delay the onset of action by 2 to 3 hours. Consider taking the first dose of the day 1 to 2 hours before eating. If you develop nausea, the medication may be taken with food.

Talk to your care team about the use of this medication in children. Special care may be needed.

Overdosage: If you think you have taken too much of this medicine contact a poison control center or emergency room at once.

NOTE: This medicine is only for you. Do not share this medicine with others.

Subcutaneous Infusions That Are Being Researched As Treatments For Pd

ABBV-951

This is a carbidopa/levodopa subcutaneous infusion system which is under investigation in a phase 3 clinical trial. The medication is delivered via a small implantable device that infuses the novel formulation of carbidopa/levodopa under the skin. The study compares the efficacy, safety and tolerability of a continuous infusion to that of orally ingested medication.

ND0612

This is a second carbidopa/levodopa subcutaneous infusion system which is under investigation in a phase 3 clinical trial , with the effects of the subcutaneous infusion being compared to that of oral medication.

Infudopa SubC

This is a third subcutaneous formulation of carbidopa/levodopa currently under investigation. A phase 1 clinical trial was recently completed which demonstrated safety and showed that adequate levodopa concentrations were reached.

While some of these will not end up being approved for use, the research is still important because we learn from it. As the trials progress, we hope that several of these medications will be approved and added to the arsenal with which we fight PD.

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What Should I Know About Storage And Disposal Of This Medication

Keep this medication in the container it came in, tightly closed, and out of reach of children. Store it at room temperature and away from excess heat and moisture .

Store cassettes containing levodopa and carbidopa enteral suspension in the refrigerator in their original carton, protected from light. Do not freeze the suspension.

Unneeded medications should be disposed of in special ways to ensure that pets, children, and other people cannot consume them. However, you should not flush this medication down the toilet. Instead, the best way to dispose of your medication is through a medicine take-back program. Talk to your pharmacist or contact your local garbage/recycling department to learn about take-back programs in your community. See the FDAs Safe Disposal of Medicines website for more information if you do not have access to a take-back program.

It is important to keep all medication out of sight and reach of children as many containers are not child-resistant and young children can open them easily. To protect young children from poisoning, always lock safety caps and immediately place the medication in a safe location â one that is up and away and out of their sight and reach.

What Are The Possible Side Effects

The most common side effects of carbidopa/levodopa therapy include:1

Dyskinesias are a common side effect of long-term levodopa therapy. Dyskinesias can impact quality of life. The severity of dyskinesia due to levodopa varies among people with PD. The risk of dyskinesia is higher inearly-onsetPD. Medicines may be added or adjusted to prevent dyskinesia. Deep brain stimulation may also be an option.3,5

These are not all the possible side effects of carbidopa/levodopa therapy. Talk to your doctor about what to expect when taking carbidopa/levodopa therapy. You should also call your doctor if you have any changes that concern you when taking carbidopa/levodopa therapy.

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Duration Of Benefit Per Dose: Carbidopa

Clinicians commonly think in terms of duration of benefit per dose.

CD-LD ER is an extended-release formulation of carbidopa-levodopa.

We performed a post-hoc analysis of the ADVANCE-PD study.

ON time per dose going from CD-LD IR to CD-LD ER increased from 2.17 h to 3.55 h.

CD-LD ER increased mean ON time per dose 1.21 h more than CD-LD IR .

Patients With No Fluctuations

In early PD, all levodopa formulations may be expected to be effective, and a long-term advantage of any one of them over the others has not been empirically studied. Candidates for conversion to ER CD/LD might include patients prone to miss IR CD/LD doses and patients intolerant of dopamine agonists. The recommended initial dosage is 95 mg TID. If the response is suboptimal, the dosing can be uptitrated to 145 mg TID . Further increases may be considered , by increments of 50 mg per ER CD/LD dose, on a weekly basis or slower.

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Carbidopa/levodopa Immediate Release Is The Original Formulation And The One That Is Most Frequently Used

This is typically the first formulation to be tried when someone is started on levodopa treatment. This medication comes in three dosages 10/100, 25/100 and 25/250. The first number refers to the milligrams of carbidopa in the pill. The second number refers to the milligrams of levodopa in the pill.

Early on in PD, a dose can last six hours or longer, but often, as PD progresses, a levodopa dose tends to relieve symptoms for shorter and shorter amounts of time. A person may take a dose of levodopa and have good symptom relief for a period of time, referred to as ON time. Then the effects of levodopa may start to wear off and symptoms of PD return for a period of time, referred to as OFF time. This phenomenon of alternating between ON and OFF time is known as motor fluctuations. There are many strategies that your doctor can try to smooth out your response to medication throughout the day and these are summarized in a recent APDA webinar.

If this is happening, one strategy is to try a different formulation of levodopa that is designed to last longer than carbidopa/levodopa immediate release. Another strategy is to try a formulation of levodopa that can be used as needed if the medication effect wears off between oral doses of medication.

Frequently Asked Questions About Sinemet

Can I stop taking Sinemet if my Parkinsons symptoms go away?

Although rare, lowering your dose of Sinemet or stopping the medication can cause high fevers and confusion, especially if youre taking certain mental health medications. If you want to stop taking Sinemet , let your provider know, so they can instruct you on how to stop the medication safely.

Can I take Sinemet with food?

Sinemet can be taken with food to lower your risk of stomach upset. Avoid eating protein-rich foods, such as meat, milk, cheese, or nuts, with the medication, because they can affect how fast and how much levodopa is absorbed by your body. This can affect how well the medication works.

Can Sinemet cause dark urine?

Yes, Sinemet can turn your urine, sweat, and saliva a dark color . This is harmless, but it can stain your clothing.

How long does it take Sinemet to work?

The medications get released into your body within 30 minutes after you take your dose of the immediate-release or orally disintegrating tablet. On the other hand, the medications are released into your body over 4 to 6 hours after you take the extended-release form. Its important that you take the medication as prescribed by your provider to get the most relief for your PD symptoms.

Whats the difference between carbidopa/levodopa and carbidopa/levodopa ER?

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How Does It Work

Dopamine is a neurotransmitter with many jobs. Dopamine is responsible for producing smooth, purposeful movement. PD damages the neurons in the brain that make dopamine. This causes the motor symptoms of PD. This includes symptoms like:1-4

• Impaired balance
• Loss of spontaneous movement

Thesemotor symptomsare related to the loss of dopamine in the brain. By the time motor symptoms of PD appear, about 60 to 80 percent of the neurons in the brain that make dopamine have already been damaged or destroyed.1-4

Dopamine cannot enter our brains. This means that dopamine by itself cannot work as a treatment for PD. However, levodopa can enter the brain. Levodopa is the building block our bodies can use to make dopamine. Levodopa is converted to dopamine in the brain. The influx of dopamine created by levodopa helps treat the motor symptoms of PD.1-4

Adding carbidopa prevents levodopa from being converted into dopamine in the bloodstream. This allows more of the drug to get to the brain. This also means that lower doses of levodopa can be given. The addition of carbidopa also reduces the risk of some side effects like nausea or vomiting.1,2

What Should I Watch For While Using This Medication

Visit your care team for regular checks on your progress. Tell your care team if your symptoms do not start to get better or if they get worse. Do not stop taking except on your care team’s advice. You may develop a severe reaction. Your care team will tell you how much medication to take.

You may get drowsy or dizzy. Do not drive, use machinery, or do anything that needs mental alertness until you know how this medication affects you. Do not stand or sit up quickly, especially if you are an older patient. This reduces the risk of dizzy or fainting spells. Alcohol may interfere with the effect of this medication. Avoid alcoholic drinks.

When taking this medication, you may fall asleep without notice. You may be doing activities like driving a car, talking, or eating. You may not feel drowsy before it happens. Contact your care team right away if this happens to you.

There have been reports of increased sexual urges or other strong urges such as gambling while taking this medication. If you experience any of these while taking this medication, you should report this to your care team as soon as possible.

You may experience a ‘wearing off’ effect prior to the time for your next dose of this medication. You may also experience an ‘on-off’ effect where the medication apparently stops working for any time from a minute to several hours, then suddenly starts working again. Tell your care team if any of these symptoms happen to you. Your dose may need adjustment.

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