Ropinirole Extended Release Tablets

REQUIP XL contains ropinirole, a non-ergoline dopamine agonist as the hydrochloride salt. The chemical name of ropinirole hydrochloride is 4-[2-(dipropylamino)ethyl]-1,3-dihydro-2H-indol2-one and the empirical formula is C16H24N2O•HCl. The molecular weight is 296.84 (260.38 as the free base). The structural formula is:

Ropinirole hydrochloride is a white to yellow solid with a melting range of 243° to 250°C and a solubility of 133 mg/mL in water.

REQUIP XL extended-release tablets are formulated as a 3-layered tablet with a central, active-containing, slow-release layer, and two placebo outer layers acting as barrier layers that control the surface area available for drug release. Each biconvex, capsule-shaped tablet contains 2.28 mg, 4.56 mg, 6.84 mg, 9.12 mg, or 13.68 mg ropinirole hydrochloride equivalent to ropinirole 2 mg, 4 mg, 6 mg, 8 mg, or 12 mg, respectively. Inactive ingredients consist of carboxymethylcellulose sodium, colloidal silicon dioxide, glyceryl behenate, hydrogenated castor oil, hypromellose, lactose monohydrate, magnesium stearate, maltodextrin, mannitol, povidone, and one or more of the following: FD&C Yellow No. 6 aluminum lake, FD&C Blue No. 2 aluminum lake, ferric oxides (black, red, yellow), polyethylene glycol 400, titanium dioxide.

REQUIP®
(RE-qwip)
(ropinirole) Tablets

REQUIP XL®
(RE-qwip)
(ropinirole) Extended-Release Tablets

If you have Parkinson's disease, read this section.

If you have Restless Legs Syndrome (RLS), read the section that follows this section.

Important Note: REQUIP XL has not been studied in Restless Legs Syndrome (RLS) and is not approved for the treatment of RLS. However, an immediate-release form of ropinirole (REQUIP) is approved for the treatment of moderate to severe primary RLS (see other side of this leaflet).

What is the most important information I should know about REQUIP and REQUIP XL?

REQUIP and REQUIP XL can cause serious side effects including:

• Falling asleep during normal activities. You may fall asleep while doing normal activities such as driving a car, doing physical tasks, or using hazardous machinery while taking REQUIP or REQUIP XL. You may suddenly fall asleep without being drowsy or without warning. This may result in having accidents. Your chances of falling asleep while doing normal activities while taking REQUIP or REQUIP XL are greater if you take other medicines that cause drowsiness. Tell your healthcare provider right away if this happens. Before starting REQUIP or REQUIP XL, be sure to tell your healthcare provider if you take any medicines that make you drowsy.
• Fainting. Fainting can happen, and sometimes your heart rate may be decreased. This can happen especially when you start taking REQUIP or REQUIP XL or your dose is increased. Tell your healthcare provider if you faint, feel dizzy, or feel light-headed.
• Decrease in blood pressure. REQUIP and REQUIP XL can decrease your blood pressure (hypotension), especially when you start taking REQUIP or REQUIP XL or when your dose is changed. If you faint or feel dizzy, nauseated, or sweaty when you stand up from sitting or lying down (orthostatic hypotension), this may mean that your blood pressure is decreased. When you change position from lying down or sitting to standing up, you should do it carefully and slowly. Call your healthcare provider if you have any of the symptoms of decreased blood pressure listed above.
• Increase in blood pressure. REQUIP XL may increase your blood pressure.
• Changes in heart rate (decrease or increase). REQUIP and REQUIP XL can decrease or increase your heart rate.
• Hallucinations and other psychotic-like behavior. REQUIP and REQUIP XL can cause or worsen psychotic-like behavior including hallucinations (seeing or hearing things that are not real), confusion, excessive suspicion, aggressive behavior, agitation, delusional beliefs (believing things that are not real), and disorganized thinking. The chances of having hallucinations or these other psychotic-like changes are higher in people with Parkinson's disease who are taking REQUIP or REQUIP XL or taking higher doses of these drugs. If you have hallucinations or any of these other psychotic-like changes, talk with your healthcare provider.
• Uncontrolled sudden movements. REQUIP and REQUIP XL may cause uncontrolled sudden movements or make such movements you already have worse or more frequent. Tell your healthcare provider if this happens. The doses of your anti-Parkinson's medicine may need to be changed.
• Unusual urges. Some patients taking REQUIP or REQUIP XL get urges to behave in a way unusual for them. Examples of this are an unusual urge to gamble, increased sexual urges and behaviors, or an uncontrollable urge to shop, spend money, or eat. If you notice or your family notices that you are developing any unusual behaviors, talk to your healthcare provider.
• Increased chance of skin cancer (melanoma). People with Parkinson's disease may have a higher chance of getting melanoma. It is not known if REQUIP and REQUIP XL increase your chances of getting melanoma. You and your healthcare provider should check your skin on a regular basis. Tell your healthcare provider right away if you notice any changes in your skin such as a change in the size, shape, or color of moles on your skin.

What are REQUIP and REQUIP XL?

• REQUIP is a short-acting prescription medicine containing ropinirole (usually taken 3 times a day) that is used to treat Parkinson's disease. It is also used to treat a condition called Restless Legs Syndrome (RLS).
• REQUIP XL is a long-acting prescription medicine containing ropinirole (taken 1 time a day) that is used only to treat Parkinson's disease but not to treat RLS.

Having one of these conditions does not mean you have or will develop the other condition.

You should not be taking more than 1 medicine containing ropinirole. Tell your healthcare provider if you are taking any other medicine containing ropinirole.

It is not known if REQUIP and REQUIP XL are safe and effective for use in children younger than 18 years of age.

Do not take REQUIP or REQUIP XL if you:

• are allergic to ropinirole or any of the ingredients in REQUIP or REQUIP XL. See the end of this page for a complete list of the ingredients in REQUIP and REQUIP XL.
• Get help right away if any of the symptoms of an allergic reaction cause problems swallowing or breathing. Call your healthcare provider if you have any of the symptoms of an allergic reaction. Symptoms of an allergic reaction may include:
  • hives
  • rash
  • swelling of the face, lips, mouth, tongue, or throat
  • itching

Before taking REQUIP or REQUIP XL, tell your healthcare provider about all of your medical conditions, including if you:

• have daytime sleepiness from a sleep disorder or have unexpected or unpredictable sleepiness or periods of sleep.
• start or stop taking other medicines while you are taking REQUIP or REQUIP XL. This may increase your chances of getting side effects.
• start or stop smoking while you are taking REQUIP or REQUIP XL. Smoking may decrease the treatment effect of REQUIP or REQUIP XL.
• feel dizzy, nauseated, sweaty, or faint when you stand up from sitting or lying down.
• drink alcoholic beverages. This may increase your chances of becoming drowsy or sleepy while taking REQUIP or REQUIP XL.
• have high or low blood pressure.
• have or have had heart problems.
• are pregnant or plan to become pregnant. It is not known if REQUIP or REQUIP XL can harm your unborn baby.
• are breastfeeding or plan to breastfeed. It is not known if REQUIP or REQUIP XL passes into your breast milk. The amount of breast milk you make may be decreased while taking REQUIP or REQUIP XL. Talk to your healthcare provider to decide if you should breastfeed while taking REQUIP or REQUIP XL.

Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Some of these medicines may increase your chances of getting side effects while taking REQUIP or REQUIP XL.

How should I take REQUIP or REQUIP XL?

• Take REQUIP or REQUIP XL exactly as directed by your healthcare provider.
• Take REQUIP or REQUIP XL with or without food.
• Do not suddenly stop taking REQUIP or REQUIP XL without talking to your healthcare provider. If you stop this medicine suddenly, you may develop fever, confusion, or severe muscle stiffness.
• Before starting REQUIP or REQUIP XL, you should talk to your healthcare provider about what to do if you miss a dose. If you have missed the previous dose and it is time for your next dose, do not double the dose.
• Your healthcare provider will start you on a low dose of REQUIP or REQUIP XL. Your healthcare provider will change the dose until you are taking the right amount of medicine to control your symptoms. It may take several weeks before you reach a dose that controls your symptoms.
• Contact your healthcare provider if you stop taking REQUIP or REQUIP XL for any reason. Do not restart without talking with your healthcare provider.
• Your healthcare provider may prescribe REQUIP or REQUIP XL alone, or add REQUIP or REQUIP XL to medicine that you are already taking for Parkinson's disease.
• You should not substitute REQUIP for REQUIP XL or REQUIP XL for REQUIP without talking with your healthcare provider.

If you are taking REQUIP:

• REQUIP tablets are usually taken 3 times a day for Parkinson's disease.

If you are taking REQUIP XL:

• Take REQUIP XL extended-release tablets 1 time each day for Parkinson's disease, preferably at or around the same time of day.
• Swallow REQUIP XL extended-release tablets whole. Do not chew, crush, or split REQUIP XL extended-release tablets.
• REQUIP XL extended-release tablets release drug over a 24-hour period. If you have a condition where medicine passes through your body too quickly, such as diarrhea, the tablet(s) may not dissolve completely and you may see tablet residue in your stool. If this happens, let your healthcare provider know as soon as possible.

What are the possible side effects of REQUIP and REQUIP XL?

REQUIP and REQUIP XL can cause serious side effects, including:

• See “What is the most important information I should know about REQUIP and REQUIP XL?”

The most common side effects of REQUIP and REQUIP XL include:

• fainting
• sleepiness or drowsiness
• hallucinations (seeing or hearing things that are not real)
• dizziness
• nausea or vomiting
• uncontrolled sudden movements
• upset stomach, abdominal pain or discomfort
• fatigue, tiredness, or weakness
• confusion
• headache
• leg swelling
• increased sweating
• constipation
• suddenly falling asleep
• high blood pressure (hypertension)

Tell your healthcare provider about any side effect that bothers you or that does not go away.

These are not all of the possible side effects with REQUIP and REQUIP XL. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

How should I store REQUIP or REQUIP XL?

• Store REQUIP or REQUIP XL at room temperature between 68°F to 77°F (20°C to 25°C).
• Keep REQUIP or REQUIP XL in a tightly closed container and out of direct sunlight.

Keep REQUIP or REQUIP XL and all medicines out of the reach of children.

General information about the safe and effective use of REQUIP or REQUIP XL:

Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use REQUIP or REQUIP XL for a condition for which it was not prescribed. Do not give REQUIP or REQUIP XL to other people, even if they have the same symptoms that you have. It may harm them.

You can ask your pharmacist or healthcare provider for information about REQUIP or REQUIP XL that is written for health professionals.

What are the ingredients in REQUIP and REQUIP XL?

The following ingredients are in REQUIP:

Active ingredient: ropinirole (as ropinirole hydrochloride)

Inactive ingredients: croscarmellose sodium, hydrous lactose, magnesium stearate, microcrystalline cellulose, and one or more of the following: carmine, FD&C Blue No. 2 aluminum lake, FD&C Yellow No. 6 aluminum lake, hypromellose, iron oxides, polyethylene glycol, polysorbate 80, titanium dioxide.

The following ingredients are in REQUIP XL:

Active ingredient: ropinirole (as ropinirole hydrochloride)

Inactive ingredients: carboxymethylcellulose sodium, colloidal silicon dioxide, glycerol behenate, hydrogenated castor oil, hypromellose, lactose monohydrate, magnesium stearate, maltodextrin, mannitol, povidone, and one or more of the following: FD&C Yellow No. 6 aluminum lake, FD&C Blue No. 2 aluminum lake, ferric oxides (black, red, yellow), polyethylene glycol 400, titanium dioxide.

REQUIP®
(RE-qwip)
(ropinirole) Tablets

If you have Restless Legs Syndrome (RLS), read this section.

If you have Parkinson's disease, read the earlier section.

Important Note: REQUIP XL has not been studied in Restless Legs Syndrome (RLS) and is not approved for the treatment of RLS.

People with RLS should take REQUIP differently than people with Parkinson's disease (see “How should I take REQUIP for RLS?” for the recommended dosing for RLS). A lower dose of REQUIP is generally needed for people with RLS, and is taken once daily before bedtime.

What is the most important information I should know about REQUIP?

REQUIP can cause serious side effects including:

• Falling asleep during normal activities. You may fall asleep while doing normal activities such as driving a car, doing physical tasks, or using hazardous machinery while taking REQUIP. You may suddenly fall asleep without being drowsy or without warning. This may result in having accidents. Your chances of falling asleep while doing normal activities while taking REQUIP are greater if you take other medicines that cause drowsiness. Tell your healthcare provider right away if this happens. Before starting REQUIP, be sure to tell your healthcare provider if you take any medicines that make you drowsy.
• Fainting. Fainting can happen, and sometimes your heart rate may be decreased. This can happen especially when you start taking REQUIP or your dose is increased. Tell your healthcare provider if you faint, feel dizzy, or feel light-headed.
• Decrease in blood pressure. REQUIP can decrease your blood pressure (hypotension), especially when you start taking REQUIP or when your dose is changed. If you faint or feel dizzy, nauseated, or sweaty when you stand up from sitting or lying down (orthostatic hypotension), this may mean that your blood pressure is decreased. When you change position from lying down or sitting to standing up, you should do it carefully and slowly. Call your healthcare provider if you have any of the symptoms of decreased blood pressure listed above.
• Hallucinations and other psychotic-like behavior. REQUIP can cause or worsen psychotic-like behavior including hallucinations (seeing or hearing things that are not real), confusion, excessive suspicion, aggressive behavior, agitation, delusional beliefs (believing things that are not real), and disorganized thinking. The chances of having hallucinations or these other psychotic-like changes are higher in people with Parkinson's disease who are taking REQUIP or taking higher doses of these drugs. If you have hallucinations or any of these other psychotic-like changes, talk with your healthcare provider.
• Uncontrolled sudden movements. REQUIP may cause uncontrolled sudden movements or make such movements you already have worse or more frequent. Tell your healthcare provider if this happens. The doses of your anti-Parkinson's medicine may need to be changed.
• Unusual urges. Some patients taking REQUIP get urges to behave in a way unusual for them. Examples of this are an unusual urge to gamble, increased sexual urges and behaviors, or an uncontrollable urge to shop, spend money, or eat. If you notice or your family notices that you are developing any unusual behaviors, talk to your healthcare provider.
• Increased chance of skin cancer (melanoma). It is not known if REQUIP increases your chance of getting melanoma. You and your healthcare provider should check your skin on a regular basis. Tell your healthcare provider right away if you notice any changes in your skin such as a change in the size, shape, or color of moles on your skin.
• Changes in Restless Legs Syndrome symptoms. REQUIP may cause Restless Legs symptoms to come back in the morning (rebound), happen earlier in the evening, or even happen in the afternoon.

What is REQUIP?

REQUIP is a prescription medicine containing ropinirole used to treat moderate-to-severe primary Restless Legs Syndrome. It is also used to treat Parkinson's disease.

Having one of these conditions does not mean you have or will develop the other condition.

You should not be taking more than 1 medicine containing ropinirole. Tell your healthcare provider if you are taking any other medicine containing ropinirole.

It is not known if REQUIP is safe and effective for use in children younger than 18 years of age.

Do not take REQUIP if you:

• are allergic to ropinirole or any of the ingredients in REQUIP. See the end of this page for a complete list of the ingredients in REQUIP.
• Get help right away if any of the symptoms of an allergic reaction cause problems swallowing or breathing. Call your healthcare provider if you have any of the symptoms of an allergic reaction. Symptoms of an allergic reaction may include:
  • hives
  • rash
  • swelling of the face, lips, mouth, tongue, or throat
  • itching

Before taking REQUIP, tell your healthcare provider about all of your medical conditions, including if you:

• have daytime sleepiness from a sleep disorder or have unexpected or unpredictable sleepiness or periods of sleep.
• start or stop taking other medicines while you are taking REQUIP. This may increase your chances of getting side effects.
• start or stop smoking while you are taking REQUIP. Smoking may decrease the treatment effect of REQUIP.
• feel dizzy, nauseated, sweaty, or faint when you stand up from sitting or lying down.
• drink alcoholic beverages. This may increase your chances of becoming drowsy or sleepy while taking REQUIP.
• have high or low blood pressure.
• have or have had heart problems.
• are pregnant or plan to become pregnant. It is not known if REQUIP can harm your unborn baby.
• are breastfeeding or plan to breastfeed. It is not known if REQUIP passes into your breast milk. The amount of breast milk you make may be decreased while taking REQUIP.

Talk to your healthcare provider to decide if you should breastfeed while taking REQUIP. Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Some of these medicines may increase your chances of getting side effects while taking REQUIP.

How should I take REQUIP?

• Take REQUIP exactly as directed by your healthcare provider.
• REQUIP tablets are usually taken once in the evening, 1 to 3 hours before bedtime.
• Take REQUIP with or without food.
• Do not suddenly stop taking REQUIP without talking to your healthcare provider. If you stop this medicine suddenly, you may develop fever, confusion, or severe muscle stiffness.
• Your healthcare provider will start you on a low dose of REQUIP. Your healthcare provider may change the dose until you are taking the right amount of medicine to control your symptoms.
• If you miss your dose, do not double your next dose. Take only your usual dose 1 to 3 hours before your next bedtime.
• Contact your healthcare provider if you stop taking REQUIP for any reason. Do not restart without talking with your healthcare provider.

What are the possible side effects of REQUIP?

REQUIP can cause serious side effects, including:

• See “What is the most important information I should know about REQUIP?”

The most common side effects of REQUIP include:

• nausea or vomiting
• drowsiness or sleepiness
• dizziness
• fatigue, tiredness, or weakness

Tell your healthcare provider about any side effect that bothers you or that does not go away.

These are not all of the possible side effects with REQUIP.Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

How should I store REQUIP?

• Store REQUIP at room temperature between 68°F to 77°F (20°C to 25°C).
• Keep REQUIP in a tightly closed container and out of direct sunlight.

Keep REQUIP and all medicines out of the reach of children.

General information about the safe and effective use of REQUIP:

Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use REQUIP for a condition for which it was not prescribed. Do not give REQUIP to other people, even if they have the same symptoms that you have. It may harm them. You can ask your pharmacist or healthcare provider for information about REQUIP that is written for health professionals.

What are the ingredients in REQUIP?

Active ingredient: ropinirole (as ropinirole hydrochloride)

Inactive ingredients: croscarmellose sodium, hydrous lactose, magnesium stearate, microcrystalline cellulose, and one or more of the following: carmine, FD&C Blue No. 2 aluminum lake, FD&C Yellow No. 6 aluminum lake, hypromellose, iron oxides, polyethylene glycol, polysorbate 80, titanium dioxide.

Ropinirole can cause side effects that may impair your thinking or reactions. Be careful if you drive or do anything that requires you to be awake and alert.

Avoid smoking, which can make ropinirole less effective.

Avoid drinking alcohol. It can increase some of the side effects of ropinirole.

Avoid getting up too fast from a sitting or lying position, or you may feel dizzy. Get up slowly and steady yourself to prevent a fall.

General Dosing Recommendations

 ·        Ropinirole extended-release tablets are taken once daily, with or without food [see Clinical Pharmacology (12.3)].

·        Tablets must be swallowed whole and must not be chewed, crushed, or divided.

·        If a significant interruption in therapy with ropinirole extended-release tablets has occurred, retitration of therapy may be warranted.

Dosing for Parkinson's Disease

The recommended starting dose of ropinirole extended-release tablets is 2 mg taken once daily for 1 to 2 weeks, followed by increases of 2 mg/day at weekly or longer intervals, based on therapeutic response and tolerability.  Monitor patients at least weekly during dose titration. Too rapid a rate of titration may lead to the selection of a dose that does not provide additional benefit, but increases the risk of adverse reactions.  

In fixed-dose studies designed to characterize the dose-response to ropinirole extended-release tablets, there was no additional therapeutic benefit shown in patients with advanced stage Parkinson’s disease taking daily doses greater than 8 mg/day, or with early stage Parkinson’s disease taking doses greater than 12 mg/day [see Clinical Studies (14.1 and 14.2)]. Although the maximum recommended dose of ropinirole extended-release tablets is 24 mg, patients with advanced Parkinson’s disease should generally be maintained at daily doses of 8 mg or lower and patients with early Parkinson’s disease should generally be maintained at daily doses 12 mg or lower.

Ropinirole extended-release tablets should be discontinued gradually over a 7-day period. 

Renal Impairment 

No dose adjustment is necessary in patients with moderate renal impairment (creatinine clearance of 30 to 50 mL/min). The recommended initial dose of ropinirole extended-release tablets for patients with end-stage renal disease on hemodialysis is 2 mg once daily. Further dose escalations should be based on tolerability and need for efficacy. The recommended maximum total daily dose is 18 mg/day in patients receiving regular dialysis. Supplemental doses after dialysis are not required. The use of ropinirole extended-release tablets in patients with severe renal impairment without regular dialysis has not been studied. 

Switching from Immediate-Release Ropinirole Tablets to Extended-Release Ropinirole Tablets

Patients may be switched directly from immediate-release ropinirole to extended-release ropinirole tablets. The initial dose of ropinirole extended-release tablets should approximately match the total daily dose of the immediate-release formulation of ropinirole, as shown in Table 1.

Table 1. Conversion from Immediate-Release Ropinirole Tablets to Extended-Release Ropinirole Tablets

Following conversion to ropinirole extended-release tablets, the dose may be adjusted depending on therapeutic response and tolerability [see Dosage and Administration (2.2)].

Effect of Gastrointestinal Transit Time on Medication Release

Ropinirole extended-release tablets are designed to release medication over a 24-hour period. If rapid gastrointestinal transit occurs, there may be risk of incomplete release of medication and medication residue being passed in the stool.

Falling Asleep during Activities of Daily Living and Somnolence

Patients treated with ropinirole extended-release tablets have reported falling asleep while engaged in activities of daily living, including driving or operating machinery, which sometimes resulted in accidents. Although many of these patients reported somnolence while on ropinirole, some perceived that they had no warning signs such as excessive drowsiness, and believed that they were alert immediately prior to the event. Some have reported these events more than 1 year after initiation of treatment.

Among the 613 patients who received ropinirole extended-release tablets in flexible-dose clinical trials (Study 1 and Study 3), <1% of patients reported sudden onset of sleep and <1% of patients reported a motor vehicle accident in which it is not known if falling asleep was a contributing factor.

In a placebo-controlled fixed-dose trial in patients with advanced Parkinson’s disease (Study 2), sudden onset of sleep was reported in 4% of 276 patients on ropinirole extended-release tabletscompared with 3% of 74 patients on placebo. In a placebo-controlled fixed-dose trial in patients with early Parkinson’s disease (Study 4), sudden onset of sleep was reported in 5% of 146 patients on ropinirole extended-release tabletscompared with 0% of 40 patients on placebo [see Adverse Reactions (6.1)]. The incidence of sudden onset of sleep was not dose-related in either trial. 

During a placebo-controlled flexible-dose trial in patients with advanced Parkinson’s disease (Study 1), somnolence was reported in 7% of 202 patients on ropinirole extended-release tablets compared with 4% of 191 patients on placebo. During a flexible-dose, active-control, crossover trial in early Parkinson’s disease (Study 3), somnolence was reported in 11% of 140 patients on ropinirole extended-release tablets compared with 15% of 149 patients on an immediate-release formulation of ropinirole tablets[see Adverse Reactions (6.1)].  

In a placebo-controlled fixed-dose trial in patients with advanced Parkinson’s disease (Study 2), somnolence was reported in 8% of 276 patients on ropinirole extended-release tablets compared with 5% of 74 patients on placebo. In a placebo-controlled fixed-dose trial in patients with early Parkinson’s disease (Study 4), somnolence was reported in 10% of 146 patients on ropinirole extended-release tablets compared with 5% of 40 patients on placebo [see Adverse Reactions (6.1)]. The frequency of reported somnolence was not dose-related. 

It has been reported that falling asleep while engaged in activities of daily living usually occurs in a setting of pre-existing somnolence, although 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 also be aware that patients may not acknowledge drowsiness or sleepiness until directly questioned about drowsiness or sleepiness during specific activities.

Before initiating treatment with ropinirole extended-release tablets, patients should be advised of the potential to develop drowsiness and specifically asked about factors that may increase the risk with ropinirole extended-release tablets such as concomitant sedating medications or alcohol, the presence of sleep disorders, and concomitant medications that increase ropinirole plasma levels (e.g., ciprofloxacin) [see Drug Interactions (7.1)]. If a patient develops significant daytime sleepiness or episodes of falling asleep during activities that require active participation (e.g., driving a motor vehicle, conversations, eating), ropinirole extended-release tablets should ordinarily be discontinued [see Dosage and Administration (2.2)]. If a decision is made to continue ropinirole extended-release tablets, patients should be advised to not drive and to avoid other potentially dangerous activities. There is insufficient information to establish that dose reduction will eliminate episodes of falling asleep while engaged in activities of daily living.

Syncope

Syncope, sometimes associated with bradycardia, was observed in association with treatment with ropinirole extended-release tablets in patients with Parkinson’s disease.

In a placebo-controlled flexible-dose trial in patients with advanced Parkinson’s disease (Study 1), syncope occurred in 1% of patients on ropinirole extended-release tablets compared with 0% of patients on placebo [see Adverse Reactions (6.1)].

In the placebo-controlled fixed-dose trials (Study 2 and Study 4), one patient on ropinirole extended-release tablets with advanced Parkinson's disease and one patient on ropinirole extended-release tablets with early Parkinson's disease experienced syncope during the titration period for ropinirole extended-release tablets. Both patients discontinued prematurely from the respective trials. 

Because the trials conducted with ropinirole extended-release tablets excluded patients with significant cardiovascular disease, patients with significant cardiovascular disease should be treated with caution.

Hypotension/Orthostatic Hypotension

Patients with Parkinson’s disease may have impaired ability to respond normally to a fall in blood pressure after standing from lying down or seated position. Patients on ropinirole extended-release tablets should be monitored for signs and symptoms of orthostatic hypotension, especially during dose escalation, and should be informed of the risk for syncope and hypotension [see Patient Counseling Information (17)].

In a placebo-controlled flexible-dose trial in patients with advanced Parkinson’s disease (Study 1), hypotension was reported as an adverse reaction in 2% of patients on ropinirole extended-release tablets, compared with 0% of patients on placebo. In this study, orthostatic hypotension was reported as an adverse reaction in 5% of patients on ropinirole extended-release tablets, and 1% of patients on placebo [see Adverse Reactions (6.1)]. Some patients experienced hypotension or orthostatic hypotension that started in the titration and persisted into the maintenance period. There was also a higher incidence for the combined adverse reaction terms of “hypotension”, “orthostatic hypotension”, “dizziness”, “vertigo”, and “blood pressure decreased” in 7% of patients on ropinirole extended-release tablets compared with 3% of patients on placebo. The increased incidence of those events with ropinirole extended-release tablets was observed in a setting in which patients were very carefully titrated, and patients with clinically relevant cardiovascular disease or symptomatic orthostatic hypotension at baseline had been excluded from this trial. The frequency of orthostatic hypotension (systolic blood pressure decrements ≥20 mm Hg) at any time during the trial was 38% for ropinirole extended-release tablets vs. 31% for placebo.

In a placebo-controlled fixed-dose trial in patients with advanced Parkinson’s disease (Study 2), a decrease in standing systolic blood pressure of ≥20 mm Hg was observed in 26% of patients on ropinirole extended-release tablets compared with 18% of patients on placebo.

In a placebo-controlled fixed-dose trial of patients with early Parkinson's disease (Study 4), a decrease in standing systolic blood pressure of ≥20 mm Hg was observed in 14% of patients on ropinirole extended-release tablets compared with 10% of patients on placebo.

Significant decrements in blood pressure unrelated to standing were also reported in some patients taking ropinirole extended-release tablets. 

Elevation of Blood Pressure and Changes in Heart Rate

The potential for elevation in blood pressure and changes in heart rate should be considered when treating patients with cardiovascular disease with ropinirole extended-release tablets.

In a placebo-controlled flexible-dose trial in patients with advanced Parkinson’s disease (Study 1), the frequency of systolic blood pressure increase (≥40mm Hg) in the semi-supine position was 8% of patients on ropinirole extended-release tablets vs. 5% of patients on placebo. In the standing position, the frequency of systolic blood pressure increase (≥40 mm Hg) was 9% for ropinirole extended-release tablets vs. 6% for placebo. There was no clear effect of ropinirole extended-release tablets on average heart rate.

In a placebo-controlled fixed-dose trial in patients with advanced Parkinson’s disease (Study 2), hypertension was reported as an adverse reaction in 3% of patients on ropinirole extended-release tablets, compared with 1% of patients on placebo [see Adverse Reactions (6.1)].

In a placebo-controlled, fixed-dose trial in patients with early Parkinson’s disease (Study 4), hypertension was reported as an adverse reaction in 5% of patients on ropinirole extended-release tablets, compared with 0% of patients on placebo [see Adverse Reactions (6.1)].

Hallucinations/Psychotic-like Behavior

In a placebo-controlled flexible-dose trial in patients with advanced Parkinson’s disease (Study 1), 8% of patients on ropinirole extended-release tablets reported hallucination, compared with 2% of patients on placebo [see Adverse Reactions (6.1)]. Hallucinations led to discontinuation of treatment in 2% of patients on ropinirole extended-release tablets and 1% of patients on placebo. The incidence of hallucination was increased in elderly patients (i.e., older than 65 years) treated with ropinirole extended-release tablets [see Use in Specific Populations (8.5)].

In a placebo-controlled fixed-dose trial in patients with advanced Parkinson’s disease (Study 2), the incidence of hallucination was 3% in patients on ropinirole extended-release tablets compared with 0% in patients on placebo [see Adverse Reactions (6.1)]. The most common adverse reaction associated with study discontinuation for any dose of ropinirole extended-release tablets was hallucination (2%).

Postmarketing reports indicate that patients may experience new or worsening mental status and behavioral changes, which may be severe, including psychotic-like behavior during treatment with ropinirole or after starting or increasing the dose of ropinirole. Other drugs prescribed to improve the symptoms of Parkinson’s disease can have similar effects on thinking and behavior. This abnormal thinking and behavior can consist of one or more of a variety of manifestations including paranoid ideation, delusions, hallucinations, confusion, psychotic-like behavior, disorientation, aggressive behavior, agitation, and delirium.

Patients with a major psychotic disorder should ordinarily not be treated with ropinirole extended-release tablets because of the risk of exacerbating the psychosis. In addition, certain medications used to treat psychosis may exacerbate the symptoms of Parkinson’s disease and may decrease the effectiveness of ropinirole extended-release tablets [see Drug Interactions (7.3)].

Dyskinesia

Ropinirole extended-release tablets may cause or exacerbate pre-existing dyskinesia in patients treated with L-dopa for Parkinson’s disease.

In a placebo-controlled flexible-dose trial in patients with advanced Parkinson’s disease (Study 1) the incidence of dyskinesia was 13% in patients on ropinirole extended-release tabletsand 3%  in patients on placebo [see Adverse Reactions (6.1)].

In a placebo-controlled, fixed-dose trial in patients with advanced Parkinson’s disease (Study 2), the incidence of dyskinesia was 7% in patients on ropinirole extended-release tablets compared with 1% in patients on placebo [see Adverse Reactions (6.1)].

Decreasing the dose of dopaminergic medications may ameliorate this adverse reaction. 

Impulse Control/Compulsive Behaviors

Reports suggest that patients can experience intense urges to gamble, increased sexual urges, intense urges to spend money, binge or compulsive eating, and/or other intense urges, and the inability to control these urges while taking one or more of the medications, including ropinirole extended-release tablets, 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, binge or compulsive eating, or other urges while being treated with ropinirole extended-release tablets. Physicians should consider dose reduction or stopping the medication if a patient develops such urges while taking ropinirole extended-release tablets.

Withdrawal-Emergent Hyperpyrexia and Confusion

A symptom complex resembling the 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 of, withdrawal of, or changes in, dopaminergic therapy. Therefore, it is recommended that the dose be tapered at the end of treatment with ropinirole extended-release tablets as a prophylactic measure [see Dosage and Administration (2.2)].

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. In the clinical development program (N = 613), 1 patient treated with ropinirole extended-release tablets and also levodopa/carbidopa developed melanoma.

For the reasons stated above, patients and providers are advised to monitor for melanomas frequently and on a regular basis when using ropinirole extended-release tablets. Ideally, periodic skin examinations should be performed by appropriately qualified individuals (e.g., dermatologists). 

Fibrotic Complications

Cases of retroperitoneal fibrosis, pulmonary infiltrates, pleural effusion, pleural thickening, pericarditis, and cardiac valvulopathy have been reported in some patients treated with ergot-derived dopaminergic agents. While these complications may resolve when the drug is discontinued, complete resolution does not always occur.

Although these adverse reactions are believed to be related to the ergoline structure of these compounds, whether other, non-ergot-derived dopamine agonists such as ropinirole, can cause them is unknown.

Cases of possible fibrotic complications, including pleural effusion, pleural fibrosis, interstitial lung disease, and cardiac valvulopathy have been reported in the development program and postmarketing experience for ropinirole. In the clinical development program (N = 613), 2 patients treated with ropinirole extended-release tablets had pleural effusion. While the evidence is not sufficient to establish a causal relationship between ropinirole and these fibrotic complications, a contribution of ropinirole cannot be excluded.

Retinal Pathology

Retinal degeneration was observed in albino rats in the 2-year carcinogenicity study at all doses tested. The lowest dose tested (1.5 mg/kg/day) is less than the maximum recommended human dose (MRHD) of 24 mg/day on a mg/m2 basis. Retinal degeneration was not observed in a 3-month study in pigmented rats, in a 2-year carcinogenicity study in albino mice, or in 1-year studies in monkeys or albino rats. The significance of this effect for humans has not been established, but involves disruption of a mechanism that is universally present in vertebrates (e.g., disk shedding).

Ocular electroretinogram (ERG) assessments were conducted during a 2-year, double-blind, multicenter, flexible-dose, L-dopa-controlled clinical trial of immediate-release ropinirole in patients with Parkinson’s disease; 156 patients (78 on immediate-release ropinirole, mean dose: 11.9 mg/day and 78 on L-dopa, mean dose: 555.2 mg/day) were evaluated for evidence of retinal dysfunction through electroretinograms. There was no clinically meaningful difference between the treatment groups in retinal function over the duration of the trial.

Binding to Melanin

Ropinirole binds to melanin-containing tissues (e.g., eyes, skin) in pigmented rats. After a single dose, long-term retention of drug was demonstrated, with a half-life in the eye of 20 days.

rOPINIRole Extended-Release Tablets 8 mg* (30 Tablets in 1 Bottle)
*Each extended-release tablet contains 9.12 mg ropinirole hydrochloride equivalent to 8 mg ropinirole
NDC 13811-642-30

rOPINIRole Extended-Release Tablets 12 mg* (30 Tablets in 1 Bottle)
*Each extended-release tablet contains 13.68 mg ropinirole hydrochloride equivalent to 12 mg ropinirole
NDC 13811-643-30

• It is used to treat Parkinson's disease.

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• Some drugs may have another patient information leaflet. Check with your pharmacist. If you have any questions about this medicine, please talk with your doctor, nurse, pharmacist, or other health care provider.
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Review Date: October 4, 2017