Mirapex ER

Name: Mirapex ER

Mirapex ER Drug Class

Mirapex ER is part of the drug class:

  • Dopamine agonists

Mirapex ER Precautions

Mirapex ER may cause serious side effects, including:

  • falling asleep during normal daily activities. Mirapex ER may cause you to fall asleep while you are doing daily activities such as driving, talking with other people, or eating.
    • Some people taking the medicine in Mirapex ER have had car accidents because they fell asleep while driving.
    • Some patients did not feel sleepy before they fell asleep while driving. You could fall asleep without any warning.
      Tell your doctor right away if you fall asleep while you are doing activities such as talking, eating, driving, or if you feel sleepier than normal for you.
  • low blood pressure when you sit or stand up quickly. You may have:
    • dizziness
    • nausea
    • fainting
    • sweating
      Sit and stand up slowly after you have been sitting or lying down.
  • unusual urges. Some people who take certain medicines to treat Parkinson’s disease, including Mirapex ER, have reported problems, such as gambling, compulsive eating, compulsive buying, and increased sex drive.
    If you or your family members notice that you are developing unusual urges or behaviors, talk to your doctor.
  • seeing visions, hearing sounds or feeling sensations that are not real (hallucinations). Your chance of having hallucinations is higher if you are elderly (age 65 or older).
    If you have hallucinations, talk with your doctor right away.
  • uncontrolled sudden movements (dyskinesia). If you have new dyskinesia or your existing dyskinesia gets worse tell your doctor.
  • skin cancer (melanoma). Some people with Parkinson’s disease may have a higher chance of having melanoma than people who do not have Parkinson’s disease. It is not known if the chance of having melanoma is higher because of the medicines to treat Parkinson’s disease, like Mirapex ER, or from the Parkinson’s disease. People who take Mirapex ER should have regular skin examinations to check for melanoma.

Do not drink alcohol while taking Mirapex ER. It can increase your chance of having serious side effects. 

Do not drive a car, operate a machine, or do other dangerous activities until you know how Mirapex ER affects you. Sleepiness caused by Mirapex ER can happen as late as 1 year after you start your treatment.

Mirapex ER Usage

  • Take Mirapex ER exactly as your doctor tells you to. Your doctor will tell you how many Mirapex ER tablets to take and when to take them.
  • Your doctor may change your dose until you are taking the right amount of medicine to control your symptoms. Do not take more or less Mirapex ER than your doctor tells you to.
  • Mirapex ER can be taken with or without food. Taking Mirapex ER with food may lower your chances of getting nausea.
  • Swallow extended release tablet whole. Do not chew, crush, or divide extended release tablets.
  • If you miss a dose, do not double your next dose. Skip the dose you missed and take your next regular dose.
  • Be sure to tell your doctor right away if you stop taking Mirapex ER for any reason. Do not start taking Mirapex ER again before speaking with your doctor. If you have Parkinson’s disease and are stopping Mirapex ER, you should stop pramipexole slowly over 7 days.

What is the most important information I should know about Mirapex ER (pramipexole)?

Follow all directions on your medicine label and package. Tell each of your healthcare providers about all your medical conditions, allergies, and all medicines you use.

What happens if I overdose?

Seek emergency medical attention or call the Poison Help line at 1-800-222-1222.

Uses of Mirapex ER

  • It is used to treat Parkinson's disease.
  • It may be given to you for other reasons. Talk with the doctor.

What are some things I need to know or do while I take Mirapex ER?

  • Tell all of your health care providers that you take this medicine. This includes your doctors, nurses, pharmacists, and dentists.
  • Avoid driving and doing other tasks or actions that call for you to be alert until you see how Mirapex ER affects you.
  • To lower the chance of feeling dizzy or passing out, rise slowly if you have been sitting or lying down. Be careful going up and down stairs.
  • Have your blood pressure checked often. Talk with your doctor.
  • Do not stop taking this medicine all of a sudden without calling your doctor. You may have a greater risk of side effects. If you need to stop Mirapex ER, you will want to slowly stop it as ordered by your doctor.
  • Avoid drinking alcohol while taking this medicine.
  • Talk with your doctor before you use other drugs and natural products that slow your actions.
  • The chance of a type of skin cancer called melanoma may be raised in people with Parkinson's disease. It is not known if Mirapex ER may also raise the chance. Have skin exams while you take this medicine. Talk with your doctor.
  • You may see something that looks like the tablet in your stool. If this happens, talk with your doctor.
  • If you are 65 or older, use Mirapex ER with care. You could have more side effects.
  • Tell your doctor if you are pregnant or plan on getting pregnant. You will need to talk about the benefits and risks of using this medicine while you are pregnant.
  • Tell your doctor if you are breast-feeding. You will need to talk about any risks to your baby.

Drug interactions

   Dopamine Antagonists

Since pramipexole is a dopamine agonist, it is possible that dopamine antagonists, such as the neuroleptics (phenothiazines, butyrophenones, thioxanthenes) or metoclopramide, may diminish the effectiveness of Mirapex ER tablets.

Clinical pharmacology

  Mechanism of Action

Pramipexole is a non-ergot dopamine agonist with high relative in vitro specificity and full intrinsic activity at the D2 subfamily of dopamine receptors, binding with higher affinity to D3 than to D2 or D4 receptor subtypes.

The precise mechanism of action of pramipexole as a treatment for Parkinson's disease is unknown, although it is believed to be related to its ability to stimulate dopamine receptors in the striatum. This conclusion is supported by electrophysiologic studies in animals that have demonstrated that pramipexole influences striatal neuronal firing rates via activation of dopamine receptors in the striatum and the substantia nigra, the site of neurons that send projections to the striatum.  The relevance of D3 receptor binding in Parkinson’s disease is unknown.

  Pharmacodynamics

The effect of pramipexole on the QT interval of the ECG was investigated in a clinical study in 60 healthy male and female volunteers. All subjects initiated treatment with 0.375 mg Mirapex ER tablets administered once daily, and were up-titrated every 3 days to 2.25 mg and 4.5 mg daily, a faster rate of titration than recommended in the label. No dose- or exposure-related effect on mean QT intervals was observed; however, the study did not have a valid assessment of assay sensitivity. The effect of pramipexole on QTc intervals at higher exposures achieved either due to drug interactions (e.g., with cimetidine), renal impairment, or at higher doses has not been systematically evaluated.

Although mean values remained within normal reference ranges throughout the study, supine systolic blood pressure (SBP), diastolic blood pressure (DBP), and pulse rate for subjects treated with pramipexole generally increased during the rapid up-titration phase, by 10 mmHg, 7 mmHg, and 10 bpm higher than placebo, respectively. Higher SBP, DBP, and pulse rates compared to placebo were maintained until the pramipexole doses were tapered; values on the last day of tapering were generally similar to baseline values. Such effects have not been observed in clinical studies with Parkinson’s disease patients, who were titrated according to labeled recommendations.

  Pharmacokinetics

Mirapex ER tablets, like immediate-release pramipexole tablets, display linear pharmacokinetics over the entire clinical dosage range.  Slow release of pramipexole from Mirapex ER tablets with once-daily administration results in the same daily maximum and minimum pramipexole plasma concentrations (Cmax, Cmin) as three times daily administration of immediate-release pramipexole tablets.

Absorption
The absolute bioavailability of pramipexole is greater than 90%, indicating that it is well absorbed and undergoes little presystemic metabolism.

Increase in systemic exposure of pramipexole following oral administration of 0.375 mg to 4.5 mg of Mirapex ER tablets was dose-proportional. For Mirapex ER tablets, steady state of exposure is reached within 5 days of continuous dosing.

Relative bioavailability of Mirapex ER tablets compared with immediate-release tablets was approximately 100%. In a repeat-dose study in healthy, normal volunteers, Mirapex ER tablets 4.5 mg administered once daily was bioequivalent with regard to Cmax and AUC over 24 hours to immediate-release pramipexole tablets 1.5 mg administered three times daily. The average time-to-peak concentration for MIRAPEX ER tablets is 6 hours. Administration of Mirapex ER tablets with food (i.e., high-fat meal) did not affect AUC but increased Cmax by approximately 20% and delayed Tmax by approximately 2 hours compared with dosing under fasted conditions; these differences are not considered to be clinically relevant [see Dosage and Administration (2.1)].

Distribution
Pramipexole is extensively distributed, having a volume of distribution of about 500 L (coefficient of variation [CV] = 20%). It is about 15% bound to plasma proteins. Pramipexole distributes into red blood cells as indicated by an erythrocyte-to-plasma ratio of approximately 2.

Metabolism
Pramipexole is metabolized only to a negligible extent (<10%). No specific active metabolite has been identified in human plasma or urine.

Elimination
Urinary excretion is the major route of pramipexole elimination, with 90% of a pramipexole dose recovered in urine, almost all as unchanged drug. The renal clearance of pramipexole is approximately 400 mL/min (CV=25%), approximately three times higher than the glomerular filtration rate. Thus, pramipexole is secreted by the renal tubules, probably by the organic cation transport system.

Pharmacokinetics in Specific Populations
Because therapy with Mirapex ER tablets is initiated at a low dose and gradually titrated upward according to clinical tolerability to obtain the optimum therapeutic effect, adjustment of the initial dose based on gender, weight, race, or age is not necessary. However, renal insufficiency causes a large decrease in the ability to eliminate pramipexole. This will necessitate dosage adjustment in patients with moderate to severe renal impairment [see Dosage and Administration (2.2)].

Gender
Pramipexole clearance is about 30% lower in women than in men, but this difference can be accounted for by differences in body weight. There is no difference in plasma half-life between males and females.

Age
Pramipexole clearance is reduced by approximately 30% in the elderly (aged 65 years or older) compared with young, healthy volunteers (aged less than 40 years). This difference is most likely due to the reduction in renal function with age, since pramipexole clearance is correlated with renal function, as measured by creatinine clearance.

Race
No racial differences in metabolism and elimination have been identified.

Hepatic Impairment
The influence of hepatic insufficiency on pramipexole pharmacokinetics has not been evaluated. Because approximately 90% of the recovered dose is excreted in the urine as unchanged drug, hepatic impairment would not be expected to have a significant effect on pramipexole elimination.

Renal Impairment
Clearance of immediate-release pramipexole was about 75% lower in patients with severe renal impairment (creatinine clearance approximately 20 mL/min) and about 60% lower in patients with moderate impairment (creatinine clearance approximately 40 mL/min) compared with healthy volunteers [see Dosage and Administration (2.2) and Warnings and Precautions (5.6)]. In patients with varying degrees of renal impairment, pramipexole clearance correlates well with creatinine clearance. Therefore, creatinine clearance can be used as a predictor of the extent of decrease in pramipexole clearance.

Drug Interactions
No specific pharmacokinetic drug interaction trials were conducted with Mirapex ER tablets since the potential for drug interactions mainly depends on the active drug substance pramipexole and not the formulation. The following interaction data were obtained using immediate-release pramipexole tablets.

Carbidopa/levodopa: Carbidopa/levodopa did not influence the pharmacokinetics of pramipexole in healthy volunteers (N=10). Pramipexole did not alter the extent of absorption (AUC) or the elimination of carbidopa/levodopa, although it caused an increase in levodopa Cmax by about 40% and a decrease in Tmax from 2.5 to 0.5 hours.

Selegiline: In healthy volunteers (N=11), selegiline did not influence the pharmacokinetics of pramipexole.

Amantadine: Population pharmacokinetic analyses suggest that amantadine may slightly decrease the oral clearance of pramipexole.

Cimetidine: Cimetidine, a known inhibitor of renal tubular secretion of organic bases via the cationic transport system, caused a 50% increase in pramipexole AUC and a 40% increase in half-life (N=12).

Probenecid: Probenecid, a known inhibitor of renal tubular secretion of organic acids via the anionic transporter, did not noticeably influence pramipexole pharmacokinetics (N=12).

Other drugs eliminated via renal secretion: Population pharmacokinetic analysis suggests that co-administration of drugs that are secreted by the cationic transport system (e.g., cimetidine, ranitidine, diltiazem, triamterene, verapamil, quinidine, and quinine) decreases the oral clearance of pramipexole by about 20%, while those secreted by the anionic transport system (e.g., cephalosporins, penicillins, indomethacin, hydrochlorothiazide, and chlorpropamide) are likely to have little effect on the oral clearance of pramipexole. Other known organic cation transport substrates and/or inhibitors (e.g., cisplatin and procainamide) may also decrease the clearance of pramipexole.

CYP interactions: Inhibitors of cytochrome P450 enzymes would not be expected to affect pramipexole elimination because pramipexole is not appreciably metabolized by these enzymes in vivo or in vitro. Pramipexole does not inhibit CYP enzymes CYP1A2, CYP2C9, CYP2C19, CYP2E1, and CYP3A4. Inhibition of CYP2D6 was observed with an apparent Ki of 30 μM, indicating that pramipexole will not inhibit CYP enzymes at plasma concentrations observed following the clinical dose of 4.5 mg/day.

Drugs affecting gastrointestinal motility or gastric pH:
Population pharmacokinetic analysis suggests that co-administration of antacids (N=6) decreased the oral clearance of pramipexole by about 25%, while H2-blockers (N=5), anticholinergics (N=27), propulsive (N=7), and proton pump inhibitors (N=16) are likely to have little effect on the oral clearance of pramipexole.

How supplied/storage and handling

  How Supplied

Mirapex ER tablets are available as follows:

0. 375 mg: white to off-white, round, bevel-edged, extended-release tablets debossed with "ER" on one side and "0.375" on the other side.
   Unit of Use Bottles of 7          NDC 0597-0109-17  
   Unit of Use Bottles of 30        NDC 0597-0109-30

0.75 mg: white to off-white, round, bevel-edged, extended-release tablets debossed with "ER" on one side and "0.75" on the other side.
   Unit of Use Bottles of 7          NDC 0597-0285-17 
   Unit of Use Bottles of 30        NDC 0597-0285-30

1.5 mg: white to off-white, oval, extended-release tablets debossed with "ER" on one side and "1.5" on the other side.
   Unit of Use Bottles of 7          NDC 0597-0113-17   
   Unit of Use Bottles of 30        NDC 0597-0113-30

2.25 mg: white to off-white, oval, extended-release tablets debossed with "ER" on one side and "2.25" on the other side.
   Unit of Use Bottles of 30        NDC 0597-0286-30   

3 mg: white to off-white, oval, extended-release tablets debossed with "ER" on one side and "3.0" on the other side.
   Unit of Use Bottles of 30        NDC 0597-0115-30

3.75 mg: white to off-white, oval, extended-release tablets debossed with "ER" on one side and "3.75" on the other side.
   Unit of Use Bottles of 30        NDC 0597-0287-30

4.5 mg: white to off-white, oval, extended-release tablets debossed with "ER" on one side and "4.5" on the other side.
   Unit of Use Bottles of 30        NDC 0597-0116-30

  Storage and Handling


Store at 25°C (77°F); excursions permitted to 15°-30°C (59°-86°F) [see USP Controlled Room Temperature]. Protect from exposure to high humidity. Store in a safe place out of the reach of children.

For the Consumer

Applies to pramipexole: oral tablet, oral tablet extended release

Along with its needed effects, pramipexole (the active ingredient contained in Mirapex ER) may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Check with your doctor immediately if any of the following side effects occur while taking pramipexole:

More common
  • Dizziness, lightheadedness, or fainting, especially when standing up suddenly from a sitting/lying position
  • drowsiness
  • hallucinations (seeing, hearing, or feeling things that are not there)
  • nausea
  • trouble sleeping
  • twitching, twisting, or other unusual body movements
  • unusual tiredness or weakness
Less common
  • Confusion
  • cough
  • difficulty with swallowing
  • double vision or other changes in vision
  • falling asleep without warning
  • fearfulness, suspiciousness, or other mental changes
  • fever
  • frequent urination
  • memory loss
  • muscle or joint pain
  • muscle weakness
  • restlessness or need to keep moving
  • swelling of the body
  • tightness in the chest
  • troubled breathing
  • writhing, twisting, or other unusual body movements
Rare
  • Abnormal thinking
  • anxiety
  • bloody or cloudy urine
  • chest pain
  • difficult, burning, or painful urination
  • dizziness
  • frequent urge to urinate
  • loss of bladder control
  • swelling of the arms or legs

Some side effects of pramipexole may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

More common
  • Constipation
  • dryness of the mouth
  • headache
  • heartburn, indigestion, or acid stomach
Less common
  • Abnormal dreams
  • decreased sexual drive or ability
  • general feeling of discomfort or illness
  • increased cough
  • increased sweating
  • itching
  • joint pain
  • loss of appetite
  • runny nose
  • skin problems, such as rash or itching
  • weight loss

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