Mirapex ER

Tell your doctor if you are pregnant or plan to become pregnant.

The FDA categorizes medications based on safety for use during pregnancy. Five categories - A, B, C, D, and X, are used to classify the possible risks to an unborn baby when a medication is taken during pregnancy.

Mirapex ER falls into category C. There are no well-controlled studies in pregnant women. Mirapex ER should be used during pregnancy only if the possible benefit outweighs the possible risk to the unborn baby.

If you take too much Mirapex ER, call your local Poison Control Center or seek emergency medical attention right away.

Taking pramipexole with other drugs that make you sleepy can worsen this effect. Ask your doctor before taking a sleeping pill, narcotic medication, muscle relaxer, or medicine for anxiety, depression, or seizures.

Tell your doctor about all your current medicines and any you start or stop using, especially:

• cimetidine; or

• medicine to treat mental illness (such as chlorpromazine, droperidol, fluphenazine, haloperidol, perphenazine, prochlorperazine, thioridazine, and others).

This list is not complete. Other drugs may interact with pramipexole, including prescription and over-the-counter medicines, vitamins, and herbal products. Not all possible interactions are listed in this medication guide.

This section provides information on the proper use of a number of products that contain pramipexole. It may not be specific to Mirapex ER. Please read with care.

Take this medicine only as directed by your doctor. Do not use more of it, do not use it more often, and do not use it for a longer time than your doctor ordered.

Read the patient information leaflet carefully before you take this medicine. Talk to your doctor if you have any questions.

You may take this medicine with or without food. Taking this medicine with food may reduce nausea.

Swallow the extended-release tablet whole. Do not break, crush, or chew it.

Dosing

The dose of this medicine will be different for different patients. Follow your doctor's orders or the directions on the label. The following information includes only the average doses of this medicine. If your dose is different, do not change it unless your doctor tells you to do so.

The amount of medicine that you take depends on the strength of the medicine. Also, the number of doses you take each day, the time allowed between doses, and the length of time you take the medicine depend on the medical problem for which you are using the medicine.

• For oral dosage form (extended-release tablets):
  • For Parkinson disease:
    • Adults—At first, 0.375 milligram (mg) once a day. Your doctor may adjust your dose as needed. However, the dose is usually not more than 4.5 mg per day.
    • Children—Use and dose must be determined by your doctor.
• For oral dosage form (tablets):
  • For Parkinson disease:
    • Adults—At first, 0.125 milligram (mg) 3 times a day. Your doctor may adjust your dose as needed. However, the dose is usually not more than 4.5 mg per day.
    • Children—Use and dose must be determined by your doctor.
  • For Restless Legs Syndrome:
    • Adults—At first, 0.125 milligram (mg) once a day 2 to 3 hours before bedtime. Your doctor may adjust your dose as needed. However, the dose is usually not more than 0.5 mg per day.
    • Children—Use and dose must be determined by your doctor.

Missed Dose

If you miss a dose of this medicine, take it as soon as possible. However, if it is almost time for your next dose, skip the missed dose and go back to your regular dosing schedule. Do not double doses.

If you miss a dose with the extended-release tablets and it is less than 12 hours since your regular time, take it as soon as you can and take your next dose at the normal time. If you miss a dose and it is more than 12 hours since your regular time, skip the missed dose and take your next dose at the normal time.

Storage

Store the medicine in a closed container at room temperature, away from heat, moisture, and direct light. Keep from freezing.

Keep out of the reach of children.

Do not keep outdated medicine or medicine no longer needed.

Ask your healthcare professional how you should dispose of any medicine you do not use.

It is very important that your doctor check your progress at regular visits. This is to allow for changes in your dose and to check for any unwanted effects.

Do not stop taking this medicine without first checking with your doctor. Your doctor may want you to gradually reduce the amount you are taking before stopping it completely.

People taking pramipexole have reported falling asleep without warning during activities of daily living, including driving, which sometimes resulted in accidents. This may happen as late as one year after taking the medicine. Make sure you know how you react to this medicine before you drive, use machines, or do anything else that could be dangerous if you are not alert, well-coordinated, or able to think or see well.

This medicine will add to the effects of alcohol and other CNS depressants (medicines that make you drowsy or less alert). Some examples of CNS depressants are antihistamines or medicine for hay fever or colds, sedatives, tranquilizers, or sleeping medicine, prescription pain medicine or narcotics, barbiturates or medicine for seizures, muscle relaxants, or anesthetics, including some dental anesthetics. Check with your doctor before taking any of the above while you are taking this medicine.

Dizziness, lightheadedness, or fainting may occur, especially when you get up suddenly from a lying or sitting position. These symptoms are more likely to occur when you begin taking this medicine, or when the dose is increased. Getting up slowly may help. If you have this problem, talk to your doctor.

Hallucinations (seeing, hearing, or feeling things that are not there) may occur in some patients. This is more common with elderly patients. If you have hallucinations, check with your doctor.

Check with your doctor right away if you have dark-colored urine, fever, muscle cramps or spasms, muscle pain or stiffness, or unusual tiredness or weakness. These may be symptoms of a condition called rhabdomyolysis.

Some people who have used this medicine had unusual changes in their behavior, such as having problems with gambling, increased sex drive, or compulsive eating. Talk with your doctor if this is a concern for you.

Do not take other medicines unless they have been discussed with your doctor. This includes prescription or nonprescription (over-the-counter [OTC]) medicines and herbal or vitamin supplements.

• If you have an allergy to pramipexole or any other part of Mirapex ER (pramipexole extended-release tablets).
• If you are allergic to any drugs like this one, any other drugs, foods, or other substances. Tell your doctor about the allergy and what signs you had, like rash; hives; itching; shortness of breath; wheezing; cough; swelling of face, lips, tongue, or throat; or any other signs.
• If you have kidney disease.
• If you are taking another drug that has the same drug in it.

This is not a list of all drugs or health problems that interact with this medicine.

Tell your doctor and pharmacist about all of your drugs (prescription or OTC, natural products, vitamins) and health problems. You must check to make sure that it is safe for you to take Mirapex ER with all of your drugs and health problems. Do not start, stop, or change the dose of any drug without checking with your doctor.

All drugs may cause side effects. However, many people have no side effects or only have minor side effects. Call your doctor or get medical help if any of these side effects or any other side effects bother you or do not go away:

• Headache.
• Upset stomach.
• Hard stools (constipation).
• Not able to sleep.
• Dizziness.
• Feeling sleepy.
• Dry mouth.
• Feeling tired or weak.
• Bad dreams.
• Loose stools (diarrhea).
• Muscle spasm.
• Weight loss.

These are not all of the side effects that may occur. If you have questions about side effects, call your doctor. Call your doctor for medical advice about side effects.

You may report side effects to the FDA at 1-800-FDA-1088. You may also report side effects at http://www.fda.gov/medwatch.

If you think there has been an overdose, call your poison control center or get medical care right away. Be ready to tell or show what was taken, how much, and when it happened.

• 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
• 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
• 1.5 mg white to off-white, oval, extended-release tablets debossed with "ER" on one side and "1.5" on the other side
• 2.25 mg white to off-white, oval, extended-release tablets debossed with "ER" on one side and "2.25" on the other side
• 3 mg white to off-white, oval, extended-release tablets debossed with "ER" on one side and "3.0" on the other side
• 3.75 mg white to off-white, oval, extended-release tablets debossed with "ER" on one side and "3.75" on the other side
• 4.5 mg white to off-white, oval, extended-release tablets debossed with "ER" on one side and "4.5" on the other side

   Falling Asleep During Activities of Daily Living and Somnolence

Patients treated with pramipexole 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 pramipexole tablets, 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 had been reported as late as one year after the initiation of treatment. In placebo-controlled clinical trials in Parkinson's disease, the sudden onset of sleep or sleep attacks were reported in 8 of 387 (2%) patients treated with Mirapex ER tablets compared to 2 of 281 (1%) patients on placebo.

In early Parkinson’s disease, somnolence was reported in 36% of 223 patients treated with Mirapex ER, median dose 3.0 mg/day, compared to 15% of 103 patients on placebo. In advanced Parkinson’s disease, somnolence was reported in 15% of 164 patients treated with Mirapex ER tablets, median dose 3 mg/day, compared to 16% of 178 patients on placebo. It has been reported that falling asleep while engaged in activities of daily living usually occurs in a setting of preexisting 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 Mirapex ER tablets, advise patients of the potential to develop drowsiness, and specifically ask about factors that may increase the risk for somnolence such as the use of concomitant sedating medications or alcohol, the presence of sleep disorders, and concomitant medications that increase pramipexole plasma levels (e.g., cimetidine) [see Clinical Pharmacology (12.3)]. If a patient develops significant daytime sleepiness or episodes of falling asleep during activities that require active participation (e.g., conversations, eating, etc.), MIRAPEX ER tablets should ordinarily be discontinued. If a decision is made to continue Mirapex ER tablets, advise patients not to drive and to avoid other potentially dangerous activities that might result in harm if the patients become somnolent. While dose reduction reduces the degree of somnolence, there is insufficient information to establish that dose reduction will eliminate episodes of falling asleep while engaged in activities of daily living.

   Symptomatic Orthostatic Hypotension

Dopamine agonists, in clinical studies and clinical experience, appear to impair the systemic regulation of blood pressure, with resulting orthostatic hypotension, especially during dose escalation. Parkinson's disease patients, in addition, appear to have an impaired capacity to respond to an orthostatic challenge. For these reasons, Parkinson's disease patients being treated with dopaminergic agonists, including MIRAPEX ER, ordinarily require careful monitoring for signs and symptoms of orthostatic hypotension, especially during dose escalation, and should be informed of this risk. In placebo-controlled clinical trials in Parkinson’s disease, symptomatic orthostatic hypotension was reported in 10 of 387 (3%) patients treated with Mirapex ER tablets compared to 3 of 281 (1%) patients on placebo. One patient of 387 on MIRAPEX ER tablets discontinued treatment due to hypotension.

   Impulse Control/Compulsive Behaviors

Case reports and the results of cross-sectional studies 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 Mirapex ER, 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 Mirapex ER. Physicians should consider dose reduction or stopping the medication if a patient develops such urges while taking MIRAPEX ER.

A total of 1056 patients with Parkinson’s disease who participated in two Mirapex ER placebo-controlled studies of up to 33 weeks duration were specifically asked at each visit about the occurrence of these symptoms. A total of 14 of 387 (4%) treated with Mirapex ER tablets, 12 of 388 (3%) treated with immediate-release pramipexole tablets, and 4 of 281 (1%) treated with placebo reported compulsive behaviors, including pathological gambling, hypersexuality, and/or compulsive buying.

   Hallucinations and Psychotic-like Behavior

In placebo-controlled clinical trials in Parkinson's disease, hallucinations (visual or auditory or mixed) were reported in 25 of 387 (6%) patients treated with Mirapex ER tablets compared to 5 of 281 (2%) patients receiving placebo. Hallucinations led to discontinuation of treatment in 5 of 387 (1%) patients on Mirapex ER tablets.

Age appears to increase the risk of hallucinations attributable to pramipexole. In placebo-controlled clinical trials in Parkinson’s disease, hallucinations were reported in 15 of 162 (9%) patients ≥65 years of age taking Mirapex ER tablets compared to 10 of 225 (4%) patients <65 years of age taking Mirapex ER tablets.

Postmarketing reports with dopamine agonists, including Mirapex ER, indicate that patients may experience new or worsening mental status and behavioral changes, which may be severe, including psychotic-like behavior during treatment with MIRAPEX ER or after starting or increasing the dose of Mirapex ER. 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 dopamine agonists, including Mirapex ER, 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 Mirapex ER [see Drug Interactions (7.1)].

   Dyskinesia

Mirapex ER tablets may potentiate the dopaminergic side effects of levodopa and may cause or exacerbate preexisting dyskinesia.

   Renal Impairment

The elimination of pramipexole is dependent on renal function [see Clinical Pharmacology (12.3)]. Patients with mild renal impairment (a creatinine clearance above 50 mL/min) require no reduction in daily dose. Mirapex ER tablets have not been studied in patients with moderate to severe renal impairment (creatinine clearance <50 mL/min) or on hemodialysis [see Dosage and Administration (2.2), Use in Specific Populations (8.6), and Clinical Pharmacology (12.3)].

   Rhabdomyolysis

In the clinical development program for immediate-release pramipexole tablets, a single case of rhabdomyolysis occurred in a 49-year-old male with advanced Parkinson's disease. The patient was hospitalized with an elevated CPK (10,631 IU/L). The symptoms resolved with discontinuation of the medication.

Advise patients to contact a physician if they experience any unexplained muscle pain, tenderness, or weakness, as these may be symptoms of rhabdomyolysis.

   Retinal Pathology

Human Data
A two-year open-label, randomized, parallel-group safety study of retinal deterioration and vision compared immediate-release pramipexole tablets and immediate-release ropinirole. Two hundred thirty four Parkinson’s disease patients (115 on pramipexole, mean dose 3.0 mg/day and 119 on ropinirole, mean dose 9.5 mg/day) were evaluated using a panel of clinical ophthalmological assessments.  Of 234 patients who were evaluable, 196 had been treated for two years and 29 were judged to have developed clinical abnormalities that were considered meaningful (19 patients in each treatment arm had received treatment for less than two years).  There was no statistical difference in retinal deterioration between the treatment arms; however, the study was only capable of detecting a very large difference between treatments.  In addition, because the study did not include an untreated comparison group (placebo treated), it is unknown whether the findings reported in patients treated with either drug are greater than the background rate in an aging population.

Animal Data
Pathologic changes (degeneration and loss of photoreceptor cells) were observed in the retina of albino rats in a 2-year carcinogenicity study. While retinal degeneration was not diagnosed in pigmented rats treated for 2 years, a thinning in the outer nuclear layer of the retina was slightly greater in rats given drug compared with controls. Evaluation of the retinas of albino mice, monkeys, and minipigs did not reveal similar changes. The potential significance of this effect for humans has not been established, but cannot be disregarded because disruption of a mechanism that is universally present in vertebrates (i.e., disk shedding) may be involved [see Nonclinical Toxicology (13.2)].

   Events Reported with Dopaminergic Therapy

Although the events enumerated below may not have been reported with the use of pramipexole in its development program, they are associated with the use of other dopaminergic drugs. The expected incidence of these events, however, is so low that even if pramipexole caused these events at rates similar to those attributable to other dopaminergic therapies, it would be unlikely that even a single case would have occurred in a cohort of the size exposed to pramipexole in studies to date.

Hyperpyrexia and Confusion
Although not reported with pramipexole in the clinical development program, 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, withdrawal of, or changes in dopaminergic therapy. If possible, avoid sudden discontinuation or rapid dose reduction in patients taking Mirapex ER tablets. If the decision is made to discontinue Mirapex ER tablets, the dose should be tapered to reduce the risk of hyperpyrexia and confusion [see Dosage and Administration (2.2)].

Fibrotic Complications
Cases of retroperitoneal fibrosis, pulmonary infiltrates, pleural effusion, pleural thickening, pericarditis, and cardiac valvulopathy have been reported in 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 events are believed to be related to the ergoline structure of these compounds, whether other, non-ergot derived dopamine agonists can cause them is unknown.

Cases of possible fibrotic complications, including peritoneal fibrosis, pleural fibrosis, and pulmonary fibrosis have been reported in the postmarketing experience with immediate-release pramipexole tablets. While the evidence is not sufficient to establish a causal relationship between pramipexole and these fibrotic complications, a contribution of pramipexole cannot be completely ruled out.

Melanoma
Epidemiologic 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 observed increased risk was due to Parkinson’s disease or other factors, such as drugs used to treat Parkinson’s disease, is unclear.

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

Applies to pramipexole: oral tablet, oral tablet extended release

General

The most common adverse reactions occurring in early Parkinson's disease when used without levodopa were somnolence, insomnia, nausea, constipation, dizziness, fatigue, asthenia, hallucinations, dry mouth, muscle spasms, and peripheral edema. In advanced Parkinson's disease when used with levodopa, the more common adverse reactions included postural hypotension, dyskinesia, extrapyramidal syndrome, insomnia, abnormal dreams, confusion, asthenia, dystonia, somnolence, hypertonia, dry mouth, amnesia, urinary frequency, dizziness, nausea, constipation, hallucinations, headache, and anorexia.

The most common adverse reactions occurring in patients receiving treatment for Restless Legs Syndrome were nausea, somnolence, fatigue, and headache.[Ref]

Nervous system

Early Parkinson's disease:
Very common (10% or more): Somnolence (up to 36%), dizziness (up to 25%), dyskinesia (17%)
Common (1% to 10%): Headache, hypesthesia, dystonia, myoclonus, akathisia, tremor, balance disorder, amnesia, abnormal thinking
Frequency not reported: Restlessness

Advanced Parkinson's disease:
Very common (10% or more): Dyskinesia (up to 47%), extrapyramidal syndrome (28%), dizziness (up to 26%),
Common (1% to 10%): Somnolence, dystonia, gait abnormalities, hypertonia, headache

Restless Legs Syndrome:
Very common (10% or more): Augmentation (12%), headache (17%)
Common (1% to 10%): Worsening of Restless Legs Syndrome, somnolence
Uncommon (0.1% to 1%): Dyskinesia
Postmarketing reports: Amnesia, hyperkinesia[Ref]

In a 26-week clinical trial, worsening of Restless Legs Syndrome (RLS) occurred in 10% of patients suddenly withdrawn from pramipexole 0.75 mg once a day compared to 2% of placebo patients; the RLS symptoms were generally considered mild. Augmentation was reported in 12% and 9% of patients receiving pramipexole 0.75 mg once a day and placebo, respectively. The incidence of augmentation increased with increasing duration of exposure.[Ref]

Psychiatric

Parkinson's disease:
Very common (10% or more): Hallucinations (17%), insomnia (27%), dream abnormalities (11%), confusion (10%)
Common (1% to 10%): Paranoid reaction, delusions, confusion, sleep attacks, sleep disorder, depression
Uncommon (0.1% to 1%): Hypersexuality, pathological gambling, delirium
Rare (less than 0.1%): Mania
Frequency not reported: Impulse control/compulsive behaviors
Postmarketing reports: New or worsening mental status and behavioral changes, binge eating, compulsive shopping

Restless Legs Syndrome:
Very common (10% or more): Insomnia (up to 13%)
Common (1% to 10%): Abnormal dreams
Uncommon (0.1% to 1%): Hypersexuality, pathological gambling, delirium
Rare (less than 0.1%): Mania
Frequency not reported: Impulse control/compulsive behaviors
Postmarketing reports: New or worsening mental status and behavioral changes, binge eating, compulsive shopping[Ref]

Gastrointestinal

Very common (10% or more): Nausea (28%), constipation (14%)
Common (1% to 10%): Dysphagia, dry mouth, diarrhea, dyspepsia, vomiting, upper abdominal pain, abdominal discomfort, salivary hypersecretion
Uncommon (0.1% to 1%): Hiccup
Frequency not reported: Hyperphagia
Postmarketing reports: Peritoneal fibrosis[Ref]

Nausea and vomiting were commonly reported early in therapy and resolved with continued therapy. While there have been postmarketing reports of fibrotic complications including peritoneal fibrosis, pleural fibrosis, and pulmonary fibrosis, the evidence is not sufficient to establish a causal relationship with use of this drug; however a contribution of treatment cannot be completely ruled out.[Ref]

Cardiovascular

Very common (10% or more): Postural hypotension (up to 53%)
Common (1% to 10%): Chest pain, general edema
Postmarketing reports: Cardia failure, syncope[Ref]

Cardiovascular side effects have included orthostatic hypotension, with or without symptoms, although the overall incidence was not significantly different from that in placebo-treated patients. In advanced Parkinson's disease trials, postural hypotension was reported in 53% (n=260) of patients receiving immediate-release pramipexole compared with 48% (n=264) of patients receiving placebo. In fixed-dose trials in early Parkinson's disease, orthostatic hypotension was shown to be dose related with a frequency 2-fold greater than placebo for doses greater than 1.5 mg/day. Among patients with advanced Parkinson's disease treated concomitantly with levodopa, orthostatic hypotension was reported much more frequently than in those with early disease and not receiving levodopa.

In a pharmacoepidemiology study, pramipexole use was associated with an increased risk of cardiac failure compared with non-use (observed risk ratio: 1.86; 95% confidence interval, 1.21 to 2.85).[Ref]

Genitourinary

Common (1% to 10%): Urinary frequency, urinary tract infection, urinary incontinence, impotence[Ref]

Musculoskeletal

One case of rhabdomyolysis occurred in a 49- year old male patient with advanced Parkinson's disease receiving pramipexole (the active ingredient contained in Mirapex ER) His creatinine phosphokinase level was elevated to 10,631 IU/L. His symptoms resolved with discontinuation of the medication.[Ref]

Common (1% to 10%): Arthritis, twitching, bursitis, myasthenia, extremity pain, back pain, muscle spasms, increased creatine phosphokinase
Very rare (less than 0.01%): Rhabdomyolysis[Ref]

Ocular

Common (1% to 10%): Vision abnormalities, accommodation abnormalities, diplopia,
Frequency not reported: Blurred vision[Ref]

Dermatologic

Common (1% to 10%): Skin disorders
Frequency not reported: Pruritus[Ref]

Respiratory

Common (1% to 10%): Dyspnea, rhinitis, pneumonia, nasal congestion, cough
Uncommon (0.1% to 1%): Pneumonia
Postmarketing reports: Pleural fibrosis, pulmonary fibrosis[Ref]

There have been postmarketing reports of fibrotic complications including peritoneal fibrosis, pleural fibrosis, and pulmonary fibrosis, the evidence is not sufficient to establish a causal relationship with use of this drug; however a contribution of treatment cannot be completely ruled out.[Ref]

Metabolic

Common (1% to 10%): Decreased weight, increased appetite, anorexia
Postmarketing reports: Increased weight[Ref]

Other

Very common (10% or more): Asthenia (up to 14%)
Common (1% to 10%): Malaise, fever, vertigo[Ref]

Endocrine

Frequency not reported: Libido disorders
Postmarketing reports: Inappropriate antidiuretic hormone secretion (SIADH)[Ref]

Hypersensitivity

Frequency not reported: Rash and other hypersensitivity reactions[Ref]

Immunologic

Common (1% to 10%): Influenza[Ref]

Some side effects of Mirapex ER may not be reported. Always consult your doctor or healthcare specialist for medical advice. You may also report side effects to the FDA.