Gocovri

Dosing Information

The initial daily dosage of GOCOVRI is 137 mg, administered orally once daily at bedtime. After one week, increase to the recommended dosage of 274 mg (two 137 mg capsules) once daily at bedtime.  GOCOVRI is not interchangeable with other amantadine immediate- or extended-release products.

Administration Information

GOCOVRI should be swallowed whole. Do not crush, chew or divide capsules. If needed, GOCOVRI may be administered by carefully opening and sprinkling the entire contents on a small amount (teaspoonful) of soft food, such as applesauce. The drug/food mixture should be swallowed immediately without chewing. Do not store mixture for future use.

GOCOVRI can be taken with or without food [see Clinical Pharmacology ( 12.3)].

Concomitant use of GOCOVRI with alcohol is not recommended [see Drug Interactions ( 7.4)].

It is recommended to avoid sudden discontinuation of GOCOVRI [see Dosage and Administration ( 2.4)].

Dosing in Patients with Renal Impairment

The initial and maximum recommended daily dosage of GOCOVRI for patients with renal impairment (creatinine clearance estimated by Modification of Diet in Renal Disease (MDRD) method) is provided below.

Discontinuation and Missed Dose

Rapid dose reduction or withdrawal of GOCOVRI may cause adverse reactions [see Warnings and Precautions ( 5.5)]. Therefore, to discontinue GOCOVRI in patients who have been on the drug for more than 4 weeks, GOCOVRI dosage should, if possible, be reduced by half for the final week of dosing.

If a dose of GOCOVRI is missed, the next dose should be taken as scheduled.

Pregnancy

Risk Summary

There are no adequate data on the developmental risk associated with use of amantadine in pregnant women. Animal studies suggest a potential risk for fetal harm with amantadine. In mice and rats, adverse developmental effects (embryolethality, increased incidence of malformations, and reduced fetal body weight) were observed when amantadine was administered to pregnant animals at clinically relevant doses [ see Data].

In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. The background risk for major birth defects and miscarriage in patients with Parkinson’s disease is unknown.

Data

Animal Data

The effects of amantadine on development have not been tested in studies conducted in animals using currently recommended methodology; however, developmental toxicity studies of amantadine have been reported in the published literature.

In mice, oral administration of amantadine (0, 10, or 40 mg/kg/day) to pregnant animals during organogenesis (gestation days 7-12) resulted in embryolethality and reduced fetal body weight at the highest dose tested, which was associated with maternal toxicity. The no-effect dose for developmental toxicity in mice (10 mg/kg/day) is less than the recommended human dose (RHD) of 274 mg/day, based on body surface area (mg/m 2).

In rats, oral administration of amantadine (0, 40 or 120 mg/kg/day) to pregnant animals during organogenesis (gestation days 7-12) resulted in embryolethality and reduced fetal body weight at the highest dose. The no-effect dose for developmental toxicity in this study (40 mg/kg/day) is approximately equal to the RHD on a mg/m 2basis.

In another study in pregnant rats, oral administration of amantadine during organogenesis (gestation days 7-14) resulted in an increase in visceral and skeletal malformations at oral doses of 50 and 100 mg/kg/day. The no-effect dose for teratogenicity in this study (37 mg/kg/day) is approximately equal to the RHD on a mg/m 2basis.

Evaluation of parturition, lactation, and post-natal development in a limited number of litters from the mouse and rat studies described above revealed reductions in live litter size and pup weights at birth at 40 mg/kg/day in mice and 120 mg/kg/day in rats.

Lactation

Risk Summary

Amantadine is excreted into human milk, but amounts have not been quantified. There is no information on the risk to a breastfed infant.

Amantadine may alter breast milk production or excretion [see Data].

The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for GOCOVRI and any potential adverse effects on the breastfed infant from GOCOVRI or from the underlying maternal condition.

Data

In published studies, amantadine reduced serum prolactin levels and the symptoms of galactorrhea in patients taking neuroleptic drugs. The effect of amantadine on milk supply has not been evaluated in nursing mothers.

Pediatric Use

The safety and effectiveness of GOCOVRI in pediatric patients have not been established.

Geriatric Use

The majority of people with Parkinson’s disease are 65 years and older. In Phase 3 clinical trials, the mean age of patients at study entry was 65 years. Of the total number of patients in clinical studies of GOCOVRI, 46% were less than 65 years of age, 39% were 65-74 years of age, and 15% were 75 years of age or older.

Hallucinations and falls occurred more frequently in patients 65 years of age or older, compared to those less than 65 years of age [see Adverse Reactions ( 6.1)].

No dose adjustment is recommended on the basis of age. GOCOVRI is known to be substantially excreted by the kidney, and the risk of adverse reactions may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function [see Dosage and Administration ( 2.3)].

. Renal Impairment

GOCOVRI is contraindicated for use in patients with end-stage renal disease (creatinine clearance values lower than 15 mL/min/1.73 m 2).

For patients with moderate renal impairment (creatinine clearance between 30 and 59 mL/min/1.73 m 2), a 50% dose reduction of GOCOVRI dosage to a starting daily dose of 68.5 mg daily at bedtime for a week, to a maximum dosage of 137 mg daily at bedtime is recommended.

For patients with severe renal impairment (creatinine clearance between 15 and 29 mL/min/1.73 m 2), a daily dose of 68.5 mg at bedtime is the recommended initial and maximum dosage [see Dosage and Administration ( 2.3)] .

Creatinine clearance values are estimated by the Modification of Diet in Renal Disease (MDRD) method.

Falling Asleep During Activities of Daily Living and Somnolence

Patients treated for Parkinson’s disease have reported falling asleep while engaged in activities of daily living, including the operation of motor vehicles, which sometimes has resulted in accidents. Patients may not perceive warning signs, such as excessive drowsiness, or they may report feeling alert immediately prior to the event. In controlled clinical trials, somnolence and fatigue were reported as adverse reactions in 4% of patients treated with GOCOVRI 274 mg and 1% for placebo.

Before initiating treatment with GOCOVRI, advise patients of the potential to develop drowsiness and specifically ask about factors that may increase the risk for somnolence with GOCOVRI, such as concomitant sedating medications or the presence of a sleep disorder. If a patient develops daytime sleepiness or episodes of falling asleep during activities that require full attention (e.g., driving a motor vehicle, conversations, eating), GOCOVRI should ordinarily be discontinued.

If a decision is made to continue GOCOVRI, patients should be advised not to 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 or daytime somnolence.

Suicidality and Depression

In controlled clinical trials, suicidal ideation or suicide attempt was reported in 2% of GOCOVRI-treated patients and 0% of placebo-treated patients. Depression or depressed mood was reported in 6% of GOCOVRI-treated patients and 1% of placebo-treated patients. Confusional state was reported in 3% of GOCOVRI-treated patients and 2% of placebo-treated patients. Apathy was reported in 2% of GOCOVRI-treated patients and 0% of placebo-treated patients.

Monitor patients for depression, including suicidal ideation or behavior. Prescribers should consider whether the benefits outweigh the risks of treatment with GOCOVRI in patients with a history of suicidality or depression.

Hallucinations/Psychotic Behavior

Patients with a major psychotic disorder should ordinarily not be treated with GOCOVRI because of the risk of exacerbating psychosis. In controlled trials, the incidence of patients who experienced visual hallucinations, auditory hallucinations, delusions, illusions, or paranoia was 25% in patients treated with GOCOVRI 274 mg, and 3% in placebo-treated patients. Hallucinations caused discontinuation of treatment in 8% of GOCOVRI-treated patients, and in 0% of placebo-treated patients.

Observe patients for the occurrence of hallucinations throughout treatment, especially at initiation, and after dose increases.

Dizziness and Orthostatic Hypotension

In controlled clinical trials, 29% of GOCOVRI-treated patients and 2% of placebo-treated patients experienced dizziness, syncope, orthostatic hypotension, presyncope, postural dizziness or hypotension. In GOCOVRI-treated patients, 3% discontinued study treatment because of dizziness, postural dizziness, or syncope, compared to 0% of placebo-treated patients.

Monitor patients for dizziness and orthostatic hypotension, especially after starting GOCOVRI or increasing the dose. Concomitant use of alcohol when using GOCOVRI is not recommended [see Drug Interactions ( 7.4)].

Withdrawal-Emergent Hyperpyrexia and Confusion

A symptom complex resembling 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 drugs that increase central dopaminergic tone.

Abrupt discontinuation of GOCOVRI may cause an increase in the symptoms of Parkinson’s disease or cause delirium, agitation, delusions, hallucinations, paranoid reaction, stupor, anxiety, depression, or slurred speech. It is recommended to avoid sudden discontinuation of GOCOVRI [see Dosing Information ( 2.4)].

Impulse Control/Compulsive Behaviors

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 GOCOVRI, that increase central dopaminergic tone. In some cases, 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 GOCOVRI. Consider dose reduction or stopping the medication if a patient develops such urges while taking GOCOVRI.