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Gocovri prescribing information
Warnings and Precautions (Corneal edema has been reported in patients taking amantadine. Symptoms include sudden onset of blurry vision, or progressive vision loss, with or without eye pain. Corneal involvement is usually bilateral. Onset can occur from a few weeks to several years after starting amantadine. Resolution of symptoms typically begins within weeks of amantadine cessation. However, corneal grafts have been required in some patients when the condition is not recognized. Permanent damage can occur if amantadine is continued. Ask patients if their vision has changed and obtain ophthalmologic examinations to rule out corneal edema should vision changes occur after initiation of therapy with GOCOVRI. If corneal edema occurs, taper and discontinue GOCOVRI [see Dosage and Administration (2.4)] . | 7/2025 |
GOCOVRI
®is indicated:
- For the treatment of dyskinesia in patients with Parkinson's disease receiving levodopa-based therapy, with or without concomitant dopaminergic medications
- As adjunctive treatment to levodopa/carbidopa in patients with Parkinson's disease experiencing "off" episodes
GOCOVRI is available as extended-release capsules for oral administration. Each capsule contains 68.5 mg or 137 mg of amantadine.
The 68.5 mg capsule is a white opaque size #2 capsule, with black printing of 'ADAMAS' on front and '85' on back of the cap and three black bands printed on body of capsule.
The 137 mg capsule is a light blue opaque size #0 capsule, with black printing of 'ADAMAS' on front and '170' on back of the cap and three black bands printed on body of capsule.
GOCOVRI is contraindicated in patients with end-stage renal disease (i.e., creatinine clearance below 15 mL/min/1.73 m
2)
GOCOVRI is an extended-release formulation. The pharmacokinetics of amantadine from 68.5 mg, 137 mg, and 274 mg of GOCOVRI are dose proportional in healthy subjects.
After a single dose bedtime administration of GOCOVRI, the median Tmaxfor plasma amantadine was around 12 hours (range 6-20 hours). The steady-state concentrations of GOCOVRI were achieved 4 days after the dose initiation. The steady-state total exposures (AUC0-tau) were 20-30% higher than after single dose, suggesting an accumulation ratio of 1.2-1.3.
A single dose crossover study of GOCOVRI established the lack of effect of high-fat, high-calorie meal on plasma amantadine pharmacokinetics; additionally, administration of entire capsule contents sprinkled on applesauce also did not affect plasma amantadine pharmacokinetics.
The volume of distribution determined after the intravenous administration of amantadine to 15 healthy subjects was 3 to 8 L/kg, suggesting potential extravascular distribution. Amantadine is approximately 67% bound to plasma proteins over a concentration range of 0.1 to 2.0 µg/mL.
In a study with healthy volunteers after oral administration, the apparent plasma clearance of amantadine was estimated to be 0.27 ± 0.094 L/hr/kg (range 0.13 to 0.57 L/hr/kg). Amantadine is primarily excreted unchanged in the urine, and in a study of six healthy volunteers, the ratio of amantadine renal clearance to apparent plasma clearance was 0.79 ± 0.17 (mean ± SD). The mean plasma amantadine half-life at steady-state was approximately 16 hours.
Eight metabolites of amantadine have been identified in human urine. One metabolite, an N-acetylated compound, was quantified in human urine and accounted for 0-15% of the administered dose in multiple studies. The contribution of this metabolite to efficacy or toxicity is not known.
Amantadine is primarily excreted unchanged in the urine by both glomerular filtration and tubular secretion.
In an integrated analysis of five studies in healthy volunteers (n=147), the mean total amantadine clearance following administration of GOCOVRI, adjusted for body weight in kilograms, was 1.2 fold higher in males compared to females (95% CI: 1.1, 1.3, P=0.007). No dose adjustment by gender is warranted.
The renal clearance of amantadine is significantly lower in adult patients with moderate or severe renal impairment, compared to healthy adults. Since the renal pathway is a major elimination pathway, impairment in renal function can result in significant accumulation in the plasma, warranting dose adjustment. The impact of renal impairment on dose adjustment was not investigated in a dedicated study.
Based on PK simulations, the range of the total exposures (AUC0-tau) in subjects with normal renal function (creatinine clearance >90 mL/min/1.73 m2) or mild renal impairment (creatinine clearance between 60 and 89 mL/min/1.73 m2) were comparable for the same dosing regimen. However, patients with moderate renal impairment (creatinine clearance between 30 and 59 mL/min/1.73 m2) had higher exposures relative to patients with normal renal function or mild renal impairment. Severe renal impairment (creatinine clearance between 15 and 29 mL/min/1.73 m2) resulted in even higher total exposures. Dosage adjustment is recommended in patients with moderate and severe renal impairment
Amantadine is inefficiently removed by hemodialysis.
The in-vitro dissolution-release profiles showed 52% drug release after 45 minutes, and up to 95% after 2 hours, at concentrations of 40% alcohol/0.1N HCl.
In vitro studies indicate that amantadine has negligible or no inhibitory activity against cellular transporters (P-gp, BCRP, MATE2-K, OAT1, OAT3, OATP1B1, and OATP1B3) at plasma concentrations observed in patients with Parkinson's disease on a GOCOVRI 274 mg dose.
In vitro studies in MDCK-II cells demonstrated that amantadine is not a substrate of the anionic transporters OAT1 or OAT3, or the cationic transporter MATE2-K. Amantadine was a poor substrate of the cationic transporters OCT2 and MATE1. Renal elimination of amantadine may be mediated in part by one or more organic cation transporters independent of OCT2. An in vivo study demonstrated that quinidine, a known organic cation transporter inhibitor, reduced amantadine clearance by approximately 33% in humans. The clinical significance is unknown. In vitro studies show that amantadine does not significantly inhibit the enzyme activity of drug metabolizing cytochrome P450 isoforms (CYP1A2, 2B6, 2C19, 2C8, 2C9, 2D6, 2E1, 3A4, and 3A5).
The following serious adverse reactions are described in more detail elsewhere in the labeling:
- Falling Asleep During Activities of Daily Living and Somnolence[see Warnings and Precautions ()]
5.1 Falling Asleep During Activities of Daily Living and SomnolencePatients 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[see Warnings and Precautions ()]
5.2 Suicidality and DepressionIn 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[see Warnings and Precautions (])
5.3 Hallucinations/Psychotic BehaviorPatients 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[see Warnings and Precautions ()]
5.4 Dizziness and Orthostatic HypotensionIn 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 ]. - Withdrawal-Emergent Hyperpyrexia and Confusion[see Warnings and Precautions ()]
5.5 Withdrawal-Emergent Hyperpyrexia and ConfusionA 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 ]. - Corneal Edema[see]
5.6 Corneal EdemaCorneal edema has been reported in patients taking amantadine. Symptoms include sudden onset of blurry vision, or progressive vision loss, with or without eye pain. Corneal involvement is usually bilateral. Onset can occur from a few weeks to several years after starting amantadine. Resolution of symptoms typically begins within weeks of amantadine cessation. However, corneal grafts have been required in some patients when the condition is not recognized. Permanent damage can occur if amantadine is continued. Ask patients if their vision has changed and obtain ophthalmologic examinations to rule out corneal edema should vision changes occur after initiation of therapy with GOCOVRI. If corneal edema occurs, taper and discontinue GOCOVRI[see Dosage and Administration (2.4)]. - Impulse Control/Compulsive Behaviors[see Warnings and Precautions ()]
5.7 Impulse Control/Compulsive BehaviorsPatients 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.
GOCOVRI contains amantadine in an extended-release formulation. The active ingredient in GOCOVRI is amantadine hydrochloride.
The chemical name for amantadine hydrochloride is tricyclo [3.3.1.1
3,7] decan-1-amine, hydrochloride or 1-adamantanamine hydrochloride with the following structural formula:
The molecular formula is C
10H
17N•HCl and the molecular weight is 187.71 (g/mol). Amantadine hydrochloride is a white crystalline powder and is non-hygroscopic, practically insoluble in ether, sparingly soluble in methylene chloride, soluble in chloroform, and freely soluble in water, ethanol, and methanol.
GOCOVRI capsules are for oral use. Each capsule contains 68.5 mg or 137 mg amantadine (as 85 mg or 170 mg amantadine hydrochloride, respectively). Capsules also contain the following inactive ingredients: copovidone, ethylcellulose, hypromellose, magnesium stearate, medium-chain triglycerides, microcrystalline cellulose, povidone, and talc in a hard gelatin capsule.