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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:
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The molecular formula is C10H17N•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, mediumchain triglycerides, microcrystalline cellulose, povidone, and talc in a hard gelatin capsule.
The following serious adverse reactions are described in more detail elsewhere in the labeling:
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
GOCOVRI was evaluated in two double-blind, placebo-controlled efficacy trials of similar design and population: Study 1 (123 patients) and Study 2 (75 patients) [see Clinical Studies (14)]. The study population was approximately 56% male and 94% white, with a mean age of 65 years (age range from 34 years to 82 years). The mean duration of levodopa-induced dyskinesia was 4 years (range 0.1 to 14 years). Active treatment started at 137 mg once daily for one week, followed by a dose increase to 274 mg once daily. The treatment duration was 25 weeks for Study 1 and 13 weeks for Study 2. Of the 100 patients in the safety population described below, 39 patients were treated with GOCOVRI for 24 weeks. The safety data for these trials were pooled.
The most common adverse reactions reported in >10% of GOCOVRI-treated patients and more frequently than on placebo were: hallucinations, dizziness, dry mouth, peripheral edema, constipation, falls, and orthostatic hypotension.
The overall rate of discontinuation because of adverse reactions for GOCOVRI-treated patients was 20%, compared to 8% for placebo-treated patients. Adverse reactions that led to treatment discontinuation in at least 2% of patients were hallucinations (8% GOCOVRI vs. 0% placebo), dry mouth (3% GOCOVRI vs. 0% placebo), peripheral edema (3% GOCOVRI vs. 0% placebo), blurred vision (GOCOVRI 3% vs. 0% placebo), postural dizziness and syncope (GOCOVRI 2% vs. 0% placebo), abnormal dreams (GOCOVRI 2% vs. 1% placebo), dysphagia (GOCOVRI 2% vs. 0% placebo), and gait disturbance (GOCOVRI 2% vs. 0% placebo).
| Adverse Reactions | GOCOVRI 274 mg N=100 % |
Placebo N=98 % |
| Psychiatric disorders | ||
| Hallucinationsa | 21 | 3 |
| Anxietyb | 7 | 3 |
| Insomnia | 7 | 2 |
| Depression/Depressed mood | 6 | 1 |
| Abnormal dreams | 4 | 2 |
| Confusional state | 3 | 2 |
| Nervous system disorders | ||
| Dizziness | 16 | 1 |
| Headache | 6 | 4 |
| Dystonia | 3 | 1 |
| Gastrointestinal disorders | ||
| Dry mouth | 16 | 1 |
| Constipation | 13 | 3 |
| Nausea | 8 | 3 |
| Vomiting | 3 | 0 |
| General disorders and administration site conditions | ||
| Peripheral edema | 16 | 1 |
| Gait disturbance | 3 | 0 |
| Injury, poisoning and procedural complications | ||
| Fall | 13 | 7 |
| Contusion | 6 | 1 |
| Infections and infestations Urinary tract infection | 10 | 5 |
| Skin and subcutaneous tissue disorders | ||
| Livedo reticularis Pigmentation disorder | 6 3 | 0 0 |
| Metabolism and nutrition disorders Decreased appetite | 6 | 1 |
| Vascular disorders Orthostatic hypotensionc | 13 | 1 |
| Eye disorders | ||
| Blurred vision | 4 | 1 |
| Cataract | 3 | 1 |
| Dry eye | 3 | 0 |
| Musculoskeletal and connective tissue disorders | ||
| Joint swelling | 3 | 0 |
| Muscle spasms | 3 | 0 |
| Reproductive system and breast disorders | ||
| Benign prostatic hyperplasiad | 6 | 2 |
| Respiratory, thoracic and mediastinal disorders | ||
| Cough | 3 | 0 |
| a=Includes visual hallucinations and auditory hallucinations b=Includes anxiety and generalized anxiety c=Includes orthostatic hypotension, postural dizziness, syncope, presyncope, and hypotension d=The denominator is all male patients in the safety population randomized to GOCOVRI (n=54) or placebo (n=57) | ||
Other clinically relevant adverse reactions observed at <3% included somnolence, fatigue, suicide ideation or attempt, apathy, delusions, illusions, and paranoia [see Warnings and Precautions (5.1, 5.2, 5.3)].
Difference in the Frequency of Adverse Reactions by Gender
Adverse reactions reported more frequently in women treated with 274 mg of GOCOVRI (n=46), compared to men (n=54), were: dry mouth (22% women, 11% men), nausea (13% women, 4% men), livedo reticularis (13% women, 0% men), abnormal dreams (9% women, 0% men) and cataracts (7% women, 0% men).
Men treated with 274 mg of GOCOVRI reported the following adverse reactions more frequently than women: dizziness (20% men, 11% women), peripheral edema (19% men, 11%
women), anxiety (11% men, 2% women), orthostatic hypotension (7% men, 2% women) and gait disturbance (6% men, 0% women).
Difference in the Frequency of Adverse Reactions by Age
Hallucinations (visual or auditory) were reported in 31% of GOCOVRI-treated patients age
65 years and over (n=52), compared to 10% in patients below the age of 65 years (n=48). Falls were reported in 17% of GOCOVRI-treated patients age 65 and over, compared to 8% of patients below age 65. Orthostatic hypotension was reported in 8% of patients age 65 and over, compared to 2% of patients below age 65.
The following adverse reactions have been identified during postapproval use of GOCOVRI. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Nervous System Disorders: Seizure.
Corneal edema
Products with anticholinergic properties may potentiate the anticholinergic-like side effects of amantadine. The dose of anticholinergic drugs or of GOCOVRI should be reduced if atropine- like effects appear when these drugs are used concurrently.
The pH of the urine has been reported to influence the excretion rate of amantadine. Urine pH is altered by diet, drugs (e.g., carbonic anhydrase inhibitors, sodium bicarbonate), and clinical state of the patient (e.g., renal tubular acidosis or severe infections of the urinary tract).
Since the excretion rate of amantadine increases rapidly when the urine is acidic, the administration of urine acidifying drugs may increase the elimination of the drug from the body. Alterations of urine pH towards the alkaline condition may lead to an accumulation of the drug with a possible increase in adverse reactions. Monitor for efficacy or adverse reactions under conditions that alter the urine pH to more acidic or alkaline, respectively.
Because of its antiviral properties, amantadine may interfere with the efficacy of live attenuated influenza vaccines. Therefore, live vaccines are not recommended during treatment with GOCOVRI. Inactivated influenza vaccines may be used, as appropriate.
Concomitant use with alcohol is not recommended, as it may increase the potential for CNS effects such as dizziness, confusion, lightheadedness, and orthostatic hypotension [see Warnings and Precautions (5.4)], and may result in dose-dumping [see Clinical Pharmacology (12.3)].
Included as part of the PRECAUTIONS section.
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.
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.
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.
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)].
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)].
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)].
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.
Animal studies designed to evaluate the carcinogenic potential of amantadine have not been conducted.
Amantadine was negative for genotoxicity in in vitro (Ames and mammalian cell [Chinese Hamster ovary and human peripheral blood lymphocytes]) assays in the presence or absence of metabolic activation and in an in vivo mouse bone marrow micronucleus assay.
The effects of amantadine on fertility have not been adequately tested in a study in animals conducted according to current standards. In a reproduction study reported in the literature, oral administration of amantadine to male and female rats at a dose of 32 mg/kg/day resulted in impaired fertility. The no-effect dose for adverse effects on fertility (10 mg/kg/day) is less than the recommended human dose of 274 mg/day on a mg/m2 basis.
Deaths have been reported from overdose with amantadine. The lowest reported acute lethal dose was 1 gram of amantadine hydrochloride (equivalent to 0.8 g amantadine). Acute toxicity may be attributable to the anticholinergic effects of amantadine. Drug overdose has resulted in cardiac, respiratory, renal, or central nervous system toxicity. Pulmonary edema and respiratory distress (including adult respiratory distress syndrome, ARDS) have been reported with amantadine; renal dysfunction, including increased BUN and decreased creatinine clearance, can occur.
Central nervous system effects that have been reported with overdose include agitation, aggressive behavior, hypertonia, hyperkinesia, ataxia, tremor, disorientation, depersonalization, fear, delirium, psychotic reactions, lethargy, and coma. Seizures may be exacerbated in patients with prior history of seizure disorders. Hyperthermia has occurred with amantadine overdose.
For acute overdosing, general supportive measures should be employed along with immediate gastric decontamination if appropriate. Give intravenous fluids if necessary. The excretion rate of amantadine increases with acidification of urine, which may increase the elimination of the drug. Monitor patients for arrhythmias and hypotension. Electrocardiographic monitoring may be needed after ingestion because arrhythmias have been reported after overdose, including arrhythmias with fatal outcomes. Adrenergic agents, such as isoproterenol, in patients with an amantadine overdose has been reported to induce arrhythmias.
Monitor blood electrolytes, urine pH, and urinary output. Although amantadine is not efficiently removed by hemodialysis, this procedure may be useful in the treatment of amantadine toxicity in patients with renal failure.
GOCOVRI is contraindicated in patients with end-stage renal disease (i.e., creatinine clearance below 15 mL/min/1.73 m2 ) [see Clinical Pharmacology (12.3)].
The mechanism by which amantadine exerts efficacy in the treatment of dyskinesia in patients with Parkinson’s disease or as adjunctive treatment to levodopa/carbidopa in patients with Parkinson’s disease experiencing “off” episodes is unknown. Amantadine is a weak uncompetitive antagonist of the NMDA receptor. Amantadine has not been shown to possess direct anticholinergic activity in animal studies; however, it exhibits anticholinergic-like side effects such as dry mouth, urinary retention, and constipation in humans. Amantadine may have direct and indirect effects on dopamine neurons; it exerts dopaminergic-like side effects such as hallucinations and dizziness in humans.
The effect of amantadine on QT prolongation was not studied in a dedicated thorough QT study.
Alcohol consumption may increase the potential for CNS effects such as dizziness, confusion, lightheadedness, and orthostatic hypotension [see Drug Interactions (7.4)].
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 Tmax for 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.
Effect of Food
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 healthy subjects was 3 to 8 L/kg, suggesting potential extravascular 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.
Metabolism
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.
Excretion
Amantadine is primarily excreted unchanged in the urine by both glomerular filtration and tubular secretion.
Male/Female Patients
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.
Renal Impairment
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 [see Use in Special Populations (8.6) and Dosage and Administration (2.3)]. GOCOVRI is contraindicated in patients with end stage renal disease (creatinine clearance less than 15 mL/min/1.73 m2).
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).
Advise the patient to read the FDA-approved patient labeling (Patient Information).
Instruct patients and caregivers that GOCOVRI capsules should be swallowed whole and can be administered with or without food. Alternatively, GOCOVRI capsules may be opened and the contents sprinkled on applesauce; the entire contents should be consumed immediately without chewing [see Dosage and Administration (2.2)]. Advise patients to speak to their healthcare provider before discontinuation of GOCOVRI.
Advise patients that sleepiness and fatigue that have been reported with GOCOVRI and patients treated with Parkinson’s disease medications have reported falling asleep while engaged in activities of daily living. These adverse reactions may affect some patients’ ability to drive and operate machinery safely [see Warnings and Precautions (5.1)].
Instruct patients, family members, and caregivers to notify their healthcare provider if depressed mood, depression, changes in behavior or thinking, and suicidal ideation or behavior develop during treatment [see Warnings and Precautions (5.2)].
Inform patients and caregivers that hallucinations and paranoia can occur while taking GOCOVRI. Tell patients to report unreal visions, sounds, or sensations or other psychotic behavior to their healthcare provider promptly should they develop [see Warnings and Precautions (5.3)].
An increased incidence of dizziness, orthostatic hypotension, and syncope was observed with administration of GOCOVRI. Caution patients against standing rapidly after sitting or lying down, especially if they have been doing so for prolonged periods and especially at the initiation of treatment with GOCOVRI [see Warnings and Precautions (5.4)].
Advise patients to contact their healthcare provider before stopping GOCOVRI. Tell patients to inform their healthcare provider if they develop withdrawal symptoms such as fever, confusion, or severe muscle stiffness [see Warnings and Precautions (5.5)].
Inform patients about the potential for visual changes including vision loss with administration of GOCOVRI. Advise patients to inform their healthcare provider if they develop visual symptoms such as blurred vision, with or without eye pain, or vision loss [see Warnings and Precautions (5.6)].
Inform patients of the potential for experiencing intense urges to gamble, increased sexual urges, intense urges to spend money, binge eating, and other intense urges and the inability to control these urges while taking one or more of the medications that increase central dopaminergic tone, that are generally used for the treatment of Parkinson’s disease [see Warnings and Precautions (5.7)].
Certain medications can cause an interaction with GOCOVRI. Advise patients and/or caregivers to inform their healthcare provider of all the medicines the patient is taking, including over-the-counter medicines, dietary supplements, and herbal products. Inform patients that live influenza vaccines and consumption of alcohol are not recommended during treatment with GOCOVRI [see Drug Interactions (7.1, 7.2, 7.3, 7.4)].
