Gocovri Drug Information
Generic name: AMANTADINE
Influenza A M2 Protein Inhibitor [EPC]
Uses of Gocovri
- 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 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
Dosage & Administration of 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 substitutable 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. Concomitant use of GOCOVRI with alcohol is not recommended.
It is recommended to avoid sudden discontinuation of GOCOVRI.
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. 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.
| 1 Increase, if needed, after one week of the initial dosage | |
| Creatinine Clearance | Dosage |
| Mild renal impairment (60 to 89 mL/min/1.73 m 2 ) | Initial dosage: 137 mg once daily at bedtime. After one week, increase to recommended dosage of 274 mg once daily at bedtime. |
| Moderate renal impairment (30 to 59 mL/min/1.73 m 2 ) | Initial dosage: 68.5 mg once daily at bedtime Maximum recommended dosage: 137 mg once daily at bedtime 1 |
| Severe renal impairment (15 to 29 mL/min/1.73 m 2 ) | 68.5 mg once daily at bedtime |
| End Stage Renal Disease (below 15 mL/min/1.73 m 2 ) | Contraindicated |
Side Effects of Gocovri
Clinical Trial Experience
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. 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.
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. 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). 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 Vision: Corneal edema
| 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) | ||
| Adverse Reactions | GOCOVRI 274 mg N=100 % | Placebo N=98 % |
| Psychiatric disorders | ||
| Hallucinations a | 21 | 3 |
| Anxiety b | 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 | 6 | 0 |
| Pigmentation disorder | 3 | 0 |
| Metabolism and nutrition disorders | ||
| Decreased appetite | 6 | 1 |
| Vascular disorders | ||
| Orthostatic hypotension c | 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 hyperplasia d | 6 | 2 |
| Respiratory, thoracic and mediastinal disorders | ||
| Cough | 3 | 0 |
Warnings & Cautions for Gocovri
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.
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.
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.
Corneal Edema
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.
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.
Drug Interactions with Gocovri
Other Anticholinergic Drugs 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.
Drugs Affecting
Urinary pH 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.
Live Attenuated Influenza Vaccines 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.
Alcohol
Concomitant use with alcohol is not recommended, as it may increase the potential for CNS effects such as dizziness, confusion, lightheadedness, and orthostatic hypotension, and may result in dose-dumping.
Pregnancy Safety for Gocovri
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.
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 ). The no-effect dose for developmental toxicity in this study (40 mg/kg/day) is approximately equal to the RHD on a mg/m 2 basis.
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. 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.
Pediatric Use of Gocovri
Pediatric Use The safety and effectiveness of GOCOVRI in pediatric patients have not been established.
Contraindications for Gocovri
GOCOVRI is contraindicated in patients with end-stage renal disease (i.e., creatinine clearance below 15 mL/min/1.73 m 2 ).
Overdosage Information for Gocovri
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.
Clinical Studies of Gocovri
Overview of Studies The efficacy of GOCOVRI for the treatment of dyskinesia in patients with Parkinson's disease and for the adjunctive treatment to levodopa/carbidopa in patients with Parkinsons's disease experiencing "off" episodes was assessed in two randomized, double-blind, placebo-controlled efficacy trials: Study 1 and Study 2. Key inclusion criteria in both studies included at least 1 hour of troublesome dyskinesia time during the day and at least mild functional impact because of dyskinesia. Study 1 was conducted in 121 (modified Intention to Treat (mITT) population) Parkinson's disease patients with dyskinesia in the United States (US) and Canada.
The duration of treatment in Study 1 was up to 25 weeks. Study 2 was conducted in 75 (mITT population) patients with dyskinesia in the US, Germany, France, Spain, and Austria. The duration of treatment was 13 weeks.
In both studies, the primary efficacy endpoint was the change in total score of the Unified Dyskinesia Rating Scale (UDysRS) between baseline and Week 12. Key secondary endpoints derived from a Parkinson's disease home diary included changes from baseline to Week 12 in ON time without troublesome dyskinesia and OFF time. Patients in Study 1 and Study 2 were treated with a stable dose of levodopa, with 32% of patients on levodopa monotherapy.
Patients were also treated with concomitant dopamine agonists (54%) and/or MAO-B inhibitors (44%). Table 2: UDysRS Total Score at Week 12 for, there was a significant increase in ON time without troublesome dyskinesia, and a significant decrease in OFF time between baseline and Week 12 in patients treated with GOCOVRI, compared with placebo (Table 3). Table 3: PD Home Diary Results at Week 12 for
| mITT Population | Study 1 | Study 2 | |||
|---|---|---|---|---|---|
| Placebo (N=58) | GOCOVRI 274 mg (N=63) | Placebo (N=38) | GOCOVRI 274 mg (N=37) | ||
| UDysRS total score, LS Mean (SE) | Change from Baseline | -8.0 (1.64) | -15.9 (1.62) | -6.3 (2.08) | -20.7 (2.20) |
| Treatment Difference | -7.9 (2.30) | -14.4 (3.03) | |||
| P-value | 0.0009 | <0.0001 | |||
| mITT Population | Study 1 | Study 2 | |||
|---|---|---|---|---|---|
| Placebo (N=58) | GOCOVRI 274 mg (N=63) | Placebo (N=38) | GOCOVRI 274 mg (N=37) | ||
| ON Time w/o Troublesome Dyskinesia, LS Mean (SE) | Change from Baseline | 0.8 (0.43) | 3.6 (0.43) | 2.1 (0.53) | 4.0 (0.56) |
| Treatment Difference | 2.7 (0.61) | 1.9 (0.78) | |||
| P-value | <0.0001 | 0.0168 | |||
| OFF Time, LS Mean (SE) | Change from Baseline | 0.3 (0.26) | -0.6 (0.27) | 0.6 (0.31) | -0.5 (0.34) |
| Treatment Difference | -0.9 (0.37) | -1.1 (0.46) | |||
| P-value | 0.0171 | 0.0199 | |||
Drug information sourced from the FDA. This content is for informational purposes only and does not constitute medical advice. Consult a healthcare professional before making any medication decisions.
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