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Feb.02.2021

Amantadine

Indications/Dosage

Labeled

  • drug-induced extrapyramidal symptoms
  • dyskinesia
  • influenza A virus infection
  • parkinsonism
  • Parkinson's disease
  • seasonal influenza prophylaxis

Off-Label

  • fatigue
  • Huntington's Disease (Huntington's Chorea)
  • neuroleptic malignant syndrome
† Off-label indication

For the treatment of idiopathic parkinsonism or Parkinson's disease

Oral dosage (immediate-release capsules, oral solution, or tablets)

Adults

100 mg PO twice daily for monotherapy in younger adults. For geriatric adults, patients with serious medical illness, or those receiving other antiparkinsonian drugs: 100 mg PO once daily for 1 to several weeks, then increase to the usual dose of 100 mg PO twice daily. If loss of effectiveness occurs, benefit may be regained by increasing the dose to 300 mg/day in divided doses. Alternatively, a drug holiday period of several weeks may be helpful; then dosing may be reinitiated with improved effectiveness. Max: Rarely, a patient may require up to 400 mg/day PO in divided doses, but closely monitor.[28049]

Oral dosage (extended-release tablets only; e.g., Osmolex ER)

Adults

Initially, 129 mg PO once daily in the morning. May increase dose at weekly intervals as needed. Max: 322 mg/day PO (administered as a 129 mg and 193 mg ER tablet given once daily in the morning). SWITCHING FROM IMMEDIATE- OR EXTENDED-RELEASE (ER) AMANTADINE PRODUCTS: Osmolex ER is not interchangeable with other products. For patients unable to tolerate more than 100 mg/day of immediate-release amantadine, there is no equivalent dose/regimen of amantadine ER tablets. DISCONTINUATION: Do not discontinue abruptly. Reduce the dose gradually from higher doses to 129 mg/day for 1 to 2 weeks before discontinuing.[62887]

For the treatment of dyskinesia associated with Parkinson's disease in patients receiving levodopa-based therapy, with or without concomitant dopaminergic medications

Oral dosage (extended-release capsules only; e.g., Gocovri ER capsules)

Adults

137 mg PO once daily at bedtime, initially. After 1 week, increase to the recommended dose of 274 mg PO once daily at bedtime. Cautious dosing based on renal function is recommended in geriatric patients. SWITCHING FROM IMMEDIATE- OR EXTENDED-RELEASE (ER) AMANTADINE PRODUCTS: Gocovri is not interchangeable with other products. DISCONTINUATION: Rapid dose reduction or withdrawal may cause adverse reactions. If discontinuing after more than 4 weeks of use, the dose should typically be reduced by half for the final week of dosing, if possible.[62262]

For the treatment of drug-induced extrapyramidal symptoms (EPS)

Oral dosage (immediate-release capsules, oral solution, or tablets)

Adults

100 mg PO twice daily. Occasionally, patients with drug-induced EPS may require up to 300 mg/day PO in divided doses, but patients receiving more than 200 mg/day should be monitored closely.[28049]

Geriatric Adults

100 mg PO once daily, initially. May titrate to 100 mg PO twice daily. Occasionally, patients with drug-induced EPS may require up to 300 mg/day PO in divided doses, but patients receiving more than 200 mg/day should be monitored closely.[28049]

Oral dosage (Extended-release tablets; e.g., Osmolex ER)

Adults

129 mg PO once daily in the morning, initially. May increase at weekly intervals as needed. Max: 322 mg/day PO (administered as a 129 mg and 193 mg ER tablet given once daily in the morning). SWITCHING FROM IMMEDIATE- OR EXTENDED-RELEASE (ER) AMANTADINE PRODUCTS: Osmolex ER is not interchangeable with other products. For patients unable to tolerate more than 100 mg/day of immediate-release amantadine, there is no equivalent dose/regimen of amantadine ER tablets. DISCONTINUATION: Do not discontinue abruptly. Reduce the dose gradually from higher doses to 129 mg/day for 1 to 2 weeks before discontinuing.[62887]

For the treatment of chorea associated with Huntington's Disease (Huntington's Chorea)†

Oral dosage (Immediate-release capsules, oral solution, or tablets)

Adults

Dosage not FDA-approved. 300 to 400 mg/day PO, divided and given in 3 to 4 divided doses, has been studied. If needed, the dose may be slowly titrated over 3 to 4 days at initiation to minimize adverse effects. Amantadine was evaluated in 2 randomized, placebo-controlled crossover trials, each with 2 weeks of active treatment. One trial demonstrated that amantadine 300 mg/day (n = 24) improved coordination, balance, and mental alertness in 19 of 24 subjects (p = 0.006). After treatment, significant increases in quality of life scores occurred with amantadine (3.9 +/- 0.7) compared to placebo (2.95 +/- 0.7, p less than 0.001). Chorea severity of 6 body parts, judged blindly by investigators via video of subjects, did not change significantly. During the second trial, maximum chorea severity, as measured by the Unified Huntington's Disease Rating Scale, significantly decreased by 18% (p = 0.0007) among subjects who received amantadine 400 mg/day (n = 22). Wide variations in antichoreic effects were noted among subjects. The long-term efficacy of amantadine for the treatment of Huntington's chorea is unknown.[52476] [52484] [52485]

For the treatment of multiple-sclerosis associated fatigue†

Oral dosage (immediate-release capsules, oral solution, or tablets)

Adults

Dosage not established. 100 mg PO twice daily is the commonly used dosage from clinical trials.[62263] The results of trials with amantadine have been of varied design, have included low numbers of participants and have been of short study durations (3 and 6 weeks); patients have reported inconsistent improvements in fatigue, but documentation of positive impact on daily function and life-quality are lacking.[43115] [43118] [62263] Despite these limitations, amantadine is the only oral treatment that is recommended by clinical guidelines for MS-related fatigue.[62264]

For the treatment of neuroleptic malignant syndrome†

Oral dosage (immediate-release capsules, oral solution, or tablets)

Adults

Several case reports have documented marked improvements in symptoms associated with neuroleptic malignant syndrome (NMS). Amantadine 100 mg PO twice daily has been used for as long as 3 weeks.[24182] [62265]

For the treatment of uncomplicated influenza A virus infection

Oral dosage (immediate-release capsules, oral solution, or tablets)

Adults

200 mg/day PO, given as a single dose or in 2 divided doses. Start treatment as soon as possible and continue for 24 to 48 hours after the symptoms resolve.[28049] Initiation of treatment within 48 hours of illness onset confers the greatest benefit; however, antiviral therapy started after 48 hours may still be beneficial in severe, complicated, progressive illness or hospitalized patients. The CDC recommends against use due to resistance.[62315]

Geriatric Adults

100 mg PO once daily. Start treatment as soon as possible and continue for 24 to 48 hours after the disappearance of signs and symptoms.[28049] Initiation of treatment within 48 hours of illness onset confers the greatest benefit; however, antiviral therapy started after 48 hours may still be beneficial in severe, complicated, progressive illness or hospitalized patients. The CDC recommends against use due to resistance.[62315]

Children and Adolescents 9 to 17 years

100 mg PO twice daily. Start treatment as soon as possible and continue for 24 to 48 hours after the symptoms resolve.[28049] Initiation of treatment within 48 hours of illness onset confers the greatest benefit; however, antiviral therapy started after 48 hours may still be beneficial in severe, complicated, progressive illness or hospitalized patients. The CDC recommends against use due to resistance.[62315]

Children 1 to 8 years

4.4 to 8.8 mg/kg/day PO, given in 2 divided doses (Max: 150 mg/day). Start treatment as soon as possible and continue for 24 to 48 hours after the symptoms resolve.[28049] Initiation of treatment within 48 hours of illness onset confers the greatest benefit; however, antiviral therapy started after 48 hours may still be beneficial in severe, complicated, progressive illness or hospitalized patients. The CDC recommends against use due to resistance.[62315]

For seasonal influenza prophylaxis for infections due to influenza A virus

Oral dosage (immediate-release capsules, oral solution, and tablets)

Adults

200 mg/day PO, given as a single dose or 2 divided doses. Start prophylaxis in anticipation of an outbreak or before or after known exposure and continue for at least 10 days after a known exposure. If used with the influenza virus vaccine, continue for 2 to 4 weeks after the vaccine has been given.[28049] The CDC recommends against use due to resistance.[62315]

Geriatric Adults

100 mg PO once daily. Start prophylaxis in anticipation of an outbreak or before or after known exposure and continue for at least 10 days after a known exposure. If used with the influenza virus vaccine, continue for 2 to 4 weeks after the vaccine has been given.[28049] The CDC recommends against use due to resistance.[62315]

Children and Adolescents 9 to 17 years

100 mg PO twice daily. Start prophylaxis in anticipation of an outbreak or before or after known exposure and continue for at least 10 days after a known exposure. If used with the influenza virus vaccine, continue for 2 to 4 weeks after the vaccine has been given.[28049] The CDC recommends against use due to resistance.[62315]

Children 1 to 8 years

4.4 to 8.8 mg/kg/day PO, given in 2 divided doses (Max: 150 mg/day). Start prophylaxis in anticipation of an outbreak or before or after known exposure and continue for at least 10 days after a known exposure. If used with the influenza virus vaccine, continue for 2 to 4 weeks after the vaccine has been given.[28049] The CDC recommends against use due to resistance.[62315]

Therapeutic Drug Monitoring

Maximum Dosage Limits

  • Adults

    400 mg/day PO for immediate-release capsules, oral solution, or tablets; 274 mg/day PO for extended-release capsules; 322 mg/day PO for extended-release tablets.

  • Geriatric

    400 mg/day PO for immediate-release capsules, oral solution, or tablets; 274 mg/day PO for extended-release capsules; 322 mg/day PO for extended-release tablets.

  • Adolescents

    Immediate-release capsules, oral solution or tablets: 200 mg/day PO.

    Extended-release capsules or tablets: Safety and efficacy have not been established.

  • Children

    9 years and older: 200 mg/day PO for immediate-release capsules, oral solution, or tablets. Safety and efficacy of extended-release capsules and tablets have not been established.

    1 to 8 years: 8.8 mg/kg/day PO or 150 mg/day PO, whichever is less for immediate-release capsules, oral solution, or tablets. Safety and efficacy of extended-release capsules and tablets have not been established.

  • Infants

    Safety and efficacy have not been established.

  • Neonates

    Safety and efficacy have not been established.

Patients with Hepatic Impairment Dosing

Amantadine is primarily excreted in the urine unchanged. Dosage adjustments do not appear to be necessary for immediate-release products.[28049] Recommendations for the extended-release capsules or tablets are not available.[62262][62887]

Patients with Renal Impairment Dosing

Immediate-release capsules, oral solution, or tablets in adults (e.g., Symmetrel):[28049]

CrCl greater than 50 mL/minute: No dosage adjustment needed.

CrCl 30 to 50 mL/minute: 200 mg PO for 1st day, then reduce dose to 100 mg PO daily.

CrCl 15 to 29 mL/minute: 200 mg PO for 1st day, then reduce dose to 100 mg PO on alternate days.

CrCl less than 15 mL/minute: 200 mg every 7 days.

 

Extended-release capsules in adults (e.g., Gocovri):[62262]

CrCl 60 mL/minute or greater: No dosage adjustment needed.

CrCl 30 to 59 mL/minute: 68.5 mg PO once daily at bedtime. Increase if needed after 1 week to a maximum of 137 mg once daily at bedtime.

CrCl 15 to 29 mL/minute: 68.5 mg PO once daily at bedtime.

CrCl less than 15 mL/minute: Use is contraindicated.

 

Extended-release tablets in adults (e.g., Osmolex ER):[62887]

CrCl 60 mL/minute or greater: No dosage adjustment needed.

CrCl 30 to 59 mL/minute: 129 mg PO once every 48 hours initially. May increase every 3 weeks up to a maximum of 322 mg once every 48 hours.

CrCl 15 to 29 mL/minute: 129 mg PO once every 96 hours initially. May increase every 4 weeks up to a maximum of 322 mg once every 96 hours.

CrCl less than 15 mL/minute: Use is contraindicated.

 

Intermittent hemodialysis

Amantadine is inefficiently removed by hemodialysis.

Immediate-release capsules, oral solution, or tablets (e.g., Symmetrel): 200 mg PO every 7 days in adults.[28049]

Extended-release capsules (e.g., Gocovri) or tablets (e.g., Osmolex ER): Use is contraindicated in patients with end-stage renal disease.[62262][62887]

† Off-label indication
Revision Date: 02/02/2021, 04:23:44 PM

References

24182 - Guerrero RM, Shifrar KA. Diagnosis and treatment of neuroleptic malignant syndrome. Clin Pharm 1988;7(9):697-701.28049 - Amantadine HCl capsules package insert. Princeton, NJ: Sandoz Inc; 2015 May.43115 - Pucci E, Branas P, D'Amico R, Giuliani G, et al. Amantadine for fatigue in multiple sclerosis. Cochrane Database Syst Rev 2007:CD00281843118 - Krupp LB, Coyle PK, Doscher C, et al. Fatigue therapy in multiple sclerosis: results of a double-blind, randomized, parallel trial of amantadine, pemoline, and placebo. Neurology 1995;45(11):1956-1961.52476 - Armstrong MJ, Miyasaki JM. Evidence-based guideline: Pharmacologic treatment of chorea in Huntington disease: Report of the guideline development subcommittee of the American Academy of Neurology. Neurology 2012;79:597-603.52484 - Verhagen Metman L, Morris MJ, Farmer C, et al. Huntington's disease: a randomized, controlled trial using the NMDA-antagonist amantadine. Neurology 2002;59:694-699.52485 - O'Suilleabhain P, Dewey Jr RB. A randomized trial of amantadine in Huntington disease. Arch Neurol 2003;60:996-998.62262 - Gocovri (amantadine extended-release capsules) package insert. Emeryville, CA: Adamas Pharma LLC; 2021 Jan.62263 - Tur C. Fatigue Management in Multiple Sclerosis. Curr Treat Options Neurol 2016;18(6):26. Review.62264 - National Clinical Guideline Centre (UK). Multiple Sclerosis: Management of Multiple Sclerosis in Primary and Secondary Care. London: National Institute for Health and Care Excellence (UK); (NICE Clinical Guideline No 186). 2014 Oct. Accessed: August 25 2017. Available at: www.ncbi.nlm.nih.gov/pubmedhealth/PMH0068954/pdf/PubMedHealth_PMH0068954.pdf62265 - Reulbach U, Dutsch C, Biermann T, et al. Managing an effective treatment for neuroleptic malignant syndrome. Crit Care 2007;11:R4. Review.62315 - Centers for Disease Control and Prevention (CDC). Influenza antiviral medications: Summary for clinicians, 2020-2021. Retrieved November 5, 2020. Available on the World Wide Web at https://www.cdc.gov/flu/professionals/antivirals/summary-clinicians.htm62887 - Osmolex ER (amantadine extended-release tablets) package insert. Bridgewater, NJ: Vertical Pharmaceuticals, LLC; 2018 Feb.

How Supplied

Amantadine Hydrochloride Oral capsule

Amantadine Hydrochloride 100mg Capsule (72888-0033) (AdvaGen Pharma Ltd.) nullAmantadine Hydrochloride 100mg Capsule package photo

Amantadine Hydrochloride Oral capsule

Amantadine Hydrochloride 100mg Capsule (62332-0246) (Alembic Pharmaceuticals, Inc.) null

Amantadine Hydrochloride Oral capsule

Amantadine Hydrochloride 100mg Capsule (62584-0612) (American Health Packaging) (off market)

Amantadine Hydrochloride Oral capsule

Amantadine Hydrochloride 100mg Capsule (68084-0611) (American Health Packaging) (off market)

Amantadine Hydrochloride Oral capsule

Amantadine Hydrochloride 100mg Capsule (60687-0422) (American Health Packaging) null

Amantadine Hydrochloride Oral capsule

Amantadine Hydrochloride 100mg Capsule (23155-0362) (Avet Pharmaceuticals Inc.) null

Amantadine Hydrochloride Oral capsule

Amantadine Hydrochloride 100mg Capsule (42291-0125) (AvKARE, Inc.) null

Amantadine Hydrochloride Oral capsule

Amantadine Hydrochloride 100mg Capsule (50268-0069) (AvPAK; a Division of AvKARE Inc) null

Amantadine Hydrochloride Oral capsule

Amantadine Hydrochloride 100mg Capsule (10888-5006) (Banner Life Sciences) (off market)

Amantadine Hydrochloride Oral capsule

Amantadine Hydrochloride 100mg Capsule (69387-0100) (Banner Life Sciences) (off market)

Amantadine Hydrochloride Oral capsule

Amantadine Hydrochloride 100mg Capsule (69452-0142) (Bionpharma Inc) null

Amantadine Hydrochloride Oral capsule

Amantadine Hydrochloride 100mg Capsule (69097-0926) (Cipla USA, Inc) (off market)

Amantadine Hydrochloride Oral capsule

Amantadine Hydrochloride 100mg Capsule (00527-1704) (Lannett Company, Inc.) null

Amantadine Hydrochloride Oral capsule

Amantadine Hydrochloride 100mg Capsule (00904-6630) (Major Pharmaceuticals Inc, a Harvard Drug Group Company) (off market)

Amantadine Hydrochloride Oral capsule

Amantadine Hydrochloride 100mg Capsule (00904-7042) (Major Pharmaceuticals Inc, a Harvard Drug Group Company) null

Amantadine Hydrochloride Oral capsule

Amantadine Hydrochloride 100mg Capsule (00904-7042) (Major Pharmaceuticals Inc, a Harvard Drug Group Company) null

Amantadine Hydrochloride Oral capsule

Amantadine Hydrochloride 100mg Capsule (10135-0693) (Marlex Pharmaceuticals) null

Amantadine Hydrochloride Oral capsule

Amantadine Hydrochloride 100mg Capsule (52555-0675) (Martec Pharmaceuticals Inc) (off market)

Amantadine Hydrochloride Oral capsule

Amantadine Hydrochloride 100mg Capsule (51079-0247) (Mylan Institutional LLC ) null

Amantadine Hydrochloride Oral capsule

Amantadine Hydrochloride 100mg Capsule (51079-0481) (Mylan Institutional LLC ) (off market)

Amantadine Hydrochloride Oral capsule

Amantadine Hydrochloride 100mg Capsule (00603-2163) (Par Pharmaceuticals, an Endo Company) (off market)

Amantadine Hydrochloride Oral capsule

Amantadine Hydrochloride 100mg Capsule (55289-0012) (PD-Rx Pharmaceuticals, Inc.) (off market)

Amantadine Hydrochloride Oral capsule

Amantadine Hydrochloride 100mg Capsule (17236-0849) (R&S Northeast, LLC, formerly Dixon-Shane Drug Company) (off market)

Amantadine Hydrochloride Oral capsule

Amantadine Hydrochloride 100mg Capsule (00781-2048) (Sandoz Inc. a Novartis Company) null

Amantadine Hydrochloride Oral capsule

Amantadine Hydrochloride 100mg Capsule (62269-0211) (Sandoz, Inc. a Novartis Company) (off market)

Amantadine Hydrochloride Oral capsule

Amantadine Hydrochloride 100mg Capsule (42543-0493) (Strides Pharma, Inc.) null

Amantadine Hydrochloride Oral capsule

Amantadine Hydrochloride 100mg Capsule (00677-1128) (Sun Pharmaceutical Industries, Inc.) (off market)

Amantadine Hydrochloride Oral capsule

Amantadine Hydrochloride 100mg Capsule (00677-1452) (Sun Pharmaceutical Industries, Inc.) (off market)

Amantadine Hydrochloride Oral capsule

Amantadine Hydrochloride 100mg Capsule (00182-1258) (Teva Pharmaceuticals USA) (off market)

Amantadine Hydrochloride Oral capsule

Amantadine Hydrochloride 100mg Capsule (00591-4930) (Teva/Actavis US) (off market)

Amantadine Hydrochloride Oral capsule

Amantadine Hydrochloride 100mg Capsule (52152-0309) (Teva/Actavis US) (off market)

Amantadine Hydrochloride Oral capsule

Amantadine Hydrochloride 100mg Capsule (52152-0309) (Teva/Actavis US) (off market)

Amantadine Hydrochloride Oral capsule

Amantadine Hydrochloride 100mg Capsule (00832-2012) (Upsher-Smith Laboratories, LLC) (off market)

Amantadine Hydrochloride Oral capsule

Amantadine Hydrochloride 100mg Capsule (00832-1015) (Upsher-Smith Laboratories, LLC) null

Amantadine Hydrochloride Oral capsule

Amantadine Hydrochloride 100mg Capsule (00832-1015) (Upsher-Smith Laboratories, LLC) (off market)

Amantadine Hydrochloride Oral capsule

Amantadine Hydrochloride 100mg Capsule (68382-0512) (Zydus Pharmaceuticals (USA) Inc.) null

Amantadine Hydrochloride Oral solution

Amantadine Hydrochloride 100mg/10mL Solution (60687-0239) (American Health Packaging) (off market)

Amantadine Hydrochloride Oral solution

Amantadine Hydrochloride 100mg/10mL Solution (50383-0807) (Hi-Tech Pharmacal, a subsidiary of Akorn) null

Amantadine Hydrochloride Oral solution

Amantadine Hydrochloride 50mg/5mL Solution (00056-0656) (Bristol Myers Squibb Pharma Co) (off market)

Amantadine Hydrochloride Oral solution

Amantadine Hydrochloride 50mg/5mL Solution (46287-0015) (CMP Pharma) (off market)

Amantadine Hydrochloride Oral solution

Amantadine Hydrochloride 50mg/5mL Solution (60951-0656) (Endo Pharmaceuticals Inc ) (off market)

Amantadine Hydrochloride Oral solution

Amantadine Hydrochloride 50mg/5mL Solution (50383-0807) (Hi-Tech Pharmacal, a subsidiary of Akorn) nullAmantadine Hydrochloride 50mg/5mL Solution package photo

Amantadine Hydrochloride Oral solution

Amantadine Hydrochloride 50mg/5mL Solution (60432-0093) (Morton Grove Pharmaceuticals Inc, a subsidiary of Wockhardt, Ltd.) nullAmantadine Hydrochloride 50mg/5mL Solution package photo

Amantadine Hydrochloride Oral solution

Amantadine Hydrochloride 50mg/5mL Solution (00603-1011) (Par Pharmaceuticals, an Endo Company) (off market)

Amantadine Hydrochloride Oral solution

Amantadine Hydrochloride 50mg/5mL Solution (00603-1010) (Par Pharmaceuticals, an Endo Company) (off market)

Amantadine Hydrochloride Oral solution

Amantadine Hydrochloride 50mg/5mL Solution (00121-0646) (Pharmaceutical Associates Inc Div Beach Products) nullAmantadine Hydrochloride 50mg/5mL Solution package photo

Amantadine Hydrochloride Oral solution

Amantadine Hydrochloride 50mg/5mL Solution (54838-0509) (Silarx Pharmaceuticals Inc) (off market)

Amantadine Hydrochloride Oral solution

Amantadine Hydrochloride 50mg/5mL Solution (00472-0833) (Teva/Actavis US) (off market)

Amantadine Hydrochloride Oral solution

Symmetrel 50mg/5ml Syrup (00056-0205) (Bristol Myers Squibb Pharma Co) (off market)

Amantadine Hydrochloride Oral solution

Symmetrel 50mg/5ml Syrup (63481-0205) (Endo Pharmaceuticals Inc) (off market)

Amantadine Hydrochloride Oral tablet

Amantadine Hydrochloride 100mg Tablet (62332-0586) (Alembic Pharmaceuticals, Inc.) nullAmantadine Hydrochloride 100mg Tablet package photo

Amantadine Hydrochloride Oral tablet

Amantadine Hydrochloride 100mg Tablet (69097-0925) (Cipla USA, Inc) (off market)

Amantadine Hydrochloride Oral tablet

Amantadine Hydrochloride 100mg Tablet (59746-0699) (Jubilant Cadista Pharmaceuticals Inc.) null

Amantadine Hydrochloride Oral tablet

Amantadine Hydrochloride 100mg Tablet (10135-0692) (Marlex Pharmaceuticals) null

Amantadine Hydrochloride Oral tablet

Amantadine Hydrochloride 100mg Tablet (42543-0497) (Strides Pharma, Inc.) null

Amantadine Hydrochloride Oral tablet

Amantadine Hydrochloride 100mg Tablet (00591-4920) (Teva/Actavis US) null

Amantadine Hydrochloride Oral tablet

Amantadine Hydrochloride 100mg Tablet (00832-0111) (Upsher-Smith Laboratories, LLC) null

Amantadine Hydrochloride Oral tablet

Symmetrel 100mg Tablet (00056-0108) (Bristol Myers Squibb Pharma Co) (off market)

Amantadine Hydrochloride Oral tablet

Symmetrel 100mg Tablet (63481-0108) (Endo Pharmaceuticals Inc) (off market)

Amantadine Hydrochloride Oral tablet, osmotic laser drilled

Osmolex ER 129mg Extended-Release Tablet (68025-0075) (Vertical Pharmaceuticals, LLC) null

Amantadine Hydrochloride Oral tablet, osmotic laser drilled

Osmolex ER 193mg Extended-Release Tablet (68025-0076) (Vertical Pharmaceuticals, LLC) null

Amantadine Hydrochloride Oral tablet, osmotic laser drilled

Osmolex ER 258mg Extended-Release Tablet (68025-0077) (Vertical Pharmaceuticals, LLC) null

Amantadine Hydrochloride Oral tablet, osmotic laser drilled, Amantadine Hydrochloride Oral tablet, osmotic laser drilled

Osmolex ER 322mg Daily Dosing Kit Extended-Release Tablet (68025-0074) (Vertical Pharmaceuticals Inc) null

Amantadine Oral capsule, extended release

GOCOVRI 68.5mg Extended-Release Capsule (70482-0085) (Adamas Pharmaceuticals, Inc.) null

Amantadine Oral capsule, extended release

GOCOVRI 137mg Extended-Release Capsule (70482-0170) (Adamas Pharmaceuticals, Inc.) null

Description/Classification

Description

Amantadine is a synthetic antiviral agent with dopamine agonist properties. The drug is approved for the prophylaxis and treatment of influenza A; however, the Centers for Disease Control and Prevention (CDC) recommends against using amantadine due to the development of resistant strains. Amantadine is also indicated for the treatment of drug-induced extrapyramidal reactions and motor symptoms associated with Parkinson's disease. Additionally, an extended-release capsule is approved for the treatment of dyskinesia in patients with Parkinson's disease receiving levodopa-based therapy and as an adjunct to carbidopa; levodopa in patients with Parkinson's disease experiencing 'off' episodes. Amantadine may be used off-label for multiple sclerosis-associated fatigue, neuroleptic malignant syndrome, and chorea associated with Huntington's Disease. During treatment of chronic conditions, practitioners should monitor for anticholinergic effects, new or worsening impulse control symptoms, or patient reports of falling asleep during activities of daily living.[24182][28049][43115][43118][52476][62262][62263][62264][62265][62887][62315]

Classifications

  • Central Nervous System
    • Anti-Parkinson Agents
      • Anti-Parkinson Agents, NMDA Receptor Antagonists
  • General Anti-infectives Systemic
    • Antivirals For Systemic Use
      • Adamantane Antivirals
Revision Date: 02/02/2021, 04:06:32 PM

References

24182 - Guerrero RM, Shifrar KA. Diagnosis and treatment of neuroleptic malignant syndrome. Clin Pharm 1988;7(9):697-701.28049 - Amantadine HCl capsules package insert. Princeton, NJ: Sandoz Inc; 2015 May.43115 - Pucci E, Branas P, D'Amico R, Giuliani G, et al. Amantadine for fatigue in multiple sclerosis. Cochrane Database Syst Rev 2007:CD00281843118 - Krupp LB, Coyle PK, Doscher C, et al. Fatigue therapy in multiple sclerosis: results of a double-blind, randomized, parallel trial of amantadine, pemoline, and placebo. Neurology 1995;45(11):1956-1961.52476 - Armstrong MJ, Miyasaki JM. Evidence-based guideline: Pharmacologic treatment of chorea in Huntington disease: Report of the guideline development subcommittee of the American Academy of Neurology. Neurology 2012;79:597-603.62262 - Gocovri (amantadine extended-release capsules) package insert. Emeryville, CA: Adamas Pharma LLC; 2021 Jan.62263 - Tur C. Fatigue Management in Multiple Sclerosis. Curr Treat Options Neurol 2016;18(6):26. Review.62264 - National Clinical Guideline Centre (UK). Multiple Sclerosis: Management of Multiple Sclerosis in Primary and Secondary Care. London: National Institute for Health and Care Excellence (UK); (NICE Clinical Guideline No 186). 2014 Oct. Accessed: August 25 2017. Available at: www.ncbi.nlm.nih.gov/pubmedhealth/PMH0068954/pdf/PubMedHealth_PMH0068954.pdf62265 - Reulbach U, Dutsch C, Biermann T, et al. Managing an effective treatment for neuroleptic malignant syndrome. Crit Care 2007;11:R4. Review.62315 - Centers for Disease Control and Prevention (CDC). Influenza antiviral medications: Summary for clinicians, 2020-2021. Retrieved November 5, 2020. Available on the World Wide Web at https://www.cdc.gov/flu/professionals/antivirals/summary-clinicians.htm62887 - Osmolex ER (amantadine extended-release tablets) package insert. Bridgewater, NJ: Vertical Pharmaceuticals, LLC; 2018 Feb.

Administration Information

General Administration Information

For storage information, see the specific product information within the How Supplied section.

Route-Specific Administration

Oral Administration

Oral Solid Formulations

Immediate-release capsules or tablets (e.g., Symmetrel):

  • May be administered without regard to meals.[28049]

 

Extended-release capsules (e.g., Gocovri):

  • Not interchangeable with other extended-release amantadine products.
  • Can be taken with or without food.
  • Patients should swallow the extended-release capsules whole. They should not crush, chew, or divide capsules.
  • If needed, may be administered by carefully opening and sprinkling the entire contents of capsule on a small amount (teaspoonful) of soft food, such as cool applesauce. The drug/food mixture should be swallowed immediately without chewing. Do not store mixture for future use.
  • Missed dose: If a dose is missed, it is recommended to skip the missed dose. The next dose should be taken as scheduled.[62262]

 

Extended-release tablets (e.g., Osmolex ER):

  • May be administered without regard to meals.
  • Swallow tablets whole; do not chew, crush, or divide tablets.
  • Osmolex ER has a nonabsorbable shell designed to release the drug at a controlled rate. The tablet shell is eliminated from the body; patients should not be concerned if they occasionally notice the tablet shell in their stool.[62887]

Oral Liquid Formulations

Oral solution:

  • Administer using a calibrated measuring device to ensure accurate dosing.

Clinical Pharmaceutics Information

From Trissel's 2‚Ñ¢ Clinical Pharmaceutics Database
    Revision Date: 03/16/2020, 03:49:55 PM

    References

    28049 - Amantadine HCl capsules package insert. Princeton, NJ: Sandoz Inc; 2015 May.62262 - Gocovri (amantadine extended-release capsules) package insert. Emeryville, CA: Adamas Pharma LLC; 2021 Jan.62887 - Osmolex ER (amantadine extended-release tablets) package insert. Bridgewater, NJ: Vertical Pharmaceuticals, LLC; 2018 Feb.

    Adverse Reactions

    Mild

    • abnormal dreams
    • agitation
    • anorexia
    • anxiety
    • arthralgia
    • cough
    • diarrhea
    • dizziness
    • drowsiness
    • fatigue
    • fever
    • hyperhidrosis
    • hyperkinesis
    • infection
    • insomnia
    • irritability
    • leukocytosis
    • libido decrease
    • libido increase
    • muscle cramps
    • mydriasis
    • nausea
    • paresthesias
    • photosensitivity
    • pruritus
    • rash
    • tremor
    • vomiting
    • weakness
    • xerophthalmia

    Moderate

    • amnesia
    • antimicrobial resistance
    • ataxia
    • blurred vision
    • cataracts
    • confusion
    • corneal edema
    • delirium
    • dysarthria
    • dysphagia
    • dyspnea
    • dystonic reaction
    • edema
    • elevated hepatic enzymes
    • euphoria
    • hyperbilirubinemia
    • hypertension
    • hypertonia
    • impulse control symptoms
    • leukopenia
    • livedo reticularis
    • mania
    • neutropenia
    • orthostatic hypotension
    • peripheral edema
    • psychosis
    • sinus tachycardia
    • sudden sleep onset
    • tachypnea
    • urinary retention
    • withdrawal

    Severe

    • agranulocytosis
    • anaphylactoid reactions
    • arrhythmia exacerbation
    • cardiac arrest
    • coma
    • corneal opacification
    • heart failure
    • keratitis
    • neuroleptic malignant syndrome
    • pulmonary edema
    • seizures
    • suicidal ideation
    • visual impairment

    0

    • constipation
    • depression
    • hallucinations
    • headache
    • paranoia
    • xerostomia

    Many adverse reactions associated with amantadine involve the central nervous system (CNS). Two of the most frequent (5% to 10%) adverse events reported during clinical trials of immediate-release amantadine were dizziness and insomnia. Instruct patients to avoid arising suddenly from a seated or lying position and to inform their prescribing physician if dizziness or lightheadedness occurs. Less frequent (1% to 5%) CNS adverse events observed in clinical trials of immediate-release amantadine included anxiety, ataxia, agitation, confusion, depression, drowsiness or fatigue, hallucinations, headache, irritability, nervousness, and abnormal dreams. Cases of abnormal thinking, amnesia, dysarthria or slurred speech, euphoria, hyperkinesis, psychosis, and weakness were reported in 0.1% to 1% of patients. Rare (less than 0.1%) but potentially serious CNS adverse events included oculogyric episodes, suicidal ideation, suicide attempts, and completed suicides. During clinical trial evaluation of the extended-release amantadine capsules (e.g., Gocovri), the following CNS or related effects were reported in at least 3% of patients treated with 274 mg/day of extended-release amantadine: dizziness (16%), headache (6%), dystonic reaction (3%), hallucinations (21%), anxiety (7%), insomnia (7%), depression (6%), abnormal dreams (4%), confusion (3%), gait disturbance (3%), falls (13%), and contusion (6%). Less than 3% of patients experienced somnolence, fatigue, suicidal ideation or attempt, apathy, delusions, illusions, and paranoia. Many of these events occurred in patients receiving short courses and in patients with and without prior history of psychiatric illness. The following adverse effects led to treatment discontinuation in more patients receiving amantadine than placebo: hallucinations (8%), abnormal dreams (2%), dysphagia (2%), and gait disturbance (2%). The following events were reported more frequently in patients 65 years and older than adults younger than 65 years: hallucinations (31% vs. 10%) and falls (17% vs. 8%). Women experienced abnormal dreams more frequently than men (9% vs. 0%) while men experienced dizziness (20% vs. 11%), anxiety (11% vs. 2%), and gait disturbance (6% vs. 0%) more frequently than women. Rarely (less than 0.1%), seizures have occurred with amantadine use. The threshold for seizure activity may be decreased in patients with a history of epilepsy; therefore caution is advised when administering amantadine to these individuals. Other CNS adverse events occurring during postmarketing use of immediate-release amantadine include aggression, coma, delirium, delusions, dysphagia, EEG changes, gait abnormalities, hypertonia, hypokinesia, involuntary muscle contractions, mania, paranoia, paresthesias, stupor, and tremor. Due to the voluntary nature of postmarketing reports, neither a frequency nor a definitive causal relationship can be established. Additionally, abrupt discontinuation of amantadine has been associated with adverse CNS events and may precipitate delirium, agitation, delusions, hallucinations, paranoia, stupor, anxiety, depressed state, and slurred speech.[28049] [46061] [62262] [62273] [62887]

    Some patients receiving medications that increase dopaminergic tone have reported intense and uncontrollable urges to gamble, increased sexual urges, or other intense urges. In postmarketing use of amantadine, pathologic gambling, libido increase including hypersexuality, and other impulse control symptoms have been reported. Causality due to dopaminergic agents has not been established; however, in some cases, the urges stopped after the dose was reduced or the drug was discontinued. Practitioners should inquire periodically about new or worsening impulse control symptoms in patients receiving amantadine. Likewise, patients should be instructed to report such changes while receiving amantadine. Dose reduction or discontinuation should be considered in those who experience these effects.[28049] [46061] [62262] [62273] [62887]

    Some patients treated with amantadine have reported sudden sleep onset. Some incidents have occurred while the patient was driving or performing other potentially hazardous activities. In some cases excessive drowsiness has resulted in auto accidents or other harmful events in the course of daily living. Sudden sleep onset has occurred as late as 1 year after the initiation of treatment, and the relation to the medication is not entirely clear. Prior to initiating treatment with amantadine, patients should be advised of the potential to develop somnolence and specifically asked about factors that may increase the risk of experiencing such an event such as concomitant use of sedating medications (coadministration with other CNS depressants), ethanol ingestion, and the presence of sleep disorders (e.g., narcolepsy, sleep apnea). Reassessment for drowsiness or oversedation is necessary throughout amantadine therapy because patients may not perceive warning signs, such as excessive drowsiness, or they may report feeling alert immediately prior to the event. If a patient develops significant daytime sleepiness or episodes of falling asleep during activities that require active participation (e.g., conversations, eating, etc.), amantadine should generally be discontinued. If a decision is made to continue the drug, patients should be advised against driving or operating heavy machinery or engaging in 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.[28049] [46061] [62273] [62262] [62887]

    During clinical trial evaluation of immediate-release amantadine, the following cardiopulmonary adverse events were reported in 1% to 5% of amantadine-treated patients: peripheral edema and orthostatic hypotension. Dyspnea, hypertension, and heart failure were reported in 0.1% to 1% of amantadine-treated patients. During clinical trial evaluation of 274 mg/day of the extended-release amantadine capsules (e.g., Gocovri), the following cardiopulmonary effects were reported in at least 3% of amantadine-treated patients: peripheral edema (16%), orthostatic hypotension (13%), and cough (3%). The following adverse effects led to treatment discontinuation in more patients receiving amantadine than placebo: peripheral edema (3%) and postural syncope (2%). Orthostatic hypotension was reported more frequently in patients 65 years and older than adults younger than 65 years (8% vs. 2%). Men experienced the following effects more frequently than women: peripheral edema (19% vs. 11%) and orthostatic hypotension (7% vs. 2%). Cardiopulmonary adverse events reported during postmarketing use of immediate-release amantadine include cardiac arrest, arrhythmia exacerbation (including malignant arrhythmias), hypotension, sinus tachycardia, acute respiratory failure, pulmonary edema, and tachypnea. Due to the voluntary nature of postmarketing reports, neither a frequency nor a definitive causal relationship can be established.[46060] [46061] [62262] [62887]

    During clinical trial evaluation of immediate-release amantadine, nausea was reported in 5% to 10% of amantadine-treated patients. Adverse gastrointestinal (GI) effects reported in 1% to 5% of amantadine-treated patients included anorexia, xerostomia, constipation, dry nose, and diarrhea. Vomiting occurred infrequently (0.1% to 1%). During clinical trial evaluation of the extended-release amantadine capsules (e.g., Gocovri), the following GI effects were reported in at least 3% of patients treated with 274 mg/day of extended-release amantadine: xerostomia (16%), constipation (13%), nausea (8%), vomiting (3%), and appetite decrease (6%). Xerostomia led to treatment discontinuation in more patients receiving amantadine than placebo (3%). Women experienced nausea (13% vs. 4%) and xerostomia (22% vs. 11%) more frequently than men. Some of these events may be due to amantadine-related anticholinergic effects. Amantadine associated anticholinergic effects are more likely to occur in patients with increased plasma concentrations, such as those with renal dysfunction or in the elderly. A dose reduction may alleviate these effects in some patients. Deaths have been reported from overdose with amantadine; the lowest reported acute lethal dose was 1 gram. Acute toxicity may be attributable to anticholinergic effects.[46060] [46061] [62262] [62887]

    Livedo reticularis, a reticulated vascular pattern that appears as a purple lace-like skin discoloration, may occur with amantadine therapy. During clinical trial evaluation of immediate-release amantadine, livedo reticularis was reported in 1% to 5% of amantadine-treated patients. During clinical trial evaluation of the extended-release amantadine capsules (e.g., Gocovri), livedo reticularis was reported in 6% of patients treated with 274 mg/day of extended-release amantadine. Women experienced livedo reticularis more frequently than men (13% vs. 0%). Livedo reticularis can appear 1 month to 1 year from initiation of therapy, and can be an exacerbation of a preexisting condition. Livedo reticularis is believed to be caused by abnormal capillary permeability associated with peripheral vasoconstriction which results in decreased skin temperature and peripheral blood flow. Patients with peripheral edema should be closely monitored since the edema may be indicative of livedo reticularis. Dosage reduction or amantadine discontinuation may be necessary.[28049] [46061] [62262] [62273] [62887]

    During clinical trial evaluation of immediate-release amantadine, diffuse, white, subendothelial or other corneal opacification was reported in 0.1% to 1% of amantadine-treated patients. After discontinuation the opacities will usually resolve within a few weeks. Other types of visual impairment experienced by 0.1% to 1% of patients in clinical trials of immediate-release amantadine included corneal edema, decreased visual acuity, photosensitivity, and optic nerve palsy. During clinical trial evaluation of the extended-release amantadine capsules (e.g., Gocovri), the following ophthalmic effects were reported in at least 3% of patients treated with 274 mg/day of extended-release amantadine: blurred vision (4%), cataracts (3%), and xerophthalmia (3%). Women experienced cataracts more frequently than men (7% vs. 0%). Blurred vision (3%) led to treatment discontinuation in more patients receiving amantadine than placebo. Cases of keratitis and mydriasis have been noted during postmarketing use of immediate-release amantadine. Due to the voluntary nature of postmarketing reports, neither a frequency nor a definitive causal relationship can be established. Some of these events may be due to the anticholinergic effects associated with amantadine, which are more likely to occur in patients with increased plasma concentrations, such as those with renal dysfunction or in the elderly. Because of the anticholinergic side effects and the potential for mydriasis, avoid prescribing amantadine to patients with untreated angle closure glaucoma.[28049] [46061] [62262] [62273] [62887]

    During clinical trial evaluation of immediate-release amantadine, rash (unspecified) was reported in 0.1% to 1% of amantadine-treated patients. Eczematoid dermatitis occurred in less than 0.1% of patients. During clinical trial evaluation of the extended-release amantadine capsules (e.g., Gocovri), pigmentation disorder (unspecified) was reported in 3% of patients treated with 274 mg/day of extended-release amantadine. Dermatologic adverse events reported during postmarketing use of immediate-release amantadine include pruritus, hyperhidrosis, and melanoma. Due to the voluntary nature of postmarketing reports, neither a frequency nor a definitive causal relationship can be established; however, studies indicated that patients with Parkinson's disease have a 2- to 6- fold higher risk of developing melanoma than the general population. The cause for this increased risk, whether due to the drug or disease, is unknown. Despite the lack of data, health care providers are advised to perform frequent skin examinations on patients receiving amantadine for any indication. Anaphylactoid reactions, including fever and edema, have been reported during postmarketing use of immediate-release amantadine. Similar effects should be anticipated with the extended-release formulations.[28049] [46061] [62262] [62273] [62887]

    During clinical trial evaluation of the extended-release amantadine capsules (e.g., Gocovri), the following adverse musculoskeletal effects were reported in at least 3% of patients treated with 274 mg/day of extended-release amantadine: arthralgia (joint swelling 3%) and muscle spasms (muscle cramps 3%). Involuntary muscle contractions have been reported in postmarketing use of immediate-release amantadine.[28049] [46061] [62262] [62273] [62887]

    During clinical trial evaluation of immediate-release amantadine, leukopenia and neutropenia were reported in less than 0.1% of amantadine-treated patients. Agranulocytosis and leukocytosis have been noted during postmarketing use of immediate-release amantadine. Due to the voluntary nature of postmarketing reports, neither a frequency nor a definitive causal relationship can be established.[28049] [46061] [62262] [62273] [62887]

    During clinical trial evaluation of immediate-release amantadine, adverse genitourinary (GU) effects including urinary retention and libido decrease were reported in 0.1% to 1% of amantadine-treated patients. The anticholinergic effects of amantadine may contribute to adverse reactions such as urinary retention and aggravation of prostatic hypertrophy. During clinical trial evaluation of the extended-release amantadine capsules (e.g., Gocovri), the following adverse GU effects were reported in at least 3% of patients treated with 274 mg/day of extended-release amantadine: urinary tract infection (10%) and benign prostatic hypertrophy (6% of male patients). Amantadine associated anticholinergic effects are more likely to occur in patients with increased plasma concentrations, such as those with renal dysfunction or in the elderly. Deaths have been reported from overdose with amantadine; the lowest reported acute lethal dose was 1 gram. Acute toxicity may be attributable to anticholinergic effects.[28049] [46061] [62262] [62273] [62887]

    Laboratory abnormalities noted during postmarketing use of immediate-release amantadine include elevated hepatic enzymes (i.e., ALT and AST), hyperbilirubinemia, and elevations in other laboratory tests including blood urea nitrogen (BUN), serum creatinine, alkaline phosphatase, creatine phosphokinase (CPK), gamma-glutamyltransferase (GGT), and lactate dehydrogenase (LDH). Due to the voluntary nature of postmarketing reports, neither a frequency nor a definitive causal relationship can be established.[28049] [46061] [62262] [62273] [62887]

    Cases of neuroleptic malignant syndrome (NMS) have been associated with amantadine dose reduction or abrupt discontinuation or withdrawal from therapy. Characteristic symptoms of NMS include hyperthermia, muscle rigidity, involuntary movements, mental status change and altered consciousness, autonomic dysfunction, sinus tachycardia, tachypnea, hypertension, hypotension, elevated creatine phosphokinase, leukocytosis, myoglobinuria, and increased serum myoglobin. Observe patients carefully for NMS symptoms during amantadine dosage reductions or when therapy is stopped abruptly as early diagnosis is important. Treatment of NMS includes medical monitoring, intensive symptomatic therapy, and treatment of concomitant serious medical problems. Despite a lack of data from controlled trials, bromocriptine and dantrolene have been used in the treatment of NMS.[28049] [46061] [62262] [62273] [62887]

    Antimicrobial resistance can occur during therapy with amantadine due to the development of viral mutations. Drug effectiveness may be diminished by resistance mutations or other factors such as viral virulence. Drug susceptibility patterns should be assessed when determining appropriateness of influenza A treatment with amantadine.[28049] [46061] [62273] [62262] [62887] Current information regarding viral resistance patterns can be obtained from the U.S. Centers for Disease Control (CDC).[62315]

    Revision Date: 04/28/2020, 11:39:40 AM

    References

    28049 - Amantadine HCl capsules package insert. Princeton, NJ: Sandoz Inc; 2015 May.46060 - OPEN ref (available for use)46061 - Amantadine HCl oral solution package insert. Amityville, NY: Hi-Tech Pharmacal Co., Inc.; 2015 Jan.62262 - Gocovri (amantadine extended-release capsules) package insert. Emeryville, CA: Adamas Pharma LLC; 2021 Jan.62273 - Amantadine HCl immediate-release capsules package insert. Parsippany, NJ: Actavis Pharma, Inc.; 2017 Jan.62315 - Centers for Disease Control and Prevention (CDC). Influenza antiviral medications: Summary for clinicians, 2020-2021. Retrieved November 5, 2020. Available on the World Wide Web at https://www.cdc.gov/flu/professionals/antivirals/summary-clinicians.htm62887 - Osmolex ER (amantadine extended-release tablets) package insert. Bridgewater, NJ: Vertical Pharmaceuticals, LLC; 2018 Feb.

    Contraindications/Precautions

    Absolute contraindications are italicized.

    • amantadine hypersensitivity
    • dialysis
    • renal failure
    • rimantadine hypersensitivity
    • abrupt discontinuation
    • anticholinergic medications
    • breast-feeding
    • children
    • closed-angle glaucoma
    • coadministration with other CNS depressants
    • depression
    • driving or operating machinery
    • eczema
    • ethanol ingestion
    • geriatric
    • heart failure
    • hepatic disease
    • impulse control symptoms
    • infants
    • infertility
    • melanoma
    • narcolepsy
    • neonates
    • orthostatic hypotension
    • peripheral edema
    • pregnancy
    • psychosis
    • renal impairment
    • schizophrenia
    • seizure disorder
    • sleep apnea
    • substance abuse
    • sudden sleep onset
    • suicidal ideation
    • syncope

    Serious bacterial infections may begin with influenza-like symptoms or may coexist with or occur as complications during the course of influenza. Amantadine has not been shown to prevent such complications.[28049][46061][62273]

    Amantadine is contraindicated in patients with a known amantadine hypersensitivity, rimantadine hypersensitivity, or hypersensitivity to any agent in the adamantine class.[28049] [46061] [62262]

    Because amantadine is primarily excreted unchanged in the urine, patients with renal impairment require dosage adjustments. The use of the extended-release capsules (e.g., Gocovri) or extended-release tablets (e.g., Osmolex ER) is contraindicated in patients with end-stage renal disease (e.g., those with renal failure, on dialysis, or with CrCl less than 15 mL/minute). During use of the immediate-release products, dosage adjustments are required for patients with end-stage renal disease (renal failure), including those receiving dialysis. Deaths due to systemic drug accumulation have been reported in patients with renal impairment who were prescribed higher than recommended doses of amantadine for their level of renal function. Renal function should be monitored closely and the dose adjusted accordingly. Hemodialysis removes only a negligible amount of amantadine.[28049] [46061] [62262] [62273] [62887]

    Patients should be monitored for dizziness and orthostatic hypotension, especially after starting amantadine or increasing the dose. During clinical trial evaluation of the extended-release amantadine capsules (e.g., Gocovri), more patients receiving amantadine experienced dizziness, syncope, orthostatic hypotension, presyncope, postural dizziness, or hypotension than patients receiving placebo. Patients with congestive heart failure or peripheral edema should also be cautiously treated with amantadine. Peripheral edema and congestive heart failure can be precipitated by amantadine, which is thought to induce a redistribution of fluid within the body rather than an increase in total body water. Peripheral edema can be preceded by or can accompany livedo reticularis and may require dose reduction or drug discontinuation.[28049] [46061] [62262] [62273] [62887]

    Amantadine can increase seizure activity in patients with a seizure disorder. Patients with a history of seizures should be monitored closely when amantadine is initiated.[28049] [46061] [62273]

    Patients should be monitored for depression, suicidal ideation or behavior, and hallucinations throughout treatment with amantadine. During clinical trial evaluation of the extended-release amantadine capsules (e.g., Gocovri), adverse effects including confusion, depression, depressed mood, suicidal ideation, suicide attempt, visual hallucination, auditory hallucination, delusions, illusions, and paranoia occurred in more patients receiving amantadine than placebo. Patients with a major psychotic disorder (e.g., schizophrenia, psychosis) should generally not be treated with amantadine because of the risk of exacerbating psychosis. Prescribers should consider whether the benefits outweigh the risks of treatment with amantadine in patients with a history of suicidality or depression. Suicide attempts and suicidal ideation have been reported in patients with and without a prior history of a psychiatric disorder. Because overdose has been lethal with an acute dose as low as 1 gram, amantadine should be prescribed in the smallest quantity consistent with good patient management in order to reduce the risk of overdose. A benefit versus risk assessment should be considered in patients with a substance abuse disorder, since exacerbation of symptoms may occur.[28049] [46061] [62262] [62273] [62887]

    Some patients receiving medications that increase dopaminergic tone have reported intense and uncontrollable urges to gamble, increased sexual urges, or other intense urges. Causality due to dopaminergic agents has not been established; however, in some cases the urges stopped after the dose was reduced or the drug was discontinued. Practitioners should inquire periodically about new or worsening impulse control symptoms in patients receiving amantadine. Likewise, patients should be instructed to report such changes while receiving amantadine. Dose reduction or discontinuation should be considered in those who experience these effects.[28049] [46061] [62262] [62273] [62887]

    Patients treated for Parkinson's disease have reported sudden sleep onset, such as 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. Prior to initiating treatment with amantadine, patients should be advised of the potential for somnolence and specifically asked about factors that may increase the risk of experiencing such an event such as coadministration with other CNS depressants, alcohol ingestion, or the presence of a sleep disorder (e.g., narcolepsy, sleep apnea). Assessment for somnolence is necessary throughout amantadine therapy. Patients should use caution in driving or operating machinery, or performing other potentially hazardous tasks. If a patient develops significant daytime sleepiness or episodes of falling asleep during activities that require active participation (e.g., conversations, eating, etc.), amantadine should generally be discontinued. If a decision is made to continue the drug, patients should be advised against driving or operating heavy machinery or engaging in 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. Manufacturers of amantadine products recommend against ethanol ingestion during treatment, as it may increase the potential for CNS and blood pressure effects such as hypotension, dizziness, confusion, lightheadedness, and orthostatic hypotension. With the extended-release capsule formula (e.g., Gocovri), ingestion of alcohol may result in dose-dumping.[28049] [46061] [62262] [62273] [62887]

    Caution is advisable when prescribing amantadine to patients with hepatic disease; although, no dosage adjustment is recommended. Rare cases of reversible elevated hepatic enzymes have been reported in patients receiving amantadine, although a causal relationship has not been established.[28049] [46061] [62273]

    Use caution when administering amantadine to patients with a history of recurrent eczema. Eczematoid dermatitis occurred rarely during clinical trial evaluation of immediate-release amantadine.[28049] [46061] [62273]

    Amantadine has anticholinergic effects and may cause mydriasis. Some manufacturers recommend against administering amantadine to patients with untreated closed-angle glaucoma.[28049] [46061] [62273]

    Epidemiological studies have shown that patients with Parkinson's disease have a 2- to 6-fold higher risk of developing melanoma than the general population. It is unclear if this increased risk is disease-related or associated with other factors such as the medications used to treat Parkinson's disease. Therefore, it is recommended that a qualified practitioner (e.g., dermatologist) monitor for melanomas on a regular basis during amantadine use. In addition, patients should be instructed to regularly monitor for skin changes that may indicate the presence of melanoma and to promptly report these changes to their provider.[28049] [46061] [62273] The product labels for extended-release amantadine capsules and tablets do not carry a precaution for melanoma.[62262] [62887]

    Avoid abrupt discontinuation of immediate-release or extended-release amantadine in patients with Parkinson's disease. 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 amantadine in these patients 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.[28049] [46061] [62262] [62273] When discontinuing amantadine extended-release tablets (e.g., Osmolex ER), the dose should be gradually reduced from higher doses to 129 mg daily for 1 to 2 weeks.[62887]

    There are no adequate data regarding the developmental risk associated with the use of amantadine during pregnancy. Based on available data, amantadine may have the potential to cause fetal harm; therefore, use during pregnancy should be avoided unless the potential benefits outweigh the possible risks to the fetus. Fetal malformations (Tetralogy of Fallot, tibial hemimelia, cardiovascular malformations) have been noted in 2 cases where normal doses of amantadine were used by the mother in the first trimester of human pregnancy. Published animal studies also 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.[28049] [46061] [62262] [62273] [62887]

    Until more data become available on the effects of amantadine on fertility, caution is advisable when using amantadine in patients with infertility problems. In rat studies, amantadine given at a dose equal to 32 mg/kg/day (equal to the maximum recommended human dose) resulted in impaired fertility in both male and female rats. 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. Failed human fertility has been reported when amantadine was used during in vitro fertilization; the male sperm donor had used amantadine 2 weeks prior to, and during the fertilization cycle.[28049] [46061] [62262] [62273] [62887]

    Amantadine may potentially alter breast milk production or excretion, a factor which should be taken into account when considering the use of amantadine in breast-feeding mothers. Amantadine is excreted in human milk. Amantadine is a dopamine agonist and at usual prescribed doses may inhibit lactation. In published studies, amantadine reduced serum prolactin levels and the symptoms of galactorrhea in patients taking neuroleptic drugs.[62262] The effect of amantadine on milk supply has not been evaluated in nursing mothers. Manufacturers of immediate-release amantadine recommend against use of amantadine during breast-feeding.[28049] [46061] [62273] Consider the use of alternatives based on indication for use. Oseltamivir and zanamivir are preferred alternatives to amantadine for the prophylaxis or treatment of influenza A during breast-feeding, due to resistant strains and other clinical factors.[46966] [46967] However, patient factors, local susceptibility patterns, and specific microbial susceptibility should be assessed before choosing an alternative. The developmental and health benefits of breast-feeding should be considered along with the clinical need of the mother for amantadine and any potential adverse effects on the breast-fed infant from drug treatment or from the underlying maternal condition.[62262] [62887] If a breast-feeding infant experiences an adverse effect related to a maternally ingested drug, healthcare providers are encouraged to report the adverse effect to the FDA.

    Because of an age-related decline in renal function, geriatric patients may experience amantadine drug accumulation with toxic effects; therefore, a dose reduction of immediate-release amantadine formulations is recommended in individuals who are 65 years of age or older.[28049] No dosage adjustments of the extended-release capsules (e.g., Gocovri) or extended-release tablets (e.g., Osmolex ER) are recommended in the elderly based on age alone. However, because elderly patients are more likely to have decreased renal function, it may be useful to monitor renal function to guide dose selection.[62262] [62887] Deaths due to systemic drug accumulation have been reported in patients with renal impairment who were prescribed higher than recommended doses of amantadine for their level of renal function. Amantadine exhibits significant anticholinergic effects that can be problematic in the geriatric patient and may be additive to other anticholinergic medications in any population.[28049] [62262] The federal Omnibus Budget Reconciliation Act (OBRA) regulates medication use in residents of long-term care facilities (LTCFs). According to OBRA, antiparkinson medications may cause significant confusion, restlessness, delirium, dyskinesia, nausea, dizziness, hallucinations, and agitation. In addition, there is an increased risk of postural hypotension and falls, particularly during concurrent use of antihypertensive medications. Amantadine has significant anticholinergic properties, which may problematic in the elderly.[60742]

    Immediate-release amantadine is FDA-approved for children 1 year of age and older for the prophylaxis and treatment of uncomplicated influenza A. Safety and efficacy are not established in infants or neonates.[28049] [46061] [62273] The safety and efficacy of extended-release amantadine capsules (e.g., Gocovri) and extended-release amantadine tablets (e.g., Osmolex ER) have not been established in pediatric patients.[62262] [62887]

    Revision Date: 08/27/2020, 03:55:17 PM

    References

    28049 - Amantadine HCl capsules package insert. Princeton, NJ: Sandoz Inc; 2015 May.46061 - Amantadine HCl oral solution package insert. Amityville, NY: Hi-Tech Pharmacal Co., Inc.; 2015 Jan.46966 - Greer LG, Leff RD, Rogers VL, et al. Pharmacokinetics of oseltamivir in breast milk and maternal plasma. Am J Obstet Gynecol. 2011;204:524e1-524e4.46967 - Tanaka T, Nakajima K, Murashima A, et al. Safety of neuraminidase inhibitors against novel influenza A (H1N1) in pregnant and breastfeeding women. CMAJ. 2009;181(1-2):55-58.60742 - Health Care Financing Administration. Interpretive Guidelines for Long-term Care Facilities. Title 42 CFR 483.25(l) F329: Unnecessary Drugs. Revised 2015.62262 - Gocovri (amantadine extended-release capsules) package insert. Emeryville, CA: Adamas Pharma LLC; 2021 Jan.62273 - Amantadine HCl immediate-release capsules package insert. Parsippany, NJ: Actavis Pharma, Inc.; 2017 Jan.62887 - Osmolex ER (amantadine extended-release tablets) package insert. Bridgewater, NJ: Vertical Pharmaceuticals, LLC; 2018 Feb.

    Mechanism of Action

    The mechanism by which amantadine exerts an effect in the treatment of dyskinesia associated with Parkinson's disease or as an adjunct to carbidopa; levodopa in patients with Parkinson's disease experiencing 'off' episodes is unknown. Antiparkinsonian actions are unrelated to the antiviral effects. Amantadine is a weak, uncompetitive antagonist of the N-methyl-D-aspartate (NMDA) receptor. In addition, the drug may have direct or indirect effects on dopamine neurons. It may release dopamine and norepinephrine from storage sites and inhibit the reuptake of dopamine and norepinephrine. Overall, amantadine is less effective than levodopa but can offer specific benefits such as in patients with levodopa-induced dyskinesia. Anticholinergic-like side effects have been reported and are usually more prominent in elderly patients.[28049][62262]

     

    As an antiviral, amantadine can inhibit viral replication within viral-infected cells. Amantadine appears to block the uncoating of the virus particle and subsequent release of viral nucleic acid into the host cell. This process is thought to be caused by interference with fusion of the virion coat to vacuolar membranes.[24689] Amantadine also may interfere with penetration of the cell wall by adsorbed virus. To prevent a viral infection, the drug should be present before exposure to the virus, but, if given within 24 to 48 hours of onset of symptoms, the influenza may be less severe. However, the CDC recommends against using for influenza A due to resistance in circulating strains. As in recent past seasons, there continues to be high levels of resistance (more than 99%) to adamantane agents such as amantadine among influenza A viruses. Therefore, amantadine is not recommended for antiviral treatment or chemoprophylaxis of currently circulating influenza A viruses. Check for current information on the CDC website.[62315]

    Revision Date: 02/02/2021, 04:05:32 PM

    References

    24689 - Phelps WC, Alexander KA. Antiviral therapy for human papillomaviruses: rationale and prospects. Ann Intern Med 1995;123(5):368-382.28049 - Amantadine HCl capsules package insert. Princeton, NJ: Sandoz Inc; 2015 May.62262 - Gocovri (amantadine extended-release capsules) package insert. Emeryville, CA: Adamas Pharma LLC; 2021 Jan.62315 - Centers for Disease Control and Prevention (CDC). Influenza antiviral medications: Summary for clinicians, 2020-2021. Retrieved November 5, 2020. Available on the World Wide Web at https://www.cdc.gov/flu/professionals/antivirals/summary-clinicians.htm

    Pharmacokinetics

    Amantadine is administered orally as immediate-release or extended-release formulations. The extended-release tablet (e.g., Osmolex ER) consists of an immediate-release outer layer and an extended-release core. The extended-release capsule (e.g., Gocovri) contains extended-release pellets within the capsule. Amantadine crosses the blood-brain barrier and distributes into tears, saliva, and nasal secretions. Protein binding is not clinically significant (about 67%). Some data suggest potential extravascular distribution. Amantadine is primarily excreted as the parent compound in the urine via glomerular filtration and tubular secretion. Eight metabolites of amantadine have been identified in human urine. One metabolite, an N-acetylated compound, was quantified in human urine and accounted for up to 15% of the administered dose in multiple studies. The contribution of this metabolite to the efficacy or toxicity of amantadine is not known. The average elimination half-life in adult patients with normal renal function is about 17 hours. Acidifying the urine increases the rate of excretion.[62262][62273][62887]

     

    Affected cytochrome P450 (CYP450) isoenzymes and drug transporters: None

    Route-Specific Pharmacokinetics

    Oral Route

    Amantadine is well absorbed orally. Bioavailability is 86% in the elderly and greater than 90% in young adults. Maximum plasma concentrations of the immediate-release formulation are directly related to doses up to 200 mg/day. Doses above 200 mg/day may result in a greater than proportional increase in maximum concentrations. The pharmacokinetics of the extended-release capsules and extended-release tablets are dose proportional with therapeutic dosing. The average time to peak plasma concentrations of the immediate-release formulation is about 3 hours (range: 1.5 to 8 hours). After a single bedtime dose of the extended-release capsule, the median time to maximum plasma concentrations is about 12 hours (range: 6 to 20 hours). Peak concentrations of the extended-release tablets occur in a median time of 7.5 hours (range: 5.5 to 12 hours). Steady-state concentrations of immediate-release amantadine following daily dosing are obtained in 2 to 4 days. Steady-state concentrations of the extended-release capsules are achieved 4 days after dose initiation. Administration with food does not alter the kinetics of amantadine; therefore, the various products may be administered without regard to meals.[23574][62262][62273][62887]

    Special Populations

    Hepatic Impairment

    Formal pharmacokinetic evaluations of amantadine use in patients with hepatic disease have not been conducted; amantadine is primarily eliminated unchanged in the urine.[62262][62887]

    Renal Impairment

    Compared with healthy adults, the clearance of amantadine is significantly reduced in adults with moderate to severe renal impairment. The elimination half-life increases 2- to 3-fold or greater when the creatinine clearance is less than 40 mL/minute and averages 8 days in patients on chronic maintenance hemodialysis. In pharmacokinetic simulations, the range of the total exposure in subjects with normal renal function (CrCl greater than 90 mL/minute) or mild renal impairment (CrCl 60 to 89 mL/minute) was comparable. However, patients with moderate to severe renal impairment had higher exposures relative to patients with normal renal function or mild renal impairment. Amantadine is removed in negligible amounts by hemodialysis. The manufacturers of the extended-release capsules (e.g., Gocovri) and extended-release tablets (e.g., Osmolex ER) contraindicate the use of the drug in patients with end-stage renal disease (ESRD). Dosage adjustments of the extended-release formulations are required in patients with moderate to severe renal disease.[62262][62887]

    Pediatrics

    There are no pediatric pharmacokinetic data available from the manufacturers. Weight-based dosing is used in pediatric patients 1 year and older. The safety and efficacy of immediate-release amantadine in newborns and infants below the age of 1 year have not been established.[62273] The extended-release capsules (e.g., Gocovri) and extended-release tablets (e.g., Osmolex ER) are not approved in pediatric patients.[62262][62887]

    Geriatric

    The apparent oral plasma clearance of amantadine is reduced and the plasma half-life and plasma concentrations are increased in healthy geriatric adults 60 years of age and older compared to younger adults. After administration of a single 25 mg to 75 mg dose of immediate-release amantadine to healthy, elderly male volunteers (n = 7), the average half-life was 29 hours (range: 20 to 41 hours). In a separate pharmacokinetic evaluation of 24 younger adult male volunteers who received a single 100 mg dose of immediate-release amantadine, the average half-life was 17 hours (range: 10 to 25 hours). Whether these changes are due to decline in renal function or other age related factors is not known.[62273] No dose adjustment of the extended-release capsules (e.g., Gocovri) or extended-release tablets (e.g., Osmolex ER) is recommended on the basis of age; however, 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.[62262][62887] The manufacturer of immediate-release amantadine recommends a dose reduction in individuals who are 65 years of age or older.[62273]

    Gender Differences

    In a study of young healthy subjects (n = 20), the mean renal clearance of amantadine normalized for body mass index was significantly higher in males (1.5-fold) compared to females; however, no dosage adjustments of amantadine are recommended based on gender.[62273]

    Revision Date: 02/21/2018, 10:45:46 AM

    References

    23574 - Deeter RG, Khanderia U. Recent advances in antiviral therapy. Clin Pharm 1986;5:961-76.62262 - Gocovri (amantadine extended-release capsules) package insert. Emeryville, CA: Adamas Pharma LLC; 2021 Jan.62273 - Amantadine HCl immediate-release capsules package insert. Parsippany, NJ: Actavis Pharma, Inc.; 2017 Jan.62887 - Osmolex ER (amantadine extended-release tablets) package insert. Bridgewater, NJ: Vertical Pharmaceuticals, LLC; 2018 Feb.

    Pregnancy/Breast-feeding

    pregnancy

    There are no adequate data regarding the developmental risk associated with the use of amantadine during pregnancy. Based on available data, amantadine may have the potential to cause fetal harm; therefore, use during pregnancy should be avoided unless the potential benefits outweigh the possible risks to the fetus. Fetal malformations (Tetralogy of Fallot, tibial hemimelia, cardiovascular malformations) have been noted in 2 cases where normal doses of amantadine were used by the mother in the first trimester of human pregnancy. Published animal studies also 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.[28049] [46061] [62262] [62273] [62887]

    breast-feeding

    Amantadine may potentially alter breast milk production or excretion, a factor which should be taken into account when considering the use of amantadine in breast-feeding mothers. Amantadine is excreted in human milk. Amantadine is a dopamine agonist and at usual prescribed doses may inhibit lactation. In published studies, amantadine reduced serum prolactin levels and the symptoms of galactorrhea in patients taking neuroleptic drugs.[62262] The effect of amantadine on milk supply has not been evaluated in nursing mothers. Manufacturers of immediate-release amantadine recommend against use of amantadine during breast-feeding.[28049] [46061] [62273] Consider the use of alternatives based on indication for use. Oseltamivir and zanamivir are preferred alternatives to amantadine for the prophylaxis or treatment of influenza A during breast-feeding, due to resistant strains and other clinical factors.[46966] [46967] However, patient factors, local susceptibility patterns, and specific microbial susceptibility should be assessed before choosing an alternative. The developmental and health benefits of breast-feeding should be considered along with the clinical need of the mother for amantadine and any potential adverse effects on the breast-fed infant from drug treatment or from the underlying maternal condition.[62262] [62887] If a breast-feeding infant experiences an adverse effect related to a maternally ingested drug, healthcare providers are encouraged to report the adverse effect to the FDA.

    Revision Date: 01/04/2019, 02:36:01 PM

    References

    28049 - Amantadine HCl capsules package insert. Princeton, NJ: Sandoz Inc; 2015 May.46061 - Amantadine HCl oral solution package insert. Amityville, NY: Hi-Tech Pharmacal Co., Inc.; 2015 Jan.46966 - Greer LG, Leff RD, Rogers VL, et al. Pharmacokinetics of oseltamivir in breast milk and maternal plasma. Am J Obstet Gynecol. 2011;204:524e1-524e4.46967 - Tanaka T, Nakajima K, Murashima A, et al. Safety of neuraminidase inhibitors against novel influenza A (H1N1) in pregnant and breastfeeding women. CMAJ. 2009;181(1-2):55-58.62262 - Gocovri (amantadine extended-release capsules) package insert. Emeryville, CA: Adamas Pharma LLC; 2021 Jan.62273 - Amantadine HCl immediate-release capsules package insert. Parsippany, NJ: Actavis Pharma, Inc.; 2017 Jan.62887 - Osmolex ER (amantadine extended-release tablets) package insert. Bridgewater, NJ: Vertical Pharmaceuticals, LLC; 2018 Feb.

    Interactions

    Level 2 (Major)

    • Acetaminophen; Aspirin, ASA; Caffeine
    • Acetaminophen; Butalbital; Caffeine; Codeine
    • Acetaminophen; Caffeine
    • Acetaminophen; Caffeine; Dihydrocodeine
    • Acetaminophen; Caffeine; Magnesium Salicylate; Phenyltoloxamine
    • Acetaminophen; Caffeine; Phenyltoloxamine; Salicylamide
    • Aspirin, ASA; Butalbital; Caffeine
    • Aspirin, ASA; Butalbital; Caffeine; Codeine
    • Aspirin, ASA; Caffeine
    • Aspirin, ASA; Caffeine; Dihydrocodeine
    • Aspirin, ASA; Caffeine; Orphenadrine
    • Atropine
    • Atropine; Benzoic Acid; Hyoscyamine; Methenamine; Methylene Blue; Phenyl Salicylate
    • Atropine; Difenoxin
    • Atropine; Diphenoxylate
    • Atropine; Edrophonium
    • Atropine; Hyoscyamine; Phenobarbital; Scopolamine
    • Benzoic Acid; Hyoscyamine; Methenamine; Methylene Blue; Phenyl Salicylate
    • Budesonide; Glycopyrrolate; Formoterol
    • Bupropion
    • Bupropion; Naltrexone
    • Butalbital; Acetaminophen; Caffeine
    • Caffeine
    • Caffeine; Ergotamine
    • Caffeine; Sodium Benzoate
    • Chlordiazepoxide; Clidinium
    • Ethanol
    • Glycopyrrolate
    • Glycopyrrolate; Formoterol
    • Homatropine; Hydrocodone
    • Hyoscyamine
    • Hyoscyamine; Methenamine; Methylene Blue; Phenyl Salicylate; Sodium Biphosphate
    • Indacaterol; Glycopyrrolate
    • Live Attenuated Influenza Vaccine (intranasal)
    • Methenamine; Sodium Acid Phosphate; Methylene Blue; Hyoscyamine
    • Methscopolamine
    • Metoclopramide
    • Propantheline
    • Scopolamine
    • Sulfamethoxazole; Trimethoprim, SMX-TMP, Cotrimoxazole
    • Talimogene Laherparepvec
    • Trimethoprim

    Level 3 (Moderate)

    • Acetaminophen; Pentazocine
    • Alosetron
    • Ambenonium Chloride
    • Amitriptyline
    • Amitriptyline; Chlordiazepoxide
    • Amoxapine
    • Amphetamine; Dextroamphetamine Salts
    • Benzphetamine
    • Benztropine
    • Bismuth Subsalicylate
    • Bismuth Subsalicylate; Metronidazole; Tetracycline
    • Chlorpromazine
    • Clomipramine
    • Clozapine
    • Codeine; Phenylephrine; Promethazine
    • Codeine; Promethazine
    • Cyclobenzaprine
    • Darifenacin
    • Desipramine
    • Dextromethorphan; Promethazine
    • Dicyclomine
    • Diethylpropion
    • Disopyramide
    • Donepezil
    • Donepezil; Memantine
    • Doxepin
    • Ezogabine
    • Fesoterodine
    • Flavoxate
    • Fluoxetine; Olanzapine
    • Fluphenazine
    • Galantamine
    • Haloperidol
    • Imipramine
    • Loperamide
    • Loperamide; Simethicone
    • Loxapine
    • Maprotiline
    • Memantine
    • Mepenzolate
    • Meperidine; Promethazine
    • Mesoridazine
    • Methamphetamine
    • Methylphenidate Derivatives
    • Modafinil
    • Molindone
    • Nortriptyline
    • Olanzapine
    • Orphenadrine
    • Oxybutynin
    • Pemoline
    • Pentazocine
    • Pentazocine; Naloxone
    • Perphenazine
    • Perphenazine; Amitriptyline
    • Phenothiazines
    • Phenylephrine; Promethazine
    • Pimozide
    • Prochlorperazine
    • Promethazine
    • Protriptyline
    • Rivastigmine
    • Sedating H1-blockers
    • Solriamfetol
    • Tacrine
    • Thiethylperazine
    • Thioridazine
    • Thiothixene
    • Tolterodine
    • Tricyclic antidepressants
    • Trifluoperazine
    • Trihexyphenidyl
    • Trimipramine
    • Trospium

    Level 4 (Minor)

    • Carbidopa; Levodopa
    • Carbidopa; Levodopa; Entacapone
    • Dextromethorphan; Quinidine
    • Hydrochlorothiazide, HCTZ; Triamterene
    • Levodopa
    • Quinidine
    • Triamterene
    Acetaminophen; Aspirin, ASA; Caffeine: (Major) Amantadine used concomitantly with psychostimulants, such as caffeine, can result in increased stimulant effects, such as nervousness, irritability, or insomnia, and can lead to seizures or cardiac arrhythmias. Close monitoring of the patient is recommended. [4771] Acetaminophen; Butalbital; Caffeine; Codeine: (Major) Amantadine used concomitantly with psychostimulants, such as caffeine, can result in increased stimulant effects, such as nervousness, irritability, or insomnia, and can lead to seizures or cardiac arrhythmias. Close monitoring of the patient is recommended. [4771] Acetaminophen; Caffeine: (Major) Amantadine used concomitantly with psychostimulants, such as caffeine, can result in increased stimulant effects, such as nervousness, irritability, or insomnia, and can lead to seizures or cardiac arrhythmias. Close monitoring of the patient is recommended. [4771] Acetaminophen; Caffeine; Dihydrocodeine: (Major) Amantadine used concomitantly with psychostimulants, such as caffeine, can result in increased stimulant effects, such as nervousness, irritability, or insomnia, and can lead to seizures or cardiac arrhythmias. Close monitoring of the patient is recommended. [4771] Acetaminophen; Caffeine; Magnesium Salicylate; Phenyltoloxamine: (Major) Amantadine used concomitantly with psychostimulants, such as caffeine, can result in increased stimulant effects, such as nervousness, irritability, or insomnia, and can lead to seizures or cardiac arrhythmias. Close monitoring of the patient is recommended. [4771] Acetaminophen; Caffeine; Phenyltoloxamine; Salicylamide: (Major) Amantadine used concomitantly with psychostimulants, such as caffeine, can result in increased stimulant effects, such as nervousness, irritability, or insomnia, and can lead to seizures or cardiac arrhythmias. Close monitoring of the patient is recommended. [4771] Acetaminophen; Pentazocine: (Moderate) Use pentazocine with caution in any patient receiving anticholinergic agents. Coadministration of pentazocine with amantadine may result in additive anticholinergic effects, such as urinary retention and constipation. [30029] Alosetron: (Moderate) Alosetron, if combined with drugs that possess anticholinergic properties like amantadine, may seriously worsen constipation, leading to events such as GI obstruction/impaction or paralytic ileus. [4771] Ambenonium Chloride: (Moderate) The therapeutic benefits of ambenonium may be diminished when co-administered with the antimuscarinics. Drugs known to exhibit anticholinergic properties that could potentially interfere with the cholinesterase inhibitor activity include amantadine. [42863] [4771] [6338] [6380] Amitriptyline: (Moderate) Additive anticholinergic effects and CNS effects may be seen when tricyclic antidepressants are used concomitantly with amantadine. [4771] Amitriptyline; Chlordiazepoxide: (Moderate) Additive anticholinergic effects and CNS effects may be seen when tricyclic antidepressants are used concomitantly with amantadine. [4771] Amoxapine: (Moderate) Medications with significant anticholinergic activity, like amoxapine, may potentiate the anticholinergic effects of amantadine, and may increase the risk of antimuscarinic-related side effects. [5288] Amphetamine; Dextroamphetamine Salts: (Moderate) Careful observation is required when amantadine is administered concurrently with central nervous system (CNS) stimulants. An increase in stimulant effects, such as nervousness, irritability, insomnia, tremor, seizures, or cardiac arrhythmias may occur. [46061] Aspirin, ASA; Butalbital; Caffeine: (Major) Amantadine used concomitantly with psychostimulants, such as caffeine, can result in increased stimulant effects, such as nervousness, irritability, or insomnia, and can lead to seizures or cardiac arrhythmias. Close monitoring of the patient is recommended. [4771] Aspirin, ASA; Butalbital; Caffeine; Codeine: (Major) Amantadine used concomitantly with psychostimulants, such as caffeine, can result in increased stimulant effects, such as nervousness, irritability, or insomnia, and can lead to seizures or cardiac arrhythmias. Close monitoring of the patient is recommended. [4771] Aspirin, ASA; Caffeine: (Major) Amantadine used concomitantly with psychostimulants, such as caffeine, can result in increased stimulant effects, such as nervousness, irritability, or insomnia, and can lead to seizures or cardiac arrhythmias. Close monitoring of the patient is recommended. [4771] Aspirin, ASA; Caffeine; Dihydrocodeine: (Major) Amantadine used concomitantly with psychostimulants, such as caffeine, can result in increased stimulant effects, such as nervousness, irritability, or insomnia, and can lead to seizures or cardiac arrhythmias. Close monitoring of the patient is recommended. [4771] Aspirin, ASA; Caffeine; Orphenadrine: (Major) Amantadine used concomitantly with psychostimulants, such as caffeine, can result in increased stimulant effects, such as nervousness, irritability, or insomnia, and can lead to seizures or cardiac arrhythmias. Close monitoring of the patient is recommended. [4771] (Moderate) Additive anticholinergic effects and drowsiness may be seen when orphenadrine is used concomitantly with amantadine. [5982] Atropine: (Major) Amantadine may exhibit anticholinergic activity. Antimuscarinics, such as atropine, may potentiate the anticholinergic effects of amantadine, and may increase the risk of antimuscarinic-related side effects. [4771] Atropine; Benzoic Acid; Hyoscyamine; Methenamine; Methylene Blue; Phenyl Salicylate: (Major) Additive anticholinergic effects may be seen when hyoscyamine is used concomitantly with other drugs that possess antimuscarinic effects. [4771] (Major) Amantadine may exhibit anticholinergic activity. Antimuscarinics, such as atropine, may potentiate the anticholinergic effects of amantadine, and may increase the risk of antimuscarinic-related side effects. [4771] Atropine; Difenoxin: (Major) Amantadine may exhibit anticholinergic activity. Antimuscarinics, such as atropine, may potentiate the anticholinergic effects of amantadine, and may increase the risk of antimuscarinic-related side effects. [4771] (Moderate) Concomitant administration of amantadine and diphenoxylate/difenoxin may cause an additive decrease in GI motility and should be used cautiously. [30269] [7021] Atropine; Diphenoxylate: (Major) Amantadine may exhibit anticholinergic activity. Antimuscarinics, such as atropine, may potentiate the anticholinergic effects of amantadine, and may increase the risk of antimuscarinic-related side effects. [4771] (Moderate) Concomitant administration of amantadine and diphenoxylate/difenoxin may cause an additive decrease in GI motility and should be used cautiously. [30269] [7021] Atropine; Edrophonium: (Major) Amantadine may exhibit anticholinergic activity. Antimuscarinics, such as atropine, may potentiate the anticholinergic effects of amantadine, and may increase the risk of antimuscarinic-related side effects. [4771] Atropine; Hyoscyamine; Phenobarbital; Scopolamine: (Major) Additive anticholinergic effects may be seen when hyoscyamine is used concomitantly with other drugs that possess antimuscarinic effects. [4771] (Major) Additive anticholinergic effects may be seen when scopolamine is used concomitantly with other antimuscarinics, such as amantadine. Clinicians should note that antimuscarinic effects might be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation. [4771] (Major) Amantadine may exhibit anticholinergic activity. Antimuscarinics, such as atropine, may potentiate the anticholinergic effects of amantadine, and may increase the risk of antimuscarinic-related side effects. [4771] Benzoic Acid; Hyoscyamine; Methenamine; Methylene Blue; Phenyl Salicylate: (Major) Additive anticholinergic effects may be seen when hyoscyamine is used concomitantly with other drugs that possess antimuscarinic effects. [4771] Benzphetamine: (Moderate) Careful observation is required when amantadine is administered concurrently with central nervous system (CNS) stimulants. An increase in stimulant effects, such as nervousness, irritability, insomnia, tremor, seizures, or cardiac arrhythmias may occur. [46061] Benztropine: (Moderate) Additive anticholinergic effects may be seen when benztropine is used concomitantly with other drugs that possess anticholinergic properties, such as amantadine. Clinicians should note that anticholinergic effects might be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation. Additive drowsiness may also occur. [28049] [30312] Bismuth Subsalicylate: (Moderate) Antidiarrheals decrease GI motility. Agents that inhibit intestinal motility or prolong intestinal transit time have been reported to induce toxic megacolon. The concomitant administration of amantadine may produce additive effects. [6855] [7021] [7063] Bismuth Subsalicylate; Metronidazole; Tetracycline: (Moderate) Antidiarrheals decrease GI motility. Agents that inhibit intestinal motility or prolong intestinal transit time have been reported to induce toxic megacolon. The concomitant administration of amantadine may produce additive effects. [6855] [7021] [7063] Budesonide; Glycopyrrolate; Formoterol: (Major) Additive anticholinergic effects may be seen when glycopyrrolate is used concomitantly with other drugs that possess antimuscarinic properties, such as amantadine. [28049] Bupropion: (Major) Use caution when concurrently administering bupropion and amantadine; if concurrent use is necessary, low initial dosing and slow dosage titration of bupropion should be considered. Both bupropion and amantadine have dopamine agonist effects, and coadministration may result in additive CNS dopaminergic effects. Reported adverse reactions have included neurologic side effects such as restlessness, agitation, gait disturbance, vertigo, and dizziness; some patients have required hospitalization. In reported cases, discontinuation of the drugs resulted in symptom resolution. [41057] Bupropion; Naltrexone: (Major) Use caution when concurrently administering bupropion and amantadine; if concurrent use is necessary, low initial dosing and slow dosage titration of bupropion should be considered. Both bupropion and amantadine have dopamine agonist effects, and coadministration may result in additive CNS dopaminergic effects. Reported adverse reactions have included neurologic side effects such as restlessness, agitation, gait disturbance, vertigo, and dizziness; some patients have required hospitalization. In reported cases, discontinuation of the drugs resulted in symptom resolution. [41057] Butalbital; Acetaminophen; Caffeine: (Major) Amantadine used concomitantly with psychostimulants, such as caffeine, can result in increased stimulant effects, such as nervousness, irritability, or insomnia, and can lead to seizures or cardiac arrhythmias. Close monitoring of the patient is recommended. [4771] Caffeine: (Major) Amantadine used concomitantly with psychostimulants, such as caffeine, can result in increased stimulant effects, such as nervousness, irritability, or insomnia, and can lead to seizures or cardiac arrhythmias. Close monitoring of the patient is recommended. [4771] Caffeine; Ergotamine: (Major) Amantadine used concomitantly with psychostimulants, such as caffeine, can result in increased stimulant effects, such as nervousness, irritability, or insomnia, and can lead to seizures or cardiac arrhythmias. Close monitoring of the patient is recommended. [4771] Caffeine; Sodium Benzoate: (Major) Amantadine used concomitantly with psychostimulants, such as caffeine, can result in increased stimulant effects, such as nervousness, irritability, or insomnia, and can lead to seizures or cardiac arrhythmias. Close monitoring of the patient is recommended. [4771] Carbidopa; Levodopa: (Minor) Amantadine can increase the efficiency of levodopa by its action on central nerve terminals. [4771] Carbidopa; Levodopa; Entacapone: (Minor) Amantadine can increase the efficiency of levodopa by its action on central nerve terminals. [4771] Chlordiazepoxide; Clidinium: (Major) Amantadine may exhibit anticholinergic activity. Antimuscarinics, such as clidinium, may potentiate the anticholinergic effects of amantadine, [28049] Chlorpromazine: (Moderate) Although the mechanism of amantadine is not clear, it may potentiate the actions of dopamine. Since phenothiazines are dopamine antagonists, these drugs are best avoided when possible in patients with Parkinson's disease who require amantadine therapy. Also, the anticholinergic effects of phenothiazines can be additive to those of amantadine. [43051] [66166] [66167] Clomipramine: (Moderate) Additive anticholinergic effects and CNS effects may be seen when tricyclic antidepressants are used concomitantly with amantadine. [4771] Clozapine: (Moderate) Medications with significant anticholinergic activity, such as clozapine, may potentiate the anticholinergic effects of amantadine, and may increase the risk of antimuscarinic-related side effects. [28262] [53094] [62262] [62887] Codeine; Phenylephrine; Promethazine: (Moderate) Although the mechanism of amantadine is not clear, it may potentiate the actions of dopamine. Since phenothiazines are dopamine antagonists, these drugs are best avoided when possible in patients with Parkinson's disease who require amantadine therapy. Also, the anticholinergic effects of phenothiazines can be additive to those of amantadine. [43051] [66166] [66167] Codeine; Promethazine: (Moderate) Although the mechanism of amantadine is not clear, it may potentiate the actions of dopamine. Since phenothiazines are dopamine antagonists, these drugs are best avoided when possible in patients with Parkinson's disease who require amantadine therapy. Also, the anticholinergic effects of phenothiazines can be additive to those of amantadine. [43051] [66166] [66167] Cyclobenzaprine: (Moderate) Amantadine exhibits significant anticholinergic activity. Medications with significant anticholinergic activity, like cyclobenzaprine, may potentiate the anticholinergic effects of amantadine and may increase the risk of antimuscarinic-related side effects, including constipation and urinary retention. [28049] [28425] [63923] Darifenacin: (Moderate) Additive anticholinergic effects may be seen when drugs with antimuscarinic properties like darifenacin are used concomitantly with amantadine. [4771] [7474] Desipramine: (Moderate) Additive anticholinergic effects and CNS effects may be seen when tricyclic antidepressants are used concomitantly with amantadine. [4771] Dextromethorphan; Promethazine: (Moderate) Although the mechanism of amantadine is not clear, it may potentiate the actions of dopamine. Since phenothiazines are dopamine antagonists, these drugs are best avoided when possible in patients with Parkinson's disease who require amantadine therapy. Also, the anticholinergic effects of phenothiazines can be additive to those of amantadine. [43051] [66166] [66167] Dextromethorphan; Quinidine: (Minor) Concomitant administration of quinidine with amantadine has been shown to decrease the renal clearance of amantadine. An in vivo study demonstrated that quinidine, a known organic cation transporter inhibitor, reduced amantadine clearance by approximately 33% in humans. The proposed mechanism is inhibition of the renal tubular secretion of amantadine, but the mechanism appears to be independent of OCT2 or other known renal drug transporters. The clinical significance is not known. Monitor for possible side effects of amantadine, including dizziness, confusion, nausea/vomiting, xerostomia, and anticholinergic effects. [62262] Dicyclomine: (Moderate) Additive anticholinergic effects may be seen when dicyclomine is used concomitantly with other drugs that possess anticholinergic properties, such as amantadine. Clinicians should note that anticholinergic effects might be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation. Additive drowsiness may also occur. [28049] [30090] Diethylpropion: (Moderate) Careful observation is required when amantadine is administered concurrently with central nervous system (CNS) stimulants. An increase in stimulant effects, such as nervousness, irritability, insomnia, tremor, seizures, or cardiac arrhythmias may occur. [46061] Disopyramide: (Moderate) Amantadine may exhibit anticholinergic activity. Medications with significant anticholinergic activity, such as disopyramide, may potentiate the anticholinergic effects of amantadine, and may increase the risk of antimuscarinic-related side effects. [28228] [46061] Donepezil: (Moderate) The therapeutic benefits of donepezil may be diminished when co-administered with drugs known to exhibit anticholinergic properties, inlcuding amantadine. [29640] [46060] Donepezil; Memantine: (Moderate) Amantadine is a NMDA antagonist and may lead to additive adverse effects if combined with memantine, also an NMDA antagonist. It may be prudent to avoid coadministration of amantadine with memantine. If coadministration cannot be avoided, monitor for increased adverse effects such as agitation, dizziness and other CNS events. [28049] [31418] (Moderate) The therapeutic benefits of donepezil may be diminished when co-administered with drugs known to exhibit anticholinergic properties, inlcuding amantadine. [29640] [46060] Doxepin: (Moderate) Additive anticholinergic effects and CNS effects may be seen when tricyclic antidepressants are used concomitantly with amantadine. [4771] Ethanol: (Major) Patients should avoid alcohol while taking amantadine. Concomitant use with alcohol is not recommended, as it may increase the potential for CNS effects such as dizziness, confusion, lightheadedness, and orthostatic hypotension. In addition, if the patient is using amantadine extended-release (ER), alcohol use may result in amantadine dose-dumping and toxicity. [28049] [46061] [62262] [62273] Ezogabine: (Moderate) Caution is advisable during concurrent use of ezogabine and medications that may affect voiding such as amantadine, a sedating antihistamine (H1-blocker). Ezogabine has caused urinary retention requiring catheterization in some cases. Amantadine has significant anticholinergic activity. The anticholinergic effects of amantadine on the urinary tract may be additive. Additive sedation or other CNS effects may also occur. [28049] [44800] Fesoterodine: (Moderate) Coadministration of fesoterodine and other drugs with moderate to significant anticholinergic effects such as amantadine may increase the frequency and/or severity of anticholinergic effects such as blurred vision, constipation, xerostomia, and urinary retention. Additive effects may be seen on GI smooth muscle, bladder function, the CNS, the eye, and temperature regulation. [11397] [4771] Flavoxate: (Moderate) Medications with significant anticholinergic activity may potentiate the anticholinergic effects of amantadine, and may increase the risk of antimuscarinic-related side effects. [4771] Fluoxetine; Olanzapine: (Moderate) Amantadine may exhibit anticholinergic activity. Medications with significant anticholinergic activity, such as olanzapine, may potentiate the anticholinergic effects of amantadine, and may increase the risk of antimuscarinic-related side effects. Clinicians should note that antimuscarinic effects might be seen not only on GI smooth muscle, but also on bladder function, the eye, neurologic function, and temperature regulation. [28785] [44115] [62262] [62887] Fluphenazine: (Moderate) Although the mechanism of amantadine is not clear, it may potentiate the actions of dopamine. Since phenothiazines are dopamine antagonists, these drugs are best avoided when possible in patients with Parkinson's disease who require amantadine therapy. Also, the anticholinergic effects of phenothiazines can be additive to those of amantadine. [43051] [66166] [66167] Galantamine: (Moderate) The therapeutic benefits of cholinesterase inhibitors may be diminished when co-administered with drugs known to exhibit anticholinergic properties like amantadine. [6002] Glycopyrrolate: (Major) Additive anticholinergic effects may be seen when glycopyrrolate is used concomitantly with other drugs that possess antimuscarinic properties, such as amantadine. [28049] Glycopyrrolate; Formoterol: (Major) Additive anticholinergic effects may be seen when glycopyrrolate is used concomitantly with other drugs that possess antimuscarinic properties, such as amantadine. [28049] Haloperidol: (Moderate) Although the mechanism of amantadine is not clear, it may potentiate the actions of dopamine. Since haloperidol is a dopamine antagonist, this drug is best avoided when possible in patients with Parkinson's disease who require amantadine therapy. [43051] [66166] [66167] Homatropine; Hydrocodone: (Major) Significant systemic absorption has been reported in some cases with ocular homatropine. The anticholinergic effects of homatropine may be enhanced when combined with other drugs that possess antimuscarinic properties. [4771] Hydrochlorothiazide, HCTZ; Triamterene: (Minor) Use caution. Triamterene can reduce the renal clearance of amantadine, with subsequent increased amantadine serum concentrations. The clinical significance is not known. Monitor for possible side effects of amantadine, including dizziness, confusion, nausea/vomiting, xerostomia, and anticholinergic effects. [28051] Hyoscyamine: (Major) Additive anticholinergic effects may be seen when hyoscyamine is used concomitantly with other drugs that possess antimuscarinic effects. [4771] Hyoscyamine; Methenamine; Methylene Blue; Phenyl Salicylate; Sodium Biphosphate: (Major) Additive anticholinergic effects may be seen when hyoscyamine is used concomitantly with other drugs that possess antimuscarinic effects. [4771] Imipramine: (Moderate) Additive anticholinergic effects and CNS effects may be seen when tricyclic antidepressants are used concomitantly with amantadine. [4771] Indacaterol; Glycopyrrolate: (Major) Additive anticholinergic effects may be seen when glycopyrrolate is used concomitantly with other drugs that possess antimuscarinic properties, such as amantadine. [28049] Levodopa: (Minor) Amantadine can increase the efficiency of levodopa by its action on central nerve terminals. [4771] Live Attenuated Influenza Vaccine (intranasal): (Major) Do not administer the intranasal live attenuated influenza vaccine (LAIV) 2 weeks before or 48 hours after administration of amantadine, unless medically indicated. Inactivated influenza vaccines may be used, as appropriate. Because of its antiviral properties, amantadine may interfere with the efficacy of live attenuated influenza vaccines. Therefore, live influenza virus vaccines are not recommended during treatment with amantadine. Consult currently recommended guidance on the use of antiviral drugs against influenza. [28049] [46061] [62262] [62273] [62887] Loperamide: (Moderate) Antidiarrheals decrease GI motility. Agents that inhibit intestinal motility or prolong intestinal transit time have been reported to induce toxic megacolon. Other drugs that also decrease GI motility, such as amantadine, may produce additive effects with antidiarrheals if used concomitantly. [4771] [6855] [7021] [7063] Loperamide; Simethicone: (Moderate) Antidiarrheals decrease GI motility. Agents that inhibit intestinal motility or prolong intestinal transit time have been reported to induce toxic megacolon. Other drugs that also decrease GI motility, such as amantadine, may produce additive effects with antidiarrheals if used concomitantly. [4771] [6855] [7021] [7063] Loxapine: (Moderate) Although the mechanism of amantadine is not clear, it may potentiate the actions of dopamine. Since loxapine is a dopamine antagonist, this drug is best avoided when possible in patients with Parkinson's disease who require amantadine therapy. [43051] [66166] [66167] Maprotiline: (Moderate) Amantadine may exhibit anticholinergic activity. Medications with significant anticholinergic activity, such as maprotiline, may potentiate the anticholinergic effects of amantadine. Clinicians should note that antimuscarinic effects might be seen not only on GI smooth muscle, but also on bladder function, the eye, neurologic function, and temperature regulation. [28759] [4771] Memantine: (Moderate) Amantadine is a NMDA antagonist and may lead to additive adverse effects if combined with memantine, also an NMDA antagonist. It may be prudent to avoid coadministration of amantadine with memantine. If coadministration cannot be avoided, monitor for increased adverse effects such as agitation, dizziness and other CNS events. [28049] [31418] Mepenzolate: (Moderate) Medications with significant anticholinergic activity may potentiate the anticholinergic effects of amantadine, and may increase the risk of antimuscarinic-related side effects. [46061] Meperidine; Promethazine: (Moderate) Although the mechanism of amantadine is not clear, it may potentiate the actions of dopamine. Since phenothiazines are dopamine antagonists, these drugs are best avoided when possible in patients with Parkinson's disease who require amantadine therapy. Also, the anticholinergic effects of phenothiazines can be additive to those of amantadine. [43051] [66166] [66167] Mesoridazine: (Moderate) Although the mechanism of amantadine is not clear, it may potentiate the actions of dopamine. Since phenothiazines are dopamine antagonists, these drugs are best avoided when possible in patients with Parkinson's disease who require amantadine therapy. Also, the anticholinergic effects of phenothiazines can be additive to those of amantadine. [43051] [66166] [66167] Methamphetamine: (Moderate) Amantadine used concomitantly with psychostimulants can result in increased stimulant effects, such as nervousness, irritability, or insomnia, and can lead to seizures or cardiac arrhythmias. Close monitoring of the patient is recommended. [46061] Methenamine; Sodium Acid Phosphate; Methylene Blue; Hyoscyamine: (Major) Additive anticholinergic effects may be seen when hyoscyamine is used concomitantly with other drugs that possess antimuscarinic effects. [4771] Methscopolamine: (Major) Additive anticholinergic effects may be seen when methscopolamine is used concomitantly with other drugs that possess antimuscarinic properties, such as amantadine. [4771] Methylphenidate Derivatives: (Moderate) Use of amantadine with methylphenidate derivatives, which are CNS stimulants, requires careful observation. Coadministration may increase the risk of stimulant effects, such as nervousness, irritability, insomnia, tremor, seizures, or cardiac arrhythmias. [46061] Metoclopramide: (Major) Metoclopramide is a central dopamine antagonist and can antagonize the actions of dopamine agonists such as amantadine. In addition, metoclopramide may cause extrapyramidal reactions (e.g., acute dystonic reactions, pseudo-parkinsonism, akathisia, tardive dyskinesia), and rarely, neuroleptic malignant syndrome. The manufacturer of metoclopramide does not specifically contraindicate the use of metoclopramide and dopamine agonists; however, coadministration should be avoided if possible. [28049] [28953] [30478] Modafinil: (Moderate) Use of amantadine with modafinil, a CNS stimulant, requires careful observation. Coadministration may increase the risk of stimulant effects, such as nervousness, irritability, insomnia, tremor, seizures, or cardiac arrhythmias. [28049] [28529] [46061] Molindone: (Moderate) Although the mechanism of amantadine is not clear, it may potentiate the actions of dopamine. Since molindone is a dopamine antagonist, this drug is best avoided when possible in patients with Parkinson's disease who require amantadine therapy. [43051] [66166] [66167] Nortriptyline: (Moderate) Additive anticholinergic effects and CNS effects may be seen when tricyclic antidepressants are used concomitantly with amantadine. [4771] Olanzapine: (Moderate) Amantadine may exhibit anticholinergic activity. Medications with significant anticholinergic activity, such as olanzapine, may potentiate the anticholinergic effects of amantadine, and may increase the risk of antimuscarinic-related side effects. Clinicians should note that antimuscarinic effects might be seen not only on GI smooth muscle, but also on bladder function, the eye, neurologic function, and temperature regulation. [28785] [44115] [62262] [62887] Orphenadrine: (Moderate) Additive anticholinergic effects and drowsiness may be seen when orphenadrine is used concomitantly with amantadine. [5982] Oxybutynin: (Moderate) Additive anticholinergic effects may be seen when oxybutynin is used concomitantly with drugs with moderate to significant anticholinergic effects such as amantadine. Clinicians should note that anticholinergic effects might be seen not only on bladder smooth muscle, but also on GI function, the eye, and temperature regulation. With many of the listed agents, additive drowsiness may also occur when combined with oxybutynin. [28049] [29796] Pemoline: (Moderate) Amantadine used concomitantly with psychostimulants can result in increased stimulant effects, such as nervousness, irritability, or insomnia, and can lead to seizures or cardiac arrhythmias. Close monitoring of the patient is recommended. [46061] Pentazocine: (Moderate) Use pentazocine with caution in any patient receiving anticholinergic agents. Coadministration of pentazocine with amantadine may result in additive anticholinergic effects, such as urinary retention and constipation. [30029] Pentazocine; Naloxone: (Moderate) Use pentazocine with caution in any patient receiving anticholinergic agents. Coadministration of pentazocine with amantadine may result in additive anticholinergic effects, such as urinary retention and constipation. [30029] Perphenazine: (Moderate) Although the mechanism of amantadine is not clear, it may potentiate the actions of dopamine. Since phenothiazines are dopamine antagonists, these drugs are best avoided when possible in patients with Parkinson's disease who require amantadine therapy. Also, the anticholinergic effects of phenothiazines can be additive to those of amantadine. [43051] [66166] [66167] Perphenazine; Amitriptyline: (Moderate) Additive anticholinergic effects and CNS effects may be seen when tricyclic antidepressants are used concomitantly with amantadine. [4771] (Moderate) Although the mechanism of amantadine is not clear, it may potentiate the actions of dopamine. Since phenothiazines are dopamine antagonists, these drugs are best avoided when possible in patients with Parkinson's disease who require amantadine therapy. Also, the anticholinergic effects of phenothiazines can be additive to those of amantadine. [43051] [66166] [66167] Phenothiazines: (Moderate) Although the mechanism of amantadine is not clear, it may potentiate the actions of dopamine. Since phenothiazines are dopamine antagonists, these drugs are best avoided when possible in patients with Parkinson's disease who require amantadine therapy. Also, the anticholinergic effects of phenothiazines can be additive to those of amantadine. [43051] [66166] [66167] Phenylephrine; Promethazine: (Moderate) Although the mechanism of amantadine is not clear, it may potentiate the actions of dopamine. Since phenothiazines are dopamine antagonists, these drugs are best avoided when possible in patients with Parkinson's disease who require amantadine therapy. Also, the anticholinergic effects of phenothiazines can be additive to those of amantadine. [43051] [66166] [66167] Pimozide: (Moderate) Although the mechanism of amantadine is not clear, it may potentiate the actions of dopamine. Since pimozide is a dopamine antagonist, this drug should be avoided when possible in patients with Parkinson's disease who require amantadine therapy. [43051] [66166] [66167] Prochlorperazine: (Moderate) Although the mechanism of amantadine is not clear, it may potentiate the actions of dopamine. Since phenothiazines are dopamine antagonists, these drugs are best avoided when possible in patients with Parkinson's disease who require amantadine therapy. Also, the anticholinergic effects of phenothiazines can be additive to those of amantadine. [43051] [66166] [66167] Promethazine: (Moderate) Although the mechanism of amantadine is not clear, it may potentiate the actions of dopamine. Since phenothiazines are dopamine antagonists, these drugs are best avoided when possible in patients with Parkinson's disease who require amantadine therapy. Also, the anticholinergic effects of phenothiazines can be additive to those of amantadine. [43051] [66166] [66167] Propantheline: (Major) Additive anticholinergic effects may be seen when propantheline is used concomitantly with other antimuscarinics, such as amantadine. Clinicians should note that antimuscarinic effects might be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation. [4771] Protriptyline: (Moderate) Additive anticholinergic effects and CNS effects may be seen when tricyclic antidepressants are used concomitantly with amantadine. [4771] Quinidine: (Minor) Concomitant administration of quinidine with amantadine has been shown to decrease the renal clearance of amantadine. An in vivo study demonstrated that quinidine, a known organic cation transporter inhibitor, reduced amantadine clearance by approximately 33% in humans. The proposed mechanism is inhibition of the renal tubular secretion of amantadine, but the mechanism appears to be independent of OCT2 or other known renal drug transporters. The clinical significance is not known. Monitor for possible side effects of amantadine, including dizziness, confusion, nausea/vomiting, xerostomia, and anticholinergic effects. [62262] Rivastigmine: (Moderate) Concurrent use of amantadine and rivastigmine should be avoided if possible. Rivastigmine inhibits acetylcholinesterase, the enzyme responsible for the degradation of acetylcholine, and improves the availability of acetylcholine. Amantadine may exhibit significant anticholinergic activity, thereby interfering with the therapeutic effect of rivastigmine. [41681] [46060] Scopolamine: (Major) Additive anticholinergic effects may be seen when scopolamine is used concomitantly with other antimuscarinics, such as amantadine. Clinicians should note that antimuscarinic effects might be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation. [4771] Sedating H1-blockers: (Moderate) Medications with significant anticholinergic activity may potentiate the anticholinergic effects of amantadine, and may increase the risk of antimuscarinic-related side effects. Additive drowsiness may also occur. [28049] [48306] Solriamfetol: (Moderate) Monitor for dopamine-mediated effects including nausea, vomiting, dizziness, tremor, and changes in moods or behaviors if solriamfetol, a central dopamine and norepinephrine reuptake inhibitor, is administered with other dopaminergic drugs, such as amantadine. Caution is recommended since this combination has not been evaluated. [64026] Sulfamethoxazole; Trimethoprim, SMX-TMP, Cotrimoxazole: (Major) Avoid concurrent use of amantadine and trimethoprim. A single case of toxic delirium has been reported after coadministration of trimethoprim and amantadine. Amantadine is an OCT2 substrate and trimethoprim is an OCT2 inhibitor. [43890] [55864] [62262] Tacrine: (Moderate) The therapeutic benefits of tacrine may be diminished when co-administered with drugs known to exhibit anticholinergic properties, such as amantadine. [6002] [6338] Talimogene Laherparepvec: (Major) Consider the risks and benefits of treatment with talimogene laherparepvec before administering acyclovir or other antivirals to prevent or manage herpetic infection. Talimogene laherparepvec is a live, attenuated herpes simplex virus that is sensitive to acyclovir; coadministration with antiviral agents may cause a decrease in efficacy. [60260] Thiethylperazine: (Moderate) Although the mechanism of amantadine is not clear, it may potentiate the actions of dopamine. Since phenothiazines are dopamine antagonists, these drugs are best avoided when possible in patients with Parkinson's disease who require amantadine therapy. Also, the anticholinergic effects of phenothiazines can be additive to those of amantadine. [43051] [66166] [66167] Thioridazine: (Moderate) Although the mechanism of amantadine is not clear, it may potentiate the actions of dopamine. Since phenothiazines are dopamine antagonists, these drugs are best avoided when possible in patients with Parkinson's disease who require amantadine therapy. Also, the anticholinergic effects of phenothiazines can be additive to those of amantadine. [43051] [66166] [66167] Thiothixene: (Moderate) Although the mechanism of amantadine is not clear, it may potentiate the actions of dopamine. Since thiothixene is a dopamine antagonist, this drug is best avoided when possible in patients with Parkinson's disease who require amantadine therapy. [43051] [66166] [66167] Tolterodine: (Moderate) Additive anticholinergic effects may be seen when drugs with antimuscarinic properties like tolterodine are used concomitantly with other drugs with moderate to significant anticholinergic effects such as amantadine. Clinicians should note that additive antimuscarinic effects may be seen not only on GI smooth muscle, but also on bladder function, the CNS, the eye, and temperature regulation. Additive drowsiness may also occur, depending on the interacting agent. [28049] Triamterene: (Minor) Use caution. Triamterene can reduce the renal clearance of amantadine, with subsequent increased amantadine serum concentrations. The clinical significance is not known. Monitor for possible side effects of amantadine, including dizziness, confusion, nausea/vomiting, xerostomia, and anticholinergic effects. [28051] Tricyclic antidepressants: (Moderate) Additive anticholinergic effects and CNS effects may be seen when tricyclic antidepressants are used concomitantly with amantadine. [4771] Trifluoperazine: (Moderate) Although the mechanism of amantadine is not clear, it may potentiate the actions of dopamine. Since phenothiazines are dopamine antagonists, these drugs are best avoided when possible in patients with Parkinson's disease who require amantadine therapy. Also, the anticholinergic effects of phenothiazines can be additive to those of amantadine. [43051] [66166] [66167] Trihexyphenidyl: (Moderate) Amantadine may exhibit anticholinergic activity, as may trihexyphenidyl. These drugs are not commonly used together. Both trihexyphenidyl and amantadine have significant anticholinergic activity and the combination may increase the risk of anticholinergic-related side effects. Clinicians should note that such effects might be seen not only on GI smooth muscle, but also on bladder function, the eye, neurologic function, and temperature regulation. Monitor for effects such as confusion, constipation, dizziness, difficulty with urination, dry mouth and eyes, and changes in vision. [28049] [30336] [62262] [62887] [63923] Trimethoprim: (Major) Avoid concurrent use of amantadine and trimethoprim. A single case of toxic delirium has been reported after coadministration of trimethoprim and amantadine. Amantadine is an OCT2 substrate and trimethoprim is an OCT2 inhibitor. [43890] [55864] [62262] Trimipramine: (Moderate) Additive anticholinergic effects and CNS effects may be seen when tricyclic antidepressants are used concomitantly with amantadine. [4771] Trospium: (Moderate) Additive anticholinergic effects may be seen when drugs with antimuscarinic properties like trospium and amantadine are used concomitantly. In addition, some drugs which are actively secreted by the kidney, such as amantadine, may interact with trospium by competing for renal tubular secretion, further enhancing the possibility for anticholinergic side effects. Clinicians should note that additive antimuscarinic effects may be seen not only on GI smooth muscle, but also on bladder function and temperature regulation. While CNS-related side effects such as drowsiness and blurred vision are not typically noted with trospium, they may occur in some patients. [28049] [29236] [46061] [59643]
    Revision Date: 06/22/2021, 02:35:00 AM

    References

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    Monitoring Parameters

    • neurologic function
    • serum creatinine/BUN

    US Drug Names

    • GOCOVRI
    • OSMOLEX ER
    • Symmetrel
    ;