Amantadine HCL (Symmetrel)

By | 2013-06-08

Antiviral (Influenza A); Nmda Antagonist

Highlights Of Prescribing Information

Antiviral drug with NMDA antagonist properties; may be useful in adjunctive therapy of chronic pain in small animals & treatment of equine influenza in horses

Very limited clinical experience; dogs may exhibit agitation & GI effects, especially early in therapy

Large interpatient variations of pharmacokinetics in horses limit its therapeutic usefulness

Overdoses are potentially very serious; fairly narrow therapeutic index in dogs & cats; may need to be compounded

Extra-label use prohibited (by FDA) in chickens, turkeys & ducks

What Is Amantadine HCL Used For?

While amantadine may have efficacy and clinical usefulness against some veterinary viral diseases, presently the greatest interest for its use in small animals is as a NMDA antagonist in the adjunctive treatment of chronic pain, particularly those tolerant to opioids.

Amantadine has also been investigated for treatment of equine-2 influenza virus in the horse. However, because of expense, interpatient variability in oral absorption and other pharmacokinetic parameters, and the potential for causing seizures after intravenous dosing, it is not commonly used for treatment.

In humans, amantadine is used for treatment and prophylaxis of influenza A, parkinsonian syndrome, and drug-induced extrapyramidal effects. As in veterinary medicine, amantadine’s effect on NMDA receptors in humans are of active interest, particularly its use as a co-analgesic with opiates and in the reduction of opiate tolerance development.

Pharmacology/Actions

Like ketamine, dextromethorphan and memantine, amantadine antagonizes the N-methyl-D-aspartate (NMDA) receptor. Within the central nervous system, chronic pain can be maintained or exacerbated when glutamate or aspartate bind to this receptor. It is believed that this receptor is particularly important in allodynia (sensation of pain resulting from a normally non-noxious stimulus). Amantadine alone is not a particularly good analgesic, but in combination with other analgesics (e.g., opiates, NSAIDs), it is thought that it may help alleviate chronic pain.

Amantadine’s antiviral activity is primarily limited to strains of influenza A. While its complete mechanism of action is unknown, it does inhibit viral replication by interfering with influenza A virus M2 protein.

Amantadine’s antiparkinsonian activity is not well understood. The drug does appear to have potentiating effects on dopaminergic neurotransmission in the CNS and anticholinergic activity.

Pharmacokinetics

The pharmacokinetics of this drug have apparently not been described in dogs or cats. In horses, amantadine has a very wide interpatient variability of absorption after oral dosing; bioavailability ranges from 40-60%. The elimination half-life in horses is about 3.5 hours and the steady state volume of distribution is approximately 5 L/kg.

In humans, the drug is well absorbed after oral administration with peak plasma concentrations occurring about 3 hours after dosing. Volume of distribution is 3-8 L/kg. Amantadine is primarily eliminated via renal mechanisms. Oral clearance is approximately 0.28 L/hr/kg; half-life is around 17 hours.

Before you take Amantadine HCL

Contraindications / Precautions / Warnings

In humans, amantadine is contraindicated in patients with known hypersensitivity to it or rimantadine, and in patients with untreated angle-closure glaucoma. It should be used with caution in patients with liver disease, renal disease (dosage adjustment may be required), congestive heart failure, active psychoses, eczematoid dermatitis or seizure disorders. In veterinary patients with similar conditions, it is advised to use the drug with caution until more information on its safety becomes available.

In 2006, the FDA banned the use of amantadine and other influenza antivirals in chickens, turkeys and ducks.

Adverse Effects

There is very limited experience in domestic animals with amantadine and its adverse effect profile is not well described. It has been reported that dogs given amantadine occasionally develop agitation, loose stools, flatulence or diarrhea, particularly early in therapy. Experience in cats is limited; an adverse effect profile has yet to be fully elucidated, but the safety margin appears to be narrow.

Reproductive / Nursing Safety

In humans, the FDA categorizes amantadine as a category C drug for use during pregnancy (Animal studies have shown an adverse effect on the fetus, hut there are no adequate studies in humans; or there are no animal reproduction studies and no adequate studies in humans). High dosages in rats demonstrated some teratogenic effects.

Amantadine does enter maternal milk. The manufacturer does not recommend its use in women who are nursing. Veterinary significance is unclear.

Overdosage / Acute Toxicity

Toxic dose reported for cats is 30 mg/kg and behavioral effects may be noted at 15 mg/kg in dogs and cats.

In humans, overdoses as low as 2 grams have been associated with fatalities. Cardiac dysfunction (arrhythmias, hypertension, tachycardia), pulmonary edema, CNS toxicity (tremors, seizures, psychosis, agitation, coma), hyperthermia, renal dysfunction and respiratory distress syndrome have all been documented. There is no known specific antidote for amantadine overdose. Treatment should consist of gut emptying, if possible, intensive monitoring and supportive therapy. Forced urine acidifying diuresis may increase renal excretion of amantadine. Physostigmine has been suggested for cautious use in treating CNS effects.

How to use Amantadine HCL

Amantadine HCL dosage for dogs:

As adjunctive therapy for chronic pain:

a) 1.25-4 mg/kg PO ql2-24h. Usually use 3 mg/kg PO once daily as an adjunct with a NSAID May require 5-7 days to have a positive effect. ()

b) Approximate dose is 3-5 mg/kg PO once daily. ()

c) To decrease wind-up: 3-5 mg/kg PO once daily for one week ()

Amantadine HCL dosage for cats:

As adjunctive therapy for chronic pain:

a) 3 mg/kg PO once daily. May be useful addition to NSAIDs; not been evaluated for toxicity. May need to be compounded. ()

b) Approximate dose is 3-5 mg/kg PO once daily. ()

c) 3 mg/kg PO once daily. ()

Amantadine HCL dosage for horses:

For acute treatment of equine-2 influenza: a) 5 mg/kg IV q4h ()

Monitoring

■ Adverse effects (GI, agitation)

■ Efficacy

Client Information

■ When used in small animals, the drug must be given as prescribed to be effective and may take a week or so to show effect.

■ Gastrointestinal effects (loose stools, gas, diarrhea) or some agitation may occur, particularly early in treatment. Contact the veterinarian if these become serious or persist.

■ Overdoses with this medication can be serious; keep well out of reach of children and pets.

Chemistry / Synonyms

An adamantane-class antiviral agent with NMDA antagonist properties, amantadine HCL occurs as a white to practically white, bitter tasting, crystalline powder with a pKa of 9. Approximately 400 mg are soluble in 1 mL of water; 200 mg are soluble in 1 mL of alcohol.

Amantadine HCL may also be known as: adamantanamine HCL, Adekin, Amanta, Amantagamma, Amantan, Amantrel, Amixx, Antadine, Antiflu-DES, Atarin, Atenegine, Cerehramed, Endantadine, Infectoflu, Influ-A, Lysovir, Mantadine, Mantadix, Mantidan, Padiken, Symadine, Symmetrel, Viroifral and Virucid.

Storage / Stability

Tablets, capsules and the oral solution should be stored in tight containers at room temperature. Limited exposures to temperatures as low as 15°C and as high as 30°C are permitted. Avoid freezing the liquid.

Dosage Forms / Regulatory Status

Veterinary-Labeled Products: None

Human-Labeled Products:

Amantadine HCL Tablets & Capsules: 100 mg; Symmetrel (Endo); generic; (Rx)

Amantadine HCL Syrup: 10 mg/mL in 480 mL; Symmetrel (Endo); generic; (Rx)

In 2006, the FDA banned the extra-label use of amantadine and other influenza antivirals in chickens, turkeys and ducks.