Flumadine

Adamantane Antivirals

May be administered without regard to meals.

Compounding Oral Suspension from Tablets (Final Concentration = 10 mg/mL):
NOTE: These directions are provided by the manufacturer for use only during emergency situations, for patients who have difficulty swallowing tablets, or when lower doses are needed.
Calculate the dose needed for the duration of therapy and round up to the nearest 100 mg designation (i.e. round 750 mg up to 800 mg) to calculate the number of 100 mg rimantadine tablets required to compound the oral suspension.
Calculate the total volume of oral suspension to generate a final concentration of 10 mg/mL (i.e. a total treatment dose of 800 mg requires a volume of 80 mL).
Use Ora-Sweet as the vehicle for compounding. Other vehicles have not been evaluated.
Place the required number of rimantadine tablets into a clean mortar and grind the tablets into a fine powder.
Slowly add approximately 1/3 of the total volume of Ora-Sweet to the mortar while triturating until a uniform suspension is achieved.
Transfer the suspension to an amber glass or PET plastic bottle. Other types of bottles have not been evaluated.
Slowly add the second 1/3 of the total volume of Ora-Sweet to the mortar and rinse the mortar and pestle by a triturating motion and transfer the contents to the bottle. Repeat this step with the final 1/3 of the total Ora-Sweet volume.
Shake well to ensure a homogenous suspension and have the patient shake the bottle gently prior to each use.
Provide an oral dosing device (graduated oral syringe or spoon) to measure the appropriate dose.
Compounded suspension is stable for 14 days at room temperature.

seizures / Delayed / 0-0.3
bronchospasm / Rapid / 0-0.3
heart failure / Delayed / 0-0.3
AV block / Early / Incidence not known

ataxia / Delayed / 0.3-1.0
dyspnea / Early / 0.3-1.0
depression / Delayed / 0.7-0.7
euphoria / Early / 0-0.3
confusion / Early / 0-0.3
hallucinations / Early / 0-0.3
palpitations / Early / 0-0.3
hypertension / Early / 0-0.3
sinus tachycardia / Rapid / 0-0.3
edema / Delayed / 0-0.3
galactorrhea / Delayed / 0-0.3
dysphagia / Delayed / Incidence not known
stomatitis / Delayed / Incidence not known
constipation / Delayed / Incidence not known
antimicrobial resistance / Delayed / Incidence not known

nausea / Early / 2.8-2.8
insomnia / Early / 2.1-2.1
anxiety / Delayed / 1.3-2.1
dizziness / Early / 0.7-1.9
vomiting / Early / 1.7-1.7
anorexia / Delayed / 1.6-1.6
xerostomia / Early / 1.5-1.5
abdominal pain / Early / 1.4-1.4
headache / Early / 1.4-1.4
asthenia / Delayed / 1.4-1.4
dyspepsia / Early / 0.3-1.0
diarrhea / Early / 0.3-1.0
fatigue / Early / 1.0-1.0
drowsiness / Early / 0.3-1.0
agitation / Early / 0.3-1.0
rash / Early / 0.3-1.0
tinnitus / Delayed / 0.3-1.0
dysgeusia / Early / 0-0.3
hyperkinesis / Delayed / 0-0.3
tremor / Early / 0-0.3
cough / Delayed / 0-0.3
pallor / Early / 0-0.3
syncope / Early / 0-0.3
parosmia / Delayed / 0-0.3
hypoesthesia / Delayed / Incidence not known
fever / Early / Incidence not known
diaphoresis / Early / Incidence not known
lacrimation / Early / Incidence not known
ocular pain / Early / Incidence not known
increased urinary frequency / Early / Incidence not known

Flumadine

Rx

Oral antiviral agent
Indicated for prophylaxis and treatment of seasonal influenza A virus infections in patients 17 years and older, and for prophylaxis only in children (1 to 16 years)
CDC and IDSA recommend against use due to high resistance

100 mg PO twice daily for 7 days. Initiation of treatment within 48 hours of illness confers the greatest benefit; however, antiviral therapy started after 48 hours may still be beneficial in severe, complicated, or progressive illness or hospitalized patients. The CDC recommends against use due to resistance.

100 mg PO twice daily for 7 days; however, a dose reduction to 100 mg PO once daily for 7 days is recommended in elderly nursing home patients. Initiation of treatment within 48 hours of illness confers the greatest benefit; however, antiviral therapy started after 48 hours may still be beneficial in severe, complicated, or progressive illness or hospitalized patients. The CDC recommends against use due to resistance.

100 mg PO twice daily for 7 days. Initiation of treatment within 48 hours of illness confers the greatest benefit; however, antiviral therapy started after 48 hours may still be beneficial in severe, complicated, or progressive illness or hospitalized patients. The CDC recommends against use due to resistance.

100 mg PO twice daily. Safety and efficacy of prophylactic use beyond 6 weeks has not been determined. The CDC recommends against use due to resistance.

100 mg PO twice daily; however, a dose reduction to 100 mg PO once daily is recommended in elderly nursing home patients. Safety and efficacy of prophylactic use beyond 6 weeks has not been determined. The CDC recommends against use due to resistance.

100 mg PO twice daily. Safety and efficacy of prophylactic use beyond 6 weeks has not been determined. The CDC recommends against use due to resistance.

5 mg/kg/dose PO once daily (Max: 150 mg/day). Safety and efficacy of prophylactic use beyond 6 weeks has not been determined. The CDC recommends against use due to resistance.

The manufacturer recommends the adult dose be reduced to 100 mg PO once daily in patients with severe liver disease.

NOTE: Renal dosage adjustments are for adult patients.
CrCl 30 mL/minute or more: No dosage adjustment needed.
CrCl less than 30 mL/minute: Extend rimantadine dosing interval to every 24 hours (i.e., 100 mg PO once daily in adults).
 
Hemodialysis
Hemodialysis does not contribute to the removal of rimantadine.

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.

Flumadine/Rimantadine/Rimantadine Hydrochloride Oral Tab: 100mg

200 mg/day PO.

200 mg/day PO; 100 mg/day PO in elderly nursing home patients.

200 mg/day PO.

10 to 12 years: 200 mg/day PO.
1 to 9 years: 5 mg/kg/day PO or 150 mg/day PO, whichever is less.

Safety and efficacy have not been established.

Safety and efficacy have not been established.

Rimantadine's exact mechanism of action is unknown. Rimantadine 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, thereby producing a virustatic effect. Because uncoating is an early part of the viral replication cycle, rimantadine, if administered early, serves as an effective agent in preventing further viral shedding.
 
Studies suggest that a virus protein specified by the virion M2 gene plays a role in the susceptibility of the influenza A virus to inhibition by rimantadine. Substitutions at any of the 5 amino acid positions in the transmembrane domain of M2 confer resistance to rimantadine. The most common substitution causing resistance is S31N (H1N1 influenza A, including swine-origin influenza A, and H3N2 influenza). Less common substitutions that cause resistance include A30F, V27A, V30A, and L26F. Resistance to rimantadine confers cross-resistance to amantadine and vice-versa.
 
Influenza viruses are classified into 3 distinct types, influenza A, influenza B, and influenza C. Influenza A is further divided into subtypes based on their hemagglutinin (H or HA) and neuraminidase (N or NA) activity. At least 16 distinct HAs (H1 to H16) and 9 NAs (N1 to N9) have been described. Influenza infection may be attributed to either influenza A virus or influenza B virus. Influenza A virus subtypes include H1N1 and H3N2. In 2009, a novel influenza A H1N1 virus (previously referred to as swine influenza) was identified; this virus is included in season influenza A viruses. Human cases of influenza illness from the avian H5N1 virus (commonly known as avian flu) have been reported since 1997. Human infections with avian H7N9, H5N2, H5N8, H9N2, H7N7, and H7N3 viruses have also been described.

Rimantadine is administered orally. Protein binding is approximately 40% (albumin as the major binding protein), with extensive metabolism by the liver to 3 distinct hydroxylated metabolites and 1 conjugated metabolite. These metabolites and the parent drug account for 74 +/- 10% (n=4) of a single 200 mg oral dose of rimantadine excreted in the urine over 72 hours. The half-life of rimantadine is 25.4 +/- 6.3 hours (range: 13 to 65 hours). Urinary excretion of unchanged rimantadine accounts for less than 25% of the dose in healthy subjects.
 
Affected cytochrome P450 isoenzymes and drug transporters: none

The absorption of rimantadine is similar for both tablets and syrup. The mean peak plasma concentration after a single oral 100 mg dose is 74 +/- 22 ng/mL (range 45 to 138 ng/mL). The time to peak plasma concentration is 6 +/- 1 hours in healthy adults (age 20 to 44 years). After a 10-day course of 100 mg PO twice daily in healthy volunteers, systemic drug exposure (AUC) values were approximately 30% greater than predicted from a single dose. Plasma trough levels at steady state ranging between 118 and 468 ng/mL.

Rimantadine is classified as an FDA pregnancy risk category C drug. No adequate and well-controlled studies have been conducted in pregnant women. In animal studies, rimantadine 200 mg/kg/day (11-time the maximum recommended human dose (MRHD)) was embryotoxic in rats, causing increased fetal resorption. In rabbits receiving 50 mg/kg/day (0.1-times MRHD), no embryotoxic events were observed. According to the manufacturer, use during pregnancy should be avoided unless the potential benefits outweigh the possible risks to the fetus.

It is unknown if rimantadine is excreted in human milk, and data regarding use during breast-feeding are limited; however, it is concentrated at amounts greater than maternal serum concentration in the milk of rats and adverse effects have been noted in rat offspring. Due to the potential for infant toxicities, the manufacturer advises against use in nursing mothers. Oseltamivir and zanamivir may be potential alternatives to consider during breast-feeding. However, patient factors, local susceptibility patterns, and specific microbial susceptibility should be assessed before choosing an alternative. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally ingested drug, health care providers are encouraged to report the adverse effect to the FDA.