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NEURAMINIDASE INHIBITORS

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Zanamivir and oseltamivir are selective inhibitors of influenza A and B virus neuraminidase (sialidase). Neuraminidase inhibitors are analogues of sialic acid. They block the active site of neuraminidase and leave uncleaved sialic acid residues on the surfaces of host cells and influenza viral envelopes. Viral hemagglutinin binds to uncleaved sialic acid residues, with resultant viral aggregation at the host cell surface and a reduction in the amount of virus that is released and can infect other cells.

Specific Substances

    A) OSELTAMIVIR (SYNONYM)
    1) (3R,4R,5S)-4-Acetylamino-5-amino-3(1-ethyl
    2) propoxy)-1-cyclohexene-1-carboxylic acid,
    3) ethyl ester, phosphate (1:1)
    4) Ethyl (3R,4R,5S)-4-acetamido-5-amino-3-(1-ethylpropoxy)-1-cyclohexene-1-carboxylate
    5) GS 4104
    6) Ro-640796
    7) Molecular Formula: C16-H28-N2-O4 (free base)
    8) CAS 196618-13-0
    PERAMIVIR (SYNONYM)
    1) CAS 229614-55-5
    ZANAMIVIR (SYNONYM)
    1) 5-Acetamide-2,6-anhydro-,3,4,5-trideoxy-4-
    2) guanidino-D-glycero-D-galacto-non-2-enonic acid
    3) 4-Guanidino-2,4-dideoxy-2,3-dehydro-N-
    4) acetylneuraminic acid
    5) 4-Guanidino-Neu5Ac2en
    6) GG-167
    7) GR-121167X
    8) Molecular Formula: C12-H20-N4-O7
    9) CAS 139110-80-8

    1.2.1) MOLECULAR FORMULA
    1) OSELTAMIVIR: C15H34N4O7
    2) PERAMIVIR: C16H28N2O4
    3) ZANAMIVIR: C12H20N4O7

Available Forms Sources

    A) FORMS
    1) OSELTAMIVIR: Available as follows: 30 mg capsules (light yellow hard capsules); 45 mg (grey hard gelatin capsules); 75 mg capsules (grey/light yellow hard gelatin capsules) and an oral suspension which after reconstitution contains 25 mL of suspension equivalent to 300 mg oseltamivir base (Prod Info TAMIFLU, 2008).
    2) ZANAMIVIR: It is available as a dry powder that is self-administered via oral inhalation by using a plastic dispenser (Rotadisk) (Prod Info RELENZA(R) oral inhalation powder, 2008).
    B) USES
    1) OSELTAMIVIR is approved for the treatment of uncomplicated acute illness caused by influenza infection in patients 1 year and older who have been symptomatic for no more than 2 days. Oseltamivir is also indicated for influenza prophylaxis in patients 1 year and older (Prod Info TAMIFLU, 2008).
    2) ZANAMIVIR is used for the treatment of uncomplicated acute illness caused by influenza virus due to influenza A and B virus in adults and pediatric patients 7 years of age and older who have been symptomatic for no more than 2 days . It is also indicated for the prophylaxis of influenza in adults and pediatric patients 5 years of age and older (Prod Info RELENZA(R) oral inhalation powder, 2008).
    3) Neither drug appears to be effective in preventing serious influenza-related complications such as bacterial or viral pneumonia or exacerbation of chronic diseases (Winquist et al, 1999).

Overview

Life Support

    A) This overview assumes that basic life support measures have been instituted.

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) USES: Neuraminidase inhibitors, oseltamivir and zanamivir, are used to treat or prevent influenza A and B infections.
    B) PHARMACOLOGY: Zanamivir and oseltamivir are selective inhibitors of influenza A and B virus neuraminidase (sialidase). Neuraminidase inhibitors are analogues of sialic acid, blocking the active site of neuraminidase and leaving uncleaved sialic acid residues on the surfaces of host cells and influenza viral envelopes. Viral hemagglutinin binds to uncleaved sialic acid residues, resulting in viral aggregation at the host cell surface and a reduction in the amount of virus released that can infect other cells.
    C) TOXICOLOGY: Toxic effects of neuraminidase inhibitors are often minimal and difficult to distinguish from the signs and symptoms of influenza infection.
    D) EPIDEMIOLOGY: Neuraminidase inhibitor overdose is rare and may occur due to therapeutic error. Severe toxicity from isolated ingestion is rarely reported. A majority of patients will have only mild symptoms.
    E) WITH THERAPEUTIC USE
    1) Common mild adverse effects with therapeutic neuraminidase inhibitor use include nausea, vomiting, diarrhea, headache, transient elevation in hepatic enzymes, and exacerbation of bronchospasm in patients with underlying chronic respiratory disease. Uncommon adverse effects include dizziness, vertigo, dysrhythmias, syncope, bradycardia, hemorrhagic colitis, dermatitis, rash, eczema, urticaria, serious skin reactions (eg, erythema multiforme, Stevens-Johnson Syndrome, toxic epidermal necrolysis), hepatitis, cough, dyspnea, bronchitis, seizures, confusion, agitation, anxiety, abnormal behavior, hallucinations, delirium, transient lymphopenia and neutropenia, and acute allergic reactions, including anaphylaxis. It is often difficult to elicit which adverse effects may actually be due to the underlying illness rather than the neuraminidase inhibitor.
    F) WITH POISONING/EXPOSURE
    1) MILD TO MODERATE TOXICITY: A majority of patients with neuraminidase inhibitor overdose will have only mild toxicity. Signs and symptoms commonly include nausea, vomiting, abdominal pain, and diarrhea. Pruritus, dizziness, and tremors have also been reported.
    2) SEVERE TOXICITY: In cases of severe toxicity, patients may very rarely develop neuropsychiatric illness including agitation, delirium, hallucinations, and psychosis. This appears to be common with high-dose therapy for critically ill patients with influenza, although whether the cause is directly due to oseltamivir toxicity or the underlying illness remains unclear.
    0.2.20) REPRODUCTIVE
    A) Oseltamivir and peramivir are classified as FDA pregnancy category C, and zanamivir is classified as FDA pregnancy category B. In one study, oseltamivir and zanamivir were associated with an increased risk of transient hypoglycemia in infants born to women exposed to one or both of the neuraminidase inhibitors. Oseltamivir and its carboxylate salt form were detected in human breast milk after maternal use, but at concentrations significantly lower than the recommended infant dose.

Laboratory Monitoring

    A) Monitor vital signs and mental status following significant overdose.
    B) Neuraminidase inhibitor serum concentrations are not widely available or clinically useful.
    C) Monitor serum electrolytes, renal function, CPK, and hepatic enzymes in patients with evidence of toxicity.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) MANAGEMENT OF MILD TO MODERATE TOXICITY
    1) Treatment is predominantly symptomatic and supportive care.
    B) MANAGEMENT OF SEVERE TOXICITY
    1) Treatment is symptomatic and supportive. Treat agitation with benzodiazepines. Treat seizures with IV benzodiazepines; barbiturates or propofol may be needed if seizures persist or recur.
    C) DECONTAMINATION
    1) PREHOSPITAL: A majority of patients with neuraminidase inhibitor overdose will have only mild toxicity. Prehospital gastrointestinal decontamination is generally not recommended because of the potential for persistent seizures and subsequent aspiration.
    2) HOSPITAL: Gastrointestinal decontamination is typically not necessary for the treatment of neuraminidase inhibitors given the minimal toxicity associated. Consider activated charcoal only if coingestants with significant toxicity are involved.
    D) AIRWAY MANAGEMENT
    1) Patients with neuraminidase inhibitor toxicity typically do not require intubation for the ingestion; however, it may be required for treatment of underlying influenza illness. Ensure adequate ventilation and perform endotracheal intubation early in patients with severe allergic reactions.
    E) ANTIDOTE
    1) None.
    F) ENHANCED ELIMINATION PROCEDURE
    1) Hemodialysis has not been studied for neuraminidase inhibitor toxicity; however, given the drugs' very large volumes of distribution (16 to 26 L), it would not be expected to be useful.
    G) PATIENT DISPOSITION
    1) HOME CRITERIA: A patient with an inadvertent exposure, that remains asymptomatic can be managed at home.
    2) OBSERVATION CRITERIA: Patients with known large ingestions, should be observed for 6 hours for signs of toxicity.
    3) ADMISSION CRITERIA: Patients who develop persistent GI symptoms with nausea, vomiting, and diarrhea may require admission to the hospital for hydration and antiemetics. Patients with suspected neuropsychiatric symptoms may require admission for symptomatic treatment with benzodiazepines and monitoring.
    4) CONSULT CRITERIA: Contact a local poison center for a toxicology consult for any patient with suspected neuraminidase inhibitor toxicity with more than mild symptoms.
    H) PHARMACOKINETICS
    1) OSELTAMIVIR: 80% absorption from the GI tract. Protein binding: 42% (3% metabolite oseltamivir carboxylate). Vd: 23 to 26 L. Metabolism: extensively hydrolyzed by esterases in the blood and tissues to its active form oseltamivir carboxylate. Oseltamivir is neither a substrate for, nor an inhibitor, of cytochrome P450 enzymes. Renal excretion: greater 99%; elimination half-life: 6 to 10 hours. ZANAMIVIR: provided as an orally inhaled powder, with only 4% to 17% systemic bioavailability but a predominant local action in the nasal and oropharynx. Vd: 16 L. Metabolism: minimal to no metabolism. Renal excretion: excreted unchanged in the urine. Elimination half-life: 2.5 to 5.1 hours.
    I) DIFFERENTIAL DIAGNOSIS
    1) Toxicity is commonly indistinguishable from the underlying influenza illness and the effects of other medications (eg, antihistamines, quinolones) with the potential to cause delirium. Patients with neuropsychiatric symptoms may have a presentation similar to patients with CNS infection or ICU delirium.
    0.4.3) INHALATION EXPOSURE
    A) Intranasal inhalation of zanamivir has been associated with minimal or no adverse effects. Treatment is symptomatic and supportive.

Range Of Toxicity

    A) TOXICITY: In clinical trials, oseltamivir oral doses up to 1000 mg have resulted only in nausea and vomiting. Intravenous doses of zanamivir up to 600 mg were well tolerated in healthy volunteers. Additionally, for zanamivir, up to 1200 mg/day IV for 5 days have been given to volunteers with minimal effects. Zanamivir intranasal doses up to 96 mg/day were administered to volunteers with no or minimal adverse effects. Oseltamivir-associated neuropsychiatric symptoms have occurred with high-dose therapy at 150 mg/kg two times daily for 2 days in a patient with influenza.
    B) THERAPEUTIC DOSE: ADULT: OSELTAMIVIR: TREATMENT: 75 mg orally twice a day for 5 days. PROPHYLAXIS: 75 mg orally once a day for 10 days after last known exposure to an ill confirmed case. ZANAMIVIR: TREATMENT: Two 5 mg inhalations (10 mg total) twice per day. PROPHYLAXIS: Two 5 mg inhalations (10 mg total) once per day. PEDIATRIC: OSELTAMIVIR: Children older than 1 year and weighing 15 kg or less: 30 mg orally twice daily for 5 days. Children weighing 15.1 to 23 kg: 45 mg orally twice daily for 5 days. Children weighing 23.1 to 40 kg: 60 mg orally twice daily for 5 days. Children weighing 40.1 kg or more: 75 mg orally twice daily for 5 days. ZANAMIVIR: Dosing for children 7 years of age or older: 10 mg (2 oral inhalations) twice daily for 5 days.

Clinical Effects

Summary Of Exposure

    A) USES: Neuraminidase inhibitors, oseltamivir and zanamivir, are used to treat or prevent influenza A and B infections.
    B) PHARMACOLOGY: Zanamivir and oseltamivir are selective inhibitors of influenza A and B virus neuraminidase (sialidase). Neuraminidase inhibitors are analogues of sialic acid, blocking the active site of neuraminidase and leaving uncleaved sialic acid residues on the surfaces of host cells and influenza viral envelopes. Viral hemagglutinin binds to uncleaved sialic acid residues, resulting in viral aggregation at the host cell surface and a reduction in the amount of virus released that can infect other cells.
    C) TOXICOLOGY: Toxic effects of neuraminidase inhibitors are often minimal and difficult to distinguish from the signs and symptoms of influenza infection.
    D) EPIDEMIOLOGY: Neuraminidase inhibitor overdose is rare and may occur due to therapeutic error. Severe toxicity from isolated ingestion is rarely reported. A majority of patients will have only mild symptoms.
    E) WITH THERAPEUTIC USE
    1) Common mild adverse effects with therapeutic neuraminidase inhibitor use include nausea, vomiting, diarrhea, headache, transient elevation in hepatic enzymes, and exacerbation of bronchospasm in patients with underlying chronic respiratory disease. Uncommon adverse effects include dizziness, vertigo, dysrhythmias, syncope, bradycardia, hemorrhagic colitis, dermatitis, rash, eczema, urticaria, serious skin reactions (eg, erythema multiforme, Stevens-Johnson Syndrome, toxic epidermal necrolysis), hepatitis, cough, dyspnea, bronchitis, seizures, confusion, agitation, anxiety, abnormal behavior, hallucinations, delirium, transient lymphopenia and neutropenia, and acute allergic reactions, including anaphylaxis. It is often difficult to elicit which adverse effects may actually be due to the underlying illness rather than the neuraminidase inhibitor.
    F) WITH POISONING/EXPOSURE
    1) MILD TO MODERATE TOXICITY: A majority of patients with neuraminidase inhibitor overdose will have only mild toxicity. Signs and symptoms commonly include nausea, vomiting, abdominal pain, and diarrhea. Pruritus, dizziness, and tremors have also been reported.
    2) SEVERE TOXICITY: In cases of severe toxicity, patients may very rarely develop neuropsychiatric illness including agitation, delirium, hallucinations, and psychosis. This appears to be common with high-dose therapy for critically ill patients with influenza, although whether the cause is directly due to oseltamivir toxicity or the underlying illness remains unclear.

Vital Signs

    3.3.3) TEMPERATURE
    A) WITH THERAPEUTIC USE
    1) ZANAMIVIR: FEVER: In a 10-day influenza prophylaxis study of adults and children at least 5 years of age, temperature regulation disturbances (fever and/or chills) were reported in 5% of patients who received zanamivir 10 mg inhaled once daily (n=1068) compared with 4% of patients who received placebo (n=1059) (Prod Info RELENZA(R) oral inhalation powder, 2012).

Heent

    3.4.5) NOSE
    A) WITH THERAPEUTIC USE
    1) ZANAMIVIR: Intranasal zanamivir has resulted in an incidence of local nasal intolerance not significantly different from placebo (experimental infection study). A slightly higher incidence with zanamivir is reported for epistaxis/blood in mucus (4% to 5%), mucosal erosion/ulcer (2% to 4%) (Hayden et al, 1996; Freund et al, 1999).

Cardiovascular

    3.5.2) CLINICAL EFFECTS
    A) CONDUCTION DISORDER OF THE HEART
    1) WITH THERAPEUTIC USE
    a) OSELTAMIVIR: Dysrhythmias have been reported with oseltamivir phosphate use during postmarketing surveillance (Prod Info TAMIFLU(R) oral capsules, oral suspension, 2014a).
    b) ZANAMIVIR: Dysrhythmias have been reported during postmarketing surveillance of zanamivir (Prod Info RELENZA(R) oral inhalation powder, 2012).
    c) ZANAMIVIR: LACK OF EFFECT: No clinically significant changes in vital signs, spirometry, or ECG, were observed in clinical trials of intranasal zanamivir (Freund et al, 1999).
    B) SYNCOPE
    1) WITH THERAPEUTIC USE
    a) ZANAMIVIR: Syncope has been reported during postmarketing surveillance of zanamivir (Prod Info RELENZA(R) oral inhalation powder, 2012).
    C) BRADYCARDIA
    1) WITH THERAPEUTIC USE
    a) OSELTAMIVIR: CASE REPORTS: Two cases of bradycardia following oseltamivir treatment were described. A 39-year-old woman, who presented with cough and infiltrates one day after pregnancy termination because of amnionitis, was initiated on oseltamivir 75 mg twice daily. Sinus bradycardia was observed 2 days later, gradually decreasing to 40 to 45 beats per minute (bpm) at rest. Oseltamivir was discontinued, and she had no other dysrhythmias and was asymptomatic 2 days later. The second case involved a 24-year-old woman, with hypertension and on fluoxetine for an eating disorder, who received oseltamivir 75 mg twice daily for a presumptive diagnosis of H1N1 influenza; roxithromycin and bronchodilator inhalations were also initiated. The following day, her oseltamivir dose was doubled due to dyspnea, but reduced back to the standard dose the next day. Her heart rate of 79 bpm at admission decreased to 45 bpm by the following morning. Subsequently, she had repeated episodes of bradycardia, with occasional dizziness or pre-syncope (mean heart rate, 51 bpm). At this time, her respiratory symptoms had resolved, and oseltamivir and fluoxetine were discontinued. Both patients had normal thyroid function, cardiac enzymes, and ECG. Both cases scored a 3 on the Naranjo adverse event scale, suggesting a possible drug related adverse effect (Karplus et al, 2010).

Respiratory

    3.6.2) CLINICAL EFFECTS
    A) COUGH
    1) WITH THERAPEUTIC USE
    a) ZANAMIVIR: Cough has occurred in prophylaxis studies (7 to 17% of patients) of intranasal zanamivir and may be due to either the active drug or the vehicle (lactose powder) (Prod Info RELENZA(R) oral inhalation powder, 2012).
    b) ZANAMIVIR: In a study of pediatric patients (5 to 12 years of age) without acute influenza-like illness, cough was reported in 16% of patients who received a prophylactic regimen of zanamivir (n=132) compared with 8% of patients who received placebo (n=145) (Prod Info RELENZA(R) oral inhalation powder, 2012).
    B) BRONCHOSPASM
    1) WITH THERAPEUTIC USE
    a) ZANAMIVIR: Inhaled zanamivir may worsen or precipitate severe bronchospasm, including fatalities, in patients with or without underlying airway disease. One out of 13 asthma patients reported bronchospasm following an intranasal dose of zanamivir in a clinical trial (Prod Info RELENZA(R) oral inhalation powder, 2012; CDC, 1999).
    C) BRONCHITIS
    1) WITH THERAPEUTIC USE
    a) ZANAMIVIR: Bronchitis has been reported with therapeutic use of zanamivir (Prod Info RELENZA(R) oral inhalation powder, 2012).
    D) DYSPNEA
    1) WITH THERAPEUTIC USE
    a) ZANAMIVIR: Dyspnea has been reported during postmarketing surveillance of zanamivir (Prod Info RELENZA(R) oral inhalation powder, 2012).

Neurologic

    3.7.2) CLINICAL EFFECTS
    A) HEADACHE
    1) WITH THERAPEUTIC USE
    a) ZANAMIVIR: In clinical trials comparing zanamivir to placebo in influenza infected patients, headache was a common adverse effect but the rates appeared similar to the placebo group (Prod Info RELENZA(R) oral inhalation powder, 2012).
    B) DIZZINESS
    1) WITH THERAPEUTIC USE
    a) Dizziness and vertigo have been reported infrequently as adverse effects with these agents and may occur following overdose (Prod Info RELENZA(R) oral inhalation powder, 2012; Prod Info TAMIFLU(R) oral capsules, oral suspension, 2014a; Freund et al, 1999).
    2) WITH POISONING/EXPOSURE
    a) OSELTAMIVIR: In a retrospective study of data obtained from the Texas Poison Center Network (TPCN), 80 cases of oseltamivir ingestions (with no other concurrent agents) were identified. Oseltamivir mean dose used by 56 (70%) patients was 145.1 mg (range 7.5 to 900 mg). One patient developed dizziness (Forrester, 2010).
    C) SEIZURE
    1) WITH THERAPEUTIC USE
    a) OSELTAMIVIR: Seizures have been reported with oseltamivir phosphate use during postmarketing surveillance (Prod Info TAMIFLU(R) oral capsules, oral suspension, 2014a).
    b) ZANAMIVIR: Seizures have been reported during postmarketing surveillance of zanamivir (Prod Info RELENZA(R) oral inhalation powder, 2012). Patients with influenza, particularly pediatric patients and patients with encephalitis or encephalopathy, may have an increased risk of seizures early in their illness (Williamson & Pegram, 2000).
    D) CLOUDED CONSCIOUSNESS
    1) WITH THERAPEUTIC USE
    a) OSELTAMIVIR: Confusion has been reported with oseltamivir phosphate use during postmarketing surveillance (Prod Info TAMIFLU(R) oral capsules, oral suspension, 2014a).
    b) ZANAMIVIR: Confusion has been reported during postmarketing surveillance of zanamivir. Patients with influenza, particularly pediatric patients, may have an increased risk of seizures, confusion, and abnormal behavior early in their illness (Prod Info RELENZA(R) oral inhalation powder, 2012).
    E) PSYCHOMOTOR AGITATION
    1) WITH THERAPEUTIC USE
    a) OSELTAMIVIR: Agitation has been reported with oseltamivir phosphate use during postmarketing surveillance (Prod Info TAMIFLU(R) oral capsules, oral suspension, 2014a).
    b) ZANAMIVIR: Abnormal behavior (with some cases leading to injury), including agitation, has been reported during postmarketing surveillance of zanamivir. Neuropsychiatric events, often with abrupt onset and rapid resolution, have been reported primarily among pediatric patients (Prod Info RELENZA(R) oral inhalation powder, 2012).
    2) WITH POISONING/EXPOSURE
    a) OSELTAMIVIR: In a retrospective study of data obtained from the Texas Poison Center Network (TPCN), 80 cases of oseltamivir ingestions (with no other concurrent agents) were identified. Oseltamivir mean dose used by 56 (70%) patients was 145.1 mg (range 7.5 to 900 mg). Two patients developed agitation (Forrester, 2010).
    F) ANXIETY
    1) WITH THERAPEUTIC USE
    a) OSELTAMIVIR: Anxiety has been reported with oseltamivir phosphate use during postmarketing surveillance (Prod Info TAMIFLU(R) oral capsules, oral suspension, 2014a).
    b) ZANAMIVIR: Anxiety has been reported during postmarketing surveillance of zanamivir (Prod Info RELENZA(R) oral inhalation powder, 2012).
    G) TREMOR
    1) WITH POISONING/EXPOSURE
    a) OSELTAMIVIR: In a retrospective study of data obtained from the Texas Poison Center Network (TPCN), 80 cases of oseltamivir ingestions (with no other concurrent agents) were identified. Oseltamivir mean dose used by 56 (70%) patients was 145.1 mg (range 7.5 to 900 mg). One patient developed tremor (Forrester, 2010).

Gastrointestinal

    3.8.2) CLINICAL EFFECTS
    A) NAUSEA AND VOMITING
    1) WITH THERAPEUTIC USE
    a) OSELTAMIVIR: Nausea and vomiting have been the primary adverse effects of oral oseltamivir, occurring in less than 10% of patients (Prod Info TAMIFLU(R) oral capsules, oral suspension, 2014a; CDC, 1999; Anon, 1999; (Anon, 1999a); Hayden et al, 1997; p 22; p 21). There has been no significant correlation between incidence and dose (Wood et al, 1997).
    b) ZANAMIVIR: Following inhaled/intranasal zanamivir, gastrointestinal symptoms (unspecified) appear to be only slightly higher than placebo group (not significant difference) (Hayden et al, 1997). Nausea and/or diarrhea have been reported in 3% of patients in clinical trials, and vomiting has been reported in 1% of patients (Prod Info RELENZA(R) oral inhalation powder, 2012).
    2) WITH POISONING/EXPOSURE
    a) OSELTAMIVIR: Oral doses of oseltamivir as high as 1000 mg have only resulted in nausea and/or vomiting in clinical trials (Prod Info TAMIFLU(R) oral capsules, oral suspension, 2014a).
    b) OSELTAMIVIR: In a retrospective study of data obtained from the Texas Poison Center Network (TPCN), 80 cases of oseltamivir ingestions (with no other concurrent agents) were identified. Oseltamivir mean dose used by 56 (70%) patients was 145.1 mg (range 7.5 to 900 mg). Nausea and vomiting were observed in 3 and 6 patients, respectively (Forrester, 2010).
    B) ABDOMINAL PAIN
    1) WITH POISONING/EXPOSURE
    a) OSELTAMIVIR: In a retrospective study of data obtained from the Texas Poison Center Network (TPCN), 80 cases of oseltamivir ingestions (with no other concurrent agents) were identified. Oseltamivir mean dose used by 56 (70%) patients was 145.1 mg (range 7.5 to 900 mg). Three patients developed abdominal pain (Forrester, 2010).
    C) DIARRHEA
    1) WITH POISONING/EXPOSURE
    a) OSELTAMIVIR: In a retrospective study of data obtained from the Texas Poison Center Network (TPCN), 80 cases of oseltamivir ingestions (with no other concurrent agents) were identified. Oseltamivir mean dose used by 56 (70%) patients was 145.1 mg (range 7.5 to 900 mg). One patient developed diarrhea (Forrester, 2010).
    D) HEMORRHAGIC COLITIS
    1) WITH THERAPEUTIC USE
    a) OSELTAMIVIR: Hemorrhagic colitis has been reported with oseltamivir phosphate use during postmarketing surveillance (Prod Info TAMIFLU(R) oral capsules, oral suspension, 2014a).
    b) OSELTAMIVIR: CASE REPORT: A case report described oseltamivir-induced acute hemorrhagic colitis in a 40-year-old woman, with symptoms of abdominal pain, diarrhea, and hematochezia occurring approximately 4 hours after receiving the first dose for influenza A therapy. Colonoscopy revealed circumferential hemorrhagic colitis with longitudinal erosions, mimicking ischemic colitis, in the descending colon; presence of mucosal hemorrhage and submucosal edema was evident in histopathological analysis of the lesion. There was immediate improvement in hemorrhagic colitis upon discontinuation of oseltamivir. The patient had no other risk factors for ischemia and a lymphocyte transformation test was positive for oseltamivir, but not for her other medications (clarithromycin, acetaminophen) (Nakagawa et al, 2011).

Hepatic

    3.9.2) CLINICAL EFFECTS
    A) LIVER ENZYMES ABNORMAL
    1) WITH THERAPEUTIC USE
    a) OSELTAMIVIR: Abnormal liver function tests have been reported with oseltamivir phosphate use during postmarketing surveillance (Prod Info TAMIFLU(R) oral capsules, oral suspension, 2014a).
    b) ZANAMIVIR: Intranasal administration of zanamivir has resulted in transient transaminase elevations (2% to 21% of patients) in clinical trials; incidence with placebo is reported to be 2% to 14% (Hayden et al, 1996). There was no relationship to dose in the clinical trials.
    B) INFLAMMATORY DISEASE OF LIVER
    1) WITH THERAPEUTIC USE
    a) OSELTAMIVIR: Hepatitis has been reported with oseltamivir phosphate use during postmarketing surveillance (Prod Info TAMIFLU(R) oral capsules, oral suspension, 2014a).

Hematologic

    3.13.2) CLINICAL EFFECTS
    A) LEUKOPENIA
    1) WITH THERAPEUTIC USE
    a) ZANAMIVIR: Lymphopenia and neutropenia have been reported in clinical trials of zanamivir, but appeared to be transient (Prod Info RELENZA(R) oral inhalation powder, 2012).

Dermatologic

    3.14.2) CLINICAL EFFECTS
    A) SKIN FINDING
    1) WITH THERAPEUTIC USE
    a) OSELTAMIVIR: Dermatologic adverse effects associated with oseltamivir phosphate therapy during postmarketing surveillance include dermatitis, rash, eczema, urticaria, and rarely, serious skin reactions, including erythema multiforme, Stevens-Johnson Syndrome, and toxic epidermal necrolysis (Prod Info TAMIFLU(R) oral capsules, oral suspension, 2014a).
    b) ZANAMIVIR: Erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis, facial edema, and rash have been reported during postmarketing surveillance of zanamivir (Prod Info RELENZA(R) oral inhalation powder, 2012).
    2) WITH POISONING/EXPOSURE
    a) OSELTAMIVIR: In a retrospective study of data obtained from the Texas Poison Center Network (TPCN), 80 cases of oseltamivir ingestions (with no other concurrent agents) were identified. Oseltamivir mean dose used by 56 (70%) patients was 145.1 mg (range 7.5 to 900 mg). Two patients developed pruritus (Forrester, 2010).

Musculoskeletal

    3.15.2) CLINICAL EFFECTS
    A) ENZYMES/SPECIFIC PROTEIN LEVELS - FINDING
    1) WITH THERAPEUTIC USE
    a) ZANAMIVIR: In zanamivir clinical trials, increases in creatine phosphokinase (CPK) have occurred. The increases appeared to be minor and transient (Prod Info RELENZA(R) oral inhalation powder, 2012).

Immunologic

    3.19.2) CLINICAL EFFECTS
    A) HYPERSENSITIVITY REACTION
    1) WITH THERAPEUTIC USE
    a) ZANAMIVIR: Allergic-like reactions, including oropharyngeal edema, serious skin rashes, and anaphylaxis, have been reported during postmarketing surveillance of zanamivir (Prod Info RELENZA(R) oral inhalation powder, 2012).

Reproductive

    3.20.1) SUMMARY
    A) Oseltamivir and peramivir are classified as FDA pregnancy category C, and zanamivir is classified as FDA pregnancy category B. In one study, oseltamivir and zanamivir were associated with an increased risk of transient hypoglycemia in infants born to women exposed to one or both of the neuraminidase inhibitors. Oseltamivir and its carboxylate salt form were detected in human breast milk after maternal use, but at concentrations significantly lower than the recommended infant dose.
    3.20.2) TERATOGENICITY
    A) ANIMAL STUDIES
    1) OSELTAMIVIR: In animal studies, minimal maternal toxicity was noted in rats administered oral oseltamivir 1500 mg/kg/day (100 times the human exposure) and marked maternal toxicity was noted in rabbits administered oral oseltamivir 500 mg/kg/day (50 times the human exposure) (Prod Info TAMIFLU(R) oral capsules, oral suspension, 2014).
    2) PERAMIVIR: Studies in rats revealed no teratogenic effects at exposures following 600 mg/kg IV bolus, approximately 8 times the human recommended dose. However, continuous IV infusion caused fetal anomalies (eg, reduced renal papilla, dilated ureters). The no-observed-adverse-effect-level (NOAEL) was 0.8-fold the human recommend dose. In rabbits, exposures following 600 mg/kg caused maternal toxicity (eg, decreased food consumption and body weights) and developmental toxicity (eg, abortion, premature delivery). The NOAEL was 8-fold the human recommend dose (Prod Info RAPIVAB(TM) intravenous injection solution, 2014).
    3) ZANAMIVIR: Rat studies of fertility and early embryonic development showed no effects on fertility, mating performance, or early embryonic development at any dose level for zanamivir (Prod Info RELENZA(R) oral inhalation powder, 2008; Freund et al, 1999). No teratogenic effects were reported in rats or rabbits when zanamivir was administered intravenously at the maximum dosage of 90 mg/kg/day for one month (Dines et al, 1998).
    3.20.3) EFFECTS IN PREGNANCY
    A) PREGNANCY CATEGORY
    1) OSELTAMIVIR
    a) The US Food and Drug Administration has classified oseltamivir as pregnancy category C (Prod Info TAMIFLU(R) oral capsules, oral suspension, 2014).
    2) PERAMIVIR
    a) The US Food and Drug Administration has classified peramivir as pregnancy category C (Prod Info RAPIVAB(TM) intravenous injection solution, 2014) .
    3) ZANAMIVIR
    a) The US Food and Drug Administration has classified zanamivir as pregnancy category B (Prod Info RELENZA(R) oral inhalation powder, 2008).
    B) OSELTAMIVIR
    1) PLACENTAL BARRIER
    a) A case report described significant levels of oseltamivir in the cord blood of a 29-year-old woman at 29 weeks' gestation, indicating that oseltamivir crosses the placenta. The critically ill woman was diagnosed with pneumonia and was treated with oseltamivir 75 mg twice daily, in addition to antibiotics; the dose of oseltamivir was increased to 150 mg twice daily after 3 days. As the clinical situation had not improved by day 6 of hospital admission, a cesarean section was performed. Plasma concentrations of oseltamivir and its active metabolite, oseltamivir carboxylate, were measured in maternal blood, which was drawn just prior to the cesarean section, and in the venous umbilical cord blood, which was collected after the cord was clamped (approximately 5 hours after the last dose of oseltamivir). When compared with ex vivo placental models, a considerably higher fetal transfer rate of both substances was measured (23.5% and 73.4%, respectively vs 8.5% and 6.6%, respectively). The high maternal blood concentration of oseltamivir carboxylate may have been due to the relatively high dose of oseltamivir while the higher fetal transfer rates may have been due to alteration of the expression of multidrug resistance protein, placental metabolism of the drug, fetal metabolism, and/or fetal accumulation (Meijer et al, 2012).
    2) TRANSIENT HYPOGLYCEMIA
    a) In an observational cohort study comparing pregnancy outcomes among women and infants following in utero exposure to neuraminidase inhibitors (n=86) with women and infants not exposed (n= 860), an increased risk of late transient hypoglycemia was observed among infants presumed to be exposed to the antivirals. Women in the exposed group were prescribed oseltamivir (n=81) or zanamivir (n=2) or both (n=3) during various trimesters of pregnancy. In the exposed group, 4 (4.7%) infants born to women prescribed a neuraminidase inhibitor developed late transient hypoglycemia greater than 6 hours after birth compared with 10 (1.2%) infants born to women who were not exposed (crude odds ratio (OR), 4; 95% confidence interval (CI), 1.26 to 12.76) (Svensson et al, 2011).
    C) PERAMIVIR
    1) There are no adequate and well-controlled studies of peramivir use in human pregnancy, and the effects on the developing fetus are unknown. Due to the lack of human safety data, peramivir should be used in pregnant women only if clinically necessary (Prod Info RAPIVAB(TM) intravenous injection solution, 2014).
    D) ZANAMIVIR
    1) TRANSIENT HYPOGLYCEMIA
    a) In an observational cohort study comparing pregnancy outcomes among women and infants following in utero exposure to neuraminidase inhibitors (n=86) with women and infants not exposed (n= 860), an increased risk of late transient hypoglycemia was observed among infants presumed to be exposed to the antivirals. Women in the exposed group were prescribed oseltamivir (n=81) or zanamivir (n=2) or both (n=3) during various trimesters of pregnancy. In the exposed group, 4 (4.7%) infants born to women prescribed a neuraminidase inhibitor developed late transient hypoglycemia greater than 6 hours after birth compared with 10 (1.2%) infants born to women who were not exposed (crude odds ratio (OR), 4; 95% confidence interval (CI), 1.26 to 12.76) (Svensson et al, 2011).
    E) LACK OF EFFECT
    1) OSELTAMIVIR
    a) Published prospective and retrospective studies of about 1500 women given oseltamivir during pregnancy suggest that it does not increase the risk of birth defects compared to placebo (including about 400 women exposed to oseltamivir during the first trimester). However, the risk cannot be definitively assessed because some of such studies used small sample sizes, used different control groups, or did not provide dosage information (Prod Info TAMIFLU(R) oral capsules, oral suspension, 2014).
    b) The Roche Global Safety Database was searched for all exposures to oseltamivir in pregnant women over 13 years up to April 30, 2012 to evaluate the safety of oseltamivir in pregnant women and to assess fetal and birth outcomes. In 2128 pregnant women, pregnancy outcomes including spontaneous abortions (2.9%; 61/2128), therapeutic abortions (1.8%; 39/2128) and preterm deliveries (4.2%; 84 of 2000 live births) were lower than rates reported in the general population (ie, women with or without influenza). Fetal outcomes were known for 1875 births. Of these live births, 81 cases of birth defects were reported. Eleven cases (ie, body systems included the heart, CNS, ear and eye) occurred during the sensitive period of gestation and were possibly attributable to oseltamivir, 53 cases did not occur during a sensitive period of gestation or were attributed to other factors, and inadequate information was available to evaluate the remaining 17 cases (Wollenhaupt et al, 2014).
    c) An observational cohort study compared pregnancy outcomes among women and infants following in utero exposure to neuraminidase inhibitors (n=86) with women and infants not exposed (n= 860). Women in the exposed group were prescribed oseltamivir (n=81) or zanamivir (n=2) or both (n=3) during various trimesters of pregnancy. Study results showed no significantly increased risks of birth-related death, preterm birth, low birth weight, small for gestational age, or low Apgar score among infants born to women prescribed neuraminidase inhibitors during pregnancy (Svensson et al, 2011).
    d) A retrospective cohort study of 337 women exposed to oseltamivir during pregnancy compared with 674 unexposed pregnant women showed no significant association between oseltamivir exposure during pregnancy and adverse pregnancy outcomes. Compared with the unexposed group, the exposed group did not have a significantly different risk for pregnancy loss (hazard ratio [HR], 1.52; 95% CI, 0.8 to 2.91), preterm birth (adjusted odds ratio [aOR], 0.64; 95% CI, 0.31 to 1.27), or neonatal pathology (aOR, 0.62; 95% CI, 0.23 to 1.54). Looking at exposure only during organogenesis (from day 1 to day 56 of gestation), 1 out of 49 (2%) exposed infants and 1 out of 99 (1%) unexposed infants had a congenital anomaly (crude odds ratio, 2; 95% CI, 0.13 to 32). A congenital heart defect was detected prior to 2 years of age in a male infant whose mother received oseltamivir during the first month of pregnancy; however, the mother also took salicylic acid, acetaminophen, tuaminoheptane, escitalopram, and oxomemazine during the first trimester (Beau et al, 2014).
    e) In a retrospective cohort study, oseltamivir use during pregnancy was not significantly associated with maternal toxicity, stillbirth, or fetal malformations. Over a 5-year period, the pregnancy outcomes of influenza patients who received oseltamivir (n=135) or a M2 ion channel inhibitor (amantadine, rimantadine, or both; n=104) during the first (13%), second (32%), or third (55%) trimesters were compared with a control group (n=82,097). Neonates exposed to oseltamivir had no increased risk of stillbirth (0% vs 0% vs 1%), major malformations (1% vs 0% vs 2%), or minor malformations (19% vs 15% vs 22%) compared with M2 ion channel inhibitors or compared with controls. In a subgroup analysis, liveborn, singleton neonates exposed to oseltamivir or M2 ion channel inhibitors had a significantly increased risk of necrotizing enterocolitis compared with controls (0.8% and 1% vs 0.02%; p less than 0.001). One neonate had second-trimester exposure to oseltamivir and was delivered at 29 weeks of gestation weighing 1200 g. The other had second-trimester exposure to amantadine and was delivered at 32 weeks of gestation weighing 844 g. It is thought that the increased risk of necrotizing enterocolitis was due to prematurity rather than antiviral exposure or maternal influenza (Greer et al, 2010).
    2) ZANAMIVIR
    a) An observational cohort study compared pregnancy outcomes among women and infants following in utero exposure to neuraminidase inhibitors (n=86) with women and infants not exposed (n= 860). Women in the exposed group were prescribed oseltamivir (n=81) or zanamivir (n=2) or both (n=3) during various trimesters of pregnancy. Study results showed no significantly increased risks of birth-related death, preterm birth, low birth weight, small for gestational age, or low Apgar score among infants born to women prescribed neuraminidase inhibitors during pregnancy (Svensson et al, 2011).
    b) Within a clinical study, 3 women taking zanamivir became pregnant. A spontaneous miscarriage occurred in one (not considered related to zanamivir therapy), one pregnancy was intentionally terminated, and one pregnancy resulted in a healthy baby born 2 weeks early (Freund et al, 1999).
    F) ANIMAL STUDIES
    1) PERAMIVIR
    a) Studies in rats revealed no teratogenic effects at exposures following 600 mg/kg IV bolus, approximately 8 times the human recommended dose. However, continuous IV infusion caused fetal anomalies (eg, reduced renal papilla, dilated ureters). The no-observed-adverse-effect-level (NOAEL) was 0.8-fold the human recommend dose. In rabbits, exposures following 600 mg/kg caused maternal toxicity (eg, decreased food consumption and body weights) and developmental toxicity (eg, abortion, premature delivery). The NOAEL was 8-fold the human recommend dose (Prod Info RAPIVAB(TM) intravenous injection solution, 2014).
    3.20.4) EFFECTS DURING BREAST-FEEDING
    A) BREAST MILK
    1) OSELTAMIVIR and its carboxylate salt form were detected in human breast milk after maternal use, but at concentrations significantly lower than the recommended infant dose. Seven mothers (ages 19 to 24) each received a single 75-mg dose of oseltamivir phosphate within 48 hours after delivery. Plasma and breast milk concentrations were evaluated at baseline and 0.5, 1, 2, 4, 8, 12, and 24 hours after dosing. The total plasma and breast-milk concentrations (in nanograms(ng)/hr per mL) for oseltamivir phosphate were 155.6 +/- 57.9 and 143.4 +/- 73.4, respectively. Oseltamivir carboxylate concentrations were 2611.7 +/- 349 and 569 +/- 405.8, respectively. At steady state (12 to 24 hours), the mean concentration of oseltamivir phosphate detected in breast milk was 2.8 ng/mL, which corresponds to an approximate exposure of 2.1 mcg/day (or 0.76 mcg/kg) for a 2.75-kg infant ingesting 750 mL of breast milk daily. This concentration is significantly lower than the recommended oseltamivir infant dose of 1 to 7 mg/kg/day (Greer et al, 2011). Limited data show that oseltamivir and oseltamivir carboxylate are present in human milk (even at low levels), but are not likely to lead to toxicity in the breastfed infant. Caution should be used when administering oseltamivir to a nursing mother (Prod Info TAMIFLU(R) oral capsules, oral suspension, 2014).
    2) PERAMIVIR: It is unknown whether peramivir is excreted in human milk. However, studies in rats have shown that peramivir is excreted into milk at levels below the maternal plasma concentration, approximately 0.5-fold the levels (AUC) in maternal blood. A decision should be made whether or not to nurse, taking into consideration the potential benefits of peramivir to the mother and the potential risks to the infant (Prod Info RAPIVAB(TM) intravenous injection solution, 2014).
    3) ZANAMIVIR is excreted into milk of lactating rats. It is not known if this drug is excreted into human milk (Prod Info RELENZA(R) oral inhalation powder, 2008).
    3.20.5) FERTILITY
    A) LACK OF EFFECT
    1) Oseltamivir lacked an effect on fertility, mating performance, or early embryonic development at any dose level. Doses of oseltamivir administered to female rats 2 weeks before mating, during mating and until Day 6 of pregnancy were 50, 250, and 1500 mg/kg/day. Doses of oseltamivir were administered to male rats 4 weeks before mating, during, and for 2 weeks after mating. The highest dose was approximately 100 times the human systemic exposure (AUC 0 to 24 hours) of oseltamivir carboxylate (Prod Info TAMIFLU(R) oral capsules, oral suspension, 2014).
    2) In studies in rats, peramivir lacked an effect on fertility at does up to 600 mg/kg/day, approximately 8 times the exposure of the human recommended dose (Prod Info RAPIVAB(TM) intravenous injection solution, 2014).

Carcinogenicity

    3.21.4) ANIMAL STUDIES
    A) LACK OF EFFECT
    1) Peramivir was not carcinogenic in rats when administered doses of 600 mg/day (0.2 to 0.5 times the human dose) (Prod Info RAPIVAB(TM) intravenous injection solution, 2014).

Genotoxicity

    A) OSELTAMIVIR, ZANAMIVIR: Both oseltamivir and zanamivir were found to be non-mutagenic in the Ames, human lymphocyte chromosome and mouse micronucleus tests (Prod Info Tamiflu(TM), oseltamivir, 2001; Prod Info Relenza(R), zanamivir for inhalation, 2001). Oseltamivir carboxylate was reported to be non-mutagenic in the Ames and mouse lymphoma cell mutation tests (Prod Info Tamiflu(TM), oseltamivir, 2001).
    B) PERAMIVIR: Intravenous peramivir was not mutagenic or clastogenic in the Ames bacterial reverse mutation assay, the Chinese hamster ovary chromosomal aberration test, and the in vivo mouse micronucleus test (Prod Info RAPIVAB(TM) intravenous injection solution, 2014).

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Monitor vital signs and mental status following significant overdose.
    B) Neuraminidase inhibitor serum concentrations are not widely available or clinically useful.
    C) Monitor serum electrolytes, renal function, CPK, and hepatic enzymes in patients with evidence of toxicity.
    4.1.2) SERUM/BLOOD
    A) BLOOD/SERUM CHEMISTRY
    1) Monitor serum electrolytes, renal function, and hepatic enzymes in patients with evidence of toxicity.
    2) Monitor CPK and hepatic function following acute exposures. Transient elevations of CPK levels and liver enzymes have been reported in clinical trials (Prod Info Relenza(R), zanamivir for inhalation, 2001).
    B) HEMATOLOGIC
    1) Monitor CBC in symptomatic patients. Lymphopenia and neutropenia have been reported in clinical trials of zanamivir, but have been transient (Prod Info Relenza(R), zanamivir for inhalation, 2001).
    4.1.4) OTHER
    A) OTHER
    1) PULMONARY FUNCTION TESTS
    a) Patients with underlying respiratory disease may experience bronchospasm and/or decline in lung function when treated with intranasal inhaled zanamivir. Monitor lung function and FEV1 or peak expiratory flow rate in these patients.

Methods

    A) CHROMATOGRAPHY
    1) Morris et al (1995) described a liquid chromatography method, using direct injection with column switching, for the determination of zanamivir in human urine following intranasal administration. A quantitation range of 0.3 to 100 micrograms/milliliter for the assay is reported (Morris et al, 1995).
    2) In clinical trials, serum zanamivir concentrations were determined by Ionspray LC-MS/MS (tandem solid phase extraction) and urine concentrations were determined by direct injection using HPLC column switching (UV detection) (Hussey E, Hayden F & Grosse C et al, 1995).

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Patient Disposition

    6.3.1) DISPOSITION/ORAL EXPOSURE
    6.3.1.1) ADMISSION CRITERIA/ORAL
    A) Patients who develop persistent GI symptoms with nausea, vomiting, and diarrhea may require admission to the hospital for hydration and antiemetics. Patients with suspected neuropsychiatric symptoms may require admission for symptomatic treatment with benzodiazepines and monitoring.
    6.3.1.2) HOME CRITERIA/ORAL
    A) A patient with an inadvertent exposure, that remains asymptomatic can be managed at home.
    6.3.1.3) CONSULT CRITERIA/ORAL
    A) Contact a local poison center for a toxicology consult for any patient with suspected neuraminidase inhibitor toxicity with more than mild symptoms.
    6.3.1.5) OBSERVATION CRITERIA/ORAL
    A) Patients with known large ingestions, should be observed for 6 hours for signs of toxicity.

Monitoring

    A) Monitor vital signs and mental status following significant overdose.
    B) Neuraminidase inhibitor serum concentrations are not widely available or clinically useful.
    C) Monitor serum electrolytes, renal function, CPK, and hepatic enzymes in patients with evidence of toxicity.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) Gastrointestinal decontamination is typically not necessary for the treatment of neuraminidase inhibitors given the minimal toxicity associated.
    6.5.2) PREVENTION OF ABSORPTION
    A) Gastrointestinal decontamination is typically not necessary for the treatment of neuraminidase inhibitors given the minimal toxicity associated. Consider activated charcoal only if coingestants with significant toxicity are involved.
    B) ACTIVATED CHARCOAL
    1) CHARCOAL ADMINISTRATION
    a) Consider administration of activated charcoal after a potentially toxic ingestion (Chyka et al, 2005). Administer charcoal as an aqueous slurry; most effective when administered within one hour of ingestion.
    2) CHARCOAL DOSE
    a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).
    1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).
    b) ADVERSE EFFECTS/CONTRAINDICATIONS
    1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
    2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).
    6.5.3) TREATMENT
    A) SUPPORT
    1) MANAGEMENT OF MILD TO MODERATE TOXICITY
    a) Treatment is predominantly symptomatic and supportive care.
    2) MANAGEMENT OF SEVERE TOXICITY
    a) Treatment is symptomatic and supportive. Treat agitation with benzodiazepines. Treat seizures with IV benzodiazepines; barbiturates or propofol may be needed if seizures persist or recur.
    B) MONITORING OF PATIENT
    1) Monitor vital signs and mental status following significant overdose.
    2) Neuraminidase inhibitor serum concentrations are not widely available or clinically useful.
    3) Monitor serum electrolytes, renal function, CPK, and hepatic enzymes in patients with evidence of toxicity.
    C) SEIZURE
    1) SUMMARY
    a) Attempt initial control with a benzodiazepine (eg, diazepam, lorazepam). If seizures persist or recur, administer phenobarbital or propofol.
    b) Monitor for respiratory depression, hypotension, and dysrhythmias. Endotracheal intubation should be performed in patients with persistent seizures.
    c) Evaluate for hypoxia, electrolyte disturbances, and hypoglycemia (or, if immediate bedside glucose testing is not available, treat with intravenous dextrose).
    2) DIAZEPAM
    a) ADULT DOSE: Initially 5 to 10 mg IV, OR 0.15 mg/kg IV up to 10 mg per dose up to a rate of 5 mg/minute; may be repeated every 5 to 20 minutes as needed (Brophy et al, 2012; Prod Info diazepam IM, IV injection, 2008; Manno, 2003).
    b) PEDIATRIC DOSE: 0.1 to 0.5 mg/kg IV over 2 to 5 minutes; up to a maximum of 10 mg/dose. May repeat dose every 5 to 10 minutes as needed (Loddenkemper & Goodkin, 2011; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008).
    c) Monitor for hypotension, respiratory depression, and the need for endotracheal intubation. Consider a second agent if seizures persist or recur after repeated doses of diazepam .
    3) NO INTRAVENOUS ACCESS
    a) DIAZEPAM may be given rectally or intramuscularly (Manno, 2003). RECTAL DOSE: CHILD: Greater than 12 years: 0.2 mg/kg; 6 to 11 years: 0.3 mg/kg; 2 to 5 years: 0.5 mg/kg (Brophy et al, 2012).
    b) MIDAZOLAM has been used intramuscularly and intranasally, particularly in children when intravenous access has not been established. ADULT DOSE: 0.2 mg/kg IM, up to a maximum dose of 10 mg (Brophy et al, 2012). PEDIATRIC DOSE: INTRAMUSCULAR: 0.2 mg/kg IM, up to a maximum dose of 7 mg (Chamberlain et al, 1997) OR 10 mg IM (weight greater than 40 kg); 5 mg IM (weight 13 to 40 kg); INTRANASAL: 0.2 to 0.5 mg/kg up to a maximum of 10 mg/dose (Loddenkemper & Goodkin, 2011; Brophy et al, 2012). BUCCAL midazolam, 10 mg, has been used in adolescents and older children (5-years-old or more) to control seizures when intravenous access was not established (Scott et al, 1999).
    4) LORAZEPAM
    a) MAXIMUM RATE: The rate of intravenous administration of lorazepam should not exceed 2 mg/min (Brophy et al, 2012; Prod Info lorazepam IM, IV injection, 2008).
    b) ADULT DOSE: 2 to 4 mg IV initially; repeat every 5 to 10 minutes as needed, if seizures persist (Manno, 2003; Brophy et al, 2012).
    c) PEDIATRIC DOSE: 0.05 to 0.1 mg/kg IV over 2 to 5 minutes, up to a maximum of 4 mg/dose; may repeat in 5 to 15 minutes as needed, if seizures continue (Brophy et al, 2012; Loddenkemper & Goodkin, 2011; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008; Sreenath et al, 2009; Chin et al, 2008).
    5) PHENOBARBITAL
    a) ADULT LOADING DOSE: 20 mg/kg IV at an infusion rate of 50 to 100 mg/minute IV. An additional 5 to 10 mg/kg dose may be given 10 minutes after loading infusion if seizures persist or recur (Brophy et al, 2012).
    b) Patients receiving high doses will require endotracheal intubation and may require vasopressor support (Brophy et al, 2012).
    c) PEDIATRIC LOADING DOSE: 20 mg/kg may be given as single or divided application (2 mg/kg/minute in children weighing less than 40 kg up to 100 mg/min in children weighing greater than 40 kg). A plasma concentration of about 20 mg/L will be achieved by this dose (Loddenkemper & Goodkin, 2011).
    d) REPEAT PEDIATRIC DOSE: Repeat doses of 5 to 20 mg/kg may be given every 15 to 20 minutes if seizures persist, with cardiorespiratory monitoring (Loddenkemper & Goodkin, 2011).
    e) MONITOR: For hypotension, respiratory depression, and the need for endotracheal intubation (Loddenkemper & Goodkin, 2011; Manno, 2003).
    f) SERUM CONCENTRATION MONITORING: Monitor serum concentrations over the next 12 to 24 hours. Therapeutic serum concentrations of phenobarbital range from 10 to 40 mcg/mL, although the optimal plasma concentration for some individuals may vary outside this range (Hvidberg & Dam, 1976; Choonara & Rane, 1990; AMA Department of Drugs, 1992).
    6) OTHER AGENTS
    a) If seizures persist after phenobarbital, propofol or pentobarbital infusion, or neuromuscular paralysis with general anesthesia (isoflurane) and continuous EEG monitoring should be considered (Manno, 2003). Other anticonvulsants can be considered (eg, valproate sodium, levetiracetam, lacosamide, topiramate) if seizures persist or recur; however, there is very little data regarding their use in toxin induced seizures, controlled trials are not available to define the optimal dosage ranges for these agents in status epilepticus (Brophy et al, 2012):
    1) VALPROATE SODIUM: ADULT DOSE: An initial dose of 20 to 40 mg/kg IV, at a rate of 3 to 6 mg/kg/minute; may give an additional dose of 20 mg/kg 10 minutes after loading infusion. PEDIATRIC DOSE: 1.5 to 3 mg/kg/minute (Brophy et al, 2012).
    2) LEVETIRACETAM: ADULT DOSE: 1000 to 3000 mg IV, at a rate of 2 to 5 mg/kg/min IV. PEDIATRIC DOSE: 20 to 60 mg/kg IV (Brophy et al, 2012; Loddenkemper & Goodkin, 2011).
    3) LACOSAMIDE: ADULT DOSE: 200 to 400 mg IV; 200 mg IV over 15 minutes (Brophy et al, 2012). PEDIATRIC DOSE: In one study, median starting doses of 1.3 mg/kg/day and maintenance doses of 4.7 mg/kg/day were used in children 8 years and older (Loddenkemper & Goodkin, 2011).
    4) TOPIRAMATE: ADULT DOSE: 200 to 400 mg nasogastric/orally OR 300 to 1600 mg/day orally divided in 2 to 4 times daily (Brophy et al, 2012).

Inhalation Exposure

    6.7.1) DECONTAMINATION
    A) Move patient from the toxic environment to fresh air. Monitor for respiratory distress. If cough or difficulty in breathing develops, evaluate for hypoxia, respiratory tract irritation, bronchitis, or pneumonitis.
    B) OBSERVATION: Carefully observe patients with inhalation exposure for the development of any systemic signs or symptoms and administer symptomatic treatment as necessary.
    C) INITIAL TREATMENT: Administer 100% humidified supplemental oxygen, perform endotracheal intubation and provide assisted ventilation as required. Administer inhaled beta-2 adrenergic agonists, if bronchospasm develops. Consider systemic corticosteroids in patients with significant bronchospasm (National Heart,Lung,and Blood Institute, 2007). Exposed skin and eyes should be flushed with copious amounts of water.
    6.7.2) TREATMENT
    A) BRONCHOSPASM
    1) Patients with underlying respiratory disease may experience bronchospasm and/or decline in lung function when treated or overdosed with intranasal inhaled zanamivir. Monitor lung function and FEV1 or peak expiratory flow rate in these patients. When bronchospasm occurs, administer a rapid-acting inhalational bronchodilator.
    2) BRONCHOSPASM SUMMARY
    a) Administer beta2 adrenergic agonists. Consider use of inhaled ipratropium and systemic corticosteroids. Monitor peak expiratory flow rate, monitor for hypoxia and respiratory failure, and administer oxygen as necessary.
    3) ALBUTEROL/ADULT DOSE
    a) 2.5 to 5 milligrams diluted with 4 milliliters of 0.9% saline by nebulizer every 20 minutes for three doses. If incomplete response, administer 2.5 to 10 milligrams every 1 to 4 hours as needed OR administer 10 to 15 milligrams every hour by continuous nebulizer as needed. Consider adding ipratropium to the nebulized albuterol; DOSE: 0.5 milligram by nebulizer every 30 minutes for three doses then every 2 to 4 hours as needed, NOT administered as a single agent (National Heart,Lung,and Blood Institute, 2007).
    4) ALBUTEROL/PEDIATRIC DOSE
    a) 0.15 milligram/kilogram (minimum 2.5 milligrams) diluted with 4 milliliters of 0.9% saline by nebulizer every 20 minutes for three doses. If incomplete response administer 0.15 to 0.3 milligram/kilogram (maximum 10 milligrams) every 1 to 4 hours as needed OR administer 0.5 mg/kg/hr by continuous nebulizer as needed. Consider adding ipratropium to the nebulized albuterol; DOSE: 0.25 to 0.5 milligram by nebulizer every 20 minutes for three doses then every 2 to 4 hours as needed, NOT administered as a single agent (National Heart,Lung,and Blood Institute, 2007).
    5) ALBUTEROL/CAUTIONS
    a) The incidence of adverse effects of beta2-agonists may be increased in older patients, particularly those with pre-existing ischemic heart disease (National Asthma Education and Prevention Program, 2007). Monitor for tachycardia, tremors.
    6) CORTICOSTEROIDS
    a) Consider systemic corticosteroids in patients with significant bronchospasm. PREDNISONE: ADULT: 40 to 80 milligrams/day in 1 or 2 divided doses. CHILD: 1 to 2 milligrams/kilogram/day (maximum 60 mg) in 1 or 2 divided doses (National Heart,Lung,and Blood Institute, 2007).
    B) Treatment should include recommendations listed in the ORAL EXPOSURE section when appropriate.

Enhanced Elimination

    A) HEMODIALYSIS
    1) Hemodialysis has not been studied for neuraminidase inhibitor toxicity; however, given the drugs' very large volumes of distribution (16 to 26 L) (Prod Info TAMIFLU(R) oral capsules, oral suspension, 2014a; Waghorn & Goa, 1998; p 265), it would not be expected to be useful.

Range Of Toxicity

Summary

    A) TOXICITY: In clinical trials, oseltamivir oral doses up to 1000 mg have resulted only in nausea and vomiting. Intravenous doses of zanamivir up to 600 mg were well tolerated in healthy volunteers. Additionally, for zanamivir, up to 1200 mg/day IV for 5 days have been given to volunteers with minimal effects. Zanamivir intranasal doses up to 96 mg/day were administered to volunteers with no or minimal adverse effects. Oseltamivir-associated neuropsychiatric symptoms have occurred with high-dose therapy at 150 mg/kg two times daily for 2 days in a patient with influenza.
    B) THERAPEUTIC DOSE: ADULT: OSELTAMIVIR: TREATMENT: 75 mg orally twice a day for 5 days. PROPHYLAXIS: 75 mg orally once a day for 10 days after last known exposure to an ill confirmed case. ZANAMIVIR: TREATMENT: Two 5 mg inhalations (10 mg total) twice per day. PROPHYLAXIS: Two 5 mg inhalations (10 mg total) once per day. PEDIATRIC: OSELTAMIVIR: Children older than 1 year and weighing 15 kg or less: 30 mg orally twice daily for 5 days. Children weighing 15.1 to 23 kg: 45 mg orally twice daily for 5 days. Children weighing 23.1 to 40 kg: 60 mg orally twice daily for 5 days. Children weighing 40.1 kg or more: 75 mg orally twice daily for 5 days. ZANAMIVIR: Dosing for children 7 years of age or older: 10 mg (2 oral inhalations) twice daily for 5 days.

Therapeutic Dose

    7.2.1) ADULT
    A) NOVEL INFLUENZA A, H1N1 2009
    1) IMPORTANT NOTE: As of June 23, 2010, the emergency use authorization allowing the unapproved use of oseltamivir, zanamivir and peramivir will no longer be in effect for the 2009 H1N1 influenza(US Food and Drug Administration, 2010).
    B) INFLUENZA
    1) OSELTAMIVIR: Dosage for adults and adolescents older than 13 years old, for treatment of influenza, with normal renal function is 75 mg orally twice daily for 5 days. PROPHYLAXIS: Dosage for adults and adolescents greater than 13 years old following close contact with an infected individual is 75 mg once daily for at least 10 day or up to 6 weeks during a community outbreak; therapy should begin with 2 days of exposure (Prod Info TAMIFLU(R) oral capsules, oral suspension, 2012).
    2) PERAMIVIR: Dosage for adults age 18 years or older for treatment of influenza is 600 mg as a single dose via IV infusion for 15 to 30 minutes within 2 days of symptom onset (Prod Info RAPIVAB(TM) intravenous injection solution, 2014).
    3) ZANAMIVIR: Dosage for persons older than 12 years old, for treatment of influenza, is 2 inhalations (total dose of 10 mg) twice daily for 5 days. PROPHYLAXIS: Dosage for person adults and pediatric patient 5 years of age and older is 10 mg once daily for 10 days; the dose should be given at the same time each day (Prod Info RELENZA(R) powder for inhalation, 2008).
    7.2.2) PEDIATRIC
    A) NOVEL INFLUENZA A, H1N1 2009
    1) TREATMENT
    a) : IMPORTANT NOTE: As of June 23, 2010, the emergency use authorization allowing the unapproved use of oseltamivir, zinamivir and peramivir will no longer be in effect for the 2009 H1N1 influenza (US Food and Drug Administration, 2010).
    B) SEASONAL INFLUENZA
    1) OSELTAMIVIR
    a) CHILDREN AGES 2 WEEKS TO LESS THAN 1 YEAR: 3 mg/kg/dose orally twice daily for 5 days (Prod Info TAMIFLU(R) oral capsules, oral suspension, 2012).
    b) CHILDREN AGES 1 TO 12 YEARS OF AGE WEIGHING 15 KG OR LESS: 30 mg orally twice daily for 5 to 10 days (Prod Info TAMIFLU(R) oral capsules, oral suspension, 2012).
    c) CHILDREN AGES 1 TO 12 YEARS OF AGE WEIGHING MORE THAN 15 KG AND UP TO 23 KG: 45 mg orally twice daily for 5 to 10 days (Prod Info TAMIFLU(R) oral capsules, oral suspension, 2012).
    d) CHILDREN AGES 1 TO 12 YEARS OF AGE WEIGHING MORE THAN 23 KG AND UP TO 40 KG: 60 mg orally twice daily for 5 to 10 days (Prod Info TAMIFLU(R) oral capsules, oral suspension, 2012).
    e) CHILDREN AGES 1 TO 12 YEARS OF AGE WEIGHING MORE THAN 40 KG: 75 mg orally twice daily for 5 to 10 days (Prod Info TAMIFLU(R) oral capsules, oral suspension, 2012).
    2) ZANAMIVIR
    a) Pediatric patients 7 years and older may receive 2 inhalations (total dose of 10 mg) twice daily for 5 days. PROPHYLAXIS: Recommended dose in pediatric patients 5 years of age and older in a household setting is 10 mg once daily for 10 days (Prod Info RELENZA(R) powder for inhalation, 2008).

Maximum Tolerated Exposure

    A) ADULT
    1) OSELTAMIVIR: In clinical trials, oral doses as high as 1000 mg have resulted only in nausea and/or vomiting (Prod Info Tamiflu(TM), oseltamivir, 2001). There have been no reports of overdoses at the time of this review.
    2) OSELTAMIVIR: In a retrospective study of data obtained from the Texas Poison Center Network (TPCN), 80 cases of oseltamivir ingestions (with no other concurrent agents) were identified. Oseltamivir mean dose used by 56 (70%) patients was 145.1 mg (range 7.5 to 900 mg). Overall, moderate effects, minor effects, and no effects were observed in 5% (n= 4; mean dose: 190 mg), 15% (n= 12; mean dose: 245.5 mg), and 80% (n=64; mean dose 124.3 mg) of cases, respectively. The following adverse effects were observed: vomiting (n=6), abdominal pain (n=3), nausea (n=3), pruritus (n=2), agitation (n=2), diarrhea (n=1), dizziness (n=1), hallucinations (n=1), and tremor (n=1) (Forrester, 2010).
    3) OSELTAMIVIR: Oseltamivir associated neuropsychiatric symptoms have occurred with high-dose therapy at 150 mg/kg two times daily for two days in a patient with influenza (Nakamura et al, 2010).
    4) ZANAMIVIR: Intravenous doses of zanamivir (up to 600 mg) in healthy volunteers were tolerated with minimal or no adverse effects (Freund et al, 1999). Intravenous doses of up to 1200 mg/day for 5 days have been given to volunteers with minimal adverse effects, similar to those seen in clinical trials at recommended doses (Prod Info Relenza(R), zanamivir for inhalation, 2001).
    5) ZANAMIVIR: Intranasal doses as high as 96 mg/day were administered to volunteers and were well tolerated with no or minimal adverse effects (Freund et al, 1999).
    B) ANIMAL DATA
    1) OSELTAMIVIR: In mice toxicity studies, oral doses up to 100 milligrams/kilogram/day were well tolerated. In rat studies, oral doses up to 800 milligrams/kilogram/day were well tolerated with no deaths, clinical signs, changes in organ appearance, or histopathological alterations (Sidwell et al, 1998).

Serum Plasma Blood Concentrations

    7.5.1) THERAPEUTIC CONCENTRATIONS
    A) THERAPEUTIC CONCENTRATION LEVELS
    1) ADULT
    a) ZANAMIVIR - Median serum concentrations in a clinical trial following intranasal doses of 3.6 milligrams twice daily to 16 milligrams six times daily ranged from 46 to 67 nanograms/milliliter (Hussey E, Hayden F & Grosse C et al, 1995).

Pharmacology Toxicology

Pharmacologic Mechanism

    A) Oseltamivir (GS 4104) is the ethyl ester prodrug of GS 4071, a selective inhibitor of influenza A and B neuraminidase (Li et al, 1998; Anon, 1999) Wood et al, 1997). GS 4071 is structurally similar to zanamivir; the glycerol moiety of zanamivir has been replaced by lipophilic side chains (Mendel et al, 1998).
    B) These antiviral agents selectively inhibit both influenza virus A and B neuraminidase, which cleaves terminal sialic acid residues from carbohydrate moieties on the surfaces of host cells and influenza virus envelopes. This process causes the release of progeny viruses from infected cells. Neuraminidase inhibitors are analogues of sialic acid. They block the active site of neuraminidase and leave uncleaved sialic acid residues on the surfaces of host cells and influenza viral envelopes. Viral hemagglutinin binds to uncleaved sialic acid residues, with resultant viral aggregation at the host cell surface and a reduction in the amount of virus that is released and can infect other cells (Winquist et al, 1999; Li et al, 1998; Mendel et al, 1998; (Anon, 1999a); Kim et al, 1999; Dines et al, 1998).
    C) GS 4071 has demonstrated potency comparable to zanamivir with respect to inhibition of neuraminidase and influenza A/B virus replication in vitro (Li et al, 1998; (Mendel et al, 1998). In animal studies, oral oseltamivir produced high concentrations of GS 4071 in the upper respiratory tract (p 25; Mendel et al, 1998) and effectively prevented and treated influenza virus infection (Mendel et al, 1998; Anon, 1997a).

Physicochemical

Physical Characteristics

    A) OSELTAMIVIR PHOSPHATE is a white crystalline solid (Prod Info TAMIFLU(R) oral capsules, suspension, 2008).
    B) PERAMIVIR is a clear, iso-osmotic, sterile, nonpyrogenic solution (Centers for Disease Control and Prevention, 2009).
    C) ZANAMIVIR is a white to off-white powder with a solubility of approximately 18 mg/mL in water at 20 degrees C (Prod Info RELENZA(R) oral inhalation powder, 2008).

Molecular Weight

    A) OSELTAMIVIR (FREE BASE): 312.4; OSELTAMIVIR PHOSPHATE: 410.4 (Prod Info TAMIFLU(R) oral capsules, suspension, 2008)
    B) PERAMIVIR: 382.45 (Centers for Disease Control and Prevention, 2009)
    C) ZANAMIVIR: 332.3 (Prod Info RELENZA(R) oral inhalation powder, 2008)

References

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