Zanamivir

In randomized controlled trials, 2% to 3% of zanamivir recipients developed ALT or AST elevations above twice the upper limit of the normal range, but a similar rate was found in placebo-treated patients. Despite widespread use, there is little evidence that zanamivir when used by inhalation causes liver injury, either in the form of asymptomatic serum enzyme elevations or clinically apparent liver disease. In pilot studies of intravenous zanamivir for severe influenza, serum enzyme elevations have been reported in ~10% of patients, occasionally with jaundice, but the role of zanamivir versus the underlying severe viral infection has not been defined.

/SIGNS AND SYMPTOMS/ Bronchospasm and decline in lung function have been reported in some patients receiving relenza. Many but not all of these patients had underlying airways disease such as asthma or chronic obstructive pulmonary disease. Because of the risk of serious adverse events and because efficacy has not been demonstrated in this population, /zanamivir/ is not generally recommend for treatment of patients with underlying airways disease. Some patients with serious adverse events during treatment with /zanamivir/ have had fatal outcomes, although causality was difficult to assess. /Zanamivir/ should be discontinued in any patient who develops bronchospasm or decline in respratory function; immediate treatment and hospitalization may be required. Some patients without prior pulmonary disease may also have respiratory abnormalities from acute respiratory infection that could resemble adverse drug reactions or increase patient vulnerability to adverse drug reactions.

Drug-Induced Liver Injury Severity and Toxicity (DILIst)

Zanamivir

DILI Negative

Oral; Respiratory (inhalation)

DOI:10.1016/j.drudis.2019.09.022

/LABORATORY ANIMALS: Chronic Exposure or Carcinogenicity/ In 2-year carcinogenicity studies conducted in rats and mice using a powder formulation administered through inhalation, zanamivir induced no statistically significant increases in tumors over controls. The maximum daily exposures in rats and mice were approximately 23 to 25 and 20 to 22 times, respectively, greater than those in humans at the proposed clinical dose based on AUC comparisons.

/LABORATORY ANIMALS: Chronic Exposure or Carcinogenicity/ An increase in lymphoma incidence over controls was seen male rats given a high dose (30 to 50 mg/kg/day); there was no dose relationship.

/LABORATORY ANIMALS: Developmental or Reproductive Toxicity/ Embryo/fetal development studies were conducted in rats (dosed from days 6 to 15 of pregnancy) and rabbits (dosed from days 7 to 19 of pregnancy) using the same IV doses. Pre- and post-natal developmental studies were performed in rats (dosed from day 16 of pregnancy until litter day 21 to 23). In all studies, intravenous (1, 9, and 90 mg/kg/day) instead of the inhalational route of drug administration was used. No malformations, maternal toxicity, or embryotoxicity were observed in pregnant rats or rabbits and their fetuses. Because of insufficient blood sampling timepoints in both rat and rabbit reproductive toxicity studies, AUC values were not available. However, in a subchronic study in rats at the 90-mg/kg/day IV dose, the AUC values were greater than 300 times the human exposure at the proposed clinical dose.

/LABORATORY ANIMALS: Developmental or Reproductive Toxicity/ An additional embryo/fetal study, in a different strain of rat, was conducted using subcutaneous administration of zanamivir, 3 times daily, at doses of 1, 9, or 80 mg/kg during days 7 to 17 of pregnancy. There was an increase in the incidence rates of a variety of minor skeleton alterations and variants in the exposed offspring in this study. Based on AUC measurements, the high dose in the study produced an exposure greater than 1,000 times the human exposure at the proposed clinical dose. However, the individual incidence rate of each skeletal alteration or variant, in most instances, remained within the background rates of the historical occurrence in the strain studied.

/GENOTOXICITY/ Zanamivir was not mutagenic in in vitro and in vivo genotoxicity assays which included bacterial mutation assays in S. typhimurium and E. coli , mammalian mutation assays in mouse lymphoma, chromosomal aberration assays in human peripheral blood lymphocytes, and the in vivo mouse bone marrow micronucleus assay.

Bronchospasm and decline in lung function have been reported in some patients receiving relenza. Many but not all of these patients had underlying airways disease such as asthma or chronic obstructive pulmonary disease. Because of the risk of serious adverse events and because efficacy has not been demonstrated in this population, /zanamivir/ is not generally recommend for treatment of patients with underlying airways disease.

While data specific to zanamivir were not located(SRC, 2006), the literature suggests that some pharmaceutically active compounds originating from human and veterinary therapy are not eliminated completely in municipal sewage treatment plants and are therefore discharged into receiving waters(1). Wastewater treatment processes often were not designed to remove them from the effluent(2). Selected organic waste compounds may be degrading to new and more persistent compounds that may be released instead of or in addition to the parent compound(2). Studies have indicated that several polar pharmaceutically active compounds can leach through subsoils into aquifers(1).

/SRP:/ Basic treatment: Establish a patent airway. Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if needed. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Monitor for pulmonary edema and treat if necessary ... . Monitor for shock and treat if necessary ... . Anticipate seizures and treat if necessary ... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with normal saline during transport ... . Do not use emetics. For ingestion, rinse mouth and administer 5 ml/kg up to 200 ml of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool ... . Cover skin burns with dry sterile dressings after decontamination ... . /Poison A and B/

/SRP:/ Advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who is unconscious, has severe pulmonary edema, or is in respiratory arrest. Positive pressure ventilation techniques with a bag valve mask device may be beneficial. Monitor cardiac rhythm and treat arrhythmias as necessary ... . Start an IV with D5W /SRP: "To keep open", minimal flow rate/. Use lactated Ringer's if signs of hypovolemia are present. Watch for signs of fluid overload. Consider drug therapy for pulmonary edema ... . For hypotension with signs of hypovolemia, administer fluid cautiously. Watch for signs of fluid overload ... . Treat seizures with diazepam (Valium) ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Poison A and B/

Agents used in the prophylaxis or therapy of VIRUS DISEASES. Some of the ways they may act include preventing viral replication by inhibiting viral DNA polymerase; binding to specific cell-surface receptors and inhibiting viral penetration or uncoating; inhibiting viral protein synthesis; or blocking late stages of virus assembly.

Compounds or agents that combine with an enzyme in such a manner as to prevent the normal substrate-enzyme combination and the catalytic reaction.

Absolute bioavailability is very low following oral administration (2%). Following oral inhalation, bioavailability is 4% to 17%.

It is excreted unchanged in the urine with excretion of a single dose completed within 24 hours. Unabsorbed drug is excreted in the feces.Zanamivir is renally excreted as unchanged drug.

2.5 - 10.9 L/h [Following oral inhalation 10 mg]

Protein binding: Very low (<10%).

Orally inhaled zanamivir is systemically absorbed, approximately 4% to 17%.

Elimination: Renal: Excreted unchanged in the urine with excretion of a single dose completed within 24 hours. Total clearance ranges from 2.5 to 10.9 L/hr. Fecal: Unabsorbed drug is secreted in the feces.