Zanamivir

Treatment emergent resistance is rare with zanamivir. Selection of influenza resistant viruses is more likely to occur following treatment with antiviral medicinal products in immunocompromised patients, including treatment with Dectova; it is, therefore, important to monitor for resistance and consider switching to alternative therapies where appropriate.

IV administration

Adults and children (aged 6 years and over with a body weight of 50 kg or above) with creatinine clearance (CLcr) or clearance by continual renal replacement therapy (CL_CRRT) <80 mL/min should receive an initial 600 mg dose followed by twice-daily maintenance dosing according to their renal function (Table 1).

Table 1. Initial and maintenance dose regimens for adults and children (6 years and over with a body weight of 50 kg or above) with renal impairment:

^* CL_cr or CL_CRRT units in mL/min for adolescents 13 years to less than 18 years, or in mL/min/1.73m² for children 6 years to less than 13 years.

Children and adolescents (6 years to less than 18 years with a body weight less than 50 kg), and infants and children (6 months to less than 6 years) with creatinine clearance (CL_cr) or clearance by continual renal replacement therapy (CL_CRRT) <80 mL/min should receive an initial dose followed by an appropriate twice-daily maintenance dose as shown in Tables 2, 3 and 4.

Table 2. Initial and maintenance dose regimens for children and adolescents (6 years to less than 18 years, with a body weight less than 50 kg) with renal impairment:

^* CL_cr or CL_CRRT units in mL/min for adolescents 13 years to less than 18 years, or in mL/min/1.73m² for children 6 years to less than 13 years.

Table 3. Initial and maintenance dose regimens for infants and children (6 months to less than 6 years, with a body weight of 42.8 kg or above) with renal impairment:

Table 4. Initial and maintenance dose regimens for infants and children (6 months to less than 6 years, with a body weight less than 42.8 kg) with renal impairment:

For patients on intermittent haemodialysis or intermittent peritoneal dialysis, the dose should be given after completion of the dialysis session.

For patients receiving continuous renal replacement therapy, the dose should be selected using the appropriate CRRT clearance (CL_CRRT in mL/min).

Due to the limited experience, patients with severe asthma require a careful consideration of the risk in relation to the expected benefit, and zanamivir should not be administered unless close medical monitoring and appropriate clinical facilities are available in case of bronchoconstriction. In patients with persistent asthma or severe COPD, management of the underlying disease should be optimised during therapy with zanamivir.

Should zanamivir be considered appropriate for patients with asthma or chronic obstructive pulmonary disease, the patient should be informed of the potential risk of bronchospasm with zanamivir and should have a fast acting bronchodilator available. Patients on maintenance inhaled bronchodilating therapy should be advised to use their bronchodilators before taking zanamivir.

Oral inhalation

Systemic exposure to zanamivir is low following administration by inhalation; however, there is no information on placental transfer of zanamivir in humans. There is a limited amount of data (less than 300 pregnancy outcomes) from the use of zanamivir in pregnant women. Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity.

As a precautionary measure, it is preferable to avoid the use of zanamivir during pregnancy, unless the clinical condition of the woman is such that the potential benefit to the mother significantly outweighs the possible risk to the foetus.

IV administration

There are limited data from the use of zanamivir in pregnant women. Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity.

Reproductive studies performed in rats and rabbits indicated that placental transfer of zanamivir occurs and there was no evidence of teratogenicity. Results from a rat peri- and post-natal study showed no clinically meaningful impairment of offspring development. However, there is no information on placental transfer in humans.

As experience is limited, the use of zanamivir in pregnancy should only be considered if the possible benefit to the patient is thought to outweigh any possible risk to the foetus.

Oral inhalation

Systemic exposure to zanamivir is low following administration by inhalation; however, there is no information on secretion of zanamivir into human breast milk. A risk to the breastfed child cannot be excluded. A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from zanamivir therapy, taking into account the benefit of breast feeding for the child and the benefit of therapy for the woman.

IV administration

It is unknown whether zanamivir is excreted in human milk. In rats, zanamivir has been shown to be secreted in low amounts into milk.

As experience is limited, the use of zanamivir in breast-feeding mothers should be considered only if the possible benefit to the mother is thought to outweigh any possible risk to the child.

Fertility

Animal studies indicate no clinically meaningful effects of zanamivir on male or female fertility.

Zanamivir has no or negligible influence on the ability to drive and use machines.

Oral inhalation

There have been rare reports of patients with previous history of respiratory disease (asthma, COPD) and very rare reports of patients without previous history of respiratory disease, who have experienced acute bronchospasm and/or serious decline in respiratory function after use of zanamivir.

The adverse events considered at least possibly related to the treatment are listed below by body system, organ class and absolute frequency. Frequencies are defined as very common (≥1/10), common (≥1/100, <1/10), uncommon (≥1/1000, <1/100), rare (≥1/10,000, <1/1000), very rare (<1/10,000), not known (cannot be estimated from the available data).

Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

Immune system disorders

Uncommon: allergic-type reactions including oropharyngeal oedema

Rare: anaphylactic/anaphylactoid reactions, facial oedema

Nervous systems disorders

Uncommon: vasovagal-like reactions have been reported in patients with influenza symptoms, such as fever and dehydration, shortly following inhalation of zanamivir.

Respiratory, thoracic and mediastinal disorders

Uncommon: bronchospasm, dyspnoea, throat tightness or constriction

Skin and subcutaneous tissue disorders

Common: rash

Uncommon: urticaria

Rare: severe skin reactions including Erythema Multiforme, Stevens-Johnson syndrome and Toxic epidermal necrolysis

Psychiatric and nervous system disorders

Convulsions and psychiatric events such as depressed level of consciousness, abnormal behaviour, hallucinations and delirium have been reported during zanamivir administration in patients with influenza. The symptoms were mainly reported in children and adolescents. Convulsions and psychiatric symptoms have also been reported in patients with influenza not taking zanamivir.

IV administration

Summary of the safety profile

The safety profile of zanamivir is based primarily on data from a single Phase II and a single Phase III study, with support from Phase I studies, a compassionate use programme, and adverse drug reactions reported for inhaled zanamivir. The frequency of adverse reactions is based on the number of reports in the adult population receiving zanamivir 600 mg twice daily intravenously in the Phase II and Phase III studies. Adverse reactions are listed by MedDRA system organ class.

The most commonly reported adverse reactions considered possibly or probably related to zanamivir are alanine aminotransferase increased (2%), aspartate aminotransferase increased (1%), hepatocellular injury (1%), diarrhoea (1%) and rash (1%). The most important serious adverse reaction was hepatocellular injury, observed in two patients (<1%).

Tabulated list of adverse reactions

The frequency of adverse reactions is defined using the following convention: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000) and not known (cannot be estimated from available data).

Paediatric population

The adverse reaction profile in the paediatric population is based on 71 patients aged ≥6 months to <18 years in the Phase II study. Overall, the safety profile in paediatric patients was similar to that observed in adults in the clinical studies.