DECTOVA 10 MG / ML SOLUTION FOR INFUSION - summary of medicine characteristics

This medicinal product is subject to additional monitoring. This will allow quick identification of new safety information. Healthcare professionals are asked to report any suspected adverse reactions. See section 4.8 for how to report adverse reactions.

Dectova 10 mg/mL solution for infusion

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each mL of solution contains 10 mg of zanamivir (as hydrate).

Each vial contains 200 mg of zanamivir (as hydrate) in 20 mL.

Excipients with known effect

Each vial contains 3.08 mmol (70.8 mg) sodium.

For the full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM

Solution for infusion

A clear, colourless solution for infusion.

4 CLINICAL PARTICULARS

4.1 Therapeutic indications

Dectova is indicated for the treatment of complicated and potentially life-threatening influenza A or B virus infection in adult and paediatric patients (aged >6 months) when:

The patient’s influenza virus is known or suspected to be resistant to antiinfluenza medicinal products other than zanamivir, and/or

Other anti-viral medicinal products for treatment of influenza, including inhaled zanamivir, are not suitable for the individual patient.

Dectova should be used in accordance with official guidance.

4.2 Posology and method of administration

Posology

Treatment with Dectova should commence as soon as possible and usually within 6 days of the onset of symptoms of influenza (see section 5.1).

Adults

The recommended dose is 600 mg twice daily for 5 to 10 days given by intravenous infusion.

Paediatric population

Adolescents, children and infants should receive a weight-based dose regimen for 5 to 10 days (Table 1).

Table 1: Weight-based dose regimen by age for infants, children and adolescents with normal renal function

The safety and efficacy of Dectova in children aged under 6 months have not been established. No data are available.

Elderly

No dose adjustment is required based on age.

Renal impairment

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 (CLCRRT) < 80 mL/min should receive an initial 600 mg dose followed by twice-daily maintenance dosing according to their renal function (Table 2).

Table 2: 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

*CLcr or CLCRRT 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 (CLcr) or clearance by continual renal replacement therapy (CLCRRT) <80 mL/min should receive an initial dose followed by an appropriate twice-daily maintenance dose as shown in Tables 3, 4 and 5.

Table 3: 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

*CLcr or CLCRRT 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 4: 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 5: 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 (CLCRRT in mL/min).

Hepatic impairment

No dose modification is required (see section 5.2).

Method of administration

Intravenous use

Dectova is administered by intravenous infusion over 30 minutes.

For instructions on dilution of the medicinal product before administration, see section 6.6.

4.3 Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

4.4 Special warnings and precautions for use

Renal impairment

Zanamivir is eliminated by renal clearance, therefore the dose of Dectova when administered intravenously must be reduced in patients with renal impairment (see section 4.2). All patients must have their renal function assessed before and regularly during treatment.

Serious hypersensitivity reactions

Anaphylactic reactions and serious skin reactions (including erythema multiforme, toxic epidermal necrolysis and Stevens-Johnson syndrome) have been reported with zanamivir (see section 4.8). If any hypersensitivity reaction occurs during infusion of Dectova, the infusion must be stopped immediately and appropriate management should be instituted.

Neuropsychiatric events

Influenza can be associated with a variety of neurological and behavioural symptoms. Neuropsychiatric events, including seizures, delirium, hallucination and abnormal behaviour, have been reported during administration of zanamivir in patients with influenza, especially in children and adolescents. Therefore, patients should be closely monitored for behavioural changes and the benefits and risks of continuing treatment should be carefully evaluated for each patient (see section 4.8).

Resistance in immunocompromised patients

Treatment emergent resistance is rare with zanamivir (see section 5.1). 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.

Limitations of the clinical data

The efficacy of Dectova for the treatment of complicated influenza A or B virus infection in adults and children aged from 6 months has been inferred from:

the in vitro activity of zanamivir;

clinical and virological activity of zanamivir compared to placebo in a human influenza challenge study;

levels of zanamivir in broncho-epithelial lining fluid and serum zanamivir from a broncho-alveolar lavage study;

serum zanamivir levels from patients with complicated influenza (see section 5.1).

Risk of bacterial infections

Dectova has not been shown to reduce the risk of bacterial complications associated with influenza infection.

Excipients

This medicinal product contains 70.8 mg sodium per vial, equivalent to 3.54% of the WHO recommended maximum daily intake of 2 g sodium for an adult.

4.5 Interaction with other medicinal products and other forms of interaction

The potential for interactions with other medicines is low, based on the known elimination pathway of zanamivir.

Zanamivir is not a substrate, inhibitor or inducer of cytochrome P450 isoenzymes nor a substrate or inhibitor of renal and hepatic transporters at clinically relevant concentrations (see section 5.2).

There was no evidence of interaction with oral oseltamivir in a clinical study.

4.6 Fertility, pregnancy and lactation

Pregnancy

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 (see section 5.3).

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 postnatal 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 Dectova in pregnancy should only be considered if the possible benefit to the patient is thought to outweigh any possible risk to the foetus.

Breast-feeding

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.

4.7 Effects on ability to drive and use machines

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

4.8 Undesirable effects

Summary of the safety profile

The safety profile of Dectova 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 Dectova 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.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows

continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked

to report any suspected adverse reactions via the Yellow Card Scheme Website: http://www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9 Overdose

There is limited experience of overdose from administration of Dectova. There is no specific antidote to treat an overdose of this medicine. Treatment of an overdose should consist of general supportive measures including monitoring of vital signs and observation of the clinical status of the patient. Zanamivir is cleared by renal excretion and is expected to be removed by haemodialysis.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Antivirals for systemic use, neuraminidase inhibitors ATC code: J05AH01

Mechanism of action

Zanamivir is an inhibitor of influenza virus neuraminidase, an enzyme that releases viral particles from the plasma membrane of infected cells and promotes virus spread in the respiratory tract.

In vitro activity

Neuraminidase inhibition occurred at very low zanamivir concentrations in vitro, with median inhibitory (IC50) values of 0.33 nM to 5.77 nM against influenza A and B strains respectively.

Resistance

Resistance selection during zanamivir treatment is rare. Reduced susceptibility to zanamivir is associated with mutations that result in amino acid changes in the viral neuraminidase or viral hemagglutinin or both. Neuraminidase substitutions conferring reduced susceptibility to zanamivir have emerged during treatment with zanamivir in human viruses and those with zoonotic potential: E119D, E119G, I223R, R368G, G370D, N434S (A/H1N1); N294S, T325I (A/H3N2); R150K (B); R292K (A/H7N9). The neuraminidase substitution Q136K (A/H1N1 and A/H3N2), confers high level resistance to zanamivir but is selected during adaptation to cell culture and not during treatment.

The clinical impact of reduced susceptibility in these viruses is unknown, and the effects of specific substitutions on virus susceptibility to zanamivir may be straindependent.

Cross-resistance

Cross-resistance between zanamivir and oseltamivir or peramivir has been observed in neuraminidase inhibition assays. A number of neuraminidase amino acid substitutions that arise during oseltamivir or peramivir treatment result in reduced susceptibility to zanamivir. The clinical impact of substitutions associated with reduced susceptibility to zanamivir and other neuraminidase inhibitors is variable and may be strain-dependent.

The H275Y substitution is the most common neuraminidase resistance substitution and is associated with reduced susceptibility to peramivir and oseltamivir. This substitution has no effect on zanamivir; therefore, viruses with the H275Y substitution retain full susceptibility to zanamivir.

Clinical efficacy

Human challenge study

A double-blind, randomised study to examine the prophylactic antiviral activity and efficacy of repeat dose zanamivir 600 mg every 12 hours intravenously compared to placebo in healthy male volunteers against infection from inoculation with influenza A/Texas/91 (H1N1) virus was conducted. Zanamivir had a significant prophylactic effect against an experimental challenge with influenza A virus as demonstrated by the low infection rate (14% vs. 100% positive serology in placebo group, p <0.005), isolation of virus by viral culture (0% vs. 100% in placebo group, p <0.005), as well as reductions in fever (14% vs. 88% in placebo group, p <0.05), upper respiratory tract illness (0% versus 100% in placebo group, p<0.005) and total symptom scores (1 vs. 44 median score in placebo group, p<0.001).

Bronchoalveolar lavage study

A Phase I, open-label study to evaluate serum and lower respiratory pharmacokinetics following administration of intravenous and inhaled zanamivir to healthy adult subjects utilising bronchoalveolar lavage fluid was conducted. The 600 mg dose given intravenously best approximated epithelial lining fluid concentrations achieved by the approved 10 mg dose of zanamivir inhalation powder which demonstrated efficacy in large clinical studies in uncomplicated influenza.

Phase III study in patients with complicated influenza

A Phase III, double-blind, study was conducted to evaluate the efficacy, antiviral activity and safety of zanamivir 600 mg twice daily intravenously compared to oral oseltamivir 75 mg twice daily and 300 mg zanamivir twice daily intravenously in hospitalised patients (>16 years of age) with influenza. The median patient age was 57 years and 35% (218/615) of patients were >65 years, of which 17% (n=103) were 65 to <75; 14% (n=84) were 75 to <85, and 5% (n=31) were >85 years of age. Patients were stratified at randomisation based on time from onset of symptoms to initiation of treatment (<4 days and 5 to 6 days). Eligible patients were not to have had >3 days of prior antiviral treatment. The initial 5 day treatment course could be extended for up to 5 additional days if clinical symptoms or patient characteristics warranted further treatment. The primary endpoint was time to clinical response (TTCR); clinical response was defined as a composite of vital sign stabilisation (temperature, oxygen saturation, respiratory status, heart rate and systolic blood pressure) or hospital discharge. The primary analysis was performed on the Influenza Positive Population (IPP) comprised of 488 patients. The study did not meet its prespecified primary objective of demonstrating superiority of 600 mg zanamivir to oral oseltamivir or to 300 mg zanamivir in TTCR. There were no significant differences in TTCR across treatment comparisons in the overall IPP or in two pre-specified subgroups (Table 6).

Table 6: Statistical comparisons of TTCR between the 600 mg zanamivir group and each other group (IPP)

This medicinal product has been authorised under ‘exceptional circumstances’.

This means that for scientific reasons it has not been possible to obtain complete information on this medicinal product.

The European Medicines Agency will review any new information which may become available every year and this SmPC will be updated as necessary.

Paediatric population

The European Medicines Agency has deferred the obligation to submit the results of studies with Dectova in one or more subsets of the paediatric population in the treatment and prevention of influenza (see section 4.2 for information on paediatric use)

5.2 Pharmacokinetic properties

The serum pharmacokinetics of zanamivir administered intravenously have been studied in healthy volunteers receiving single escalating doses from 1 to 1200 mg and repeated doses of 600 mg twice daily for 5 days. Hospitalised patients with influenza also have received 300 mg or 600 mg twice daily for 5 to 10 days.

Dose proportionality was observed in zanamivir Cmax and AUC and no accumulation of zanamivir in serum was evident after repeated intravenous doses of up to 600 mg.

Distribution

The plasma protein binding of zanamivir is very low (less than 10%). The volume of distribution of zanamivir in adults is approximately 16 litres, which approximates the volume of extracellular wa­ter.

Following twice-daily administration of zanamivir solution for infusion, pulmonary epithelial lining fluid concentrations were 60 – 65 % of the serum concentrations at the corresponding sampling time 12 hours after dosing. Following twice daily administration of 600 mg zanamivir solution for infusion, median trough zanamivir epithelial lining fluid concentrations ranged from 419 ng/mL to 584 ng/mL and were 47–66% of those in the initial bronchoalveolar sample following orally zanamivir inhalation powder 10 mg twice daily.

Biotransformation

There is no evidence that zanamivir is metabolised.

Elimination

Zanamivir is eliminated unchanged in urine by glomerular filtration. In adults with normal renal function, the elimination half-life is approximately 2–3 hours.

Elderly

The pharmacokinetics in elderly subjects was similar to young adult subjects. In the population pharmacokinetic analysis, age had no significant effect on the pharmacokinetics of zanamivir.

Paediatric population

The pharmacokinetics of zanamivir following a twice daily intravenous dose of 14 mg/kg for paediatric patients between 6 months and <6 years and 12 mg/kg for those between 6 years and <18 years of age were similar to those seen in adults who received 600 mg twice daily intravenously. The pharmacokinetics of zanamivir in subjects 6 months to <18 years of age (administered standard dose of 12 mg/kg, 14 mg/kg or 600 mg according to age and body weight) and in adult subjects (administered standard dose of 600 mg) was similar (Table 7).

Table 7: Pharmacokinetic parameters in paediatric and adult subjects

%CV = percent coefficient of variation, GM = Geometric Mean, NA = Not available

Renal impairment

The serum half-life of zanamivir increases to approximately 12–20 hours in patients with severe renal impairment (creatinine clearance < 30 mL/min). Dectova has not been studied in patients with end-stage renal disease.

There are limited data on zanamivir exposure during concomitant continuous renal replacement therapy and very limited data with dialysis.

Hepatic impairment

Zanamivir is not metabolised, therefore no effect of hepatic impairment is expected.

Race

Pharmacokinetic studies in Thai, Chinese and Japanese healthy subjects did not identify any clinically relevant differences in the pharmacokinetics of zanamivir in these populations compared with Caucasians.

Drug interactions

In vitro studies indicate that zanamivir is not an inhibitor or substrate of Breast Cancer Resistant Protein (BCRP), P-glycoprotein, Multidrug And Toxin Extrusion protein (MATE)1, MATE2-K, Organic Anion Transporter (OAT)1, OAT3, Organic Anion Transporting Polypeptide (OATP)1B1, OATP1B3 and Organic Cation Transporter (OCT)2 transporters, nor is it an inhibitor of cytochrome P450 (CYP) enzymes CYP1A2, 2B6, 2C8, 2C9, 2C19, 2D6 and 3A4.

Zanamivir is not an inducer of CYP1A2 and 2B6 and, although induction of CYP3A4 in vitro was observed at 50-fold higher than the clinically relevant concentrations, no interaction with CYP3A4 substrates is expected based on physiologically based pharmacokinetic modelling.

5.3 Preclinical safety data

Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential, or toxicity to reproduction and development, with the exception of a rat embryofoetal development study (subcutaneous administration). In the rat embryofoetal study, there was an increase in the incidence rates of a variety of minor skeletal and visceral alterations, most of which remained within the background rates of the historical occurrence in the strain studied.

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Sodium chloride

Water for injections

6.2 Incompatibilities

Dectova must not be mixed with other medicinal products except those mentioned in section 6.6.

Dectova should not be administered simultaneously with other intravenous medicinal products or prepared in solutions containing glucose or other electrolytes (see section 6.6).

6.3 Shelf life

Unopened vials

5 years.

After dilution

From a microbiological point of view, the product should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and should not be longer than 24 hours at 2°C to 8°C, unless dilution has taken place in controlled and validated aseptic conditions.

6.4 Special precautions for storage

This medicinal product does not require any special storage conditions.

For storage conditions after dilution of the medicinal product, see section 6.3.

6.5 Nature and contents of container

26 mL clear vial (type I glass) with a stopper (coated chlorobutyl rubber), an overseal (aluminium) and a plastic flip-off cap.

Pack size: 1 vial.