XOFLUZA 40mg film-coated tablets medication leaflet

Xofluza 20 mg film-coated tablets

Xofluza 40 mg film-coated tablets

Xofluza 80 mg film-coated tablets

Each tablet contains 20 mg baloxavir marboxil.

Each tablet contains 77.9 mg lactose monohydrate.

For the full list of excipients, see section 6.1.

Each tablet contains 40 mg baloxavir marboxil.

Each tablet contains 155.8 mg lactose monohydrate.

For the full list of excipients, see section 6.1.

Each tablet contains 80 mg baloxavir marboxil.

Each tablet contains 311.6 mg lactose monohydrate.

For the full list of excipients, see section 6.1.

White to light yellow, oblong shaped film-coated tablets approximately 8.6 mm in length, debossedwith “ 772” on one side and “20” on the other side.

White to light yellow, oblong shaped film-coated tablets approximately 11.1 mm in length, debossedon one side with “BXM40”.

White to light yellow, oblong shaped film-coated tablets approximately 16.1 mm in length, debossedon one side with “BXM80”.

Treatment of influenza

Xofluza is indicated for the treatment of uncomplicated influenza in patients aged 1 year and above.

Post-exposure prophylaxis of influenza

Xofluza is indicated for post-exposure prophylaxis of influenza in individuals aged 1 year and above.

Xofluza should be used in accordance with official recommendations.

Treatment of influenza

A single dose of baloxavir marboxil should be taken as soon as possible within 48 hours of symptom(s)onset.

Post-exposure prophylaxis of influenza

A single dose of baloxavir marboxil should be taken as soon as possible within 48 hours following closecontact with an individual known or suspected to have influenza (see section 5.1).

Adults, adolescents, children and infants (≥ 1 year of age)

The recommended single oral dose of baloxavir marboxil is determined by body weight (see Table 1).

Adults, adolescents and children who are unable to, or experience difficulty swallowing tablets, orthose who require enteral administration may instead receive treatment with Xofluza granules for oralsuspension. Refer to the Xofluza granules for oral suspension prescribing information.

Table 1. Baloxavir marboxil dosing by patient body weight (≥ 1 year of age)

Patient body weight Recommended oral dose< 20 kg refer to the Xofluza granules for oralsuspension prescribing information.

≥ 20 kg - < 80 kg Single dose of 40 mg taken as1 x 40 mg tablet

OR2 x 20 mg tablets≥ 80 kg Single dose of 80 mg taken as1 x 80 mg tablet

OR2 x 40 mg tablets

There are no clinical data on the use of a repeat dose of baloxavir marboxil for the treatment ofuncomplicated influenza or for post-exposure prophylaxis in any one influenza season.

No dosage adjustment is required (see section 5.2).

No dose adjustment is required for patients with mild or moderate hepatic impairment (Child-Pughclass A or B). The safety and efficacy of baloxavir marboxil has not been established in patients withsevere hepatic impairment (Child-Pugh class C).

No dose adjustment is required in patients with renal impairment (see section 5.2).

The safety and efficacy of baloxavir marboxil in children aged < 1 year has not been established. Nodata are available.

Oral use. The tablets should be taken with water.

Xofluza may be taken with or without food (see section 5.2).

Xofluza should not be taken with products that contain polyvalent cations such as laxatives, antacidsor oral supplements containing iron, zinc, selenium, calcium or magnesium (see section 4.5).

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

Xofluza contains lactose. Patients with rare hereditary problems of galactose intolerance, total lactasedeficiency or glucose-galactose malabsorption should not take this medicine.

This medicine contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially 'sodium-free’.

Effects of other medicinal products on baloxavir marboxil or its active metabolite baloxavir

Products that contain polyvalent cations may decrease plasma concentrations of baloxavir. Xofluzashould not be taken with products that contain polyvalent cations such as laxatives, antacids or oralsupplements containing iron, zinc, selenium, calcium or magnesium.

Immune response to influenza virus

Interaction studies with influenza vaccines and baloxavir marboxil have not been conducted. In studiesof naturally acquired and experimental influenza, treatment with Xofluza did not impair the humoralantibody response to influenza infection.

Interaction studies have only been performed in adults.

There are no or limited data from the use of baloxavir marboxil in pregnant women.

Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity(see section 5.3).

As a precautionary measure, it is preferable to avoid the use of Xofluza during pregnancy.

It is unknown whether baloxavir marboxil or baloxavir are excreted in human milk. Baloxavirmarboxil and its metabolites are secreted in the milk of lactating rats.

A risk to the newborns/infants cannot be excluded.

A decision must be made whether to discontinue breast-feeding or to abstain from Xofluza therapytaking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman.

No effects on male or female fertility were observed in animal studies performed with baloxavirmarboxil (see section 5.3).

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

Hypersensitivity reactions have been observed in the postmarketing setting which include reports ofanaphylaxis/anaphylactic reactions and less severe forms of hypersensitivity reactions includingurticaria and angioedema. Of these adverse reactions only urticaria has been observed in clinicalstudies with an estimated frequency category of “uncommon”.

The following adverse drug reactions have been identified from postmarketing experience withbaloxavir marboxil (Table 2) based on spontaneous case reports and cases from non-interventionalstudy programmes. Adverse drug reactions are listed according to system organ classes in

MedDRA and the corresponding frequency category estimation for each adverse drug reaction isbased on 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 beestimated from the available data).

Table 2. Adverse drug reactions from postmarketing experience in adults, adolescents andpaediatric patients

System organ class (SOC) Adverse reaction Frequency(preferred term, MedDRA)

Immune system disorders Anaphylaxis Not known

Anaphylactic reactions Not known

Hypersensitivity Not known

Skin and subcutaneous disorders Urticaria* Uncommon

Angioedema Not known

*The frequency for urticaria is based on clinical trial data from studies in adults and adolescents. The other PTs listed above were not reported in clinical studies.

The safety profile of baloxavir marboxil in paediatric patients (1 to <12 years) was determined fromdata collected from treatment and post exposure prophylaxis studies. Table 3 presents adverse drugreactions identified from clinical trial experience.

Anaphylactic reaction, anaphylaxis, urticaria and angioedema (face, eyelid and lip swelling) have beenreported postmarketing in the paediatric population (see Table 2).

Table 3. Adverse drug reactions in children from clinical trial experience

System organ class (SOC) Adverse reaction Frequency(preferred term, MedDRA)

Gastrointestinal disorders Diarrhoea Common

Vomiting Common

Skin and subcutaneous disorders Rash Common

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

Reports of overdoses with baloxavir marboxil have been received from clinical trials and duringpostmarketing experience. In the majority of cases reporting overdose, no adverse reactions werereported. Data are insufficient to determine what symptoms may be anticipated as a result of anoverdose.

No known specific antidote exists for Xofluza. In the event of overdose, standard supportive medicalcare should be initiated based on the patient’s signs and symptoms.

Baloxavir is unlikely to be significantly removed by dialysis due to high serum protein binding.

Pharmacotherapeutic group: Antivirals for systemic use, other anti-virals. ATC code: J05AX25.

Baloxavir marboxil is a prodrug that is converted by hydrolysis to baloxavir, the active form thatexerts anti-influenza activity. Baloxavir acts on the cap-dependent endonuclease (CEN), an influenzavirus-specific enzyme in the polymerase acidic (PA) subunit of the viral RNA polymerase complexand thereby inhibits the transcription of influenza virus genomes resulting in inhibition of influenzavirus replication.

In vitro activity

The 50 % inhibition concentration (IC50) of baloxavir was 1.4 to 3.1 nmol/L for influenza A virusesand 4.5 to 8.9 nmol/L for influenza B viruses in an enzyme inhibition assay.

In a MDCK cell culture assay, the median 50 % effective concentration (EC50) values of baloxavirwere 0.73 nmol/L (n=31; range: 0.20-1.85 nmol/L) for subtype A/H1N1 strains, 0.83 nmol/L (n=33;range: 0.35-2.63 nmol/L) for subtype A/H3N2 strains, and 5.97 nmol/L (n=30; range:2.67-14.23 nmol/L) for type B strains.

In a MDCK cell-based virus titre reduction assay, the 90 % effective concentration (EC90) values ofbaloxavir were in the range of 0.46 to 0.98 nmol/L for subtype A/H1N1 and A/H3N2 viruses, 0.80 to3.16 nmol/L for avian subtype A/H5N1 and A/H7N9 viruses, and 2.21 to 6.48 nmol/L for type Bviruses.

Viruses bearing the PA/I38T/F/M/N/S mutation selected in vitro or in clinical studies show reducedsusceptibility to baloxavir with changes in EC50 values ranging from 11 to 57-fold for influenza Aviruses and 2 to 8-fold for influenza B viruses.

In the three phase 3 studies of treatment of uncomplicated influenza (see below) no resistance tobaloxavir was detected in baseline isolates. In the two adult and adolescent studies, treatment-emergent mutations PA/I38T/M/N were detected in 36/370 (9.7 %) and in 15/290 (5.2 %) patientstreated with baloxavir marboxil but were not detected in any patients treated with placebo.

In the phase 3 study in paediatric patients, treatment-emergent mutations, PA/I38T/M/S were found in11 of 57 (19.3 %) influenza-infected subjects in the baloxavir marboxil treatment group.

In the phase 3 study of post-exposure prophylaxis (see below), PA/I38T/M were found in 10 of 374(2.7 %) baloxavir marboxil-treated subjects. PA/I38 substitutions were not detected in placebo-treatedsubjects, with the exception of 2 subjects who received baloxavir marboxil as rescue medication.

Baloxavir is active in vitro against influenza viruses that are considered resistant to neuraminidaseinhibitors, including strains with the following mutations: H274Y in A/H1N1, E119V and R292K in

A/H3N2, R152K and D198E in type B virus, H274Y in A/H5N1, R292K in A/H7N9.

Treatment of uncomplicated influenza

Adult and adolescent patients

Capstone 1 (1601T0831), was a phase 3 randomised, double-blind, multicentre study conducted in

Japan and the US to evaluate the efficacy and safety of a single oral tablet dose of baloxavir marboxilcompared with placebo and with oseltamivir in healthy adult and adolescent patients (aged ≥ 12 yearsto ≤ 64 years) with uncomplicated influenza. Patients were randomised to receive baloxavir marboxil(patients who weighed 40 to < 80 kg received 40 mg and patients who weighed ≥ 80 kg received80 mg), oseltamivir 75 mg twice daily for 5 days (only if aged ≥ 20 years) or placebo. Dosingoccurred within 48 hours of first onset of symptoms.

A total of 1436 patients (of which 118 were aged ≥ 12 years to ≤ 17 years) were enrolled in the 2016-2017 Northern Hemisphere influenza season. The predominant influenza virus strain in this study wasthe A/H3 subtype (84.8 % to 88.1 %) followed by the B type (8.3 % to 9.0 %) and the A/H1N1pdmsubtype (0.5 % to 3.0 %). The primary efficacy endpoint was time to alleviation of symptoms (cough,sore throat, headache, nasal congestion, feverishness or chills, muscle or joint pain, and fatigue)(TTAS). Baloxavir marboxil elicited a statistically significant reduction in TTAS when compared withplacebo (Table 4).

Table 4. Capstone 1: Time to alleviation of symptoms (baloxavir marboxil vs placebo), ITTIpopulation*

Time to Alleviation of Symptoms (Median [hours])

Baloxavir marboxil Placebo Difference between P-value40/80 mg (95 % CI) Baloxavir marboxil and(95 % CI) N=230 placebo

N=455 (95 % CI for difference)53.7 80.2 -26.5 < 0.0001(49.5, 58.5) (72.6, 87.1) (−35.8, −17.8)

CI: Confidence interval

*ITTI: The Intention-to-treat Infected population consisted of patients who received the study medicine with a confirmed diagnosis of influenza.

Confirmation of influenza was based on the results of RT-PCR on Day 1.

When the baloxavir marboxil group was compared to the oseltamivir group, there was no statisticallysignificant difference in TTAS (53.5 h vs 53.8 h respectively).

The median (95 % CI) TTAS was 49.3 (44.0, 53.1) and 82.1 (69.5, 92.9) hours for patients who weresymptomatic for > 0 to ≤ 24 hours, and 66.2 (54.4, 74.7) and 79.4 (69.0, 91.1) hours for patients whowere symptomatic for > 24 to ≤ 48 hours for baloxavir marboxil and placebo, respectively.

The median time to resolution of fever in patients treated with baloxavir marboxil was 24.5 hours(95 % CI: 22.6, 26.6) compared with 42.0 hours (95 % CI: 37.4, 44.6) in those receiving placebo. Nodifference was noted in duration of fever in the baloxavir marboxil group compared with theoseltamivir group.

Capstone 2 (1602T0832) was a phase 3 randomised, double-blind, multicentre study to evaluate theefficacy and safety of a single oral tablet dose of baloxavir marboxil compared with placebo and withoseltamivir in adult and adolescent patients (aged ≥ 12 years) with uncomplicated influenza who hadat least one host factor predisposing to the development of complications. Patients were randomised toreceive a single oral dose of baloxavir marboxil (according to weight as in Capstone 1), oseltamivir75 mg twice daily for 5 days, or placebo. Dosing occurred within 48 hours of first onset of symptoms.

Of the total 2184 patients 59 were aged ≥ 12 to ≤ 17 years, 446 were aged ≥ 65 to ≤ 74 years, 142were aged ≥ 75 to ≤ 84 years and 14 were aged ≥ 85 years. The predominant influenza viruses in thisstudy were the A/H3 subtype (46.9 % to 48.8 %) and influenza B (38.3 % to 43.5 %). The primaryefficacy endpoint was time to improvement of influenza symptoms (cough, sore throat, headache,nasal congestion, feverishness or chills, muscle or joint pain, and fatigue) (TTIS). Baloxavir marboxilelicited a statistically significant reduction in TTIS when compared with placebo (Table 5).

Table 5. Capstone 2: Time to improvement of influenza symptoms (baloxavir marboxil vsplacebo), ITTI population

Time to Improvement of Influenza Symptoms (Median [hours])

Baloxavir marboxil Placebo Difference between P-value40/80 mg (95 % CI) Baloxavir marboxil and(95 % CI) N=385 placebo

N=385 (95 % CI for difference)73.2 102.3 -29.1 < 0.0001(67.5, 85.1) (92.7, 113.1) (−42.8, −14.6)

When the baloxavir marboxil group was compared to the oseltamivir group, there was no statisticallysignificant difference in TTIS (73.2 h vs 81.0 h respectively).

The median (95 % CI) TTIS was 68.6 (62.4, 78.8) and 99.1 (79.1, 112.6) hours for patients who weresymptomatic for > 0 to ≤ 24 hours and 79.4 (67.9, 96.3) and 106.7 (92.7, 125.4) hours for patients whowere symptomatic for > 24 to ≤ 48 hours for baloxavir marboxil and placebo, respectively.

For patients infected with type A/H3 virus, the median TTIS was shorter in the baloxavir marboxilgroup compared with the placebo group but not compared with the oseltamivir group (see Table 6). Inthe subgroup of patients infected with type B virus, the median TTIS was shorter in the baloxavirmarboxil group compared with both the placebo and oseltamivir group (see Table 6).

Table 6. Time to improvement of symptoms by influenza virus subtype, ITTI population

Time to Improvement of Symptoms (Hours)

Median [95 % CI]

Virus Baloxavir marboxil Placebo Oseltamivir

A/H3 75.4 100.4 68.2[62.4, 91.6] [88.4, 113.4] [53.9, 81.0]

N=180 N=185 N=190

B 74.6 100.6 101.6[67.4, 90.2) [82.8, 115.8] [90.5, 114.9]

N=166 N=167 N=148

The median time to resolution of fever was 30.8 hours (95 % CI: 28.2, 35.4) in the baloxavir marboxilgroup compared with 50.7 hours (95 % CI: 44.6, 58.8) in the placebo group. No clear differencesbetween the baloxavir marboxil group and the oseltamivir group were observed.

The overall incidence of influenza-related complications (death, hospitalisation, sinusitis, otitis media,bronchitis, and/or pneumonia) was 2.8 % (11/388 patients) in the baloxavir marboxil group comparedwith 10.4 % (40/386 patients) in the placebo group. The lower overall incidence of influenza-relatedcomplications in the baloxavir marboxil group compared with the placebo group was mainly driven bylower incidences of bronchitis (1.8 % vs. 6.0 %, respectively) and sinusitis (0.3 % vs. 2.1 %,respectively).

Paediatric patients (aged 1 < 12 years)

Ministone-2 (CP40563) was a randomised, double-blind, multicentre, active-controlled study,designed to evaluate the safety, efficacy, and pharmacokinetics of a single oral dose of granules fororal suspension of baloxavir marboxil compared with oseltamivir in otherwise healthy paediatricpatients (aged 1 to < 12 years) with influenza-like symptoms.

A total of 173 patients were randomised in a 2:1 ratio to receive a single oral dose of baloxavirmarboxil based on body weight (2 mg/kg for patients weighing < 20 kg or 40 mg for patients weighing≥ 20 kg) or oseltamivir (dose based on body weight) for 5 days. Patients could receive paracetamo asrequired. Patients with host factors predisposing to the development of complications (14 % (25/173))were included in the study. The predominant influenza virus strain in this study was the A/H3 subtype.

The primary objective was to compare the safety of a single dose of baloxavir marboxil with 5 days ofoseltamivir administered twice daily. A secondary objective was to compare the efficacy of baloxavirmarboxil with oseltamivir based on the efficacy endpoints including time to alleviation of influenzasigns and symptoms (cough and nasal symptoms, time to return to normal health and activity andduration of fever).

Time to alleviation of influenza signs and symptoms were comparable between the baloxavir marboxilgroup (median 138.1 hours [95 % CI: 116.6, 163.2]) and the oseltamivir group (median 150 hours[95 % CI: 115.0, 165.7]) see Table 7.

Table 7 Time to Alleviation of Influenza Signs and Symptoms, ITTI population

Time to Alleviation of Symptoms (Median [hours])

Baloxavir marboxil Oseltamivir(95 % CI) (95 % CI)

N=80 N=43138.1 150.0(116.6, 163.2) (115.0, 165.7)

The median duration of fever was comparable between the baloxavir marboxil group (41.2 hours[95 % CI: 24.5, 45.7]) and the oseltamivir group (46.8 hours [95 % CI: 30.0, 53.5]).

The overall incidence of influenza-related complications (death, hospitalisation, pneumonia,bronchitis, sinusitis, otitis media, encephalitis/encephalopathy, febrile seizures, myositis) was7.4 % (6/81 patients) in the baloxavir marboxil group and 7 % (3/43 patients) in the oseltamivir group.

The incidence of otitis media was 3.7 % (3/81 patients) in the baloxavir marboxil group and4.7 % (2/43 patients) in the oseltamivir group. Sinusitis, pneumonia and bronchitis occurred in onepatient each in the baloxavir marboxil group and febrile seizures occurred in one patient in theoseltamivir group.

Post-exposure prophylaxis of influenza

Study 1719T0834 was a Phase 3, randomised, double-blind, multicentre study conducted in749 subjects in Japan to evaluate the efficacy and safety of a single oral tablet dose or a single dose ofgranulesof baloxavir marboxil compared with placebo for post-exposure prophylaxis of influenza.

Subjects were household contacts of influenza-infected index patients.

There were 607 subjects>12 years, and 142 subjects 1 to < 12 years who received either baloxavirmarboxil dosed according to weight as in the treatment studies or placebo. The majority ofsubjects(73.0 %) were enrolled within 24 hours of symptom onset in the index patient group. Thepredominant influenza virus strains in the index patients were the A/H3 subtype (48.6 %) and the

A/H1N1pdm subtype (47.5 %) followed by influenza B (0.7 %).

The primary efficacy endpoint was the proportion of household subjects who were infected withinfluenza virus and presented with fever and at least one respiratory symptom in the period from Day1 to Day 10.

There was a statistically significant reduction in the proportion of subjects with laboratory-confirmedclinical influenza from 13.6 % in the placebo group to 1.9 % in the baloxavir marboxil group (see

Table 8).

Table 8. Proportion of subjects with influenza virus, fever, and at least one respiratory symptom(baloxavir vs placebo)

Proportion of Subjects with Influenza Virus, Fever, and at least one Respiratory Symptom (%) mITT*population

Baloxavir marboxil Placebo(95 % CI) (95 % CI) Adjusted Risk Ratio(95 % CI for risk ratio) P-value

N=374 N=3751.9 13.6 0.14 < 0.0001(0.8, 3.8) (10.3, 17.5) (0.06, 0.30)

Proportion of Subjects ≥ 12 years with Influenza Virus, Fever, and at least one Respiratory Symptom(%)

N=303 N=3041.3 13.2 0.10 < 0.0001(0.4, 3.3) (9.6, 17.5) (0.04, 0.28)

Proportion of Subjects 1 to < 12 years with Influenza Virus, Fever, and at least one Respiratory

Symptom (%)

N = 71 N = 714.2 15.5 0.27 0.0339(0.9, 11.9) (8, 26) (0.08, 0.90)

* mITT: modified intention-to-treat. The mITT population included all randomised subjects who received the study medicine and had post-baseline efficacy dataavailable among household members of influenza-infected index patients. The mITT population was analysed as randomised

The European Medicines Agency has deferred the obligation to submit the results of studies with

Xofluza in one or more subsets of the paediatric population for the treatment of influenza andprevention of influenza (see section 4.2 for information on paediatric use).

After oral administration, baloxavir marboxil is extensively converted to its active metabolite, baloxavir.

The plasma concentration of baloxavir marboxil is very low or below the limit of quantitation(< 0.100 ng/mL).

Following a single oral administration of 80 mg of baloxavir marboxil, the time to achieve peakplasma concentration (Tmax) is approximately 4 hours in the fasted state. The absolute bioavailabilityof baloxavir after oral dosing with baloxavir marboxil has not been established.

A food-effect study involving administration of baloxavir marboxil to healthy volunteers under fastingconditions and with a meal (approximately 400 to 500 kcal including 150 kcal from fat) indicated thatthe Cmax and AUC of baloxavir were decreased by 48 % and 36 %, respectively, under fed conditions.

Tmax was unchanged in the presence of food. In clinical studies there were no clinically relevantdifferences in efficacy when baloxavir was taken with versus without food.

In an in-vitro study, the binding of baloxavir to human serum proteins, primarily albumin, is 92.9 % to93.9 % . The apparent volume of distribution of baloxavir during the terminal elimination phase(Vz/F) following a single oral administration of baloxavir marboxil is approximately 1180 litres in

Caucasian subjects and 647 litres in Japanese subjects.

Baloxavir is primarily metabolised by UGT1A3 to form a glucuronide with a minor contribution from

CYP3A4 to form a sulfoxide.

Drug-drug interaction studies

Based on in vitro and in vivo drug-drug interaction (DDI) studies, baloxavir marboxil and baloxavirare not expected to inhibit isozymes of the CYP or UGT families or cause relevant induction of CYPenzymes.

Based on in vitro transporter studies and in vivo DDI studies, no relevant pharmacokinetic interactionis anticipated between baloxavir marboxil or baloxavir and medicines which are substrates of thefollowing transporters: OATP1B1, OATP1B3, OCT1, OCT2, OAT1, OAT3, MATE1, or MATE2K.

Excretion

Following a single oral administration of 40 mg of [14C]-labeled baloxavir marboxil, the proportion oftotal radioactivity excreted in faeces was 80.1 % of the administered dose, with the urine accountingfor 14.7 % (3.3 % and 48.7 % of the administered dose was excreted as baloxavir in urine and faecesrespectively).

The apparent terminal elimination half-life (t1/2,z) of baloxavir after a single oral administration ofbaloxavir marboxil is 79.1, 50.3 and 29.4 hours in Caucasian adult, adolescent and paediatric subjects,respectively.

Following single oral administration of baloxavir marboxil, baloxavir exhibits linear pharmacokineticswithin the dose range of 6 mg to 80 mg.

Body weight is a significant covariate for baloxavir pharmacokinetics based on the populationpharmacokinetic analysis. Dosing recommendations for baloxavir marboxil are based on body weightin both adult and paediatric patients (see section 4.2).

A population pharmacokinetic analysis did not identify a clinically meaningful effect of gender on thepharmacokinetics of baloxavir. No dose adjustment based on gender is required.

Based on a population pharmacokinetic analysis, race is a covariate on oral clearance (CL/F) ofbaloxavir in addition to body weight; however, no dose adjustment of baloxavir marboxil based onrace is required.

A population pharmacokinetic analysis using plasma baloxavir concentrations from clinical studies insubjects aged 1 to 64 years did not identify age as a relevant covariate on the pharmacokinetics ofbaloxavir.

Pharmacokinetic data of baloxavir collected in patients aged 1 to < 12 years show that the bodyweight-adjusted dosing regimen (2 mg/kg up to 20 kg and 40 mg for ≥ 20 kg) provides similarbaloxavir exposures across the body weight categories in the paediatric population, as well as similarexposure to adults and adolescent receiving a 40 mg dose of baloxavir marboxil.

The pharmacokinetics of baloxavir in paediatric patients below 1 year of age have not beenestablished.

Pharmacokinetic data collected in 181 patients aged ≥ 65 years show that exposure to baloxavir in theplasma was similar to that in patients aged ≥ 12 to 64 years.

No clinically meaningful differences in the pharmacokinetics of baloxavir were observed in patientswith mild or moderate hepatic impairment (Child-Pugh class A and B) compared with healthy controlswith normal hepatic function.

The pharmacokinetics in patients with severe hepatic impairment have not been evaluated (seesection 4.2).

The effects of renal impairment on the pharmacokinetics of baloxavir marboxil or baloxavir have notbeen evaluated. Renal impairment is not expected to alter the elimination of baloxavir marboxil orbaloxavir.

Nonclinical data reveal no special hazards for humans based on conventional studies of safetypharmacology, acute and repeated dose toxicity.

Prolongation of PT and APTT were observed in rats at exposures at least equal to the human exposurebased on AUC0-24hr under specific experimental conditions, i.e. when fasted and when the food waseither autoclaved or radiation-treated, resulting in vitamin K limiting/deficient conditions. Theseeffects were not observed in monkey studies up to 4 weeks duration at the highest tested doseequivalent to 8-times the human exposure based on AUC0-24hr. They are considered to be of limitedclinical relevance.

Carcinogenicity studies have not been performed with baloxavir marboxil.

The pro-drug baloxavir marboxil, and its active form, baloxavir, were not considered genotoxic asthey tested negative in bacterial reverse mutation tests, micronucleus tests with cultured mammaliancells, and as baloxavir marboxil was negative in an in vivo rodent micronucleus test.

Baloxavir marboxil had no effects on fertility when given orally to male and female rats at dosesproviding exposure equivalent to 5-times the human exposure based on AUC0-24hr.

Baloxavir marboxil did not cause malformations in rats or rabbits.

The oral embryo-foetal development study of baloxavir marboxil in rats with daily doses fromgestation day 6 to 17 revealed no signs of maternal or foetal toxicity up to the highest tested doseproviding exposure equivalent to 5-times the human exposure based on AUC0-24hr.

In rabbits, a dose providing exposure equivalent to 14-times the human exposure based on AUC0-24hrfollowing the MHRD caused maternal toxicity resulting in miscarriages and significant increase inincidence of foetuses with a skeletal variation (cervical rib). The skeletal variations were reabsorbedduring the growing process of adjacent cervical vertebra. A dose providing exposure equivalent to 6-times the human exposure based on AUC0-24hr in rabbits was without adverse effects.

The pre- and postnatal study in rats did not show drug-related adverse findings in dams and pups up tothe highest tested dose providing exposure equivalent to 5-times the human exposure based on

AUC0-24hr.

Lactose monohydrate

Croscarmellose sodium (E468)

Povidone (K25) (E1201)

Microcrystalline cellulose (E460)

Sodium stearyl fumarate

Hypromellose (E464)

Talc (E553b)

Titanium dioxide (E171)

Not applicable.

Xofluza 20 mg and 40 mg film-coated tablets5 years.

Xofluza 80 mg film-coated tablets3 years.

This medicinal product does not require any special temperature storage conditions.

Store in the original package in order to protect from moisture.

Blister pack (OPA/Aluminum foil/PVC, sealed with aluminium foil).

Xofluza 20 mg film-coated tablets1 blister containing 2 film-coated tablets

Xofluza 40 mg film-coated tablets1 blister containing 1 film-coated tablet1 blister containing 2 film-coated tablets

Xofluza 80 mg film-coated tablets1 blister containing 1 film-coated tablet

Any unused medicinal product or waste material should be disposed of in accordance with localrequirements.

Roche Registration GmbH

Emil-Barell-Strasse 179639 Grenzach-Wyhlen

Germany

EU/1/20/1500/001

EU/1/20/1500/002

EU/1/20/1500/003

EU/1/20/1500/004

Date of first authorisation: 07 January 2021

Detailed information on this medicinal product is available on the website of the European Medicines

Agency http://www.ema.europa.eu.