Consumer medicine information

Xofluza

Baloxavir marboxil

BRAND INFORMATION

Brand name

Xofluza

Active ingredient

Baloxavir marboxil

Schedule

SUMMARY CMI

Xofluza^®

Consumer Medicine Information (CMI) summary

The full CMI on the next page has more details. If you are worried about using this medicine, speak to your doctor or pharmacist.

▼ This medicine is new or being used differently. Please report side effects. See the full CMI for further details.

1. Why am I using Xofluza?

Xofluza contains the active ingredient baloxavir marboxil. Xofluza is used to treat flu (influenza) and prevent flu after exposure, in people 12 years of age and older.

For more information, see Section 1. Why am I using Xofluza? in the full CMI.

2. What should I know before I use Xofluza?

Do not use if you have ever had an allergic reaction to Xofluza or any of the ingredients listed at the end of the CMI.

Talk to your doctor if you have any other medical conditions, take any other medicines, or are pregnant or plan to become pregnant or are breastfeeding.

For more information, see Section 2. What should I know before I use Xofluza? in the full CMI.

3. What if I am taking other medicines?

Some medicines may interfere with Xofluza and affect how it works.

A list of these medicines is in Section 3. What if I am taking other medicines? in the full CMI.

4. How do I use Xofluza?

For treatment of flu and prevention of flu, take as a single dose, within 48 hours after flu symptoms or exposure to an infection.
The recommended dose is 40mg if you weigh between 40kg or more, and less than 80kg. This is one 40mg tablet or two 20mg tablets. The recommended dose is 80mg if you weigh 80kg or more. This is one 80mg tablet or two 40 mg tablets. Swallow the tablets whole with a full glass of water. If possible, do not take Xofluza with dairy products, such as milk, cheese or yoghurt.
More instructions can be found in Section 4. How do I use Xofluza? in the full CMI.

5. What should I know while using Xofluza?

Things you should do	Tell your doctor if your symptoms do not start to get better or if you feel worst or develop new symptoms while taking Xofluza.
Things that would be helpful	See comments in the full CMI.
Looking after your medicine	Keep your tablets in a cool dry place where the temperature stays below 30°C.

For more information, see Section 5. What should I know while using Xofluza? in the full CMI.

6. Are there any side effects?

Tell your doctor immediately or go to emergency if you notice wheezing, trouble breathing or swallowing, skin rash, hives or blisters, dizziness, light headedness, feeling sick or vomiting, swelling of face, throat or mouth, swelling of hands, feet or dark bloody stools.

For more information, including what to do if you have any side effects, see Section 6. Are there any side effects? in the full CMI.

▼ This medicine is subject to additional monitoring. This will allow quick identification of new safety information. You can help by reporting any side effects you may get. You can report side effects to your doctor, or directly at www.tga.gov.au/reporting-problems.

FULL CMI

Xofluza^®

Active ingredient: baloxavir marboxil

Consumer Medicine Information (CMI)

This leaflet provides important information about using Xofluza. You should also speak to your doctor or pharmacist if you would like further information or if you have any concerns or questions about using Xofluza.

Where to find information in this leaflet:

1. Why am I using Xofluza?
2. What should I know before I use Xofluza?
3. What if I am taking other medicines?
4. How do I use Xofluza?
5. What should I know while using Xofluza?
6. Are there any side effects?
7. Product details

1. Why am I using Xofluza?

Xofluza is an antiviral medicine containing the active ingredient baloxavir marboxil. It attacks the flu virus and decreases its ability to reproduce.

Xofluza is used for treatment of the flu (influenza) in people over 12 years of age and older who have had flu symptoms for 48 hours or less and also used to prevent flu in patients aged 12 and above who have been in contact with someone who has confirmed flu.

Xofluza reduces the symptoms of the flu so that you feel better faster. It also reduces the amount of flu virus shed when you cough or sneeze.

You may also be less likely to develop complications of flu, such as bronchitis or sinusitis.

Xofluza has no effect on the common cold or other respiratory virus infections.

Ask your doctor if you have any questions about why Xofluza has been prescribed for you.

2. What should I know before I use Xofluza?

There is not enough information to recommend the use of Xofluza for children under the age of 12 years or weighing less than 40 kg.

Warnings

Do not use Xofluza if:

you are allergic to baloxavir marboxil, or any of the ingredients listed at the end of this leaflet.
Always check the ingredients to make sure you can use this medicine.

Check with your doctor if you:

have any other medical conditions
take any medicines for any other condition
have allergies to any other medicines, foods, preservatives or dyes.

During treatment, you may be at risk of developing certain side effects. It is important you understand these risks and how to monitor for them. See additional information under Section 6. Are there any side effects?

Pregnancy and breastfeeding

Check with your doctor if you are pregnant or intend to become pregnant.

Talk to your doctor if you are breastfeeding or intend to breastfeed.

It is not known whether Xofluza is harmful to an unborn baby when taken by a pregnant woman or if it passes into breast milk. Your doctor can discuss with you the risks and benefits involved.

3. What if I am taking other medicines?

Tell your doctor or pharmacist if you are taking any other medicines, including any medicines, vitamins or supplements that you buy without a prescription from your pharmacy, supermarket or health food shop.

Some medicines may interfere with Xofluza and affect how it works.

In particular, tell your doctor or pharmacist if you are taking:

laxatives (medicines that relieve constipation and promote regular bowel movements)
antacids (medicines that relieve heartburn)
oral supplements containing iron, zinc, selenium, calcium, magnesium

Some laxatives, antacids and oral supplements should not be taken at the same time as Xofluza as they may affect how it works.

Talk to your doctor about your choice of flu vaccine if you have taken Xofluza. Live flu vaccine available overseas as a nasal spray might not work as well if you have taken Xofluza.

Check with your doctor or pharmacist if you are not sure about what medicines, vitamins or supplements you are taking and if these affect Xofluza.

4. How do I use Xofluza?

How much to take / use

The recommended dose is 40mg if you weigh between 40kg or more, and less than 80kg. This is one 40mg or two 20mg tablets.
Take Xofluza as a single dose. The recommended dose is 80mg if you weigh 80kg or more. This is one 80mg tablet or two 40mg tablets.
You can take Xofluza with or without food.
Do not take Xofluza with calcium-rich drinks or certain laxatives, antacids or oral supplements containing iron, zinc, selenium, calcium or magnesium. If possible, do not take Xofluza with dairy products, such as milk, cheese or yogurt.
For treatment of flu, take Xofluza as a single dose as soon as possible within the first 48 hours after the start of your flu symptoms. Xofluza has only been shown to work if given during this timeframe.
For prevention of flu, take Xofluza as a single dose as soon as possible within 48 hours following exposure to a confirmed infected person.

If you use too much Xofluza

If you think that you have used too much Xofluza you may need urgent medical attention.

You should immediately:

phone the Poisons Information Centre
(by calling 13 11 26), or
contact your doctor, or
go to the Emergency Department at your nearest hospital.

You should do this even if there are no signs of discomfort or poisoning.

5. What should I know while using Xofluza?

Call your doctor straight away if you:

do not start to get better
feel worse or develop new symptoms

Xofluza is not effective in treating infections other than the flu. Other kinds of infections can appear like flu or occur along with the flu and may need different kinds of treatment.

Things that would be helpful

When you are well again, ask your doctor about having the flu vaccine. Vaccination every year is the best way to prevent the flu.

Looking after your medicine

Keep your tablets in the pack until it is time to take them.
If you take the tablets out of the pack they may not keep well.
Keep your tablets in a cool dry place away from moisture or heat, where the temperature stays below 30°C. For example, do not store it in the bathroom or near a sink, or in the car or on window sills.

Keep it where young children cannot reach it.

When to discard your medicine

Getting rid of any unwanted medicine

If you no longer need to use this medicine or it is out of date, take it to any pharmacy for safe disposal.

Do not use this medicine after the expiry date.

6. Are there any side effects?

All medicines can have side effects. If you do experience any side effects, most of them are minor and temporary. However, some side effects may need medical attention.

See the information below and, if you need to, ask your doctor or pharmacist if you have any further questions about side effects.

Some of the symptoms of an allergic reaction may include: shortness of breath; wheezing or difficulty breathing; swelling of the face, lips, tongue or other parts of the body; rash, itching or hives on the skin.

Serious side effects

Serious side effects	What to do
wheezing, trouble breathing or swallowing skin rash, hives or blisters dizziness or feeling lightheadedness feeling sick or vomiting swelling of face, throat or mouth diarrhoea	Call your doctor straight away, or go straight to the Emergency Department at your nearest hospital if you notice any of these serious side effects.

Tell your doctor or pharmacist if you notice anything else that may be making you feel unwell.

Other side effects not listed here may occur in some people.

Reporting side effects

After you have received medical advice for any side effects you experience, you can report side effects to the Therapeutic Goods Administration online at www.tga.gov.au/reporting-problems. By reporting side effects, you can help provide more information on the safety of this medicine.

Always make sure you speak to your doctor or pharmacist before you decide to stop taking any of your medicines.

7. Product details

This medicine is only available with a doctor's prescription.

Xofluza is supplied in single dose packs.

What Xofluza contains

Active ingredient (main ingredient)	baloxavir marboxil
Other ingredients (inactive ingredients)	lactose monohydrate croscarmellose sodium povidone microcrystalline cellulose sodium stearylfumarate hypromellose purified talc titanium dioxide
Potential allergens	Lactose This medicine does not contain sucrose, gluten, tartrazine or any other azo dyes.

Do not take this medicine if you are allergic to any of these ingredients.

What Xofluza looks like

Xofluza film-coated tablets are available in strengths of 20mg, 40mg and 80mg.

Xofluza 20mg tablets (AUST R 317240) are: oblong, white to light yellow, marked with "debossed with a symbol and 772" on one side and "20" on the other side.

Xofluza 20mg tablets are supplied in blister packs of 2 film coated tablets.

Xofluza 40 mg tablets (AUST R 317241) are: oblong, white to light yellow, marked with "BXM40" on one side

Xofluza 40mg tablets are supplied in blister packs of 1 and 2 film-coated tablets.

Xofluza 80mg tablets (AUST R 388092) are: white to light yellow, oblong-shaped film-coated tablets debossed on one side with "BXM80".

Xofluza 80mg is supplied in blister packs of 1 film-coated tablet.

Who distributes Xofluza

Roche Products Pty Ltd
ABN 70 000 132 865
Level 8, 30-34 Hickson Road
Sydney NSW 2000
Medical enquiries: 1800 233 950

Please check with your pharmacist for the latest Consumer Medicine Information.

This leaflet was prepared in December 2023.

Published by MIMS April 2025

BRAND INFORMATION

Brand name

Xofluza

Active ingredient

Baloxavir marboxil

Schedule

1 Name of Medicine

Baloxavir marboxil.

2 Qualitative and Quantitative Composition

Each 20 mg film-coated tablet contains 20 mg baloxavir marboxil.
Each 40 mg film-coated tablet contains 40 mg baloxavir marboxil.
Each 80 mg film-coated tablet contains 80 mg baloxavir marboxil.

Excipients with known effect.

Each 20 mg tablet contains 77.9 mg of sugars as lactose monohydrate.
Each 40 mg tablet contains 155.8 mg of sugars as lactose monohydrate.
Each 80 mg tablet contains 311.6 mg of sugars as lactose monohydrate.
For the full list of excipients, see Section 6.1.

3 Pharmaceutical Form

Film-coated tablets.
Xofluza 20 mg tablets are white to light yellow, oblong-shaped film-coated tablets debossed with symbol and "772" on one side and "20" on the other side.
Xofluza 40 mg tablets are white to light yellow, oblong-shaped film-coated tablets debossed on one side with "BXM40".
Xofluza 80 mg tablets are white to light yellow, oblong-shaped film-coated tablets debossed on one side with "BXM80".

4 Clinical Particulars

4.1 Therapeutic Indications

Treatment of influenza.

Xofluza is indicated for the treatment of uncomplicated influenza in patients 12 years of age and older who have been symptomatic for no more than 48 hours and who are: otherwise healthy, or at high risk of developing influenza complications.

Prophylaxis of influenza.

Xofluza is indicated for the post-exposure prophylaxis of influenza in patients aged 12 years of age and older following contact with an individual who has confirmed influenza.
Vaccination is the preferred method of routine prophylaxis against infection with influenza virus.

4.2 Dose and Method of Administration

General.

Xofluza may be taken with or without food (see Section 5.2 Pharmacokinetic Properties). Avoid co-administration of Xofluza with calcium-fortified beverages, polyvalent cation-containing laxatives, antacids or oral supplements, e.g. calcium, iron, magnesium, selenium, or zinc. Where possible, avoid co-administration of Xofluza with dairy products (see Section 4.5).

Treatment of influenza.

A single oral dose of Xofluza should be taken within 48 hours of symptom onset.

Prophylaxis of influenza.

A single dose of Xofluza should be taken as soon as possible within 48 hours following close contact with an individual who has confirmed influenza.

Dose.

Treatment or post-exposure prophylaxis of adults and adolescents (≥ 12 years of age). The recommended dose of Xofluza depending on body weight is shown in Table 1.

Dosage modifications. No dose reductions of Xofluza are recommended.
Special populations.

Hepatic impairment.

No dose adjustment is required in patients with mild (Child-Pugh class A) to moderate (Child-Pugh class B) hepatic impairment (see Section 5.2, Pharmacokinetics in special populations, Hepatic impairment). Xofluza has not been studied in patients with severe hepatic impairment.

Renal impairment.

The safety and efficacy of Xofluza has not been studied in patients with renal impairment. A change in dose is not required for patients with renal impairment (see Section 5.2, Pharmacokinetics in special populations, Renal impairment).

Elderly.

No dosage adjustment is recommended in elderly patients (see Section 5.2, Pharmacokinetics in special populations, Elderly).

Paediatric populations.

The safety and efficacy of Xofluza in patients < 12 years of age has not been established. For patients ≥ 12 years weighing at least 40 kg, see Table 1.

4.3 Contraindications

Xofluza is contraindicated in patients with a known hypersensitivity to baloxavir marboxil or to any of the excipients (see Section 4.8, Post-marketing experience).

4.4 Special Warnings and Precautions for Use

Influenza viruses change over time, and factors such as the virus type or subtype, emergence of resistance, or changes in viral virulence could diminish the clinical benefit of antiviral medicines. Consider available information on drug susceptibility patterns for circulating influenza virus strains when deciding whether to use Xofluza (see Section 5.1 Pharmacodynamic Properties, Viral resistance).

Hypersensitivity.

Hypersensitivity reactions after use of Xofluza have been reported in post-marketing surveillance. While in several cases a definitive causal relationship could not be confirmed, cases of hypersensitivity (including anaphylaxis, facial/throat swelling, skin eruptions and urticaria) have been attributed to exposure to baloxavir. Appropriate treatment should be instituted if an allergic-like reaction occurs or is suspected.

Use in hepatic impairment.

The safety and efficacy of Xofluza in patients with severe hepatic impairment has not been studied. See Section 4.2, Dose, Special populations, Hepatic impairment; Section 5.2, Pharmacokinetics in special populations, Hepatic impairment.

Use in renal impairment.

The safety and efficacy of Xofluza in patients with renal impairment has not been studied. See Section 4.2, Dose, Special populations, Renal impairment; Section 5.2 Pharmacokinetics in special populations, Renal impairment.

Use in the elderly.

The safety and efficacy of Xofluza for the treatment of influenza in geriatric patients age ≥ 65 years and weighing at least 40 kg have been established. See Section 4.2, Dose, Special populations, Elderly; Section 5.2, Pharmacokinetics in special populations, Elderly.

Paediatric use.

The safety and efficacy in paediatric patients (< 12 years of age and/or weighing < 40 kg) has not been established.

Effects on laboratory tests.

No data available.

4.5 Interactions with Other Medicines and Other Forms of Interactions

No clinically significant drug-drug interactions are anticipated between baloxavir marboxil or its active metabolite, baloxavir, and substrates, inhibitors, or inducers of cytochrome P450 (CYP enzymes), substrates or inhibitors of uridine 5'-diphospho-glucuronosyltransferase (UDP-glucuronosyltransferase, UGT) enzyme, or gut or renal transporters.
Polyvalent cation containing products may decrease plasma concentrations of baloxavir. Xofluza should not be taken with calcium-fortified beverages, polyvalent cation containing laxatives or antacids, or oral supplements containing iron, zinc, selenium, calcium, magnesium. Where possible, avoid co-administration of Xofluza with dairy products.
The concurrent use of Xofluza with intranasal live attenuated influenza vaccine (LAIV) has not been evaluated. Concurrent administration of antiviral drugs may inhibit viral replication of LAIV and thereby decrease the effectiveness of LAIV vaccination. Interactions between inactivated influenza vaccines and Xofluza have not been evaluated.

Effects of other medicines on baloxavir marboxil or its active metabolite baloxavir.

Baloxavir marboxil and baloxavir are substrates for P-glycoprotein (P-gp). Itraconazole, an inhibitor of P-gp, increased the C_max and AUC_0-inf of baloxavir 1.33-fold and 1.23-fold, respectively. These increases are not considered to be clinically meaningful.
Probenecid, an inhibitor of UGT enzyme, decreased the C_max and AUC_0-inf of baloxavir by 21% and 25%, respectively. These decreases are not considered to be clinically meaningful.

Effects of baloxavir marboxil or its active metabolite baloxavir on other medicines.

In in vitro studies at clinically relevant concentrations, baloxavir marboxil and its active metabolite, baloxavir, did not inhibit any of the following isozymes of the CYP or UGT family: CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP3A4, UGT1A1, UGT1A3, UGT1A4, UGT1A6, UGT1A9, UGT2B7 and UGT2B15 isozymes. In in vitro studies at clinically relevant concentrations, baloxavir marboxil and baloxavir did not cause significant induction of CYP1A2, CYP2B6, and CYP3A4.
In in vitro transporter studies at clinically relevant concentrations, baloxavir marboxil inhibited the efflux transporter (P-gp). Baloxavir, but not baloxavir marboxil, inhibited Breast Cancer Resistance Protein (BCRP).
Baloxavir is not an inhibitor of BSEP or OAT1 in vitro. Based on in vitro transporter studies, despite a weak in vitro inhibitory potential, baloxavir is not expected to be an in vivo inhibitor of OATP1B1, OATP1B3, OCT1, OCT2, OAT3, MATE1, or MATE2K. Hence, no relevant pharmacokinetic interaction is anticipated between baloxavir and medicines which are substrates of these transporters.
A single 40 mg dose of baloxavir marboxil did not affect the pharmacokinetics of midazolam, a substrate of CYP3A4, suggesting that baloxavir marboxil or baloxavir is not expected to affect the pharmacokinetics of co-administered drugs that are substrates of CYP3A.
A single 80 mg dose of baloxavir marboxil did not affect the pharmacokinetics of digoxin, a substrate of P-gp, suggesting that baloxavir marboxil or baloxavir is not expected to affect the pharmacokinetics of co-administered drugs that are substrates of P-gp.
A single 80 mg dose of baloxavir marboxil decreased C_max and AUC_0-inf of rosuvastatin, a substrate of BCRP, by 18% and 17%, respectively. These decreases are not considered to be clinically meaningful and indicate that baloxavir marboxil or baloxavir is not expected to affect the pharmacokinetics of co-administered drugs that are substrates of BCRP.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

Baloxavir marboxil had no effects on fertility when given orally to male and female rats at doses up to 1000 mg/kg/day, which is equivalent to 2-times the human exposure based on AUC_{0-24 hr} at the maximum recommended human dose.
(Category B3)
There are no adequate and well-controlled studies with Xofluza in pregnant women. The potential risk of Xofluza in pregnant women is unknown. Xofluza should be avoided during pregnancy unless the potential benefit justifies the potential risk to the fetus.
A tissue distribution study in pregnant rats showed that baloxavir crosses the placenta. Baloxavir marboxil did not cause malformations in rats or rabbits. The oral embryo-fetal development study of baloxavir marboxil in rats with daily doses from gestation day 6 to 17 revealed no signs of fetal toxicity up to the highest tested dose of 1000 mg/kg/day, which is equivalent to 2-times the human exposure based on AUC_{0-24 hr} at the maximum recommended human dose.
In rabbits, a dose level of 1000 mg/kg/day (equivalent to 6-times the human exposure based on AUC_{0-24 hr} following the maximum recommended human dose) caused maternal toxicity resulting in 2 miscarriages out of 19 and an increased incidence of fetuses with a skeletal variation (cervical rib), but no malformations. A dose of 100 mg/kg/day (equivalent to 3 times the human exposure based on AUC_{0-24 hr}) 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 to the highest tested dose of 1000 mg/kg/day, which is equivalent to 2-times the human exposure based on AUC_{0-24 hr}.

Labour and delivery.

The safe use of Xofluza during labour and delivery has not been established.
It is not known whether baloxavir marboxil and the active metabolite, baloxavir, are excreted in human breast milk. When dosed at 1 mg/kg, baloxavir marboxil or its metabolites are secreted in the milk of lactating rats.
A decision should be made whether to discontinue nursing or to initiate treatment with Xofluza, taking into consideration the potential benefit of Xofluza to the nursing mother and the potential risk to the infant.

4.7 Effects on Ability to Drive and Use Machines

No studies on the effects on the ability to drive and to use machines have been performed.

4.8 Adverse Effects (Undesirable Effects)

Clinical trials.

The overall safety profile of Xofluza is based on data from 2483 subjects in 18 clinical trials receiving Xofluza.

Treatment of influenza.

No adverse drug reactions have been identified based on pooled data from 3 placebo-controlled clinical studies (studies 1518T0821, CAPSTONE-1 and CAPSTONE-2) in adult and adolescent patients, in which a total of 1640 patients have received Xofluza. This includes otherwise healthy adults and adolescents and patients at high risk of developing complications associated with influenza, e.g. elderly patients and patients with chronic cardiac or respiratory disease. Of these, 1334 patients (81.3%) were adults from 18 years to 64 years or lower, 209 patients (12.7%) were adults at least 65 years of age or older, and 97 patients (5.9%) were adolescents at least 12 years to 18 years of age. Of these, 1440 patients received Xofluza at the recommended dose. The safety profile in patients at high risk was similar to that in otherwise healthy adults and adolescents.
Table 2 displays the most common adverse events (regardless of causality assessment) reported in at least 1% of adult and adolescent subjects who received Xofluza at the recommended dose in studies 1518T0821, CAPSTONE-1 and CAPSTONE-2.

Prophylaxis of influenza.

In a placebo-controlled clinical study (BLOCKSTONE), treatment emergent adverse events regardless of relationship to treatment were reported in a similar proportion of subjects in the two treatment groups (22.2%, Xofluza vs 20.5%, placebo). The most frequently reported adverse event in the total study population was nasopharyngitis, which occurred in 6.4% of subjects who received Xofluza and 6.7% on placebo. The safety profile of Xofluza administered for post-exposure prophylaxis of influenza is comparable to the safety profile established for the treatment of influenza.

Post-marketing experience.

The following adverse effects have been identified during post-marketing use of Xofluza. Because these effects are reported voluntarily from a population of uncertain size, it is not possible to reliably estimate their frequency or establish a causal relationship to Xofluza exposure.

Immune system disorder.

Anaphylaxis, anaphylactic reactions, hypersensitivity.

Skin and subcutaneous tissue disorders.

Angioedema, urticaria, rash.

Gastrointestinal disorders.

Vomiting, bloody diarrhoea, melaena, ischemic colitis.

Description of selected adverse drug reactions from post-marketing experience.

Hypersensitivity reactions have been observed in the post-marketing setting which include reports of anaphylaxis/anaphylactic reactions and less severe forms of hypersensitivity reactions including angioedema, urticaria and rash.

Reporting of suspected adverse reactions.

Reporting suspected adverse reactions after registration 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 at www.tga.gov.au/reporting-problems.

4.9 Overdose

Clinical experience.

Reports of overdose have been received from clinical trials and during post-marketing experience. In the majority of cases reporting overdose, no adverse events were reported. From the limited number of cases associated with adverse events, data are insufficient to determine what symptoms may be anticipated as a result of an overdose.

Management.

No known specific antidote exists for Xofluza. In the event of overdose, standard supportive medical care 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.
For information on the management of overdose, contact the Poison Information Centre on 13 11 26 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Baloxavir marboxil is a prodrug that is converted by hydrolysis to its active metabolite, baloxavir, the active form that exerts anti-influenza activity. Baloxavir acts on the cap dependent endonuclease (CEN), an influenza virus-specific enzyme in the polymerase acidic (PA) subunit of the viral RNA polymerase complex and thereby inhibits the transcription of influenza virus genomes resulting in inhibition of influenza virus replication. The 50% inhibition concentration (IC₅₀) of baloxavir was 1.4 to 3.1 nanomol/L for influenza A viruses and 4.5 to 8.9 nanomol/L for influenza B viruses in an enzyme inhibition assay.
Nonclinical studies demonstrate potent antiviral activity of baloxavir against influenza A and B virus in vitro and in vivo. The antiviral activity of baloxavir against laboratory strains and clinical isolates of influenza A and B viruses was determined in the MDCK cell culture assay. The median 50% effective concentration (EC₅₀) values of baloxavir were 0.73 nanomol/L (n=31; range: 0.20 to 1.85 nanomol/L) for subtype A/H1N1 strains, 0.83 nanomol/L (n=33; range: 0.35 to 2.63 nanomol/L) for subtype A/H3N2 strains, and 5.97 nanomol/L (n=30; range: 2.67 to 14.23 nanomol/L) for type B strains. In a MDCK cell-based virus titre reduction assay, the 90% effective concentration (EC₉₀) values of baloxavir were in the range of 0.46 to 0.98 nanomol/L for subtype A/H1N1 and A/H3N2 viruses, 0.80 to 3.16 nanomol/L for avian subtype A/H5N1 and A/H7N9 viruses, and 2.21 to 6.48 nanomol/L for type B viruses.
Viruses bearing the PA/I38T/M/F/N/S mutation selected in vitro or in clinical studies show reduced susceptibility to baloxavir. Baloxavir is active against neuraminidase inhibitor resistant strains including H274Y in A/H1N1, E119V and R292K in A/H3N2, and R152K and D198E in type B virus, H274Y in A/H5N1, R292K in A/H7N9.
The relationship between antiviral activity in cell culture and inhibition of influenza virus replication in humans has not been established.
Viral resistance.

Resistance monitoring during clinical development.

Influenza A virus isolates with treatment-emergent amino acid substitutions in the PA protein at position I38T/M/F/N/S associated with > 10-fold reduced susceptibility to baloxavir and influenza B virus isolates with treatment-emergent amino acid substitutions in the PA protein at position I38T associated with > 5 fold reduced susceptibility to baloxavir were observed in clinical studies. The clinical impact of this reduced susceptibility is unclear.
No pre-treatment isolates, with amino acid substitutions associated with reduced susceptibility to baloxavir, were found in the clinical studies.
In adult and adolescent subjects who had a confirmed influenza virus infection, the overall frequencies of treatment-emergent amino acid substitutions associated with reduced susceptibility to baloxavir were 3.7% (5/135), 10.1% (49/486), and 0.9% (2/228) in influenza A/H1N1, A/H3N2, and B virus infections, respectively, in pooled data from Trials 1518T0821, CAPSTONE-1, and CAPSTONE-2.
In the prophylaxis study (BLOCKSTONE), PA/I38T/M were detected in 10 of 374 subjects (2.7%) in the baloxavir treated subjects.
Prescribers should consider available information from the WHO and/or local government websites on influenza drug susceptibility patterns and treatment effects when deciding whether to use Xofluza.

Cross resistance.

No single amino acid substitution has been identified that could confer cross-resistance between baloxavir and neuraminidase inhibitors (e.g. peramivir, oseltamivir, zanamivir). However, a virus may carry amino acid substitutions associated with reduced susceptibility to baloxavir in the PA protein and to neuraminidase inhibitors in the neuraminidase and may therefore exhibit reduced susceptibility to both classes of inhibitors. The clinical relevance of phenotypic cross resistance evaluations has not been established.
Pharmacodynamic effects. At twice the expected exposure from recommended dosing, Xofluza did not prolong the QTc interval.

Clinical trials.

Clinical trials for the approved indication of treatment of patients with uncomplicated influenza and prophylaxis of influenza are described in this section.

Treatment of influenza.

Clinical trials in otherwise healthy patients.

CAPSTONE-1 (study 1601T0831).

CAPSTONE-1 is a randomised, double-blind, multicentre, placebo- and active-controlled study designed to evaluate the efficacy and safety of a single oral dose of Xofluza compared with placebo or oseltamivir in otherwise healthy adult and adolescent patients (aged ≥ 12 years to ≤ 64 years) with influenza. Patients infected with human immunodeficiency virus (HIV) or with cancer were not enrolled in this study.
A total of 1436 patients were randomised to receive treatment in the 2016-2017 Northern Hemisphere influenza season. Patients were randomised to receive 40 mg or 80 mg of Xofluza according to weight (< 80 kg or ≥ 80 kg respectively), oseltamivir 75 mg twice daily for 5 days (if aged > 20 years) or placebo. The primary efficacy population was defined as those who received study medication and had a positive influenza reverse transcription polymerase chain reaction (RT-PCR) result at trial entry.
The predominant influenza virus strain in this study was the A/H3 subtype (84.8% to 88.1%) followed by the B type (8.3% to 9.0%) and the A/H1N1pdm subtype (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). A statistically significant and clinically meaningful improvement in the primary endpoint was seen for Xofluza when compared with placebo (Table 3).

Secondary efficacy endpoints.

When the Xofluza group was compared to the oseltamivir group, there was no statistically significant difference in time to alleviation of symptoms (53.5 h vs 53.8 h respectively) (Table 4).

Resolution of fever: Following study drug administration there was faster resolution of fever in the Xofluza group compared with the placebo group. The median time to resolution of fever in patients treated with Xofluza 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. No difference was noted in duration of fever in the Xofluza group compared with the oseltamivir group.
Antiviral activity: Patients treated with Xofluza showed a rapid reduction in virus titre. The median time to cessation of viral shedding determined by virus titre was 24.0 hours (95% CI: 24.0, 48.0) in the Xofluza group compared with 72.0 hours (95% CI: 72.0, 96.0) in the oseltamivir group and 96.0 hours (95% CI: 96.0, 96.0) in the placebo group.

Study 1518T0821.

The phase 2 study was designed to evaluate the efficacy and safety of a single oral dose of Xofluza compared with placebo in otherwise healthy adult patients (aged ≥ 20 years to ≤ 64 years) with influenza. A total of 400 patients were randomised to one of three dose groups of Xofluza (10 mg, 20 mg or 40 mg) or placebo in the 2015-2016 Northern Hemisphere influenza season in Japan. The predominant influenza virus strain was A/H1N1pdm subtype (61% to 71%) followed by B subtype (21% to 24%) and A/H3N2 subtype (5% to 13%).
The median time to alleviation of symptoms (primary efficacy endpoint) was significantly shorter (p < 0.05) compared with placebo in all dose groups. At 40 mg, the median time to alleviation of symptoms was 49.5 hours (95% CI: 44.5, 64.4) versus 77.7 hours (95% CI: 67.6, 88.7) in the placebo group.

Resolution of fever (secondary efficacy endpoint).

The median time to resolution of fever was significantly reduced in all dose groups compared with placebo. At 40 mg, the median time was 28.9 hours (95% CI: 24.5, 34.7) versus 45.3 hours (95% CI: 35.6, 54.0) in the placebo group. Viral endpoint results were consistent with those in CAPSTONE-1.
Clinical trials in high risk patients.

CAPSTONE-2 (study 1602T0832).

CAPSTONE-2 is a randomised, double-blind, multicentre, placebo- and active-controlled study designed to evaluate the efficacy and safety of a single oral dose of Xofluza compared with placebo or oseltamivir in adult and adolescent patients (aged ≥ 12 years) with influenza at high risk of influenza complications (e.g. asthma or chronic lung disease, endocrine disorders, heart disease, age ≥ 65 years, metabolic disorders, morbid obesity). Patients who had cancer within the last 5 years (other than non-melanoma skin cancer), untreated HIV infection, or treated HIV infection with a CD4 count below 350 cells/mm³ in the last 6 months, were not enrolled in this study.
A total of 2184 patients were randomised to receive a single oral dose of 40 mg or 80 mg of Xofluza according to body weight (40 kg to < 80 kg or ≥ 80 kg respectively), oseltamivir 75 mg twice daily for 5 days, or placebo. The primary efficacy population was defined as those who received study medication, had a positive influenza RT-PCR at trial entry and were enrolled at sites with Good Clinical Practice (GCP) compliance.
The predominant influenza viruses in this study were the A/H3 subtype (46.9% to 48.8%) and influenza B (38.3% to 43.5%). The primary efficacy endpoint was time to improvement of influenza symptoms (cough, sore throat, headache, nasal congestion, feverishness or chills, muscle or joint pain, and fatigue). A statistically significant improvement in the primary endpoint was observed for Xofluza when compared with placebo (Table 5).

Secondary efficacy endpoints.

When the Xofluza group was compared to the oseltamivir group, there was no statistically significant difference in time to improvement of influenza symptoms (73.2 h vs 81.0 h respectively) (Table 6).

For patients infected with type A/H3 virus (predominant strain), the median time to improvement of influenza symptoms was shorter in the Xofluza group compared with the placebo group but not when compared with the oseltamivir group (Table 7). In the subgroup of patients infected with type B virus, the median time to improvement of influenza symptoms was shorter in the Xofluza group compared with both the placebo and oseltamivir group.

Resolution of fever: The proportion of patients who had fever was reduced more rapidly in the Xofluza group than in the placebo group following study drug administration. The median time to resolution of fever was 30.8 hours (95% CI: 28.2, 35.4) in the Xofluza group compared with 50.7 hours (95% CI: 44.6, 58.8) in the placebo group. No clear differences between the Xofluza group and the oseltamivir group were observed.
Incidence of influenza-related complications: The overall incidence of influenza-related complications (death, hospitalisation, sinusitis, otitis media, bronchitis, and/or pneumonia) was 2.8% (11/388 patients) in the Xofluza group compared with 10.4% (40/386 patients) in the placebo group and 4.6% (18/389 patients) in the oseltamivir group. The lower overall incidence of influenza-related complications in the Xofluza group compared with the placebo group was mainly driven by lower incidences of bronchitis (1.8% vs. 6.0%, respectively) and sinusitis (0.3% vs. 2.1%, respectively).
The proportion of patients requiring systemic antibiotics for infections secondary to influenza infection was lower in the Xofluza group (3.4%) compared with the placebo group (7.5%) and the difference between these 2 groups was statistically significant (p=0.0112). The proportion of patients requiring systemic antibiotics in the Xofluza group was comparable with the proportion in the oseltamivir group (3.9%).
Antiviral activity: Patients at high risk of influenza complications treated with Xofluza showed a rapid reduction in virus titre and a significantly shortened time to cessation of viral shedding. The median time to cessation of viral shedding determined by virus titre was 48 hours in the Xofluza group compared with 96 hours in the placebo and oseltamivir groups.

Prophylaxis of influenza.

BLOCKSTONE (study 1719T0834). BLOCKSTONE is a phase 3, randomised, double-blind, multicentre, placebo-controlled study conducted in Japan, designed to evaluate the efficacy of a single oral dose of Xofluza compared with placebo in the prevention of influenza in subjects who are household contacts of influenza-infected patients. Influenza-infected index patients were required to have onset of symptoms for ≤ 48 hours and subjects were required to have lived with the influenza-infected index patients for ≥ 48 hours.
A total of 749 subjects were randomised and received a single oral dose of Xofluza, according to body weight and age, or placebo, on Day 1. Subjects 12 years of age and over received 40 mg or 80 mg of Xofluza according to weight (40 kg to < 80 kg or ≥ 80 kg respectively). Subjects under 12 years of age were dosed according to body weight. The predominant influenza virus strains in the index patients of this study were the A/H3NX subtype (48.4% to 48.8%) and the A/H1N1pdm subtype (47.1% to 48.0%) followed by the B subtype (0.5% to 0.8%) according to household contact groups baloxavir marboxil and placebo, respectively. The primary efficacy endpoint was the proportion of household subjects who were infected with influenza virus and presented with fever and at least one respiratory symptom in the period from Day 1 to Day 10. Influenza virus positivity was assessed by reverse transcription polymerase chain reaction (RT-PCR), fever was defined as a body temperature (axillary) ≥ 37.5°C, and respiratory symptoms were defined as having a symptom of 'cough' or 'nasal discharge/nasal congestion' with a severity of '2, Moderate' or '3, Severe' as assessed in the subject diary.
There was a statistically significant reduction in the proportion of subjects with laboratory-confirmed clinical influenza from 13.6% in the placebo group to 1.9% in the Xofluza group (see Table 8).

Secondary efficacy endpoints.

The analysis for the secondary endpoint of proportion of subjects with influenza virus infection (RT-PCR positive regardless of clinical symptoms) in the period from Day 1 to Day 10 demonstrated results consistent with the primary endpoint. There was a reduction in the proportion of subjects with influenza virus infection from 30.4% (95% CI: 25.8, 35.3) in the placebo group to 13.1% (95% CI: 9.9, 16.9) in the Xofluza group.
Prophylaxis of influenza in subjects ≥ 12 years: The subgroup analysis of the primary endpoint by age revealed that for subjects 12 years of age and older, the proportion of symptomatic influenza-infected (RT-PCR positive) subjects from Day 1 to Day 10 was lower in the baloxavir marboxil group than in the placebo group (1.3% vs. 13.2%) (see Table 8).

5.2 Pharmacokinetic Properties

After oral administration, baloxavir marboxil is extensively converted to its active metabolite (baloxavir) predominantly by arylacetamide deacetylase in the gastrointestinal lumen, intestinal epithelium, and liver. The plasma concentration of baloxavir marboxil was very low or below the limit of quantitation (< 0.100 nanogram/mL).
The pharmacokinetic parameters of baloxavir in Japanese healthy adult subjects after a single oral administration of 40 mg baloxavir marboxil in the fasted and fed states are summarised in Table 9. The pharmacokinetic parameters of baloxavir in Caucasian healthy adult subjects after a single oral administration of 80 mg baloxavir marboxil in the fasted state are summarised in Table 10.
Oral drug clearance of baloxavir in the typical Asian and non-Asian patient (65 kg) was respectively 9.3 L/h and 5.4 L/h. In the Phase 3 study in otherwise healthy patients (CAPSTONE-1), mean drug exposure to baloxavir in terms of AUC_0-inf and C_max were respectively 6881 nanogram.hr/mL and 103 nanogram/mL in the typical Asian patient, and respectively 4645 nanogram.hr/mL and 70.5 nanogram/mL in the typical non-Asian patient. There were no differences in pharmacokinetic parameters between influenza patients who are otherwise healthy (CAPSTONE-1) and patients who are at high risk of complications (CAPSTONE-2).
The apparent terminal elimination half-life (t_1/2,z) of baloxavir after a single oral administration of baloxavir marboxil is 79.1 hours in Caucasian subjects and 93.9 hours in Japanese subjects (Tables 8 and 9).
Linearity/non-linearity: Following single oral administration of baloxavir marboxil, baloxavir exhibits linear pharmacokinetics in the fasted state within the dose range of 6 mg to 80 mg.

Absorption.

Following a single oral administration of 80 mg of baloxavir marboxil, peak plasma concentration (T_max) of baloxavir was reached at approximately 4 hours in the fasted state. The absolute bioavailability of baloxavir marboxil has not been established.

Food effect.

A food-effect study involving the administration of baloxavir marboxil 20 mg tablets to healthy volunteers under fasting conditions and with a moderate fat, moderate calorie meal (approximately 400 to 500 kcal including 150 kcal from fat) indicated that the C_max, AUC_0-72 and AUC_0-inf of baloxavir were decreased by 48%, 44% and 37%, respectively, under fed conditions. T_max was unchanged in the presence of food. In clinical studies with influenza patients where Xofluza was administered with or without food, no clinically relevant differences in efficacy were observed.

Distribution.

In an in vitro study, the binding of baloxavir to human serum proteins, primarily albumin, is 92.9% to 93.9%. The apparent volume of distribution of baloxavir following a single oral administration of 80 mg of baloxavir marboxil is approximately 1180 litres in Caucasian patients and 647 litres in Japanese subjects.

Metabolism.

In vitro studies revealed that arylacetamide deacetylase in the gastrointestinal lumen, intestinal epithelium, and the liver mainly contributes to the conversion from baloxavir marboxil to baloxavir, and baloxavir is primarily metabolised by UGT1A3 with minor contribution from CYP3A4.
In the human mass balance study, after administration of a single oral dose of 40 mg of [¹⁴C] labelled baloxavir marboxil, baloxavir accounted for 82.2% of the plasma AUC for total radioactivity. Baloxavir glucuronide (16.4% of the plasma AUC for total radioactivity) and (12aR,5R,11S) sulfoxide of baloxavir (1.5% of the plasma AUC for total radioactivity) were also detected in plasma.

Excretion.

Baloxavir marboxil and baloxavir are excreted mainly via the faecal route in humans. Following a single oral administration of 40 mg of [¹⁴C]-labelled baloxavir marboxil, the proportion of total radioactivity excreted was 80.1% in the faeces and 14.7% in the urine. The fraction of administered dose excreted in the urine as baloxavir was 3.3%.

Pharmacokinetics in special populations.

Hepatic impairment.

Geometric mean ratios (90% confidence interval) of C_max and AUC of baloxavir in patients with moderate hepatic impairment (Child-Pugh class B) compared to healthy controls were 0.80 (0.50 - 1.28) and 1.12 (0.78 - 1.61), respectively. Since no clinically meaningful differences in the pharmacokinetics of baloxavir were observed in patients with moderate hepatic impairment (Child-Pugh class B) compared with healthy controls with normal hepatic function, no dose adjustment is required in patients with mild or moderate hepatic impairment.
The pharmacokinetics in patients with severe hepatic impairment has not been evaluated.

Renal impairment.

The effects of renal impairment on the pharmacokinetics of baloxavir marboxil or baloxavir have not been evaluated. Renal impairment is not expected to alter the elimination of baloxavir marboxil or baloxavir. Renal excretion represents a minor pathway of elimination for baloxavir marboxil and baloxavir. A population pharmacokinetic analysis did not identify a clinically meaningful effect of renal function on the pharmacokinetics of baloxavir in patients with creatinine clearance (CrCl) 50 mL/min and above. No dose adjustment is required in patients with renal impairment.
Baloxavir is unlikely to be significantly removed by dialysis.

Age.

A population pharmacokinetic analysis using plasma baloxavir concentrations from clinical studies with baloxavir marboxil for subjects aged 12 to 64 years did not identify a clinically meaningful effect of age on the pharmacokinetics of baloxavir.

Elderly.

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

Paediatrics.

The pharmacokinetics of Xofluza in paediatric patients (< 12 years of age) has not been established.

Body weight.

Body weight had a significant effect on the pharmacokinetics of baloxavir (as body weight increases, baloxavir exposure decreases). The dose proposed in adults is 40 mg for patients with body weight 40 kg to < 80 kg and 80 mg for patients with body weight ≥ 80 kg. When dosed with the recommended weight-based dosing, no clinically significant difference in exposure was observed between body weight groups.

Gender.

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

Race.

Based on a population pharmacokinetic analysis, baloxavir exposure is approximately 35% lower in non-Asians as compared to Asians. At the recommended dose, this difference is not considered to be clinically significant and no dose adjustment based on race is required.

5.3 Preclinical Safety Data

Genotoxicity.

Baloxavir marboxil, and its active form, baloxavir, were negative in bacterial reverse mutation tests and micronucleus tests with cultured mammalian cells. Baloxavir marboxil was negative in an in vivo rodent micronucleus test.

Carcinogenicity.

Carcinogenicity studies have not been performed with baloxavir marboxil.

6 Pharmaceutical Particulars

6.1 List of Excipients

Lactose monohydrate, croscarmellose sodium, povidone, microcrystalline cellulose, sodium stearylfumarate, hypromellose, purified talc, titanium dioxide.

6.2 Incompatibilities

See Section 4.5 Interactions with Other Medicines and Other Forms of Interactions.

6.3 Shelf Life

In Australia, information on the shelf life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG). The expiry date can be found on the packaging. Xofluza should not be used after the expiry date (EXP) shown on the pack.

6.4 Special Precautions for Storage

Store below 30°C. Keep in original carton to protect from light and moisture.

6.5 Nature and Contents of Container

Xofluza 20 mg is supplied in aluminium blister packs of 2 film-coated tablets.
Xofluza 40 mg is supplied in aluminium blister packs of 1 and 2 film-coated tablets.
Xofluza 80 mg is supplied in aluminium blister pack of 1 film-coated tablet.

6.6 Special Precautions for Disposal

The release of pharmaceuticals in the environment should be minimised. Medicines should not be disposed of via wastewater and disposal through household waste should be avoided. Unused or expired medicine should be returned to a pharmacy for disposal.

6.7 Physicochemical Properties

Baloxavir marboxil has a molecular weight of 571.55 and a partition coefficient (log P) of 2.26. It is freely soluble in dimethylsulfoxide, soluble in acetonitrile, slightly soluble in methanol and ethanol and practically insoluble in water.

Chemical structure.

CAS number.

1985606-14-1.

Chemical name.

({(12aR)-12-[(11S)-7,8-Difluoro-6,11-dihydrodibenzo[b,e] thiepin-11-yl]-6,8-dioxo-3,4,6,8,12,12a-hexahydro-1H-[1,4] oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazin-7-yl}oxy)methyl methyl carbonate.

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