Consumer medicine information

Paxlovid

Nirmatrelvir; Ritonavir

BRAND INFORMATION

Brand name

Paxlovid

Active ingredient

Nirmatrelvir; Ritonavir

Schedule

SUMMARY CMI

PAXLOVID^®

Consumer Medicine Information (CMI) summary

The full CMI on the next page has more details. If you are worried about taking 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 taking PAXLOVID?

PAXLOVID is a medicine that has two different tablets; one containing the active ingredient, nirmatrelvir and the other containing the active ingredient, ritonavir.

PAXLOVID is used to treat COVID-19 in adults who are at increased risk of progression to hospitalisation or death.

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

2. What should I know before I take PAXLOVID?

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

Talk to your doctor if you have any other medical conditions or if you have reduced kidney or liver function. You must not take PAXLOVID with certain medicines because these medicines may cause serious or life-threatening side effects or affect how PAXLOVID works.

Tell your doctor if you are pregnant or plan to become pregnant, breastfeeding or planning to breastfeed. You should not be taking PAXLOVID if you are pregnant. Women of childbearing potential should be on an effective contraceptive method before starting treatment and for 7 days after stopping treatment. Tell your doctor if you are pregnant or plan to become pregnant, breastfeeding or planning to breastfeed.

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

3. What if I am taking other medicines?

Some medicines may interfere with PAXLOVID 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 take PAXLOVID?

You doctor will decide how much PAXLOVID you will need to take. It will depend on whether you have kidney problems. Nirmatrelvir must be taken together with ritonavir.

More instructions can be found in Section 4. How do I take PAXLOVID? in the full CMI

5. What should I know while taking PAXLOVID?

Things you should do	If you are of childbearing age, you should be taking a contraception while taking PAXLOVID and for 7 days after stopping treatment. Call your doctor straight away if you become pregnant while taking this medicine.
Things you should not do	Do not stop taking this medicine or change the dosage without checking with your doctor. Do not give your medicine to anyone else, even if they have the same condition as you.
Driving or using machines	There is no specific information on the effect of PAXLOVID on your ability to drive or use machines.
Looking after your medicine	Store PAXLOVID below 25°C.

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

6. Are there any side effects?

Side effects may include diarrhoea, vomiting, headache, allergic reactions, high blood pressure, aching muscle, muscle tenderness or weakness not due to exercise, changes in taste or a metallic taste in the mouth, nausea, abdominal pain and generally feeling unwell.

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

PAXLOVID^®

Active ingredient(s): nirmatrelvir and ritonavir

This medicine has provisional approval in Australia to treat COVID-19 in adults who are at increased risk of progression to hospitalisation or death. This approval has been granted on the basis of short-term efficacy and safety data. Evidence of efficacy and safety from ongoing trials continues to be gathered and assessed.

Consumer Medicine Information (CMI)

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

Where to find information in this leaflet:

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

1. Why am I taking PAXLOVID?

PAXLOVID contains the active ingredients nirmatrelvir and ritonavir.

PAXLOVID is used to treat COVID-19 in adults who are at increased risk of progression to hospitalisation or death.

2. What should I know before I take PAXLOVID?

Warnings

Do not take PAXLOVID if:

You are allergic to nirmatrelvir and/or ritonavir or any of the ingredients listed at the end of this leaflet.
You are taking any of these medicines. Taking PAXLOVID with these medicines may cause serious or life-threatening side effects or affect how PAXLOVID work:
- alfuzosin, silodosin, medicine to treat symptoms of an enlarged prostate
- ranolazine, medicine to treat chronic chest pain (angina)
- pethidine, medicine to relieve pain
- amiodarone, flecainide medicine to correct or change heart rhythm or lower blood pressure
- neratinib, apalutamide, venetoclax, medicine to treat certain types of cancers
- colchicine, medicine to treat gout
- lurasidone, clozapine medicine to treat certain mental and emotional health conditions
- eplerenone, ivabradine, medicine used to treat heart failure; eplerenone, medicine for high blood pressure
- ergometrine, medicine to stop excessive bleeding that may occur following childbirth, miscarriage or termination of pregnancy
- simvastatin, medicine to lower blood cholesterol
- eletriptan, medicine used to treat migraine headaches
- finerenone, medicine used to treat kidney disease and type 2 diabetes
- naloxegol, medicine used to treat constipation
- avanafil, vardenafil, when used for erectile dysfunction
- sildenafil, when used to treat high blood pressure in the lungs
- diazepam, medicine to assist anxiety, agitation or muscle spasms, spasticity
- triazolam, zolpidem, medicine that works in the brain to help you sleep
- tolvaptan, medicine used to treat kidney problems or low sodium levels in the blood
- carbamazepine, phenobarbital, phenytoin, primidone, medicine to treat epilepsy to prevent convulsions, fits
- rifampicin, medicine to treat tuberculosis
- lumacaftor/ivacaftor, medicine used to treat cystic fibrosis
- St. John's Wort (hypericum perforatum), a herbal remedy used for depression and anxiety

Check with your doctor if you:

Have or have had problems with your liver.
Have or have had problems with your kidneys.

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

Tell your doctor if you become pregnant or plan to become pregnant, breastfeeding or plan to breast feed. You should not breast-feed your baby while taking PAXLOVID and for 7 days after stopping treatment.

You should not be taking PAXLOVID if you are pregnant.

Women of childbearing potential should be on an effective contraceptive method before starting treatment and for 7 days after stopping treatment.

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 cause serious or life-threatening side effects or affect how PAXLOVID work. These include:

medicines listed in Section 2. What should I know before I take PAXLOVID?
tamsulosin, medicine to treat symptoms of an enlarged prostate
fentanyl, hydrocodone, oxycodone, methadone, piroxicam, medicine to treat pain
digoxin, medicine to treat certain heart conditions
lidocaine, disopyramide, medicine to correct or change heart rhythm
afatinib, abemaciclib, ceritinib, dasatinib, nilotinib, encorafenib, ibrutinib, vinblastine, vincristine, medicine to treat certain types of cancer
aripiprazole, brexpiprazole, cariprazine, haloperidol, risperidone, quetiapine, medicine to treat certain mental and emotional conditions
apixaban, clopidogrel, dabigatran, rivaroxaban, ticagrelor, warfarin, medicine to treat or prevent blood clots
clonazepam, lamotrigine, medicine to prevent or treat convulsions, fits
amitriptyline, fluoxetine, imipramine, nortriptyline, paroxetine, sertraline, medicine to treat depression
loratadine, medicine to treat allergies
atovaquone, clarithromycin, erythromycin, rifabutin, ketoconazole, isavuconazonium sulfate, voriconazole, itraconazole, medicine to treat infections
atazanavir, darunavir, efavirenz, fosamprenavir, maraviroc, nevirapine, saquinavir, tipranavir, raltegravir, zidovudine, bictegravir/ emtricitabine/ tenofovir, medicine to treat HIV
glecaprevir/pibrentasvir or sofosbuvir/ velpatasvir/ voxilaprevir, medicine to treat hepatitis C
salmeterol, medicine to treat severe lung conditions, including asthma and chronic obstructive pulmonary disease (COPD)
amlodipine, diltiazem, felodipine, nifedipine, verapamil, medicine to treat angina or lower blood pressure
ivacaftor, elexacaftor/tezacaftor/ivacaftor, tezacaftor/ivacaftor, medicine used to treat cystic fibrosis
saxagliptin, medicine used to lower blood sugar levels in patients with type 2 diabetes mellitus
ethinylestradiol, medicine to treat hormone deficiency or for contraception
ciclosporin, everolimus, tacrolimus, sirolimus, medicine to suppress the immune system
tofacitinib, upadacitinib, medicine used to treat inflammatory conditions including rheumatoid arthritis, psoriatic arthritis or ulcerative colitis
darifenacin, medicine used to decrease the urgency and the frequency of urination
sildenafil, when used to treat erectile dysfunction
tadalafil, medicine used to treat erectile dysfunction or high blood pressure in the lungs
bosentan, riociguat, medicine to treat high blood pressure in the lungs
atorvastatin, rosuvastatin, medicine to lower cholesterol
alprazolam, midazolam, suvorexant, medicine to help you sleep
clorazepate, medicine used to treat anxiety, convulsions, fits or help you sleep
bupropion, a medicine to assist in giving up smoking
betamethasone, budesonide, ciclesonide, dexamethasone, fluticasone, methylprednisolone, mometasone, triamcinolone, medicine to treat various inflammatory conditions including allergies, asthma or eczema.

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

4. How do I take PAXLOVID?

How much to take

Your doctor will decide how much PAXLOVID you will need to take. It will depend on whether you have kidney problems.

The standard dose is two 150 mg tablets of nirmatrelvir together with one 100 mg tablet of ritonavir.

If you suffer from reduced kidney function, your doctor may tell you to only take one 150 mg tablet of nirmatrelvir with one 100 mg tablet of ritonavir.

Nirmatrelvir and ritonavir tablets can be taken with or without food.

Nirmatrelvir must be taken together with ritonavir.

The tablets should be swallowed whole and not chewed, broken, or crushed.

When to take PAXLOVID

Take PAXLOVID tablets every 12 hours at about the same time each morning and evening. It will help you remember when to take it.

How to long to take PAXLOVID

PAXLOVID is to be taken for 5 days.

Continue taking PAXLOVID until you finish the pack or until your doctor recommends.

If you forget to take PAXLOVID

If you miss a dose of PAXLOVID within 8 hours of the time it is usually taken, take it as soon as you remember.

If you miss a dose by more than 8 hours, skip the missed dose and take the next dose at your regular time. Do not take 2 doses of PAXLOVID at the same time.

If you take too much PAXLOVID

If you think that you have taken too much PAXLOVID, 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 taking PAXLOVID?

Things you should do

Tell your doctor if you become pregnant or plan to become pregnant, breastfeeding or plan to breast feed. Call your doctor straight away if you become pregnant while taking this medicine.

Things you should not do

Do not stop taking this medicine or change the dosage without consulting with your doctor.

Do not give your medicine to anyone else, even if they have the same condition as you.

Driving or using machines

Be careful before you drive or use any machines or tools until you know how PAXLOVID affects you.

Drinking alcohol

No information is available

Looking after your medicine

Store PAXLOVID below 25°C.

Store it in a cool dry place away from moisture, heat, or sunlight; for example, do not store it:

in the bathroom or near a sink, or
in the car or on windowsills.

Do not take this medicine after the expiry date.

Keep it where young children cannot reach it.

Getting rid of any unwanted medicine

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

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.

Side effects

Side effects	What to do
Vomiting Diarrhoea Headache High blood pressure Aching muscle, muscle tenderness or weakness not due to exercise Changes in taste or a metallic taste in the mouth Nausea Abdominal pain Generally feeling unwell.	Speak to your doctor if you have any of these side effects and they worry you.
Severe allergic reaction, including raw, painful and/or peeling of the skin, blisters, sore throat or mouth, or fever. Signs and/or symptoms of an allergic reaction, including rash, itch, development of hives, swelling of the face (or of the tongue, lips, eyes, throat), feeling breathless, light-headed or dizzy, and feeling unwell.	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

What PAXLOVID contains

Nirmatrelvir tablet

Active ingredient (main ingredient)	nirmatrelvir
Other ingredients (inactive ingredients)	Microcrystalline cellulose Lactose monohydrate Croscarmellose sodium Colloidal silicon dioxide Sodium stearylfumarate Opadry Complete Film Coating System 05B140011 Pink.

Ritonavir tablet

Active ingredient (main ingredient)	Ritonavir
Other ingredients (inactive ingredients)	Copovidone Calcium hydrogen phosphate Sorbitan monolaurate Hypromellose Colloidal anhydrous silica Titanium dioxide Sodium stearylfumarate Macrogol 400 Hyprolose Purified talc Macrogol 3350 Polysorbate 80

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

What PAXLOVID looks like

Nirmatrelvir tablet

A pink, oval film-coated tablet debossed with 'PFE' on one side and '3CL' on the other side.

Ritonavir tablet

A white to off-white coated, oval tablet marked with the "a" logo and "NK"; or
A white to off-white coated, oval tablet marked with "NK" on one side.

Pack size

PAXLOVID is supplied in a carton of 30 tablets in five PA/Al/PVC/Al blister cards marked as "Morning Dose" and "Evening Dose" for the tablets to be taken each morning and each evening.

Australian Registration Number

PAXLOVID: AUST R 377572.

Who distributes PAXLOVID

Pfizer Australia Pty Ltd
Sydney NSW
Toll Free Number: 1800 675 229
www.pfizermedinfo.com.au

This leaflet was prepared in February 2024.

Published by MIMS April 2024

BRAND INFORMATION

Brand name

Paxlovid

Active ingredient

Nirmatrelvir; Ritonavir

Schedule

1 Name of Medicine

Paxlovid contains nirmatrelvir tablets co-packaged with ritonavir tablets.

2 Qualitative and Quantitative Composition

Each nirmatrelvir film-coated tablet contains 150 mg of nirmatrelvir.
Each ritonavir film-coated tablet contains 100 mg ritonavir.

Excipient(s) with known effect.

Each nirmatrelvir tablet contains 176 mg lactose.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Nirmatrelvir.

Nirmatrelvir tablets are oval, pink immediate-release, film-coated tablets debossed with "PFE" on one side and "3CL" on the other side.

Ritonavir.

Ritonavir tablets are white to off-white coated, oval tablets debossed with the "a" logo and "NK"; or white to off-white film coated oval tablets debossed with "NK" on one side.

4 Clinical Particulars

4.1 Therapeutic Indications

Paxlovid has provisional approval for the treatment of coronavirus disease 2019 (COVID-19) in adults 18 years of age and older, who do not require initiation of supplemental oxygen due to COVID-19 and are at increased risk of progression to hospitalisation or death (see Section 5.1 Pharmacodynamic Properties, Clinical trials).
The decision has been made on the basis of short term efficacy and safety data. Continued approval of this indication depends on the efficacy and safety data from ongoing clinical trials and post-market assessment.

4.2 Dose and Method of Administration

Nirmatrelvir must be taken together with ritonavir. Failure to correctly take nirmatrelvir with ritonavir will result in plasma levels of nirmatrelvir that will be insufficient to achieve the desired therapeutic effect.

Dosage.

The recommended dosage is 300 mg nirmatrelvir (two 150 mg tablets) with 100 mg ritonavir (one 100 mg tablet) taken together orally every 12 hours for 5 days.
Paxlovid should be taken as soon as possible after a diagnosis of COVID-19 has been made and within 5 days of symptoms onset even if baseline COVID-19 symptoms are mild. Paxlovid treatment should not be initiated in patients requiring hospitalisation due to severe or critical COVID-19. If a patient requires hospitalisation due to severe or critical COVID-19 after starting treatment with Paxlovid, the patient should complete the full 5-day treatment course at the discretion of their healthcare provider.
Paxlovid (both nirmatrelvir and ritonavir tablets) can be taken with or without food (see Section 5.2 Pharmacokinetic Properties). The tablets should be swallowed whole and not chewed, broken, or crushed.
If the patient misses a dose of Paxlovid within 8 hours of the time it is usually taken, the patient should take it as soon as possible and resume the normal dosing schedule. If the patient misses a dose by more than 8 hours, the patient should not take the missed dose and instead take the next dose at the regularly scheduled time. The patient should not double the dose to make up for a missed dose.

Dose adjustment.

Renal impairment.

Mild (eGFR ≥ 60 to < 90 mL/min/1.73 m²).

No dose adjustment is needed in patients with mild renal impairment.

Moderate (eGFR ≥ 30 to < 60 mL/min/1.73 m²).

In patients with moderate renal impairment, the dose of Paxlovid should be reduced to nirmatrelvir/ritonavir 150 mg/100 mg every 12 hours for 5 days to avoid increased toxicity due to over-exposure (this dose adjustment has not been clinically tested).

Note.

The daily blister contains two separated parts each containing 2 tablets of nirmatrelvir and one tablet of ritonavir corresponding to the daily administration at the standard dose.
Therefore, patients with moderate renal impairment should be alerted on the fact that only one tablet of nirmatrelvir with the tablet of ritonavir should be taken every 12 hours.

Severe (eGFR < 30 mL/min/1.73 m²).

Appropriate dose for patients with severe renal impairment has not yet been determined. Paxlovid is contraindicated in patients with severe renal impairment (eGFR < 30 mL/min/1.73 m²) until more data are available; the appropriate dosage for patients with severe renal impairment has not been determined (see Section 4.3 Contraindications).
Hepatic impairment.

Mild and moderate.

No dosage adjustment of Paxlovid is needed for patients with either mild (Child-Pugh Class A) or moderate (Child-Pugh Class B) hepatic impairment.

Severe.

No pharmacokinetic or safety data are available regarding the use of nirmatrelvir or ritonavir in subjects with (Child-Pugh Class C) severe hepatic impairment, therefore, Paxlovid is contraindicated in patients with severe hepatic impairment (see Section 4.3 Contraindications; Section 5.2 Pharmacokinetic Properties).
Paediatric use. The safety and efficacy of Paxlovid in paediatric patients younger than 18 years of age have not yet been established. No data are available.

4.3 Contraindications

Paxlovid is contraindicated in patients with a history of clinically significant hypersensitivity reactions to its active ingredients (nirmatrelvir/ritonavir) or any other components of the product listed in Section 6.1 List of Excipients.
Paxlovid is contraindicated in patients with severe renal impairment.
Paxlovid is contraindicated in patients with severe hepatic impairment.
Paxlovid is contraindicated with drugs that are highly dependent on CYP3A for clearance and for which elevated concentrations are associated with serious and/or life-threatening reactions (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions). Drugs listed in this section and Section 4.5 are a guide and not considered a comprehensive list of all possible drugs that may be contraindicated with Paxlovid.
Paxlovid is contraindicated with drugs that are potent CYP3A inducers where significantly reduced nirmatrelvir or ritonavir plasma concentrations may be associated with the potential for loss of virologic response and possible resistance. Paxlovid cannot be started immediately after discontinuation of any of the following medications due to the delayed offset of the recently discontinued CYP3A inducer (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

4.4 Special Warnings and Precautions for Use

Risk of serious adverse reactions due to interactions with other medicines.

Initiation of Paxlovid, a CYP3A inhibitor, in patients receiving medicinal products metabolised by CYP3A or initiation of medicinal products metabolised by CYP3A in patients already receiving Paxlovid, may increase plasma concentrations of medicinal products metabolised by CYP3A.
Initiation of medicinal products that inhibit or induce CYP3A may increase or decrease concentrations of Paxlovid, respectively.
These interactions may lead to:
Clinically significant adverse reactions, potentially leading to severe, life-threatening or fatal events from greater exposures of concomitant medications.
Clinically significant adverse reactions from greater exposures of Paxlovid.
Loss of therapeutic effect of Paxlovid and possible development of viral resistance.
Severe, life-threatening, and fatal adverse reactions due to drug interactions have been reported in patients treated with Paxlovid.
See Tables 1 and 2 for medicinal products that are contraindicated for concomitant use with Paxlovid (see Section 4.3 Contraindications) and Table 3 for potentially significant interactions with other medicinal products (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions). Consider the potential for interactions with other medicinal products prior to and during Paxlovid therapy; review concomitant medications during Paxlovid therapy and monitor for the adverse reactions associated with the concomitant medications.

Co-administration of Paxlovid with calcineurin inhibitors and mTOR inhibitors.

Consultation of a multidisciplinary group (e.g. involving physicians, specialists in immunosuppressive therapy, and/or specialists in clinical pharmacology) is required to handle the complexity of this co-administration by closely and regularly monitoring immunosuppressant serum concentrations and adjusting the dose of the immunosuppressant in accordance with the latest guidelines (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

Hypersensitivity reactions.

Anaphylaxis, hypersensitivity reactions, and serious skin reactions (including toxic epidermal necrolysis and Stevens-Johnson syndrome) have been reported with Paxlovid (see Section 4.8 Adverse Effects (Undesirable Effects)). If signs and symptoms of a clinically significant hypersensitivity reaction or anaphylaxis occur, immediately discontinue Paxlovid and initiate appropriate medications and/or supportive care.

Hepatotoxicity.

Hepatic transaminase elevations, clinical hepatitis and jaundice have occurred in patients receiving ritonavir. Therefore, caution should be exercised when administering Paxlovid to patients with pre-existing liver diseases, liver enzyme abnormalities, or hepatitis (see Section 4.2 Dose and Method of Administration, Hepatic impairment).

Risk of HIV-1 resistance development.

As nirmatrelvir is co-administered with low dose ritonavir, there may be a risk of HIV-1 developing resistance to HIV protease inhibitors in individuals with uncontrolled or undiagnosed HIV-1 infection.

Excipients.

Paxlovid contains lactose. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicine. The level of lactose within this preparation should not routinely preclude the use of this medication in those with galactosaemia.
Nirmatrelvir and ritonavir each contain less than 1 mmol sodium (23 mg) per dose, that is to say essentially 'sodium-free'.

Use in hepatic impairment.

No dosage adjustment of Paxlovid is needed for patients with either mild (Child-Pugh Class A) or moderate (Child-Pugh Class B) hepatic impairment. No pharmacokinetic or safety data are available regarding the use of nirmatrelvir or ritonavir in subjects with severe hepatic impairment (Child-Pugh Class C), therefore, Paxlovid is not recommended for use in patients with severe hepatic impairment (see Section 4.2 Dose and Method of Administration, Hepatic impairment; Section 4.3 Contraindications; Section 5.2 Pharmacokinetic Properties, Patients with hepatic impairment).

Use in renal impairment.

Systemic exposure of nirmatrelvir increases in renally impaired patients with increase in the severity of renal impairment (see Section 5.2 Pharmacokinetic Properties).
No dose adjustment is needed in patients with mild renal impairment. In patients with moderate renal impairment the dose of Paxlovid should be reduced. (See Section 4.2 Dose and Method of Administration, Renal impairment). Paxlovid is contraindicated in patients with severe renal impairment (see Section 4.3 Contraindications).

Use in the elderly.

Clinical studies of Paxlovid include participants 65 years of age and older and their data contributes to the overall assessment of safety and efficacy (see Section 4.8 Adverse Effects (Undesirable Effects); Section 5.1 Pharmacodynamic Properties, Clinical trials). Of the total number of participants in EPIC-HR randomised to receive Paxlovid (N = 1,120), 13% were 65 years of age and older and 3% were 75 years of age and older.

Paediatric use.

The safety and efficacy of Paxlovid in paediatric patients younger than 18 years of age have not yet been established. No data available.

Effects on laboratory tests.

Ritonavir has been associated with alterations in cholesterol, triglycerides, AST, ALT, GGT, CPK and uric acid (also see Section 4.4 Special Warnings and Precautions for Use, Use in hepatic impairment). For comprehensive information concerning laboratory test alterations associated with nucleoside analogues, physicians should refer to the complete product information for each of these drugs.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Paxlovid (nirmatrelvir/ritonavir) is a strong inhibitor of CYP3A and an inhibitor of CYP2D6, P-gp and OATP1B1. Co-administration of Paxlovid with drugs that are primarily metabolised by CYP3A and CYP2D6 or are transported by P-gp or OATP1B1 may result in increased plasma concentrations of such drugs and increase the risk of adverse reactions.
Medicinal products that are extensively metabolised by CYP3A and have high first pass metabolism appear to be the most susceptible to large increases in exposure when co-administered with nirmatrelvir/ritonavir. Thus, co-administration of Paxlovid with medicinal products highly dependent on CYP3A for clearance and for which elevated plasma concentrations are associated with serious and/or life threatening events is contraindicated (see Section 4.3 Contraindications, Table 1).
Nirmatrelvir does not reversibly inhibit CYP2D6, CYP2C9, CYP2C19, CYP2C8 and CYP1A2 or UGT1A1, UGT1A4, UGTA6, UGT1A9, UGT2B7 and UGTB15 in vitro at clinically relevant concentrations. Nirmatrelvir is unlikely to be an inducer of CYP1A2, CYP2C19, CYP2B6, CYP2C8 and CYP2C9 enzymes. Based on in vitro data, nirmatrelvir has a low potential to inhibit BCRP, MATE1, MATE2K, OAT1, OAT3, OATP1B3, OCT1 and OCT2.
Ritonavir has a high affinity for several cytochrome P450 (CYP) isoforms and may inhibit oxidation with the following ranked order: CYP3A4 > CYP2D6 > CYP2C9, CYP2C19 >> CYP2A6, CYP1A2, CYP2E1. Ritonavir also has a high affinity for P-glycoprotein (P-gp) and may inhibit this transporter. Ritonavir may induce glucuronidation and oxidation by CYP1A2, CYP2C8, CYP2C9 and CYP2C19 thereby increasing the biotransformation of some medicinal products metabolised by these pathways and may result in decreased systemic exposure to such medicinal products, which could decease or shorten their therapeutic effect.
Co-administration of other CYP3A4 substrates that may lead to potentially significant drug interactions should be considered only if the benefits outweigh the risks (see Table 3).
Nirmatrelvir and ritonavir are CYP3A substrates; therefore, medicinal products that induce CYP3A may decrease nirmatrelvir and ritonavir plasma concentrations and reduce Paxlovid therapeutic effect.
The drug-drug interactions listed in Tables 1 and 2 (see Section 4.3 Contraindications) and Table 3 correspond to drug-drug interactions related to ritonavir. As a conservative approach, they should also apply for Paxlovid.
Medicinal products listed in Tables 1 and 2 (see Section 4.3 Contraindications) and Table 3 are a guide and not considered a comprehensive list of all possible medicinal products that may interact with nirmatrelvir/ritonavir. The healthcare provider should consult appropriate references for comprehensive information.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

There are no human data on the effect of Paxlovid on fertility.

Nirmatrelvir.

No human data on the effect of nirmatrelvir on fertility are available.
There were no nirmatrelvir-related effects on fertility and reproductive performance in male and female rats treated orally at doses up to 1,000 mg/kg/day for 14 days before mating, resulting in systemic exposure approximately 7 times the human exposure based on unbound AUC at the recommended clinical dose.

Ritonavir.

There are no human data on the effect of ritonavir on fertility. Ritonavir produced no effects on fertility in rats.
(Category B3)
Paxlovid is not recommended during pregnancy and in women of childbearing potential not using contraception.
There are limited human data on the use of Paxlovid during pregnancy to evaluate the drug-associated risk of adverse developmental outcomes; women of childbearing potential should avoid becoming pregnant during treatment and until after 7 days after stopping Paxlovid.

Nirmatrelvir.

The potential embryo-fetal toxicity of nirmatrelvir was evaluated in rats and rabbits. Animal data with nirmatrelvir have shown developmental toxicity in the rabbit (lower fetal body weights) but not in the rat. There was no nirmatrelvir-related effect on rat embryo-fetal development up to the highest dose of 1,000 mg/kg/day (12 times the human exposure based on unbound AUC at the recommended clinical dose). In the rabbit embryo-fetal development study, adverse nirmatrelvir-related lower fetal body weights (9% decrease) were observed at the highest dose of 1,000 mg/kg/day (25 times the human exposure based on unbound AUC at the recommended clinical dose) in the presence of low magnitude effects on maternal body weight change and food consumption. These findings were not present at the intermediate dose of 300 mg/kg/day (10 x/2.8 x C_max/AUC₂₄ over the predicted clinical exposure).
There were no nirmatrelvir-related adverse effects in a pre- and postnatal developmental study in rats. In a pre- and postnatal developmental study in rats dosed with nirmatrelvir from gestation day 6 to lactation day 20, lower body weights (up to 8% lower than that of the control group on postnatal day 17) were observed in the offspring of pregnant rats at 1000 mg/kg/day (10 times the human exposure based on unbound AUC at the recommended clinical dose). No significant differences in offspring body weight were observed from PND 28 to PND 56. No body weight changes in the offspring were noted at 300 mg/kg/day (6 times the human exposure based on unbound AUC at the recommended clinical human dose).

Ritonavir.

Use of ritonavir may reduce the efficacy of combined hormonal contraceptives. Patients using combined hormonal contraceptives should be advised to use an effective alternative contraceptive method or an additional barrier method of contraception during treatment with Paxlovid, and during a menstrual cycle after stopping Paxlovid (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).
A large number of pregnant women exposed to ritonavir during pregnancy indicate no increase in the rate of birth defects compared to rates observed in population-based birth defect surveillance systems.
Based on the review of data from the US Antiretroviral (ART) Pregnancy Registry through 31 July 2016, among women exposed to ritonavir-containing antiretroviral therapy (ART) during first trimester the prevalence rate of birth defects per 100 live births (65 cases in 2983 enrolled) was 2.2% (95% CI 1.7, 2.8%). The prevalence rate of birth defects for exposure to ritonavir-containing ART during second/third trimester (97 cases in 3330 enrolled) was 2.9% (95% CI 2.4%, 3.5%). In a reference population in the US CDC's birth defects surveillance system (MACDP) the reported background rate of birth defects is 2.7%. These data largely refer to exposures where ritonavir was used in combination therapy and not at therapeutic ritonavir doses but at lower doses as a pharmacokinetic PK enhancer for other protease inhibitors, similar to the ritonavir dose used for nirmatrelvir/ritonavir.
No treatment-related malformations were observed when ritonavir was administered orally to pregnant rats or rabbits. Developmental toxicity observed in rats (early resorptions, decreased fetal body weight and ossification delays and developmental variations) occurred at a maternally toxic dosage of 75 mg/kg/day. A slight increase in the incidence of cryptorchidism was also noted in rats given 35 mg/kg/day. Developmental toxicity observed in rabbits (resorptions, decreased litter size and decreased fetal weights) also occurred at a maternally toxic dosage of 110 mg/kg/day. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.
There are no available data on the presence of nirmatrelvir in human or animal milk, the effects on the breastfed infant, or the effects on milk production.
Limited published data reports that ritonavir is present in human milk. There is no information on the effects of ritonavir on the breast-fed newborn/infant or the effects of the medicinal product on milk production. A risk to the newborn/infant cannot be excluded.
Breast feeding should be discontinued during treatment with Paxlovid and for 7 days after the last dose of Paxlovid.

4.7 Effects on Ability to Drive and Use Machines

The effects of this medicine on a person's ability to drive and use machines were not assessed as part of its registration.

4.8 Adverse Effects (Undesirable Effects)

The safety of Paxlovid is based on data from three phase 2/3 randomised, placebo controlled trials in adult participants 18 years of age and older (see Section 5.1 Pharmacodynamic Properties):
Study C4671005 (EPIC-HR) and Study C4671002 (EPIC-SR) investigated Paxlovid (nirmatrelvir/ritonavir 300 mg/100 mg) every 12 hours for 5 days in symptomatic participants with a laboratory confirmed diagnosis of SARS-CoV-2 infection. Participants had mild to moderate COVID-19 disease at baseline.
Study C4671006 (EPIC-PEP) investigated Paxlovid (nirmatrelvir/ritonavir) 300 mg/100 mg) every 12 hours for 5 or 10 days in asymptomatic household contact of individuals with a recent diagnosis of SARS-CoV-2 infection. Participants were to have a negative SARS-CoV-2 result at baseline.
Across the three studies, 3643 participants received a dose of Paxlovid and 2668 participants received a dose of placebo. The most common adverse reactions (≥1% incidence in the Paxlovid group and occurring at a greater frequency than in the placebo group) were dysgeusia (5.8% and 0.5%, respectively) and diarrhoea (2.8% and 1.8%, respectively).
In Study C4671005 (EPIC-HR), the proportions of subjects who discontinued treatment due to an adverse event were 23 (2.1%) in the Paxlovid group and 47 (4.2%) in the placebo group. The proportion of subjects with serious adverse events were 18 (1.6%) and 74 (6.6%) in the Paxlovid group and in the placebo group, respectively.
The adverse drug reactions in Table 5 are listed by system organ class and frequency. Frequencies are defined as follows: Very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1000 to < 1/100); rare (≥ 1/10,000 to < 1/1000); not known (frequency cannot be estimated from the available data).

Post-marketing experience.

In addition to the adverse events observed in clinical trials, the following adverse effects have been reported post-marketing.

Immune system disorders.

Anaphylaxis, hypersensitivity.

Gastrointestinal disorders.

Nausea, abdominal pain.

Skin and subcutaneous tissue disorders.

Toxic epidermal necrolysis, Stevens-Johnson syndrome.

General disorders and administration site conditions.

Malaise.

Reporting suspected adverse effects.

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

Treatment of overdose with Paxlovid should consist of general supportive measures including monitoring of vital signs and observation of the clinical status of the patient. There is no specific antidote for overdose with Paxlovid.
For information on the management of overdose, contact the Poisons Information Centre on 13 11 26 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Nirmatrelvir is a peptidomimetic inhibitor of the SARS-CoV-2 main protease (Mpro), also referred to as 3C-like protease (3CLpro) or nsp5 protease. Inhibition of SARS-CoV-2 Mpro renders the protein incapable of processing polyprotein precursors which leads to the prevention of viral replication. Nirmatrelvir was shown to be an inhibitor of SARS-CoV-2 Mpro (Ki=3.1 nanoM, or IC₅₀=19.2 nanoM) in a biochemical enzymatic assay. Nirmatrelvir was found to bind directly to the SARS-CoV-2 Mpro active site by X-ray crystallography.
Ritonavir inhibits the CYP3A-mediated metabolism of nirmatrelvir, thereby providing increased plasma concentrations of nirmatrelvir.

Antiviral activity.

In vitro antiviral activity. Nirmatrelvir exhibited antiviral activity against SARS-CoV-2 infection of differentiated normal human bronchial epithelial (dNHBE) cells, a primary human lung alveolar epithelial cell line (EC₅₀ value of 61.8 nanoM and EC₉₀ value of 181 nanoM) after 3 days of drug exposure.
Nirmatrelvir had similar cell culture antiviral activity (EC₅₀ values in the low nanomolar range ≤ 1.1-fold relative to USA-WA1/2020) against SARS-CoV-2 isolates belonging to the Alpha (B.1.1.7), Gamma (P.1), Delta (B.1.617.2), Lambda (C.37), Mu (B.1.621.1) and Omicron (B.1.1.529/BA.1) variants assessed in Vero E6 P-gp knockout cells. The Beta (B.1.351) variant was the least susceptible tested variant with approximately 3.7-fold reduced susceptibility relative to the USA-WA1/2020 isolate.
The antiviral activity of nirmatrelvir against the Omicron sub-variants BA.2, BA.2.12.1, BA.4, BA.4.6, BA.5, BF.7 (P252L+F294L), BF.7 (T243I), BQ.1.11, BQ.1, and XBB.1.5 was assessed in Vero E6-TMPRSS2 cells in the presence of a P-gp inhibitor. Nirmatrelvir had a median EC₅₀ value of 83 nanoM (range: 39-146 nanoM) against the Omicron sub-variants, reflecting EC₅₀ value fold-changes ≤ 1.5 relative to the USA-WA1/2020 isolate.
Nirmatrelvir showed antiviral activity in different assays than those used for the other VoCs against the Omicron variant with IC₅₀ values of 70 nanoM and 23 nanoM in the HeLa-ACE2 and Vero-TMPRSS cells compared to the SARS-CoV-2 USA-WA1/2020 strain which had IC₅₀ values of 207 nanoM and 38 nanoM in the same cell lines, respectively, using an immunostaining-based method.
Antiviral activity against SARS-CoV-2 in animal models. Nirmatrelvir showed antiviral activity in BALB/c and 129 mice infected with mouse-adapted SARS-CoV-2. Oral administration of nirmatrelvir at 300 mg/kg or 1000 mg/kg twice daily initiated 4 hours post-inoculation or 1000 mg/kg twice daily initiated 12 hours post-inoculation resulted in reduction of lung viral titers and ameliorated indicators of disease (weight loss and lung pathology) compared to placebo-treated animals.
Additionally, nirmatrelvir as a single agent and in combination with ritonavir were evaluated for antiviral efficacy in the BALB/c mouse SARS-CoV-2-MA-10 model. Ritonavir alone did not demonstrate antiviral activity against in vivo virus replication and did not contribute to disease pathology, however, the combination of ritonavir and nirmatrelvir resulted in reduced virus replication compared to nirmatrelvir or ritonavir alone and reduced lung pathology compared to ritonavir alone or dosing vehicle.

Antiviral resistance in cell culture and biochemical assays.

SARS-CoV-2 Mpro residues potentially associated with nirmatrelvir resistance have been identified using a variety of methods, including SARS-CoV-2 resistance selection, testing of recombinant SARS-CoV-2 viruses with Mpro substitutions, and biochemical assays with recombinant SARS-CoV-2 Mpro containing amino acid substitutions. Table 6 indicates Mpro substitutions and combinations of Mpro substitutions that have been observed in nirmatrelvir-selected SARS-CoV-2 in cell culture. Individual Mpro substitutions are listed regardless of whether they occurred alone or in combination with other Mpro substitutions. Note that the Mpro S301P and T304I substitutions overlap the P6 and P3 positions of the nsp5/nsp6 cleavage site located at the C-terminus of Mpro. Substitutions at other Mpro cleavage site have not been associated with nirmatrelvir resistance in cell culture. The clinical significance of these substitutions is unknown.

In a biochemical assay using recombinant SARS-CoV-2 Mpro containing amino acid substitutions, the following SARS-CoV-2 Mpro substitutions led to ≥ 3-fold reduced activity (fold change based on Ki values) of nirmatrelvir: G15S (4.4), Y54A (24.0), T135I (3.2), F140A (39.0), F140L (5.4), S144A (92.0), S144E (470), S144T (160), H164N (6.4), E166A (33.0), E166G (16.0), H172Y (230), A173V (26.0), V186G (13.0), Q189K (65.0), Q192L (28.0), Q192P (33.0), and D248E (3.7). The clinical significance of these substitutions is unknown.
Most single Mpro mutations and some double mutations identified which reduced the susceptibility of SARS-CoV-2 to nirmatrelvir resulted in an EC₅₀ shift of < 5-fold compared to wild type SARS-CoV-2. Virus containing E166V, which confers high resistance, appears to have replication defect since it either could not be generated or had a very low virus titer although double mutants E166V + T21I or L50F replicated well with growth kinetics similar to WT. Both T21I and L50F rescued the replication defect conferred by E166V and double mutants T21I + E166V and L50F + E166V, as well as E166V, are highly resistant to nirmatrelvir. In general, triple mutations and some double mutations led to EC₅₀ changes of > 5-fold to that of wild type. The clinical significance of these mutations needs to be further understood, particularly in the context of nirmatrelvir high clinical exposure (≥ 5x EC₉₀). Thus far, these mutations have not been identified as treatment-emergent mutations associated with treatment failure or hospitalisation from the EPIC-HR or the EPIC-SR study.

Viral load rebound and treatment-emergent mutations.

Post-treatment increases in SARS-CoV-2 RNA shedding levels (i.e. viral RNA rebound) in nasopharyngeal samples were observed on Day 10 and/or Day 14 in both nirmatrelvir-ritonavir and placebo recipients in the EPIC-HR study. Viral RNA rebound was detected in 4.2% (36 of 852) of placebo participants and 6.3% (54 of 862) of nirmatrelvir-ritonavir participants. The results of EPIC-HR do not suggest an association between viral RNA rebound and COVID-19 related hospitalisation or death from any cause. The clinical relevance of viral RNA rebound following Paxlovid or placebo remains unclear.
The findings of EPIC-HR suggest that the clinical relevance of treatment-emergent mutations remains unclear.

Cross-resistance.

Cross-resistance is not expected between nirmatrelvir and anti-SARS-CoV-2 monoclonal antibodies (mAb) or remdesivir based on their different mechanisms of action.

Pharmacodynamic effects.

Cardiac electrophysiology.

No clinically relevant effect of nirmatrelvir on QTcF interval was observed in a double blind, randomised, placebo-controlled, cross-over study in 10 healthy adults. The model predicted upper bound of 90% confidence interval (CI) for baseline and ritonavir adjusted QTcF estimate was 1.96 ms at approximately 4-fold higher concentration than the mean steady-state peak concentration after a therapeutic dose of nirmatrelvir/ritonavir 300 mg/100 mg.

Effects on viral RNA levels.

Changes in viral RNA levels in nasopharyngeal samples from baseline to Day 5 were evaluated in 1,454 unvaccinated people in EPIC-HR, and 816 participants in EPIC-SR (63% vaccinated against COVID-19). In EPIC-HR the mean viral load reduction in Paxlovid recipients relative to placebo was -0.744 log10 copies/mL (95% CI -0.903, -0.585). In EPIC-SR the equivalent value was -0.883 log10 copies/mL (95% CI -1.101, -0.666).

Clinical trials.

Efficacy in participants at high risk of progressing to severe COVID-19 illness (EPIC-HR).

The efficacy of Paxlovid is based on the analysis of EPIC-HR, a Phase 2/3, randomised, double-blind, placebo-controlled study in non-hospitalised symptomatic adult participants with a confirmed diagnosis of SARS-CoV-2 infection.
Eligible participants were 18 years of age and older with at least 1 of the following risk factors for progression to severe disease: diabetes, overweight (BMI > 25), chronic lung disease (including asthma), chronic kidney disease, current smoker, immunosuppressive disease or immunosuppressive treatment, cardiovascular disease, hypertension, diabetes, sickle cell disease, neurodevelopmental disorders, active cancer or medically-related technological dependence, or were 60 years of age and older regardless of comorbidities. The study excluded individuals with a known history of prior COVID-19 infection or vaccination. Participants with COVID-19 symptom onset of ≤ 5 days were included in the study.
The primary efficacy endpoint is the proportion of participants with COVID-19 related hospitalisation or death from any cause through Day 28. The analysis was conducted in the modified intent-to-treat (mITT) analysis set (all treated participants with onset of symptoms ≤ 3 days at baseline did not receive nor were expected to receive COVID-19 therapeutic monoclonal antibody (mAb) treatment), the mITT1 analysis set (all treated subjects with onset of symptoms ≤ 5 days who at baseline did not receive nor were expected to receive COVID-19 therapeutic mAb treatment), and the mITT2 analysis set (all treated subjects with onset of symptoms ≤ 5 days).
A total of 2,246 participants were randomised to receive either Paxlovid or placebo. At baseline, mean age was 46 years with 51% were male; 72% were White, 5% were Black or African American, and 14% were Asian; 45% were Hispanic or Latino; 66% of subjects had onset of symptoms ≤ 3 days before initiation of study treatment; 47% of subjects were serological negative at baseline; the mean (SD) baseline viral load was 4.63 log₁₀ copies/mL (2.87); 26% of subjects had a baseline viral load of > 10^7 (units); 6% of participants either received or were expected to receive COVID-19 therapeutic monoclonal antibody treatment at the time of randomisation and were excluded from the mITT and mITT1 analyses.
The baseline demographic and disease characteristics were balanced between the Paxlovid and placebo groups.
At the primary completion date (PCD) analysis, 697 (62.2%) participants in the Paxlovid group and 682 (60.6%) participants in the placebo group were included in the mITT analysis set. The event rate of a COVID-19-related hospitalisation or death from any cause through Day 28 in the mITT analysis set in participants who received treatment within 3 days of symptom onset was 44/682 (6.45%) in the placebo group, and 5/697 (0.72%) in the Paxlovid group. The Paxlovid group showed a 5.81% (95% CI: -7.78% to -3.84; p < 0.0001) absolute reduction, or 88.9% relative reduction in primary endpoint events compared to placebo. No deaths were reported in the Paxlovid group compared with 9 deaths in the placebo group.
Table 7 provides results of the primary endpoint in mITT1 analysis population. For the primary endpoint, the relative risk reduction in the mITT1 analysis population for Paxlovid compared to placebo was 86% (95% CI: 73%, 93%).

Consistent results were observed in the mITT and mITT2 analysis populations. A total of 1,379 subjects were included in the mITT analysis population. The event rates were 5/697 (0.72%) in the Paxlovid group, and 44/682 (6.45%) in the placebo group.
Similar trends have been observed across subgroups of participants (see Figure 1). These subgroup analyses are considered exploratory.

Efficacy in vaccinated participants with at least 1 risk factor for progression to severe COVID 19 illness (EPIC-SR).EPIC-SR was a Phase 2/3, randomised, double-blind, placebo-controlled trial in non-hospitalised symptomatic adult subjects with a laboratory confirmed diagnosis of SARS-CoV-2 infection. Eligible subjects were 18 years of age or older with COVID-19 symptom onset of ≤ 5 days who were at standard risk for progression to severe disease. The trial included previously unvaccinated subjects with no risk factors for progression to severe disease or subjects fully vaccinated against COVID-19 (i.e., completed a primary vaccination series) with at least 1 of the risk factors for progression to severe disease as defined in EPIC-HR. Through 19 Dec 2021, data cutoff, a total of 1,075 subjects were randomised (1:1) to receive Paxlovid or placebo orally every 12 hours for 5 days; of these, 63% were fully vaccinated high-risk subjects.
The primary endpoint in this trial, the difference in time to sustained alleviation of all targeted COVID-19 signs and symptoms through Day 28 among Paxlovid versus placebo recipients, was not met.
In an exploratory analysis of the subgroup of fully vaccinated subjects with at least 1 risk factor for progression to severe disease, a non-statistically significant numerical reduction (3/317 (0.9%) Paxlovid recipients versus 7/314 (2.2%) placebo recipients) relative to placebo for the secondary endpoint of COVID-19 related hospitalisation or death from any cause through Day 28 was observed.
Post-exposure prophylaxis (EPIC-PEP).EPIC-PEP was a phase 2/3, randomised, double-blind, double-dummy, placebo-controlled study assessing the efficacy of Paxlovid (administered 5 days or 10 days) in post-exposure prophylaxis of COVID-19 in household contacts of symptomatic individuals infected with SARS-CoV-2. Eligible participants were asymptomatic adults 18 years of age and older who were SARS-CoV-2 negative at screening and who lived in the same household with symptomatic individuals with a recent diagnosis of SARS-CoV-2. A total of 2957 participants were randomised (1:1:1) to receive Paxlovid orally every 12 hours for 5 days, Paxlovid orally every 12 hours for 10 days, or placebo.
The results of the primary endpoint for EPIC-PEP are presented in Table 8.

5.2 Pharmacokinetic Properties

The pharmacokinetics of nirmatrelvir/ritonavir have been studied in healthy participants and in participants with mild to moderate COVID-19.
Ritonavir is administered with nirmatrelvir as a pharmacokinetic (PK) enhancer resulting in higher systemic concentrations and longer half-life of nirmatrelvir. In healthy participants in the fasted state, the mean half-life (t_1/2) of a single dose of 150 mg nirmatrelvir administered alone was approximately 2 hours compared to 7 hours after administration of a single dose of 250 mg/100 mg nirmatrelvir/ritonavir thereby supporting a twice daily administration regimen.
Upon administration of single dose of nirmatrelvir/ritonavir 250 mg/100 mg as oral suspension formulation to healthy participants in the fasted state, the geometric mean (CV%) maximum concentration (C_max) and area under the plasma concentration-time curve from 0 to the time of last measurement (AUC_last) was 2.88 microgram/mL (25%) and 27.6 microgram.hr/mL (13%), respectively. Upon repeat-dose of nirmatrelvir/ritonavir 75 mg/100 mg, 250 mg/100 mg, and 500 mg/100 mg administered twice daily, the increase in systemic exposure at steady-state appears to be less than dose proportional. Multiple dosing over 10 days achieved steady-state on Day 2 with approximately 2-fold accumulation. Systemic exposures on Day 5 were similar to Day 10 across all doses.

Absorption.

Following oral administration of nirmatrelvir/ritonavir 300 mg/100 mg after a single dose, the geometric mean nirmatrelvir (CV%) C_max and area under the plasma concentration time curve from 0 to infinity (AUC_inf) was 2.21 microgram/mL (33) and 23.01 microgram.hr/mL (23), respectively. The median (range) time to C_max (T_max) was 3.00 hrs (1.02-6.00). The arithmetic mean (±SD) terminal elimination half-life was 6.1 (1.8) hours.
Following oral administration of nirmatrelvir/ritonavir 300 mg/100 mg after a single dose, the geometric mean ritonavir (CV%) C_max and (AUC_inf) was 0.36 microgram/mL (46) and 3.60 microgram.hr/mL (47), respectively. The median (range) time to C_max (T_max) was 3.98 hrs (1.48-4.20). The arithmetic mean (±SD) terminal elimination half-life was 6.1 (2.2) hours.

Effect of food on oral absorption.

Dosing with a high fat meal increased the exposure of nirmatrelvir (approximately 61% increase in mean C_max and 20% increase in mean AUC_last) relative to fasting conditions following administration of a 300 mg nirmatrelvir (2 x 150 mg)/100 mg ritonavir tablets.

Distribution.

The protein binding of nirmatrelvir in human plasma is approximately 69%.
The protein binding of ritonavir in human plasma is approximately 98-99%.

Metabolism.

Nirmatrelvir.

In vitro studies assessing nirmatrelvir without concomitant ritonavir suggest that nirmatrelvir is primarily metabolised by CYP3A4. Administration of nirmatrelvir with ritonavir inhibits the metabolism of nirmatrelvir. In plasma, the only drug-related entity observed was unchanged nirmatrelvir. Minor oxidative metabolites were observed in the faeces and urine.

Ritonavir.

Nearly all of the plasma radiolabel after a single oral 600 mg dose of radiolabeled ritonavir was attributed to unchanged ritonavir. Four ritonavir metabolites have been identified in man. The isopropylthiazole oxidation metabolite (M-2) is the major metabolite. The AUC of the M-2 metabolite was approximately 3% of the AUC of parent drug. Studies utilising human liver microsomes have demonstrated that CYP3A4 is the major isoform involved in ritonavir metabolism, although CYP2D6 also contributes to the formulation of M-2. The metabolites are principally eliminated in the faeces.

Excretion.

The primary route of elimination of nirmatrelvir when administered with ritonavir was renal excretion of intact drug. Approximately 49.6% and 35.3% of the administered dose of nirmatrelvir 300 mg was recovered in urine and faeces, respectively. Nirmatrelvir was the predominant drug-related entity with small amounts of metabolites arising from hydrolysis reactions in excreta. In plasma, the only drug-related entity quantifiable was unchanged nirmatrelvir.
Human studies with radiolabelled ritonavir demonstrated that the elimination of ritonavir was primarily via the hepatobiliary system; approximately 86% of radiolabel was recovered from stool, part of which is expected to be unabsorbed ritonavir.

Special populations.

The pharmacokinetics of nirmatrelvir/ritonavir based on age and gender have not been evaluated.

Racial or ethnic groups.

Systemic exposure in Japanese participants was numerically lower but not clinically meaningfully different than those in Western participants.

Patients with renal impairment.

An open-label study compared nirmatrelvir/ritonavir pharmacokinetics in healthy adult subjects and subjects with mild (eGFR ≥ 60 to < 90 mL/min/1.73 m²), moderate (eGFR ≥ 30 to < 60 mL/min/1.73 m²), and severe (eGFR < 30 mL/min/1.73 m²) renal impairment following administration of a single oral dose of nirmatrelvir 100 mg enhanced with ritonavir 100 mg administered at -12, 0, 12, and 24 hours. Compared to healthy controls with no renal impairment, the C_max and AUC of nirmatrelvir in patients with mild renal impairment was 30% and 24% higher, in patients with moderate renal impairment was 38% and 87% higher, and in patients with severe renal impairment was 48% and 204% higher, respectively. See Table 9.

Patients with hepatic impairment.

A single oral dose of 100 mg nirmatrelvir enhanced with 100 mg ritonavir at -12 hours, 0 hours, 12 hours and 24 hours in subjects with moderate hepatic impairment resulted in similar exposures compared to subjects with normal hepatic function (see Table 10).
The pharmacokinetics of nirmatrelvir/ritonavir have not been evaluated in patients with severe hepatic impairment.

Drug interaction studies conducted with nirmatrelvir/ritonavir.

CYP3A4 was the major contributor to the oxidative metabolism of nirmatrelvir, when nirmatrelvir was tested alone in human liver microsomes. Ritonavir is an inhibitor of CYP3A and increases plasma concentrations of nirmatrelvir and other drugs that are primarily metabolized by CYP3A. Despite being co-administered with ritonavir as a pharmacokinetic enhancer, there is potential for strong inhibitors and inducers to alter the pharmacokinetics of nirmatrelvir.
The effects of co-administration of Paxlovid with itraconazole (CYP3A inhibitor) and carbamazepine (CYP3A inducer) on the nirmatrelvir AUC and C_max are summarised in Table 11 (effect of other medicinal products on nirmatrelvir).

The effects of co-administration of Paxlovid with midazolam (CYP3A4 substrate) or dabigatran (P-gp substrate) on the midazolam and dabigatran AUC and C_max, respectively, are summarised in Table 12.

5.3 Preclinical Safety Data

No nonclinical safety studies have been conducted with nirmatrelvir in combination with ritonavir. Complete nonclinical development program was conducted on the individual entities (nirmatrelvir and ritonavir) and no nonclinical combination toxicity studies were performed.

Genotoxicity.

Paxlovid has not been evaluated for the potential to cause genotoxicity.

Nirmatrelvir.

Nirmatrelvir was not genotoxic in a battery of assays, including bacterial mutagenicity, chromosome aberration using human lymphoblastoid TK6 cells and in vivo rat micronucleus assays.

Ritonavir.

Ritonavir showed no mutagenic potential in a series of assays for gene mutations (S. typhimurium, E. coli and mouse lymphoma cells) and chromosomal damage (mouse micronucleus assay in-vivo and human lymphocytes in-vitro).

Carcinogenicity.

Paxlovid has not been evaluated for the potential to cause carcinogenicity.

Nirmatrelvir.

Nirmatrelvir has not been evaluated for the potential to cause carcinogenicity.

Ritonavir.

Two-year carcinogenicity studies have been conducted in rodents, at ritonavir dietary levels of 50, 100 and 200 mg/kg/day in mice, and 7, 15 and 30 mg/kg/day in rats. In male mice there was a dose dependent increase in the incidence of hepatocellular adenomas, and adenomas and carcinomas combined, both reaching statistical significance only at the high-dose. In female mice there were small, statistically significant increases in these tumour incidences only at the high-dose. In rats, there were no tumourigenic effects.

6 Pharmaceutical Particulars

6.1 List of Excipients

Nirmatrelvir.

Tablet core.

Microcrystalline cellulose, lactose monohydrate, croscarmellose sodium, colloidal anhydrous silica, sodium stearylfumarate.

Film coat.

Opadry Complete Film Coating System 05B140011 Pink.

Ritonavir.

Tablet core.

Copovidone, calcium hydrogen phosphate, sorbitan monolaurate, colloidal anhydrous silica, sodium stearylfumarate.

Film coating.

Hypromellose, titanium dioxide, macrogol 400, hyprolose, purified talc, macrogol 3350, colloidal anhydrous silica, polysorbate 80.

6.2 Incompatibilities

Incompatibilities were either not assessed or not identified as part of the registration of this medicine.

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.

6.4 Special Precautions for Storage

Store below 25°C.

6.5 Nature and Contents of Container

Paxlovid is supplied in a carton containing five PA/Al/PVC/Al blister cards marked as "Morning Dose" and "Evening Dose" for tablets to be taken each morning and each evening. Paxlovid is available in the following pack sizes (see Table 13):

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of by taking to your local pharmacy.

6.7 Physicochemical Properties

Chemical structure.

Nirmatrelvir.

Chemical Name: (1R,2S,5S)-N-((1S)-1-Cyano-2-((3S)-2-oxopyrrolidin-3-yl) ethyl)-3-((2S)-3,3-dimethyl-2-(2,2,2-trifluoroacetamido) butanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide.
The molecular formula is C₂₃H₃₂F₃N₅O₄ and the molecular weight is 499.54.

CAS number.

2628280-40-8.

Chemical structure.

Ritonavir.

Chemical Name: 10-Hydroxy-2-methyl-5-(1-methylethyl)-1-[2-(1-methylethyl)-4-thiazolyl]-3,6-dioxo-8,11-bis(phenylmethyl)-2,4,7,12-tetraazatridecan-13-oic acid, 5-thiazolylmethyl ester, [5S-(5R*,8R*,10R*,11R*)].
The molecular formula is C₃₇H₄₈N₆O₅S₂ and the molecular weight is 720.95.

CAS number.

155213-67-5.

7 Medicine Schedule (Poisons Standard)

Schedule 4 - Prescription Only Medicine.

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Nirmatrelvir; Ritonavir

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