Consumer medicine information

Celsentri

Maraviroc

BRAND INFORMATION

Brand name

Celsentri

Active ingredient

Maraviroc

Schedule

SUMMARY CMI

CELSENTRI

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.

1. Why am I taking CELSENTRI?

CELSENTRI contains the active ingredient maraviroc. CELSENTRI is used in combination with other medicines to treat HIV.

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

2. What should I know before I take CELSENTRI?

Do not use if you have ever had an allergic reaction to maraviroc 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 take CELSENTRI? in the full CMI.

3. What if I am taking other medicines?

Some medicines may interfere with CELSENTRI 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 CELSENTRI?

The usual dosage is either 150 mg, 300 mg or 600 mg twice a day.
The dose you take will depend on whether you are taking any other medicines with CELSENTRI.
Swallow the tablets whole with a glass of water. Do not chew.
CELSENTRI can be taken with or without food

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

5. What should I know while taking CELSENTRI?

Things you should do	Remind any doctor, dentist or pharmacist you visit that you are taking CELSENTRI. Tell your doctor immediately if you become pregnant whilst taking CELSENTRI.
Things you should not do	Do not stop using this medicine suddenly or change the dose without talking to your doctor. Do not take this medicine to treat any other complaints.
Driving or using machines	Be careful before you drive or use any machines or tools until you know how CELSENTRI affects you. CELSENTRI may cause dizziness and light-headedness in some people.
Looking after your medicine	Store CELSENTRI below 30°C. Keep this medicine in the pack until it is time to take it.

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

6. Are there any side effects?

Side effects that have been reported include diarrhoea, constipation, nausea or vomiting, stomach pain or discomfort, indigestion, dizziness, abnormal sense of taste, problems sleeping or abnormal sleep, rash, loss of appetite, muscle spasms or pain, cough, joint pain, fever, colds, upper respiratory tract infections or flu-like symptoms.

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.

FULL CMI

CELSENTRI

Active ingredient(s): maraviroc

Consumer Medicine Information (CMI)

This leaflet provides important information about using CELSENTRI. 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 CELSENTRI.

Where to find information in this leaflet:

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

1. Why am I taking CELSENTRI?

CELSENTRI contains the active ingredient maraviroc. CELSENTRI belongs to a group of medicines called CCR5 blockers.

CELSENTRI is used in combination with other medicines to treat human immunodeficiency virus (HIV).

CELSENTRI reduces the amount of HIV in your body and helps your immune system. It stops the HIV-1 virus entering the CD-4 cells in your blood (also called T-cells). These are the cells in your immune system that the HIV virus attacks.

CELSENTRI works by blocking the most common entry point into the CD-4 cells – called the 'CCR5 receptor'. Because the virus cannot enter the cell, it cannot attack it, and this prevents further damage to your immune system.

CELSENTRI only stops the HIV-1 virus entering the cell, not HIV-2 (another rarer kind of the HIV virus). CELSENTRI also only stops types of HIV-1 virus that enter using the CCR5 receptor. As a result, your doctor would have done a blood test to check what strain of HIV-1 virus you have before they prescribed you this medicine.

You can still pass on HIV when taking this medicine through sexual activity or through passing on blood or bodily secretions which carry the HIV virus.

CELSENTRI does not cure HIV. You should use proper precautions to prevent transmission of HIV to others from occurring. Discuss with your doctor the precautions needed to avoid infecting other people.

2. What should I know before I take CELSENTRI?

Warnings

Do not use CELSENTRI if:

you are allergic to maraviroc, 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
have liver problems, hepatitis B or hepatitis C infection so that your liver function can be monitored
have a history of low blood pressure, low blood pressure upon standing up (known as postural hypotension) or are taking any medicine to lower your blood pressure
have kidney problems
have heart problems
take any medicines for any other condition

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.

It is not known if CELSENTRI can harm your unborn child. Your doctor can discuss with you the benefits and risks of taking CELSENTRI whilst pregnant.

Talk to your doctor if you are breastfeeding or intend to breastfeed. You should not breastfeed if you are infected with HIV because the virus can be transmitted through breastmilk. It is not known whether the active ingredient in CELSENTRI can pass into your breastmilk. Therefore, you should not breastfeed whilst taking CELSENTRI.

Children

CELSENTRI has not been studied in children less than 18 years of age.

Clinical Trials

More treatment-naïve patients in clinical trials using CELSENTRI had treatment failures and developed resistance to lamivudine compared to patients using efavirenz.

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 CELSENTRI and affect how it works.

efavirenz, etravirine, raltegravir, lopinavir, darunavir, delavirdine, elvitegravir, atazanavir, nelfinavir, indinavir, saquinavir, boceprevir, telaprevir – medicines used to treat HIV or hepatitis C infections
ketoconazole, itraconazole – medicines used to treat fungal infections
clarithromycin, telithromycin, rifampicin, rifabutin – medicines used to treat bacterial infections
medicines containing St John's Wort (hypericum perforatum). St John's Wort can prevent CELSENTRI from working properly. Therefore, you should not take St John's Wort together with CELSENTRI
carbamazepine, phenobarbital, phenytoin – medicines used to treat seizures

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

4. How do I take CELSENTRI?

How much to take

The usual dosage is either 150 mg, 300 mg or 600 mg twice a day.
The dose you take will depend on whether you are taking any other medicines with CELSENTRI. Your doctor will tell you the dose to take and when to take these others medicines.
Follow the instructions provided and use CELSENTRI until your doctor tells you to stop.

It is important to take all your anti-HIV medicines as prescribed and at the right time of day. This can help your medicines to work better. It also lowers the chance of your medicines becoming less effective in fighting HIV (also known as drug resistance).

How to take CELSENTRI

Swallow the tablet whole with a drink of water. Do not chew the tablet.
You can take CELSENTRI with or without food.

If you forget to take CELSENTRI

CELSENTRI should be taken regularly at the same time each day.

If it is almost time for your next dose, skip the dose you missed and take your next dose when you are meant to.

Otherwise take it as soon as you remember and then go back to taking CELSENTRI as you would normally.

Do not take a double dose to make up for the dose you missed.

If you take too much CELSENTRI

If you think that you have used too much CELSENTRI, 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.

Symptoms of an overdose may include dizziness or light-headedness when you stand up. If this happens, lie down until you feel better and when you get up, get up slowly.

5. What should I know while taking CELSENTRI?

Things you should do

Call your doctor straight away if you:

become pregnant whilst taking CELSENTRI

Remind any doctor, dentist or pharmacist you visit that you are using CELSENTRI.

Stay in regular contact with your doctor

CELSENTRI helps to control your condition, but it is not a cure for HIV infection. You need to keep taking it everyday to stop your illness from getting worse. Because CELSENTRI does not cure HIV infections, you may still develop other infections and illnesses linked to HIV.

Things you should not do

Do not stop using this medicine or change the dose
Do not start taking any other medicines without first speaking to your doctor
Do not give this medicine to anyone else, even if their symptoms seem similar to yours.
Do not use this medicine to treat any other complaints unless your doctor tells you to.

Driving or using machines

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

CELSENTRI may cause dizziness and light-headedness in some people.

Looking after your medicine

Follow the instructions in the carton on how to take care of your medicine properly.

Store it in a cool dry place (below 30°C) 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 window sills.

Keep it where young children cannot reach it.

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.

Within the first few weeks of treatment with anti-HIV medicines, some people, particularly those that have been HIV positive for some time, may develop inflammatory reactions (e.g. pain, redness, swelling, high temperature) which may resemble an infection and may be severe. It is thought that these reactions are caused by a recovery in the body's ability to fight infections, previously suppressed by HIV.

If you become concerned about any new symptoms, or any changes in your health after starting HIV treatment, discuss with your doctor immediately.

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

Less serious side effects

Less serious side effects	What to do
diarrhoea constipation nausea or vomiting stomach pain or discomfort indigestion dizziness abnormal sense of taste problems sleeping or abnormal sleep rash loss of appetite muscle spasms or pain cough joint pain fever colds, upper respiratory tract infections or flu-like symptoms	Speak to your doctor if you have any of these less serious side effects and they worry you.

Serious side effects

Serious side effects

What to do

weakness, tiredness, headaches, being short of breath, dizziness and looking pale, fainting
signs of frequent infections such as fever, severe chills, sore throat or mouth ulcers
loss of appetite, vomiting and/or upper right stomach pain, feeling generally unwell, fever, itching
yellowing of the skin and eyes
passing less or more urine than normal or a change in the colour of your urine, dark coloured urine
unexpected muscle aches or pain, paralysis or weakness
signs of infection such as
- meningitis – fever, nausea, vomiting, headache, stiff neck and sensitivity to bright light
- pneumonia – fever, chills, shortness of breath, cough, phlegm and occasionally blood
bleeding problems such as
- bleeding or bruising more easily than normal, nosebleeds
- bleeding from the back passage (rectum)
convulsions, fits or seizures, shaking or tremors
swollen glands in the neck, armpit or groin
any mental problems, such as
- epilepsy or fits
- loss of reflexes
- hallucinations
inability to move the muscles in the face
tingling or burning sensation in the hands or feet
lower back pain
feeling dizzy, faint or light headed when standing up

Call your doctor straight away.

Very serious side effects

Very serious side effects

What to do

chest pain or angina
severe upper stomach pain, often with nausea or vomiting
shortness of breath, wheezing or difficulty breathing
swelling of the face, lips, tongue or other parts of the body
blisters and peeling skin around the mouth, nose, eyes and genitals
widespread skin rash, itching or hives on the skin
signs of a stroke – collapse, numbness or weakness of the arms or legs, headache, dizziness and confusion, visual disturbance, difficulty swallowing, slurred speech and loss of speech
meningitis – fever, nausea, vomiting, headache, stiff neck and sensitivity to bright light

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.

Possible chance of infection or cancer

Although there is no evidence from clinical trials of an increase in serious infections or cancer, CELSENTRI affects other immune system cells and therefore may potentially increase your chance of getting other infections or cancer.

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.

What CELSENTRI contains

Active ingredient (main ingredient)	maraviroc
Other ingredients (inactive ingredients)	calcium hydrogen phosphate magnesium stearate microcrystalline cellulose sodium starch glycollate The film-coating (Opadry II Blue (85G20583)) contains: indigo carmine CI73015 macrogol 3350 polyvinyl alcohol soya lecithin talc titanium dioxide

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

What CELSENTRI looks like

150 mg film-coated tablets are blue in colour, oval shaped and marked "MVC 150" on one side.

Available in blister packs of 60 tablets. AUST R 137329.

300 mg film-coated tablets are blue in colour, oval shaped and marked "MVC 300" on one side.

Available in blister packs of 60 tablets. AUST R 137331

Who distributes CELSENTRI

ViiV Healthcare Pty Ltd
Level 4, 436 Johnston Street
Abbotsford, VIC 3067
Australia

Trademarks are owned by or licenced to the ViiV Healthcare group of companies.

This leaflet was prepared in October 2022.

Version 9.0.

Published by MIMS December 2022

BRAND INFORMATION

Brand name

Celsentri

Active ingredient

Maraviroc

Schedule

1 Name of Medicine

Maraviroc.

2 Qualitative and Quantitative Composition

Each film-coated tablet contains either 150 or 300 mg of maraviroc.
Tablets contain no excipients with a known effect. For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Celsentri 150 mg and 300 mg film-coated tablets.
Celsentri is supplied for oral administration in two strengths: 150 and 300 mg blue, biconvex, oval film-coated tablets debossed with "MVC" followed by the tablet strength on one tablet side.

4 Clinical Particulars

4.1 Therapeutic Indications

Celsentri, in combination with other antiretroviral medicinal products, is indicated for adult patients infected with only CCR5-tropic HIV-1.
The use of other active agents with Celsentri is associated with a greater likelihood of treatment response.

4.2 Dose and Method of Administration

Therapy should be initiated by a physician experienced in the management of HIV infection.
The following points should be considered when initiating therapy with Celsentri:
Tropism testing using an assay with appropriate validation and sensitivity, resistance testing and treatment history should guide the use of Celsentri.
Adult patients infected with only CCR5-tropic HIV-1 should use Celsentri.
CCR5 tropism should be confirmed using a highly sensitive, appropriately validated tropism assay prior to initiation of Celsentri therapy. Outgrowth of pre-existing low-level CXCR4 or dual/mixed-tropic HIV-1 not detected by tropism testing at screening has been associated with virologic failure on Celsentri.
Celsentri is not recommended in patients with dual/mixed or CXCR4-tropic HIV-1.
In treatment-naïve subjects, more subjects treated with Celsentri experienced virologic failure and developed lamivudine resistance compared to efavirenz.
The safety and efficacy of Celsentri have not been established in children younger than 18 years of age.

Adults.

The recommended dose of Celsentri is 150 mg, 300 mg or 600 mg twice daily depending on interactions with concomitant antiretroviral therapy and other medicinal products (see Table 1; see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).
Celsentri can be taken with or without food.

Children.

The safety and efficacy for the use of Celsentri in children younger than 18 years of age has not been established. Therefore, use in children is not recommended (see Section 4.4 Special Warnings and Precautions for Use; Section 5.2 Pharmacokinetic Properties).

Elderly.

There is limited experience in patients above 65 years of age; therefore, caution should be exercised when administering Celsentri in elderly patients (see Section 4.4 Special Warnings and Precautions for Use; Section 5.2 Pharmacokinetic Properties).

Renal impairment.

Table 2 provides dosing recommendations for patients based on renal function and concomitant medications.

Hepatic impairment.

Limited data in mild and moderate hepatic impairment patients demonstrated small increase in the mean C_max of maraviroc, suggesting no dose adjustment is required. However, Celsentri should be used with caution in patients with hepatic impairment (see Section 4.4 Special Warnings and Precautions for Use; Section 5.2 Pharmacokinetic Properties).

4.3 Contraindications

Hypersensitivity to the active substance or to any of the excipients (see Section 2 Qualitative and Quantitative Composition; Section 6.1 List of Excipients).

4.4 Special Warnings and Precautions for Use

Initiating therapy.

The following points should be considered when initiating therapy with Celsentri (see Section 4.1 Therapeutic Indications; Section 4.2 Dose and Method of Administration; Section 5.1 Pharmacodynamic Properties, Pharmacodynamic effects):
Tropism testing, resistance testing and treatment history should guide the use of Celsentri.
The viral tropism cannot be predicted by treatment history or assessment of stored samples.
Adult patients infected with only CCR5-tropic HIV-1 should use Celsentri.
CCR5 tropism should be confirmed using a highly sensitive tropism assay prior to initiation of Celsentri therapy. Outgrowth of pre-existing low-level CXCR4- or dual/mixed-tropic HIV-1 not detected by tropism testing at screening has been associated with virologic failure on Celsentri.
Celsentri is not recommended in patients with dual/mixed or CXCR4-tropic HIV-1.
In treatment-naïve subjects, more subjects treated with Celsentri experienced virologic failure and developed lamivudine resistance compared to efavirenz. The main reason for discontinuations in the efavirenz group was treatment-related adverse events (see Section 5.1 Pharmacodynamic Properties, Clinical trials, Table 14).
The safety and efficacy of Celsentri have not been established in children younger than 18 years of age.

Severe skin and hypersensitivity reactions.

Hypersensitivity reactions including severe and potentially life-threatening events have been reported in patients taking Celsentri, in most cases concomitantly with other drugs associated with these reactions. These reactions were characterised by features including rash, constitutional findings, and sometimes organ dysfunction and hepatic failure. Cases of Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN) and drug rash with eosinophilia and systemic symptoms (DRESS) have been reported (see Section 4.8 Adverse Effects (Undesirable Effects)). Discontinue maraviroc and other suspect agents immediately if signs or symptoms of severe skin or hypersensitivity reactions develop. Delay in stopping maraviroc treatment or other suspect drugs after the onset of rash may result in a life-threatening reaction. Clinical status including liver aminotransferases should be monitored and appropriate therapy initiated.

Cardiovascular safety.

Use with caution in patients at increased risk for cardiovascular events. Eleven patients (1.3%) who received Celsentri had cardiovascular events that may be linked to coronary heart diseases including myocardial ischemia and/or infarction during the Phase 3 studies in CCR5-tropic patients in treatment-experienced studies [total exposure of 609 patient-years (309 patient-years for BD + 300 patient-years for OD)], while no patients who received placebo had such events (total exposure 111 patient-years). These patients generally had cardiac disease or cardiac risk factors prior to Celsentri use, and the relative contribution of Celsentri to these events is not known.

Postural hypotension.

When Celsentri was administered in studies with healthy volunteers at doses higher than the recommended dose, cases of symptomatic postural hypotension were seen at a greater frequency than with placebo. Caution should be used when administering Celsentri in patients on concomitant medicinal products known to lower blood pressure. Celsentri should also be used with caution in patients with severe renal insufficiency, have risk factors for, or have a history of postural hypotension.
Patients with severe renal insufficiency who are treated with potent CYP3A inhibitors or boosted protease inhibitors (PIs) have an increased risk of experiencing postural hypotension due to an increase in maraviroc concentrations (see Section 4.2 Dose and Method of Administration; Section 4.5 Interactions with Other Medicines and Other Forms of Interactions; Section 5.2 Pharmacokinetic Properties).
Patients with cardiovascular co-morbidities could be at increased risk of cardiovascular adverse events triggered by postural hypotension.

Immune reconstitution syndrome.

In HIV infected patients with severe immune deficiency at the time of starting of highly active antiretroviral therapy (HAART), an inflammatory reaction to asymptomatic or residual opportunistic pathogens may arise and cause serious clinical conditions, or aggravation of symptoms. Typically, such reactions have been observed within the first few weeks or months of initiation of HAART. Relevant examples are cytomegalovirus retinitis, generalised and/or focal mycobacterial infections, and pneumonia caused by Pneumocystis jiroveci (formerly known as Pneumocystis carinii). Any inflammatory symptoms should be evaluated and treatment initiated when necessary. Autoimmune disorders (such as Graves' disease, polymyositis and Guillain-Barre syndrome) have also been reported to occur in the setting of immune reconstitution, however, the time to onset is more variable, and can occur many months after initiation of treatment and sometimes can be an atypical presentation.

Tropism.

Celsentri should be taken as part of an antiretroviral combination regimen. Celsentri should optimally be combined with other antiretrovirals to which the patient's virus is susceptible (see Section 5.1 Pharmacodynamic Properties, Pharmacodynamic effects).
Changes in viral tropism occur over time in HIV-1 infected patients. Therefore, there is a need to start therapy shortly after a tropism test.

Dose adjustment.

Physicians should ensure that appropriate dose adjustment of Celsentri is made when Celsentri is co-administered with potent CYP3A4 inhibitors and/or inducers since maraviroc concentrations and its therapeutic effects may be affected (see Section 4.2 Dose and Method of Administration; Section 4.5 Interactions with Other Medicines and Other Forms of Interactions). Refer to the respective prescribing information of the other medicinal products used in combination with Celsentri.

Information for patients.

Patients should be advised that antiretroviral therapies including Celsentri have not been shown to prevent the risk of transmission of HIV to others through sexual contact or contamination with blood. They should continue to use appropriate precautions. Patients should also be informed that Celsentri is not a cure for HIV-1 infection.

Potential risk of infections.

Celsentri antagonises the CCR5 co-receptor located on some immune cells, and therefore could potentially increase the risk of developing infections. The overall incidence and severity of infections, as well as AIDS defining category C infections, was comparable in the treatment groups during the Phase 3 studies of Celsentri. Patients should be monitored closely for evidence of infections while receiving Celsentri.

Potential risk of malignancy.

While no increase in malignancy has been observed in patients receiving Celsentri in Phase 3 studies, due to this drug's mechanism of action it could affect immune surveillance and lead to an increased risk of malignancy. Long-term follow-up is required to more fully assess whether Celsentri increases the risk of malignancy.

Use in hepatic impairment.

An increase in hepatic adverse reactions with Celsentri was observed during studies of treatment-experienced patients with HIV infection, although there was no overall increase in ACTG Grade 3/4 liver function test abnormalities (see Section 4.8 Adverse Effects (Undesirable Effects)).
Hepatotoxicity accompanied by severe rash or systemic allergic reaction including potentially life-threatening events has been reported. Hepatic laboratory parameters including ALT, AST, and bilirubin should be obtained prior to starting Celsentri and at other time points during treatment as clinically indicated. If rash or symptoms or signs of hepatitis or allergic reaction develop, hepatic laboratory parameters should be monitored. Discontinuation of Celsentri should be strongly considered in any patient with signs or symptoms of acute hepatitis, in particular if drug related hypersensitivity is suspected or with increased liver transaminases combined with rash or other systemic symptoms of potential hypersensitivity (e.g. pruritic rash, eosinophilia or elevated IgE).
There are limited data in patients with hepatitis B and/or C virus co-infection (see Section 5.1 Pharmacodynamic Properties, Clinical trials). Caution should be exercised when treating these patients. In case of concomitant antiviral therapy for hepatitis B and/or C, please refer to the relevant prescribing information for these medicinal products.
Patients with pre-existing liver dysfunction, including chronic active hepatitis, can have an increased frequency of liver function abnormalities during combination antiretroviral therapy and should be monitored according to standard practice.
The safety and efficacy of Celsentri have not been specifically studied in patients with significant underlying liver disorders. Since there is limited experience in patients with reduced hepatic function, therefore, Celsentri should be used with caution in this population (see Section 4.2 Dose and Method of Administration; Section 5.2 Pharmacokinetic Properties).

Use in renal impairment.

The safety and efficacy of Celsentri have not been specifically studied in patients with renal impairment, therefore, Celsentri should be used with caution in this population.
Study A4001075 evaluated the pharmacokinetics and safety of Celsentri in combination with saquinavir/ritonavir in participants with mild and moderate renal impairment compared to healthy adult volunteers (see Section 5.2 Pharmacokinetic Properties, Renal impairment).
All 18 participants received saquinavir/ritonavir 1000/100 mg in addition to 150 mg maraviroc at different dose frequencies: healthy volunteers - every 12 hours (n = 6); mild renal impairment - every 24 hours (n = 6); moderate renal impairment - every 48 hours (n = 6). Treatment duration was 7 days.
The most frequently reported treatment-related adverse event by preferred term was blood creatinine increased, reported in eight (8) of the twelve (12) participants with mild and moderate renal impairment. Nocturia, considered study drug related, was reported by 6 of the 12 participants with mild and moderate renal impairment. Patients in the study with normal renal function demonstrated a decrease in mean creatinine clearance over the course of the study, though no patient with normal function had decreased creatinine clearance reported as an adverse event.
On the basis of these results it is recommended that renal function is monitored if patients on maraviroc are co-administered saquinavir/ritonavir. The effect of this drug interaction on renal function in patients with severe renal failure has not been studied. The effect of multiple dose treatment with maraviroc without concomitant CYP3A4 has not been studied.
Table 2 provides dose and/or interval adjustment guidelines for patients with renal impairment with and without co-administered potent CYP3A4 inhibitors (see Section 4.2 Dose and Method of Administration; Section 4.5 Interactions with Other Medicines and Other Forms of Interactions; Section 5.2 Pharmacokinetic Properties).

Use in the elderly.

There were insufficient numbers of patients aged 65 and over in the clinical studies to determine whether they respond differently from younger patients. In general, caution should be exercised when administering Celsentri in elderly patients, also reflecting the greater frequency of decreased hepatic and renal function, of concomitant disease and other drug therapy (see Section 4.2 Dose and Method of Administration; Section 5.2 Pharmacokinetic Properties).

Paediatric use.

The safety and efficacy of Celsentri in paediatric patients have not been established, therefore, use in children is not recommended (see Section 4.2 Dose and Method of Administration; Section 5.2 Pharmacokinetic Properties).

Effects on laboratory tests.

See Section 4.8 Adverse Effects (Undesirable Effects), Tables 5 and 8.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Maraviroc is metabolised by cytochrome P450 CYP3A. Maraviroc is also a substrate for P-glycoprotein, OATP1B1 and MRP2 in vitro. Co-administration of Celsentri with medicinal products that induce those enzymes and transporters may decrease maraviroc concentrations and reduce its therapeutic effects. Co-administration of Celsentri with medicinal products that inhibit those enzymes and transporters may increase maraviroc plasma concentrations. Dose adjustment of Celsentri is recommended when Celsentri is co-administered with potent CYP3A4 inhibitors and/or inducers. Further details for concomitantly administered medicinal products are provided below (see Table 3; see Section 4.2 Dose and Method of Administration, Table 1).
In vitro studies have shown that maraviroc does not inhibit OATP1B1, MRP2 or any of the major P450 enzymes at clinically relevant concentrations (CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 and CYP3A4). Maraviroc had no clinically relevant effect on the pharmacokinetics of midazolam, the oral contraceptives ethinylestradiol and levonorgestrel, or urinary 6β-hydroxycortisol/cortisol ratio, suggesting no inhibition or induction of CYP3A4 in vivo. At higher exposure of maraviroc a potential inhibition of CYP2D6 cannot be excluded. Based on the in vitro and clinical data, the potential for maraviroc to affect the pharmacokinetics of co-administered medicinal products is low.
Renal clearance accounts for approximately 23% of total clearance of maraviroc when maraviroc is administered without CYP3A4 inhibitors. As both passive and active processes are involved, there is the potential for competition for elimination with other renally eliminated active substances. However, in vitro studies have shown that maraviroc is not a substrate for and does not inhibit any of the major renal uptake inhibitors at clinically relevant concentrations (OAT1, OAT3, OCT2 OCTN1, and OCTN2). Additionally, co-administration of Celsentri with tenofovir (substrate for renal elimination) and cotrimoxazole (contains trimethoprim, a renal cation transport inhibitor) showed no effect on the pharmacokinetics of maraviroc. In addition, co-administration of Celsentri with lamivudine/zidovudine showed no effect of maraviroc on lamivudine (primarily renally cleared) or zidovudine (non-P450 metabolism and renal clearance) pharmacokinetics.
Maraviroc inhibits P-glycoprotein (P-gp) in vitro (IC₅₀ is 183 microM). Systemic effects on P-gp are unlikely to be of relevance. Maraviroc could inhibit P-gp in the gut and may thus affect the bioavailability of certain drugs. However, maraviroc does not significantly affect the pharmacokinetics of digoxin in vivo, suggesting that maraviroc neither inhibits nor induces the activity of P-glycoprotein.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

Maraviroc did not impair mating or fertility of male or female rats and did not affect sperm of male rats at oral doses up to 1000 mg/kg/day. Systemic exposure to free maraviroc at this dose level was 39-fold higher than the estimated free clinical AUC_0-24h for a 300 mg twice daily dose.
(Category B1)
Embryofetal development studies were conducted in rats and rabbits at oral doses up to 1000 and 200 mg/kg/day, respectively. Systemic exposure to free maraviroc at these doses was 40 (rats) and 35 times (rabbits) the free clinical AUC_0-24h for a 300 mg twice daily dose. The animal studies revealed no evidence of harm to the embryo or fetus except for an increase in pre-implantation loss in rats dosed with maraviroc at a maternotoxic dose of 1000 mg/kg/day from 2 weeks prior to mating to gestation day 7.
Pre- and postnatal development studies were performed in rats at oral doses up to 1000 mg/kg/day (relative exposure to free maraviroc, 28). The only effect in the offspring was a slight increase in motor activity in high-dose male rats at both weaning and as adults, while no effects were seen in females. Other developmental parameters of these offspring, including fertility and reproductive performance, were not affected by the maternal administration of maraviroc.
No meaningful clinical data on exposure during pregnancy are available. Animal studies do not indicate direct or indirect harmful effects with respect to pregnancy, embryofetal development, parturition or postnatal development. Celsentri should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Health experts recommend that where possible HIV infected women do not breast feed their infants in order to avoid transmission of HIV. In settings where formula feeding is not feasible, local official lactation and treatment guidelines should be followed when considering breastfeeding during antiretroviral therapy.
It is expected that maraviroc will be secreted into human milk based on animal data, although this has not been confirmed in humans.

4.7 Effects on Ability to Drive and Use Machines

There have been no studies to investigate the effect of Celsentri on the ability to perform tasks that require judgement, motor or cognitive skills. However, patients should be informed about the possible occurrence of symptoms related to postural hypotension such as dizziness when taking Celsentri. If affected, patients should avoid potentially hazardous tasks such as driving, cycling or operating machinery.

4.8 Adverse Effects (Undesirable Effects)

The following adverse effects are discussed in other sections of the Product Information:
Hepatotoxicity (see Section 4.4 Special Warnings and Precautions for Use);
Cardiovascular effects (see Section 4.4 Special Warnings and Precautions for Use).

Studies in treatment-experienced patients.

The safety profile of Celsentri is primarily based on 840 HIV-infected patients who received at least one dose of Celsentri during two Phase 3 trials. A total of 426 of these patients received the indicated twice daily dosing regimen.
Assessment of treatment-emergent adverse events is based on the pooled data from two studies in patients with CCR5-tropic HIV-1 (MOTIVATE-1 and MOTIVATE-2). The median duration of maraviroc therapy for patients in these studies was 48 weeks, with the total exposure on Celsentri twice daily at 309 patient-years versus 111 patient-years on placebo + OBT. The population was 89% male and 84% white, with mean age of 46 years (range 17-75 years). Patients received dose equivalents of 300 mg maraviroc once or twice daily.
The most common adverse events reported with Celsentri twice daily therapy with frequency rates higher than placebo, regardless of causality, were upper respiratory tract infections, cough, pyrexia, rash and dizziness. Additional adverse events that occurred with once daily dosing at a higher rate than both placebo and twice daily dosing were diarrhoea, oedema, influenza, oesophageal candidiasis, sleep disorders, rhinitis, parasomnias and urinary abnormalities. In these two studies, the rate of discontinuation due to adverse events was 5% for patients who received Celsentri twice daily + optimised background therapy (OBT) as well as those who received OBT alone. Most of the adverse events reported were judged to be mild to moderate in severity. The data described below occurred with Celsentri twice daily dosing.
The total number of patients reporting infections were 233 (55%) and 84 (40%) in the Celsentri twice daily and placebo groups, respectively. Correcting for the longer duration of exposure on Celsentri compared to placebo, the exposure-adjusted frequency (rate per 100 subject years) of these events was 133 for both Celsentri twice daily and placebo.
Dizziness or postural dizziness occurred in 8% of patients on either Celsentri or placebo, with 2 patients (0.5%) on Celsentri permanently discontinuing therapy (1 due to syncope, 1 due to orthostatic hypotension) versus 1 subject on placebo (0.5%) permanently discontinuing therapy due to dizziness.
Treatment-emergent adverse events, regardless of causality, from studies MOTIVATE-1 and MOTIVATE-2 are summarised in Table 4. Selected events occurring at ≥ 2% of patients and at a numerically higher rate in patients treated with Celsentri + OBT are included; events that occurred at the same or higher rate on OBT alone are not displayed.

Laboratory abnormalities.

Table 5 shows the treatment-emergent grade 3-4 laboratory abnormalities that occurred in ≥ 2% of patients receiving Celsentri.

MOTIVATE 1 and MOTIVATE 2 were unblinded after the Week 48 visit of the last enrolled patient, and eligible patients could switch to an open-label phase of Celsentri twice daily extending to week 96. A subsequent observational phase extending to 5 years on treatment was conducted to assess the incidence of the following long-term safety selected endpoints; death, AIDS defining events, hepatic failure, MI/cardiac ischemia, malignancies, rhabdomyolysis, and other serious infectious events. The incidence of these selected endpoints was consistent with those seen at earlier time points in the studies and listed in Table 6.

Study in treatment-naïve patients.

Treatment-emergent adverse events. Treatment-emergent adverse events, regardless of causality, from the MERIT study, a double-blind comparative controlled study in which 721 treatment-naïve patients received Celsentri 300 mg BID (N = 360) or efavirenz (N = 361) in combination with zidovudine/lamivudine for 96 weeks, are summarized in Table 7. Selected events occurring at ≥ 2% of patients and at a numerically higher rate in patients treated with Celsentri are included; events that occurred at the same or higher rate on efavirenz are not displayed.

Laboratory abnormalities.

See Table 8.

Less common adverse events in clinical trials.

The following adverse events occurred in < 2% of Celsentri-treated patients. These events have been included because of their seriousness and either increased frequency on Celsentri or are potential risks due to the mechanism of action. Events attributed to the patient's underlying HIV infection are not listed.

Blood and lymphatic system.

Marrow depression and hypoplastic anaemia.

Cardiac disorders.

Unstable angina, acute cardiac failure, coronary artery disease, coronary artery occlusion, myocardial infarction, myocardial ischemia (see Section 4.4 Special Warnings and Precautions for Use).

Hepatobiliary disorders.

Hepatic cirrhosis, hepatic failure, cholestatic jaundice, portal vein thrombosis, hypertransaminaseamia, jaundice.

Infections and infestations.

Endocarditis, infective myositis, viral meningitis, pneumonia, treponema infections, septic shock, Clostridium difficile colitis, meningitis.

Musculoskeletal and connective tissue disorders.

Myositis, osteonecrosis, rhabdomyolysis, blood CK increased.

Neoplasms benign, malignant and unspecified (including cysts and polyps).

Abdominal neoplasia, anal cancer, basal cell carcinoma, Bowen's disease, cholangiocarcinoma, diffuse large B-cell lymphoma, metastases to liver, oesophageal carcinoma, nasopharyngeal carcinoma, squamous cell carcinoma, tongue neoplasia (malignant stage unspecified), anaplastic large cell lymphomas T- and null-cell types, bile duct neoplasms malignant, endocrine neoplasms malignant and unspecified.

Nervous system disorders.

Cerebrovascular accident, convulsions and epilepsy, tremor (excluding congenital).
In HIV infected patients with severe immune deficiency at the time of initiation of combination antiretroviral therapy (CART), an inflammatory reaction to asymptomatic or residual opportunistic infections may arise (see Section 4.4 Special Warnings and Precautions for Use).
Hepatotoxicity and hepatic failure with allergic features have been reported in association with Celsentri in clinical trials and post marketing (see Section 4.4 Special Warnings and Precautions for Use).
After unblinding of the study following the last subject's week 96 visit, subjects could be eligible for continued treatment during the open-label extension phase of the study with the same study drug to which they had been randomised. Safety results at week 240 on treatment were consistent with those seen at week 96.

Post marketing experience.

Very rarely, severe hypersensitivity reactions have been reported. These included drug rash with eosinophilia and systemic symptoms (DRESS), severe cutaneous reactions (Stevens-Johnson syndrome and toxic epidermal necrolysis) as well as hepatotoxicity and hepatic failure with allergic features.
In rare cases, postural hypotension which can result in syncope has been reported.

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

The highest dose administered in clinical studies was 1200 mg. The dose limiting adverse reaction was postural hypotension.
Prolongation of the QT interval was seen in dogs and monkeys at free plasma concentrations of maraviroc 6 and 12 times, respectively, to those expected in humans at the maximum recommended dose of 300 mg twice daily. However, no clinically significant QT prolongation compared to OBT alone was seen in the Phase 3 clinical studies using the recommended dose of maraviroc or in a specific pharmacokinetic study to evaluate the potential of Celsentri to prolong the QT interval.
There is no specific antidote for overdose with Celsentri. Treatment of overdose should consist of general supportive measures including keeping the patient in a supine position, careful assessment of patient vital signs, blood pressure and ECG.
If indicated, elimination of unabsorbed active Celsentri should be achieved by emesis. Administration of activated charcoal may also be used to aid in removal of unabsorbed active substance. Since Celsentri is moderately protein bound, dialysis may be beneficial in removal of this medicine.
For information on the management of overdose, contact the Poisons Information Centre on 131 126 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacological actions.

Pharmacotherapeutic group: Antivirals for systemic use, Other antivirals.
ATC code: J05AX09.

Mechanism of action.

Maraviroc is a member of a therapeutic class called CCR5 antagonists. Maraviroc selectively binds to the human chemokine receptor CCR5, preventing CCR5-tropic HIV-1 from entering cells.

Pharmacodynamic effects.

Antiviral activity in cell culture. Maraviroc inhibits the entry and replication of CCR5-tropic laboratory strains and clinical isolates of HIV-1 in models of acute T-cell infection. The in vitro IC₅₀ (50% inhibitory concentration) for maraviroc against the replication of HIV-1 group M isolates (subtypes A to J and circulating recombinant form AE) and group O isolates ranged from 0.1 to 4.5 nanoM (0.05 to 2.3 nanogram/mL). HIV-1 clinical isolates resistant to nucleoside analogue reverse transcriptase inhibitors (NRTI), non-nucleoside analogue reverse transcriptase inhibitors (NNRTI), protease inhibitors (PI) and enfuvirtide were all susceptible to maraviroc in cell culture.
When used with other antiretroviral agents in vitro, the combination of maraviroc produced additive/synergistic antiviral effects with protease inhibitors (amprenavir, atazanavir, indinavir, lopinavir, nelfinavir, ritonavir and saquinavir) and was generally additive with the NRTIs (abacavir, didanosine, emtricitabine, lamivudine, stavudine, tenofovir, zalcitabine and zidovudine) and the NNRTIs (delavirdine, efavirenz and nevirapine). Maraviroc was additive/synergistic with the HIV fusion inhibitor enfuvirtide. Protein binding studies have shown that the antiviral activity of maraviroc decreases on average 2-fold in conditions where plasma proteins are present.
Maraviroc has no antiviral activity in cell culture against viruses that can use CXCR4 as their entry co-receptor (dual-tropic or CXCR4-tropic viruses, collectively termed 'CXCR4-using' virus below). The antiviral activity of maraviroc against HIV-2 has not been evaluated.
Virologic escape. Virologic escape from maraviroc can occur via two routes: the emergence of pre-existing virus which can use CXCR4 as its entry co-receptor (CXCR4-using virus) or the selection of virus that continues to use exclusively drug-bound CCR5 (CCR5-tropic virus).
Resistance in cell culture. HIV-1 variants with reduced susceptibility to maraviroc have been selected in cell culture following serial passage of two CCR5-tropic clinical viral isolates. The maraviroc-resistant viruses remained CCR5-tropic and there was no conversion from a CCR5-tropic virus to a CXCR4-using virus.

Phenotypic resistance.

Concentration response curves for the maraviroc-resistant viruses were characterised by curves that did not reach 100% inhibition in assays using serial dilutions of maraviroc (< 100% maximal percentage inhibition (MPI)), consistent with the resistant viruses being able to use CCR5 as a coreceptor for cell entry even when maraviroc is bound. Traditional EC₅₀ fold-change was not a useful parameter to measure phenotypic resistance, as those values were sometimes unchanged despite significantly reduced sensitivity.

Genotypic resistance.

Mutations were found to accumulate in the gp120 envelope glycoprotein (the viral protein that binds to the CCR5 co-receptor). The position of these mutations was not consistent between different isolates. Hence, the relevance of these mutations to maraviroc susceptibility in other viruses is not known.
Tropism switching from CCR5- to CXCR4-tropic variants occurred spontaneously in vitro in maraviroc-treated and control cultures, and represents a theoretical mechanism for maraviroc resistance in vivo.

Cross-resistance.

HIV-1 clinical isolates resistant to NRTIs, NNRTIs, PIs and enfuvirtide were all susceptible to maraviroc in cell culture. Maraviroc-resistant viruses that emerged in cell culture remained sensitive to the fusion inhibitor enfuvirtide and the protease inhibitor saquinavir.
Resistance in vivo. The two mechanisms of virologic escape observed in vivo include the unmasking of CXCR4-using virus and the selection of virus that continues to use CCR5 but with reduced susceptibility to maraviroc, as indicated by a maximal plateau of inhibition of < 95%. Both routes to virologic escape have been observed in clinical studies of both treatment-naïve and treatment-experienced patients.
CXCR4-using virus presence at virological failure appears to originate from a pre-existing viral population. Resistance of CCR5-tropic virus through the increase of EC₅₀ fold-change does not appear to be an important mechanism of failure.
Sequencing of the V3 loop of virus with reduced susceptibility to maraviroc has identified changes in the amino acid sequence for the majority; however, no signature mutation has been identified. Mutations within Gp160 but outside of the V3 loop, contributing to the maraviroc resistance phenotype have been reported but appear uncommon.
Treatment-experienced patients. In the pivotal studies (MOTIVATE 1 and MOTIVATE 2), 7.6% of patients had a change in tropism result from CCR5-tropic to CXCR4-tropic or dual/mixed-tropic between screening and baseline (a period of four-six weeks).

Failure with CXCR4-using virus.

CXCR4-using virus was detected in approximately 55% of patients who failed treatment on maraviroc, as compared to 6% of patients who experienced treatment failure in the Optimised Background Therapy (OBT) alone arm. To investigate the likely origin of the on treatment CXCR4-using virus, a detailed clonal analysis was conducted on virus from 20 representative patients (16 patients from the maraviroc arms and 4 patients from the OBT alone arm) in whom CXCR4-using virus was detected. This analysis indicated that CXCR4-using virus emerged from a pre-existing CXCR4-using reservoir not detected at baseline, rather than from mutation of CCR5-tropic virus present at baseline. An analysis of tropism following failure of maraviroc therapy with CXCR4-using virus in patients with CCR5 virus at baseline, demonstrated that the virus population reverted back to CCR5 tropism in 33 of 36 patients with more than 35 days of follow-up. At the time of failure with CXCR4-using virus, the resistance pattern to other antiretrovirals appears similar to that of the CCR5-tropic population at baseline, based on available data. Hence, in the selection of a treatment regimen, it should be assumed that viruses forming part of the previously undetected CXCR4-using population (i.e. minor viral population) harbours the same resistance pattern as the CCR5-tropic population.

Failure with CCR5-tropic virus.

Phenotypic resistance: in patients with CCR5-tropic virus at time of treatment failure with maraviroc, 22 out of 58 patients had virus with reduced sensitivity to maraviroc. Additionally, CCR5-tropic virus from 2 of these treatment failure patients had ≥ 3-fold shifts in EC₅₀ values for maraviroc at the time of failure, but the significance of this is unclear. In the remaining patients, there was no evidence of virus with reduced sensitivity as identified by exploratory virology analyses on a representative group. The latter group had markers of low exposure, in some cases associated with poor compliance. A clinically-validated cut-off value for reduced virological response has not yet been established. Therefore, continued use of maraviroc after treatment failure cannot be generally recommended regardless of the viral tropism seen.
Treatment-naïve patients. In the pivotal study of treatment-naïve patients (MERIT week 96), 13/343 (3.8%) had a change in tropism result from CCR5-tropic to CXCR4-tropic or dual/mixed-tropic in the four-six week interval between screening and baseline during which time no treatment was administered.

Failure with CXCR4-using virus.

In the analysis of week 96 data, using a time to loss of virologic response (HIV-1 RNA < 50 copies/mL) endpoint, CXCR4-using virus was detected at failure in approximately 24/86 (28%) of the patients with CCR5-tropic virus at baseline and who failed treatment on maraviroc, as compared to none of patients who experienced treatment failure in the efavirenz arm. A retrospective analysis of tropism at Screening was performed using a modified tropism assay with enhanced sensitivity (100% x 4 virus detection at 0.3% prevalence compared with 10% with the original assay). Data from enrolled patients who originally screened with the R5 virus, but who screened retrospectively with CXCR4-using virus, were censored. Of the remaining subjects with CCR5-tropic virus at Baseline and who experienced virologic failure, CXCR4-using virus was detected in 17% (11/65) as compared to none in the efavirenz arm.
A detailed clonal analysis was conducted for two previously antiretroviral treatment-naïve patients enrolled in a Phase 2a monotherapy study and who had CXCR4-using virus observed after 10 day treatment with maraviroc. Consistent with the detailed clonal analysis conducted in treatment-experienced patients, the CXCR4-using variant was found to be preexisting prior to starting therapy.
All but one (11/12; 92%) of the maraviroc failures failing with CXCR4 or dual/mixed-tropic virus also had genotypic and phenotypic resistance to the background drug lamivudine at failure and 33% (4/12) developed zidovudine-associated resistance substitutions.

Failure with CCR5-tropic virus.

Phenotypic resistance: in patients with CCR5-tropic virus at time of treatment failure with maraviroc, 6 out of 38 patients had virus with reduced sensitivity to maraviroc. In the remaining 32 patients, there was no evidence of virus with reduced sensitivity as identified by exploratory virology analyses on a representative group. One additional subject had a ≥ 3-fold shift in EC₅₀ value for maraviroc at the time of failure.

Clinical trials.

The clinical efficacy and safety of Celsentri is derived from analyses of data from three ongoing studies in adult patients infected with CCR5-tropic HIV-1: MOTIVATE-1 A4001027 and MOTIVATE-2 A4001028, in antiretroviral treatment-experienced adult patients and MERIT A4001026 in treatment-naïve patients. These studies are supported by a 48-week study in antiretroviral treatment-experienced adult patients infected with dual/mixed-tropic HIV-1, A4001029.
Studies in CCR5-tropic treatment-experienced patients. The clinical efficacy of Celsentri (in combination with other antiretroviral medicinal products) on plasma HIV RNA levels and CD4+ cell counts have been investigated in two pivotal ongoing, randomised, double-blind, multicentre studies (MOTIVATE-1 and MOTIVATE-2, n = 1076) in patients infected with CCR5-tropic HIV-1. The primary objective of these studies was to assess whether Celsentri added to OBT provided an additional reduction in plasma HIV-1 RNA level compared with OBT alone, based on the mean changes from baseline in plasma HIV-1 RNA level at Week 48. Efficacy analyses were performed on the full analysis set and per protocol populations. Patients were analysed as both As Treated and As Randomised to assess the effect on the results of subjects receiving treatments other than those to which they were randomised.
Patients who were eligible for these studies had prior exposure to at least three antiretroviral medicinal product classes [≥ 1 nucleoside reverse transcriptase inhibitors (NRTI), ≥ 1 non-nucleoside reverse transcriptase inhibitors (NNRTI), ≥ 2 protease inhibitors (PI), and/or enfuvirtide] or documented resistance to at least one member of each class. Patients were randomised in a 2:2:1 ratio to maraviroc 300 mg (dose equivalent) once daily, maraviroc 300 mg twice daily or placebo in combination with an OBT consisting of three to six antiretroviral medicinal products (excluding low-dose ritonavir). The OBT was selected on the basis of the patient's prior treatment history and baseline genotypic and phenotypic viral resistance measurements.
Table 9 illustrates the demographic and baseline characteristics of patients from the pooled analysis from the MOTIVATE-1 and MOTIVATE-2 studies.

Limited numbers of patients from races other than Caucasian were included in the pivotal clinical studies, therefore very limited data are available in these patient populations.
After 24 weeks of therapy, the mean change in plasma HIV-1 RNA from baseline to week 24 was -1.96 log₁₀ copies/mL for patients receiving Celsentri 300 mg twice daily + OBT compared to -0.99 log₁₀ copies/mL for patients receiving OBT alone. The mean increase in CD4+ counts was higher on Celsentri 300 mg twice daily + OBT (106.34 cells/mm³) than on OBT alone (57.37 cells/mm³). The proportion of subjects with HIV-1 RNA < 400/< 50 copies/mL was 60.8%/45.3% for patients receiving Celsentri 300 mg twice daily + OBT, compared to 27.8%/23% for patients receiving OBT alone (see Table 10).

Studies in non-CCR5-tropic treatment-experienced patients. Study A4001029 was an exploratory, randomised, double-blind, multicentre trial to determine the safety and efficacy of Celsentri in patients infected with dual/mixed or CXCR4-tropic HIV-1. The inclusion/exclusion criteria were similar to those for MOTIVATE-1 and MOTIVATE-2 above and the patients were randomised in a 1:1:1 ratio to Celsentri once daily, Celsentri twice daily or OBT alone. The mean changes in viral load and CD4+ counts are shown in Table 11.

Study in treatment-naïve patients. Study A4001026 is a randomised, double-blind, multicenter study in patients infected with CCR5-tropic HIV-1 classified by the original Trofile tropism assay. The primary objective was to assess whether antiviral activity (plasma viral load < 400/50 copies/mL at week 48) of Celsentri in combination zidovudine/lamivudine was non-inferior to a reference regimen of efavirenz plus zidovudine/lamivudine. Patients were required to have plasma HIV-1 RNA ≥ 2000 copies/mL and could not have: 1) previously received any antiretroviral therapy for > 14 days, 2) an active or recent opportunistic infection or a suspected primary HIV-1 infection, or 3) phenotypic or genotypic resistance to zidovudine, lamivudine, or efavirenz. Patients were randomized in a 1:1:1 ratio to Celsentri 300 mg once daily, Celsentri 300 mg twice daily, or efavirenz 600 mg once daily, each in combination with zidovudine/lamivudine. The efficacy and safety of Celsentri are based on the comparison of Celsentri twice daily versus efavirenz. A one-sided 97.5% confidence interval (CI) was constructed based on the normal approximation to the binomial distribution for the treatment difference in percentages stratified by the randomisation strata (screening viral load and geographic region). A step down procedure was used to control for multiple comparisons (i.e. < 400 and < 50). Non-inferiority was to be concluded if the lower bound of the one-sided 97.5% CI was > -10%. In a pre-planned interim analysis at 16 weeks, the Celsentri 300 mg once per day treatment arm failed to meet the pre-specified criteria for demonstrating non-inferiority and was discontinued.
The demographic and baseline characteristics of the Celsentri and efavirenz treatment groups were comparable (Table 12). Patients were stratified by screening HIV-1 RNA levels and by geographic region. The median CD4 cell counts and mean HIV-1 RNA at baseline were similar for both treatment groups.

The treatment outcomes through week 48 for the treatment-naïve study (MERIT) are shown in Table 13. Treatment outcomes (responders) include reanalysis of the screening samples using a more sensitive tropism assay, enhanced sensitivity Trofile HIV tropism assay, which became available after the Week 48 analysis.

The primary efficacy endpoints were defined as the percentage of patients with HIV-1 RNA undetectable by the standard method (< 400 copies/mL and < 50 copies/mL). After 48 weeks of combination therapy with zidovudine/lamivudine, maraviroc 300 mg BID demonstrated non-inferiority to efavirenz 600 mg QD in the proportion of patients with undetectable viral load measured at < 400 copies/mL but not at < 50 copies/mL (lower bound of 97.5% CI > -10% for non-inferiority). However, reanalysis of the data following rescreening of the samples using the enhanced sensitivity tropism assay demonstrated non-inferiority for maraviroc 300 mg BID compared to efavirenz 600 mg QD in the proportion of patients with viral loads of < 400 copies/mL and < 50 copies/mL.
The median increase from baseline in CD4+ cell counts at Week 48 was 157 cells/mm³ for the Celsentri arm compared to 127 cells/mm³ for the efavirenz arm.
The treatment outcomes at 96 weeks for the treatment-naïve patients study (MERIT) are shown in Table 14. Treatment outcomes are based on reanalysis of the screening samples using the enhanced sensitivity tropism assay. Approximately 15% of the patients identified as CCR5-tropic virus in the original analysis had CXCR4-using virus. Screening with the enhanced sensitivity version of the Trofile tropism assay reduced the number of maraviroc virologic failures with CXCR4-using virus at failure to 12 compared to 24 when screening with the original Trofile HIV tropism assay. The main reason for discontinuation in the maraviroc BID treatment group was treatment failure while the main reason for discontinuation in the efavirenz group was treatment-related adverse events (see Section 4.4 Special Warnings and Precautions for Use) (Table 14).

Note.

The nucleoside backbone used in study A4001026 was zidovudine/lamivudine.

The median increase from baseline in CD4+ cell counts at week 96 was 184 cells/mm³ for the Celsentri arm compared to 155 cells/mm³ for the efavirenz arm.
Tropism.

Treatment-experienced (MOTIVATE-1 and MOTIVATE-2).

In the majority of cases, treatment failure on maraviroc was associated with detection of CXCR4-using (i.e. CXCR4- or dual/mixed-tropic) virus which was not detected by the tropism assay prior to treatment. CXCR4-using virus was detected at failure in 54.8% of patients who failed treatment on maraviroc, as compared to 5.9% of patients who experienced treatment failure in the placebo arm. To investigate the likely origin of the on-treatment CXCR4-using virus, a detailed clonal analysis was conducted on virus from 20 representative patients (16 patients from the maraviroc arms and 4 patients from the placebo arm) in whom CXCR4-using virus was detected at treatment failure. From analysis of amino acid sequence differences and phylogenetic data, CXCR4-using virus in these patients emerged from a low level of pre-existing CXCR4-using virus not detected by the tropism assay (which is population based) prior to treatment rather than from a co-receptor switch from CCR5-tropic virus to CXCR4-using virus resulting from mutation in the virus.
At Week 48 patients failing maraviroc BID with CXCR4-using virus had a lower median increase in CD4+ cell counts from baseline (+41 cells/mm³) than those patients failing with CCR5-tropic virus (+162 cells/mm³). The median increase in CD4+ cell count in patients failing in the placebo arm was +6.5 cells/mm³.

Treatment-naïve (MERIT).

In a 96-week study of antiretroviral treatment-naïve patients, 14% (12/85) who had CCR5-tropic virus at screening with an enhanced sensitivity tropism assay (Trofile) and failed therapy on maraviroc had CXCR4-using virus at the time of treatment failure. A detailed clonal analysis was conducted in two previously antiretroviral treatment-naïve patients enrolled in a Phase 2a monotherapy study who had CXCR4-using virus detected after 10 days treatment with maraviroc. Consistent with the detailed clonal analysis conducted in treatment-experienced patients, the CXCR4-using variants appear to emerge from outgrowth of a pre-existing undetected CXCR4-using virus. Screening with an enhanced sensitivity tropism assay reduced the number of maraviroc virologic failures with CXCR4- or dual/mixed-tropic virus at failure to 12 compared to 24 when screening with the original tropism assay.
Patients who had CCR5-tropic virus at baseline and failed maraviroc therapy with CXCR4-using virus had a median increase in CD4+ cell counts from baseline of +113 cells/mm³ while those patients failing with CCR5-tropic virus had an increase of +135 cells/mm³. The median increase in CD4+ cell count in patients failing in the efavirenz arm was + 95 cells/mm³. This data is a summary for a cohort of patients identified as virologic failures using the TLOVR algorithm based on a response cut-off of plasma HIV-1 RNA < 50 copies/mL.

Studies on patients co-infected with hepatitis B and/or hepatitis C virus.

The hepatic safety of maraviroc in combination with other antiretroviral agents was assessed in patients who were stable on their current antiretroviral treatment (ART).
The participating patients were HIV-1 infected patients with baseline HIV RNA < 40 copies/mL, coinfected with Hepatitis C and/or Hepatitis B Virus on concurrent antiretroviral therapy (3 to 6 drugs excluding low-dose ritonavir) and were evaluated in a multi-centre, randomized, double-blinded, placebo-controlled study. All participants with Hepatitis B received a highly active antiretroviral therapy regimen active against HBV or HBV specific antivirals.
The primary objective assessed the incidence of Grade 3 and 4 ALT abnormalities (> 5 x upper limit of normal (ULN) if baseline ALT ≤ ULN; or > 3.5 x baseline if baseline ALT > ULN) at Week 48.
In total, 137 participants were enrolled, randomised and treated, 70 to the maraviroc group, 67 to the placebo group. Overall 21 (15%) participants discontinued from treatment prior to Week 48: 12 (17%) in the maraviroc group and 9 (13%) in the placebo group. A total of 25 participants discontinued from the study through Week 48: 14 (20.0%) in the maraviroc group and 11 (16.4%) in the placebo group. 2 participants in each group discontinued study drug but remained on study prior to Week 48. At Week 48 the 2 participants in the maraviroc continued in the study off drug, but the 2 participants in the placebo arm (who were being followed off study drug) discontinued from the study.
The majority of participants were male (85%), White (79.6%) or Black (17.5%). The age range was 28-75 years.
In the maraviroc group baseline Child-Pugh scores were Class A, n = 64; and Class B, n = 6; 22 were positive at baseline HBV, 48 for HCV; 2 had both HBV and HCV.
In the placebo group, baseline Child-Pugh scores were Class A, n = 59; Child-Pugh Class B, n = 8; 22 were positive at baseline HBV, 47 were positive for HCV and 2 were positive for both HBV and HCV.
One participant in each treatment arm was observed to meet the primary endpoint by Week 48.

Note.

The study was not powered to detect treatment difference between the groups for the intended safety endpoint, the number of participants was small, at baseline the patients were stable on existing ART with preserved liver function and the number of premature discontinuations during the study was large.

5.2 Pharmacokinetic Properties

Absorption.

The absorption of maraviroc is variable with multiple peaks. Median peak maraviroc plasma concentrations are attained at two hours (range 0.5-4 hours) following single oral doses of 300 mg commercial tablet administered to healthy volunteers. The pharmacokinetics of oral maraviroc are not dose proportional over the dose range of 1-1200 mg.
The absolute bioavailability of a 100 mg dose is 23% and is predicted to be 33% at 300 mg. Maraviroc is a substrate for the efflux transporter P-glycoprotein.

Effect of food on oral absorption.

Co-administration of a 300 mg tablet with a high fat breakfast reduced maraviroc C_max and AUC by 33% in healthy volunteers. There were no food restrictions in the studies that demonstrated the efficacy and safety of maraviroc (see Section 5.1 Pharmacodynamic Properties, Clinical trials). Therefore, maraviroc can be taken with or without food at the recommended doses (see Section 4.2 Dose and Method of Administration).

Distribution.

Maraviroc is bound (approximately 76%) to human plasma proteins and shows moderate affinity for albumin and alpha-1 acid glycoprotein. The volume of distribution of maraviroc is approximately 194 L.
Preclinical data indicate low cerebrospinal fluid exposure with concentrations of maraviroc in the CSF of rats approximately 10% of free plasma concentrations.

Metabolism.

Studies in humans and in vitro studies using human liver microsomes and expressed enzymes have demonstrated that maraviroc is principally metabolised by the cytochrome P450 system, with CYP3A being the major metabolising enzyme. In vitro studies indicate that polymorphic enzymes CYP2C9, CYP2D6 and CYP2C19 do not contribute significantly to the metabolism of maraviroc.
Maraviroc is the major circulating component (accounting for approximately 42% of drug related radioactivity) following a single oral dose of 300 mg [¹⁴C]-maraviroc. The most significant circulating metabolite in humans is a secondary amine (approximately 22% of plasma radioactivity) formed by N-dealkylation. This polar metabolite has no significant pharmacological activity. Other metabolites are products of mono-oxidation and are only minor components of plasma drug related radioactivity.

Excretion.

A mass balance/excretion study was conducted using a single 300 mg dose of ¹⁴C-labelled maraviroc. Approximately 20% of the radiolabel was recovered in the urine and 76% was recovered in the faeces over 168 hours. Maraviroc was the major component present in urine (mean of 8% dose) and faeces (mean of 25% dose). The remainder was excreted as metabolites. After intravenous administration (30 mg), the half-life of maraviroc was 13.2 hours, 22% of the dose was excreted unchanged in the urine and the values of total clearance and renal clearance were 44.0 L/hour and 10.2 L/hour respectively.